117402257 the pharmaceutical regulatory process

The Pharmaceutical Regulatory Process

Copyright © 2005 by Marcel Dekker

DRUGS AND THE PHARMACEUTICAL SCIENCES

Executive EditorJames SwarbrickPharmaceuTech, Inc.

Pinehurst, North Carolina

Advisory Board

Larry L. AugsburgerUniversity of Maryland

Baltimore, Maryland

Jennifer B. DressmanJohann Wolfgang Goethe University

Frankfurt, Germany

Jeffrey A. HughesUniversity of Florida College of

PharmacyGainesville, Florida

Trevor M. JonesThe Association of the

British Pharmaceutical IndustryLondon, United Kingdom

Vincent H. L. LeeUniversity of Southern California

Los Angeles, California

Jerome P. SkellyAlexandria, Virginia

Geoffrey T. TuckerUniversity of Sheffield

Royal Hallamshire HospitalSheffield, United Kingdom

Harry G. BrittainCenter for Pharmaceutical PhysicsMilford, New Jersey

Anthony J. HickeyUniversity of North Carolina School ofPharmacyChapel Hill, North Carolina

Ajaz HussainU.S. Food and Drug AdministrationFrederick, Maryland

Hans E. JungingerLeiden/Amsterdam Centerfor Drug ResearchLeiden, The Netherlands

Stephen G. SchulmanUniversity of FloridaGainesville, Florida

Elizabeth M. ToppUniversity of Kansas School ofPharmacyLawrence, Kansas

Peter YorkUniversity of Bradford School ofPharmacyBradford, United Kingdom


DRUGS AND THE PHARMACEUTICAL SCIENCESA Series of Textbooks and Monographs

1. Pharmacokinetics, Milo Gibaldi and Donald Perrier

2. Good Manufacturing Practices for Pharmaceuticals: A Plan for TotalQuality Control, Sidney H. Willig, Murray M. Tuckerman, and William S.Hitchings IV

3. Microencapsulation, edited by J. R. Nixon

4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa andPeter Jenner

5. New Drugs: Discovery and Development, edited by Alan A. Rubin

6. Sustained and Controlled Release Drug Delivery Systems, edited by Joseph R. Robinson

7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher T.Rhodes

8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz

9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney

10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner and Bernard Testa

11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by James W. Munson

12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky

13. Orphan Drugs, edited by Fred E. Karch

14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts,Biomedical Assessments, Yie W. Chien

15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldiand Donald Perrier

16. Good Manufacturing Practices for Pharmaceuticals: A Plan for TotalQuality Control, Second Edition, Revised and Expanded, Sidney H. Willig,Murray M. Tuckerman, and William S. Hitchings IV

17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger

18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry

19. The Clinical Research Process in the Pharmaceutical Industry, edited by Gary M. Matoren

20. Microencapsulation and Related Drug Processes, Patrick B. Deasy

21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roeand T. Colin Campbell

22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme


23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and RobertA. Nash

24. Anticancer and Interferon Agents: Synthesis and Properties, edited by Raphael M. Ottenbrite and George B. Butler

25. Pharmaceutical Statistics: Practical and Clinical Applications, SanfordBolton

26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gud-zinowicz

27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos

28. Solubility and Related Properties, Kenneth C. James

29. Controlled Drug Delivery: Fundamentals and Applications, Second Edition,Revised and Expanded, edited by Joseph R. Robinson and Vincent H.Lee

30. New Drug Approval Process: Clinical and Regulatory Management, editedby Richard A. Guarino

31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien

32. Drug Delivery Devices: Fundamentals and Applications, edited byPraveen Tyle

33. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives, editedby Peter G. Welling and Francis L. S. Tse

34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato

35. Transdermal Drug Delivery: Developmental Issues and ResearchInitiatives, edited by Jonathan Hadgraft and Richard H. Guy

36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, editedby James W. McGinity

37. Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-Sellassie

38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch

39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su, and Shyi-Feu Chang

40. Modern Pharmaceutics: Second Edition, Revised and Expanded, editedby Gilbert S. Banker and Christopher T. Rhodes

41. Specialized Drug Delivery Systems: Manufacturing and ProductionTechnology, edited by Praveen Tyle

42. Topical Drug Delivery Formulations, edited by David W. Osborne and Anton H. Amann

43. Drug Stability: Principles and Practices, Jens T. Carstensen


44. Pharmaceutical Statistics: Practical and Clinical Applications, SecondEdition, Revised and Expanded, Sanford Bolton

45. Biodegradable Polymers as Drug Delivery Systems, edited by MarkChasin and Robert Langer

46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S. Tseand James J. Jaffe

47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong andStanley K. Lam

48. Pharmaceutical Bioequivalence, edited by Peter G. Welling, Francis L. S.Tse, and Shrikant V. Dinghe

49. Pharmaceutical Dissolution Testing, Umesh V. Banakar

50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded, YieW. Chien

51. Managing the Clinical Drug Development Process, David M. Cocchettoand Ronald V. Nardi

52. Good Manufacturing Practices for Pharmaceuticals: A Plan for TotalQuality Control, Third Edition, edited by Sidney H. Willig and James R.Stoker

53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan

54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J.Hickey

55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by Adrian D.Nunn

56. New Drug Approval Process: Second Edition, Revised and Expanded,edited by Richard A. Guarino

57. Pharmaceutical Process Validation: Second Edition, Revised and Ex-panded, edited by Ira R. Berry and Robert A. Nash

58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra

59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A.Walters and Jonathan Hadgraft

60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck

61. Pharmaceutical Particulate Carriers: Therapeutic Applications, edited byAlain Rolland

62. Drug Permeation Enhancement: Theory and Applications, edited by DeanS. Hsieh

63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan

64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls

65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie

66. Colloidal Drug Delivery Systems, edited by Jörg Kreuter


67. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives,Second Edition, edited by Peter G. Welling and Francis L. S. Tse

68. Drug Stability: Principles and Practices, Second Edition, Revised and Ex-panded, Jens T. Carstensen

69. Good Laboratory Practice Regulations: Second Edition, Revised andExpanded, edited by Sandy Weinberg

70. Physical Characterization of Pharmaceutical Solids, edited by Harry G.Brittain

71. Pharmaceutical Powder Compaction Technology, edited by Göran Alder-born and Christer Nyström

72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher T. Rhodes

73. Microencapsulation: Methods and Industrial Applications, edited by SimonBenita

74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone

75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidtand Michael Montagne

76. The Drug Development Process: Increasing Efficiency and CostEffectiveness, edited by Peter G. Welling, Louis Lasagna, and Umesh V.Banakar

77. Microparticulate Systems for the Delivery of Proteins and Vaccines, editedby Smadar Cohen and Howard Bernstein

78. Good Manufacturing Practices for Pharmaceuticals: A Plan for TotalQuality Control, Fourth Edition, Revised and Expanded, Sidney H. Willigand James R. Stoker

79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms: SecondEdition, Revised and Expanded, edited by James W. McGinity

80. Pharmaceutical Statistics: Practical and Clinical Applications, Third Edi-tion, Sanford Bolton

81. Handbook of Pharmaceutical Granulation Technology, edited by Dilip M.Parikh

82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded,edited by William R. Strohl

83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts and Richard H. Guy

84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpé

85. Development of Biopharmaceutical Parenteral Dosage Forms, edited by John A. Bontempo

86. Pharmaceutical Project Management, edited by Tony Kennedy


87. Drug Products for Clinical Trials: An International Guide to Formulation •Production • Quality Control, edited by Donald C. Monkhouse and Christopher T. Rhodes

88. Development and Formulation of Veterinary Dosage Forms: SecondEdition, Revised and Expanded, edited by Gregory E. Hardee and J.Desmond Baggot

89. Receptor-Based Drug Design, edited by Paul Leff

90. Automation and Validation of Information in Pharmaceutical Processing, edited by Joseph F. deSpautz

91. Dermal Absorption and Toxicity Assessment, edited by Michael S. Robertsand Kenneth A. Walters

92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu,and Roger Phan-Tan-Luu

93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III

94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMRSpectroscopy, David E. Bugay and W. Paul Findlay

95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain

96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products,edited by Louis Rey and Joan C. May

97. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,Third Edition, Revised and Expanded, edited by Robert L. Bronaugh andHoward I. Maibach

98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches,and Development, edited by Edith Mathiowitz, Donald E. Chickering III,and Claus-Michael Lehr

99. Protein Formulation and Delivery, edited by Eugene J. McNally

100. New Drug Approval Process: Third Edition, The Global Challenge,edited by Richard A. Guarino

101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid

102. Transport Processes in Pharmaceutical Systems, edited by Gordon L.Amidon, Ping I. Lee, and Elizabeth M. Topp

103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A.Kotkoskie

104. The Clinical Audit in Pharmaceutical Development, edited by Michael R.Hamrell

105. Pharmaceutical Emulsions and Suspensions, edited by Francoise Nielloudand Gilberte Marti-Mestres

106. Oral Drug Absorption: Prediction and Assessment, edited by Jennifer B.Dressman and Hans Lennernäs


107. Drug Stability: Principles and Practices, Third Edition, Revised andExpanded, edited by Jens T. Carstensen and C. T. Rhodes

108. Containment in the Pharmaceutical Industry, edited by James P. Wood

109. Good Manufacturing Practices for Pharmaceuticals: A Plan for TotalQuality Control from Manufacturer to Consumer, Fifth Edition, Revised andExpanded, Sidney H. Willig

110. Advanced Pharmaceutical Solids, Jens T. Carstensen

111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second Edition,Revised and Expanded, Kevin L. Williams

112. Pharmaceutical Process Engineering, Anthony J. Hickey and DavidGanderton

113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer, and RachelF. Tyndale

114. Handbook of Drug Screening, edited by Ramakrishna Seethala and Prabhavathi B. Fernandes

115. Drug Targeting Technology: Physical • Chemical • Biological Methods,edited by Hans Schreier

116. Drug–Drug Interactions, edited by A. David Rodrigues

117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian and Anthony J. Streeter

118. Pharmaceutical Process Scale-Up, edited by Michael Levin

119. Dermatological and Transdermal Formulations, edited by Kenneth A.Walters

120. Clinical Drug Trials and Tribulations: Second Edition, Revised andExpanded, edited by Allen Cato, Lynda Sutton, and Allen Cato III

121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded, edited byGilbert S. Banker and Christopher T. Rhodes

122. Surfactants and Polymers in Drug Delivery, Martin Malmsten

123. Transdermal Drug Delivery: Second Edition, Revised and Expanded,edited by Richard H. Guy and Jonathan Hadgraft

124. Good Laboratory Practice Regulations: Second Edition, Revised andExpanded, edited by Sandy Weinberg

125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and PackageIntegrity Testing: Third Edition, Revised and Expanded, Michael J. Akers,Daniel S. Larrimore, and Dana Morton Guazzo

126. Modified-Release Drug Delivery Technology, edited by Michael J.Rathbone, Jonathan Hadgraft, and Michael S. Roberts

127. Simulation for Designing Clinical Trials: A Pharmacokinetic-Pharma-codynamic Modeling Perspective, edited by Hui C. Kimko and Stephen B.Duffull


128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharmaceutics,edited by Reinhard H. H. Neubert and Hans-Hermann Rüttinger

129. Pharmaceutical Process Validation: An International Third Edition, Revisedand Expanded, edited by Robert A. Nash and Alfred H. Wachter

130. Ophthalmic Drug Delivery Systems: Second Edition, Revised and Ex-panded, edited by Ashim K. Mitra

131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and Sean M. Sullivan

132. Biomarkers in Clinical Drug Development, edited by John C. Bloom and Robert A. Dean

133. Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassieand Charles Martin

134. Pharmaceutical Inhalation Aerosol Technology: Second Edition, Revisedand Expanded, edited by Anthony J. Hickey

135. Pharmaceutical Statistics: Practical and Clinical Applications, FourthEdition, Sanford Bolton and Charles Bon

136. Compliance Handbook for Pharmaceuticals, Medical Devices, andBiologics, edited by Carmen Medina

137. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products:Second Edition, Revised and Expanded, edited by Louis Rey and Joan C.May

138. Supercritical Fluid Technology for Drug Product Development, edited byPeter York, Uday B. Kompella, and Boris Y. Shekunov

139. New Drug Approval Process: Fourth Edition, Accelerating Global Reg-istrations, edited by Richard A. Guarino

140. Microbial Contamination Control in Parenteral Manufacturing, edited by Kevin L. Williams

141. New Drug Development: Regulatory Paradigms for Clinical Pharmacologyand Biopharmaceutics, edited by Chandrahas G. Sahajwalla

142. Microbial Contamination Control in the Pharmaceutical Industry, edited byLuis Jimenez

143. Generic Drug Development: Solid Oral Dosage Forms, edited by LeonShargel and Izzy Kanfer

144. The Pharmaceutical Regulatory Process, edited by Ira R. Berry

ADDITIONAL VOLUMES IN PREPARATION

Drug Delivery to the Oral Cavity: Molecules to Market, edited by TapashGhosh and William R. Pfister


Marcel Dekker New York

The PharmaceuticalRegulatory Process

Ira R. BerryInternational Regulatory Business Consultants, L.L.C.,

Maplewood, New Jersy, U.S.A.


Although great care has been taken to provide accurate and current information,neither the author(s) nor the publisher, nor anyone else associated with thispublication, shall be liable for any loss, damage, or liability directly or indirectlycaused or alleged to be caused by this book. The material contained herein is notintended to provide specific advice or recommendations for any specific situation.

Trademark notice: Product or corporate names may be trademarks or registeredtrademarks and are used only for identification and explanation without intentto infringe.

Library of Congress Cataloging-in-Publication DataA catalog record for this book is available from the Library of Congress.

ISBN: 0-8247-5464-6

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Preface

Welcome to the world of regulations and controls over the pharma-ceutical industry. This is not necessarily a negative concept but israther a necessary framework under which pharmaceutical productscan be assured to provide safe and efficacious use. This book willtrace the development and history of pharmaceutical regulationsfrom their early beginnings to the present time. The process isnever ending in that regulatory agencies such as the U.S. Food andDrug Administration (FDA), and industry, are constantly striving toimprove the regulatory process – through the enactment of legisla-tion and revised regulations and guidances.

The book is divided into two sections – the legal basis for reg-ulation and FDA requirements for product approvals and after. Inthe pharmaceutical regulatory process, there are a legal basis, gov-ernment regulatory requirements, academia influence and industryperspective. The needs and bases for these groups must be directedtoward the same common goal – to provide safe and effective medi-cines. It is in this framework that the book aims to provide the readerwith a basic understanding of the process by which pharmaceuticalproducts are approved by the Food and Drug Administration forcommercial sale and marketing in the United States. The book isintended to be an introduction to the regulatory requirements andprocedures utilized by pharmaceutical companies to comply withthese requirements. In addition, the book is intended to be a tooland source of information for the pharmaceutical industry pro-fessional who wishes more advanced training in pharmaceuticalregulations.

iii


The first section of the book deals with chapters that discuss thelegal background and history of the product approval process. A

Cosmetic describes the creation of FDA and the

high level of public health by monitoring pharmaceutical productsafety and efficacy. The next chapters deal with pharmaceutical com-pany, or sponsor, requirements for preparing product submissions in

very significant as a turning point for regulations pertaining to thepharmaceutical industry and this chapter traces the changes in theregulatory requirements of the approval process for ‘‘new’’ drugs, ornew chemical entities. Following this chapter, is the ‘‘FDARegulation of Biological Products’’ that describes the requirementsfor biological products as compared to pharmaceutical chemicalproducts. Following these are the chapters ‘‘Generic Drug ApprovalProcess: Pre-1984 History Concerning Generic Drugs’’ and ‘‘Generic

Approval Process: Post 1984: Hatch-Waxman thatdescribe the corresponding requirements to obtain regulatoryapproval of ‘‘generic’’ drugs.

The chapter, ‘‘Food and Drug Administration ModernizationAct’’, addresses the efforts that have been underway to streamlinethe regulatory process, as expressed by Congress – with a specificexample applicable to antibiotic products. Product approval require-ments for antibiotics followed a different pathway in earlier yearsand are described in the chapter ‘‘FDA’s Antibiotic RegulatoryScheme: Then and Now’’. Patent issues influence the approval pro-cess for all pharmaceutical products and are described in the nextchapter, ‘‘Pioneer and Generic Drugs: Balance Between Product LifeCycle Extension and Anti-Competitive Behavior’’. With the approvaltimelines associated with pharmaceutical products being as long asthey are, and with efforts to shorten the approval times by providingFDA with additional resources, the next chapter focuses on ‘‘TheInfluence of the Prescription Drug User Fee Act on the ApprovalProcess’’. Pharmaceutical products are not approved by FDA withoutdemonstration of bioavailability or bioequivalence, perhaps as part ofa clinical research program, and the next chapter addresses ‘‘ClinicalResearch Requirements for New Drug Applications’’.

iv Preface


chapter on ‘‘Pharmaceutical Regulation Before and After the Food,

reasons for its existence – to protect the consumer in sustaining aDrug, and Act’’

compliance with regulatory requirements. The chapter, ‘‘New DrugApproval Process: Before and After 1962’’ follows. The year 1962 was

Drug Reform’’

The second section of the book addresses the FDARequirements for Product Approvals and After. The section beginswith a chapter on ‘‘Active Pharmaceutical Ingredients’’. There arespecific requirements for manufacturers of active pharmaceuticalingredients (or bulk pharmaceutical chemicals), mostly contained inDrug Master Files and expressed by Good Manufacturing Practice forAPIs, in order that a drug product license application may beapproved. The next chapter deals with the process for ‘‘ObtainingApproval of New Drug Applications and Abbreviated New DrugApplications from a Chemistry, Manufacturing, and ControlsPerspective’’, i.e., the requirements for a new drug product sponsorin preparing a product submission for approval. Following is a chap-ter describing the process of a generic drug sponsor in ‘‘ObtainingApproval of a Generic Drug’’. A drug product license application willnot be approved without consideration being given to the complianceprofile and manufacturing practices followed by the listed manufac-turers in the application and ‘‘Current Good Manufacturing Practiceand the Drug Approval Process’’ is the chapter that follows. In pre-paration of a product application for approval, attention is given toanticipating any changes that may be required to the manufacturingand control process after the product application is approved. Thismatter is discussed in the chapter ‘‘CMC Post-Approval RegulatoryAffairs: Constantly Managing Change’’. The next chapter deals

keeping with all these requirements for product approval, it is appro-priate to next consider ‘‘Ways and Means to U.S. Registration ofForeign Drugs’’. In today’s world, it is imperative to addressthe issues of registration of pharmaceutical products in the globalmarketplace and the next chapter deals with the ‘‘Common Tech-nical Document – Quality (M4-Q): One Regulatory Participant’sPerspective’’. In addition, computerization is becoming more promi-nent in today’s standards and we consider ‘‘21 CFR Part 11Compliance and Beyond’’. We must consider also the methods usedin promoting pharmaceutical products, which are very differenttoday as compared to past years, and the following chapter doesthis, ‘‘Marketing and Advertising/Promotion: The Impact of Govern-ment Regulations’’. The major emphasis in this book is on the pro-cess and issues relating to the approval process for registration ofprescription drugs; however, we have a very important sector of thehealth care market devoted to over-the-counter drugs so the next

Preface v


with ‘‘The Influence of the USP on the Drug Approval Process’’. In

chapter focuses on ‘‘Approval and Marketing of Nonprescription orOTC Human Drugs’’.

The totality of the book has presented a comprehensive reviewof the history and background for the current pharmaceutical regu-latory process in the U.S., in a global environment. With the back-ground in place, the book further describes the steps and currentrequirements to obtain regulatory approval. It can be used as a train-ing tool for individuals beginning to work in regulatory affairs, com-pliance and quality as well as to provide a general understanding ofthe regulatory process to all pharmaceutical industry and regulatoryagency personnel.

I want to extend my personal gratitude to the contributingauthors who have given their personal time to write this book andprovide an education that is not attainable otherwise.

Ira R. Berry

vi Preface


Contributors

Ann Begley Kirkpatrick and Lockhart LLP, Washington, D.C.,U.S.A.

Barbara A. Binzak Buchanan Ingersoll Professional Corporation,Washington, D.C., U.S.A.

Nicholas Buhay Food and Drug Administration, Rockville,Maryland, U.S.A.

Richard L. Burcham BPI Technologies, Arlington, Texas, U.S.A.

Edward M. Cohen Consultant in Pharmaceutical Sciences,Newtown, Connecticut, U.S.A.

James N. Czaban Heller Ehrman White & McAuliff LLP,Washington, D.C., U.S.A.

Loren Gelber Andrx Corporation, Davie, Florida, U.S.A.

Daniel Glassman Bradley Pharmaceuticals Inc., Fairfield, NewJersey, U.S.A.

Gene Goldberg Bradley Pharmaceuticals Inc., Fairfield, NewJersey, U.S.A.

AlbertoGrignolo PAREXEL International Corporation,Waltham,Massachusetts, U.S.A.

Marc S. Gross Darby & Darby, P.C., New York, New York, U.S.A.

vii


Jill E. Kompa PAREXEL International Corporation, Waltham,Massachusetts, U.S.A.

Kristin Behrendt Kosinski Darby & Darby, P.C., New York,New York, U.S.A.

Max S. Lazar FDA Regulatory Compliance Consulting, Surprise,Arizona, U.S.A.

Natasha Leskovsek Heller Ehrman White & McAuliff LLP,Washington, D.C., U.S.A.

Leo J. Lucisano GlaxoSmithKline, Research Triangle Park,North Carolina, U.S.A.

S.PeterLudwig Darby&Darby, P.C., NewYork, NewYork, U.S.A.

Philip W. McGinn, Jr. Bradley Pharmaceuticals Inc., Fairfield,New Jersey, U.S.A.

William J. Mead Consultant, Rowayton, Connecticut, U.S.A.

Kevin A. Miller GlaxoSmithKline, Research Triangle Park, NorthCarolina, U.S.A.

Patricia E. Pahl Olsson, Frank & Weeda, P.C., Washington, D.C.,U.S.A.

Michael P. Peskoe Palmer & Dodge, Boston, Massachusetts,U.S.A.

Robert G. Pinco Buchanan Ingersoll Professional Corporation,Washington, D.C., U.S.A.

David L. Rosen Gray Cary Ware & Freidenrich, LLP,Washington, D.C., U.S.A.

Marc J. Scheineson Alston & Bird LLP, Washington, D.C.,U.S.A.

Richard J. Schwen PAREXEL International Corporation,Waltham, Massachusetts, U.S.A.

Dhiren N. Shah Aventis Pharmaceuticals, Kansas City, Missouri,U.S.A.

Atul R. Singh Darby & Darby, P.C., New York, New York, U.S.A.

viii Contributors


David Skarinsky PAREXEL International Corporation,Waltham, Massachusetts, U.S.A.

John P. Swann Food and Drug Administration, Rockville,Maryland, U.S.A.

Arthur Y. Tsien Olsson, Frank & Weeda, P.C., Washington, D.C.,U.S.A.

Ubrani V. Venkataram Food and Drug Administration,Rockville, Maryland, U.S.A.

Irving L. Wiesen Law Offices of Irving L. Wiesen, Esq., Stamford,Connecticut, U.S.A.

Gary Yingling Kirkpatrick and Lockhart LLP, Washington, D.C.,U.S.A.

Contributors ix


Contents

iiiContributors vii

Food, Drug, and Cosmetic ActJohn P. Swann 1

2. The New Drug-Approval Process—Before andAfter 1962Michael P. Peskoe 47

3. FDA Regulation of Biological ProductsJames N. Czaban and Natasha Leskovsek 73

4. Generic Drug Approval Process: Pre-1984 HistoryConcerning Generic DrugsDavid L. Rosen 99

5. Generic Drug Approval Process, Post-1984:Hatch-Waxman ReformMarc S. Gross, S. Peter LudwigKristin Behrendt Kosinski and Atul R. Singh 107

6. Food and Drug Administration Modernization ActArthur Y. Tsien and Patricia E. Pahl 165

7. FDA Antibiotic Regulatory Scheme: Then and NowIrving L. Wiesen 241

xi


Preface

1. Pharmaceutical Regulation Before and After the

8. Pioneer and Generic Drugs: Balance BetweenProduct Life Cycle Extension andAnticompetitive BehaviorRobert G. Pinco and Barbara A. Binzak 257

9. The Influence of the Prescription Drug User Fee Acton the Approval ProcessMarc J. Scheineson 323

10. Clinical Research Requirements for NewDrug ApplicationsGary Yingling and Ann Begley 349

11. Active Pharmaceutical IngredientsMax S. Lazar 377

12. Obtaining Approval of New Drug Applications andAbbreviated New Drug Applications from aChemistry, Manufacturing, and Controls PerspectiveDhiren N. Shah 393

13. Obtaining Approval of a Generic DrugLoren Gelber 415

14. Current Good Manufacturing Practice and theDrug Approval ProcessNicholas Buhay 455

15. CMC Post-approval Regulatory Affairs: ConstantlyManaging ChangeLeo J. Lucisano and Kevin A. Miller 469

16. The Influence of the USP on the Drug ApprovalProcessEdward M. Cohen 499

17. Ways and Means to U.S. Registration ofForeign DrugsAlberto Grignolo, Jill E. Kompa, Richard J. Schwenand David Skarinsky 517

18. Common Technical Document—Quality (M4-Q):One Regulatory Participant’s PerspectiveUbrani V. Venkataram 547

xii Contents


19. 21 CFR Part 11 Compliance and BeyondRichard L. Burcham 583

20. Marketing and Advertising/Promotion:The Impact of Government RegulationsDaniel Glassman, Philip W. McGinn, Jr.,and Gene Goldberg 609

21. Approval and Marketing of Nonprescription or OTCHuman DrugsWilliam J. Mead 655

Contents xiii


1

Pharmaceutical Regulation Beforeand After the Food, Drug, and

Cosmetic Act

JOHN P. SWANN

Food and Drug Administration

Rockville, Maryland, U.S.A.

1. INTRODUCTION: NINETEENTH-CENTURYBACKGROUND TO DRUG REGULATIONIN THE UNITED STATES

Federal drug regulation in nineteenth-century America was afleeting phenomenon, limited in part by a lack of both scientificcapacity and sustained political exigency. Citizens stood abetter chance of being safeguarded by their own states,though the legislation and enforcement varied widely in thisperiod. But by the turn of the twentieth century, Connecticut,

1


Georgia, Illinois, Iowa, the Oklahoma territory, California, andmost other states had outlawed drug adulteration and/or fail-ure to label a medicine that had morphine, cocaine, digitalis,nux vomica, chloroform, cantharides, strychnine, ergot, or ahost of other substances (1,2). Typically, violations were con-sidered misdemeanors and penalized accordingly. But absent afederal proscription, it was all the protection a citizen mighthope for.

Still, there were some notable though short-lived develop-ments at the national level. Baltimore physician James Smith,inspired by the marketing of spurious smallpox vaccine, con-vinced Congress to pass a law in 1813 to ensure the provision ofreliable vaccine. Under this law, the president appointed a so-called vaccine agent (Smith) ‘‘to preserve the genuine vaccinematter, and to furnish the same to any citizen of the UnitedStates, whenever it may be applied for, through the medium ofthe post office.’’ The blame for a smallpox outbreak in NorthCarolina in 1822 was assigned to vaccine supplied by the vac-cine agent, though this was never proven. But the impact of theevent led to repeal of the vaccine act and restoration to statesof the responsibility for pure and effective smallpox vaccine (3).

The publication of the United States Pharmacopoeia(USP) in 1820 was a milestone in the history of drug regulationbecause it established a national compendium of drug stan-dards to help respond to what medical and pharmaceuticalprofessionals observed to be an increasingly corrupt drugsupply. Ultimately it would prove to be unique among mostlegally recognized publications of this kind in the worldbecause it was, and still is, a private venture. There had beenoccasional local compilations of standard drugs and their prep-aration, the first of which was the Lititz Pharmacopoeia of1778. But the convention that assumed responsibility for anational collection of drug standards and their preparationhad something broader in mind.

Led by New Hampshire native Lyman Spalding, 11physician-delegates from medical societies and schools acrossthe country, representing four districts, met in Washington inJanuary 1820 to discuss drafts and recommendations from dis-trict proceedings and what would and would not be included

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in the USP. The first USP aimed ‘‘to select from amongsubstances which possess medical power, those, the utility ofwhich is most fully established and best understood; and toform from them preparations and compositions, in whichtheir powers may be exerted to the greatest advantage’’ (4).The USP thus endeavored to elevate the pharmaceutical arma-mentarium in a way that would make both the practice ofmedicine and the practice of pharmacy more reliable (5–8).

The first federal law that addressed pharmaceuticalsin general invoked the USP as well as other pharma-copoeias. Lewis Caleb Beck’s 1846 publication, Adulterationof Various Substances Used in Medicine and the Arts, withthe Means of Detecting Them: Intended as a Manual forthe Physician, the Apothecary, and the Artisan, revealed anAmerican marketplace rife with adulterated medicines.Opium, one of the most valued medicines, was most frequentlysubjected to fraud, mixed with all manner of deceptive ingre-dients, such as gum arabic, sand, and lead. Beck identifiedmany other drugs commonly adulterated, including tartaremetic, quinine, and rhubarb. It was a state of affairs perhapsbest captured by British statesman and pharmacist Jacob Bell,who related the widespread belief abroad that drugs renderedunsuitable by decay or fraud were still ‘‘good enough forAmerica’’ (9).

If Beck’s book provided the scientific evidence why theUnited States needed a law to protect the drug supply, thenthe Mexican-American War (1846–1848) provided the politicalimpetus. Many in Congress blamed adulterated drugs for themassive wartime deaths. In truth, considering the drugs thenavailable, it would have made little difference whether or notthe drugs were pure. Squalid camps, inadequate nutrition, andan understaffed medical corps were largely responsible fordeaths due to disease—about 10% of the total fighting forceeach year, a rate seven times the mortality rate due tocombat (10). The continuing prevalence of drug adulterationin the 1840s, particularly evident in the ports, produced, asJames Harvey Young showed, ‘‘a sense of outrage.’’ SenatorJohn Davis of Massachusetts believed that, ‘‘If we can stop theimportation of the spurious drug from abroad, we shall

History of Pharmaceutical Regulation 3


know how to deal with those who may choose to go into theiradulteration in the United States’’ (11). Such sentiments, com-bined with Congress’s conception of pharmaceutical fraud inthe Mexican conflict and the documentation supplied by Beck,helped shape a law that attempted to bring some order tothe chaos.

The Drug Import Law, signed by President James K. Polkon June 26, 1848, required the examination of all drugs thatcame into the ports of New York, Boston, Philadelphia,Baltimore, Charleston, and New Orleans for ‘‘quality, purity,and fitness for medical purposes.’’ The law identified the USPas well as the pharmacopoeias and dispensatories ofEdinburgh, London, France, and Germany as the source ofstandards used by the port examiners in their appraisals.Drugs had to be labeled with the name of the manufacturerand the place of preparation. The Secretary of the Treasurywas authorized to appoint suitably qualified personnel ateach of these ports. Any drug so adulterated or deterioratedto fall short of the standard of purity or strength as establishedby these compendia would not pass the customhouse. Theowner or consignee could request a reexamination by an ana-lytical chemist endorsed by the medical profession and thelocal school of medicine or pharmacy. But if that analysisupheld the port examiner, the violative drug would be eitherremoved by the owner or destroyed by the port (12).

Initially, the law was enforced vigorously by thoseappointed by Secretary of the Treasury Robert J. Walker.In the first few months, the New York port was reportedto have turned away over 90,000 pounds of drugs. Someeven hoped, like Senator Davis, that it might be possibleto address the problem of domestic traffic in problematicaldrugs. However, the impact of the law soon diminished. Inpart, this was due to inadequately developed methods of anal-ysis, a problem that pharmacists in particular tried to rectify.But the problem also rested in the appointment of unquali-fied individuals to special examiner positions, appointmentswhich began to be awarded more on the basis of politicaldebts than the suitable qualifications as stated in the law.By 1860 Edward Squibb announced that the law was barely

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enforced any more, and that remained the case despite theefforts of some physicians and pharmacists for the remainderof the century (13–15).

2. EARLY REGULATION OF BIOLOGICALTHERAPIES

The next significant milestone in the history of regulating ther-apeutic products in the United State followed a major advance-ment in biological therapeutics. In 1890 Emil von Behring andShibasaburo Kitasato, working at the Robert Koch Institute inBerlin, announced that they had successfully treated diph-theria by injecting patients with blood serum of animalsimmunized against the pathogen. The last two decades of thenineteenth century witnessed the identification of nearly twodozen microorganisms responsible for disease, and the workof von Behring, Kitasato, Louis Pasteur, Emile Roux, andothers applied these discoveries to develop and refine biologicaltreatments for these diseases (16,17).

State and local public health laboratories and a few com-mercial concerns soon began producing their own diphtheriaantitoxin once European scientists perfected the productionmethodology. On the eve of this milieu, Joseph Kinyoun,head of the Hygienic Laboratory of the U.S. Marine HospitalService (later renamed the Public Health Service), warned theSurgeon General in November 1894 of ‘‘. . . what will evidentlyensue in our country. Many persons will, during the ensuingyear, commence to prepare the [antidiphtheria] serum as abusiness enterprise, and there will, without a doubt, be manyworthless articles called antitoxin thrown upon the market. Allthe serum intended for sale should be made or tested by com-petent persons. The testing, in fact, should be done by disin-terested parties. The danger with us is perhaps greater thancould exist here [in Germany] under any circumstances’’ (18).Early in 1895, the Hygienic Laboratory developed a standarddiphtheria antitoxin for distribution (19–21). Businesses, asKinyoun suspected, indeed took up production, but it wasthe antitoxin manufactured by a municipal public health



laboratory that launched a movement for regulatory interven-tion (see Fig. 1).

In October 1901 the St. Louis Health Department pro-duced a batch of antitoxin that killed 13 children being treated

Figure 1 This cartoon from Puck, 1880, deftly captures the fear ofvaccination with unreliable vaccine matter. (Courtesy of WilliamHelfand.)

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for diphtheria; the cause of death in each case was tetanus. Aninvestigation led by the city council and the health departmentrevealed that the consulting bacteriologist who had producedthe antitoxin had used a horse that contracted and later died oftetanus. The bacteriologist allegedly was aware of the horse’scondition but failed to destroy the product or otherwise preventits distribution. Though he was unaware of the tainted sourceof the antitoxin, the janitor in the laboratory had responsibilityfor bottling the product; he complicated recovery of the anti-toxin by initially claiming the antitoxin had been destroyed.The incident in St. Louis was not isolated. There were otheraccidents involving biological medicines, such as about 100cases of postvaccination tetanus that occurred in Camden,New Jersey, also in the Fall of 1901, where nine children died.

But it was the St. Louis disaster that was specificallyinvoked (22) in the hearings on a bill that proposed bringingproduction of biologics under federal control. Introduced onApril 5, 1902, President Theodore Roosevelt signed theBiologics Control Act on July 1, 1902, virtual light speed com-pared to the quarter-century it took for the admittedly morecomprehensive and much more hotly contested Food andDrugs Act of 1906 (23). The Hygienic Laboratory was respon-sible for enforcement of the 1902 legislation.

Drawing upon extant legislation in Europe, this lawrequired manufacturers of any biological medicine or analo-gous product to be licensed annually by the government, andlicensure was predicated on a satisfactory and unannouncedinspection of the establishment. All aspects of productioncould be examined, including records. Samples of licensed prod-ucts were obtained on the open market and tested at theHygienic Laboratory for purity and potency. Licenses couldbe suspended pending correction of a manufacturing or productdefect, and violation of the law was subject to a fine of up to$500 and/or imprisonment for up to one year. While there cer-tainly were cases of license suspensions, there appears to belittle evidence that the Hygienic Laboratory pursued fines orimprisonment under the law until the early 1960s (24–26).The number of licenses issued by the Hygienic Laboratorygrew quickly, from 13 concerns licensed to produce mostly



diphtheria antitoxin and smallpox vaccine in 1904, to twodozen operations producing about 20 different medicines in1908, to 41 establishments licensed for over 100 biologics in1921 (27–30).

3. FEDERAL AND PRIVATE REGULATION OFDRUGS IN THE EARLY TWENTIETHCENTURY

Other federal agencies offered limited regulation over pharma-ceuticals beginning in the early twentieth century. The PostOffice Department, for example, was able to prosecute someproducts that were otherwise beyond the reach of the govern-ment under the postal fraud laws of 1872 and 1895 (31,32).These laws prohibited the use of mail to collect money underfraudulent pretenses. Violations resulted in a fraud order,wherein the offending mail was intercepted and returned tothe sender. Thus in 1928 the Post Office secured a fraudorder, upheld on appeal, against Tuberclecide, a worthlesstreatment for tuberculosis, and years earlier againstHabitina, an alleged drug addiction cure that contained bothmorphine and heroin (33,34). The Federal Trade Commission(FTC) exercised its jurisdiction over drug advertising fromtime to time following its establishment in 1914. For example,it attempted to regulate Marmola, a hazardous thyroid prepa-ration intended for weight reduction, on two occasions in the1920s and 1930s (35). The Wheeler-Lea Amendment of 1938clarified FTC’s unique authority over all drug advertising,though jurisdiction over prescription drug advertising wastransferred to the U.S. Food and Drug Administration (FDA)in 1962 (36–38).

Ironically, probably the most significant effort to regulateprescription drugs prior to 1938 was a private venture that wasvoluntary, under the American Medical Association (AMA).Shortly after the turn of the century the AMA and theAmerican Pharmaceutical Association (APA) combinedresources to press for the establishment of a federal authoritythat would certify drugs—and thus help rid the landscape of

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patent medicines. These not only posed a threat to the publichealth, they represented some competition for physicians.Nostrums certainly played an important role in the retail busi-ness of many pharmacists, but others in the professionexcoriated their sale. The AMA abandoned the idea of federalcertification and instead formed its own Council on Pharmacyand Chemistry in 1905, a 15-member group that included phy-sicians, pharmacists, pharmacologists, chemists, and govern-ment representatives. The AMA Board of Trustees chargedthe council to publish an annual volume of proprietary phar-maceuticals approved by the council that were not, accordingto pharmacopoeial rules, permitted in the USP (39–41).

Manufacturers submitted to the council evidence to sup-port any claims made for the drug and a proposed name, andthe council relied heavily on the advice of outside consultantsto evaluate these data. An accepted drug would be included inits compendium, New and Nonofficial Remedies (NNR), whichentitled the firm to label its drug with the council’s ‘‘accepted’’seal. But under the council’s rules, no pharmaceutical would beadmitted to NNR if it had ‘‘unwarranted, exaggerated or mis-leading statements as to therapeutic value.’’ Moreover, a drugwould not be accepted if its firm derived substantial earningsfrom products not listed in NNR. But rejection by the councilmeant more than just failure to appear in NNR or enhance itslabel. Unaccepted drugs were denied the right to advertise inthe family of AMA journals (42–45).

The council terminated its acceptance program in 1955,due largely to the AMA’s depletion of cash reserves and a grow-ing apathy for the program within the association, according toone informed observer (46). However, the council continuedto publish its compendium of drugs for reference use ofthe profession. With the proscriptive element of the programinactivated, the possibility existed in which a drug mightbe advertised in the Journal of the American MedicalAssociation (JAMA) for an indication not supported in NNR(47). Moreover, firms were less compelled to submit the sort ofevidence to the council that they had in the past, such that thecouncil’s consultants had to search for supplemental data onNNR candidates elsewhere. Still, NNR included comparative



assessments of a drug’s efficacy, something FDA did not dowhen the efficacy statutes were passed (48–50).

4. THE DRUG MARKETPLACE AT THE TURNOF THE CENTURY

Federal regulation over the bulk of the drug supply was stillnonexistent at the turn of the twentieth century. It was amenac-ing marketplace. Despite the existence of several comprehen-sive drug compendia—including the USP—there were nolegally required standards of identity for drugs, whether thepharmaceutical were prescribed by a physician and dispensedby a pharmacist (so-called ethical drugs) or purchased directlyby the consumer for self-medication. Some of the manufacturersof the former by this time had quality-control procedures inplace and produced standardized drugs of predictable therapeu-tic response. Parke-Davis was the first firm to subscribe to thisapproach, introducing 20 chemically assayed fluidextracts ofbotanicals by 1883 (51,52). Parke-Davis and Mulford were theearly leaders in the production of biologicals, a venture thatby definition and by law required the institutionalization ofscience. Incorporating science was, as Jonathan Liebenaupoints out, good business for drug manufacturers even at thisearly stage. And they made sure their clientele knew it (53).

But science was still very much in its infancy for most ofthe American pharmaceutical industry at the turn of the cen-tury. It was an expensive proposition, and many companychiefs remained to be convinced that more (or any) scienceand research necessarily meant more business (54). To besure, even the ethical industry had its share of scientificallyquestionable products. One of Eli Lilly and Company’s bestsellers at this time was Succus Alterans, a blood purifier andtreatment for rheumatism, syphilis, and a variety of skin dis-eases that Lilly supposedly derived from a Creek Indian remedy(55). In 1889 Smith Kline & French purchased the D. B. HandCompany and then manufactured and distributed the Handline of products, still under the Hand brand. This inventoryconsisted of teething lotions, colic cures, croup and cough

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medicine, worm elixir, and other preparations advertised forinfants and children. Like so many other pediatric productsof other firms at this time, these Hand medicines typicallycontained alcohol, opium, and chloral hydrate (56–58).

But regardless of the extent to which the ethical industrymarketed nostrums, it paled next to the patent medicine indus-try, those who vended William Radam’s Microbe Killer, Mrs.Winslow’s Soothing Syrup, Swaim’s Panacea, Benjamin Bye’sSoothing Balmy Oils to cure cancer, Dr. Hollick’s AphrodisiacRemedy, and on and on (59). Nostrums were omnipresent inlate nineteenth-century America, their rise, not coincidentally,paralleling that of advertising. Products appealed to exotica,the medical knowledge of Native Americans, death, religion,patriotism, mythology, and eventually new developments inscience. Nothing but the size of the bottle prevented patentmedicines makers from claiming anything and putting any-thing in their products (see At the same time, the

equipped to deal with most diseases. If there were a demand forcancer and arthritis cures, baldness remedies, bust developers,manhood restorers, a cure could be supplied. And if there werenot a demand, that too could be manufactured.

The nostrum industry undoubtedly knew how tomarket itswares, but companies also promoted their interests in moresurreptitious ways. For example, they subdued any curiosityin the press with their economic strength. By the 1890s,patent medicine manufacturers used so-called ‘‘red clauses’’ intheir advertising contracts to muzzle newspapers and maga-zines. The contracts would be voided if a state law regulatingnostrums were passed. Thus, not only were many editorialssilent on the need for such laws, they actively campaignedagainst them.

5. THE FEDERAL FOOD AND DRUGS ACTOF 1906

Such was the pharmaceutical landscape in America as thetwentieth century began. A few muckraking journalists



Fig.biomedical sciences awaited elaboration, leaving medicine ill-

2).

helped reveal the red clauses, the false testimonials, the nos-trums laden with harmful ingredients, the unfounded cures forcancer, tuberculosis, syphilis, narcotic addiction, and otherserious as well as self-limited diseases. The most influentialpatent medicine expose was a 10-part series entitled ‘‘TheGreat American Fraud,’’ by Samuel Hopkins Adams, whichbegan in Collier’s on October 7, 1905, and ended the followingFebruary. A subsequent series by Adams examined doctorswho advertised fake clinics. That same month saw the publica-tion of another work that, more than any other single event,

Figure 2 Hunt’s Remedy, manufactured since 1850, illustrates theunrestricted claims and eye-catching advertising imagery that char-acterized many patent medicines at the turn of the twentieth cen-tury. This particular advertisement was used for the design of a 1998U.S. postage stamp to commemorate the 1906 Food and Drugs Act.

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spurred on passage of a comprehensive federal law. Socialistwriter Upton Sinclair published The Jungle, a fact-based novelabout immigrant life in the meatpacking industry of Chicago.Sinclair’s shocking and revolting story was verified by govern-ment undercover investigators.

The search for a federal law to correct abuses in the foodand drug marketplace began long before Adams and Sinclairinitiated their investigations. Congress received the first bill toaddress these concerns in January 1879, though that versionaddressed only foods; some months later another bill, this timeencompassing drugs as well as foods, was introduced in theHouse. Every session of Congress for the next 25 years consid-ered at least one sweeping food and drug control bill (60).Those who believed they would be adversely affected by anomnibus law managed to thwart passage of the dozens ofbills that were introduced during this span. But their oppo-nents obviously were equal to the task—or at least persistent.

Many championed a food and drug law, but one personmore than any other was responsible for keeping the need forsuch a law squarely in front of both Congress and the people.Harvey Washington Wiley was a chemist on the faculty ofPurdue University when he came to Washington in 1883 tobecome the fourth chief chemist in the Department ofAgriculture. From the time of his arrival in the capital, Wileywas an enthusiastic, infectious, and effective champion forremedial legislation. When he was not stumping for a law, hewas publishing extensively on the proliferation of food adul-teration (61). His forceful personality and commitment toreform brought together important but disparate groups tohelp lobby Capitol Hill, including state food and drug officials,the General Federation of Women’s Clubs, the AmericanPharmaceutical Association, and the American MedicalAssociation (62–64).

On June 30, 1906, President Roosevelt signed the Foodand Drugs Act into law (65), nearly 4 years to the day afterhe signed the Biologics Control Act. The law prohibited inter-state commerce in adulterated or misbranded foods and drugs.It was unlawful to add an ingredient to a food that wouldrepresent a health hazard, result in a filthy or decomposed



product, conceal damage, or substitute for the food itself. If themanufacturer chose to label the weight or measure of the food,that had to be done accurately. A food or drug label could notbe false or misleading in any particular.

A drug under the act was any substance intended for thecure, mitigation, or prevention of disease in humans or ani-mals. It could not be sold in any condition of purity, strength,or quality other than that stated in the USP or the NationalFormulary, unless the specific variation from that standardwere stated on the label. The presence and amount of 11 dan-gerous ingredients, including heroin, morphine, cocaine, andalcohol, had to be labeled on all drugs (and foods). Violativegoods were subject to seizure and, if upheld by the court,destruction. Infractions were considered misdemeanors, andthose behind the offense could be fined up to $500 and impris-oned for up to one year. The Bureau of Chemistry of theDepartment of Agriculture, the home of more chemists thananywhere else in the U.S. government (66), was assigned toenforce the law and promulgate regulations (67).

6. APPLYING THE NEW LAW TO DRUGS

One immediate impact of the law was to persuade many patentmedicine manufacturers to remove ingredients from theirpreparations that were subject to labeling. Therapeutic claims,however, were another story. The Bureau of Chemistry quicklyapplied the law to products that bore false therapeutic claims,based on a charge of misbranding. About 100 such cases weremade in 5 years (68). However, when the bureau tried to moveagainst Dr. Johnson’s Mild Combination Treatment forCancer, the firm prevailed over the bureau in court. The casereached the Supreme Court in 1911, which ruled in a 6-3 deci-sion against the government. The majority believed that the1906 act pertained only to ingredients of a product, its identity.Moreover, the Court believed that the Bureau of Chemistrywas capable of making an informed judgment about a drug’scontents, ‘‘but hardly so as to medical effects.’’ Finally, basedon an earlier case involving the Post Office, the court argued

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that ideas about therapeutics were still too far ranging to cometo definitive conclusions (69).

President William Howard Taft asked Congress to developa legislative solution for the 150 pending drug misbrandingcases, as well as those yet to come. Among these cases, accord-ing to the president, were ‘‘some of the rankest frauds bywhich the American people were ever deceived’’ (70).Congress responded in 1912 with the Sherley Amendment,couched as severely as members believed possible withoutinfringing on expressions of opinion. The new law prohibitedstatements about a product’s ingredients or its curative ortherapeutic effect that were false and fraudulent (71,72).However, to establish fraud meant that the bureau of chemis-try had to show that the manufacturer knew the product wasworthless—that there was intent to defraud the consumer.This proved to be difficult in many cases.

For example, Lee Barlett, a former shirt salesman fromPittsburgh, promoted a medicine called Banbar, an extract ofthe horsetail weed, as an effective treatment for diabetes.Barlett sold Banbar for $12 a pint, a hefty price in the 1920s,but it allowed diabetics to take their medicine orally ratherthan administering injections of insulin, which FrederickBanting and his colleagues at the University of Toronto hadintroduced in 1923. The government took Barlett to court forselling a misbranded drug. Elliott P. Joslin, the internationallyrecognized authority on diabetes, was the plaintiff’s principalwitness. On the basis of the 12,000 diabetic patients he sawevery year, Joslin testified that insulin—combined with dietand exercise— was the only effective treatment for this disease.The defense offered hundreds of testimonial letters on behalf ofBanbar. The jury found in favor of the defense, despite the factthat the government presented death certificates—attributedto diabetes—for individuals who had submitted these testimo-nials (73).

Under Wiley, enforcement of the Food and Drugs Actweighed heavily toward foods. Of the first 1000 actions takenby the bureau up to 1911, fewer than one quarter dealt withdrugs. And those drug actions typically addressed patent med-icines; as seen above, false therapeutic claims were a driving



force for action. Official drugs such as belladonna and asafetidawere the subject of fewer than 100 of these actions. Most defen-dants did not challenge the bureau, but rather paid their fines,adjusted their labeling, and continued to advertise as before,since the latter was beyond the reach of the 1906 law (74).

Carl Alsberg followed Wiley as chief chemist in 1912, andhe continued to favor foods. But he also focused more attentionon ethical drugs. To address these, the bureau developed newanalyses for crude drugs, and by the 1920s bureau scientistspioneered biological assays for ergot, digitalis, and other drugs,which were adopted by the USP (75) (see Fig. 3). The bureaualso monitored drugs dispensed by pharmacists in the Districtof Columbia (believing state pharmacy boards were the moreappropriate monitor elsewhere) beginning in the 1910sand found substantial deviations from official standards.

Figure 3 Pharmacologists in the Bureau of Chemistry employedbiological assays to develop the first reference standards issued toindustry to promote compliance with the testing requirements forselect pharmaceuticals in USP X (1926).

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By the early 1930s FDA and the American PharmaceuticalAssociation reached an agreement as to what would be consid-ered reasonable tolerances for dispensed drugs (76).

When Walter Campbell succeeded Alsberg in 1921, herevitalized the drug regulatory effort, beginning with theappointment of George Hoover, a physician and chemist, tohead drug regulation. The bureau consequently expanded itsinterests from crude drugs to tablets, discovering fairly widevariations from official standards. But by this time, when theRepublicans came to power and the policy was made to be morecooperative with business, court action began to be supercededby negotiation. Hoover met with the pharmaceutical industry’strade associations, the American Drug ManufacturersAssociation and the American Pharmaceutical ManufacturersAssociation, which in turn formed so-called contact committeesto investigate the tablet problems in cooperation with thebureau. The committees helped improve tableting technologiesand negotiated with the bureau over allowable deviations fromthe labeled amount of active ingredient. But in the NewDeal era, drug regulation took a less collaborative tone withindustry (77).

7. TOWARD THE 1938 FOOD, DRUG, ANDCOSMETIC ACT

The 1906 act was arguably the pinnacle of Progressive Eralegislation, but the difficulty of prosecuting medicines withfalse therapeutic claims was just one of many shortcomingsof the 1906 act. Foods did not have standards, cosmetics andmedical devices were unregulated, the penalties imposed by thelaw were paltry relative to the crime, with the exception of the11 ingredients there was no required listing of drug ingredi-ents, factory inspections—though interpreted and executed bythe bureau as warranted under the law—were not explicitlyauthorized, and though the law prohibited a food that wasmade to be unsafe, there was no similar protection for drugs.By the 1920s, and increasing considerably after FranklinRoosevelt became president in 1932, FDA began to publicize



rather creatively the more egregious examples of deceptive andhazardous products that were on the market and perfectlywithin the law, an argument for a new comprehensive law(78). Indeed, shortly after FDR’s inauguration, Congressbegan considering bills that would replace the Food andDrugs Act and plug the holes left in consumer protection leg-islation (79).

The public’s vulnerability became dramatically clear inOctober 1937. Months after the introduction of the wonderdrug sulfanilamide, the S. E. Massengill Company of Bristol,Tennessee, began investigating a liquid dosage form for thedrug. Their investigation consisted of finding a solvent inwhich the drug would dissolve (sulfanilamide was known tobe stubbornly insoluble) and flavoring and coloring the prep-aration so as to be especially useful for children and othersnot inclined toward tablets. Quality control amounted to littlemore than an organoleptic appraisal. Harold Watkins, the com-pany chemist, selected diethylene glycol as the vehicle for thesulfa without testing the solvent or even examining the medicalliterature. Had he at least bothered to look, the latter certainlyattested to the glycol’s poisonous nature. He didn’t bother test-ing it himself, he claimed, because glycols were related to gly-cerine, which had long been used in medicines. The companythus began shipping its Elixir Sulfanilamide from Tennesseeand its Kansas City office in early September.

On October 11, a representative from the Tulsa CountyMedical Society contacted the AMA to inform them that sev-eral deaths in the Oklahoma county appeared to be associatedwith the Massengill product. The physician wanted to knowwhat the AMA’s Council on Pharmacy and Chemistry couldtell them about the preparation. Neither Elixir Sulfanilamidenor any Massengill product had ever been accepted by theCouncil. The Food and Drug Administration heard about thesuspicious deaths 3 days after the AMA, from a New Yorkphysician with ties to Massengill. FDA learned the Elixir wasinvolved in all the Tulsa fatalities, at which point the agencydispatched its chief medical officer and one of its finest fieldinvestigators to Bristol to investigate. They learned that

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proprietor Samuel E. Massengill issued an inadequate recallnotice and that 240 gallons remained unaccounted for.

FDA dedicated virtually its entire field force to trackingdown the remaining product—though forced to rely on a tech-nical error for legal cause. Nothing in the 1906 act prohibitedunsafe drugs. Rather, FDA was allowed to seize ElixirSulfanilamide because it was misbranded; an elixir, by defini-tion, had to employ alcohol, and the Massengill medicine ofcourse had none. Most physicians and pharmacists encoun-tered by FDA investigators during the frantic recovery effortwere helpful, but some were uncooperative and even obstruc-tive, no doubt to deflect personal responsibility and liability.Much was recovered from warehouses, pharmacy shelves, andmedicine cabinets But overall, Elixir Sulfanilamide killed atleast 107, mostly in the South.

Many were children, such as the 6-year-old girl from Tulsa

Nidiffer, wrote to President Roosevelt on November 9th:‘‘Tonight Mr. Roosevelt that little voice is stilled. The firsttime I ever had occasion to call in a doctor for her and she wasgiven the Elixir of Sulfanilamide. Tonight our little home isbleak and full of despair. . . . Even the memory of her is mixedwith sorrow for we can see her little body turning to and fro andhear that little voice screaming with pain and it seems as tho itdrives me insane. . . . Tonight President Roosevelt as you enjoyyour little grandchildren of whom we read about, it is my pleathat you will take steps to prevent such sales of drugs that willtake little lives and leave such suffering behind. . . .’’ (80–82).

The bills to correct the gaps in the 1906 act had beendelayed and diluted over the previous 5 years. However, theimpact of the Elixir Sulfanilamide tragedy was to strengthenthe drug provisions of the latest bills and in fact propel passageof the law itself. Roosevelt signed the bill on June 25, 1938 (83).The Food, Drug, and Cosmetic Act brought medical devices andcosmetics under regulation, provided for standards of identityfor foods, prohibited once and for all false therapeutic claims ondrug labeling, required that drugs be labeled with adequatedirections for use, authorized factory inspections (which hadbeen executed anyway under the bureau’s interpretation of



who perished in this ordeal (see Fig. 4). Her mother, Marie

Figure 4 The face of a drug disaster. This excerpt from a movingletter to President Roosevelt from Mrs. J. Nidiffer of Tulsa describesher anguish and helplessness over the loss of her six-year-old daugh-ter, Joan Marlar. Ironically, sulfanilamide saved the life of FDR’s sonjust one year earlier, not long after American clinicians got theirhands on the drug.

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the old law), instituted court injunctions for violative products,corrected abuses in the quality and packaging of foods, insti-tuted adequate drug manufacturing controls (84), and, mostimportant from the standpoint of the history of drug regula-tion, mandated that all new drugs had to be shown by themanufacturer to be safe before they could be marketed—thebirth of the new drug application. The premarket provision,inspired by the fear of another Elixir Sulfanilamide disaster,had an immediate impact, with over 6000 thousand new drugapplications (NDAs) filed in the first 9 years, and 13,000 by1962 (85).

8. DRUG REGULATION AND THE POSTWARCHEMOTHERAPEUTIC REVOLUTION

One early development under the drug provisions of the 1938act concerned self-medication. The law called for adequatedirections for use by the patient, and by 1940 FDA issuednearly 30 detailed warning statements to be labeled on a vari-ety of drugs. For example, bromides were labeled with thefollowing: ‘‘Warning: Frequent or continued use may lead tomental derangement, skin eruptions or other serious effects.Do not take more than the dosage recommended. Not to betaken by those suffering from kidney disease’’ (86).

However, it was FDA’s opinion within weeks of the lawthat some drugs simply could not be labeled with adequatedirections. For example, the use of a sulfa drug in a venerealdisease was hardly routine, complicated as it was by both theadverse reactions that many of the early sulfas produced andthe identification and progress of the disease. In other words,FDA ruled that in some cases medical expertise had to beinvolved in the medication process for the drug to be safe.The agency identified an increasing number of drugs thathad to be labeled for dispensing only on the order of a physicianor dentist—the birth of another standard of modern medi-cine, the prescription drug (87–90). This created confusionabout how a drug would be categorized—prescription or non-prescription—and who would have primary responsibility for



that designation. The absence of statutory direction wasresolved in 1951 when the Durham-Humphrey Amendmentwas passed. That law established broad parameters for decid-ing which drugs merited designation as prescription legendstatus and which could be available over the counter (91).

The illegal sale of two groups of prescription drugs,amphetamines and barbiturates, took up more of FDA’s drugenforcement time in the 1940s, 1950s, and 1960s than all otherdrug violations under the 1938 act combined. At first theagency focused on pharmacies, some of which were either sell-ing these drugs over the counter without a prescription orincessantly refilling old prescriptions that did not authorizeany refills. By the mid-1950s, FDA’s attention turned to thetrucking industry, a major source of traffic in these pharma-ceuticals, where some spectacular and highly publicized high-way crashes were directly connected to the use ofamphetamines and barbiturates (92). Eventually many otherdrugs prone to abuse, such as hallucinogens, were consolidatedfor special interdiction by FDA under the Drug Abuse ControlAmendments of 1965 (93,94). However, 3 years later that func-tion was transferred to what would become the DrugEnforcement Administration (DEA).

The introduction of the sulfa drugs, beginning with sulfa-nilamide in 1935, launched a revolution in chemotherapy.Statutes and regulations did their best to keep track of newtherapies. For example, literally hours before expiration of thepatent on insulin (and the University of Toronto’s oversight ofquality control in the production of the hormone) in 1941,Congress passed the Insulin Amendment to require FDA totest every batch of insulin produced for strength, quality, andpurity to ensure its safety and effectiveness (95). A similar lawin 1945 provided for FDA certification of batches of penicillin—a continuation of service provided by FDA beginning in 1943 tothe War Production Board for penicillin headed for troops. Asadditional antibiotics were discovered, laws were passed toaccommodate them (96–98).

As mentioned above, companies flooded FDA with drugapplications at the outset. The agency received an average ofover 100 NDAs monthly from 1938 to 1941 because sponsors

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were apparently unsure of what constituted a new drug. NDA1596, received on August 30, 1939, and approved on September20, 1939, was for 4-H Household Cough Syrup, consisting ofhorehound, molasses, and vinegar. The Aiellos Ped-ValeCompany submitted NDA 407 on January 12, 1939, forAiellos Foot Remedy Powder, made up solely of boric acid;FDA approved the application on April 1 of that year. Duringthis period seven firms and one physician submitted NDAs foraspirin that were approved by FDA. Interestingly, in January1945 the agency ruled that the indications for aspirin were sowell known to consumers that directions for use were notrequired. Aspirin lollipops, though, were a different matter,requiring a physician’s prescription (99–102).

The application submission rate slowed during World WarII and the early post-war years to about 300 annually.However, it picked up again in the 1950s to approximately500 each year, when research funds flooded laboratoriesalmost as fast as pathbreaking new medicines flooded the mar-ketplace. Upon the end of hostilities in Europe, the Committeeon Medical Research of the Office of Scientific Research andDevelopment disbursed remaining wartime research funds tothe National Institutes of Health (NIH). That, together withstrong congressional support, launched in full force the modernera of autonomously peer-reviewed extramural funding of bio-medical research at NIH (103).

In addition, the pharmaceutical industry accelerated atrend that began in the period between the wars, pouringmore and more revenue into research and development(104,105). That decision might have been made a little easierby the success of their wartime experience with penicillin, syn-thetic anti-infective agents, and other drugs. Thus, a host ofantibiotics, diuretics, ataractics, corticosteroids, antispasmod-ics, and other classes of drugs proliferated during that decade(106,107). Of course, the number of supplements grew as thebase number of NDAs increased. And then there were somedrugs that yielded scores or even hundreds of NDAs, such asdiethylstilbestrol and rauwolfia serpentina. David Caversreports that the latter led to applications from 319 differentfirms and was included in 2500 different medicines (108).



9. COMING TO GRIPS WITH EFFICACYBEFORE 1962

Another drug regulation policy was growing increasinglyimportant in the 1950s—the relationship between drug safetyand drug efficacy. The idea of federally mandated effectivenessin medicines was nothing new at this time. For example, reg-ulations issued by the National Institute of Health (formerlythe Hygienic Laboratory) in 1934 required that biologics had towork: ‘‘[A] license for new products shall not be granted with-out satisfactory evidence of therapeutic or prophylactic effi-ciency’’ (109). This formalized a policy that had been in placefor years.

In the late 1930s FDA promulgated a rule requiring man-ufacturers of oral or otherwise inert ovary, suprarenal, pitui-tary, prostate, pineal, and mammary extracts to label theirproducts with a statement that such an article ‘‘does not con-tain any known therapeutically useful constituent of the glandsmentioned.’’ Of course, even under the 1906 act, actions takenagainst patent medicines that made false therapeutic claimswere implicitly driven by efficacy considerations (considera-tions that the Supreme Court believed were ahead of theirtime). The Insulin Amendment, Penicillin Amendment, andthe other antibiotic amendments literally invoked efficacy asa prerequisite for certification by FDA. Reviews of certainNDAs that claimed to treat serious diseases such as pneumoniacertainly took efficacy into account (110). The concept that incertain cases a drug could not be safe without being effectivewas employed but never pressed forward as an official policy—until Hepasyn came along.

The Hepasyn story began in the early 1930s, when variousresearchers observed that cancerous tissue bore a high concen-tration of the amino acid, arginine, which appeared to promotecell division in tumors. Some tried to exploit this observationby applying the liver enzyme arginase, which helps to hydro-lyze arginine, as a possible treatment to control tumorgrowth. Success was fleeting for most. However, dentistWesley G. Irons, working as an anatomist at the Schools ofPharmacy and Dentistry at the University of California at

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San Francisco in the 1940s, claimed to have success treatinganimal tumors with arginase. When his funding fell through atthe university, Irons was offered funding and laboratory spaceat the San Francisco College of Mortuary Science, a source forcadavers in Irons’s classes.

The mortuary school reserved commercial rights to Irons’swork and served as the manufacturing establishment forHepasyn, the name they gave to arginase. In November 1950the school arranged with a Hollywood clinician to test arginase,and within a year 100 patients had received the substance.Eventually the Hollywood physician began treating othercancer patients on an ambulatory basis once a week at themortuary school. The story became even more curious afterIrons and the school parted company, but the San Franciscoschool submitted an NDA late in 1953. FDA inspectors visitedthe mortuary school and found serious production problems,such as organoleptic sterility testing. The NDA itself, thoughthe sponsors claimed to have data on 175 patients, containedresults with only 10. FDA, not surprisingly, considered theapplication incomplete and requested more data. As problem-atical as the manufacturing operation was, FDA chose to focus

By October 1955 the application was deemed completeenough for a review. The agency’s strategy was made clear toa medical officer in San Francisco: ‘‘We have given consider-able thought to the proper handling of this application andhave decided in conjunction with [General Counsel William]Goodrich that since this preparation is ineffective in the treat-ment of malignant disease its use is not safe in such situations.In other words, while section 505 does not refer to efficacy weare going to try and take the position that efficacy is so inti-mately bound up in the use of this material that the lack ofefficacy will make it unsafe for use’’ (111). The Hepasyn reviewthus was not going to be just another NDA evaluation. Rather,it was to be a blatant stand on therapeutics and the law. FDA’sexpectation or hope was that the San Francisco College ofMortuary Science, its application denied on the basis of lackof efficacy, would appeal the decision in an administrativehearing.



on the clinical evidence submitted by the college (see Fig. 5).

In late December of that year, FDA Commissioner GeorgeLarrick informed the college that its NDA was denied becauseof misleading statements and omissions, because of inadequatemanufacturing and control procedures, and because ‘‘safetyhas not been proven because of lack of proof of efficacy indiseases that are invariably fatal unless treated with adequate

Figure 5 The San Francisco College of Mortuary Science served asthe manufacturer, ambulatory clinic, and new drug application spon-sor for a cancer treatment. FDA used this opportunity to press for aformalized policy mandating an efficacy requirement in some drugs.(Courtesy of the San Francisco History Center, San Francisco PublicLibrary.)

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efficacious means’’ (112). While there was not a surfeit of bonafide treatments for the cancers Hepasyn claimed to benefit,there certainly were some. An approved yet ineffectiveHepasyn, the reasoning went, would lead some patients todelay or possibly avoid treatment with established effectivetreatments. Larrick informed the mortuary school that if theNDA were not withdrawn, a hearing notice—as provided in the1938 act to sponsors who wished to petition adverse NDA deci-sions by FDA—would be issued next month. Led by medicalofficer Barbara Moulton, FDA continued to assemble its casefor a hearing. Medical director Albert Holland observed thatthis case ‘‘may well be a precedent-establishing case no matterwhich way the courts decide it.’’ But in the end the courtswould not have the opportunity, as the San Francisco schoolwithdrew the application rather than face the hearing (113).

FDA had another chance to press the safety-efficacy policya few years later, and this time the drug firm was more accom-modating. On September 9, 1959, FDA approved EatonLaboratories’ application for Altafur (furaltadone), a systemicantibacterial agent. However, FDA’s reevaluation of the NDAas a rising number of neurological and other adverse reactionscame to light led the agency to question the efficacy of Altafur(114). Among other issues, FDA believed there were insuffi-cient reports in the application from experts in the treatmentof infectious diseases, and certain claims would have requiredunattainable plasma levels even at triple the recommendeddosage. The agency did not explain why these issues were notapparent at the time of the application.

Eaton Laboratories submitted additional data, but FDAsaid that evaluation of those data should be done in thevenue of a formal hearing over suspension of the AltafurNDA; its lack of effectiveness did not justify its toxicity. Thehearing began in January 1961 and lasted several weeks. Thehearing examiner was persuaded by the testimony of MaxwellFinland of Harvard, George Jackson of Illinois, and otherexperts on infectious diseases who disputed Altafur’s claim oftherapeutic value. The examiner decided that efficacy wasindeed relevant to Altafur’s safety considering the diseasestreated—diseases amenable to effective treatment by other,



less toxic drugs on the market. The NDA for Altafur was sus-pended in August 1962, less than 2 months before Congresspassed the Kefauver-Harris Drug Amendments (115,116).

10. KEFAUVER, KEVADON, AND A NEWAPPROACH TO DRUG REGULATION

Estes Kefauver of Tennessee was not the first senator to voiceconcern about increasing cost of drugs. Fellow DemocratWarren Magnuson of Washington had heard complaints fromconstituents and also learned about the rising cost of drugs inAmerica as a member of the Labor, Health, Education, andWelfare Subcommittee. But Kefauver, chairman of theSubcommittee on Antitrust and Monopoly since January1957, was in a position to explore this development in depth.Thus, in December 1959, following an extensive investigationby his staff that began the previous year, Kefauver initiatedhearings into administered prices in the pharmaceutical indus-try. The early testimony provided some headline-grabbing sta-tistics into how the pharmaceutical industry arrived at drugprices. For example, the committee learned that the Germanfirm Schering had purchased bulk estradiol progynon (forsymptoms associated with menopause) from Roussell ofFrance for resale in the United States. When the committeecompared the cost of the bulk product and what Scheringcharged for tablets produced therefrom, they discerned amarkup of 7000% (117). The Schering president objected thatsuch a hyperbolic figure ignored the costs of manufacturing,advertising, distribution, and research on this drug. Kefauverreplied that Schering would have incurred no research costs forthis Roussell drug itself.

When the hearings shifted into a study of drug costs as afunction of research expenses in the industry, A. Dale Console,a former medical director at Squibb, testified that researchindeed leads to many failures, but that ‘‘the problem arisesout of the fact that [firms] market so many of their failures’’(118). The hearings thus took on another dimension by inves-tigating advertising practices of the pharmaceutical industry

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and the delivery of information about their drugs to doctors.Records subpoenaed by Kefauver from the 22 largest firmsrevealed that in 1958 they expended an average of one fourthof their gross income on advertising. Investment in detail menrepresented a considerable portion of that expense, as esti-mates for the same year indicated a detail force for the industryof 15,000, or one for every 10 doctors (119).

The committee also heard about the relationship betweenFDA and the pharmaceutical industry. Former FDA medicalofficer Barbara Moulton, described an acquiescent agency,frequently and inappropriately deferring to the wishes of firms.The committee’s inquiry into Henry Welch, director of theAntibiotic Division at FDA, who developed a lucrative businessin medical reprint sales with drug companies, revealed a high-ranking regulatory official who was, at minimum, far too cozywith regulated interests (120). After 10 months of hearings,Kefauver’s committee had raised a number of concerns, con-cerns that soon would be reflected in proposed legislation,introduced by Kefauver on April 12, 1961 (121–124).

Kefauver first addressed patents in his bill, severely cur-tailing the monopoly that drug companies would have on theirproducts (an outgrowth of another facet of the hearings). Thebill also gave FDA increased authority over drug production,distribution, and advertising. Food and Drug’s inspectionauthority would be enhanced to uphold stronger quality-control standards in a system reminiscent of that applied tobiologics. Advertising would include explicit and prominentwarnings, again responding to problematical issues duringthe hearings. The law would extend FDA’s role for batch certi-fication of selected antibiotics to all such drugs, not just thosecovered by the amendments up to the early 1950s. The drugclearance provision of the 1938 act, in which a drug applicationbecame effective after 60 days unless prevented by specificFDA action, would be ended under this bill. Finally, sponsorswould have to shows drugs to be effective as well as safe (125).

Opposition emerged quickly. The AMA, for example, cameout strenuously opposed to the effectiveness requirement,arguing that only the physician can make a determination ifa drug works or not. The industry, operating in part through



its trade association, the Pharmaceutical ManufacturersAssociation, worked vehemently against elements of the billthat would affect its profits and force firms to advertise adrug’s adverse reactions as well as its indications. The supportof the White House was tepid at best (126). The process ofnegotiation, dilution, and revision ensued once Kefauver’s billcleared his subcommittee, proceeded to a parent committee,and then to the full Senate. However, unbeknownst toKefauver and his colleagues, at this time a drug disaster wasdeveloping that would have an impact on Kefauver’s lawanalogous to the legislative effect of the Elixir Sulfanilamidetragedy.

On September 12, 1960, the William S. Merrell Companyof Cincinnati submitted an application for Kevadon, knowngenerically as thalidomide. Merrell was the U.S. licensee forthe German firm Chemie Grunenthal, which introduced thissedative in Europe in 1956. The application was routed toFrances Kelsey, who had replaced Barbara Moulton. Kelsey’ssuperiors believed this apparently straightforward NDA wouldbe appropriate for a newcomer. However, Kelsey found thechronic toxicity data inadequate to support the safety of thedrug and the labeling unsuitable. Merrell continued to appenddata to the application, which Kelsey continued to find inade-quate to the task. The contacts between Merrell and Kelsey orher superiors thereafter occurred almost weekly until thespring, as the firm was rushing to make a March 1 launchdate for Kevadon. At this time Kelsey also was deeply involvedin FDA’s administrative hearing with Eaton Laboratories overAltafur.

But crucial news emerged in February 1961, when themedical officer read a report in the December 1960 issue ofthe British Medical Journal that associated long-term use ofthalidomide with peripheral neuritis. When representativesfrom Merrell met with Kelsey in May to discuss this revelation(which Merrell believed rather inconsequential, assuming theeffects were reversible), Kelsey requested evidence thatKevadon would be safe in pregnancy. Although the requestwas based on a theoretical consideration stemming from theneurological side effect, it was consistent with Kelsey’s own

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training as a pharmacologist at the University of Chicago, andit was shared by her medical officer colleagues at FDA. Merrelland outside clinical investigators representing the companycontinued to argue that Kevadon was effective and safe relativeto the barbiturates, the firm now hoping to meet a November1961 launch in time for the holidays.

But on the last day of that month, Merrell reported toKelsey that thalidomide had been withdrawn from Germany,where use of the drug had been correlated with severe congen-ital abnormalities. On March 8, 1962, Merrell withdrew itsNDA for Kevadon. The United States narrowly escaped thefate of many other countries. But the agency learned in Aprilfor the first time the true scale of Merrell’s investigation. Over1100 doctors received Kevadon (the agency had assumed fromthree to six dozen investigators were involved), and the inves-tigation involved about 20,000 patients, 624 of whom werepregnant. Despite assurances by Merrell that a recall hadbeen completed, field investigators discovered that over25,000 doses were still unaccounted for in August, promptingan Elixir Sulfanilamide–like national search for outstandingsamples of the drug. Seventeen cases of thalidomide-inducedphocomelia occurred in the U.S., seven of which were docu-mented to be caused by thalidomide obtained outside of theMerrell study (127–129).

The shock of what might have happened with thalidomidewrested the drug regulation reform bill from congressionalinertia, and President Kennedy, surrounded by Kefauver,Kelsey, and others, signed the bill into law on October 10,1962 (130) (see Much had changed from the bill

to cut costs via patent adjustments were long gone, as was thebiologics-like system of licensing (although firms had to regis-ter). Manufacturers had to prove that their drugs were effec-tive as well as safe—not just drugs introduced from that pointforward, but all new drugs introduced since 1938. FDA’s con-trol over the clinical investigation of drugs was clarified andstrengthened, and a surprise provision required experimentalsubjects to give informed consent. Safety, effectiveness, andreliability of a drug would be further provided for by requiring



Fig.Kefauver introduced, but some elements remained. Attempts

6).

that production adhere to current good manufacturing prac-tice, although that provision was made clear in FDA regula-tions as far back as the early 1940s (131). New drug clearancewould no longer be based on an application becoming effectiveautomatically after 60 days unless FDA action indicated other-wise; a new drug now could be marketed only with FDA’sassent. Oversight of prescription drug advertising was trans-ferred from FTC to FDA. And finally, drug inspectors wouldhave enhanced access to establishment records other thanfinancial or personnel documents (132).

11. CONCLUSION

The 1962 law was a landmark in the history of drug regulation,and no law since has been as sweeping in its coverage of the

Figure 6 President Kennedy hands Senator Kefauver one of thepens used to sign the 1962 Drug Amendments. Among those lookingon is Frances Kelsey, standing second from left.

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pharmaceutical enterprise. But subsequent laws and regula-tions stand out, too, for many reasons. For example, the risein the consumer movement certainly had an impact on drugregulation. The issuance of the first patient package insert in1970, for oral contraceptives, followed pointed protest bywomen’s health advocates against AMA’s opposition to thisprecedent in patient education (133). The Vitamins andMinerals Amendment (Proxmire Amendment) of 1976, whichprevented FDA from limiting potency of supplements or regu-lating them as drugs, was due in no small part by organizedefforts of consumers to inundate their members of Congressand FDA with letters of protest on a scale unheard of at thattime (134,135). The National Organization for Rare Disordersled the effort behind the Orphan Drug Act of 1983 to persuadepharmaceutical companies to develop drugs, otherwise unpro-fitable, for diseases with small patient populations (136,137).

In the same year, as part of an overall revision of investi-gational new drug (IND) procedures (the IND rewrite), FDAproposed so-called treatment-use INDs, expanding physicianand patient access to experimental drugs for therapeuticrather than investigational purposes in patients ‘‘with seriousdiseases or conditions, for whom alternative therapies do notexist or cannot be used’’ (138–140). However, there were sev-eral restrictions to treatment INDs, such as the need to have afirm request treatment IND status, to be treated by a physicianskilled in therapy of that disease, and to have no other thera-pies available. Activists representing HIV and AIDS victims,families, and friends engaged FDA directly on this issue andhelped not only to relax these restrictions but refocus the over-all drug development and evaluation process. FDA thereafterwould consult with sponsors to plan more efficient clinical stu-dies of drugs for life-threatening and severely debilitating dis-eases, modeled on the testing and evaluation of AZT (141,142).Moreover, continuing pressure by AIDS activists for expeditedaccess to experimental therapies figured in a policy announcedby FDA Commissioner Frank Young in July 1988. Individualswould be allowed to return to the country with a 3-monthsupply of any drug desired as long as the agency ensuredthat the product was not fraudulent, counterfeit, or harmful,



and if the traveler presented the name and address of thephysician responsible for the treatment. The volleying overIND and NDA policies between FDA and the AIDS communitycontinued into the 1990s (143).

The history of drug regulation has come full circle, fromthe second decade of the nineteenth century, when a Marylandphysician persuaded Congress to pass a law to ensure genuinesmallpox vaccine, to the first decade of the twenty-first cen-tury, when the United States again faced smallpox vaccinationas a policy issue. In between we have witnessed a vast array ofstimuli to changes in the way drugs are regulated. Therapeuticdisaster and concomitant outrage, of course, are perhaps themost visible sources for tectonic shifts in policy. But politicalupheaval, organized social action, institutionalization of profes-sional authority, the political and economic strength of thedrug industry, the will and whims of all three branches ofgovernment, the manner in which the fourth estate capturesand conveys regulatory issues, and basic shifts in therapeuticsitself all have had an impact on the way this country regulatesdrugs. FDA often refers to itself as a science-based regulatoryagency, but the context for drug regulation over the past200 years has been and will always be much broader thanscience and law.

NOTES AND REFERENCES

1. AJ Wedderburn. A Compilation of the Pharmacy and Drug Lawsof the Several States and Territories. Bulletin 42, Division ofChemistry, U.S. Department of Agriculture. Washington, DC:GPO, 1894, passim.

2. G Sonnedecker, G Urdang. Legalization of drug standards understate laws in the United States of America. Food Drug CosmeticLaw Journal 8: 741–760, 1953.

3. PB Hutt, RA Merrill. Food and Drug Law: Cases and Materials.2nd ed. Westbury, NY: Foundation Press, 1991, pp. 660–661(quote from p. 660). I am indebted to Peter Hutt for bringingthis important development to my attention.

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4. Pharmacopoeia of the United States of America. Boston:Charles Ewer, 1820, p. 17.

5. G Sonnedecker. The Founding Period of the U.S. Pharma-copeia: I. European Antecedents. Pharmacy in History 35:151–162, 1993.

6. G Sonnedecker. The Founding Period of the U.S. Pharma-copeia: II. A National Movement Emerges. Pharm. Hist. 36:3–25, 1994.

7. G Sonnedecker. The Founding Period of the U.S. Pharma-copeia: III. The First Edition. Pharm. Hist. 36: 103–122,1994.

8. L Anderson, GJ Higby. The Spirit of Voluntarism, A Legacy ofCommitment and Contribution: The United StatesPharmacopeia. Rockville, MD: USP, 1995, pp. 7–25.

9. Quoted in C Ridgway. Good Enough for America! The DrugImport Law of 1848. Seminar paper, University of Wisconsin,Madison, WI, 1986. Cited in: JH Young. Pure Food: Securingthe Federal Food and Drugs Act of 1906. Princeton, NJ:Princeton University Press, 1989, p. 7.

10. Young. Pure Food, pp. 6–7.

11. Congressional Globe. 30th Cong., 1st sess., 1 December 1847–15 August 1848, p. 858.

12. Drug Import Act. Public Law [30–45]. 9 U.S. Stat. 237, 26June 1848 (quote is from Sec. 1).


14. M Okun. Fair Play in the Marketplace: The First Battle forPure Food and Drugs. DeKalb, IL: Northern Illinois UniversityPress, 1986, pp. 14–15.

15. G Sonnedecker. Contributions of the pharmaceutical professiontoward controlling the quality of drugs in the nineteenth cen-tury. In: JB Blake, ed. Safeguarding the Public: HistoricalAspects of Medicinal Drug Control. Baltimore: Johns HopkinsUniversity Press, 1970, pp. 105–111.

16. HF Dowling. Fighting Infection: Conquests of theTwentieth Century. Cambridge, MA: Harvard UniversityPress, 1977.



17. HA. Lechevalier, M Solotorovsky. Three Centuries ofMicrobiology. New York: McGraw-Hill, 1965; New York:Dover, 1974.

18. Treasury Department, Marine Hospital Service. Annual Reportof the Supervising Surgeon-General of the Marine-HospitalService of the United States for the Fiscal Year 1895.Washington, DC: GPO, 1896, p. 327.

19. Treasury Department, Marine Hospital Service. Annual Report1895, pp. 329–335.

20. RA Kondratas. Biologics Control Act of 1902. In: The EarlyYears of Federal Food and Drug Control. Madison, WI:American Institute of the History of Pharmacy, 1982, p. 11.

21. The laboratory notebook that documents the HygienicLaboratory’s work (in the possession of the Center forBiologics Evaluation and Research, Food and DrugAdministration, Bethesda, Maryland) and a sample of the stan-dard itself (in the possession of the Division of Science,Medicine, and Society, National Museum of AmericanHistory, Smithsonian Institution, Washington, D.C.) wereincorporated as part of an exhibit, ‘‘Safety for Millions: TheBiologics Control Act of 1902 Centennial,’’ National Museumof American History, Smithsonian Institution, Washington,DC, September 2002.

22. U.S. Congress, House. Sale of Viruses, Etc., in the District ofColumbia. Report No. 2713, to Accompany H. R. 15289, 57thCong., 1st sess., 27 June 1902, pp. 6–7 (testimony of George M.Kober, Acting Chairman, Medical Society of the District ofColumbia, Washington, DC, 16 April 1902). Reproduced in:Legislative History of the Regulation of Biological Products.N. p.: Division of Biologics Standards, National Institutes ofHealth, Department of Health, Education, and Welfare, 1967.

23. Biologics Control Act. Public Law 57–244. 32 U.S. Stat. 728,1 July 1902.

24. Perhaps it is more accurate to say that any charges broughtunder the 1902 act or under its consolidation in the 1944Public Health Service Act were not contested. The suit broughtby the government against John P. Calise and the WestchesterBlood Bank in 1962 for altering expiration dates appears to be

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the first litigated case of any kind under the 1902 BiologicsAct.

25. JM Solomon. Legislation and regulation in blood banking.In: M Schaeffer, ed. Federal Legislation and the ClinicalLaboratory. Boston: G. K. Hall, 1981, p. 150.

26. PB Hutt, personal communication, 12 September 2002, whosuspects that Calise might have been the first case.

27. Kondratas. Biologics Control Act of 1902.

28. Treasury Department, Public Health and Marine-HospitalService. Annual Report of the Surgeon-General of the U.S.Public Health and Marine-Hospital Service of the UnitedStates for the Fiscal Year 1904. Washington, DC: GPO,1904, p. 372.

29. Treasury Department, Public Health and Marine-HospitalService. Annual Report of the Surgeon-General of the U.S.Public Health and Marine-Hospital Service of the UnitedStates for the Fiscal Year 1908. Washington, DC: GPO,1909, p. 44.

30. Center for Biologics Evaluation and Research, Food and DrugAdministration. Science and the Regulation of BiologicalProducts: From a Rich History to a Challenging Future. N.p.: [CBER], 2002.

31. 17 U.S. Stat. 322–323, 18 June 1872.

32. 28 U.S. Stat. 963, 2 March 1895.

33. JH Young. The Medical Messiahs: A Social History of HealthQuackery in Twentieth-Century America. Princeton, NJ:Princeton University Press, 1967; rev. ed., 1992, pp. 66 ff.,86–87.

34. LF Kebler. Public Health Conserved through theEnforcement of Postal Fraud Laws. Am J Public Health 12:678–683, 1922.

35. Young. Medical Messiahs, pp. 122–128.

36. Young. Medical Messiahs, pp. 296–315.

37. Wheeler-Lea Amendments. Public Law 75–447. 52 U.S. Stat.111, 21 March 1938.



38. M Handler. The control of false advertising under the Wheeler-Lea Act. Law Contemp Problems 6: 91–110, 1939.

39. M Fishbein. A History of the American Medical Asso-ciation. Philadelphia: W. B. Saunders, 1947, pp. 226–227,235–236.

40. A Smith. The Council on Pharmacy and Chemistry and thechemical laboratory. In: Fishbein. American MedicalAssociation, pp. 876–877, 884–885.

41. JG Burrow. The prescription drug policies of the AmericanMedical Association. In: Blake. Safeguarding the Public,pp. 113–114.

42. P Starr. The Social Transformation of American Medicine.New York: Basic Books, 1982, p. 133.

43. H Marks. The Progress of Experiment: Science andTherapeutic Reform in the United States, 1900–1990.Cambridge: Cambridge University Press, 1997, pp. 23–41.

44. Smith. Council on Pharmacy and Chemistry and the ChemicalLaboratory, pp. 870 ff.

45. AE Smith. The Council on Pharmacy and Chemistry. J AmMed Assoc 124: 434 ff., 1944.

46. HF Dowling. Medicines for Man: The Development,Regulation, and Use of Prescription Drugs. New York: AlfredA. Knopf, 1970, pp. 170–177.

47. It was more than a possibility; see the case of Clarin(heparin potassium), as discussed in U.S. Congress, Senate,Subcommittee on Antitrust and Monopoly of the Committeeon the Judiciary. Drug Industry Antitrust Act. Hearingspursuant to S. Res. 52 on S. 1552, 87th Cong., 1st sess.,13 and 15 September 1961 and 12–13, 18–29 December 1961,Part 5. Washington, DC: GPO, 1962, pp. 2587–2588.Reproduced in: A Legislative History of the Federal Food,Drug, and Cosmetic Act and Its Amendments 20: 329–330.

48. J Bishop. Drug evaluation programs of the AMA, 1905–1966.J Am Med Assoc 196: 122–123, 1966.

49. New program of operation for evaluation of drugs. J Am MedAssoc 158: 1170–1171, 1955.

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50. HF Dowling. The impact of the new drug laws on the Councilon Drugs of the American Medical Association. Clin Res 13:162–165, 1965.

51. MK Weikel. Research as a function of pharmaceutical industry:The American formative period. M. S. thesis, University ofWisconsin, Madison, WI, 1962, pp. 29–36.

52. DL Cowen. The role of the pharmaceutical industry. In: Blake.Safeguarding the Public, p. 73.

53. J Liebenau. Medical Science and Medical Industry: TheFormation of the American Pharmaceutical Industry.Baltimore: Johns Hopkins University Press, 1987, passim,but especially, pp. 57–78.

54. JP Swann. Academic Scientists and the PharmaceuticalIndustry: Cooperative Research in Twentieth-CenturyAmerica. Baltimore: Johns Hopkins University Press, 1988,pp. 9–23.

55. JH Madison. Eli Lilly: A Life, 1885–1977. Indianapolis: IndianaHistorical Society, 1989, pp. 27, 52.

56. JH Young. ‘Even to a sucking infant’: nostrums and children.In: American Health Quackery: Collected Essays by JamesHarvey Young. Princeton, NJ: Princeton University Press,1992, pp. 135, 138.

57. GL Nelson, ed. Pharmaceutical Company Histories, vol. 1.Bismarck, ND: Woodbine, 1983, p. 161.

58. J Liebenau. A case unresolved: Mrs. George vs. Dr. Hand andhis colic cure. Pharm Hist 31: 135–138, 1989.

59. The best source on the history of patent medicines remains JHYoung. The Toadstool Millionaires: A Social History of PatentMedicines in America before Federal Regulation. Princeton,NJ: Princeton University Press, 1961. Young’s MedicalMessiahs and his American Health Quackery also addressthis subject.


61. Wiley typically emphasized the problem of food adulterationas a more serious public health issue than drug adulteration,perhaps in part because of his scientific background.



62. On Wiley and his time, see HW Wiley. An Autobiography.Indianapolis: Bobbs-Merrill, 1930.

63. OE Anderson. The Health of a Nation: Harvey W. Wiley andthe Fight for Pure Food. Chicago: University of Chicago Press,1958.

64. Young. Pure Food.

65. Food and Drugs Act of 1906. Public Law 59-384. 34 U.S. Stat.768, 30 June 1906.

66. A Thackray, JL PT Carroll, RF Bud. Chemistryin America, 1876–1976: Historical Indicators. Dordrecht:D. Reidel, 1985, pp. 126–131.

67. For bibliographic information on the variety of regulations

on the History of the Food and Drug Administration:Published Primary Sources: Sources on Regulation andEnforcement.

68. A Sellers, ND Grundstein. Administrative Procedure andPractice in the Department of Agriculture under the Federal

parts. Part I: 12 (files, FDA History Office, Rockville, MD).

69.Federal Food and Drugs Act. Washington, DC: GPO, 1934,pp. 267–269 (quote is from p. 268).

70. Quoted in Young. Drugs and the 1906 Law, p. 149.

71. Sellers, Grundstein. Administrative Procedure and Practice. 1:14–15, n. 31.

72. Sherley Amendment of 1912. Public Law 62-301. 37 U.S. Stat.416, 23 August 1912.

73. RdeF Lamb. American Chamber of Horrors. New York: Farrarand Rinehart, 1936, pp. 64–68.

74. Young. Drugs and the 1906 Law, pp. 147–152.

75. Young, Drugs and the 1906 Law, pp. 149–152.

76. JP Swann. FDA and the practice of pharmacy: prescriptiondrug regulation to 1951. Pharm Hist 36: 57–59, 1994.

40 Swann


<http://www.fda.gov/oc/history/resourceguide/

issued by the bureau at this time, see A Guide to Resources

MG White, OH Gates. Decisions of Courts in Cases under the

Sturchio,

sources.html>, 18 January 2002.

Food, Drug, and Cosmetic Act of 1938. 308-page typescript in 2

http://www.fda.gov

http://www.fda.gov

77. Young. Drugs and the 1906 Law, pp. 153–156.

78. On the effort by FDA to promote the need for a new law, seeG. Kay. Healthy Public Relations: The FDA’s 1930s LegislativeCampaign. Bull Hist Med 75: 446–487, 2001.

79. The standard source on the construction of the 1938 Food,Drug, and Cosmetic Act is CO Jackson. Food and Drug Legis-lation in the New Deal. Princeton, NJ: Princeton UniversityPress, 1970.

80. An excellent source on the Elixir Sulfanilamide disaster is JHYoung. Sulfanilamide and diethylene glycol. In: J Parascandola,JC Whorton. Chemistry and Modern Society: Historical Essaysin Honor of Aaron J. Ihde. American Chemical SocietySymposium Series 228. Washington, DC: American ChemicalSociety, 1983, pp. 105–125.

81. Elixir of Death. RubinTarrant Productions, History Channel,11 December, 2003.

82. The letter quoted is reproduced in the files, FDA HistoryOffice, Rockville, MD.

83. Food, Drug, and Cosmetic Act. Public Law 75–717. 52 U.S.Stat. 1040, 25 June 1938.

84. A recent article has shed light on this provision of the act,largely forgotten by those who would believe a requirementfor good manufacturing practices began in 1962 (or evenlater). DE Cooper. Adequate Controls for New Drugs: GoodManufacturing Practice and the 1938 Federal Food, Drug,and Cosmetic Act. Pharm. Hist. 44: 12–23, 2002.

85. DF Cavers. The Evolution of the Contemporary System ofDrug Regulation under the 1938 Act. In: Blake. Safeguardingthe Public, pp. 167–168.

86. Warning Statements for Drug Preparations. TC-14, 1November 1940. Reproduced in: VA Kleinfeld, CW Dunn.Federal Food, Drug, and Cosmetic Act: Judicial andAdministrative Record, 1938–1949. Chicago: CommerceClearing House, c. 1949, pp. 574–578; quote is from p. 577.

87. HM Marks. Revisiting ‘The Origins of Compulsory DrugPrescriptions.’ Am J Public Health 85: 109–115, 1995.



88. Swann. FDA and the Practice of Pharmacy.

89. To Distributors of Sulfanilamide and Related Drugs. TC-1, 26August 1938. Reproduced in: Kleinfeld, Dunn. Federal Food,Drug, and Cosmetic Act, p. 561.

90. The generalization about prescription drugs applies, of course,only to nonnarcotic drugs. The latter could be dispensed onlyunder a doctor’s authorization under the Harrison NarcoticAct of 1914.

91. An Act to Amend the Federal Food, Drug, and Cosmetic Act.Public Law 82-215. 65 U.S. Stat. 648, 26 October 1951.

92. The illegal trade in amphetamines and barbiturates in thetrucking industry received dramatic treatment on televisionin the early 1960s: 330 Independence SW. The Dick PowellTheater, NBC, 20 March 1962.

93. Drug Abuse Control Amendments of 1965. Public Law 89-74.79 U.S. Stat. 226, 15 July 1965.

94. JP Swann. Drug abuse control under FDA, 1938–1968. PublicHealth Rep 112: 83–86, 1997.

95. Insulin Amendment of 1941. Public Law 77-366. 55 U.S. Stat.851, 22 December 1941.

96. Penicillin Amendment of 1945. Public Law 79-139. 59 U.S.Stat. 462, 6 July 1945.

97. Streptomycin Amendment. Public Law 80-16. 61 U.S. Stat.11, 10 March 1947.

98. Aureomycin Amendment of 1949. Public Law 81-164. 63 U.S.Stat. 409, 13 July 1949, which accounted for chlortetracycline,chloramphenicol, and bacitracin.

99. Cavers. In: Blake. Drug Regulation under the 1938 Act,p. 167.

100. Directions for Use. TC-426, 22 January 1945. Reproduced in:Kleinfeld, Dunn. Federal Food, Drug, and Cosmetic Act,p. 746.

101. Lollipops Containing Aspirin. TC-130, 7 March 1940.Reproduced in: Kleinfeld, Dunn. Federal Food, Drug, andCosmetic Act, p. 620.

42 Swann


102. Specific NDAs were collected from NDA summary data, files,FDA History Office, Rockville, MD.

103. RH Mandel. A Half Century of Peer Review, 1946–1996.Bethesda, MD: Division of Research Grants, NationalInstitutes of Health, 1996, especially pp. 16 ff.

104. Swann. Academic Scientists and the Pharmaceutical Industry.

105. R Landau, B Achilladelis, A Scriabine. PharmaceuticalInnovation: Revolutionizing Human Health. Philadelphia:Chemical Heritage Press, 1999, pp. 72 ff.

106. P de Haen. Compilation of New Drugs, 1940 thru 1975.Pharmacy Times 1976; 42 (no. 3): 40–75.

107. P de Haen. New Drug Parade: A Historical Minireview,1954–1982. Poster exhibit presentation. Drug InformationAssociation Annual Meeting, Washington, D.C., 28 July1983. Englewood, CO: Paul de Haen International, 1983.

108. Cavers. Drug Regulation under the 1938 Act, pp. 164(rauwolfia), 167 (NDA submission rates).

109. U.S. Department of the Treasury, Public Health Service.Regulations for the Sale of Viruses, Serums, Toxins andAnalogous Products in the District of Columbia and inInterstate Traffic. Misc. Publication No. 10, Approved 13March 1934. Washington, DC: GPO, 1934, p. 3.

110. JP Swann. Sure cure: public policy on drug efficacy before1962. In GJ Higby, EC Stroud. The Inside Story ofMedicines: A Symposium. Madison, WI: American Instituteof the History of Pharmacy, 1997, pp. 228–232, 235–237.

111. GA Granger to RW Weilerstein, 14 October 1955, NDA 9214,Misc. File IV, FDA Records, Rockville, MD.

112. Quoted in Swann. Sure Cure, p. 244.

113. The Hepasyn case is drawn from Swann. Sure Cure, pp.237–246 (Holland quote is from p. 244).

114. Around the same time, an HEW-requested review of anti-biotic decisions made by FDA in the wake of the HenryWelch affair, conducted by the National Research Council,led to a similar conclusion. See Swann. Sure Cure, p. 248.



115. M Mintz. The Therapeutic Nightmare. Boston: HoughtonMifflin, 1965, pp. 54–56.

116. Swann. Sure Cure, pp. 246–250.

117. R Harris. The Real Voice. New York: Macmillan, 1964, pp.59–64.

118. Quoted in Harris. The Real Voice, pp. 78–79.

119. Harris. The Real Voice, pp. 88–91.

120. RE McFadyen. FDA’s Regulation and Control of Antibiotics inthe 1950s: The Henry Welch Scandal, Felix Martı-Ibanez, andCharles Pfizer and Co. Bull. Hist. Med. 53: 159–169, 1979.

121. Harris. The Real Voice, captures the hearings succinctly,though weighted toward Kefauver’s perspective; the preced-ing description draws from pp. 5–116.

122. RE McFadyen. Estes Kefauver and the drug industry. Ph.D.dissertation, Emory University, Atlanta, GA, 1973.

123. The complete hearings are reproduced in A LegislativeHistory of the Federal Food, Drug, and Cosmetic Act andIts Amendments 17: 178–558 (Report No. 448, pursuant toS. Res. 52, a study of administered prices in the drug indus-try, 27 June 1961); 17: 559–807 (Hearings, Part 1; 5, 6, 18–21, 25 July 1961); 18: 1–212 (Hearings, Part 1; cont.); 18:213–944 (Hearings, Part 2; exhibits and appendices); 19: 1–799 (Hearings, Part 3; 16–18, 31 October 1961 and 1, 9November 1961); 19: 800–899 (Hearings, Part 4; 7–9December 1961); 20: 1–313 (Hearings, Part 4; cont.); 20:314–797 (Hearings, Part 5; 13, 15 September 1961, 12–13and 18–20 December 1961). In addition, the hearingsbefore the Committee on Interstate and Foreign Commercein the House of Representatives on the Drug IndustryAct of 1962 (H. R. 11581 and 11582), under ChairmanOren Harris of Arkansas, 19–22 June 1962 and 20–23August 1962, are reproduced in A Legislative History of theFederal Food, Drug, and Cosmetic Act and Its Amendments21: 170–883.

124. On Kefauver in general, see CL Fontenay. Estes Kefauver:A Biography. Knoxville: University of Tennessee Press,1980.

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125. U.S. Congress, Senate. S. 1552. A bill to amend and supple-ment the antitrust laws with respect to the manufacture anddistribution of drugs, and for other purposes, 87th Cong., 1stsess., 12 April 1961. Reproduced in: A Legislative History ofthe Federal Food, Drug, and Cosmetic Act and ItsAmendments 17: 121–144.

126. Harris. The Real Voice, pp. 123–153.

127. The preceding account is drawn from U.S. Congress, Senate,Subcommittee on Reorganization and InternationalOrganizations of the Committee on Government Operations.Interagency Coordination in Drug Research and Regulation.Hearings pursuant to S. Res. 276, 87th Cong., 2d sess., 1, 9August 1962, Part 1 of 2. Washington, DC: GPO, 1963,pp. 75 ff.

128. RE McFadyen. Thalidomide in America: a brush with tragedy.Clio Med 11: 79–86, 1976.

129. P Knightley, H Evans, E Potter, M Wallace. Suffer theChildren: The Story of Thalidomide. New York: VikingPress, 1979, which provides the most detail to this story.

130. Two months earlier Kennedy conferred on Kelsey thePresident’s Award for Distinguished Federal Civilian Service(the highest award for federal civilian service) for work that‘‘. . . prevented a major tragedy of birth deformities in theUnited States . . .;’’ Presentation of The President’s Awardfor Distinguished Federal Civilian Service. Program, theWhite House, 7 August 1962, files, FDA History Office. Seethe report that made public Kelsey’s role in the Kevadonreview: M Mintz. ‘Heroine’ of FDA Keeps Bad Drug OffMarket. Washington Post, 15 July 1962.

131. JP Swann. The 1941 sulfathiazole disaster and the birth ofgood manufacturing practices. PDA J Pharmaceut SciTechnol 53: 148–153, 1999.

132. Drug Amendments of 1962. Public Law 87–781. 76 U.S. Stat.780, 10 October 1962.

133. See LV Marks. Sexual Chemistry: A History of theContraceptive Pill. New Haven, CT: Yale University Press,2001, pp. 150–152.



134. Health Research and Health Services Amendments of 1976.Public Law 94–278. 90 U.S. Stat. 401, 22 April 1976.

135. RD Apple. Vitamania: Vitamins in American Culture. NewBrunswick, NJ: Rutgers University Press, 1996.

136. Orphan Drug Act. Public Law 97–414. 96 U.S. Stat. 2049, 4January 1983.

137. LR Basara, M Montagne. Searching for Magic Bullets:Orphan Drugs, Consumer Activism, and PharmaceuticalDevelopment. New York: Haworth Press, PharmaceuticalProducts Press, 1994, pp. 143 ff.

138. 48 Fed Reg 26721, 26728-26730, 26742–26743, 9 June 1983.

139. Cf. 52 Fed Reg 8850–8857, 19 March 1987.

140. 52 Fed Reg 19466–19477, 22 May 1987, which reproposed andthen finalized the proposal—after 4 years. This citation item-ized several diseases as illustrations of those normally consid-ered immediately life-threatening, including advanced AIDScases, advanced congestive heart failure, and severe combinedimmunodeficiency syndrome, as well as examples of seriousdiseases, such as Alzheimer’s disease, advanced Parkinson’sdisease, and active advanced lupus. Treatment INDs wouldnot apply to those suffering the latter group of serious dis-eases (p. 19467).

141. 53 Fed Reg 41516–41524, 44144.

142. The President’s Task Force on Regulatory Relief certainlyhad a significant role as well in this reappraisal of the drugapproval process.

143. For a summary of investigational drug revisions and the roleof AIDS activists, see JH Young. AIDS and the FDA. In: CHannaway, V Harden, J Parascandola. AIDS and the PublicDebate. Amsterdam: IOS Press, 1995, pp. 54–66.

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2

The New Drug-Approval Process—Before and After 1962

MICHAEL P. PESKOE

Palmer & Dodge

Boston, Massachusetts, U.S.A.

1. INTRODUCTION

The history of the regulation of pharmaceuticals in the UnitedStates has been an evolving one, shaped by both historicalevents and perceptions of medical need. It has also beenaffected significantly by the ongoing tensions between the var-ious societal components involved either directly or indirectlyin the process: what are now commonly known as ‘‘stake-holders.’’ These include the pharmaceutical industry; the gov-ernment [mostly as represented by the U.S. Food and DrugAdministration (FDA) and its predecessor agencies]; the con-suming public (either represented by proxy by the government,

47


or by self-appointed consumer groups, but rarely by consumersthemselves); and the medical profession. It has also been shapedin part by the general evolution of administrative and regula-tory practice during the past 40 years. Although the regulationof pharmaceuticals predates significantly the regulation ofthe subject matter of many other modern regulatory agencies,such as the Environmental Protection Agency (EPA), theFederal Aviation Administration (FAA), the National Trafficand Motor Vehicle Safety Agency (NHTSA), the ConsumerProtection Safety Commission (CPSC), and the Federal TradeCommission (FTC), its recent evolution has been affected bythe development of modern tenets of American administrativelaw and practice.

While the need for federal government approval of phar-maceuticals prior to their marketing has been a fundamentalpart of the regulatory landscape for more than 60 years, it wasnot always so. Notwithstanding the greatly diminished con-troversy over this policy that exists today, particularly withrespect to government’s prior approval of drug effectiveness,pressures continue to be applied to the approval system. Thesepressures result from both external events and market forces.As a consequence, the country’s drug approval regulatorysystem still presents an interesting study of the evolution ofa regulatory system almost 100 years old, yet still fluid andsubject to continuing change.

2. THE FEDERAL FOOD AND DRUGS ACTOF 1906

Known as the Wiley Act, in honor of Henry A. Wiley, thefirst director of the government’s Office of Chemistry in theDepartment of Agriculture, and also as the Pure Food andDrugs Act, this first foray into actual government regulationof drugs embodies concepts that still remain in the currentlegislation, though in a secondary role. The act proscribedthe manufacture and interstate shipment in the United Statesof adulterated or misbranded drugs (or foods), making both

48 Peskoe


criminal (a misdemeanor).

1. ‘‘Adulterated’’ and ‘‘misbranded’’ were defined in thelaw, in a manner more limited than today. Theformer was defined essentially as noncompliancewith the United States Pharmacopeia or NationalFormulary, or generally if strength or purity fellbelow the ‘‘professional standard or quality’’ underwhich the drug was sold.

2. The latter proscribed any statement in either thepackage or label of a drug regarding the article orits ingredients that was false or misleading in anyparticular, or if the drug were an imitation of anotherdrug, or if the packaging were removed, or failedto contain a statement on the label of the quantityof any alcohol or other named potentially toxicsubstances.

3. No prior approval requirements were contained inthe statute, nor is there any suggestion they wereentertained. Rather, the act was essentially a truth-in-labeling statute, directed in part at controllingthe manufacture and sale of worthless and poten-tially dangerous patent medicines and requiring thegovernment to find illegal conduct after the fact if itwished to prosecute.

3. THE 1912 SHIRLEY AMENDMENT

In a 1911 Supreme Court decision, United States v. Johnson(4), involving a criminal indictment for the interstate shipmentof medicine falsely labeled as a cure for cancer, the Court foundthat the proscription in the 1906 law against the misbrandingof drugs dealt only with false statements as to characteristicsof identity, such as strength, quality, or purity, but not withclaims of effectiveness. As a result, in 1912 Congress addedlanguage to the misbranding provisions that proscribed, inthe case of drugs, ‘‘any statement regarding curative or thera-peutic effect, which is false and fraudulent’’ (5). Although

Drug-Approval Before and After 1962 49


extending the statute’s enforcement reach to fraudulent claimsof efficacy, the amendment gave FDA no premarket approvalpower over drugs or related products.

4. 1938 FEDERAL FOOD, DRUG ANDCOSMETIC ACT

4.1. Statutory Drug-Approval Provisions

In 1933, Congress began a 5-year effort at amending the 1906Act that would ultimately create the framework of human drugregulation that exists today. Between the initiation of congres-sional debate and passage, over 100 children died from takinga drug called Elixir Sulfanilimide, in which a manufacturerplaced a well-known and accepted drug, sulfanilimide, into anew vehicle, diethylene glycol (now used in antifreeze), thatwas unfortunately fatally toxic to those who took it.

As enacted, the new Federal Food, Drug and Cosmetic Actof 1938 added the first requirements for premarket approvalof drugs. It defined both ‘‘drugs’’ and ‘‘new drugs’’ in a mannerstill utilized today: the former to encompass the wide range ofmedicants sold or likely to be sold to alleviate human disease,and the latter in a manner that would effectively subject toprior approval every new drug entity and product and, afterthe agency’s lawyers were through interpreting the law, olderones as well.

As enacted in 1938, ‘‘new drug’’ was defined as follows (6):

Sec. 201 . . .

(p) The term ‘‘new drug’’ means—

(1) Any drug the composition of which is such that such drug isnot generally recognized, among experts qualified by scientificand experience to evaluate the safety of drugs, as safe for useunder the conditions prescribed, recommended, or suggested inthe labeling thereof, except that such a drug not so recognizedshall not be deemed to be a ‘‘new drug’’ if at any time prior toenactment it was subject to the Food and Drugs Act of 1906, asamended, and if at such time its labeling contained the samerepresentations concerning the conditions of its use; or

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(2) Any drug the composition of which is such that such drug, asa result of investigations to determine its safety for use undersuch conditions, has become so recognized, but which has not,otherwise than in such investigations, been used to a materialextent or for a material time under such conditions.

At the same time that it defined ‘‘new drug,’’ the newlaw prohibited the introduction or delivery for introductioninto interstate commerce of any new drug unless an applicationfiled pursuant to the new act was ‘‘effective with respect to suchdrug’’ (7). This was the initial premarket approval requirementfor drugs.

A new drug application (NDA) was required to contain‘‘full reports of investigations which have been made to showwhether or not such drug is safe for use’’ (8), as well as articlesused as components, a full statement of composition, methodsused in and facilities and controls used for manufacturing, pro-cessing and packing the drug, samples of the drug as requiredby the Secretary, and specimens of labeling (9).

An application would become effective on the sixtieth dayafter filing, unless the effective date was postponed in writingto such time, not to exceed 180 days, as the agency determinednecessary ‘‘to study and investigate the application’’ (10).In other words, an application would become effective withoutfurther action by the agency within 60 days unless the agencystopped it from becoming so. The agency’s ability to so fore-stall an application from becoming effective was limitedto 180 days (11). Provisions were also included establishingrequirements for the agency’s decision not to approve an appli-cation (12). These included provisions that the investigationsdid not include adequate tests by all methods reasonablyapplicable to show whether or not the drug was safe for useunder the conditions set forth in labeling, that such testsshow that the drug is unsafe for use under those conditions,that the methods for manufacture, processing or packing areinadequate to preserve identity, strength, quality, and purity,or whether the information submitted in the application oron the basis of any other information was insufficient to deter-mine whether the drug was unsafe for use. However, the



agency was required, in reaching any such conclusion, toprovide both notice and an opportunity for hearing to anyapplicant whose application was determined not worthy ofapproval (13).

The new statute also empowered the agency specificallyto suspend the effectiveness of an approved application, againfollowing notice and opportunity for hearing, if it found thatclinical experience, new test methods, or even methods notthought applicable at the time of approval showed the drugto be unsafe for use under its labeled indications or that theapplication was found to contain any untrue statement ofmaterial fact (14).

Should a manufacturer contest the agency’s order sus-pending the effectiveness of an application, its recourse wasfiling an action in federal district court (15). In keeping withwhat are now modern tenets of administrative law, any newfactual matters were required to be presented to the agencybefore any adjudication by the court. The agency conclusionsas to any findings of fact were deemed conclusive (16). Finally,the new law imposed an obligation on the agency to developregulations exempting drugs solely for investigational use fromthe above restrictions (17).

The statutory framework enacted in 1938 is still the modelin use today, with additions and modifications as outlinedin the remainder of this chapter up to 1997. In establishingglobal criteria for premarket approval contained in the conceptof ‘‘new drug,’’ the new law all but assured from that timeforward that government would now evaluate drugs prior totheir marketing. Definitions were written broadly: not only‘‘new drug’’ but the definition of ‘‘drug’’ itself was written tobe inclusive (18). Moreover, by including within the new drugdefinition the concept of ‘‘general recognition,’’ requiring thata determination of safety be recognized based on the views ofexperts, Congress gave the agency power to establish high bar-riers to market entry. On the other hand, the new law gavesignificant credence to an approval earned under the statute;withdrawal of an application, once approved, was not madeparticularly easy for the government to accomplish.

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4.2. The 1938 ‘‘Grandfather’’ Provisions and‘‘Old Drug’’ Status

Two provisions deserve special comment. The statute didexempt or ‘‘grandfather’’ certain drugs from the new drugrequirements. This exemption included any drug marketedunder the 1906 act whose labeling had not changed (19).Thus, at least in this respect, the law did not portend to reachbackwards unless an existing drug’s labeling had at some pointbeen changed. The second exemption concerned those drugsthat might be determined to be ‘‘not new,’’ that is, where ‘‘gen-eral recognition’’ of safety might already exist. In that theexemption from ‘‘new drug’’ status was obviously desirable todrug manufacturers, this would be a future area of contention.

Finally, the ‘‘new drug’’ definition also seemed to create asituation in which ‘‘new drug’’ status was fluid, in which a drugthat might be ‘‘new’’ today would at some point no longer be soand would no longer be subject to the myriad requirementsapplicable only to new drugs. This was contained in the second‘‘new drug’’ definition, which stated, in essence, that a drugrecognized by experts as safe for labeled conditions on the basisof tests conducted to establish safety, but not otherwise, and notused to a ‘‘material extent’’ or for a ‘‘material time’’ under suchconditions, would nonetheless still be a new drug (20). The con-verse of this, that such a drug used for a material extent or for amaterial time would no longer be a ‘‘new drug,’’ suggests thatsuch a drug might ultimately graduate to a post–‘‘new drug’’status. To date, no post-1938 prescription drug has done so.

4.3. Regulation of Antibiotics and Insulin

In 1941 Congress added new special approval provisions to the1938 act regarding drugs composed wholly or partly of insulin.Unlike the existing provisions, section 506 required that, priorto distribution, insulin be batch-certified by the agency ‘‘if suchdrug has such characteristics identity . . . strength, quality andpurity . . . as necessary to insure safety and efficacy of use’’(21).This was essentially a requirement that the agency itself testa sample of each batch of insulin prior to release by the manu-facturer and stemmed from concern that insulin manufactured



from live organisms required further protections compared toother drugs.

Similarly, in 1945 batch-certification requirements forpenicillin were added in a new section 507 and were modeledafter the insulin requirements (22). Over the next severalyears, the requirements were extended to additional antibio-tics, culminating in an extension to all antibiotics in 1962 (23).The added requirements stemmed from the fact that antibio-tics were derived from microorganisms, resulting in a concernthat actual batch testing by the government should be requiredas a condition of marketing. Although these sections includeda specific requirement for effectiveness, it was assumed aspart of the certification process that appropriate proof of iden-tity, strength, quality, and purity would necessarily permit aconclusion regarding effectiveness. Ultimately, due to theadded expense to the agency of supporting a batch-certificationlaboratory and growing confidence in the manufacturing pro-cesses of both insulin and antibiotics, both products wereexempted from certification. Later, as part of legislationadopted in 1997, both sections were repealed (24). Insulinand antibiotics are now regulated like other new drugs.

5. THE DRUG EFFECTIVENESS AMENDMENTSOF 1962

5.1. Approval Provisions

The modern era of drug regulation begins with the drug-effectiveness amendments of 1962. These amendments addedthe requirement that all new drugs be proven effective as wellas safe and far more detailed requirements for the safetytesting of new drugs prior to marketing, the latter as a directresult of the thalidomide tragedy that occurred in Europe (andalmost in the United States) in the latter 1950s and early1960s. The addition of an effectiveness requirement was madeexceedingly complicated by the added requirement that alldrugs whose safety and effectiveness were established between1938 and 1962 would be made retroactively subject to the neweffectiveness standard.

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The 1962 amendments accomplished these objectives inseveral ways. Initially, the statutory definition of ‘‘new drug’’in section 201(p) of the act was amended by adding the words‘‘and effectiveness’’ following ‘‘safety’’ where it appeared inthe section (25). Thus, any drug whose effectiveness wasnot a matter of ‘‘general recognition’’ by experts qualified byscientific training and experience to evaluate effectivenesswould be a new drug for that additional reason and subjectto premarket approval requirements for effectiveness as wellas safety.

The requirement for general recognition of effectivenesshas been the cornerstone of the agency’s now generally accep-ted interpretation of the section that once a new drug, alwaysa new drug. As noted previously, section 201(p)(2) of the actprovided an alternative new drug definition: a drug’s safety oreffectiveness could be recognized (as opposed to ‘‘generallyrecognized’’) on the basis of investigations, but the drugwould still be a new drug if it had not been used to a materialextent or for a material time. This suggested a possibility thatnew drugs ultimately could ‘‘graduate’’ from new drug statusover time, ending their need to be subject to an effective newdrug application and similarly ending their obligation tocomply with numerous requirements applicable to new drugs,but not to ‘‘not new drugs.’’ It is this potential statutorymovement from new drug to not new drug status that hasnot been acknowledged by FDA, nor sought by manufacturers,at least for the past three decades; nor has the issue been givenpublicity in the numerous statutory amendments to the actthat have occurred during the past 15 years.

Other significant changes in the FDA approval processwere also implemented by the 1962 amendments. Perhapsmost importantly, the amendments replaced the ‘‘passiveapproval’’ mechanism of the 1938 act, which permitted anNDA to become effective automatically after a 60-day period,with an active approval scheme. Section 505(c) of the actprovided that (20):

Within one-hundred and eighty days after the filing of anapplication under subsection (b), or such additional period as



may be agreed upon by the Secretary, and the applicant, theSecretary shall either—

(A) approve the application if he then finds that none ofthe grounds for denying approval . . . applies, or

(B) give the applicant notice of an opportunity for hearingbefore the Secretary . . . on the question whether suchapplication is approvable.

The new legislation also expanded significantly the provi-sions of the 1938 act regarding the statutory bases for refusingto approve a submitted application [section 505(d)] and for with-drawing approval of an approved application [section 505(e)].

With respect to the refusal to approve an application, thestatute left the existing provisions regarding lack of safetyintact, but added to them the following proscription regardingthe new effectiveness requirement (27):

If the Secretary finds that, evaluated on the basis of theinformation submitted to him as part of the application and anyother information before him with respect to such drug, there isa lack of substantial evidence that the drug will have the effectit purports or is represented to have under the conditions ofuse prescribed, recommended, or suggested in the proposedlabeling thereof . . .he shall issue an order refusing to approvethe application. . . . As used in this subsection . . . the term‘‘substantial evidence’’ means evidence consisting of adequateand well-controlled investigations, including clinical investiga-tions, by experts qualified by scientific training and experienceto evaluate the effectiveness of the drug involved, on the basisof which it could fairly and responsibly be concluded by suchexperts that the drug will have the effect it purports or isrepresented to have under the conditions of use prescribed,recommended, or suggested in the labeling or proposed labelingthereof.

Thus, unlike the statutory safety test, which requiredsimply that studies demonstrate safety, the statutory testof effectiveness, set forth ironically in the statutory sectioncontaining criteria for withholding approval, was legislated asone of ‘‘substantial evidence’’ requiring ‘‘adequate and well-controlled investigations, including clinical investigations by

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experts qualified . . . to evaluate the effectiveness of the druginvolved’’ (28). This requirement of substantial evidence ofeffectiveness would play a paramount role in the decadesfollowing the 1962 enactment in enabling FDA to set the barhigh before approving a drug as safe and effective (29).

With respect to those provisions concerning the withdra-wal of an approved (i.e., effective) application, the amendmentsadded provisions for the withdrawal of an application shouldthere be new information, evaluated together with the evidenceavailable when the application was approved, that there wasa lack of substantial evidence that the drug would have theeffect it was represented to have according to its labeling (30).The amendments also added new provisions for the immediatesuspension of the effectiveness of an application should theSecretary find an imminent hazard to the public health.The authority to implement this section was reserved to theSecretary, and was not delegable to the FDA (31).

In response to the then recent thalidomide episode, Con-gress also greatly expanded the statutory provisions regardingthe investigation of drugs. While the 1938 act had simplyauthorized the promulgation of regulations exempting suchdrugs from the prohibition against interstate shipment ofunapproved new drugs, the 1962 amendments directedthat the regulations consider including the submission toFDA, before the undertaking of any clinical tests usingsuch a drug, reports of preclinical tests (including animaltests) adequate to justify the proposed animal tests (32),signed agreements between investigators and sponsors ofinvestigations that patients to whom the drug administeredwill be under the investigator’s direct or indirect supervi-sion(33), and the establishment and maintenance of recordsobtained as a result of the investigational use that willenable the Secretary to evaluate the safety and effective-ness of the drug in the event of the filing of a new drug appli-cation (34).

What was not optional under the amendments, however,was that any such clinical trial exemption be conditioned on therequirement that investigators certify to sponsors that anystudy subjects be informed that the drugs were investigational



and obtain their consent (except where not feasible or contraryto the best interests of the study subjects) (35). As a result ofthese provisions and the regulations that followed, and not-withstanding the regulatory provision that such an exemptionwill become effective automatically after 30 days unless delayedby the agency (36), there is no area of FDA regulation wherethe agency has more unrestricted power than in its oversightof clinical investigations.

5.2. The 1962 Grandfather Clause

The amended new drug definition also extended the categoryof drugs not subject to the new drug provisions, i.e., thoseconsidered ‘‘grandfathered.’’ First, in section 201(p), it essen-tially extended the 1938 grandfather clause through the 1962enactment so that a drug that was subject to the 1938 clause(because it was subject to the 1906 Act and its labeling hadnot been changed) and exempt thereby from the new drugprovisions would continue to be exempt, now from the neweffectiveness requirement as well, if its labeling had continuedto remain unchanged. The number of drugs that continue tomeet these criteria has never been fully documented; it issafe to say that FDA views the category as an anachronismand, to the extent that it is required to focus on any suchdrugs as part of a regulatory event, it has had little difficultyarguing successfully that grandfather status is no longerapplicable.

A new grandfather provision was enacted in 1962 thatwould, when the criteria were met, exempt such a drug fromthe effectiveness but not the safety provisions of the act.Section 107(c)(4) of the 1962 amendments specified a four-part test: on the day immediately preceding the enactmentdate, October 10, 1962, the drug was commercially sold in theUnited States, was not a new drug as defined by then in effectsection 201(p) (meaning that it was generally recognized assafe on that date), was not subject to a new drug applicationon that date (meaning under the 1938 act), and was intendedfor use solely for its labeled indications as they existed on thatday (in short, its labeling could not have changed).

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5.3. The DESI Review and the Imposition ofEffectiveness on Pre-1962 Drugs

The addition of an effectiveness requirement in 1962 was mademore complicated for the agency by the added requirement thatall new drugs approved solely for safety under the 1938 Act besubject to the new effectiveness standard unless grandfathered(see above).

‘‘Transitional amendments’’ enacted as section 107(c)implemented this legislative scheme in the following manner(37). First, any new drug application that was ‘‘effective’’ onthe day before the new amendments were enacted (the enact-ment date) was deemed approved as of the enactment date(38); the new effectiveness amendments did not apply to anysuch ‘‘deemed approved’’ application as long as the applicationwas not withdrawn or suspended when intended solely for useunder its preenactment date indications (but not as to anychanged indications) (39), and the provision permitting with-drawal of an approved application for a lack of substantialevidence of effectiveness as to existing uses was determinednot to apply until one of the following events occurred: theexpiration of a 2-year period beginning on the enactment dateor the withdrawal or suspension of the application (40).

These provisions effectively applied the new effectivenessstandard on October 10, 1964, to all drugs approved under the1938 Act and permitted their withdrawal if effectiveness hadnot been established. All post-1938–approved applications hadbeen simply ‘‘deemed’’ approved under the 1962 amend-ments for a 2-year grace period (41). While withdrawal for lackof effectiveness was not automatic, first requiring the agencyto initiate and conduct withdrawal proceedings under section505(e), the premarket approval requirements of the statutepermitted the agency to allege that effectiveness had not beenestablished, shifting the burden on pre-1962 applicants to thenproduce the necessary information to demonstrate substantialevidence of effectiveness in order to prevent withdrawal.

Due to administrative difficulties attendant to imple-mentation of this section, FDA ultimately contracted with out-side groups, notably the National Academy of Sciences and



National Research Council, to review the available data, usuallyas compiled by manufacturers, on all pre-1962–approved drugs,and to make recommendations to FDA on whether thereexisted for those drugs the substantial evidence of effectivenessnow required by the statute. This process became known as theDrug Efficacy Review Implementation, or ‘‘DESI’’ Review, andtook the better part of 25 years, until the mid-1980s, to com-plete, though even to this day certain drugs remain on themarket in a state of regulatory limbo, with no final determina-tions having been made as to their effectiveness under the 1962standard (42).

5.4. Important Legal Developments Regardingthe 1962 Amendments

The 1962 amendments to the drug-approval process, particu-larly the increased burdens for prior approval for ‘‘new drugs,’’generated significant efforts by various components of thepharmaceutical industry to avoid the added regulation imposedby the new amendments, particularly insofar as they rewrotethe rules applicable to drugs already on the market. This alsoresulted from the significant procedural protections writteninto the earlier law, and continued in the new law, for appli-cations that had already become ‘‘effective.’’ Over the nexttwo decades, certain disagreements involving the agency’sinterpretation of the amended new drug, ‘‘grandfather,’’ andeffectiveness provisions of the statute wound their way throughthe courts, culminating in several court decisions that ulti-mately both supported the agency’s strict ‘‘high bar’’ and inclu-sive interpretation of the new amendments and set the tone ofthe agency’s review policies for the next several decades.

In USV Pharmaceutical Corp. v. Weinberger (43), decidedin 1973, the issues were the scope of the grandfather and tran-sitional amendments enacted in 1962. This manufacturer hadproducts containing the same active ingredient, some of whichwere covered by pre-1962 NDAs, and some of which werenot. Of the criteria found in the 1962 grandfather exemption,one was that the drug not be covered by an effective applicationon the effective date. The Court found that, while new drug

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applications were intended and applied to individual products,in this instance it would consider none of the products tobe lawfully subject to the exemption even though they wereliterally not subject to an NDA at the time, as the exemptionwas intended to treat all products whether or not of differentmanufacturers containing the same active ingredient the same,that is, as either new or not new. The court also found that amanufacturer was not capable of deactivating an existing NDAso as to also avail himself of the exemption. The net effect ofthe opinion was to include any drug that had at any time beensubject to the new drug provisions enacted in 1938 to also besubject to the effectiveness requirements enacted in 1962.

In Weinberger v. Bentex Pharmaceuticals, Inc. (44), deci-ded at the same time as USV, the Court squarely faced thequestion of who decided what constituted general recognitionof effectiveness—FDA or the courts. In this case, the Courtinterpreted the Act as authorizing FDA, subject to judicialreview, as the locus of jurisdiction on the new drug questionfor both individual drugs and classes of drugs, determiningthat such questions were to be administratively determinedby the agency, and not de novo in the courts.

In Ciba Corp. v. Weinberger (45), again decided at the sametime as USV and Bentex, the Court further established FDA, inthe context of its withdrawal of pre-1962 NDAs for the manu-facturer’s failure to establish effectiveness, as the administra-tive agency responsible for making new drug determinations inan administrative setting, reviewable in the Court of Appeals,but not subject to having the new drug issue litigated in othercourt proceedings.

Finally, in the last and probably the most important case,Weinberger v. Hynson, Westcott & Dunning (46), also decidedwith the other cases noted, the Court reviewed the withdrawalof the NDA of a drug subject to the transitional amendmentsof the 1962 Act, that is, one approved under the 1938 Act forsafety but ostensibly lacking substantial evidence of effective-ness, and thus subject to proceedings for NDA withdrawal. Inso doing, it sustained the validity of FDA’s then new SummaryJudgment regulations, which permitted the agency, followingpublication of a Notice of Opportunity for Hearing, to then



deny a hearing and summarily withdraw the NDA when theapplicant did not tender information in response sufficient tomake a prima facie showing that it could demonstrate substan-tial evidence of effectiveness through the statutory standardrequiring adequate and well-controlled clinical investigations.In addition, the Court also sustained FDA’s view that whethera drug’s effectiveness was supported by substantial evidencewas part of the new drug determination, and not simply require-ments that must be met following a new drug determination.This case and the others decided with it effectively made allpost-1938 drugs new drugs subject to NDA requirements foreffectiveness and largely closed the door on the efforts ofcompanies to avoid the requirements for adequate and well-controlled studies by claiming ‘‘not-new-drug’’ status underthe ‘‘new-drug’’ definition.

This 1973 ‘‘grand slam’’ for FDA in the U.S. SupremeCourt regarding the scope of the 1962 amendments was thebeginning of a multidecade trend in which the agency seemedrelatively invincible in its efforts to expand the statute, in bothits old and new drug provisions, particularly regarding theeffectiveness requirements of the Act (47). Under the rubricof ‘‘protecting the public health,’’ FDA was able to establishand maintain through several significant court victories itsexpansionist view of its mandate to control the new drug pro-cess at both the macro and micro levels. Other cases decided inthe next several years further solidified that mindset.

In 1975, the Supreme Court decided United States v. Park(48). While involving a criminal prosecution of a senior man-ager of a national food company for sanitation failures, it affir-med earlier cases establishing strict criminal liability for seniorcompany managers for violations of the Act, including, theore-tically, violations involving the drug provisions of the act.

In 1979, in United States v. Rutherford (49), the SupremeCourt held that drugs for terminally ill patients whose safetyor effectiveness were unproven were subject to the new drugprovisions of the Act. In this case, notwithstanding that allparties conceded that the cancer patients involved were surelyto die from their disease, and that no other remedies wereavailable, the Court refused to allow the sale of laetrile, an

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unproven cancer remedy, by finding an implied exception tothe safety and effectiveness requirements.

In 1983, in United States v. Generix Drug Corp. (50), theCourt resolved the additional question of the application of thenew drug definition to generic versions of approved drugs.While innovator drugs were subject to NDAs, generic versionswere not, and the question before the Court was whether the‘‘new drug’’ definition applied to them. Specifically, did thenew drug definition apply only to the active ingredient, poten-tially exempting generic products from new drug regulation,or each specific product, both innovator and generic, therebysubjecting all versions of the drug to the new drug provisions.Again, the Court sustained FDA’s expansive reading of the newdrug definition, concluding that the new drug-licensing provi-sions were applicable to individual products, including eachseparate generic product, and not merely the active ingredient.It relied in its opinion on the fact that each generic productwould be different, at least in inactive ingredients or excipi-ents, from the innovator, raising issues of safety and effective-ness warranting premarket review.

By the time the Generix case was decided, FDA’s viewof the regulatory world of new drugs was essentially institu-tionalized. The new drug provisions were seen to apply to allprescription drug products, both brand and generic, and onceapplied to a drug product, were attached indefinitely. Littleattention was paid then, or has been paid since, to the notionthat drugs in new drug status could evolve to a post-, non-regulated, old drug status, notwithstanding inferences bothin the new drug definition as well as in several court opinionsthat such was Congress’s original intent.

6. THE POST-1962 ERA

The two decades after 1962 were not ones of substantial legis-lative attention to the new drug-approval process. Other issueswere more prominent. The growth in public financing of drugpurchases under Medicaid caused a revolution in the public’sperception of the value of generic drugs. While industry



complained continuously about delays in getting drugs throughFDA’s approval mechanism, Congress did not engage the issue.Efforts to rewrite the Federal Food, Drug and Cosmetic Actthat were initiated in the late 1970s came to naught, whileFDA revised its own IND and NDA regulations in a mannerthat, while clarifying certain concepts such as compassionateINDs and adverse drug reporting, embraced the notion thatFDA’s requirements for proof of safety and effectiveness wouldnot be relaxed in order to promote innovation or for drugs foruse in treating serious and fatal diseases, notwithstandingthe lack of alternatives for either patients or doctors.

6.1. The Orphan Drug Act of 1983

In 1982, recognizing that certain diseases involved only smallnumbers of patients and were thus being largely ignored bypharmaceutical companies due to the lack of financial incen-tives to development, Congress initiated legislation specifi-cally directed at this problem. The Orphan Drug Act of 1983provided federal financial incentives for drug developmentheretofore unavailable and also presaged other significantlegislative developments that would come years later (51).

As enacted, the Orphan Drug Act applied to drugs forany disease or condition ‘‘which occurs so infrequently in theUnited States that there is no reasonable expectation that thecost of developing and making available in the United Statesa drug for such disease or condition will be recovered fromsales in the United States for such drug.’’ It provided twomajor financial incentives to companies that would undertaketo develop these products. First, the act provided a tax creditbased on clinical trial expenses. Second, it provided a 7-year‘‘exclusivity’’ for any nonpatentable drug, during which timeFDA would be unable to approve an NDA or biological productlicense for the same drug for the same disease or condition. Ona nonfinancial level, and to some extent foretelling later legis-lative developments, FDA was mandated to provide prospectiveorphan drug candidate applicants with ‘‘written recommen-dations for the non-clinical and clinical investigations’’ thatthe agency believed would be necessary for approval. This

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provision dented, perhaps for the first time, FDA’s viewthat manufacturers were entirely responsible for the develop-ment of the studies required for approval, and that it wasnot FDA’s role to prejudge trial design, and by inference dataproduced from such design, prior to submission of the datafor approval (52).

In 1984 and 1985, Congress further amended the actto make its enticement provisions more appealing. To reducecomplexity regarding qualifications for orphan drug exclusiv-ity, the test was made far more objective and inclusive: anorphan disease was defined as any disease or condition thataffected fewer than 200,000 persons in the United States, orthat affected more than 200,000 persons but for which therewas still no reasonable expectation that development costs couldbe recovered from sales (53). Second, the exclusivity provisionwas changed to no longer be contingent on the availabilityof patent protection; all orphan drugs approved would receivea 7-year exclusivity under which FDA would not be permittedto approve the same drug for the same disease or condition(54). At the same time, FDA took the position that, whileit would assist in the development of appropriate trials forapproval, and while the law did provide incentives previouslyunavailable to development initiatives, it did not in any wayreduce the scientific burden on manufacturers to establisheffectiveness based on adequate and well-controlled clinicaltrials (55).

6.2. The Era of Shifting Priorities

Two events merged in the latter years of the 1980s andcontinued through the early 1990’s that, together, signifi-cantly altered the FDA’s implementation of the require-ments for investigation and approval of new drugs. TheAIDS crisis was one; while FDA was able to fend off thedemands of cancer patients in the 1970s and 1980s who desiredaccess to unproven cancer drugs, it was not able to curtailaccess to unproven AIDS therapies by patients afflictedwith an unexpected, and unremittingly lethal, new disease.The second event was more subtle. For years the industry



had relentlessly criticized the Agency for what it perceivedas the delay in getting it to act on pending applications.Review and approval times could stretch into years, forno apparent reason, despite a long-standing legislative provi-sion requiring Agency action on pending NDAs within 180 daysof filing. Comparisons were frequently made during this periodto approval times in other developed countries, mostly theUnited Kingdom, where it was often said drug-approval timeswere substantially less for the same drugs than in the UnitedStates—a so-called drug lag—with no apparent loss in safety.

Unlike the cancer population, AIDS victims were youngpeople who were suffering egregiously before invariably losingtheir lives in their prime, rather than, as with most cancerpatients, if not in old, than at least in middle age. They alsoshared other characteristics. Manywere homosexualmales frommiddle class families living in the same neighborhoods in majorurban areas and were able to coalesce into an active politicalforce, no doubt enhanced by the support of their healthy, orat least not-yet-sick, colleagues. A further distinction from thecancer patients of the previous decade was the position of themedical establishment, always a force in FDA decisions andpolicy, if not always an apparent force. Unlike the cancer sce-nario, where doctors at least had some drugs and procedures tooffer, for AIDS they had none that were remotely promising,leaving them as hopeless as their patients.

FDA’s adherence to the regulatory system that had servedwell for two decades, a reliance on scientific proof of safety andeffectiveness prior to permitting the marketing of any drug nomatter how serious the disease or the availability of alternativetherapies, did not play well to an audience of suffering anddying young men and their frustrated physicians. FDA reliedinitially on its traditional safety valve for making availableunproven drugs, the ‘‘compassionate IND,’’ under which drugsunder investigation could be made available with the sponsor’sconsent to individual practitioners for individual patients out-side of study protocols. This, however, was woefully insufficientin scope to deal with a growing national epidemic, andFDA’s initial reliance became problematic. The combinationof pressures from constant criticism based on supposed drug

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lag together with the Agency’s inability to handle the AIDScrisis fostered two reform movements that have altered itsapproval processes, perhaps permanently.

On the issue of drug lag, and to respond to agency repre-sentations that at least some of that issue was based on limitedresources, Congress undertook to impose, against the agency’swill, at least initially, ‘‘user fees.’’ These fees, common else-where in government, are simply the government’s chargingfor the performance of its services—in this particular case,its licensing function. Resisted initially by FDA as a potentialintrusion of its independence, it has now become an acceptedpart of the new medical product landscape, providing fundsto the Agency to enhance its approval performance, thoughat some cost to the traditional opaqueness of the approval pro-cesses that had previously existed. While not necessarilyimpacting the actual requirements for approval, the user feelegislation (56) did tacitly recognize, if not validate, the indus-try’s dissatisfaction with the approval process, and essentiallyrequired FDA, in return for its new funding source, to makethe process more responsive to industry desires in two funda-mental ways—the time required for agency action on applica-tions, and providing industry with more awareness of the statusof applications and access to the agency during the process.

6.3. The User Fee Act of 1992

The Prescription Drug User Fee Act of 1992 (PDUFA), begin-ning with fiscal year 1993 and continuing for 5 years, requiredset fees for each new drug application (and biological productlicenser supplement containing clinical data, though not bio-equivalence data), to be paid in part at the time of submissionand prior to approval. These fees were not insignificant, setat the outset in 1993 at $100,000 for a full NDA, and halfthat for a supplement, to $233,000 in 1997. Certain exemp-tions, such as one for certain small businesses, were included.It also required certain establishment fees and product fees.

Documentation on the concessions (euphemistically refer-red to as ‘‘performance goals’’) made by FDA in 1992 is notreadily available; however, documentation provided with the


Copyright © 2005 by Marcel Dekker .

renewal of user fees in 1997 indicates that both review timesand more transparency in the approval process were upper-most in the minds of reformers. Action was expected on 90%of ‘‘standard’’ applications within 12 months, and on ‘‘priority’’applications, those for serious diseases, within 6 months.Actual approval was not necessarily expected but, rather,FDA’s initial review of the application and the issuance ofan approval letter. Other measurements involved 12-monthreview of standard efficacy supplements, 6-month review ofpriority efficacy supplements, and 6-month review of manufac-turing supplements. These criteria were made more restrictivein the years following 1997. Other actions involved responsesto requests for meetings, scheduling meeting dates, issuanceof minutes following meetings, responding to sponsor clinicalhold responses, dispute resolution, study protocol assessments,and simplifying action letters, all of which were designed to givemanufacturers a more reliable sense of the agency’s actions onpending applications, as well as make it more difficult for theagency to modify its views or position on such applications (57).

The dynamic of the user fee legislation seems to be univer-sally seen as positive. Similar legislation has now been enactedfor both animal drugs and medical devices. For detailed infor-mation on the effects of this legislation and for subsequentchanges in the approval requirements resulting from the AIDSepidemic see the chapters in this book regarding PDUFA andthe FDA Modernization Act of 1997.

REFERENCES AND NOTES

1. Wiley Act, Pub. L. 59–384, 34 Stat. 768 (1906), sec. 1, 2.

2. Wiley Act, sec. 7.

3. Wiley Act, sec. 8.

4. 221 U.S. 488 (1911).

5. 37 Stat. 416 (1912).

6. 1938 Act, Pub. L. No. 75–717, 52 Stat. 1040 (1938), sec. 201( p).

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7. 1938 Act, sec. 505(a).

8. 1938 Act, sec. 505(b)(1)(A).

9. 1938 Act, secs. 505(b)(1)(B)–505(b)(1)(F).

10. 1938 Act, sec. 505(c).

11. Id.

12. 1938 Act, sec. 505(d).

13. Id.

14. 1938 Act, sec. 505(e).

15. 1938 Act, sec. 505(h).

16. Id.

17. 1938 Act, sec. 505(i).

18. 1938 Act, sec. 201(g).

19. 1938 Act, sec. 201(p).

20. 1938 Act, sec. 201(p)(2).

21. 55 Stat. 851 (1941).

22. 59 Stat. 463(1945).

23. 76 Stat. 780, 785(1962). See Hutt and Merrill, Food andDrug Law, Cases and Materials, Foundation Press (1991),pp. 521–522.

24. Pub. L. 105–115 (1997).

25. Federal Food, Drug and Cosmetic Act, (FDCA) sec. 201(p)(1),sec. 201(p)(2), 21 U.S.C. 321(p)(1), (p)(2); Pub. L. 87–781(1962).

26. FDCA, sec. 505(c); 21 U.S.C. 355(c).

27. FDCA, sec. 505(d); 21 U.S.C. 355(d).

28. Id.

29. As with the 1938 Act, the act provided significant proceduralprotections to manufacturers whose applications were notdeemed worthy of approval, including notice, and opportunityfor hearing, which, if granted, was contemplated to be a fulladministrative hearing.



30. The requirement for ‘‘new information’’ is considered by theagency to include a reevaluation of existing information, ratherthan requiring wholly new information as a prerequisite forwithdrawal.

31. FDCA, sec. 505(e), 21 U.S.C. 355(e). See, also, 21 CFR2.5.

32. FDCA, sec. 505(i)(1), 21 U.S.C. 355(i)(1).

33. FDCA, sec. 505(i)(2), 21 U.S.C. 355(i)(2).

34. FDCA, sec. 505(i)(3), 21 U.S.C. 355(i)(3).

35. FDCA, sec.505(i), 21 U.S.C. 355(i).

36. See 21 CFR 312.40.

37. Sec. 107(c), pub. l. 87–781 (1962).

38. Sec. 107(c)(2).

39. Sec. 107(c)(3)

40. Sec. 107(c)(3)(B)

41. Secs. 107(c)(2) and 107(c)(3)(B).

42. A ‘‘News Along the Pike’’ publication of FDA dated December3, 2003, reports that, under the DESI review, FDA evaluated3,443 drugs having 16,000 claims, removing 1,099 of themfrom the market.

43. 412 U.S. 655 (1973).

44. 412 U.S. 645 (1973).

45. 412 U.S. 640 (1973).

46. 412 U.S. 609 (1973).

47. FDA did not win every case. Nor does this discussion beginto discuss the judicial history. Rather, it includes the twocases that best reflect the agency’s success at persuading theCourt, under the mantra of protecting the public health, toread the new drug definition expansively. One significant lossby the Agency involved its efforts, through regulation, to con-trol the distribution of the drug methadone. FDA believed that‘‘safe’’ under section 505 included the potential for possible mis-use, rather than simply inherent safety, and could thus regu-late post-approval distribution of a new drug. In American

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Pharmaceutical Ass’n. v. Weinberger, 530 F.2d 1054 (D. C.Cir.1976); affirming 377 F. Supp. 824 (D.C. D.C., 1974), thecourts disagreed, interpreting safety to mean inherent safetyfor the uses in labeling, thus invalidating postapproval distri-bution restrictions. Regardless of this opinion, FDA hassuccessfully controlled postapproval distribution of certainpotentially toxic drugs through ‘‘voluntary’’ arrangements withmanufacturers reached during the approval process.

48. 421 U.S. 658 (1975).

49. 442 U.S. 544 (1979).

50. 460 U.S. 453 (1983).

51. 96 Stat. 2049 (1983). The diseases used as examples were notnecessarily obscure. Muscular distrophy, for example, widelyknown through annual telethons, was a principal example,and was particularly noteworthy in that a well-known actor,Jack Klugman, whose brother suffered from the disease, usedhis then significant celebrity status to promote the legislationand enhance its passage. Another example, amytrophic lateralsclerosis, was also well known as Lou Gherig’s disease. Theorphan drug provisions are codified at sections 525–528 ofthe FDCA, 21 U.S.C. 360aa–360dd.

52. In providing for tax credits and exclusivity, this legislationpresaged similar, but far more controversial provisions in the1984 Drug Price Competition and Patent Term RestorationAct, and later in the Pediatric Exclusivity Act. It appearsthat such provisions are now routinely considered appropriateto entice and reward manufacturers to develop new drugs ornew uses for existing drugs.

53. 98 Stat. 2815 (1984).

54. 99 Stat. 387 (1985).

55. In an attempt to provide some additional level of competition,FDA has taken the position that it will not consider orphandrugs to be the same, despite similarities, if a second manufac-turer can show ‘‘clinical benefit,’’ and will thereby permit sucha manufacturer to break the 7-year exclusivity. See 21 CFR 316.

56. P. L. 102–571 (1992).

57. See letter from Donna Shalala to Thomas Bliley, November 12,1977.



3

FDA Regulation of BiologicalProducts

JAMES N. CZABAN and NATASHA LESKOVSEK

Heller Ehrman White & McAuliff LLP

Washington, D.C., U.S.A.

1. INTRODUCTION

Federal regulation of biological products (or simply ‘‘biologics’’)is paradoxical in that biologics encompass some of the mostadvanced, cutting edge medical technology, yet they are regu-lated in significant part under the framework of the oldest U.S.law governing therapeutic products. For a variety of scientific,historical, legal, and political reasons, the federal regulatoryscheme for biological products has been, and to some extentremains, fragmented and unsettled. For example, the fact that,legally speaking, most biologics also meet the statutory defini-tions for other product classes (i.e., drugs, medical devices) has

73


resulted in the U.S. Food and Drug Administration (FDA)approving and regulating different types of biologics in all ofits organizational Centers [the Center for Biologics Evalua-tion and Research (CBER), the Center for Drug Evaluationand Research (CDER), the Center for Devices and RadiologicalHealth (CDRH), the Center for Food Safety and Applied Nutri-tion (CFSAN), and the Center for Veterinary Medicine (CVM)],with some products being regulated in different respects bymore than one Center simultaneously.

Also, advances in medical technology have spawned newand previously unimagined product categories that haveposed classification conundrums which challenge FDA’s abilityto determine how (or if ) the new products may be regulatedunder the often rigid legal constraints posed by regulatory sta-tutes. In addition, public and congressional responses to publichealth crises have periodically shed an unflattering light onexisting regulatory processes and the responsible administra-tive organizations, leading to sometimes abrupt changes in theoversight scheme for biological products. And, more recently,pressure from patients and regulated industry for greaterresponsiveness and accountability in the review and approvalof biotechnology-derived products has led FDA itself to,once again, consolidate most therapeutic product review andapproval authority within one organizational unit.

The legal and regulatory category known as biologicscomprises a broad and diverse array of products for curative,preventative, and diagnostic purposes. The purpose of this chap-ter is not, and could not be, to present a detailed scientificdiscussion of all, or any one, of the many products or tech-nologies within the biologics category. Nor will there be anextended focus on the most common pathway for biologicreview and approval, because under the modern regulatoryscheme most therapeutic biologics follow the same approvalpathway as traditional pharmaceuticals—an IND, followedby phase 1, 2, and 3 clinical trials, a marketing application(for biologics a ‘‘BLA’’ as opposed to the NDA for pharmaceu-ticals), and postapproval oversight of safety, marketing, andgood manufacturing compliance. This common approval path-

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way is discussed in Chapter 2.

Rather, this chapter will present an historical overview ofhow biologics have been regulated in the past, and how thoseregulatory processes have evolved over time. Where regulationof certain biological products (e.g., blood, tissue, gene therapytechnology) differs from the standard model, those differenceswill be explained and discussed. One area of particular focuswill be the inherently overlapping nature of most biologics asboth ‘‘biologics’’ and as ‘‘drugs’’ or ‘‘devices’’ (i.e., combinationproducts) and the unique regulatory challenges this overlapposes. This chapter will conclude with a few observations andpredictions about future trends in the regulation of biologicalproducts in the twenty-first century.

1.1. What Are Biologics?

The term ‘‘biologic’’ is subject to several different meanings,depending upon the scientific or legal context in which theterm is used. Generally speaking, from a scientific standpointa biologic is a compound consisting of, or derived from, allor part of a living organism, and used for therapeutic or diag-nostic purposes. However, to determine whether it may regu-late a particular product as a biologic (as opposed to as a drug,a device, a combination product, or a nonregulated article),FDA must first look to the governing statutory provisions ofthe Public Health Service Act (PHSA) and the Federal Food,Drug and Cosmetic Act (FDCA). Because these statutes’ defi-nitions are not comprehensive nor always clear, FDA also reliesupon its own regulations and internal policies to determinethe nature and scope of its regulatory authority in particularsituations.

1.2. Statutory and Regulatory Definitions

Legally speaking, the term ‘‘biologic’’ is somewhat ill-definedand is subject to overlapping definitions and regulatory schemeswithin FDA’s jurisdictional purview. As discussed in greaterdetail later in this chapter, these definitional distinctions andvagaries result in many difficult but intriguing product-specificquestions, the answers to which can have a profound impact

FDA Regulation of Biological Products 75


on the nature and degree of FDA oversight of a particularproduct.

The Public Health Service Act (PHSA) defines ‘‘biologicalproduct’’ as

‘‘a virus, therapeutic serum, toxin, antitoxin, vaccine, blood,blood component or derivative, allergenic product, or analogousproduct, or arsphenamine or derivative of arsphenamine (or anyother trivalent organic arsenic compound), applicable to theprevention, treatment, or cure of a disease or condition ofhuman beings’’ (1).

FDA has, by regulation, further defined the types of prod-ucts included within the PHSA definition of ‘‘biologic’’ asfollows (2):

1. A virus is interpreted to be a product containingthe minute living cause of an infectious disease andincludes but is not limited to filterable viruses, bac-teria, rickettsia, fungi, and protozoa.

2. A therapeutic serum is a product obtained fromblood by removing the clot or clot components andthe blood cells.

3. A toxin is a product containing a soluble substancepoisonous to laboratory animals or to man in dosesof 1 milliliter or less (or equivalent in weight) of theproduct, and having the property, following the injec-tion of nonfatal doses into an animal, of causing tobe produced therein another soluble substance whichspecifically neutralizes the poisonous substance andwhich is demonstrable in the serum of the animalthus immunized.

4. An antitoxin is a product containing the soluble sub-stance in serum or other body fluid of an immunizedanimal which specifically neutralizes the toxin againstwhich the animal is immune.

In addition, ‘‘trivalent organic arsenicals’’ are defined by FDAto mean ‘‘arsphenamine and its derivatives (or any other tri-valent organic arsenic compound) applicable to the prevention,treatment, or cure of diseases or injuries of man’’ (3).



‘‘Radioactive biological products’’ are biological products‘‘labeled with a radionucleotide or intended solely to be labeledwith a radionucleotide’’ (4).

FDA has also established regulatory criteria by which prod-ucts will be deemed ‘‘analogous’’ to a biologic listed in thePHSA, and therefore also deemed to be a ‘‘biologic.’’ Specifi-cally, FDA has established that a product is analogous to avirus if it is ‘‘prepared from or with a virus or agent actuallyor potentially infectious, without regard to the degree of viru-lence or toxicogenicity of the specific strain used’’ (5). Productsare analogous to a therapeutic serum if they are ‘‘composed ofwhole blood or plasma or contain some organic constituent orproduct other than a hormone or an amino acid, derived fromwhole blood, plasma, or serum’’ (6). And products are analo-gous to a toxin or antitoxin if they are ‘‘intended, irrespectiveof its source of origin, to be applicable to the prevention, treat-ment, or cure of disease or injuries of man through a specificimmune process’’ (7).

The FDCA does not include a definition of ‘‘biologic,’’although it does include numerous provisions by which FDAexercises regulatory oversight of such products. Significantly,virtually all ‘‘biologics’’ as defined by the PHSA also fall within‘‘drug’’ and/or ‘‘device’’ definitions under the FDCA.

1.3. ‘‘Applicable to’’ Versus ‘‘Intended Use’’

Under the FDCA, a ‘‘drug’’ includes any article ‘‘intended foruse in the diagnosis, cure, mitigation, treatment, or preventionof disease in man’’ (8), and a ‘‘device’’ includes ‘‘an instrument,apparatus, implement, machine, contrivance, implant, in vitroreagent, or other similar or related article, including anycomponent, part or accessory, which is intended for use inthe diagnosis of disease or other conditions, or in the cure,mitigation, treatment, or prevention of disease’’ (9). Bothdrugs and devices include other articles ‘‘intended to affectthe structure or any function of the body of man,’’ but drugsdo not include food or dietary supplements (which are regu-lated separately), and devices do not include an article which‘‘achieve[s] its primary intended purpose through chemical



action within or on the body . . . and which is not dependentupon being metabolized for the achievement of its primaryintended purpose’’ (such articles would be regulated as drugs).Moreover, certain products that are, in a sense, biologics canbe ‘‘dietary supplements,’’ for example, dried animal bloodproducts intended for ingestion to ‘‘supplement the diet.’’

The PHSA definition of biologic does not explicitly includethe critical legal concept of a product’s ‘‘intended use,’’ which isa key element of the ‘‘drug’’ and ‘‘device’’ definitions of theFDCA. Under the traditional ‘‘intended use’’ concept, a com-pany’s own statements about its product, especially in theproduct’s labeling (whether approved or not) will affect the pro-duct’s status as a drug, device, food, cosmetic, or other.Generally speaking, a product that is not intended for therapeu-tic, curative, or diagnostic purposes cannot be a drug or a device.The PHSA uses the arguably broader concept of whether theproduct ‘‘is applicable’’ to the prevention, treatment, or cure ofdisease such that a company’s actual intent is not dispositive ifthe product itself could be used for such purposes.

Moreover, unlike the FDCA’s drug and device definitions,the PHSA definition of ‘‘biological’’ does not mention diagno-sis, but FDA has filled this definitional ‘‘gap’’ by expanding the‘‘applicability’’ concept to encompass diagnostic uses as a basisfor falling within the ‘‘biologic’’ definition. Specifically, FDA’sregulations provide that (10): ‘‘A product is deemed applicableto the prevention, treatment, or cure of diseases or injuries ofman irrespective of the mode of administration or applicationrecommended, including use when intended through adminis-tration or application to a person as an aid in diagnosis, or inevaluating the degree of susceptibility or immunity possessedby a person, and including also any other use for purposes ofdiagnosis if the diagnostic substance so used is prepared fromor with the aid of a biological product.’’

1.4. Tissue

An increasingly important area of biologic development involvesthe use of human tissue and derivatives or components thereof.However, tissue is not defined by statute as a biological, even



though it meets the general lay definition. Yet FDA currentlyregulates some tissue, and has clearly signaled its intent toassert broader jurisdiction over such products. The agency’scurrent approach, as of the time of this writing, to regulatingsuch products is highly fragmented, as its existing tissue regu-lations are narrow in scope, applying only to human tissueintended for transplantation that is recovered, processed,stored, or distributed in a manner that does not change thetissue’s function or characteristics. Establishment registrationand listing regulations for human cells, tissue, and cellular-and tissue-based products became effective on January 21,2004, 21C.F.R. Part 1271. Moreover, FDA’s tissue regulationsdo not apply to tissue products that are otherwise regulatedas drugs, biologics, or medical devices. In addition, vascularizedhuman organs for transplantation, blood and blood products,secreted or extracted human products such as milk, collagen,and cell factors (but not including semen), minimally manipu-lated bone marrow for homologous use (i.e., for use in thetissue donor)(so long as such tissue is not combined with adrug or device), and nonhuman cells, tissues, and organs, arenot considered ‘‘tissues’’ for purposes of FDA’s existing andproposed tissue regulations (11).

1.5. Gene Therapy

FDA also regulates the use of gene therapy, which can be broadlydefined as a medical intervention based on modification of thegenetic material of living cells. Such cells may be modified exvivo for subsequent administration, or may be altered in vivoby administration directly to the patient. Gene therapy may beintended to prevent, treat, cure, diagnose, or mitigate diseaseor injuries in humans, and the intended effects of gene therapycan be permanent or short term, depending on the conditionbeing treated or cured (12). FDA asserts regulatory jurisdictionover gene therapy in much the same way as it regulates drugsand therapeutic biologics, but due to the novelty and difficultyof gene therapy technology, no gene therapy product has yetbeen approved by FDA for commercialization. Several high-profile scandals in leading gene therapy research centers, as



well as periodic scares regarding the incidence of leukemia ingene therapy recipients, have led FDA to halt all gene therapytrials at various times. The repeated need to deal with inter-ruptions in the research process and respond to high-profilefindings in an area of intense public scrutiny have delayedthe development of approvable gene therapies.

1.6. Transgenic Animals and Xenotransplantation

Transgenic animals include genetically and cellularly modifiedfood animals—fish, dairy cows, and meat-producing animals—that are engineered to grow faster, resist disease, produce milkcontaining therapeutic drugs or vaccines, etc. FDA will regu-late transgenic animals and their products under the theorythat such animals contain a new animal drug or biologic asdefined by law or regulations (13). Thus, primary regulatoryoversight is being handled by the Center for Veterinary Medi-cine, with input by other Centers as appropriate. In evaluatingtransgenic animals, issues of food safety, environmental safety,target animal safety, effectiveness claims, quality controls, andlabeling and promotional activities will be important (14). Simi-lar concerns, and especially food safety concerns, are beingconsidered by FDA in connection with the cloning of livestockfor commercial purposes. The National Academy of Scienceshas played an important role in assessing the safety of animalbiotechnology (15).

Xenotransplantation is defined by FDA as any procedurethat involves the transplantation, implantation, or infusion intoa human recipient of either (a) live cells, tissues, or organsfrom a nonhuman animal source, or (b) human body fluids,cells, tissues or organs that have had ex vivo contact with livenonhuman animal cells, tissues, or organs (16). FDA has beenon the global forefront of xenotransplantation regulation, withits 1996 issuance of a Xenotransplantation Action Plan. Recentguidance has provided more specific direction with respect tothe safety concerns surrounding source animal screening andtesting, Good Manufacturing Practices, and long-term clinicalsafety evaluation. The potential for cross-species infection,



as with transgenic animal food and drug products, remains ofparamount concern.

1.7. Human Cloning

The myriad social, ethical, and legal questions surrounding thelegality and regulation of human cloning is approaching FDAat an ever-faster pace. FDA has consistently taken the approachthat all cloning studies involving human subjects require anIND and that the ‘‘major unresolved safety questions pertain-ing to the use of cloning technology to create a human being,[require that] until those questions are appropriately addressedin the IND, FDA [will] not permit any such investigationto proceed (18,19). FDA’s approach, together with multilateralbans on human cloning in other countries, have presentlypushed any human cloning research off-shore where any reportof successful results must be carefully scrutinized.

2. STATUTORY HISTORY OF BIOLOGICSREGULATION

Federal regulation of biologics dates back to 1902, with passageof the Biologics Control Act (also known as the Virus-Toxin

cursor of the National Institutes of Health (NIH) to regulatethe commercial production of vaccines, serums, toxins and anti-toxins, and similar products to ensure their safety, purity, andpotency (20). These statutory standards for biologics approval—safety, purity, and potency—still apply today and are aprimary distinguishing factor in the regulation and approvalprocess for biologics versus drugs (efficacy, as discussed below,was added as an approval criterion in 1934).

The Biologics Control Act also required products to belabeled with the name, the name, address, andlicense number of the manufacturer, and an expiration date.The Hygienic Laboratory enforced the Act by setting productstandards, conducting establishment inspections and analysesof marketed samples, and revoking licenses in the case of



product

Law) (Table 1). The Biologics Control Act authorized the pre-

violations. The Act also gave the Hygienic Laboratory rule-making authority. Early regulations dealt with proceduresfor licensing and inspection, but in 1934 regulations were pro-mulgated requiring a showing of efficacy as a condition forgranting of new biologics licenses (21). The earliest licensedproducts included smallpox and rabies vaccines and diphtheriaand tetanus antitoxins.

2.1. The Public Health Service Act

The Biologics Control Act was recodified and incorporatedinto the Public Health Service Act in 1944 without significantsubstantive change. However, the PHSA established theLaboratory of Biologics Control as the licensing authority forbiological products and required for the first time that biologics

Table 1 History of Biological Products Regulation

1894 Public health labs produce diphtheria antitoxin1901 Thirteen children die of tetanus due to contaminated

diphtheria antitoxin1902 Biologics Control Act1906 The Food and Drug Act1912 Public Health Service created1930 National Institutes of Health1937 Division of Biologics Control1938 Food, Drug and Cosmetic Act1940 Rh blood group system1941 Cohn fractionation of blood1944 The Public Health Service Act (Laboratory of Biologics Control)1948 National Microbiological Institute1950 First live polio vaccine in humans1955 Cutter polio vaccine incident; Division of Biologics

Standards created1962 Kefauver-Harris drug amendments1972 Bureau of Biologics to FDA1973 New provisions of PHS Act1980s Biotechnology era1982 National Center for Drugs and Biologics1988 Center for Biologics Evaluation and Research1992 Prescription Drug User Fee Act1997 Food and Drug Administration Modernization Act2003– ???

Source: Adapted from Ref. 20.



establishments also be subject to separate licensure (22).In 1948 the National Microbiological Institute at NIH tookadministrative control over the regulation of biological prod-ucts. As a result, the regulation of biological products wasintegrated with the scientific research at NIH. The stronginfluence of the Public Health Service medical corps, whostaffed and continue to staff the biological regulatory adminis-tration, and the influence of science at NIH have been strongfactors in the cultural environment of the regulatory evalua-tion and approval processes for biological products.

The Laboratory of Biologics Control became a politicalvictim of medical tragedy in 1955. In the spring of 1955, defec-tive polio vaccine batches resulted in hundreds of cases of polio,in what became known as the ‘‘Cutter incident.’’ As a result,regulatory authority over biological products was transferred tothe Division of Biologics Standards, a newly created division ofNIH. Concurrently, vaccine testing regulations were strength-ened, particularly those concerning manufacturing and testingrequirements for marketed biological products.

In 1972 the NIH Division of Biologics Standards wastransferred to FDA and renamed the Bureau of Biologics. ThePHS Act lacked many of the analogous statutory provisions ofthe federal Food, Drug, and Cosmetic Act (then known asthe Food and Drug Act) which pertained to drugs. Therefore,FDA promulgated regulations for various activities of biologicmanufacturers under the Food and Drug Act, including theinvestigational new drug process (IND), good manufacturingpractices (GMPs), advertising and promotion, and the legal con-cepts of adulteration and misbranding of biologics (23), effec-tively applying the new drug ‘‘substantial evidence’’ criteria tobiological products (24).

The ability to regulate biological products through both thePHSA and FDCA provisions is especially important because ofthe difficult nature of characterization for some biological pro-ducts. The emphasis on manufacturing controls and the abilityto impose rigorous lot release requirements enables FDA tofulfill its mandate of protecting the public health.

In 1982 the Bureau of Biologics merged with the Bureauof Drugs to form the National Center for Drugs and Biologics



(NCDB). In 1987 the Center for Biologics Evaluation andResearch name was coined. Thus, throughout its history,CBER has been strongly linked with science and research,but the complexity of the regulatory subject matter for whichit is responsible has kept this federal entity a regulatory‘‘hot potato.’’

2.2. Food, Drug And Cosmetic Act Applicabilityto Regulation of Biologics

As described above, with the 1972 transfer of biologics regula-tory authority to the Bureau of Biologics, FDA incorporatedFood and Drug Act principles in the regulation of biologics.However, Section 351 of the PHSA (42 U.S.C. x 262) hasremained the primary source of FDA authority to regulatebiologics, particularly for the standards of safety, purity, andpotency.

Both FDA and the federal courts have interpreted theFDCA statute and implementing regulations to read on to thePHSA requirements for biologics. Federal courts have upheldFDA’s position that biologics under the PHS Act are also drugsunder the Food and Drug Act. For example, in a 1962 criminalindictment under the FDCA, a federal district court in NewYork held that ‘‘. . .whole human blood referred to in theindictment [against the defendants] would constitute a ‘drug’within the meaning of the [Federal Food, Drug, and CosmeticAct] statute’’ (25).

Over time, biological products have been made subjectto FDCA statutory provisions including advertising, the INDprocess, establishment registration and product listing, inspec-tions, exports, and user fees (26). A number of legislative amend-ments to the FDCA since 1972, although titularly focused ondrugs, have in fact included biologics within their scope, suchas the Orphan Drug Act of 1982 and the Prescription DrugUser Fee Act (PDUFA) of 1992 (27). Most notably, the Foodand Drug Administration Modernization Act of 1997 (FDAMA)(28) made significant revisions to the biologics approval processand regulations. Section 123 of FDAMA eliminated the sepa-rate need for licensure of biologics establishments and products



(ELAs and PLAs), codifying the singular Biologics LicenseApplication (BLA) in use today.

2.3. FDA Enforcement for Biologics

Inspection of biologics-manufacturing facilities and processesis of critical importance since the manufacturing processoften defines the biological product. In 1998, FDA began a‘‘Team Biologics’’ initiative (29), which has brought regulatorsand technical specialists together for the efficient inspection oflicensed biologics manufacturers. The Team Biologics modelhas been imported to other FDA inspectional activities andpermits comprehensive, consistent approaches when assess-ing compliance from regulated industry. Factors such asthe history of the master and working cell bank (for cellularor gene therapy) are highlighted in the Team Biologicsapproach in order to ensure that the statutory requirementsof safety, purity, and potency are being met. Other inspectionalareas of concern for biologics manufacturers are environ-mental monitoring, bioburden control, area classification, andtraining.

FDA enforcement activity related to a Team Biologicsinspection can take a number of forms, owing to the abilityof biologics regulators to choose from either PHSA or FDCAtools or both. If a biological product may pose a danger to thepublic health, the FDCA as a criminal statute lends enforce-ment tools of injunction and seizure, which are complementedby PHSA authority to suspend licenses immediately.

3. REGULATORY APPROVAL PROCESSESFOR BIOLOGICS

On June 30, 2003 FDA was nearing completion of its efforts toconsolidate responsibility for the review of certain therapeuticbiological products into the Center for Drug Evaluation andResearch (30). This latest in the history of transferring controlof biologics regulatory authority was intended for thepurported benefits of regulatory consistency and efficiency.



CDER now has oversight of monoclonal antibodies, cytokines,growth factors, enzymes, interferons (including recombinantversions), proteins intended for therapeutic use that areextracted from animals or microorganisms, and immunothera-pies. Vaccines, blood, blood derivatives, and blood products,gene therapy, cell therapy, and tissue transplantation remainwith CBER.

The characteristics of biologics that contribute to theirspecific areas of regulatory concern include the fact that theyare created by or extracted from living organisms; they are lessdefined physicochemically than pharmaceutical drugs (and areless pure); they have higher molecular weights; most are sterileinjections; they are less stable, while their degradation is morecomplex; and finally, they are often immunogenic, which limitsthe relevance of preclinical testing in animals to the humanexperience. For biologics, the manufacturing process definesthe product, and for this reason there are few categoricalregulatory guidances on classes of biologics and great emphasison an individual product’s chemistry, manufacturing, and con-trol information. Thus, in the regulatory approval process forBiologics License Applications (BLAs), reviewers have height-ened concern regarding new safety information and previouslyunseen adverse events. This translates into a higher rate ofclinical holds for biologic INDs relative to drug INDs. In otherrespects, the BLA-approval process runs parallel to the NDA-approval process, emphasizing the same objectives for phase I(safety and toxicity), phase II (dose ranging), and phase III(indication, safety, and efficacy) studies.

3.1. Biologic Combination Products

On December 31, 2002, FDA launched its Office of Combina-tion Products specifically to handle the regulatory complexitiesassociated with drug, biologic, and medical device combina-tions (31). Examples of biologic combination products includelumbar fusion cages containing genetically engineered humanprotein bone grafts (biologic/device) (32) or the use of Peginterferon alfa-2a with ribavirin for the treatment of patientswith chronic hepatitis C (biologic/drug) (33).



Designation of a primary review center for a combinationproduct is based upon the primary mode of action of theproduct. The primary mode of action is currently determinedby the Office of the Ombudsman in response to a Requestfor Determination (RFD), as outlined in 21 C.F.R. Part 3.If the primary mode of action is that of a biologic, thenCBER has primary jurisdiction for reviewing the combinationand receives collaborative input from CDER or CDRH as rele-vant (34). The primary mode of action determination is basedupon a number of different factors, including chemical, physi-cal or biological composition, manufacturing and formulationprocess, mechanisms of action of each moiety, proposed clinicalindication and effects induced, and schedule of use, dose, andadministration.

3.2. Therapeutic Biologics

As discussed above, FDA’s statutory authority for the licensureof biologics for commercial use is pursuant to Section 351 ofthe Public Health Service Act. Prior to licensure, the clinicalinvestigation of these products is regulated under the druginvestigation (IND) or medical device investigation (IDE) regu-lations. While there are no separate regulations governinginvestigational biologics, CBER controls the regulatory over-sight of biologics INDs (35). The regulations governing theuse of investigational biologics are set forth in Part 312 ofTitle 21 of the Code of Federal Regulations.

The IND process culminates in the filing of a BLA, whichis similar to an NDA in both content and format but placesgreater emphasis on product-manufacturing processes to assurethe purity of the product and that specific standards are met.The fundamental standard for approval of a BLA is the same asfor an NDA: a showing that the product is safe and effective forits labeled indication, as demonstrated in human clinical trials.The process for BLA submission and review is also the sameas for an NDA. FDA has 60 days following BLA submissionto determine whether an application is filed, and thereafter180 days to review the application and either approve or refuseto approve the application (36). Upon completion of review,



FDA issues either an approval letter or a letter requestingadditional information (approvable, not approvable, or ‘‘com-plete response’’) (37). Often final labeling needs to be nego-tiated prior to an approvable letter being superceded by finalapproval.

The basic BLA includes all preclinical and clinical infor-mation concerning the biologic, as well as a full descriptionof the manufacturing methods employed (38). Manufacturingprocess description must include, as relevant: complete descrip-tion of the source material (including characterization ofrelevant cell banking systems) and the product; completedescription of bulk substance production of bulk, including fer-mentation, harvest and purification procedures, process vali-dation, and testing; complete description of manufacturingsteps for production through finishing, including formulation,filling, labeling, and packaging [including all steps performedat outside (e.g., contract) facilities]; data demonstrating consis-tency of manufacture; formulation development studies, whereappropriate, or rationale for selection of formulation; completedescription of lots and manufacturing process utilized forclinical studies; data demonstrating absence or removal ofadventitious agents where such agents are potentially present;and complete data demonstrating equivalency to clinical trialproduct when significant changes in manufacturing processesor facilities have occurred.

FDA approval of therapeutic biologics often involvesinput from the public and the advisors and consultants onCBER’s product category–specific Advisory Committees. Advi-sory committee membership can be set to include experts inthe particular therapeutic area of a candidate product, prom-ising a robust discussion of the BLA.

3.3. Vaccines

Vaccine products within CBER’s regulatory jurisdiction includelive attenuated vaccines, DNA vaccines, and tumor vaccines.While most people are familiar with childhood preventivevaccines that have contributed to a significant reductionin vaccine-preventable diseases, new therapeutic vaccines



for the treatment of cancer and other diseases are also beingreviewed by CBER.

The review and approval process for vaccines is tailored,as with all therapies, to the ultimate indication being sought bya sponsor. The size of the patient database required—i.e., thenumber and duration of experience with human exposure—can vary from several hundred to several thousand, dependingupon the intended use. The general BLA process regulationsare codified at 21 C.F.R. Part 601, while the IND regulations of21 C.F.R. Part 312 apply to the investigational use of biologics.

Vaccine clinical development follows the same generalpathway as for drugs and other biologics. A sponsor whowishes to begin clinical trials with a vaccine must submitan IND to FDA. The IND describes the vaccine, its methodof manufacture, and quality-control tests for release. Alsoincluded are information about the vaccine’s safety and abilityto elicit a protective immune response (immunogenicity) inanimal testing, as well as the proposed clinical protocol forstudies in humans.

Premarketing (prelicensure) vaccine clinical trials aretypically done in three phases, as is the case for any drug orbiologic. Initial human studies, referred to as phase 1, are safetyand immunogenicity studies performed in a small number ofclosely monitored subjects. Phase 2 studies are dose-rangingstudies and may enroll hundreds of subjects. Finally, phase 3trials typically enroll thousands of individuals and providethe critical documentation of effectiveness and importantadditional safety data required for licensing. At any stage ofthe clinical or animal studies, if data raise significant con-cerns about either safety or effectiveness, FDA may requestadditional information or studies or may halt ongoing clinicalstudies.

If successful, the completion of all three phases of clinicaldevelopment can be followed by the submission of a BLA. Tobe considered, the license application must provide the multi-disciplinary FDA reviewer team (medical officers, microbiol-ogists, chemists, biostatisticians, etc.) with the efficacy andsafety information necessary to make a risk/benefit assessmentand to recommend or oppose the approval of a vaccine. Also



during this stage, the proposed manufacturing facility under-goes a preapproval inspection during which production ofthe vaccine as it is in progress is examined in detail.

Following FDA’s review of a license application for a newindication, the sponsor and the FDA may present their findingsto FDA’s Vaccines and Related Biological Products AdvisoryCommittee (VRBPAC). This non-FDA expert committee (scien-tists, physicians, biostatisticians, and a consumer representa-tive) provides advice to the Agency regarding the safety andefficacy of the vaccine for the proposed indication.

FDA is very involved with its external constituentswhen it comes to vaccine review, approval, and postmarketingrisk assessment. Vaccine approval requires the provision of ade-quate product labeling to allow health care providers to under-stand the vaccine’s proper use, including its potential benefitsand risks, to communicate with patients and parents, and tosafely deliver the vaccine to the public. FDA and CBER relyheavily upon the CDC and childhood vaccine experts in settingthe vaccine schedule for childhood immunizations, and FDAworks closely with CDC also to annually choose the constitu-ents of the influenza vaccine, which varies seasonally.

Postmarketing risk assessment also factors heavily forvaccine approvals, since all adverse events cannot be antic-ipated until a larger population is inoculated. CBER andthe U.S. Centers for Disease Control and Prevention (CDC)jointly manage the Vaccine Adverse Event Reporting System(VAERS), a cooperative program for vaccine safety. VAERS isa postmarketing safety surveillance program, collecting infor-mation about adverse events (side effects) that occur after theadministration of U.S. licensed vaccines.

In the postmarketing phase, FDA continues to oversee theproduction of vaccines in order to ensure continuing safety.After licensure, monitoring of the product and of productionactivities, including periodic facility inspections, must continueas long as the manufacturer holds a license for the product.If requested by FDA, manufacturers are required to submitto FDA the results of their own tests for potency, safety, andpurity for each vaccine lot. They may also be required tosubmit samples of each vaccine lot to FDA for testing.



However, if the sponsor describes an alternative procedure thatprovides continued assurance of safety, purity, and potency,CBER may determine that routine submission of lot releaseprotocols (showing results of applicable tests) and samples isnot necessary.

3.4. Biologic Devices

In addition to the Public Health Service Act and Food Drugand Cosmetic Act, biologic devices are also subject to device-related FDA statutes. For instance, in vitro diagnostics andmedical devices used in blood banks to process biologicalproducts (such as kits used to screen for HIV and hepatitis)are delegated to CBER by the Intercenter Agreement betweenCBER and the Center for Devices and Radiological Health (39)and are regulated under the Medical Device Amendments of1976 and 1992 and the Safe Medical Devices Act of 1990 (40).

The review and approval of biologic devices is interactivebetween CBER and CDRH, particularly with respect to in vitrodiagnostic devices. The Medical Device User Fee and Moderni-zation Act of 2002 imposes commitments for 510(k) and PMAreview times on both CBER and CDRH for biologic devices.The regulatory framework that pertains to devices includesthe Investigational Device Exemption (IDE) and HumanitarianUse Device (HUD).

Clinical investigations of certain in vitro diagnostic bio-logic devices are exempt from IND regulations if the productsare intended to be used in diagnostic procedures that confirmthe diagnoses made by other, medically established diagnosticproducts or procedures and they are labeled and shipped inconformance with FDA (seefor labeling and shipping requirements) (41).

3.5. Tissue and Somatic Cell Therapy

CBER regulates human tissue intended for transplantationunder 21 C.F.R. Part 1270. The Part 1270 regulatory schemeis limited to requiring tissue establishments to screen andtest donors, prepare and follow written procedures for the



x312.160C.F.R.regulations 21

prevention of the spread of communicable disease, and main-tain records (42).

Cellular and tissue-based products at this time are on thecusp of full regulation. Under a Reinventing Tissue Regulationplan begun in 1997, new regulations are set to be codified at21 C.F.R. Part 1271 (43). The plan produced several proposedrules, beginning in 1998, which described a new approach to theregulation of human cells, tissues, and cellular and tissue-basedproducts (HCT/Ps). This new approach included, among otherthings, requirements for donor suitability screening (effectiveMay 25, 2005) (44), registration and listing of tissue establish-ments (effective January 21, 2004) (45), and the development ofGood Tissue Practices (not finalized as of this writing) (46)(collectively, the 21 C.F.R. Part 1271 regulations).

The HCT/P establishment registration and listing rulebecame effective on January 21, 2004 (47). HCT/P researchsponsors and product developers have to consider whethertheir products meet the ‘‘minimal manipulation’’ and ‘‘homo-logous use’’ standards, since IND and licensure requirementswere being phased in ‘‘to permit the development of licensingstandards for those products where possible’’ (48).

3.4. Blood and Blood Products

Blood product regulation is one area in which FDA signifi-cantly regulates both the product and process of marketinga therapeutic. CBER regulates the collection of blood andblood components used for transfusion or for the manufactureof pharmaceuticals derived from blood and blood components,such as clotting factors, and establishes standards for the prod-ucts themselves (49). Many CBER standards for blood prod-ucts are presently published as guidance documents but arein the process of being updated through notice and commentrulemaking, under the Blood Action Plan, as described below.

While whole blood is not subject to FDA approval, it issubject to a range of other regulatory requirements designedto ensure the safety of transfusion recipients from bloodborneinfectious diseases such as human immunodeficiency virus(HIV), hepatitis, Creutzfeld-Jakob disease (CJD, the human



variant of bovine spongiform encephalopathy), etc. Blood-derived products are subject to heightened regulatory require-ments, including preapproval for therapeutic and diagnosticproducts. CBER also regulates blood banking devices, asdescribed above, including cell separators, blood collectioncontainers, and HIV screening tests.

In addition to licensing blood products, CBER developsand enforces quality standards, inspects blood establishments,and monitors reports of errors, accidents, and adverse clinicalevents. FDA has significantly increased its oversight of theblood industry in recent years, particularly with the 1997Blood Action Plan (50). The Blood Action Plan is focused onFDA’s ability to respond to emerging infectious diseases (suchas West Nile virus) and the updating of its regulations to reflectgreater coordination with CDC, thus increasing safety of theblood supply while at the same time maintaining sufficientsupply in an era of increased donor deferral.

FDA requires all blood and blood component manufactur-ers to adhere to current GoodManufacturing Practices (cGMP),as outlined at 21 C.F.R. Part 606. FDA inspects all blood facil-ities at least every 2 years, and ‘‘problem’’ facilities are inspec-ted more often. Blood establishments are now held to qualitystandards comparable to those expected of pharmaceuticalmanufacturers; in years past, exemptions of certain practiceswere more frequent. All owners or operators of establishmentsthat engage in the manufacturing of blood products arerequired to register, pursuant to Section 510 of the FDCA (51).

CBER works closely with other parts of the PHS to iden-tify and respond to potential threats to blood safety, to developsafety and technical standards, to monitor blood supplies, andto help industry promote an adequate supply of blood and bloodproducts.

3.7. Gene Therapy

Gene therapy is one area where CBER’s historical roots inthe NIH are continued. While FDA has primary jurisdictionfor review and approval of gene therapy products, NIH’sRecombinant DNA Advisory Committee (RAC) is responsible



for oversight and public discussion of clinical gene transferresearch. NIH also evaluates the quality of the science involvedin human gene therapy research and funds gene transferresearch. Although more than 200 gene therapy trials werepurportedly being conducted under INDs as recently as 2002,no BLA for gene therapy has yet been submitted or approved.

CBER’s 1998 Guidance for Human Somatic Cell Therapyand Gene Therapy remains the most formal representationof FDA’s requirements for gene therapy clinical trials andproduct approval (52). As with most true biologics, the absenceof categorical class requirements makes both guidance andrulemaking in this area difficult, with much regulatory discre-tion being exercised by the regulatory scientists within CBER.Safety issues continue to be of paramount concern in the over-sight of gene therapy trials, as discussed above.

3.8. Generic Biologics

Although the subject of increasing debate, FDA’s ability toapprove a generic biologic, ‘‘me-too’’ biologic, comparable bio-logic or biogeneric—under any name—remains unsettled atpresent. Spiraling health care costs, particularly prescriptiondrug costs, have placed increasing pressure on FDA regulatorsto permit approval of generic biologics. From a statutory per-spective, the PHSA does not contain provisions that relate toapproval of generic biologics in the way that the Hatch-Waxman Amendments changed the FDCA.

However, the convergence of economic pressure and scien-tific advances in developing generic versions of innovator bio-logics, is both pushing and supporting FDA’s intent to release aguidance document that address scientific approval standardsfor certain generic biologic products. Lester Crawford, ActingFDA Commissioner, recently confirmed in 2004 Congressionaltestimony, the Agency is getting ready to release a guidancedocument on approval criteria for generic versions of certainbiologics. Most likely, this anticipated guidance document willspecifically address standards for approval of generic humangrowth hormone products. The guidance is also expected todraw on FDA’s September 2003 draft guidance concerning



comparability protocols for Chemistry, Manufacturing, andControl (CMC) changes to protein drug products and biologicalproducts. Comparability protocols are used, and have histori-cally been used, for post approval changes to a product’s man-ufacture. In the case of a biologic product, CMC changes cantheoretically and actually create an entirely new product thatwould otherwise require approval of a full BLA. Therefore,comparability protocols have traditionally been used by BLAsponsors to gain approval for CMC changes without having torepeat clinical studies, and are thus an attractive regulatoryprecedent to the approval of a generic biologic (53).

The most significant impediment to the approval of a gen-eric biologic is the absence of many analytic standards thatare available for drugs. Specifically, product characterization/identity, purity, the assessment of pharmacokinetic param-eters, manufacturing, and analytic processes will be critical fora sponsor to demonstrate if FDA is to approve a biologic withoutproduct-specific clinical data. It would seem that the mostlikely candidates for the first generic biologics would be thoseproducts that fit the definition of biologics but that have his-torically been regulated as drugs by CDER, including fibrino-lytics, somatotropins, and insulin. The FDCA Section 505(b)(2)approval pathway, under which sponsors may rely upon theagency’s prior findings of safety and efficacy for a productbut which permits FDA to require clinical evidence, has beenconsidered one potential mechanism for the approval of genericbiologics without legislative change. The need for a bridgingclinical trial to demonstrate safety and lack of immunogenicityfor the generic biologic is understood even among most propo-nents of generic biologics. The recent integration of CBER’sOffice of Therapeutics Research and Review (OTRR) could bea harbinger of more unified review standards for biologics anddrugs, and ultimately for the approval of generic biologics.

FDA’s interest in developing mechanisms to supportapproval of generic biologics has garnered the attention ofthe biotechnology industry and individual companies, whohave already launched direct attacks on FDA’s authority topursue such policies. In 2003 the Biotechnology IndustryOrganization (BIO) filed a Citizen Petition with FDA



challenging the Agency’s legal authority, and the scientific fea-sibility, of FDA approval of generic biologics under 505(b)(2)NDAs. FDA affirmed its previously asserted general authoritiesunder section 505(b)(2), but deferred a response on BIO’sscientific arguments to a later date. More recently, on April8, 2004, Genentech filed a petition directly aimed at preventingFDA from even issuing the expected similarity guidance.Genentech’s position is that any FDA guidance documentwould inherently and unlawfully reflect the agency’s ‘‘use’’ ofGenentech’s proprietary trade secret data previously submittedto FDA for the sole and limited purpose of seeking approval ofGenentech products. More specifically, Genentech attacks theFDA’s ability lawfully to approve specific ‘‘generic’’ versions ofGenentech products under a comparability guidance, becauseto do so would require FDA to specifically refer to, and com-pare, Genentech’s crucial proprietary manufacturing processesto the proposed generic company’s processes.

As FDA pursues its pending guidance and addresses themounting legal challenges thereto, key members of Congress,including SenatorHatch, are expressing growing interest in pur-suing a statutory pathway for generic biologic approvals. Whilespecific Congressional proposals have not been widely circulatedat the time of this writing, a legislative approach would not beexpected to address detailed scientific questions, but rather toestablish a general pathway, giving FDA authority to considerappropriate information as necessary to approve generic biolo-gics. New Congressional authorization would effectively bluntmany, but perhaps not all, legal objections in ways that agencyaction alone could not. But, as in the case of past legislativereforms to FDA authority and processes, the agency and Con-gress appear to be pursuing the issue of generic biologics in par-allel, and at some point in the perhaps not too distant future,those paths will converge and result in concrete legislation.

REFERENCES

1. 42 U.S.C. x 262(i).

2. 21 C.F.R. x 600.3(h).



3. 21 C.F.R. x 600.3(i).

4. 21 C.F.R. x 600.3(ee).

5. 21 C.F.R. x 600.3(h)(5)(i).

6. 21 C.F.R. x 600.3(h)(5)(ii).

7. 21 C.F.R. x 600.3(h)(5)(iii).

8. 21 U.S.C. x 321(g)(1)(B).

9. 21 U.S.C. x 321(h)(1).

10. 21 C.F.R. x 600.3( j).

11. 21 C.F.R. x 1270.3.

12. See 58 Fed Reg 53,248, 53,250 (Oct. 14, 1993).

13. Lewis, Carol, A new kind of fish story: the coming of biotech animals,

14. Matheson III, John C., Transgenic fish developments: are transgeniccatfish in our future?, Slide Presentation to the Catfish Farmers of

15. FDA Veterinarian Newsletter, Sept./Oct. 2001,

16. Guidance for industry: source animal, product, preclinical and clinicalissues concerning the use of xenotransplantation products in humans

17. Reference removed.

18.

19. March 28, 2001 CBER warning letter to cloning technol-

20.

21. Id.

22. Id.

23. See 37 Fed Reg 16679 (August 18, 1972) (biologics efficacy review); 38Fed Reg 2965 (Jan. 31, 1973)(registration of Blood Banks); 39 Fed Reg18,614 (Dec. 17, 1974)(biologic advertising).

24. Biological products: procedures for review of safety, effectiveness, andlabeling, 37 Fed Reg 16679 (Aug. 18, 1972), 38 Fed Reg 4319 (Feb. 13,1973).

25. U.S. v. Calise, 217 F. Supp. 705 (S.D.N.Y. 1962).

26. See 21 U.S.C. xx352(n), 355(i), 360, 374, 379(h) and 382.

27. P.L. 94-414 (Orphan Drug Act) and P.L. 102-571 (Prescription DrugUser Fee Act of 1992).



FDA Consumer, Jan-Feb. 2001, http://www.fda.gov/fdac/features/2001/101_fish.html.

America, (Feb. 1999), available at http://www.fda.gov/cvm/biotechnol-ogy/catfish/sld001.htm.

(April 2003), available at http://www.fda.gov/cber/gdlns/clinxeno.pdf

http://www.fda.cvm/index/fdavet/2001/Sep_Oct.htm#update

gov/

http://www.fda.gov/oc/ohrt/irbs/irbletr.html.

FDA, Science and the regulation of biological products, at 13, http://

ogy associations, available at http://www.fda.gov/cber/ltr/ aaclone.htm

www.fda.gov/cber/inside/cberbkp1.pdf (2002)

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

28. P.L. 105-115.

29. Compliance Program Guidance 7341.001 Inspection of LicensedTherapeutic Drug Processors.

30. At the time of writing, the CBER/CDER consolidation is finishedthrough phase II. See

31.

32.

33.

34. 21 U.S.C. x353(g)(1)(C).

35.new drug approval requirements of the Food and Drug Act, investiga-tional drugs, thus permitting their shipment in interstate commerce,subject to limitations imposed by FDA. The FDA’s regulations specifi-cally provide that investigational biologics also fall within this exemp-tion from the new drug regulations.

36. 21 C.F.R. x 314.100(a).

37. Id.

38. 21 C.F.R. 601.2(a).

39.

40. 94-295 (1976 Amendments), P.L. 102-300 (1992 Amendments)and P.L. 101-629 (the SMDA).

41. 21 C.F.R. x 312.2(b)(2)(i)

42. 21 C.F.R. Part 1270.

43. 66 Fed Reg 1508 (January 8, 2001).

44. 64 Fed Reg 52696 (September 30, 1999) (Donor Suitability proposedrule).

45. 66 Fed Reg 5447 (January 19, 2001) (Establishment Registration andListing final rule).

46. 66 FedReg 1508 (January 8, 2001) (Good Tissue Practices proposed rule).

47. 68 Fed Reg 2689 (January 21, 2003).

48. Id at 2985.

49. 21 C.F.R. Parts 606 and 640.

50.

51. 21 C.F.R. x607.7(a) (Establishment Registration and Product Listing ofBlood Banks and Other Firms Manufacturing Human Blood and BloodProducts).

52.

53. Comparability protocols: chemistry, manufacturing and controls infor-mation (February 2003); available at



ANS01188.html

http://www.fda.gov/bbs/topics/NEWS/2002/NEW00862.html

http://www.fda.gov/cber/approvltr/pegihof120302L.htm

21 C.F.R. xx312.2(a), 601.21. FDCA Section 505(i) exempts from the

Available at http://www.fda.gov/oc/ombudsman/bio-dev.htm

P.L.

http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01155.html

http://www.fda.gov/cber/blood/bap.htm

http://www.fda.gov/cber/gdlns/somgene.htm

http://www.fda.cmprprot.htm

gov/cber/gdlns/

http://www.fda.gov/bbs/topics/ANSWERS/2003/

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

4

Generic Drug Approval Process:Pre-1984 History Concerning

Generic Drugs

DAVID L. ROSEN

Gray Cary Ware & Freidenrich, LLP

Washington, DC, U.S.A.

1. INTRODUCTION

Before enactment of the Drug Price Competition and PatentTerm Restoration Act (the Hatch-Waxman Act), AbbreviatedNew Drug Applications (ANDAs) were permitted for duplicateversions of drug products, though only for drugs first approvedby the U.S. Food and Drug Administration (FDA) between 1938and 1962. Generally, such drugs were subject to the DrugEfficacy Study Implementation (DESI) program andwere deter-mined to be both safe and effective or were otherwise removed

99


from the market. Products were eligible candidates for ANDAsif they were the same as an already approved drug in termsof dosage form, route of administration, strength, active ingre-dient, indication(s), and other conditions for using the drugproduct. Certain drug products were required to demonstratebioequivalence if they were determined by FDA to have anactual or potential bioavailability problem and if appropriatemethodology and standards were available to conduct suchtesting.

In addition, FDA regulations permitted the submission ofANDAs for ‘‘similar’’ and ‘‘related’’ products only if the Agencymade a specific determination, following a company’s specificinquiry, letter, or citizen petition, that an ANDA was appro-priate for the particular product. FDA made such a determina-tion upon evaluating the nature of the proposed product inview of the efficacy and safety of the product initially marketedbetween 1938 and 1962.

2. THE 1938 FEDERAL FOOD, DRUG, ANDCOSMETIC ACT

The Federal Food, Drug, and Cosmetic Act (FD&C Act) asenacted by the U.S. Congress in 1938 established a premarketclearance system for new drugs under which companies seekingFDA approval were required to submit new drug applications(NDAs), including, among other items, data demonstrating thesafety of the respective drug products. The FD&C Act providedthat the NDAs would automatically become effective if a brand-name drug was proven to be safe so that the drug product couldbe legally marketed within a specific time period unless theFDA affirmatively refused to approve the specific NDA.

In addition to drug products marketed under an NDA thathad been approved or become effective, many brand-name andgeneric products marketed without an effective NDA wereidentical, similar, or related to drug products having effectiveNDAs. Drug manufacturers who were marketing such drugproducts had determined that their products were generallyrecognized as safe (GRAS) or had received an advisory opinion

100 Rosen


from the Agency that an NDA was not required becausetheir products were GRAS and determined by FDA not to be‘‘new drugs.’’

3. THE 1962 AMENDMENT TO THE FD&C ACT

In 1962 Congress amended the FD&C Act to require affirma-tive approval by FDA of NDAs before marketing of drug prod-ucts. The 1962 Kefauver-Harris amendment required thatdrug companies demonstrate the effectiveness of a drug prod-uct in addition to safety requirements imposed under the1938 FD&C Act. Under x505(b) of the amended Act, NDAswere (and still are) required to contain, among other items,‘‘full reports of investigations which have been made to showwhether or not such drug is safe for use and whether such drugis effective.’’

For products marketed prior to 1962, drug companieswere required to submit data to demonstrate the effectivenessof their drug products. Congress also instructed FDA to reviewall drug products that obtained NDA approval from 1938 to1962 in order to evaluate whether such products were effective.The evaluation of these drug products and the implementationof the findings of the evaluation were carried out under theDESI program. FDA contracted with the National Academy ofSciences/National Research Counsel (NAS/NRC), which estab-lished expert panels to review the submitted clinical dataand make recommendations to FDA about the effectivenessof the specific drug products included in the DESI program,based on the data submitted, as to whether a drug productshould be considered effective, probably effective, possiblyeffective, or ineffective, but not an approved form of treat-ment since other treatments are better, safer, or moreconvenient.

FDA reviewed and considered the recommendations of theNAS/NRC expert panels concerning the effectiveness of DESIdrug products and published its conclusions in the FederalRegister. The Federal Register notices, commonly referred

Generic Drug Approval Pre-1984 101


to as DESI notices, set forth revised conditions for marketingspecific drug products. The revised conditions for marketingset forth in the Federal Register notices not only applied tothe specific brand-name product for which efficacy data weregenerated but also provided conditions for obtaining FDAapproval to market a duplicate generic version of the product.FDA administratively established the policy to approve genericversions of DESI-reviewed drug products without express stat-utory authority for such an abbreviated approval process, butno one ever challenged the Agency’s authority in this matter.

If a drug manufacturer had a pre-1962 new drug appli-cation in effect for a brand-name drug product, FDA proces-sed the application to approval if the manufacturer submitteda supplemental NDA that provided revised labeling to con-form the product’s indications for use to those determinedto be effective in the DESI review. The manufacturer alsowas required to comply with other revised conditions for mar-keting the product as set forth in the Federal Register notice.Such conditions could include reformulation of the ingredientscontained in the product, changes in strength of individualingredients, changes in dosage form, and other revisions of thelabeling.

As noted above, however, many drug products on themarket were identical in active ingredient(s) and indication(s)or very similar or in some manner related to the drug productsfound effective in the DESI review but for which no new drugapplication had ever been submitted. With respect to productsfor which no NDA was ever submitted and duplicate or genericversions thereof, in implementing the DESI program, FDAconcluded that each such drug product was a ‘‘new drug’’that required its own approved new drug application before itcould be legally marketed (3). (The definition of ‘‘new drug’’under the FD&C Act applies to the drug product rather than tothe generic active ingredient.) FDA also issued a statement ofpolicy that revoked the earlier advisory opinions that drugscould be marketed without preclearance by the agency. FDA’spolicy revoking earlier advisory opinions concerning the mar-keting of products earlier deemed not to be new drugs waspublished in the Federal Register in 1968 (4).

102 Rosen


4. THE ABBREVIATED NEW DRUGAPPLICATION PROCEDURE FORPRE-1962 DRUGS

To provide a mechanism for approval of duplicate generic prod-ucts based on the DESI evaluation, FDA established a proce-dure for submission of ANDAs. This procedure was set forth inFederal Register notices (4,5). After FDA had reviewed theconclusions of the NAS/NRC experts and found that a particu-lar drug product was effective and suitable for ANDAs, FDApublished in the Federal Register a DESI notice announcingthese conclusions. Subsequently, any manufacturer of a dupli-cate of the drug not already holding an approved NDA wasthen required to submit an ANDA to obtain approval tomarket the duplicate version of the approved drug within adefined period of time (2).

Approval of an ANDA was based on the proposition thatthe evidence of effectiveness necessary for approval of an NDAhad been provided by the brand-name company, reviewed, andaccepted during the DESI process. The evidence of safety of thedrug had been determined on the basis of information includedin the brand-name company NDA and through the subsequentpostmarketing experience with the drug. The informationrequired for an ANDA must demonstrate the generic drugapplicant’s ability to manufacture a product meeting appropri-ate standards of identity, strength, quality, and purity equiva-lent in both safety and effectiveness to the brand-name drugwhose safety and effectiveness was established during thecourse of the DESI review. The ANDA was required to containinformation on the generic drug product’s formulation, manu-facture, quality control procedures, testing, facilities, stability,dissolution profile (where applicable), and labeling. In addition,the DESI notice also identified other data and information thatFDA required in an ANDA for a specific drug product, typicallydata on the in vivo bioavailability of the proposed generic drugproduct comparing it to the brand-name drug product. Thecriteria used to establish bioequivalence was known as the‘‘75/75 rule,’’ where 75% of the subjects were required tohave concentrations in the plasma between 75 and 125%



when the proposed generic drug product was compared to thebrand-name drug product. The data required to be submit-ted, reviewed, and determined by FDA to support approvalof the ANDA was the same kind of chemistry, manufacturingand controls, labeling, and related product quality informa-tion required for a full NDA but did not include the reportsof investigations establishing the safety and effectiveness ofthe drug, which was already established through the DESIprogram.

For brand-name drug products approved by FDA after1962, however, FDA declined to establish an abbreviatedreview process. These drug products had not been subject tothe DESI review. As a condition of approval for brand-namedrug products introduced after 1962, companies were requiredto submit adequate and well-controlled studies to establishboth the safety and effectiveness of the drugs. There was nostatutory provision for an abbreviated process for generic ver-sions of brand-name drug products approved after 1962, andFDA therefore required a full NDA in order to approve ageneric version of a post-1962 brandname drug.

Just prior to the passage of the Drug Price Competitionand Patent Term Restoration Act (commonly referred to asthe Hatch-Waxman Amendments to the FD&C Act), theFederal Circuit issued a significant decision affecting patentinfringement (7). The court held that using a drug to performthe necessary tests for generic approval of a drug constitutedinfringement of the patent if that testing was performedprior to the expiration of the patent. This decision had theeffect of essentially extending the monopoly associated withdrug patents, since under the Bolar rule (7), generic companiescould not even begin testing a brand for the purposes of devel-oping a generic copy (for example, beginning formulationdevelopment or performing bioequivalence testing) until afterthe expiration of the patent. In the Hatch-Waxman Amend-ments, Congress explicitly overturned this decision andincluded an express legislative provision that it would not bean act of infringement to make, use, or sell any patented inven-tion solely to develop and submit applications for approvalof drugs.

104 Rosen


5. LITERATURE-SUPPORTED NDAs FORGENERIC VERSIONS OF POST-1962BRAND-NAME DRUGS

In the 1970s FDA recognized that requiring applicants to repeatcostly and time-consuming preclinical and clinical researchfor duplicate versions of certain brand-name drug products ini-tially approved after 1962 with long marketing histories andextensive published support in the literature was not an effi-cient use of scarce research resources. FDA established a ‘‘paperNDA’’ policy whereby a company could obtain approval of anNDA for these certain generic versions of brand-name drugsunder x505 based solely upon the existence of published scien-tific literature to provide safety and efficacy information in con-junction with bioequivalence data. Companies seeking approvalthrough the paper NDA route were required to review and eva-luate both preclinical and clinical literature to establish safetyand effectiveness. This information satisfied/met the full reportof investigation requirements of x505(b) of the FD&C Act.

FDA announced the paper NDA policy via a memorandumwithout following ‘‘notice-and-comment’’ rulemaking proce-dures. FDA claimed that it was just interpreting the NDA sub-mission and approval requirements of x505 of the FD&C Act.The paper NDA policy was later challenged in court on both sub-stantive and procedural grounds, and found to be lawful (8,9).

While the paper NDA process provided an alternativeroute to obtain approval for drug products, including dupli-cates of certain brand-name drugs first approved by FDA after1962, this approval route ultimately proved to be of limitedlong-term applicability and usefulness to the generic industrysince there was not enough published literature deemed byFDA to meet the statutory requirement of full reports ofadequate and well-controlled studies to establish safety andeffectiveness for the vast majority of post-1962 drug prod-ucts. In fact, only approximately 11 drug products approvedafter 1962 were deemed by FDA to satisfy the full reportrequirements for approval.

As a result of the limited applicability and utility of thepaper NDA process to be a viable mechanism for approval of



duplicate versions of brand-name drugs approved after 1962,Congress and FDA received significant pressure from the gen-eric industry and healthcare and patient advocates to establisha broader policy to authorize generic drug approvals forpost-1962 NDA-approved drug products to reduce drug costs.

In 1983 FDA began drafting proposed regulations to estab-lish an abbreviated new drug application review process for post-1962 generic drugs. FDA, however, delayed issuing proposedregulations. The National Association of Pharmaceutical Manu-facturers, representing generic drug manufacturers, then insti-tuted a lawsuit seeking declaratory judgment that FDA couldlawfully establish a post-1962 generic drug policy. Before thelawsuit was adjudicated, Congress enacted the Drug PriceCompetition and Patent Term Restoration Act of 1984, whichstatutorily established an abbreviated review process for post-1962 generic drug approvals under x505(b)(2) of the FD&C Act.

REFERENCES

1. Chief, Review Support Branch, Division of Generic Drugs,Office of Drug Standards, Bureau of Drugs, personal commu-nication.

2. 35 Fed Reg 11273, July 14, 1970.

3. United States v. Generix Drug Corp., 460 U.S. 453 (1983).

4. 33 Fed Reg 7758, May 28, 1968.

5. 34 Fed Reg 2673, February 27, 1969.

6. 35 Fed Reg 6574, April 24, 1970.

7. Roche Products, Inc. v. Bolar Pharmaceuticals Co., Inc., 733F.2d 858 (Fed. Cir.), cert. denied, 469 U.S. 856 (1984).

8. Burroughs Wellcome Co. v. Schweiker, 649 F. 2d 221 (4th Cir.1981).

9. Upjohn Mfg. Co. v. Schweiker, 681 F. 2d 480 (6th Cir. 1982).

10. Beers DO. Generic and Innovator Drugs: A Guide to FDAApproval Requirements, 5th ed.

106 Rosen


5

Generic Drug Approval Process,Post-1984: Hatch-Waxman Reform

MARC S. GROSS, S. PETER LUDWIG,KRISTIN BEHRENDT KOSINSKI,

and ATUL R. SINGH

Darby & Darby, P.C.

New York, New York, U.S.A.

1. OVERVIEW OF GENERIC DRUG APPROVALPROCESS UNDER HATCH-WAXMAN

The regulatory scheme for approval of generic drugs changedin April 1984 with the enactment of the Drug Price Competi-tion and Patent Term Restoration Act of 1984, commonlyknown as the Hatch-Waxman or Waxman-Hatch Act (1). TheAct was intended to balance the interests of consumers,the brand-name/(innovator) pharmaceutical industry, and thegeneric drug industry to ‘‘make available more low cost generic

107


drugs [and] to create a new incentive for increased expendi-tures for research and development of certain products whichare subject to pre-market approval’’ (2). In fewer than 20 yearssince enactment of the statute, generic drugs increased from19 to 47% of prescriptions filled for pharmaceuticals and evenin 1994 accounted for savings to consumers of $8–10 billion (3).

Breaking new ground, Title I of Hatch-Waxman author-ized the marketing of generic drugs upon approval of Abbre-viated New Drug Applications (ANDAs) (4). Under the Act, anANDA can be approved upon submission of evidence that theactive ingredient of the generic drug is the ‘‘bioequivalent’’ of adrug previously approved by the U.S. Food and Drug Adminis-tration (FDA) after submission of a full New Drug Application(NDA), without having to submit studies establishing the safetyand efficacy of the drug (5). Hatch-Waxman contains similarprovisions respecting ANDAs and so-called 505(b)(2) applica-tions, or paper NDAs, for which evidence of safety and efficacyof the drug must be submitted but can be based on third-partypublished data rather than full safety and efficacy testing (6).

Title II of Hatch-Waxman provided for specific extensionsof patents covering drugs (and other products) subject to‘‘regulatory review’’ by the FDA and other governmental agen-cies (7). This provision was intended to balance the benefitsof ANDA practice by providing brand-name drug companieswith the restoration of portions of the terms of their drugpatents lost during the testing period required for approvalof the drugs. Patent term adjustments under 35 U.S.C. x156(Section 156 extensions), as well as patent extensions imple-mented 10 years after enactment of Hatch-Waxman pursuantto the Uruguay Round of Negotiations under the GeneralAgreement on Tariffs and Trade (8), authorized extended drugpatent terms providing patent marketing exclusivities to inno-vator companies.

The Hatch-Waxman statutory scheme incorporates severalprovisions relating to the submission and approval of bothANDAs and 505(b)(2) applications subject to such patent andother marketing exclusivities for listed drugs granted to brand-name companies. Thus, the Act specifically provides that it isnot an act of patent infringement to use a patented invention

108 Gross et al.


‘‘solely for uses reasonably related to the development and sub-mission of information’’ for FDA or other governmentalapproval (9). On the other hand, Hatch-Waxman provides thatan applicant for an ANDA or a 505(b)(2) applicant must makean appropriate certification respecting marketing of the genericdrug vis-a-vis any patents for the same drug that are listedby the brand-name NDA holder in the FDA’s list of ApprovedDrug Products with Therapeutic Equivalence Evaluations(the Orange Book) (10).

Where the generic applicant certifies that there are nopatents listed in the Orange Book (Paragraph I Certification)or that any listed patents have previously expired (ParagraphII Certification), it may enter the marketplace immediatelyupon FDA approval. Where the applicant certifies that anylisted patent has not yet expired but will expire on a particulardate (Paragraph III Certification), the FDA may approve theANDA and make it effective as of the patent expiration date.

Where the applicant for generic approval intends to marketthe drug prior to expiration of any patent(s) listed in theOrange Book, it makes a certification that, in its opinion, thepatent(s) are not infringed or are invalid (Paragraph IV Certi-fication), and it notifies the NDA holder and patent owneraccordingly (11). In such instance the statute provides thatthe NDA holder/patent owner may then initiate a patentinfringement action against the applicant for generic approvaland the FDA must suspend approval of the ANDA or Section505(b)(2) application for up to 30 months (the ‘‘30-monthstay’’), subject to an earlier court determination, or the listedpatent(s) expire (12).

In an effort to encourage generic drug entry into the phar-maceutical market, the Hatch-Waxman Act provides a com-mercial incentive to those generic companies who are the firstto file ANDAs incorporating Paragraph IV Certificationschallenging infringement or validity of Orange Book–listedbrand-name pharmaceutical patents. Thus, in the event thelisted brand-name patent(s) are adjudged to be invalid or notinfringed prior to their normal expiration date(s), the firstgeneric filer entitled to approval of its ANDA receives a 180-dayexclusivity period, duringwhich no other ANDA can be approved

Generic Drug Approval Post-1984 109


for the same product (13). In such circumstances, the first entityto file an ANDA can be the only generic marketer for 180 days.

In addition, Hatch-Waxman incorporates several provi-sions limiting the filing or approval of ANDAs and 505(b)(2)applications in view of marketing ‘‘exclusivities’’ previouslyobtained by a brand-name NDA holder. Chief among such lim-itations is a 5-year bar on submitting an application for genericdrug approval following approval of an NDA on a ‘‘new chemi-cal entity’’ (NCE) (14) and a 3-year bar on obtaining approvalof a generic drug application following approval of an NDAbased on new clinical investigations respecting a previouslyapproved drug (15). The FDA approval scheme for ANDAscontaining Paragraph I, II, III, or IV Certifications is illus-trated in Figures 1 and 2 (16).

As of the preparation of the present text, substantialadministrative and statutory modifications have recently beenincorporated in the Hatch-Waxman regulatory scheme in an

Figure 1 ANDA patent certifications.

110 Gross et al.


effort to speed the approval and marketing of generic drugs.The principal change made is designed to limit brand-namecompanies to the opportunity to obtain a single 30-month stayof approval of ANDA or 505(b)(2) applications for the resolu-tion of patent infringement litigation respecting listed drugpatents. The recent changes are considered in detail below.

Accordingly, the discussion in this chapter includes ‘‘Appli-cations for FDA Approval to Market a New Drug: Patent

Figure 2 Paragraph IV certifications.



Submission and Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applica-tions Certifying That a Patent Claiming a Drug Is Invalidor Will Not Be Infringed,’’ effective as of August 18, 2003(the 2003 Rule Changes) (17). The FDA anticipated thatsome of the 2003 Rule Changes might be challenged; however,as of this writing they remain in effect in their published formsave for certain modifications required for consistency with thesubsequent statutory amendments noted below (18).

The following discussion also references the amendmentsto the Hatch-Waxman Act enacted as part of Title XI of theMedicare Prescription Drug Improvement, and ModernizationAct of 2003, signed into law by President Bush on December 8,2003 (the 2003 Statutory Changes) (19).

2. LISTING PATENTS IN THE ORANGE BOOK

2.1. Requirements

In 1984, Hatch-Waxman required for the first time, each NDAapplicant to identify any patent that claims the drug for whichthe NDA was submitted or a method of using such drug thatthe applicant believed could reasonably be asserted againstpotential generic infringers (20). The patent information mustbe submitted in or during the pendency of the NDA or, if apatent eligible for listing in the Orange Book is granted afterapproval of the NDA (or even after the filing of an ANDAseeking approval of a generic equivalent of the listed product),within 30 days after grant of the patent (21). Under Hatch-Waxman, the generic applicant must make a patent certifica-tion as to each such listed patent (22) and, if the patent is notlisted until after filing of the ANDA, amend its applicationaccordingly (23). On the other hand, if the brand-name com-pany fails to submit the patent information for listing in theOrange Book within the 30-day period after the grant ofthe patent, the generic applicant need not submit an amendedcertification and the patent owner may not initiate an infringe-ment suit under 35 U.S.C. x271(e)(2) (24).

112 Gross et al.


The patents for which information must be submitted inconnection with an NDA include those directed to the drugsubstance (active ingredient), the drug product (formulationor composition), and methods of use (indications) approvedfor the listed drug product (25). The patents thus submittedto FDA are listed by it in the Orange Book (26); these are theso-called listed patents or Orange Book patents.

Since enactment of Hatch-Waxman, brand-name compa-nies have submitted patents for listing in the Orange Bookdirected to a wide range of subject matter, including differentforms of the active drug substance, e.g., anhydrous or hydra-ted forms, salts, enantiomers or crystal forms of the active sub-stance, different formulations of the drug, metabolites formedin patients after administration of the drug, and methods ofuse of the drug whether or not previously approved by FDA(27). The listing of multiple patents in the Orange Book hascompelled ANDA and 505(b)(2) applicants to make multiplepatent certifications and, in some instances, has resulted inthe imposition of multiple 30-month stays of generic productapprovals, with consequent delays of generic entry into themarket.

Under present practice, FDA does not review the propri-ety of patents submitted by NDA holders for listing in theOrange Book on the ground that it ‘‘does not have the exper-tise to review patent information’’ (28). Rather, if the accuracyor relevance of patent information submitted for listing in theOrange Book is disputed by an ANDA or 505(b)(2) applicant, itmust notify FDA, and the agency will then ask the NDA holderto confirm the correctness of the patent information and, unlessthe NDA holder withdraws or amends its patent information,FDA ‘‘will not change the patent information in the . . . [OrangeBook]’’ (29). The agency’s failure to review patent listings inthe Orange Book for possible delisting has provoked substan-tial controversy and prompted proposals for reform.

The 2003 Rule Changes embodied FDA’s response to pre-vious criticisms of its procedures respecting patent listings.Under the new regulations, drug substances that contain thesame active ingredients as the subjects of NDAs but in differ-ent physical forms, i.e., polymorphs (30), must be submitted



for listing in the Orange Book. An NDA holder or patent ownermust, however, establish that a polymorph claimed in a patentwill ‘‘perform the same as the drug product described in theNDA with respect to such characteristics as dissolution, solu-bility, and bioavailability’’ (31) for listing. To establish such‘‘sameness’’ for a polymorph, the NDA holder or patent ownermust submit detailed test data in five different categories,utilizing forms specified in the 2003 Rule Changes (32).

Further in accordance with the 2003 Rule Changes, thelisting of product-by-process patents (33) is permitted, pro-vided, however, that to be submitted for listing ‘‘the product-by-process patent must claim the drug product that is thesubject of the NDA’’ and the drug product must be novel (34).

In addition, the 2003 Rule Changes prohibit the submis-sion for listing of patents that claim packaging, metabolites, orintermediates [in addition to the previous prohibition againstthe submission of process patents claiming methods of makingdrug substances (active ingredients)] (35). Packaging is dis-tinct from finished dosage forms for approved drug products,which must be submitted for listing (36). A metabolite is defi-ned by FDA as a ‘‘chemical compound that results after theactive ingredient of the drug has broken down inside the body’’;metabolites may not be submitted for listing since they are notthe active ingredients described in NDAs (34). Finally, inter-mediates, ‘‘materials that are produced during preparationof the active ingredient and are not present in the finisheddrug product,’’ may not be submitted for listing (34). FDAconsiders intermediates as ‘‘in-process materials,’’ as distin-guished from drug substances or components in a finisheddrug product (34).

2.2. Challenges to Listing

In several cases ANDA applicants have sought to compel FDAto delist patents improperly listed in the Orange Book. Thoseefforts have been without success, the Court of Appeals forthe Federal Circuit holding that delisting is a private right ofaction both barred by the FDCA and not a recognized defenseto a claim of patent infringement (37). While the Federal

114 Gross et al.


Circuit held out the possibility that a generic company mightsecure federal jurisdiction on some other basis (38) (e.g., byan action against the listing company in a counterclaim to apatent infringement suit), any attempt by a generic company toseek delisting would involve substantial additional delays,during which it would be barred from the market by reasonof the continued patent listing in the Orange Book.

In its 2003 Rule Changes, FDA declined to create anyadministrative procedures for challenging patent listings orfor delisting patents. Instead, it affirmed its long-standingview that it has only a ministerial role in overseeing OrangeBook listings (39). However, in an effort to ‘‘reduce confusionand help curb attempts to take advantage of this process [theHatch-Waxman administrative scheme]’’(40), the agency hasrestricted the types of patents and supporting evidence requi-red for listing (Sec. 2.1) and permitted NDA holders/patentowners one 30-month stay of approval of an ANDA filed afterOrange Book listings (Sec. 9.1.2).

In the 2003 Statutory Changes, no changes were made inthe types of patents that must be submitted for listing in theOrange Book; however, the amendments provide a remedy forimproper listings. Thus, in the event of the filing of a patentinfringement action based on an ANDA or 505(b)(2) application,the applicant may assert a counterclaim to correct or delete thepatent listing if the patent does not claim the approved drugor an approved method of use (41). The counterclaim may notinclude an award for damages. No such action for improperlisting may be brought in the absence of a patent infringementaction brought by the patent owner or NDA holder. Thisprovision is effective as to any proceeding under Section 505that was pending on or after December 8, 2003, regardlessof the date on which the proceeding was commenced (42).

3. ABBREVIATED NEW DRUG APPLICATIONS

3.1. The ‘‘Listed’’ Drug

Under Section 505( j) of Hatch-Waxman, an ANDA may befiled for a generic version of any ‘‘listed drug’’ (43). Any drug



for which an NDA has previously been approved is deemed tobe a listed drug and is listed by FDA in the Orange Book (44).Drugs previously approved under ANDAs are regarded as listeddrugs (45). Antibiotics are also regarded as listed drugs (46).

An ANDA must include all of the information requiredin an NDA except—significantly, full reports of investigationsdemonstrating that the drug is safe and effective in use. Addi-tionally, the ANDA must show (a) that the labeling of the drugfor which the ANDA is sought is the same as the approvedlabeling for the listed drug, (b) that the generic drug, itsroute of administration, dosage form, and strength are thesame as the listed drug or supply such information respectingany differences as the FDA may require, (c) that the genericdrug is bioequivalent to the listed drug, and (d) that informa-tion is supplied regarding the status of any Orange Book–listedpatents on the approved drug (47).

3.2. Establishing Equivalence to the Listed Drug

Initially, an ANDA filer must show that the conditions of useidentified in its proposed labeling have been previously appro-ved for the listed drug on which the ANDA is based (48).According to the statute, the ANDA must incorporate thesame labeling as that previously approved for the listed drug,except for any changes required because of differences appro-ved on the basis of a suitability petition (see orbecause the generic drug and the listed drug are ‘‘producedor distributed by different manufacturers’’ (49). Changes in

regulations include the listing of differences in expiration date,formulation, bioavailability, pharmacokinetics, or revisionsmade to comply with current FDA labeling guidelines (50).Consistent with the case law, the current regulation also speci-fically authorizes the ‘‘omission of an indication or other aspectof labeling protected by patent or accorded exclusivity undersection 505( j)(4)(D) of the act’’ (51). This provision, coupled

mechanism for avoiding infringement of listed method-of-usepatents for which generic applicants do not seek approval.

116 Gross et al.


with a Section (viii) Statement (see Sec. 7.1), has provided a

3.4)

the proposed labeling that may be approved under the FDA

Sec.

In addition to the labeling requirement, an ANDA appli-cant must establish, if the listed drug has only one active ingre-dient, that its new drug is the same as that of the listed drug(52) or, if the listed drug has more than one active ingredient,that its active ingredients are the same as those of the listeddrug or, if one of the active ingredients is different, that FDAhas approved a suitability petition for the new drug and thatthe different active ingredient is both an active ingredient of adifferent listed drug or of a drug that is not a ‘‘new drug’’within the meaning of Hatch-Waxman (53).

Finally, the ANDA must show that the new drug is ‘‘bio-equivalent’’ to the listed drug (54). As defined in the statute, ageneric drug is considered to be bioequivalent to a listed drugif (a) the rate and extent of absorption of the respective drugsdo not significantly differ from one another or (b) there is nosignificant difference in the extent of absorption of the respec-tive drugs and the rate of absorption of the respective drugs isintentional, reflected in the proposed labeling of the genericdrug, not essential to achieving effective concentrations, andis considered medically insignificant (55).

FDA may exercise discretion in determining whether theevidence submitted to show bioequivalence is adequate (56)and in a proper case may waive the requirement for proof ofbioequivalence (57).

3.3. Additional Requirements

Although FDA does not require safety testing data in supportof an ANDA, it may consider safety questions associated withthe identity or concentrations of the inactive ingredients of thegeneric drug. Thus, approval of an ANDA may be denied if theagency finds that the inactive ingredients are unsafe underthe conditions set forth in the proposed labeling for the drugor the composition of the drug is unsafe because of the type orquantity of the inactive ingredients in the composition (58).The regulations specify a number of changes in the inactiveingredients of a generic product on which the agency maypredicate a ‘‘reasonable basis to conclude that one or more ofthe inactive ingredients of the proposed drug or its composition



raises serious questions of safety’’ (59) and refuse approval.The FDA thus has considerable latitude in determiningwhether the identity or amounts of inactive ingredients in ageneric drug may adversely affect the safety of the drug.

3.4. Suitability Petitions for Drugs That Differfrom a Listed Drug

If a party wants to submit an ANDA for a new drug thatdiffers in specific respects from the listed drug to that theANDA refers, it may submit a suitability petition to FDA seek-ing permission to file such an application (60). Such petitionsmay be filed where the new drug has (a) a different activeingredient, (b) a different route of administration, (c) a differ-ent dosage form, or (d) a different strength from the listed drug(60). Any different active ingredient must be within the ‘‘samepharmacological or therapeutic class’’ as the active ingredientin the listed drug, and the modified drug must be expectedto have ‘‘the same therapeutic effect’’ as the listed drug (61).When the party filing a suitability petition seeks approval toincorporate a different active ingredient in a listed drug havingmore than one active ingredient, it must establish that theother active ingredients of the new drug are the same as theactive ingredients of the listed drug, that the different activeingredient is an active ingredient of a different listed drug, orthat the different active ingredient is an active ingredient ofa drug that is not a ‘‘new drug’’ under the FDCA (62).

Consistent with the statutory provisions, a suitability peti-tion should be granted unless FDA finds that investigationsmust be conducted to show the safety and efficacy of the modi-fied drug or of any of (i) its active ingredients, (ii) route ofadministration, (iii) dosage form, or (iv) strength, which differfrom the listed drug, or that the drug may not be adequatelyevaluated for approval as safe and effective on the basis of theinformation required in an ANDA (63).

The procedure for submitting a suitability petition is setforth in the FDA regulations (64). The petition must identifythe listed drug, incorporate a copy of the proposed labeling forthe generic product (as well as a copy of the approved labeling

118 Gross et al.


for the listed drug), and make the several specific showingsoutlined in the regulation. Under the statute, a suitability peti-tion must, in theory, be either approved or disapproved within90 days of the date the petition is submitted (65).

3.5. Removal of Orange Book Listing of a Drug

Hatch-Waxman specifies that listing of a drug in the OrangeBook will be terminated if its approval is withdrawn or suspen-ded or it is withdrawn from sale for safety or efficacy reasons(66). FDA will not approve an ANDA when the approval ofthe NDA for the reference-listed drug has been withdrawn orsuspended and the FDA has ‘‘published a notice of opportunityfor hearing to withdraw approval of the listed drug’’ or whenthe Secretary has determined that the listed drug has beenwithdrawn from sale for safety or efficacy reasons (67).

Withdrawal of approval of a listed drug may occur where,after due notice and opportunity for hearing, FDA finds thatthe drug is unsafe for use under the conditions for which it wasapproved, that there is a lack of substantial evidence that thedrug is effective under the conditions set forth in the productlabeling, or that the NDA contained any untrue statement ofmaterial fact (68). An ANDA holder may submit written com-ments on the notice of opportunity for hearing issued on theproposed withdrawal of the related listed drug, and, in theevent it is granted a hearing, the ANDA holder may participateas a nonparty participant (69). If the Secretary of Health andHuman Services finds that continued use of the drug presents‘‘an imminent hazard to the public health’’ (70) and the FDAenters a final decision withdrawing approval of the listed drug,any ANDA whose holder submitted such comments will bewithdrawn (71).

4. APPROVAL OF GENERIC DRUGS UNDERSECTION 505(b)(2)

This section of Hatch-Waxman provides for approval of certaindrugs for which full safety and efficacy investigations required



for NDAs under Section 505(b)(1) are not required. The appli-cations may apply to situations in which the applicant has notobtained a ‘‘right of reference or use’’ from the party for whichthe full safety and efficacy investigations were previouslyconducted (72).

FDA interprets the provisions of Section 505(b)(2) to sanc-tion reliance by a generic applicant on the safety and/or efficacydata submitted in a prior NDA for the related listed drug (73).Hence the ‘‘paper NDA’’ denomination, because the applicantrelies on laboratory and clinical data from a third party. As ofthis writing, a number of 505(b)(2) applications have been filedfor approval of salts differing from the NDA-approved salts ofthe same active ingredients, the generic applicants relying ondata previously submitted to FDA by the NDA holders (74).In one such instance, the NDA holder/patent owner unsuccess-fully challenged the foregoing FDA interpretation by CitizenPetition (75).

As noted below, 505(b)(2) applicants must make patentcertifications and comply with patent notice provisions analo-gous to those required for ANDA applicants (76). Because ofthe similar requirements, FDA may refuse to accept 505(b)(2)applications for drugs that are duplicates of listed drugs andare eligible for approval of ANDAs under Section 505( j) (77).

4.1. Reliance Upon Literature

Investigations relied upon by a 505(b)(2) applicant may includeboth studies that it owns and reports from studies owned bythird parties. Such studies may include both clinical and animalsafety and efficacy tests. FDA views all such tests submittedin a 505(b)(2) application as having been ‘‘relied upon’’ by the505(b)(2) applicant (78).

4.2. Variants of Listed Drugs

505(b)(2) applications are necessary for new generic drugs thatdiffer sufficiently from the prior listed drugs that suitabilitypetitions for filing ANDAs (Sec. 5.2.3) would not be approved.For example, this is the case where the listed drug has only oneactive ingredient (79). Accordingly, as indicated above, the filing

120 Gross et al.


of a 505(b)(2) application is appropriate where, for example,the generic drug for which approval is sought is a differentsalt from one that is the active ingredient of a listed drug (60).

5. FDA ACTION ON ANDAs AND 505(b)(2)APPLICATIONS

In general, an ANDA or 505(b)(2) application may not be sub-mitted within 5 years after the approval of an NDA for a NewChemical Entity (NCE), unless the application contains a Para-graph IV Certification (in which case the application may besubmitted on the fourth anniversary of the approval of theNDA) (80). FDA interprets the term ‘‘new chemical entity’’as set forth in this section of Hatch-Waxman as referring tothe ‘‘active moiety’’ of the previously approved NDA, i.e., themolecule or ion (excluding the groups that form an ester or saltor other noncovalent derivative of the molecule) that is respon-sible for the physiological or pharmacological action of the drug(81). An ANDA or 505(b)(2) application may, however, be filedafter the fourth anniversary of the NDA approval for an NCEwhere the application contains a Paragraph IV Certificationof noninfringement or invalidity of a listed patent relating tothe approved drug (82).

Under Hatch-Waxman, FDA must approve an ANDAunless it finds that the methods and facilities of the appli-cant are inadequate to assure the identity, strength, quality,and purity of the drug or the information submitted in theapplication is insufficient to meet the further statutory require-ments (83). On the other hand, since a 505(b)(2) application isbasically an NDA, it must meet each of the requirements foran NDA save that it may rely upon investigations of safety andefficacy that were not conducted by the applicant and for whichit has not obtained a right of reference (78).

The statute provides the agency must complete itsreview of the sufficiency of an ANDA or 505(b)(2) applicationwithin 180 days of initial receipt of the application (84). Duringthe review period FDA may either approve or disapprove the



application. If it disapproves the application, it must givethe applicant notice (a ‘‘not approvable letter’’) and provide itwith the opportunity to amend the application, withdraw it, orrequest a hearing to challenge the agency’s grounds for deny-ing approval (85). The opportunity to request a hearing isdesigned to provide the applicant with the opportunity to con-test the grounds asserted by the agency for denying approval ofthe application (86). Alternatively, if FDA approves the ANDAor 505(b)(2) application, the effective date of approval may bedelayed (14) on any of the various grounds indicated below.

6. PATENT CERTIFICATIONS

6.1. Types of Certifications

An applicant for an ANDA or a Section 505(b)(2) NDAmust certify to FDA that, in its opinion and to the best of itsknowledge, with respect to each listed patent that claims thedrug or a use of the drug for which the applicant is seekingapproval (22):

1. The patent information which the NDA holder isrequired to file (including the identification of anylisted patent) has not in fact been filed (a Paragraph ICertification),

2. The listed patent has expired (a Paragraph IICertification)

3. The listed patent will expire on some specified dateand the ANDA or 505(b)(2) applicant does not intendto commence marketing the drug for which it seeksapproval until after that date (a Paragraph IIICertification)

4. The listed patent is invalid or will not be infringed bythe manufacture, use, or sale of the drug for whichthe ANDA or 505(b)(2) application is submitted

The FDA regulations provide that Paragraph IV Certificationmay be based on unenforceability of the listed patent as well asnoninfringement or invalidity thereof (87).

122 Gross et al.


6.2. Content of Certifications

Paragraph I Certification simply permits the ANDA or 505(b)(2)applicant to inform FDA that the NDA holder has not listedany patents that might affect the agency’s approval of theapplication (88). Similarly, Paragraph II Certification servesto inform FDA that a previously listed Orange Book patenthas expired and would not have any effect on approval by theagency. In like manner, a Paragraph III Certification informsFDA when a listed patent will expire, thus providing notice tothe agency that the ANDA or 505(b)(2) application should not

Paragraph IV Certification, on the other hand, imposescertain obligations on (a) the ANDA or 505(b)(2) applicant,(b) the owner of the listed patent, and (c) FDA. The initialobligation is imposed on the applicant, who must include astatement in its application that it will provide notice of itsapplication and the basis for its position to the owner of eachlisted patent and the holder of the NDA for the listed drug orthe representatives thereof (89).

7. NOTICE TO PATENT OWNER ANDHOLDER OF NDA FOR LISTED DRUG

The notice required of the ANDA or 505(b)(2) applicantmust state that an application containing bioavailability or bio-equivalency data has been submitted to FDA to obtain approvalto engage in the commercial manufacture, use, or sale of thelisted drug before the expiration of the patent as to whichthe certification has been made (90). The notice must includea ‘‘detailed statement of the factual and legal basis of the app-licant’s opinion that the patent is not valid or will not beinfringed’’ (90).

FDA regulations provide that the notice of ‘‘factual andlegal basis’’ must set forth a detailed statement for each claimof the listed patent for which a Paragraph IV Certification issubmitted and provide a ‘‘full and detailed explanation of whythe claim is not infringed’’ and/or such an explanation of the



be approved prior to that date (see Fig. 2).

grounds supporting the allegation of invalidity (or, alternati-vely, unenforceability) of each such claim (91). The regulationsfurther require that the notice given by the ANDA applicantmust identify the ANDA number, the established name, if any,of the proposed drug product, the active ingredient, strengthand dosage form of the proposed drug product, and the patentnumber and expiration date of each of the listed patentsbelieved to be invalid, unenforceable, or not infringed (92).

Under the 2003 Rule Changes, a generic applicant whosubmits an amended or supplemental Paragraph IV Certifica-tion is not required to provide a notice of the factual and legalbasis for its certification to the listed patent owner or NDAholder (93). On the other hand, under the 2003 StatutoryChanges, when an amended or supplemental Paragraph IVCertification is made, the applicant must give the notice offactual and legal basis to the patent owner/NDA holder (90).The amendment to the Act essentially reverses the 2003 RuleChanges with respect to providing notice of an amended orsupplemental Paragraph IV Certification.

Under the 2003 Statutory Changes, when Paragraph IVCertification is in the ANDA or 505(b)(2) application, the noticemust be given no later than 20 days after the postmark date onthe notice from FDA of filing of the application (94). When thecertification is in an amendment or supplement to the genericapplication, the notice must be given at the same time as thesubmission of the amendment or supplement (95).

Assuming compliance with the procedural requirements,FDA presumes the notice to be effective upon receipt by thepatent owner and NDA holder and counts the day followingthe date of receipt as the first day of the 45-day period providedin Hatch-Waxman for possible commencement of infringementlitigation, as described below (96).

Brand-name companies have in some infringement actions(predicated on Paragraph IVCertifications) asserted that ANDAapplicants have not satisfied the requirement to provide suffi-cient notice of the factual and legal basis for asserting non-infringement or invalidity of listed patents and sought courtorders remedying allegedly deficient notices. To date, no suchorders have been issued (97).

124 Gross et al.


7.1. Section viii Statement of Listed Use PatentsThat Do Not Cover Indications for WhichApproval Is Sought

Hatch-Waxman provides that Paragraph IV Certifications neednot be made in ANDAs or 505(b)(2) applications with respectto Orange Book–listed use patents which do not claim a use forwhich the applicant seeks approval. In this instance, the sta-tute (and the FDA rules) provides that the applicant may filea statement that the use patent does not claim such a use (98).A Section viii Statement is significant since it may avoid thesubmission of a Paragraph IV Certification and thus precludethe patent owner from commencing an infringement suit andinvoking the 30-month stay of approval of the generic drug.

FDA has disclaimed any role in assessing whether a usepatent covers an indication for which an ANDA or 505(b)(2)applicant seeks approval (99). Moreover, it has taken the posi-tion that it must accept the representations by the NDA holderas to the scope of the use patent and, in a number of instances,held that Section viii Statements are improper and insteadrequired Paragraph IV Certifications (100). FDA’s approachhas been specifically endorsed by the courts (101). In anothercase, however, a trial court ordered FDA to accept an ANDAapplicant’s Section viii Statement in lieu of a Paragraph IVCertification (102). This court did not take issue with FDA’spolicy of ‘‘deference to NDA holders’ characterizations of thescope of use patents’’ but found on the facts of the specific casethat the patent owner had consistently distinguished the useclaimed in the method patent in question from the indicationfor which the ANDA applicant sought approval.

In order to refine its treatment of Section viii Statements,FDA, in its 2003 Rule Changes, modified the declaration requi-red of an NDA holder for listing of a method-of-use patent.It now requires that the declarant must ‘‘. . .describe eachindividual method of use [and identify the related patentclaim(s)] for which a patent is submitted for listing, andidentify the corresponding language found in the labeling ofthe approved NDA that corresponds to that method of use’’(103). By requiring greater particularity in the declaration,



FDA may take a more substantive role in evaluating the pro-priety of Paragraph IV Certifications vis-a-vis Section viiiStatements.

7.2. Amending ANDAs or 505(b)(2)Applications to Make Paragraph IV Certifications

When an ANDA or 505(b)(2) applicant amends its applicationto make a Paragraph IV Certification, the statute requires it tonotify the listed patent owner and NDA holder accordingly(90). Under previous regulations, this requirement is made ifthe generic applicant amends a Paragraph III Certification to aParagraph IV Certification or adds a Paragraph IV Certifica-tion when a patent is listed in the Orange Book during thependency of the application (104). A notice of the factual andlegal basis for the Paragraph IV Certification must be sent‘‘at the same time that the amendment . . . is submittedto FDA’’ (104). FDA regulations do not require ANDA or505(b)(2) applicants to amend their prior certifications if theNDA holder failed to provide the requisite patent informationwithin 30 days after patent issuance or if their applicationsoriginally contained appropriate patent certifications (105).

In accordance with the 2003 Rule Changes, an ANDAor 505(b)(2) applicant that amends its application to add aParagraph IV Certification is only required to provide noticeto the NDA holder and patent owner if (a) the application didnot already contain a Paragraph IV Certification; or (b) therewas not a full opportunity for the NDA holder to obtain a30-month stay (106). The FDA suggested that when the ANDAor 505(b)(2) applicant is not required to provide noticeof its subsequent Paragraph IV Certification(s) to the NDAholder and patent owner, multiple 30-month stays may beavoided (107).

However, as pointed out above, the 2003 StatutoryChanges still require notice of amended or supplemental Para-graph IV Certifications; the 2003 Act provides, however, foronly a single 30-month stay of FDA approval upon the initia-tion of an infringement suit based on a patent listed in theOrange Book prior to the filing as to which a Paragraph IV

126 Gross et al.


Certification was made in the ANDA or 505(b)(2) application—not the amendment or supplementation—of such application

8. SUBMISSION OF AN ANDA OR 505(b)(2)APPLICATION AS AN ACT OF PATENTINFRINGEMENT

As part of the effort to balance the rights of brand-name andgeneric pharmaceutical manufacturers, the Hatch-WaxmanAct provided that the development of information by or forgeneric drug companies for the purpose of preparing ANDAsor 505(b)(2) applications does not constitute patent infringe-ment. Thus, Hatch-Waxman amended the patent statute toprovide that ‘‘[i]t shall not be an act of infringement to make,use, offer to sell, or sell . . . a patented invention . . . solely for usesreasonably related to the development and submission of infor-mation under a Federal law which regulates the manufacture,use, or sale of drugs’’ (108).

On the other hand, Hatch-Waxman provided that the sub-mission of an ANDA or 505(b)(2) application asserting non-infringement or invalidity of a listed patent (requiring aParagraph IV Certification) may be treated as (what theSupreme Court has characterized as) an ‘‘artificial act ofinfringement’’ (109). Thus, the patent statute was amendedto specify that ‘‘[i]t shall be an act of infringement tosubmit . . . [an ANDA or 505(b)(2) application] . . . if the purposeof such submission is to obtain [FDA] approval . . . to engage inthe commercial manufacture, use, or sale of a drug . . . claimedin a patent before the expiration of such patent’’ (110).

Hatch-Waxman provides that a patent owner has 45 daysafter receiving notice of a Paragraph IV Certification tosue the ANDA (or 505(b)(2)) applicant for infringement (12).The applicant is required to notify FDA ‘‘immediately’’ uponthe filing of suit within the 45-day period (111). If the pat-entee does not file an infringement action within the 45-dayperiod, FDA may immediately approve the ANDA or 505(b)(2)



(112) (see Sec. 9.1.2).

application; if, on the other hand, the patent owner initiatessuit, FDA cannot approve the application until the expirationof the 30-month stay for resolution of the litigation, as morefully set forth below (12).

Accordingly, upon receipt of notice of Paragraph IVCertifications, brand-name pharmaceutical companies havefrequently sued ANDA and 505(b)(2) applicants during the45-day notice period to forestall generic competition inthe marketplace for the 30-month period(s) sanctioned byHatch-Waxman (112).

8.1. Scope of Infringement Actions CommencedUnder 35 U.S.C. x271(e)(2)

The artificial act of infringement under 35 U.S.C. x271(e)(2) islimited to the assertion of infringement based on Paragraph IVCertifications (12). In turn, Paragraph IV Certifications aredirected to Orange Book–listed patents which claim the refer-enced listed drugs or uses for the listed drugs for which theapplicant seeks approval. Thus, the statute cannot be reliedupon as a basis for jurisdiction of infringement actions pre-dicated on patents directed to methods of manufacture oflisted drugs. Nor is it an act of infringement under x271(e)(2)to submit an ANDA for approval to market a listed drugfor a different indication from one covered in a listed usepatent (113).

NDA holders/patent owners are authorized to list patentsin the Orange Book that they believe ‘‘could reasonably beasserted . . . [against an unlicensed party] engaged in the man-ufacture, use or sale of the drug . . .’’ (20). In the past, ANDA or505(b)(2) applicants could not seek patent delisting in infringe-ment suits based on Orange Book–listed patents (114).A number of antitrust suits were, however, commenced predi-cated on the mala fides of Orange Book listings (115).Moreover, as indicated in Sec. 2.2, under the 2003 StatutoryChanges an ANDA or 505(b)(2) filer sued on the basis ofa Paragraph IV Certification may file a counterclaim seekingan order requiring the NDA holder to correct or delete thelisting (41).

128 Gross et al.


8.2. Right of ANDA or 505(b)(2) Applicantsto Seek Declaratory Judgments

Hatch-Waxman precludes an ANDA or 505(b)(2) applicant frominitiating a declaratory judgment action for noninfringement orinvalidity of a listed patent within the 45-day period after receiptof its notice of the factual and legal basis for its Paragraph IVCertification (116). This provision facilitates initial commence-ment of a patent infringement suit and the consequent30-month stay in accordance with the statutory scheme.

On the other hand, it has been held that an ANDA or 505(b)(2) applicantmay seek a declaratory judgment during the 45-dayperiod on other grounds or file a counterclaim in the infringe-ment suit for a declaratory judgment that it is not infringingother, unlisted patents (117). In either instance, it need only beshown that there is an actual controversy between the parties.

The 2003 Statutory Changes further sanction the com-mencement of an action for declaratory judgment of nonin-fringement of a patent for which a Paragraph IV Certificationhas been made, provided that: (a) the NDA holder or, patentowner did not file an infringement suit within 45 days afterreceiving notice of such certification (118) and (b) in any casein which the notice from the ANDA or 505(b)(2) applicantasserts noninfringement, the notice is accompanied by a docu-ment offering confidential access to the ANDA or 505(b)(2)application for the sole purpose of determining whether aninfringement action should be brought (119). The documentoffering confidential access must contain such restrictions asto persons entitled to access and the use and disposition of anyinformation accessed as would apply had a protective orderbeen entered to protect trade secrets and confidential businessinformation. A request for access under an offer of confidentialaccess is considered an acceptance of the terms and restrictionsin the offer and creates an enforceable contract. Any ANDA or505(b)(2) application to which confidential access is providedmay be redacted by the applicant to remove information notrelevant to any issue of patent infringement. Any actionfor declaratory judgment brought subject to the foregoingprovisions must meet the case or controversy requirements of



28 U.S.C. 2201 (120) and can only be commenced in the judicialdistrict in which the defendant has its principal place of busi-ness or a regular and established place of business (121).

The propriety of such declaratory judgment actions maywell be the basis for future litigation. As stated in an ‘‘expla-natory statement’’ in the conference committee report preced-ing enactment of the 2003 Statutory Changes, it was intendedthat the courts apply the ‘‘reasonable apprehensions’’ test fordetermining whether a suit presents a ‘‘case or controversy’’supporting jurisdiction in a manner that provides genericdrug manufacturers appropriate access to declaratory judg-ment relief to the extent required by Article III of theConstitution (122).

9. DELAYS IN THE APPROVAL OF ANDAsAND 505(b)(2) APPLICATIONS

9.1. Patent-Related Delays

9.1.1. Delays Attributable to Patent TermExtensions

Delays in approval of ANDAs or 505(b)(2) applications may beprolonged because of extensions of the listed patents on whichParagraph IV Certifications must be made. Such extensionsmay be obtained because of patent term adjustments under35 U.S.C. x156 or because of the 20-year term provisions underthe URAA.

Section 156 Term Adjustments

To be eligible for a term adjustment under Section 156:

1. A patent relating to a drug product must be in forcewhen the application for term adjustment is filed inthe U.S. Patent and Trademark Office (123)

2. The term of the patent must not have been pre-viously extended (124)

3. An application for the adjustment must be filed bythe patent owner or its agent and must meet certainformal requirements (125)

130 Gross et al.


4. The drug product covered by the patent must havebeen subject to an FDA review period before its com-mercial marketing or use (126)

5. The FDA approval for commercial marketing or useafter such review period must be the first commercialmarketing or use of the drug product (127)

The scope of any drug product patent extended underSection 156 shall, during the extension period, be limitedto any ‘‘use approved for the product’’ (a) under the FDAlaw (128) (b) on or after the expiration of the review periodon which the extension was based (129).

The period of term extension may not exceed 5 years (130),but may be shorter depending upon the delay in obtainingregulatory approval as determined by a specific calculation(131). Under this provision, the period of the extension isreduced by any delays in the regulatory review procedure attri-butable to the NDA applicant (132). In any case, the patentterm may not be extended for more than 14 years after the dateof approval of the NDA for the drug product (133).

The scope of a patent claiming a drug product is limitedduring the period of term extension to any FDA-approveduse(s) (134). One court held that, during the extensionperiod, a patent is also limited to the specific approved formof an approved drug, e.g., to the approved salt, notwithstandinggeneric product claims (that embraced other active agentseffective for the same use as the approved product) incorpo-rated in the extended patent (135). On appeal, however, theFederal Circuit held that, during the extension period, the gen-eric product claims were not so limited (136).

URAA Extensions

The URAA conformed U.S. patent law with foreign law byproviding that the term of a U.S. patent issued on or after June8, 1995, extends 20 years from its effective filing date, ratherthan 17 years from its issue date. Thus, a patent issuing afterJune 8, 1995, claiming an effective U.S. filing date less than3 years before its issue date is entitled to a term of 20 yearsfrom the effective filing date. On the other hand, a patentissued on an application filed after June 8, 1995, but claiming



an effective filing date more than 3 years before its issue date isentitled to the 20-year term from the effective filing date (andwill thus be in force less than the historical 17-year patentterm from the issue date) (137). Accordingly, the effect of aprior listed patent on an ANDA or 505(b)(2) application maydepend on its term under the URAA provisions.

9.1.2. The 30-Month Stay

cant certifies that patent information on a listed drug has notbeen submitted to FDA (a Paragraph I Certification) or thatthe patent or patents claiming the listed drug or the use of thedrug for which the applicant seeks approval have previouslyexpired (a Paragraph II Certification), FDA may approvethe application immediately (138). On the other hand, whenan ANDA or 505(b)(2) applicant certifies that the patent orpatents listed in the Orange Book for the listed drug willexpire on a specified future date (a Paragraph III Certifica-tion), the approval will be made effective as of that date(139). Last but not least, when an ANDA or 505(b)(2) applicantcertifies that the patent or patents listed in the Orange Bookrespecting the drug would not be infringed by the proposedgeneric drug product or that the patent or patents are invalidor unenforceable, the FDA will, if an infringement action iscommenced by the patent owner or NDA holder within the45-day notice period, defer approval for the 30-month stayperiod, as discussed below (12).

By delaying approval of an ANDA or 505(b)(2) applicationunder which a generic applicant seeks to enter the marketprior to expiration of a listed patent or patents, the stay provi-sion protects the brand-name company’s exclusive market pend-ing completion of the infringement litigation. At the same time,the 30-month stay enables the generic applicant to obtaina judicial determination of infringement and validity of anylisted patents without incurring the liability it might otherwiserisk were it marketing the generic drug and facing a possibleaward of damages based on the patent owner’s lost profits.(As a general matter, this potential liability could be more

132 Gross et al.


As illustrated in Figure 1, when an ANDA or a 505(b)(2) appli-

than the generic company’s total revenue from the sales of itsdrug, in view of the typical differences in the prices and profitsof brand-name and generic products.)

The ‘‘30-month stay’’ is in fact somewhat of a misnomer.Hatch-Waxman provides that if an infringement action is initia-ted during the 45-day notice period, approval of an ANDA or505(b)(2) application is delayed until the earlier of expirationof the 30-month period, or the date of a district court decisionholding the patent(s) invalid or not infringed (12). Alternatively,the 30-month stay may be modified if before the expiration ofthat period the court hearing the infringement action deter-mines that the patent is valid and infringed, grants a prelimin-ary injunction, or determines that one of the parties has notreasonably cooperated in expediting the action (140).

Prior to the effective date of the 2003 Rule Changes andenactment of the 2003 Statutory Changes, the generic filer wasrequired to submit a Paragraph IV Certification as to eachlater-issued patent listed in the Orange Book subsequent tothe filing of its application, subject to certain conditions(104). When the generic applicant submitted a Paragraph IVCertification as to the newly listed patent(s), upon commen-cing an infringement suit within the requisite period thebrand-name company could obtain a new 30-month delay ofFDA approval (141). Nor was it necessary for the multiple30-month stays to run consecutively; it was possible for gapsto exist between sequential stays (142).

The grant of multiple 30-month stays of generic entry andconsequent abuse of the Hatch-Waxman regulatory scheme,coupled with continuing dramatic increases in prescriptiondrug costs (143), led to several proposals for change. Thus,an FTC study in 2001–2002 culminated in the July 2, 2002,report (3) which made the following principal recommendation:‘‘Permit only one automatic 30-month stay per drug prod-uct per ANDA to resolve infringement disputes over patentslisted in the Orange Book prior to the filing date of the genericapplicant’s ANDA’’ (144).

On July 31, 2002, the U.S. Senate passed the McCain-Schumer Bill (145), which proposed, among other changes,eliminating the automatic 30-month stay of approval of ANDAs



or 505(b)(2) applications after suit by a brand-name companybased on a Paragraph IV Certification and, subject to otherqualifications, restricting such stay to patents listed within30 days after approval of the NDAs.

On October 21, 2002, the White House announced presi-dential action to ‘‘lower prescription drug prices by improvingaccess to generic drugs’’ (146). President Bush referred to pro-posed regulatory action by FDA to implement the prior FTCrecommendations, among other things, to allow one 30-monthautomatic stay based on infringement suits involving ANDAs.During the same week, FDA issued a detailed memorandumoutlining its proposed rule making (147). Specifically, it pro-posed that an ANDA or 505(b)(2) applicant would not have toprovide a notice of invalidity or non-infringement of a patentwhen the ANDA or 505(b)(2) application already containeda Paragraph IV Certification as to another patent, and thepatent owner would thus only be entitled to a single30-month stay for the resolution of infringement litigationbased on the previous Paragraph IV Certification.

As discussed above (Section 7.2), in accordance with the2003 Rule Changes an NDA holder/patent owner could notobtain multiple 30-month stays provided it had one ‘‘full oppor-tunity’’ to obtain a single 30-month stay after receiving noticefrom an ANDA or 505(b)(2) applicant of its Paragraph IVCertification. The one ‘‘full opportunity’’ proviso was inten-ded to preclude avoidance of the 30-month stay provision byan ANDA or 505(b)(2) filer who (a) makes a Paragraph IVCertification but withdraws its application or changes to aParagraph III Certification after giving notice but before the45 days for filing an infringement action expires and before suitis filed or (b) makes a Paragraph IV Certification but changesits certification after it has been sued and the 30-month stayhas commenced.

On the other hand, the ‘‘full opportunity’’ provision wouldhave precluded a second 30-month stay where an ANDA or505(b)(2) applicant changed its Paragraph IV Certification toa Paragraph III Certification after an infringement suit wasfiled and the 30-month stay had commenced (e.g., following a

134 Gross et al.


court order finding infringement) and thereafter amended itsapplication to add a new Paragraph IV Certification (148).

The 2003 Statutory Changes have simplified and furtherrestricted the grant of the 30-month stay. Thus, the staymay now only be obtained with respect to patents listed inthe Orange Book prior to the filing of the ANDA or 505(b)(2)application; no 30-month stay will be triggered as to anypatents listed after the filing date of the ANDA or 505(b)(2)application (12).

9.1.3. 180-Day Marketing Exclusivity for ANDAs

Hatch-Waxman provides a specific incentive to generic drugcompanies to file ANDAs seeking approval to market genericforms of listed drugs prior to expiration of brand-name compa-nies’ patents for such drugs, namely the right to 180 days ofmarketing exclusivity vis-a-vis later ANDA filers (13). There isno comparable exclusivity accorded a 505(b)(2) applicant whomay successfully challenge the validity or infringement of anasserted listed patent. Interpretation of the 180-day exclusivityprovision has led to considerable controversy (and changes inagency positions), as discussed below.

9.1.4. Separate Exclusivity Periods for DifferentDosage Forms and Different Listed Patents

Before the 2003 Statutory Changes, the Hatch-Waxman Actdid not specify whether separate 180-day exclusivities wouldbe accorded to independent ANDA applicants who may firstmake Paragraph IV Certifications for different dosage formsof the same listed drug or to those independent Paragraph IVfilers who may be the first to certify as to different listedpatents for the same listed drug (149). The FDA thus fashionedindividual regulatory policies as to each of these situations.

Initially, the agency awarded separate 180-day exclusivityperiods to different ANDA filers based upon the priority of theirParagraph IV Certifications respecting different strengths ofthe same listed drug. That policy was challenged and upheldas a reasonable exercise of the agency’s discretion under theAdministrative Procedures Act (APA) (150).



Similarly, neither the statute nor the FDA regulationsspecifically provided for single or multiple exclusivities basedupon priority of Paragraph IV Certifications as to multiplelisted patents relating to a single drug. In one case the agencyinterpreted its regulations to warrant separate exclusivityawards to two different generic applicants based on the priorityof their Paragraph IV Certifications respecting two differentlisted patents (151). In a subsequent proceeding involving 12listed patents, the FDA decided that the award of independentexclusivity periods to either of two Paragraph IV filers wouldresult in a blocking situation where neither party could begiven approval until the other party’s exclusivity as to certainpatents had run. The agency decided that any 180-day exclu-sivity award would be shared between the two applicants (152).In yet another more recent case, FDA refused to provide anyshared exclusivity where there was no possibility of blockingexclusivities (153).

The 2003 Statutory Changes eliminate the possibilityof independent exclusivity periods for different generic appli-cants, different dosage forms of the listed drug, or differentlisted patents. Only one 180-day exclusivity period may beobtained for a listed drug, and that period is based on patentsfor which a Paragraph IV Certification is first made by anygeneric applicant (13). Under the amendments to the statute,multiple ‘‘first applicants’’ who submit substantially completeANDAs with Paragraph IV Certifications on the same day andsubsequently obtain approval of their applications are eligiblefor 180-day exclusivity (154). These ‘‘first applicants’’ obtainshared exclusivity during the one 180-day exclusivity period.

9.1.5. Commercial Marketing of the GenericDrug by a First Applicant Triggers180-Day Exclusivity

Prior to enactment of the 2003 Statutory Changes, Hatch-Waxman provided that the 180-day exclusivity provision wouldbe triggered, inter alia, on the date the FDA received notice ofthe first commercial marketing by any first ANDA applicant(155). This could occur (a) in the relatively rare instance in

136 Gross et al.


which an ANDA applicant commenced marketing after the 30-month stay and prior to a court decision in an infringementaction predicated on its filing (156), (b) where the owner ofthe listed patent had not sued for infringement, or (c) wherethe ANDA applicant had agreed not to market the listed drugpursuant to a settlement of infringement litigation. In one caserelating to the last-mentioned situation, FDA had interpretedthe statutory reference to ‘‘commercial marketing of the drugunder the previous application’’ as embracing marketingby the ANDA applicant under license from the NDA holderafter settlement of its litigation. Since more than 180 dayshad passed after commencement of such use, the agency con-cluded that the 180-day period had run and that other genericmanufacturers could commence marketing. Upon attackunder the Administrative Procedures Act, the court heldthat FDA’s interpretation of the statutory language was rea-sonable and denied a preliminary injunction to the first filer(157).

Under the 2003 Statutory Changes, the 180-day exclusiv-ity period is only triggered by commercial marketing of thelisted drug by any first ANDA applicant(s) (158). As pointedout in Section 9.1.6, the decision of a court (on either thedistrict court or appellate court level) does not directly triggerthe 180-day exclusivity period, but may be the precursor ofa ‘‘forfeiture event’’ for which the exclusivity period may beforfeited by the first applicant.

9.1.6. The Effect of a ‘‘Court Decision’’ onApproval of an ANDA and Triggeringof 180-Day Exclusivity

Prior to enactment of the 2003 Statutory Changes, the 180-dayexclusivity could be effective, inter alia, on the ‘‘date of a deci-sion of a court’’ in an infringement action based a ParagraphIV Certification (159). FDA initially interpreted the date of thecourt decision as the date on which ‘‘the court . . . enters finaljudgment from which no appeal can be or has been taken’’(160). Subsequently, in response to a number of adverse courtdecisions the agency amended its rules to provide that with



respect to ANDAs containing Paragraph IV Certifications filedafter March 2000, a decision of a trial court would trigger the180-day exclusivity (161). In later litigation in which a trialcourt held a patent invalid and the patent owner and genericapplicant had subsequently entered into a settlement agree-ment, it was held that the 180-day exclusivity period wastriggered by the trial court decision (162).

In yet another case, a court held that the 180-day exclu-sivity period would commence as of the date of a decisiondismissing a declaratory judgment action for lack of subjectmatter jurisdiction where the plaintiff generic company lackedreasonable apprehension of a patent infringement suit (163).Such holding was inconsistent with a previously proposedFDA rule and caused the agency to withdraw the prior regula-tion (164). In its subsequently published notice FDA wasconstrained to indicate that it would continue ‘‘to make180-day exclusivity decisions on an issue-by-issue basis . . .[and] will also carefully evaluate possible options for futurerule making addressing 180-day exclusivity and the timing ofANDA approvals’’ (165).

Under the 2003 Statutory Changes, approval of an ANDAor 505(b)(2) application may be made effective on the date onwhich a district court enters a judgment holding the listedpatent invalid or not infringed, permitting (but not requiring)subsequent commercial marketing and based thereon,commencement of the 180-day exclusivity period (166).

9.1.7. The First ANDA Applicant(s) Makinga Paragraph IV Certification isAwarded Exclusivity

Prior to enactment of the 2003 Statutory Changes, FDA regar-ded only the first applicant making a Paragraph IV Certifica-tion to be entitled to the 180-day exclusivity. In the event of anadverse decision in an infringement suit against the ParagraphIV applicant, FDA regulations provide that it must amend itscertification to a Paragraph III Certification indicating thatit will not seek approval to market the generic product until

138 Gross et al.


the expiration of the listed patent (167). In its subsequentlywithdrawn August 1999 proposed rule, FDA had proposedthat only the first Paragraph IV filer could be eligible forthe 180-day exclusivity and would lose such award if it amen-ded its certification to a Paragraph III certification for anyreason (168).

In one case in which the first filer amended its certifica-tion to a Paragraph III Certification after settlement with thepatent holder, FDA asserted that the first filer retained itsexclusivity, but the court found this ‘‘‘best of all worlds’’’ inter-pretation in favor of the first filer to be ‘‘inconsistent with [the]purpose of Hatch-Waxman’’ and that the first filer’s 180-dayexclusivity period had already run (169). In a subsequentcase the first Paragraph IV filer settled its litigation with thepatent holder, but did not amend its certification to a Para-graph III Certification. FDA concluded it should treat theParagraph IV Certification as though it had been changed toa Paragraph III Certification, but the court disagreed, findingsuch construction unreasonable under the Administrative Pro-cedures Act. The court did not reach the rights of the later filerbecause it found that the exclusivity period had run after thefirst filer had settled with the patent owner and commencedcommercial marketing under the NDA.

In a further example of a disputed interpretation of the180-day exclusivity provisions, the FDA initially concludedthat exclusivity could only be awarded to a Paragraph IVfiler that had successfully prevailed in its litigation with thepatent owner (170). Following multiple adverse court decisions,the agency issued a Guidance indicating that it would no longerenforce this ‘‘successful defense’’ requirement (171) and there-after issued an interim rule removing the requirement (172).Further, it has been held that the first Paragraph IV filermay obtain exclusivity even when it is not sued based on thecertification (173).

Under the 2003 Statutory Changes, the amendment by afirst applicant of the Paragraph IV Certification for all of thepatents for which it has submitted such a certification is aforfeiture event for which the first applicant will forfeit its180-day exclusivity period (174).



9.1.8. Transfer or Waiver of Exclusivity

Prior to the 2003 Statutory Changes, the Hatch-Waxman Actdid not provide that the 180-day exclusivity may be transferredfrom one Paragraph IV filer to another or waived in favor ofa subsequent filer. Nevertheless, the FDA permitted transferor waiver in particular, complex factual contexts. Thus, theagency permitted a first Paragraph IV filer to waive its market-ing exclusivity in favor of a subsequent filer where the exclu-sivity period had commenced and the first filer had not yetobtained agency approval and thus could not obtain the benefitof exclusivity (175).

More recently, FDA interpreted the statute to permitsharing the potential 180-day exclusivity where two ParagraphIV filers had differing priorities with respect to the multiplelisted patents asserted by the prior NDA holder/patent owner(176). Subsequently, when the trial court held that the sharingapplicants infringed various of the listed patents, the FDApermitted waiver of the exclusivity in favor of a third filerwhose generic product was held not to infringe the patents inquestion (177).

As indicated above, the 2003 Statutory Changes expresslyprovide that 180-day exclusivity may be forfeited based uponany of a number of distinct ‘‘forfeiture event(s)’’ and that in theevent of such forfeiture no subsequent filer will be eligible for a180-day exclusivity period (178).

9.1.9. Forfeiture of Exclusivity

The events defined in the 2003 Statutory Changes for whichthe first applicant may forfeit the 180-day exclusivity periodinclude:

1. The later of (a) its failure to market the drug 75 daysafter approval of its application or 30 months afterfiling of the application whichever is earlier or (b) asto the first applicant or any other applicant thathas received tentative approval of its application, atleast one of the following has occurred: (i) 75 daysafter a final decision or order in an infringement or

140 Gross et al.


declaratory judgment action holding the patentinvalid or not infringed, (ii) a court has signed asettlement order or consent decree entering a finaljudgment that the patent is invalid or not infringed,or (iii) the patent has been withdrawn from listingby the NDA holder (179).

2. Its withdrawal of the application, or if the FDA con-siders the application to have been withdrawn asa result of an administrative determination thatthe application did not meet the requirements forapproval (180).

3. It amends or withdraws its Paragraph IV Certifi-cation (181).

4. It fails to obtain tentative approval of its applicationwithin 30 months after filing (182).

5. It enters into an agreement with another ANDA app-licant, the NDA holder, or the patent owner, whichhas been held in a final decision in an action broughtby the Federal Trade Commission or Attorney Generalto violate the antitrust laws (183).

6. All of the patents as to which the ANDA filer hadfiled a Paragraph IV Certification have expired (184).

As provided in, event 1, forfeiture of the 180-day exclusiv-ity period cannot be promised on the failure of the first appli-cant to market the drug within the 75-day period after itseffective approval date or after 30 months of its applicationdate unless there has previously been, inter alia, so a finaldecision that the patent is invalid or not infringed.

As noted above, in the event of any such forfeiture, nosubsequent ANDA filer will be eligible for the 180-day exclu-sivity (177).

9.2. Delays in ANDA or 505(b)(2) ApprovalsBased on Other Marketing Exclusivities

Hatch-Waxman contains several other exclusivity provisionsthat delay approval of ANDAs and 505(b)(2) applications. Ofprincipal interest is the 5-year marketing exclusivity for newchemical entities (NCEs) (14), the 3-year marketing exclusivity



for new or supplemental NDAs supported by new clinicalinvestigations (15), and the 6-month exclusivity for pediatricstudies.

With the exception of the pediatric exclusivity provisions,each of these marketing exclusivities was added to Hatch-Waxman in 1984 in last-minute negotiations with a group ofbrand-name drug companies that objected to the terms origin-ally negotiated prior to enactment of the legislation. Theseprovisions were thus added to provide additional protectionfor the brand-name companies in the form of additional delaysin the approval of generic drugs.

9.2.1. Five-Year Exclusivity for NewChemical Entities

The 5-year NCE exclusivity applies to drugs that do not con-tain any active ingredient, including any ester or salt thereof,which has been approved in any prior NDA after the 1984enactment of Hatch-Waxman.

The NCE exclusivity differs from the other marketingexclusivities in that it prohibits the submission of an ANDAor 505(b)(2) application—not merely its approval—prior toexpiration of the exclusivity period (14). In view of the periodrequired to obtain approval of the ANDA or 505(b)(2) applica-tion, this provision effectively extends NCE exclusivity beyond5 years.

Moreover, an ANDA or 505(b)(2) application incorporat-ing a Paragraph IV Certification may be submitted 4 years afterapproval of an NDA entitled to NCE exclusivity. However,if an infringement action is commenced within the fifth yearof the NCE exclusivity, the statute provides that the 30-monthstay pending the patent infringement proceeding will be exten-ded, if necessary, so that the period after approval of the appli-cation entitled to NCE exclusivity totals 712 years, equal to thesum of the 5-year marketing exclusivity plus the 30-month stay(14). Thus, an ANDA or 505(b)(2) application incorporating aParagraph IV Certification may be filed within the fifth year ofan NCE marketing exclusivity, but may not be approved until712 years after the grant of the application entitled to NCE

142 Gross et al.


exclusivity if the brand-name patent holder initiates an infrin-gement suit as discussed above.

9.2.2. Three-Year Exclusivities for NDAsor Supplemental NDAs Based onNew Clinical Investigations

The 3-year exclusivity provisions prohibit approval—not sub-mission—of an ANDA or a 505(b)(2) application for 3 yearsafter approval of an NDA or supplemental NDA approvedon the basis of ‘‘reports of new clinical investigations (otherthan bioavailability studies) essential to the approval . . . andconducted or sponsored by the person submitting the NDA orsupplemental NDA (15).

9.2.3. Pediatric Exclusivity

In 1997, and again in 2002, the FDCA was amended to providea new form of exclusivity, a 6-month period for conductingpediatric studies of listed drugs (185). The pediatric exclusivitydelays the approval of ANDAs and 505(b)(2) applications for anadditional 6 months after expiration of any pertinent listedpatents and extends the 5-year and 3-year marketing exclu-sivities for 6 months (186). The pediatric exclusivity was origi-nally effective as to NDAs filed before January 1, 2002, and asof this writing has been extended to NDAs submitted prior toOctober 1, 2007 (187).

Pediatric exclusivity applies both to previously approveddrugs and drugs that are the subject of pending NDAs. Theprocedures for obtaining pediatric exclusivity are describedelsewhere in this text.

If a 6 month pediatric exclusivity has been accorded a parti-cular drug, an additional 6 month exclusivity may be added tothe 3-year exclusivity for a supplemental NDA (188). A second6-month pediatric exclusivity may not, however, further delayANDA approvals subject to patent certifications (189).

The 2002 amendment to the pediatric exclusivity provi-sions further specifies that the omission of any approved pedia-tric indication from the labeling for an ANDA will not furtherdelay approval of the generic drug (190).



10. WITHDRAWAL OF APPROVALOF AN ANDA

As indicated in Section 3.5, the FDA may withdraw or suspendapproval of an ANDA when the approval of the listed drug onwhich the ANDA relies is either withdrawn or suspended.Further, approval of an ANDA or a 505(b)(2) application maybe withdrawn on the basis of evidence showing that the drug isunsafe for use or ineffective or that the ANDA or 505(b)(2)application contains any untrue statement of material fact(68). A further provision sanctioning the withdrawal of appro-val of ANDAs was added by the Generic Drug EnforcementAct of 1992. That amendment specifically provides that theFDA must withdraw approval of an ANDA if it finds thatthe approval ‘‘was obtained, expedited, or otherwise facilitatedthrough bribery, payment of an illegal gratuity, or fraud ormaterial false statement’’ (191) or may withdraw approval ofan ANDA if it finds that the applicant has ‘‘repeatedly demon-strated a lack of ability to produce the drug . . . and has intro-duced, or attempted to introduce, such adulterated ormisbranded drug into commerce’’ (192).

11. CITIZEN PETITIONS

FDA states that the appropriate procedure for challengingany of its actions is the filing of a ‘‘citizen petition,’’ a writtenrequest that the FDA take specific action (193), in accordancewith its regulations (194). Citizen petitions are commonlyemployed to challenge the agency’s actions in connection withexclusivity claims or other matters pertinent to the approval ofANDAs or 505(b)(2) applications.

FDA regulations provide the agency with 180 days torespond to a citizen petition (195). Such a response permitsthe agency to provide an explanation of its position in advanceof litigation. Where, however, a petitioner fears that agencyaction will not be stayed and it will be irreparably harmed, itgenerally seeks judicial intervention without further delay.

144 Gross et al.


A party dissatisfied with FDA’s action on a citizen petitionmay seek judicial review in district court. FDA contends thatthe petitioner must first obtain a final decision on a citizenpetition before it seeks judicial relief and will raise the exhaus-tion of administrative remedies defense in any law suit notpreceded by the determination of a citizen petition (196).

12. REFORM AND FUTURE CONTROVERSY

The 2003 Rule Changes and 2003 Statutory Changes haveeffected a number of modifications of the Hatch-Waxman regu-latory scheme designed to facilitate more rapid introductionof generic drugs into the marketplace. Such changes includethe elimination of the listing of metabolite patents and therestrictions on the listing of polymorph patents in the OrangeBook and the limitation to a single 30-month stay of ANDAor 505(b)(2) application approvals. Further, the addition ofthe multiple grounds for forfeiture of the 180-day exclusivityperiod were designed to increase the penalties for collusivesettlements and, again, hasten market entry. In addition, thechanges in the litigation scheme to permit counterclaims forimproper Orange Book listings and declaratory judgment pro-ceedings seeking determinations of noninfringement or inva-lidity of listed patents that have not been asserted on the basisof a Paragraph IV certification are designed to decrease furtherbars to generic entry.

On the other hand, as frequently occurs in the law, changebegets further dispute. Hence, future litigation may ensue, forexample, on the priority of adjudicating Paragraph IV infringe-ment claims and delisting counterclaims and the proprietyof declaratory judgment actions even when constitutionallypermissible.

It is clear that these and other issues will be the subjectof future litigation, and that the Hatch-Waxman statutory/regulatory scheme will be under further review and subjectto additional modification in the foreseeable future because ofthe continuing competition between brand-name and generic



marketers, political pressures brought about by upwardlyspiraling drug prices, and the ongoing efforts to balance theinfluence of brand name and generic drugs on the nationalhealth care system.

REFERENCES

1. Pub. L. No. 98-417, 98 Stat. 1585, Federal Food, Drug, andCosmetic Act (FDCA), Human Drug Approval Provisions,FDCA Section 505, 21 U.S.C. x355. Provisions similar to thosediscussed herein have been enacted for the approval of animaldrugs in the Generic Animal Drug and Patent Term RestorationAct of 1988, Pub. L. 100-670, 102 Stat. 3971 (1988). The animaldrug approval provisions are outside the scope of this discussion.

2. Glaxo, Inc. v. Novopharm, Ltd., 110 F.3d 1562, 1568 (Fed.Cir. 1997) (quoting H. R. Rep. No. 98-857 (I), at 14-15 (1984),reprinted in 1984 U.S.C.C.A.N. 2647, 2647–48).

3. July 2002 U.S. Federal Trade Commission (FTC) Report,‘‘Generic Drug Entry Prior to Patent Expiration: An FTCStudy’’ (the July 2002 FTC Report), pp i and 9 (citing ‘‘HowIncreased Competition from Generic Drugs Has Affected Pricesand Returns in the Pharmaceutical Industry,’’ CongressionalBudget Office (July 1998) at 31).

4. FDCA Section 505( j), codified at 21 U.S.C. Section 355( j). Forconvenience, 21 U.S.C. Section 355, et seq. are referred to hereinby the appropriate FDCA sections, namely Sections 505 et seq.

5. A generic drug is ‘‘bioequivalent’’ to a previously approved drugif the extent and rate of absorption of the respective drugs donot differ significantly from one another. FDCA Section505( j)(8)(B).

6. FDCA Section 505(b)(2).

7. Pub. L. 98–417, Title II (1984), and Pub. L. 100–670, Title II(1988) (creating 35 U.S.C. x156, and amending 35 U.S.C. xx271and 282).

8. Pub. L. 103–465, 108 Stat. 4809 (1994), the Uruguay RoundAgreements Act (URAA).

146 Gross et al.


9. 35 U.S.C. x 271(e)(1). In its latest interpretation of the scope ofthe exemption, the Federal Circuit has held that x 271(e)(1)does not preclude patent infringement by drug developmentactivities ‘‘far beyond those necessary to acquire informationfor FDA approval of a patented pioneer drug already on themarket.’’ Integra Life Sciences I, Ltd. v. Merck KGaA, 331 F.3d860, 867 (Fed. Cir. June 6, 2003).

10. FDCA Section 505( j)(2)(A)(vii), (viii), [ANDAs]; and Section505(b)(2)(A)(iv) [Section 505(b)(2) applications]. The ‘‘OrangeBook’’ was so named because it was published by the FDA withorange covers.

11. FDCA Section 505( j)(2)(A)(vii)(IV) [ANDAs]; 21 Code ofFederal Regulations (‘‘CFR’’) 314.94(a)(12)(i)(A)(4), [ANDAs];and FDCA Section 505(b)(2)(A)(iv) [Section 505(b)(2) applica-tions]. Under the FDA’s 2003 modified regulations (the ‘‘2003Rule Changes’’ herein) discussed below, the notice require-ments were not required for all Paragraph IV Certificationsin order to provide only a single 30-month stay per listed drug

in this respect in the 2003 statutory amendment to 21 U.S.C.Section 355 under the Medicare Prescription Drug Improve-ment and Modernization Act of 2003 (MPDIMA), Title XIAccess to Affordable Pharmaceuticals (the ‘‘2003 StatutoryChanges’’ herein). The amended statute requires the noticewith all Paragraph IV Certifications, whether made in genericdrug applications or in amendments or supplements to suchapplications. For convenience, the amended statutory sections,21 U.S.C. Section 355, et. seq., are referred to herein by theappropriate FDCA Sections, namely Sections 505, et. seq., andby their proposed MPDIMA Sections.

12. FDCA Section 505( j)(5)(B)(iii); amended by MPDIMA Section1101(a)(2)(A) [ANDAs]; and Section 505(c)(3)(C) amendedby MPDIMA Section 1101(b)(2)(B) [Section 505(b)(2) applica-tions].

13. FDCA Section 505( j)(5)(B)(iv) [ANDAs] amended by MPDIMASection 1102(a) (1)(iv)(I); there is no comparable exclusivityperiod for the first filer of a Section 505(b)(2) application.

14. FDCA Section 505( j)(5)(D)(ii) amended by MPDIMA Section1101(a)(2)(B) [ANDAs]; and Section 505(c)(3)(D)(ii) amended



product (see Sec. 9.1.2). The regulatory changes were nullified

by MPDIMA Section 1101(b)(2)(C) [Section 505(b)(2) applica-tions].

15. FDCA Section 505( j)(5)(D)(iii) and (iv) amended by MPDIMASection 1101(a)(2)(B) [ANDAs]; and Section 505(c)(3)(D)(iii)amended by MPDIMA Section 1101(b)(2)(C) [Section 505(b)(2)applications].

16. July 2002 FTC Report, pp. 6, 8.

17. Amendments to 21 CFR Part 314, 68 Fed Reg 36676 (June 18,2003).

18. 68 Fed Reg 36676, 36695–6 (June 18, 2003); 69 Fed Reg 11309(Mar. 10, 2004).

19. MPDIMA, Title XI—Access to Affordable Pharmaceuticals,amendments to 21 U.S.C. Section 355.

20. FDCA Section 505(b)(1) and (c)(2).

21. FDCA Sections 505(b)(1) and (c)(2); and 21 CFR 314.94(a)(12)(B)(vi).

22. FDCA Section 505( j)(2)(A)(vii) [ANDAs]; and Section 505(b)(2)(A) [505(b)(2) applications].

23. 21 CFR 314.94(a)(12)(B)(vi) [ANDAs]; and 21 CFR 314.52(d)[505(b)(2) applications]. Under the 2003 Statutory Changes anANDA or 505(b)(2) applicant must give notice to the patentholder within 20 days from the date the FDA acknowledgesfiling of the ANDA or 505(b)(2) application, or at the time atwhich the applicant submits an amendment or supplement tothe application. FDCA Section 505( j)(2)(B)(ii) amended bySection 1101(a)(1)(A)[ANDAs]; and FDCA Section 505(b)(3) (B)amended by MPDIMA Section 1101(b)(1)(A) [505(b)(2) applica-tions].

24. 21 CFR 314.94(a)(12)(B)(vi); Abbott Labs., Inc. v. Zenith Labs.,Inc., 35 USPQ2d 1161 (N.D. Ill. 1995) (dismissing claim forpatent infringement where plaintiff failed to list patentwithin 30-day period after issuance of patent).

25. 21 CFR 314.53(b).

26. 21 CFR 314.53(e) and 314.3(b).

27. See October 24, 2002, proposed FDA rulemaking, ‘‘Applica-tions for FDA Approval to Market a New Drug: Patent Listing

148 Gross et al.


Requirements and Application of 30-Month Stays on Approvalof Abbreviated New Drug Applications Certifying That aPatent Claiming a Drug Is Invalid or Will Not Be Infringed,’’21 CFR Part 314 [Docket No. 02N-0417], RIN 0910-AC48Section II A.

28. 59 Fed Reg 50338, 50343 (Oct. 3, 1994) (‘‘The agency believesthat its scarce resources would be better utilized in reviewingapplications rather than reviewing patent claims.’’).

29. 21 CFR 314.53(f ); Abbreviated New Drug ApplicationRegulations, 54 Fed Reg 28872, 28910 (July 10, 1989) (‘‘Indeciding whether a claim of patent infringement could reason-ably be asserted . . . the agency will defer to the informationsubmitted by the NDA applicant.’’); see also AaiPharma v.Thompson, 296 F.3d 227 (4th Cir. 2000); and Watson Pharms.,Inc. v. Henney, 194 F. Supp. 2d 442, 445 (D. Md. 2001).

30. 21 CFR 314.53(b) (2003). As used in the rule, polymorphs‘‘include chemicals with different crystalline structures, differ-ent waters of hydration, solvates, and amorphous forms.’’ 68Fed Reg 36676, 36678 (June 18, 2003).

31. 68 Fed. Reg. 36676, 36678 (June 18, 2003).

32. 21 CFR 314.53(b), (c) (2003). The categories include: (i) a fulldescription of the polymorphic form, including its physical andchemical characteristics and stability; its synthesis; the processcontrols used during manufacture and packaging; and suchspecifications and analytical methods as necessary to assureits identity, strength, quality, and purity; (ii) the executedbatch record for a drug product containing the polymorphand documentation that the batch was manufactured underGMP conditions; (iii) demonstration of bioequivalence betweenthe executed batch of the drug product containing the poly-morph and the drug product described in the NDA; (iv) a listof all components used in the manufacture of the polymorph-containing drug product and a statement of the composition ofthe drug product; a statement of the specifications and analy-tical methods for each component as are necessary to demon-strate pharmaceutical equivalence and comparable productstability; and (v) comparative in vitro dissolution testing on12 dosage units, the executed test batch and NDA product.68 Fed Reg 36676, 36679 (June 18, 2003).



33. As used in the rules, a product-by-process patent is one that‘‘claims a product by describing or listing process steps to whollyor partially define the claimed product.’’ 68 Fed Reg 36676,36679 (June 18, 2003). Under U.S. patent law a product byprocess patent claim is directed to the product, i.e., is a ‘‘pro-duct claim’’ but defines the product by reference to the stepsused to make the product.

34. 68 Fed Reg 36676, 36680 (June 18, 2003).

35. 21 CFR 314.53(b) (2003).

36. FDA lists current dosage forms which may be listed as includ-ing metered aerosols, capsules, metered sprays, gels, andpre-filled drug delivery systems. 68 Fed Reg 36676, 36680(June 18, 2003).

37. See Mylan Pharms., Inc. v. Thompson, 268 F.3d 1323 (Fed.Cir. 2001), cert. denied, 123 S. Ct. 340 (2002); and Andrx v.Biovail Corp., 276 F.3d 1368 (Fed. Cir. 2002).

38. See Mylan, 268 F.3d at 1329 and 1333, n.3; and Andrx, 276F.3d at 1379, n.8. Subsequently, in AaiPharma v. Thompson,296 F.3d at 235-43, the Court of Appeals for the Fourth Circuitheld that the FDA’s ‘‘purely ministerial approach’’ to OrangeBook listing was not arbitrary and capricious under theAdministrative Procedure Act (APA), but approved of anti-trust actions brought against NDA holders who use improperOrange Book listings to extend monopoly power. 296 F.3dat 243.

39. 68 Fed Reg 36676, 36684 (June 18, 2003).

40. 68 Fed Reg 36676 (June 18, 2003).

41. MPDIMA Section 1101(a)(2)(C)(ii)[ANDAs]; and MPDIMASection 1101(b)(2)(D)(ii)[505(b)(2) applications].

42. MPDIMA Section 1101(c)(i).

43. FDCA Section 505( j)(2) and (4).

44. FDCA Section 505( j)(7).

45. FDCA Section 505( j)(7)(A)(ii).

46. 54 Fed. Reg. 28872 (July 10, 1989).

47. FDCA Section 505( j)(2)(A).

150 Gross et al.


48. FDCA Section 505( j)(2)(A)(i).

49. FDCA Section 505( j)(2)(A)(v).

50. 21 C.F.R. 314.70.

51. 21 C.F.R. 314.94(a)(8)(iv). See Bristol-Myers Squibb Co. v.Shalala, 91 F.3d 1493, 1496 (D.C. Cir. 1996). (Bristol-MyersSquibb’s complaint seeking to enjoin FDA from approving anANDA for captopril, which omitted an approved indication fortreating diabetic nephropathy, was remanded to the trial courtwith instructions to dismiss.)

52. FDCA Section 505( j)(2)(A)(ii)(I).

53. FDCA Section 505( j)(2)(A)(ii)(I), (II), and (III).

54. FDCA Section 505( j)(2)(A)(iv).

55. FDCA Section 505( j)(8)(B).

56. FDCA Section 505( j)(8)(A)(ii) amended by MPDIMA Section1103(a)(1); FDCA Section 505( j)(8)(c) amended by MPDIMASection 1103(a)(2); Schering Corp. v. Sullivan, 782 F. Supp.645 (D.D.C. 1992), vacated for mootness, 995 F.2d 1103 (D.C.Cir. 1993); Schering Corp. v. FDA, 51 F.3d 390 (3rd Cir. 1995);and Fisons Corp. v. Shalala, 860 F. Supp. 859 (D.D.C. 1994).

57. In Fisons, 860 F. Supp. at 866, the court approved an FDAregulation permitting the waiver of a specific type of in vivotesting for categories of drugs where in vivo bioequivalencewas self-evident based on other bioequivalence data in theapplication.

58. FDCA Section 505( j)(4)(H).

59. 21 CFR 314.127(a)(8)(ii)(A)(1)-(7) (1997).

60. FDCA Section 505( j)(2)(C).

61. FDCA Section 505( j)(2)(A)(iii).

62. FDCA Section 505( j)(2)(A)(ii)(III).

63. FDCA Section 505( j)(2)(C)(i) and (ii).

64. 21 CFR 314.93.

65. FDCA Section 505( j)(2)(C); and 21 CFR 314.93(e).

66. FDCA Section 505( j)(7)(C).



67. FDCA Section 505( j)(4)(I); and 21 CFR 314.127(a)(9) and(a)(11) (1997).

68. FDCA Section 505(e).

69. 21 CFR 314.151(b)(2).

70. 21 CFR 314.151(c)(7); and 21 CFR 314.150(a)(1).

71. 21 CFR 314.150(c)(7).

72. FDCA Section 505(b)(2); the ‘‘Right of Reference or Use’’simply refers to approval by the prior party, generally theNDA holder, to the generic applicant to refer to or use itsprior safety or efficacy investigations. 21 CFR 314.3(b). Whensuch a ‘‘Right of Reference or Use’’ is relied upon by a505(b)(2) applicant, it is required to provide in its applicationa written statement by the owner of the data from each suchinvestigation that the applicant may rely on such data in sup-port of the application and that it will provide the FDA accessto the underlying raw data supporting the report of the inves-tigation. 21 CFR 314.50(g)(3).

73. Draft Guidance For Industry Applications Covered byx505(b) (2), Center for Drug Evaluation and Research,October 1999.

74. For example, 505(b)(2) Application No. 021-435 filed byDr. Reddy’s Laboratories for approval of amlodipine maleate,relying on data submitted by Pfizer in its NDA for amlodipinebesylate (NORVASC�).

75. Citizen Petition by Pfizer Inc. and Pharmacia Corporation,No. 01P-0323 (filed July 27, 2001), and Amendment to CitizenPetition (Apr. 4, 2002); and Pfizer Inc. Citizen Petition datedOctober 11, 2002.

76. FDCA Section 505(b)(2)(A) and (3).

77. 21 CFR 314.101(d)(9).

78. 21 CFR 314.3.

79. FDCA Section 505( j)(4)(C)(i).

80.

81. 21 CFR 314.108(a).

152 Gross et al.


See Ref. 14, supra; and 21 CFR 314.108(b)(2).

82. 21 CFR 314.108(b)(2).

83. FDCA Section 505( j)(4)(A) [ANDAs]; and Section 505(d)(1)[505(b)(2) applications].

84. FDCA Section 505( j)(5)(A) [ANDAs]; and Section 505(c)(1)[505(b)(2) applications].

85. 21 CFR 314.127 [ANDAs]; and 21 CFR 314.125 [505(b)(2)applications]. Notwithstanding the theoretical opportunity fora hearing, the FDA may deny a hearing if it concludes thereare no material factual issues to be determined.

86. FDCA Section 505( j)(5)(C) amended by MPDIMA Section1101(a)(2)(B) [ANDAs]; and Section 505(c)(1) [505(b)(2)applications].

87. See Merck Co., Inc. v. Danbury Pharmacal, Inc., 694 F. Supp. 1(D. Del. 1988), aff’d, 873 F.2d 1418 (Fed. Cir. 1989). 21 CFR314.94 (a)(12)(i)(A)(4).

88. 21 CFR 314.94(a)(12)(ii); the regulations specify that this cer-tification be in the following form: In the opinion and to thebest knowledge of (name of applicant), there are no patentsthat claim the listed drug referred to in this application orthat claim a use of the listed drug. A certification to substan-tially the same effect is required with respect to 505(b)(2)applications. 21 CFR 314.50(i)(1)(i)(B)(ii).

89. FDCA Section 505( j)(2)(B)(i) amended by MPDIMA Section1101(a)(1)(A) [ANDAs]; and Section 505(b)(3) amended byMPDIMA Section 1101(b)(1)(A) [505(b)(2) applications]; 21CFR 314.95(a)(1).

90. FDCA Section 505( j)(2)(B)(ii) amended by MPDIMA Section1101(a)(1)(A) [ANDAs]; FDCA Section 505(b)(3)(B) amendedby MPDIMA Section 1101(b)(1)(A) [505(b)(2) applications].

91. 21 CFR 314.95(c)(6) and 21 CFR 314.94 (a)(12) (i)(A)(4).

92. 21 CFR 314.95(c)(2)-(5).

93. 21 CFR 314.95(a)(3); 69 Fed Reg 11309 (Mar. 10, 2004).

94. FDCA Section 505( j)(2)(B), amended by MPDIMA, Section1101(a)(1)(A) [ANDAs], and FDCA Section 505(b)(3)(B)amended by MPDIMA Section 1101(b)(1)(A) [505(b)(2)applications].



95. FDCA Section 505( j)(2)(B)(ii) amended by MPDIMA Section1101 (a)(1)(A) [ANDAs], and FDCA Section 505(b)(3)(B),amended by MPDIMA Section 1101 (b)(1)(A)[505(b)(2) applica-tions]. The prior law had no time limit. This raised issues as tothe effective filing date of an ANDA, Paragraph IV, and whowas the first to file for the purpose of awarding 180 days ofmarket exclusivity. In a suit filed by Purepac against FDA onOctober 29, 2003 in the District of Columbia, Purepac allegedthat it was entitled to first-to-file status because a ParagraphIV Certification in an original ANDA is deemed effectively sub-mitted on the date it is received by FDA and that the date ofnotification to the patent holder is irrelevant. ‘‘The PinkSheet,’’ Vol. 65, No. 46, p.12 (November 17, 2003). In thisinstance FDA awarded first-to-file status to Ivax based uponits original ANDA with a Paragraph IV Certification, sub-mitted one day prior to Purepac’s notice to the NDA holderof its amended ANDA with a Paragraph IV Certification. ‘‘ThePink Sheet,’’ Vol. 65, No. 46, p.12 (November 17, 2003). Pure-pac later withdrew its action against the FDA and agreed toshare 180-day exclusivity with Ivax. ‘‘The Pink Sheet,’’ Vol. 65,No. 48, p.17 (December 1, 2003).

96. 21 CFR 314.95(f ); and Section 505( j)(5)(B)(iii). FDA requiresthe ANDA applicant to provide it with a return receipt or otherevidence of the date of receipt of the notice by the patentowner and NDA holder. 21 CFR 314.95(e).

97. In AstraZeneca AB v. Mutual Pharm. Co., 221 F. Supp. 2d 528(E.D. Pa. 2002), the court denied such relief, holding that theANDA applicant’s notice was sufficient in that it alerted thepatent owner to the applicant’s claim of noninfringement.However, in two other cases courts have held that insufficientnotices could ultimately be relied upon in litigation in supportof an award of attorney’s fees for willful infringement.Yamanouchi Pharm. Co. Ltd. v. Danbury Pharmacal, Inc.,231 F.3d 1339, 1347-48 (Fed. Cir. 2000); Eli Lilly & Co. v.Zenith Goldline Pharms., Inc., 2001 WL 1397304, at *25-26(S.D. Ind. Oct. 29, 2001).

98. Section 505( j)(2)(A)(viii) [ANDAs]; Section 505(b)(2)(B)[505(b)(2) applications]; and 21 CFR 314.94(a)(12)(iii).

99. See Patent Provisions Rulemaking, 59 Fed Reg 50338, 50345(Oct. 3, 1994) (‘‘FDA does not have the resources to review

154 Gross et al.


patent information for its accuracy and relevance to anNDA.’’); Proposed ANDA Rules, 54 Fed Reg 28872, 28909(July 10, 1989) (‘‘because the FDA has no experience in thefield of patents, the agency has no basis for determiningwhether a use patent covers the use sought by the genericapplicant’’).

100. See Proposed ANDA Rules, 54 Fed Reg 28872, 28909 (July 10,1989) (‘‘The agency believes that [this] approach more fairlyimplements Congress’ intent that patent owners receive pre-approval notice of potentially infringing patents.’’)

101. See AaiPharm, Inc. v. Thompson, 296 F.3d 227, 241 (4th Cir.2002) (‘‘[T]he whole point of the Act’s [P]aragraph IV[C]ertification scheme is to let private parties sort out theirrespective intellectual property rights through patent infrin-gement suits while the FDA focuses on its primary taskof ensuring the drugs are safe and effective. This division oflabor is appropriate because the FDA has no expertise inmaking patent law judgment.’’); Watson Pharm., Inc. v.Henney, 194 F. Supp. 2d 442, 445 (D. Md. 2001) (‘‘[theFDA] has no expertise—much less any statutory franchise—to determine matters of substantive patent law. In makingits decision to list a patent, therefore it is entirely appropriateand reasonable for the FDA to rely on the patentee’s declara-tion as to coverage, and to let the patent infringement issuesplay out in other, proper arenas . . . ’’).

102. Purepac Pharm. Co. v. Thompson, 238 F. Supp. 2d 191 (D.D.C.2002). Purepac, 238 F. Supp. 2d at 205. Warner-Lambert, thepatent owner, had consistently represented to FDA thatthe patent in question claimed the use of the drug gabapentinto treat neurodegenerative diseases—not epilepsy—theonly approved indication for the drug, the prior patent forthe epilepsy use having expired. Purepac sought only approvalfor the epilepsy indication. Based upon the specific record, thecourt ordered FDA to vacate its decision not to approvePurepac’s ANDA because it did not include a Paragraph IVCertification respecting the indication for the treatment ofneurodegenerative disease for which Purepac did not seekapproval (and which had not been previously approved bythe agency.) In view of the court’s decision, FDA subsequentlydelisted the patent and required that the applicants with



pending ANDAs for gabapentin products withdraw any priorcertifications or Section viii Statements as to that patent. SeeJanuary 28, 2003 letter from Gary Buehler, Director Office ofGeneric Drugs, FDA to ‘‘ANDA Applicant for Gabapentin’’(January 28, 2003 Buehler letter) (available at

In a subsequent decision, the court found that FDA hadacted within its discretion in precluding another genericapplicant (Torpharm) from maintaining a Paragraph IVCertification as to the patent in question and asserting 180-day exclusivity based on that patent. Torpharm v. Thompson,260 F. Supp. 2d 69 (D.D.C. Apr. 25, 2003).

103. 68 Fed Reg 36676, 36682 (June 18, 2003).

104. 21 CFR 314.95(d); In the Torpharm case, the court held thatit was within the discretion of FDA to hold that the operativedate (assuming proper notice) for the filing of an amendedParagraph IV Certification was the date of receipt of the cer-tification (260 F. Supp. 2d at 81-82) and that the penalty foran applicant’s failure to provide notice at the same time as itsamended certification was postponement of the effective dateof the certification to the date of transmission of the noticeof the amendment (260 F. Supp. 2d at 78-79).

105. 21 C.F.R. 314.94(a)(12)(vi); 68 Fed Reg 36676, 36684 (June18, 2003).

106. 21 CFR 314.52(a)(3); 314.95(a)(3) (2003).

107. 68 Fed Reg 36676, 36688 (June 18, 2003).

108. 35 U.S.C. x271(e)(1).

109. 35 U.S.C. x271(e)(2); Eli Lilly & Co. v. Medtronic, Inc., 496U.S. 661, 678 (1990).

110. 35 U.S.C. x271(e)(2).

111. 21 CFR 314.107(f )(2).

112. See July 2002 FTC Report, p. 14 [‘‘The data revealed 75 drugproducts, out of a total of 104 NDAs (72 percent), in whichthe brand-name company sued the first generic applicant.’’].

113. Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348 (Fed. Cir.2003). [In another case involving the drug gabapentin (see

156 Gross et al.


www.fda.gov/cder/ogd/75350.479pat.pdf ).http://

http://www.fda.gov

http://www.fda.gov

could not assert infringement of the patent directed to theunapproved use for treating neurodegenerative diseases, whereboth the patent on the listed products and the approved indi-cation (the treatment of epilepsy) had previously expired.Though Apotex had submitted a Paragraph IV Certification,the court noted that it was effectively a Section viii Statementof a nonapplicable use patent.] See also Allergan, Inc. v. AlconLabs, 324 F.3d 1322 (Fed. Cir. 2003); cert. denied, 2003 U.S.Lexis 8602 (December 1, 2003).

114. See Mylan Pharms., 268 F.3d at 1331 (Fed. Cir. 2001) (‘‘Areview of the amendments shows no explicit provisions allowingan accused infringer to defend against infringement by challen-ging the propriety of the Orange Book listing of the patent.’’).

115. See In re Buspirone Anti-Trust Litig., 185 F. Supp. 2d 363(S.D.N.Y. 2002), in which the District Court held thatthe brand name defendant was not entitled to Noerr-Pennington immunity against claims arising out of its alleg-edly fraudulent listing of an Orange Book patent. As of thiswriting, this case is on appeal.

116. FDCA Section 505( j)(5)(C)(i)(I)(aa) amended by MPDIMASection 1101 (a)(2)(C) [ANDA]; FDCA Section 505(c)(3)(D)(i)(I)(aa) amended by MPDIMA Section 1101(b)(2)(D) [505(b)(2) applications].

117. Kos Pharmaceuticals, Inc. v. Barr Laboratories, Inc., 242 F.Supp. 2d 311 (S.D.N.Y. 2003).

118. FDCA Section 505( j)(5)(C)(i)(I)(bb) amended by MPDIMASection 1101(a)(2)(C) [ANDAs}; FDCA Section 505(c)(3)(D)(i)(I)(bb) amended by MPDIMA Section 1101(b)(2)(D) [505(b)(2) applications].

119. FDCA Section ( j)(5)(C)(i)(I)(cc) amended by MPDIMA Section1101(a)(2)(c) [ANDAs]; FDCA Section 355(c)(3)(D)(i)(cc)amended by MPDIMA Section 1101(b)(2)(D) [505(b)(2) appli-cations].

120. 35 U.S.C. 271(e)(5), created by MPDIMA Section 1101(d).

121. FDCA Section 505( j)(5)(C)(i)(II) amended by MPDIMASection 1101(a)(2)(C) [ANDAs]; FDCA Section 505(c)(3)(D)(i)(II) amended by MPDIMA Section 1101(b)(2)(D).



Ref. 101 and 102 above) the court held that Warner-Lambert

122. MPDIMA Conference Agreement at 386. See Dr. Reddy’sLaboratories, Ltd. v. Pfizer Inc., 2003 WL 21638254 (D.N.J.,July 8, 2003; and Teva Pharmaceuticals USA, Inc. v. PfizerInc., 2003 U.S. Dist.LEXIS 21940 (D. Mass., December 8,2003).

123. 35 U.S.C. x 156(a)(1).

124. 35 U.S.C. x 156(a)(2).

125. 35 U.S.C. x 156(a)(3).

126. 35 U.S.C. x 156(a)(4).

127. 35 U.S.C. x 156(a)(5).

128. 35 U.S.C. x 156(b)(1)(A)(i).

129. 35 U.S.C. x 156(b)(1)(B).

130. 35 U.S.C. x 156(g)(6)(A).

131. 37 CFR 1.775.

132. 35 U.S.C. x 156(c).

133. 35 U.S.C. x 156(c)(3).

134. 35 U.S.C. x 156(b)(1).

135. Pfizer Inc. v. Dr. Reddy’s Laboratories, Inc., Civil Action No.02-CV-2829, 2002 WL 31833744 (D.N.J. filed June 12, 2002).(The trial court granted Dr. Reddy’s motion to dismiss thecomplaint where Pfizer had obtained approval of an NDA foramlodipine besylate and Dr. Reddy sought approval of a505(b)(2) application for amlodipine maleate.)

136. Pfizer Inc. v. Dr. Reddy’s Laboratories, Inc., 359 F.3d 1361(Fed. Cir. 2004).

137. 35 U.S.C. x 154(a)(2). Under a transitional provision, patentsin force on June 8, 1995 (without prior term adjustment) areentitled to a term of 20 years from their effective filing datesor 17 years from their issue dates, whichever is greater.

138. FDCA Section 505( j)(5)(B)(i) [ANDAs]; and Section 505(c)(3)(A) [505(b)(2) applications].

139. FDCA Section 505( j)(5)(B)(ii) [ANDAs]; and Section 505(c)(3)(B) [505(b)(2) applications].

158 Gross et al.


140. By way of example, a 30-month stay had been reduced forlack of reasonable cooperation by the brand name companyin Andrx Pharms., Inc. v. Biovail Corp., 175 F. Supp. 2d1362, 1375 (S.D. Fla. 2001), rev’d, 276 F.3d 1368, 1376(Fed. Cir. 2002), and extended because of failure of a gen-eric company to reasonably cooperate in Eli Lilly Co. v.ZenithGoldline Pharms., Inc., 2001 WL 238090 (S.D. Ind.Mar. 8, 2001). An extension of the 30-month stay wasdenied in Zeneca Ltd. v. Pharmachemie B.V., 16 F. Supp. 2d112 (D. Mass. 1998).

141. GlaxoSmithKline obtained five overlapping 30-monthstays, commencing in 1998 and extending to September2003, by the multiple listing of several patents related tothe drug paroxetine, followed by sequential infringementsuits against Apotex, one of several generic ANDAapplicants. July FTC Report, pp. 51–52 and 33–34. See alsoFDA Proposed Rule on Patent Listing Requirements and30-Month Stays on ANDAs, 67 Fed Reg 65448, 65454-56(Oct. 24, 2002).

142. July 2002 FTC Report, p. 44.

143. It has been reported that drug costs increased almost 16% in2001, more than either the cost of hospitals’ or doctors’ ser-vices. Wall Street Journal, January 30, 2003, p.1, ‘‘President’sPlans for Medicare Hit Republican Flack.’’

144. July 2002 FTC Report, p. ii.

145. Senate Bill entitled ‘‘Greater Access to Affordable Pharma-ceuticals Act of 2001’’ (GAAP), S. 812, H.R. 1862.

146. White House October 21, 2002 Press Release, entitled‘‘President Takes Action to Lower Prescription Drug Pricesby Improving Access to Generic Drugs.’’

147. 67 Fed Reg 65448, et seq. (Oct. 24, 2002).

148. 68 Fed Reg 36676, 36688-90 (June 18, 2003).

149. The statute and FDA regulations required that ANDAs maybe separately filed for individual dosage forms of the samelisted drug. 21 CFR 314.92(a)(1).

150. Apotex, Inc. v. Shalala, 53 F. Supp. 2d 454 (D.D.C. 1999),aff’d, 1999 WL 956686 (D.C. Cir. Oct. 8, 1999). Subsequently,



separate 180-day marketing exclusivities were accorded toBarr Laboratories as the first to make a Paragraph IVCertification as to the 10 mg and 20 mg dosage formsof fluoxetine hydrochloride (Eli Lilly’s Prozac�), andDr. Reddy’s Laboratories as the first to make such a certifica-tion as to the 40 mg dosage form of the same drug, followingthe court decision holding the last-to-expire of Lilly’slisted patents invalid.

151. August 2, 1999 Response to Citizen’s Petitions re: cisplatin,Docket No. 99P-1271/PSA 1 and PSA 2.

152. November 16, 2001, letter from Gary Buehler, Director Officeof Generic Drugs, FDA, to Andrx Pharmaceuticals andGenPharm, Inc. Re: Omeprazole Delayed-Release Capsules(available atNeither Andrx nor GenPharm was subsequently accordedexclusivity, the District Court having held that the listedpatents in question are valid and infringed by their respectivedosage forms. In re Omeprazole Patent Litig., 222 F. Supp. 2d423 (S.D.N.Y. 2002).

153. January 28, 2003, Buehler letter regarding gabapentin.

154. FDCA Section 505( j)(5)(B)(iv)(II)(bb) amended by MPDIMASection 1101(a)(1).

155. FDCA Section 505( j)(5)(B)(iv)(I) (prior to the 2003 StatutoryChanges)

156. Generally, ANDA applicants are reluctant to so proceedbecause of the magnitude of potential damages in the eventof an adverse determination in infringement litigation.

157. Mylan Pharms., Inc. v. Thompson, 2001 WL 1654781 (N.D.W.Va. 2001).

158. FDCA Section 505( j)(5)(B)(iv)(I) amended by MPDIMASection 1102(a)(1).

159. FDCA Section 505( j)(5)(B)(iv)(II) (prior to the 2003 StatutoryChanges).

160. 64 Fed Reg 42873 (Aug. 6, 1999).

161. 65 Fed Reg 43233 (July 13, 2002); Guidance for Industry,Court Decisions, ANDA Approvals, and 180-Day Exclusivity

160 Gross et al.


www.fda.gov/cder/ogd/shared_exclusivity.htm).

http://www.fda.gov

Under the Hatch-Waxman Amendments to the Federal Food,Drug, and Cosmetic Act (March 2000), published at 65 FedReg 16922 (Mar. 30, 2000), citing TorPharm, Inc. v. Shalala,1997 U.S. Dist. LEXIS 21983 (D.D.C. Sept. 15, 1997), appealwithdrawn and remanded, 1998 U.S. App. LEXIS 4681 (D.C.Cir. Feb. 5, 1998), vacated No. 97–1925 (D.D.C. Apr. 9, 1998);Mova Pharm. Corp. v. Shalala, 140 F.3d 1060 (D.C. Cir.1998); Granutec, Inc. v. Shalala, 46 U.S.P.Q. 2d 1398 (4thCir. 1998); and Mylan Pharms., Inc. v. Shalala, 81 F. Supp.2d 30 (D.D.C. 2000).

162. Mylan Pharms., Inc. v. Henney, 94 F. Supp. 2d 36, 58(D.D.C. 2000), vacated as moot sub nom; and Pharma-chemie B.V. v. Barr Labs., Inc., 276 F.3d 627, 632 (D.C. Cir.2002).

163. Teva Pharms., USA, Inc. v. FDA, 182 F.3d 1003 (D.C. Cir.1999).

164. 67 Fed Reg 66593 (Nov. 1, 2002), ‘‘180-Day Generic DrugExclusivity For Abbreviated New Drug Applications,’’ with-drawing proposed rule published in 64 Fed Reg 42873 (Aug.6, 1999).

165. 67 Fed Reg 66594 (Nov. 1, 2002).

166. FDCA Section 505( j)(5)(B)(iii)(I) amended by MPDIMASection 1102(a)(1).

167. 21 CFR 314.94(a)(12)(viii)(A).

168. 64 Fed Reg 42873 (Aug. 6, 1999).

169. Mylan Pharms., Inc. v. Henney, 94 F. Supp. 2d 36, 41, 57-58(D.D.C. 2000), vacated as moot sub nom.

170. 21 CFR 314.107(c)(1) (1997), revoked in 63 Fed Reg 59712(Nov. 5, 1998).

171. FDA, ‘‘Guidance for Industry: 180 Day Generic DrugExclusivity Under the Hatch-Waxman Amendments toFederal Food, Drug and Cosmetic Act,’’ 63 Fed Reg 37890(July 14, 1998), citing Mova Pharm. Corp. v. Shalala, 955F. Supp. 128 (D.D.C. 1997), aff’d, 140 F.3d 1060 (D.C. Cir.1998); and Genentech, Inc. v. Shalala, 1998 WL 153410(4th Cir. 1998); see also Andrx Pharms., Inc. v. Friedman,No. 98–0099 (D.D.C. Mar. 30, 1998).



172. 63 Fed Reg 59710 (Nov. 5, 1998).

173. Purepac Pharm. Co. v. Friedman, 162 F.3d 1201 (D.C. Cir.1998).

174. FDCA Section 505( j)(5)(D)(i)(III) amended by MPDIMASection 1101(a)(2).

175. In Boehringer Ingleheim Corp. v Shalala, 993 F. Supp. 1(D.D.C. 1997), the court denied a temporary restrainingorder seeking to preclude approval of a waiver byGenPharm Inc. of an exclusive period to market ranitidinehydrochloride in favor of Granutec, Inc., a later filer. Thecourt concluded that FDA’s interpretation of the statute,approving the waiver agreement between GenPharm andGranutec, was not arbitrary and capricious, and an abuse ofdiscretion or otherwise in violation of the APA.

176. November 16, 2001, letter from Gary Buehler, Director Officeof Generic Drugs, FDA, to Andrx Pharmaceuticals andGenPharm, Inc. re. Omeprazole Delayed-Release Capsules

177. Andrx and GenPharm were thus able to waive exclusivity infavor of Kremers Urban Development Co. (Kudco) andSchwarz Pharma, Inc. which the trial court had held not toinfringe the various omeprazole dosage form patents heldvalid by the trial court. See Astra Aktiebolag v. AndrxPharms., Inc., 222 F. Supp. 2d 423 (S.D.N.Y. 2002).

178. MPDIMA Section 1102(a)(2)(D).

179. MPDIMA Section 1102(a)(2)(D)(i)(I).

180. MPDIMA Section 1102(a)(2)(D)(i)(II).

181. MPDIMA Section 1102(a)(2)(D)(i)(III).

182. MPDIMA Section 1102(a)(2)(D)(i)(IV).

183. MPDIMA Section 1102(a)(2)(D)(i)(V).

184. MPDIMA Section 1102(a)(2)(D)(i)(VI).

185. The Food and Drug Administration Modernization Act of1997, Public Law 105-115 (1997), Section 111; and BestPharmaceuticals for Children Act, Public Law 107-109(2002), Section 505a(b)(2)(B).

162 Gross et al.


(available at www.fda.gov/cder/ogd/shared_exclusivity.htm).

http://www.fda.gov

186. FDCA Section 505a(b)(1) [ANDAs] and FDCA Section505a(c)(1) [505 (b)(2) applications].

187. FDCA Section 505a(a)(n).

188. FDCA Section 505a(b)(1)(ii) [ANDAs] and (c)(1)(ii) [505(b)(2)applications].

189. FDCA Section 505a(g).

190. FDCA Section 505a(l).

191. FDCA Section 335c(a)(1).

192. FDCA Section 335c(a)(2).

193. 21 CFR 10.30.

194. 21 CFR 10.25(a), 10.30.

195. 21 CFR 10.30(e)(2).

196. 21 CFR 10.45(b), (c).



6

Food and Drug AdministrationModernization Act

ARTHUR Y. TSIEN and PATRICIA E. PAHL

Olsson, Frank & Weeda, P.C.


1. INTRODUCTION

The Food and Drug Administration Modernization Act(FDAMA), Public Law No. 105–115, was enacted on November21, 1997. This Act made numerous changes to the Federal Food,Drug and Cosmetic Act and the regulation of food, drugs,devices, and biological products. This chapter summarizesFDAMA’s effects upon the regulation of drugs and biologicals.

FDAMA was major and complex legislation. The U.S.Food and Drug Administration (FDA) has had to promulgatenumerous guidances, policies, and regulations to implement

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FDAMA’s provisions. Some parts of FDAMA have been testedin litigation; courts have held some FDAMA provisions to be inviolation of the law.

Important provisions of FDAMA include the following:

Modernizing the regulation of biological productsEliminating the batch certification and monograph

requirements for insulin and antibioticsStreamlining the approval processes for drug and biolo-

gical manufacturing changesReducing the need for environmental assessment as part

of a product applicationCodifying FDA regulations and practice to increase

patient access to experimental drugs and to acceleratereview of important new medications

Creating a database on clinical trials patients can accessRequiring advance notice when a manufacturer plans to

discontinue certain drugsPermitting manufacturers to disseminate information

about unapproved uses of drugs under certain limitedcircumstances

Allowing a firm to disseminate peer-reviewed journalarticles about an off-label indication of its productunder certain circumstances

Allowing drug companies to provide economic informa-tion about their products to formulary committees,managed care organizations, and similar large-scalebuyers of health-care products

Creating exemptions for compounded drug productsOtherwise reducing or simplifying many regulatory

obligations of manufacturers

This chapter is subdivided into six topical areas:

Pediatric StudiesClinical InvestigationsDrug Applications and ApprovalsDrug Manufacturing and CompoundingInformation Dissemination and LabelingFDA Management and Policies

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Each topical area is further divided into sections that corre-spond to applicable sections of FDAMA, such as Data Require-ments for Drugs and Biologics, Pilot and Small-ScaleManufacture, and Dissemination of Information on New Uses.Each section discusses the FDAMA requirements, and anyimplementing guidances, regulations, and policies, as well asany litigation that has altered the applicability and enforce-ment of that section of FDAMA.

2. PEDIATRIC STUDIES AND EXCLUSIVITY

2.1. Pediatric Studies of Drugs

Section 111 of the Food and Drug AdministrationModernization Act (FDAMA), pediatric studies of drugs, pro-vides the Food and Drug Administration (FDA) with authorityto request pediatric studies for a drug and to grant 6 monthsof extra market exclusivity to the sponsor or manufacturer(1). FDA has the authority to make this request if, prior toapproval of an application that is submitted under 21 U.S.C.§355(b)(1), FDA determines that data regarding the use ofthe new drug in pediatric populations may produce healthbenefits in that population. This provision also allows FDAto request pediatric studies for drugs that are already mar-keted. The provision was scheduled to expire on January 1,2002.

In a revised guidance document issued in September1999, FDA provided industry with guidance in interpretingthe new provision until superseded by regulations or new gui-dance (2). The guidance focuses on how studies may qualifyfor pediatric exclusivity under the new section. A pediatricstudy is defined as at least one clinical investigation (that,at FDA’s discretion, may include pharmacokinetic studies) inthe pediatric age groups in which a drug is anticipated to beused. Generally, an application filed under section 505(b)(1) ofthe Food, Drug and Cosmetic Act (FDC Act) (21 U.S.C. §355(b)(1)) will qualify for pediatric exclusivity if all of the

Food and Drug Administration Modernization Act 167


following have occurred (3):

1. FDA issued a ‘‘Written Request’’ for pediatricstudies:

a. before the approval of the new drug application(NDA), or

b. for an active moiety approved for adults and/orpart of the pediatric population for an approvedindication that occurs in the pediatric populationand appears on the List of Approved Drugs forWhich Additional Pediatric Information MayProduce Health Benefits in the PediatricPopulation (‘‘the List’’)

2. The sponsor submitted reports of the requested stu-dies after FDA made the Written Request

3. The sponsor submitted studies that responded com-pletely to the Written Request

4. The sponsor submitted reports of the studies inaccordance with a written agreement or, if therewas no written agreement, in accordance with com-monly accepted scientific principles

5. The sponsor submitted reports of the studies inaccordance with FDA’s requirements for filing

6. FDA accepted the reports of the studies

While a sponsor cannot submit studies for pediatric exclu-sivity prior to receiving a Written Request from FDA, a sponsormay obtain a Written Request by submitting proposedpediatric study requests addressing the pediatric studiesnecessary to use the active moiety appropriately in pediatricsubpopulations.

The guidance also details how over-the-counter (OTC)drugs approved under section 505(b) may qualify for pediatricexclusivity (4). Products that contain an antibiotic, where theantibiotic was the subject of any application for marketingreceived before November 21, 1997 (an ‘‘old antibiotic’’), arenot eligible to receive pediatric exclusivity unless (a) the anti-biotic has or obtains orphan drug exclusivity under section 527

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of the Act and (b) the requirements for pediatric exclusivityare met.

On May 20, 1998, FDA published the list of drugsapproved for use in adults for indications that occur in thepediatric population (5). The list is updated annually, asrequired by law.

In January 2001, FDA submitted a status report toCongress on the pediatric exclusivity provision (6). Threedays after the provision was scheduled to sunset, Congresspassed and the President signed into law an extension of thepediatric study provision, the ‘‘Best Pharmaceuticals forChildren Act’’ (7). The new law includes some additional provi-sions, which include applying studies to neonates, requiringadequate representation of racial and ethnic groups, establish-ing an Office of Pediatric Therapeutics, requiring certain labelchanges in exchange for the grant of exclusivity, and mandat-ing public dissemination of pediatric information.

2.2. FDA’s Pediatric Rule and SubsequentCourt Challenge

FDA proposed what is known as the Pediatric Rule in 1997;it became effective April 1, 1999 (8). The regulations requiredthat manufacturers of certain new and marketed drugs andbiological products conduct studies to provide adequate label-ing for the use of these products in children. The regulationauthorized FDA to require pediatric studies for certain drugsand new indications if the drug product under investigationwould likely be used in a ‘‘substantial number of pediatricpatients’’ or would provide a ‘‘meaningful therapeutic benefit’’to pediatric patients over existing treatments (9). Under thePediatric Rule, FDA could also require pediatric studies of mar-keted drugs if either of these conditions applied and inadequatelabeling could pose significant risks. While the FDAMA pedia-tric studies provision provided sponsors with the incentivesto conduct the studies that sponsors said were necessary,the Pediatric Rule, according to FDA, was necessary to‘‘address some of the gaps left by the pediatric exclusivityprovision’’ (10).



FDA’s Pediatric Rule was challenged in court. On October17, 2002, the U.S. District Court for the District of Columbiaruled that FDA did not have the authority to issue thePediatric Rule and barred FDA from enforcing it. Althoughthe government decided not to pursue an appeal in thecourts, FDA has stated its intention to work with Congressin an effort to enact legislation requiring pharmaceutical man-ufacturers to conduct appropriate pediatric clinical trials (11).

3. CLINICAL INVESTIGATIONS

3.1. Information Programs on Clinical Trials forSerious or Life-Threatening Diseases

Section 113 of FDAMA, Information Programs on ClinicalTrials for Serious or Life-Threatening Diseases (12), directsthe Secretary of Health and Human Services (DHHS) to estab-lish, maintain, and operate a data bank of information on clin-ical trials for drugs to treat serious or life-threatening diseasesand conditions. It thus creates a public resource for informa-tion on studies being conducted under FDA’s investigationalnew drug (IND) regulations (21 C.F.R. Part 312). Section 113of FDAMA requires that information provided through theClinical Trials Data Bank be in a form that can be readilyunderstood by the public (13).

In response, the National Institutes of Health (NIH),through its National Library of Medicine (NLM) and withinput from FDA and others, developed the Clinical TrialsData Bank. The Clinical Trials Data Bank contains (a) infor-mation about federally and privately funded clinical trials forexperimental drug and biological products for treating patientswith serious or life-threatening diseases or conditions, (b) adescription of the purpose of each experimental drug, (c)patient eligibility criteria, (d) a description of the location ofclinical trial sites, and (e) a point of contact for patients want-ing to enroll in the trial (14).

FDA has issued a guidance document for clinical investi-gators and sponsors that (a) provides recommendations for

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industry on the submission of protocol information to theClinical Trials Data Bank (including information about thetypes of clinical trials for which submissions are requiredunder section 113 of the Modernization Act, as well as thecontent of those submissions) and (b) addresses proceduralissues, including how to submit required and voluntary proto-col information to the Clinical Trials Data Bank (15). The gui-dance also addresses issues related to submitting certificationto HHS that disclosure of information for a particular protocolwould substantially interfere with the timely enrollment ofsubjects in the clinical investigation.

3.2. Clinical Investigations

The 1962 Drug Amendments to the FDC Act (16), passedunanimously by Congress, for the first time in history requiredthat pharmaceutical companies establish by ‘‘substantial evi-dence’’ the effectiveness of a drug prior to marketing it. Theterm ‘‘substantial evidence’’ was defined as ‘‘evidence consist-ing of adequate and well-controlled investigations, includingclinical investigations, by experts qualified by scientific train-ing and experience to evaluate the effectiveness of the druginvolved, on the basis of which it could fairly and responsiblybe concluded by such experts that the drug will have the effectit purports or is represented to have under the conditions ofuse prescribed’’ (17). Because the FDC Act uses the plural‘‘investigations,’’ FDA had, since the Amendments wereenacted, required drug manufacturers to submit at least two‘‘adequate and well-controlled’’ studies showing the effective-ness of the drug (18).

Section 115 of FDAMA amended the definition of substan-tial evidence in section 505(d) of the FDC Act to clarify thatFDA, at its discretion, may make exception to the generalrequirement that there be more than one adequate and well-controlled investigation to support an effectiveness determina-tion (19). As a practical matter, however, FDA’s general view isthat, in most cases, two studies will still be required to estab-lish safety and efficacy adequately (20).



Section 115 also amended section 505(b)(1) of the FDCAct to direct FDA to ‘‘review and develop guidance, as appro-priate, on the inclusion of women and minorities in clinicaltrials . . . ’’ (21). To meet this requirement, the Center forDrug Evaluation and Research (CDER) established an ad hocworking group, ‘‘FDAMA Women and Minorities WorkingGroup,’’ with representation from the agency and theNational Institutes of Health. In 1998, the Working Groupissued a report, after consulting with industry. There was aconsensus that no additional guidance is needed at this time,and the Group offered to confer with the agency if this situa-tion should change in the future (22).

3.3. Streamlining Clinical Research on Drugs

Section 117 of FDAMA, Streamlining Clinical Research,amended section 505(i) of the FDC Act by codifying some ofFDA’s procedures for handling applications for INDs, includingthe clinical hold procedure.

As amended by FDAMA, section 505(i)(2) now providesthat an initial IND application must include information onstudy design, ‘‘adequate reports of basic information,’’ certifiedby the applicant to be accurate, necessary to assess safety,adequate chemistry, manufacturing and controls information,and ‘‘primary data tabulations from animal or human studies’’(23). A clinical investigation may begin 30 days after FDAreceives an IND submission meeting these requirements.This provision, in fact, built on an FDA guidance that hadalready significantly reduced the size of IND submissions.

Section 117 of FDAMA also establishes procedural andsubstantive requirements for clinical holds (24). FDA may atany time prohibit a clinical investigation from starting or con-tinuing by issuing a clinical hold, but FDA must specify thebasis for a clinical hold and confirm its determination in writ-ing. This document must include ‘‘the specific informationavailable to the Secretary which served as the basis for suchclinical hold’’ (25). In December 1998, FDA published a finalrule implementing this provision (26). The rule amended theIND clinical hold requirements, set forth in 21 C.F.R. § 312.42,

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to state that the agency will respond in writing to a sponsor’srequest that a clinical hold be removed from an investigationwithin 30 calendar days of the agency’s receipt of the requestand the sponsor’s complete response to the issue(s) that led tothe clinical hold.

FDAMA also amended the statute to specify the standardfor issuing a clinical hold, which is that the drug ‘‘representsan unreasonable risk to the safety’’ of the subjects of the inves-tigation or other reasons established by FDA through regula-tion (27). The IND regulations issued by FDA are required toprovide that investigators will inform subjects that drugs arebeing used for investigational purposes and will obtain consent‘‘except where it is not feasible or it is contrary to the bestinterests’’ of the subjects (28).

3.4. Expanded Access to InvestigationalTherapies and Diagnostics

Section 402 of FDAMA, Expanded Access to InvestigationalTherapies and Diagnostics, added section 561 to the FDC Act(29). The new section was intended to authorize expandedaccess to drugs and devices that are still undergoing investiga-tion. In many ways, the statutory provision simply codifiedexisting agency practices.

Section 561 applies to drugs and devices intended for usein ‘‘serious’’ diseases and conditions in emerging situations.The term ‘‘serious’’ was intended by Congress to be construedbroadly, to include diseases that, while not life-threatening,could be devastating to patients and their families. FDA mayauthorize shipments of investigational drugs and devices underthese circumstances. This provision merely codified existingFDA drug regulations (30).

Section 561(b) allows physicians to request that a manu-facturer provide an investigational drug or device for a parti-cular patient if (a) the physician determines that there is nocomparable or satisfactory therapy and the probable risk fromthe drug is not greater than the probable risk from the disease;(b) FDA determines there is sufficient evidence of safety andeffectiveness to support use in the particular case; (c) FDA



determines that providing the drug or device will not interferewith initiation, conduct, or completion of clinical trials; and (d)the sponsor or clinical investigator submits a protocol consis-tent with the IND or investigational device exemption(IDE) regulations for treatment use in small numbers ofpatients (31).

Section 561(c) authorizes expanded access to investiga-tional drugs and devices under ‘‘treatment protocols.’’ Again,this provision largely codified FDA’s ‘‘treatment IND’’ regula-tions. The statute also authorized the agency to disseminateinformation about the availability of drugs and devices underthese expanded access protocols.

Section 561(d) authorizes FDA to terminate expandedaccess at any time if the requirements of this section are nolonger being met.

While FDA’s Center for Devices and Radiological Health(CDRH) has issued a guidance document describing thatCenter’s activities to implement section 402 of FDAMA,CDER has not.

3.5. Reports of Postmarketing Approval Studies

Section 130 of FDAMA, Reports of Postmarketing ApprovalStudies, added section 506B to the FDC Act (32). This sectionprovides FDA with additional authority for monitoring the pro-gress of postmarketing studies that drug and biologics appli-cants have agreed to conduct. Under section 506B(a),applicants who are required by FDA, or who have enteredinto an agreement with FDA, to conduct a postmarketingstudy are now required to provide the agency with an annualreport on the status of the study until it is completed or termi-nated. These annual reports must address the progress of thestudy or the reasons for the failure of the applicant to conductthe study (33).

Section 506B also requires FDA to keep the public andmedical community informed about the postmarketing obliga-tions and activities of applicants. More specifically, under sec-tion 506B(c), FDA is required to develop and publish annuallyin the Federal Register a report on the status of postmarketing

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studies that applicants have agreed to conduct and for whichstatus reports have been submitted (34). For these purposes,section 506B(b) indicates that any information necessary toidentify the sponsor of a study and establish the status of astudy and the reasons, if any, for any failure to carry out thestudy, shall be considered public information (35).

On December 1, 1999, the agency published in the FederalRegister a proposed rule to implement section 506B (36). OnOctober 30, 2000, the agency published the final rule (37), andby Federal Register notice published on February 20, 2001 (38),FDA delayed the effective date of the rule until April 30, 2001.The final rule makes several changes to the existing regula-tions for approved human drugs and licensed biologicalproducts, to incorporate the statutory provisions describedabove (39).

In addition, on April 3, 2001, FDA’s Center for BiologicsEvaluation and Research (CBER) issued a draft guidance to‘‘complement [ . . . ] the rule by describing in greater detailthe content, format, and timing of the postmarketing studyreports required by section 506B’’ (40). The guidance alsodescribes (a) FDA’s timeframes for reviewing the statusreports it receives; (b) how FDA will make information aboutpostmarketing studies public; and (c) what that informationwill be (41).

Section 130(b) of FDAMA directed FDA to submit a spe-cial postmarketing study report to Congress by October 1, 2001(42). In this report, FDA is required to: (a) summarize thestatus reports that have been submitted under section 506B;(b) evaluate the performance of applicants in fulfilling theirpostmarketing study commitments; (c) evaluate the agency’stimeliness in reviewing the postmarketing studies it hasreceived; and (d) make any necessary legislative recommenda-tions concerning postmarketing studies. On March 12, 2002,FDA issued its report to Congress (43). The report discussedthe need for postmarketing studies, including acceleratedapproval clinical benefit studies, and deferred pediatric studies,the agency’s experience with postmarketing studies, and FDA’ssteps to implement the provisions of Section 130 of FDAMAon postmarketing studies. FDA also noted the need for more



resources ‘‘to optimize its efforts in surveillance of applicantcompliance with postmarketing commitments and to conducttimely review of information resulting from completed post-marketing studies’’ (44).

4. DRUG APPLICATIONS AND APPROVALS

4.1. Fast Track Drugs—Expedited Studyand Approval

Section 112 of FDAMA, Expedited Study and Approval, addedsection 506 to the FDC Act (45). Section 506 was added toexpedite the development and approval of new drugs thataddress unmet medical needs relating to serious or life-threa-tening conditions. The section did not actually represent anyradical or innovative thinking but rather essentially codifiedFDA’s existing accelerated approval regulations (46) underwhich drugs for serious or life-threatening conditions couldbe approved based on surrogate endpoints. The statute did,however, expand that ‘‘fast track’’ system to include clinicalendpoints as well.

Section 506(a) provides that sponsors may request ‘‘fasttrack’’ designation concurrently with filing of the IND or atany time thereafter (47). FDA must act on requests within 30days. Section 506(b) includes the various standards forapproval, limitations, and conditions, taken from FDA’s exist-ing accelerated approval regulations, with the addition of clin-ical endpoints (48).

Section 506(c) provides for submission and review of a‘‘rolling’’ NDA for a fast track drug. To expedite the reviewprocess, FDA may begin reviewing portions of the NDA as theyare ready rather than waiting for the complete application tobe submitted and filed (49).

On November 18, 1998, FDA announced a guidance forindustry regarding Policies and Procedures for Fast TrackProducts (50). In the guidance, FDA explained that Section506 authorizes it to take actions appropriate to facilitate thedevelopment and expedite the review of an application for such

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a product, and that these actions ‘‘are not limited to thosespecified in the fast track provision but also encompass existingFDA programs to facilitate development and review of productsfor serious and life-threatening conditions,’’ which include bothFDA’s regulations on accelerated review, and the ‘‘priorityreview’’ designation procedures used by both the CDER andCBER (51). In the guidance, FDA discusses the regulations,policies, and procedures related to facilitating developmentand expediting review of promising therapies for serious andlife-threatening conditions for which there is an unmet medicalneed. The intent of the guidance is to ‘‘clarify the criteria andprocesses for designation of fast track products and to presenta coherent, integrated description of the diverse activities andpolicies that can facilitate development and expedite review ofdrugs that demonstrate the potential to advance the treatmentof serious and life-threatening illnesses’’ (52).

The guidance elaborates upon the criteria for qualificationin the fast track drug development program—the drug mustbe for treatment of a serious or life-threatening condition; andthe drug must demonstrate the potential to address an unmetmedical need for that condition.

4.1.1. Definition of Serious or Life-ThreateningCondition

The seriousness of a condition generally is based on its impacton such factors as survival, day-to-day functioning, or the like-lihood that the disease, if left untreated, will progress from aless severe condition to a more serious one. Acquired immuno-deficiency syndrome (AIDS), all other stages of human immu-nodeficiency virus (HIV) infection, Alzheimer’s dementia,heart failure, cancer, and many other diseases are ‘‘serious.’’Many chronic illnesses that are generally well managed byavailable therapy can have serious outcomes, such as asthma,rheumatoid arthritis, diabetes mellitus, systemic lupus erythe-matosus, depression, and many other diseases. For a conditionto be serious, the condition should be associated with morbiditythat has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient,



but the morbidity need not be irreversible if it is persistent orrecurrent (53).

For a product to be in a fast track drug development pro-gram, it must not only be used in patients with a serious con-dition, it must be intended to treat a serious aspect of thatcondition. For example, a therapeutic product would be consid-ered to treat a serious condition if it is being evaluated foreffects on a serious symptom of the condition. A preventiveproduct would be considered to treat a serious condition if itis being evaluated for its ability to prevent the condition. Aproduct that is intended to treat a condition while avoidingthe side effects of currently accepted treatments might be con-sidered to treat a serious condition if the side effects avoidedare serious. FDA may designate the development of such atherapy as a fast track drug development program when (a)currently accepted therapy is widely used despite an unavoid-able serious risk; (b) serious outcomes are a significant publichealth issue; and (c) the new therapy shows significant poten-tial to have a substantially improved overall safety profile withat least similar efficacy (54).

4.1.2. Demonstrating the Potential to AddressUnmet Medical Needs

Section 506(a) of the FDC Act further requires that the drugdemonstrate the potential to address unmet medical needs. Anunmet medical need is a medical need that is not addressedadequately by an existing therapy. If no therapy exists for aserious condition, there is an obvious unmet medical need, anda new treatment effective in that condition would meet thisaspect of the criteria for fast track designation (55).

Where there is available therapy for the condition, thedevelopmental program for the new agent would addressunmet medical needs if it evaluated any of the following (56):

Improved effect on serious outcomes of the condition thatare affected by alternate therapies.

Effect on serious outcomes of the condition not known tobe affected by the alternatives.

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Ability to provide benefits in patients who are unableto tolerate or are unresponsive to alternative agents.

Ability to provide benefit similar to those of alternativeswhile avoiding serious toxicity that is present inexisting therapies.

Ability to provide benefit(s) similar to those of alter-natives but with improvement in some factor, such ascompliance or convenience, that is shown to lead toimproved effects on serious outcomes.

The type of information needed to demonstrate thepotential of a drug to address unmet medical needs woulddepend on the stage of drug development. FDA will relyon summaries of available data to determine whether thepotential to address unmet medical needs has been demon-strated (57).

4.1.3. Process for the Designation of a Drug as aProduct in a Fast Track Drug DevelopmentProgram

A sponsor may submit a request for fast track designationat the time of original submission of its IND, or at anytime thereafter prior to receiving marketing approval ofits BLA or NDA. A request for fast track designationshould be submitted as an amendment to the sponsor’sIND (58).

In general, the submission to support a request for fasttrack designation should establish that the criterianecessary for designation are met, i.e., (a) that the drugis intended to treat a serious or life threateningcondition, and (b) that the drug has the potential toaddress unmet medical needs.

A submission for fast track designation should contain alldiscussion and supporting documentation needed topermit a reviewer to assess whether the criteria for fasttrack designation are met. Any data or publishedreports that support assertions made in the discussionsection of the fast track submission and that have not



previously been submitted to the sponsor’s IND shouldbe included in the submission.

FDA will respond to a request for fast track desig-nation within 60 calendar days of receipt of therequest (59).

It is foreseeable that, for certain products in fast trackdrug development programs, it will become apparent that thedevelopment programs do not continue to meet the criteriafor fast track designation. If the sponsor recognizes that thefast track drug development program will no longer be pur-sued, the sponsor should inform FDA. Additionally, FDA maychoose to send a letter notifying the sponsor that the programis no longer classified as a fast track drug developmentprogram (60).

4.1.4. Programs for Expediting Developmentand Review

The guidance further sets out other specific programs that areavailable to a sponsor in a fast track drug development pro-gram. With the exception of the submission of portions of aBLA/NDA before submission of the entire application, theseother programs described in the guidance been established inregulations under authority separate from FDAMA. Therefore,products that are not in drug development programs that havebeen designated as fast track may also be able to take advan-tage of these programs. The guidance provides more informa-tion on these regulatory programs (61).

If an applicant seeks approval of a product in a fast trackdrug development program based on evidence of an effect on aless than well-established surrogate endpoint, FDA may grantaccelerated approval based on a determination that the effecton the surrogate endpoint is reasonably likely to predict clinicalbenefit. Drug approval under the accelerated approval regula-tions may also be based on demonstrated clinical effects thatare reasonably likely to predict such benefit (62). Section506(b) essentially codifies these accelerated approval regula-tions (63).

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4.2. Data Requirements for Drugs and Biologics

Section 118 of FDAMA, data requirements for drugs andbiologics, required FDA, within 12 months of the statute’senactment, to issue a guidance describing when abbreviatedreports may be submitted in lieu of the full reports for clin-ical and non-clinical studies that are required to be includedin an NDA or biologics license application (BLA). This provi-sion responded to the regulated industry’s concern that drugdevelopment and approval times had increased in the UnitedStates (beyond the time required in Europe and Japan) inpart because of the increasing demands of NDA reviewers forindividual case report forms and other detailed sup-porting data, whereas reviewers in other countries rely to amuch greater extent on summary or abbreviated studyreports.

In August 1999, FDA issued the mandated guidance,which was intended to advise sponsors of the circumstanceswhen full study reports, abbreviated reports, and synopsescan be used to submit data concerning the effectiveness ofnew drugs and biological products (64). Generally, as set outin the Guidance, full study reports should be submitted for allclinical and human pharmacology investigations that contri-bute to the evaluation of effectiveness for the proposed indi-cation or that otherwise support information included inlabeling. Abbreviated reports should be submitted for studiesthat are not intended to contribute to the evaluation of producteffectiveness or provide definitive information on clinicalpharmacology, but about which the reviewer needs sufficientinformation to determine that the study results do notcast doubt on the drug’s effectiveness claims or the descriptionof the clinical pharmacology. Synopses should be submittedfor studies that are not relevant to the evaluation of producteffectiveness or clinical pharmacology, but that provide infor-mation the reviewer needs to evaluate the safety data from thestudy (65).

For clinical efficacy and safety studies, FDA describesthe following scheme for the submission of reports or



synopses:

1. Studies for which full reports should be submitted:Full study reports should ordinarily be submitted for allstudies from clinical investigations of drugs or biologi-cal products that are the subject of very limited clinicaldevelopment programs (i.e., programs with a total offewer than six clinical trials from any phase of drugdevelopment).

Full study reports should also be submitted forclinical effectiveness studies that (a) evaluate a dose,regimen, patient population, and indication for whichmarketing approval is sought, and (b) are capable bydesign, conduct, and enrollment of assessing the effec-tiveness of the product.

Examples include:

� Studies providing the basis for dose recommenda-

tions (e.g., dose-comparison studies).� Controlled studies identified by the applicant as

contributing directly to substantial evidence ofeffectiveness.

� Controlled studies that support an intended com-

parative claim.� Controlled studies of different indications (e.g.,

stages of disease, different study populations) ordosage forms or regimens if they are intended toprovide support for approval (66).

2. Studies for which abbreviated reports should besubmitted:Abbreviated reports should be submitted for studiesthat do not meet the above criteria, and that meet thefollowing conditions: (a) the studies are not intended tocontribute to the evaluation of product effectiveness,and (b) the reviewer needs sufficient informationabout the studies to determine that their results donot, in fact, cast doubt on the effectiveness claims forthe product. Abbreviated reports should contain fullsafety reports.

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Examples of studies that should be submitted as abbre-viated reports include:

� Studies with active controls that do not provide the

primary or substantiating evidence of effectiveness.� Studies of related indications for which marketing

approval is not being sought.� Studies not designed as efficacy studies or designed

as efficacy studies for different indications thatcontribute significant information about productsafety.

� Studies of doses or dosage forms not intended

for marketing (unless they are intended toprovide significant substantiating evidence of effec-tiveness) (67).

3. Studies for which synopses should be submitted:Some studies are generally only examined in sufficientdepth to assess if they cast doubt on the safety of theproduct for the proposed indication. For these studies,complete safety information should be included in theIntegrated Summary of Safety part of the NDA.

Examples of studies that should be submitted assynopses include:

� Studies of unrelated indications for which market-

ing approval is not being sought.� Studies evaluating routes of administration for

which marketing approval is not being sought.� Incomplete studies—those that enroll fewer than

one third of intended patients, unless stopped forsafety reasons or for inability to show efficacy.

� Early general phase 1 safety-tolerance studies (68).

For pharmacokinetic, bioavailability, and clinical pharma-cology studies, FDA describes the following scheme for thesubmission of reports or synopses:

1. Studies for which full reports should be submitted:

� Clinical pharmacology and biopharmaceutics stu-

dies that support labeling statements.



� The most relevant (e.g., best designed) in a seriesof similar studies. When studies in a series are notin agreement, all studies of that type should besubmitted as full reports.

� Dose ranging studies for phase 2 and 3 studies.� Bioavailability and bioequivalence studies that

compare performance of the formulation ordosage form used in clinical trials to that intendedfor marketing.

� One representative assay validation study for eachanalytical method at each analytical site (69).

2. Studies for which abbreviated reports should besubmitted:

� Less relevant studies in a series of similar studies(see above).

� Bioavailability/bioequivalence studies not assessingperformance of material used in clinical trials rela-tive to dosage forms intended for marketing (70).

3. Studies for which synopses should be submitted:

� Studies have been shown to have defects, such asin design, that render them incapable of support-ing a useful and/or relevant conclusion.

� Bioavailability/bioequivalence studies not assessingperformance of material used in clinical trials rela-tive to dosage forms intended for marketing.

� Discontinued studies.� Studies from abandoned indications (71).

The guidance describes in great detail the precise contentof abbreviated clinical reports and synopses. Generally, FDAinstructs the applicant to look to the requirements for thesubmission of data set out in the International Conference onHarmonisation (ICH) Guidance (72).

For clinical efficacy studies, an abbreviated report shouldcontain a full report of information related to safety and enoughinformation to allow the reviewers to fully assess whether theefficacy results, if any, cast doubt on the effectiveness of theproduct for the proposed indication. The abbreviated study

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report should contain only selected sections from the ICH gui-dance. The Abbreviated Studies Guidance explains which sec-tions from the ICH guidance the applicant may omit (73). Anabbreviated report should include all safety informationincluded in a full report, whereas efficacy information shouldbe concise and not as comprehensive as in a full report.

An abbreviated clinical pharmacology and biopharmaceu-tics study report should include generally the same elements asan efficacy study report, and also include:

Summary tables of mean values, standard deviations orcoefficients of variation, confidence intervals andobserved ranges, along with sample size.

For assay validation studies, assay performance should besummarized in enough detail for the reviewer to assessthe adequacy of the assay performance.

Formulation information including batch or lot numbersand qualitative and quantitative composition (74).

A synopsis should contain sufficient information to allowthe reviewer to assess whether the results cast doubt on thesafety of the product for the proposed indication. The synopsisshould summarize the study, including sufficient data to illus-trate results. An example of the structure and content of asynopsis is described in the ICH guidance. A synopsis shouldcontain, among other things, the study protocol and protocolamendments and a complete discussion of the safety data fromthese studies (75).

4.3. Content and Review of Applications

Section 119 of FDAMA, Content and Review of Applications,amended section 505(b) of the FDC Act to improve the processfor FDA review of NDAs and BLAs (76). Parallel amendmentswere made in section 505( j) for abbreviated NDAs (77). Section505(b)(4)(A) now provides that FDA must issue guidance forreviewers relating to ‘‘promptness in conducting the review,technical excellence, lack of bias and conflict of interest, andknowledge of regulatory and scientific standards’’ (78). Thesestandards must ‘‘apply equally to all individuals’’ who review



applications. As of April 27, 1999, FDA determined that itsexisting guidance documents were sufficient to satisfy this stat-utory requirement (79).

Section 505(b)(4)(B) requires FDA to meet with a sponsorupon receiving reasonable written request for the purpose ofreaching agreement on the design of pivotal trials. Agency min-utes must be prepared and made available to the sponsor (80).Sections 505(b)(4)(C) and (D) state that any agreement onstudy design at such a meeting must be put in writing (81).After testing begins, the agreement cannot be changed unilat-erally by FDA unless the director of the reviewing divisionissues a written decision that ‘‘a substantial scientific issueessential to determining the safety or effectiveness of thedrug has been identified after the testing has begun’’ (82).Upon request, the director must meet with the sponsor todocument the scientific issue on which this decision is based.

In February 2000, FDA issued a guidance for industryentitled ‘‘Formal Meetings with Sponsors and Applicants forPDUFA Products’’ (83). The guidance sets out the proceduresof CDER and CBER for formal meetings between FDA andsponsors regarding the development and review of productsin human drug applications as defined in section 735(1) ofthe FDC Act, i.e., products covered by the Prescription DrugUser Fee Act (PDUFA) (84). This guidance document describesprocedures for requesting, scheduling, conducting, and docu-menting such formal meetings for PDUFA drug products.

There are three categories of meetings between sponsorsor applicants for PDUFA products and CDER or CBER staff:Type A, Type B, and Type C. Each type of meeting is subject todifferent procedures:

Type A Meeting—one that is immediately necessary foran otherwise stalled drug development program toproceed (i.e., a critical path meeting). Type A meetingsgenerally are reserved for dispute resolution, clinicalholds, and special protocol assessments (discussedfurther below). Type A meetings should be scheduledto occur within 30 days of FDA’s receipt of a writtenrequest from the sponsor for a meeting.

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Type B Meeting—includes (a) pre-IND meetings; (b)certain end of phase 1 meetings; (c) end of phase 2/pre-phase 3 meetings; and (d) pre-NDA/BLA meetings.FDA will honor sponsor requests for Type B meetingsexcept under very unusual circumstances. Type Bmeetings should be scheduled to occur within 60 daysof the Agency’s receipt of the sponsor’s written request.FDA expects to grant only one of each of the Type Bmeetings for each potential application.

Type C Meeting—any meeting other than a Type A orType B meeting between FDA and a sponsor orapplicant regarding the development and review of aPDUFA drug product’s application. Type C meetingsshould be scheduled to occur within 75 days of theAgency’s receipt of the sponsor’s written request (85).

The sponsor should make the meeting request in writingto the appropriate division director within the applicable officewithin FDA. The request should be submitted as an amend-ment to an application, unless the request is made prior to thesubmission of an IND. The sponsor should contact the appro-priate review division to determine to whom it should send themeeting request.

Any meeting request should include adequate informa-tion, including the following:

1. Product name and application number (if applicable).2. Chemical name and structure.3. Proposed indication(s).4. The type of meeting being requested (i.e., Type A,

Type B, or Type C).5. A brief statement of the purpose of the meeting.6. A list of the specific objectives/outcomes expected

from the meeting.7. A preliminary proposed agenda, including estimated

amounts of time needed for each agenda item anddesignated speaker(s).

8. A draft list of specific questions, grouped by disci-pline.



9. A list of all individuals (including titles) who willattend the proposed meeting from the sponsor’sorganization and consultants.

10. A list of FDA staff (or particular disciplines)the sponsor requests participate in the proposedmeeting.

11. The approximate date on which the sponsor willsend supporting documentation to the review divi-sion.

12. Suggested dates and times for the meeting (86).

The review division should respond to the sponsor within 14days of receipt of the meeting request (87).

The sponsor must submit an ‘‘information package’’ toFDA in advance of the meeting—at least 2 weeks prior to aType A meeting, 4 weeks prior to a Type B meeting, and 2weeks prior to a Type C meeting. The information packageshould be paginated with a table of contents, appropriateindices, appendices, cross-references, and tabs differentiatingsections. Hard copies of the information package should beprovided for each FDA participant, with an extra five copiesfor consultation (88). The cover letter should clearly identifythe date, time, and subject of the meeting. Generally, the pack-age should include items 1–8 discussed above (updated asappropriate) and the following (89):

A list of specific questions grouped by disciplineClinical data summary (as appropriate)Preclinical data summary (as appropriate)Chemistry, manufacturing, and controls information (as

appropriate)

An FDA recorder will prepare minutes of any formal meet-ing with a sponsor for a PDUFA product. Sponsors may pro-vide a draft of the firm’s minutes in writing or may identify atthe end of the meeting the critical outcomes they believe shouldbe included in the meeting documentation. The sponsor shouldsubmit draft minutes promptly for FDA to consider them (90).Sponsors and applicants may notify FDA of significant differ-ences in understanding regarding the content of the official

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minutes of a meeting and, eventually, seek an appeal of FDA’sresponse (91).

In addition, in May 2002, FDA issued another guidanceentitled ‘‘Special Protocols Assessment’’ (92). The SpecialProtocols Assessment Guidance provides the CDER andCBER procedures for evaluating issues related to the adequacy(e.g., design, conduct, and analysis) of certain proposed studiesconducted under section 735(1) of the FDC Act (93) andPDUFA. The PDUFA goals for special protocol assessmentand agreement provide that, upon request of the product spon-sor of a PDUFA drug product, FDA will evaluate within 45days a sponsor’s proposed protocol to assess whether the pro-tocol meets scientific standards and regulatory requirements.As the PDUFA goals for protocol assessment are broader andmore specific than those required by FDAMA, the SpecialProtocols Assessment Guidance focuses on procedures toachieve the PDUFA goals. The FDAMA protocol assessmentrequirements will also be fulfilled by achieving the PDUFAgoals.

The Special Protocols Assessment Guidance sets out theprocedures applicants would use for requesting special protocolassessment. Protocols supporting NDAs, BLAs, and efficacysupplements to approved NDAs and BLAs may all be eligiblefor review under this guidance. Three types of protocols relatedto PDUFA products are eligible for the special protocol assess-ment procedures: (a) animal carcinogenicity protocols; (b) finalproduct stability protocols, and (c) clinical protocols for phase 3trials, where the data will form the primary basis for an effi-cacy claim (94).

The following procedures apply (95):

CDER and CBER generally recommend that a sponsorsubmit a protocol intended for special protocol assess-ment to the Agency at least 90 days prior to theanticipated start of the study. FDA will not provide anassessment if the study has already begun.

A sponsor interested in an assessment on a carcinogeni-city protocol should notify FDA at an end-of-phase-2meeting or send a letter stating an intent to request



special protocol assessment at least 30 days prior tosubmitting the request. The sponsor should submitrelevant background information so FDA can reviewreference material related to carcinogenicity protocoldesign prior to receiving the carcinogenicity protocol.

Generally, a standard stability protocol will be based onthe principles described in applicable agency stabilityguidance documents.

For special protocol assessment of a protocol for a clinicaltrial that will form the primary basis of an efficacyclaim in an NDA or BLA, the sponsor should have had ameeting with the review division. However, if FDA isalready familiar with the proposed clinical trial and hasan understanding of the questions that will be raisedregarding the protocol (for instance with efficacysupplements), FDA can provide a special protocolwithout requiring a meeting.

The sponsor should submit each protocol for assessmentas a separate amendment to the sponsor’s IND. The coverletter should clearly identify the submission as a Request forSpecial Protocol Assessment. The request should be submittedto the appropriate review division in CDER or applicationsdivision in CBER (96). The Special Protocols AssessmentGuidance sets out in detail those who should receive a copyof the cover letter requesting an assessment (97).

In the request for special protocol assessment, the sponsorshould pose focused questions concerning specific issuesregarding, among other things, the protocol and protocoldesign and/or data analysis for the proposed investigation.The sponsor should also describe, in a separate document,information, data, and assumptions that will assist theagency in evaluating the protocol. This discussion mightinclude the following (98):

Information to assess the role of the study in the overalldevelopment of the drug.

Information supporting the proposed trial, includingpower calculations, the choice of study endpoints, andother critical design features.

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Description of any anticipated regulatory outcomes, suchas approval of a claim and proposed labeling.

Information on product characterization, manufacturing,specifications, strengths, container closure, and otherinformation, if the sponsor seeks FDA assessment of astability protocol. If the information is contained in theIND, it can be submitted by cross-reference.

As stated in the PDUFA goals, the applicable team withinFDA reviewing the protocol will send comments within 45calendar days of receipt of the sponsor’s request for the specialprotocol assessment. If a sponsor submits a revised protocol,for any reason, while FDA is still reviewing the previous sub-mission, the new submission has the effect of restarting the45-calendar-day review clock (99). FDA can ask an advisorycommittee, members of a committee, or others such as specialgovernment employees and consultants to review protocols(100). If a sponsor requests a meeting with FDA after receivinga special protocol assessment letter, FDA will handle thematter as a request for a Type A meeting under the PDUFAgoals for meeting management (101).

The guidance emphasizes that all agreements and dis-agreements between FDA, and the sponsor regarding specialprotocol assessments should be clearly documented in writing(102). A special protocol assessment can document FDA’sagreement that the design and planned analysis of a studyadequately address objectives in support of a regulatory sub-mission. Having agreed to the design, execution, and analysesproposed in a protocol reviewed under this process, FDA isgenerally bound to that determination and may not laterchange its views, unless public health concerns becomeevident that were unrecognized at the time of protocol assess-ment under this process (103). Documented special protocolassessments are binding on the agency and should not bechanged at any time, except under the following circum-stances (104):

Failure of a sponsor to follow a protocol that was agreedupon



If the relevant data, assumptions, or information providedby the sponsor are found to be false or omit relevantfacts.

Changes in personnel, whether at the sponsor or at FDA,should not affect any documented special protocol assess-ment (105).

4.4. Requirements for Radiopharmaceuticals

Section 122 of FDAMA, Requirements for Radiopharmaceuti-cals, required FDA to promulgate regulations governing theapproval of radiopharmaceuticals (106). Proposed regulationswere required to be issued within 180 days of enactment ofFDAMA, with final regulations due within 18 months ofenactment.

Accordingly, on May 22, 1998, FDA proposed to amend itsdrug and biologics regulations by adding provisions that wouldclarify the evaluation and approval of in vivo radiopharmaceu-ticals used in the diagnosis or monitoring of diseases (107). Theproposed regulations describe certain types of indications forwhich FDA may approve diagnostic radiopharmaceuticals andalso set forth criteria that the agency would use to evaluate thesafety and effectiveness of a diagnostic radiopharmaceuticalunder the FDC Act and the Public Health Service (PHS) Act.A final rule was issued May 17, 1999, and became effectiveJuly 16, 1999 (108).

In accordance with the requirements of FDAMA, thefinal rule added new regulations pertaining to the reviewand approval of in vivo radiopharmaceuticals used for diag-nosis and monitoring. The new regulations are set forth in21 C.F.R. Parts 315 and 601 and are intended to ‘‘comple-ment and clarify existing regulations on the approval ofdrugs and biologics’’ in 21 C.F.R. Parts 314 and 601. Theregulations define a diagnostic radiopharmaceutical as oneof (109):

An article that is intended for use in the diagnosis ormonitoring of a disease or a manifestation of a disease

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in humans and that exhibits spontaneous disintegrationof unstable nuclei with the emission of nuclear particlesor photons

Any nonradioactive reagent kit or nuclide generatorthat is intended to be used in the preparation of sucharticle

FDA’s determination of the safety and effectiveness of adiagnostic radiopharmaceutical includes consideration of thefollowing (110):

The proposed use of the diagnostic radiopharmaceuticalin the practice of medicine

The pharmacological and toxicological activity of thediagnostic radiopharmaceutical

The estimated absorbed radiation dose of the diagnosticradiopharmaceutical

A diagnostic radiopharmaceutical may be indicated for thefollowing uses, among others (111):

Structure delineationFunctional, physiological, or biochemical assessmentDisease or pathology detection or assessmentDiagnostic or therapeutic patient management

Where a diagnostic radiopharmaceutical is not intended toprovide disease-specific information, the proposed indicationmay refer to a biochemical, physiological, anatomical, orpathological process or to more than one disease or condition(112).

FDA will assess the effectiveness of a diagnostic radio-pharmaceutical by evaluating its ability to provide useful clin-ical information for its proposed indications for use. Thisevaluation may depend upon one or more of the following cri-teria established in a defined clinical setting (113):

The claim of structure delineation is established bydemonstrating the ability to locate anatomical struc-tures and to characterize their anatomy.

The claim of functional, physiological, or biochemicalassessment is established by demonstrating reliable



measurement of function(s) or physiological, biochem-ical, or molecular process(es).

The claim of disease or pathology detection or assess-ment is established by demonstrating that thediagnostic radiopharmaceutical has sufficient accuracyin identifying or characterizing the disease orpathology.

The claim of diagnostic or therapeutic patient man-agement is established by demonstrating that thetest is useful in diagnostic or therapeutic patientmanagement.

Factors to be considered in the safety assessment of adiagnostic radiopharmaceutical include the following (114):

The radiation doseThe pharmacology and toxicology of the radiopharmaceu-

ticalThe risks of an incorrect diagnostic determinationThe adverse reaction profile of the drugResults of human experience with the radiopharmaceu-

tical for other usesResults of any previous human experience with the

carrier or ligand of the radiopharmaceutical when thesame chemical entity as the carrier or ligand has beenused in a previously studied product

To establish the safety of a diagnostic radiopharmaceuti-cal, FDA may require, among other information, the followingtypes of data (115):

Pharmacology dataToxicology dataClinical adverse event dataRadiation safety assessment.

The radiation safety assessment must establish the radia-tion dose by radiation dosimetry evaluations in humans andappropriate animal models. The maximum tolerated doseneed not be established (116).

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4.5. Insulin and Antibiotics

Section 125 of FDAMA, Insulin and Antibiotics, eliminatedthe approval and batch certification requirements for insulinand antibiotics in sections 506 and 507, respectively, of theFDC Act and made them subject instead to the NDA require-ments of section 505 that apply generally to new drugs. OnMay 13, 1998, FDA issued a direct-to-final rule implementingthese provisions (117). The rule repealed the agency’s regula-tions governing certification of drugs containing insulin andmade conforming amendments to other sections of its regula-tions. The agency used a direct final rulemaking for thisaction because it expected that there would be no significantadverse comment on the rule, given that most of the amend-ments in the rule are a direct result of the repeal of thestatutory certification provision and the remainder, in theagency’s view, repealed or updated out-of-date, noncontrover-sial regulations dealing with insulin. The rule became effec-tive September 25, 1998 (118).

Under section 125, the nonpatent market exclusivity pro-visions applicable to other products covered by an NDA wouldhenceforth also apply for any antibiotic NDA submitted to FDAafter November 1997. Section 125 further specified that anti-biotics approved by FDA under section 507 of the FDC Actprior to the enactment of FDAMA will be deemed to be subjectto approved NDAs and abbreviated NDAs (depending onwhether they were approved through the full or abbreviatedprocess under section 507) (119). The market exclusivity provi-sions of the FDC Act were not, however, made applicable tosuch applications. On January 24, 2000, FDA issued a proposedrule to implement the market exclusivity provisions of section125 (120), but this rule has not yet been finalized.

Notwithstanding the repeal of sections 506 and 507 of theFDCA and FDA’s implementing regulations, section 125 leftexisting law in place with respect to exports, so that unap-proved insulin and antibiotic products would continue to beexportable under section 801(e) of the FDC Act, withoutregard to the more restrictive requirements of section 802 forother unapproved new drugs (121).



4.6. Approval of Supplemental Applications forApproved Products

Section 403 of FDAMA, Approval of Supplemental Applicationsfor Approved Products, set forth requirements relating toFDA’s approval of supplemental applications (122). The provi-sions were added out of a congressional recognition that manydrugs and biologics are used off-label because NDA or BLAholders have no incentive to submit a supplemental applicationfor new conditions of use. Congress therefore wanted theagency to reduce the disincentives to the submissions ofthese applications by reducing the cost and increasing theefficiency of handling them within the agency (123).

Subsection (a) required FDA to publish in the FederalRegister by May 1998, standards for the prompt review of sup-plemental applications for approved articles. Subsection (b)required FDA to issue final guidance that would (1) clarifythe circumstances in which published materials may be thebasis for approval of a supplemental application; (2) specifydata requirements, in order to avoid duplicating data thathas been submitted previously; and (3) define supplementalapplications that are eligible for priority review (124). OnMay 15, 1998, FDA issued a guidance implementing section403 (125).

In the guidance, FDA set out its performance goals forreviews of efficacy supplements. The guidance defines whichsupplements are eligible for priority review. Under CDER’spolicy, an application or supplement for a drug product willreceive a priority review when the product, if approved,would be a significant improvement compared to marketedproducts, including nondrug products/therapies in the treat-ment, diagnosis, or prevention of a disease (126). CBER’s stan-dard operating procedures specify that a biological productoriginal or supplemental application will receive priorityreview where the product, if approved, ‘‘would be a significantimprovement in the safety or effectiveness of the treatment,diagnosis or prevention of a serious or life-threatening disease’’(127). FDA will use these same criteria to determine whetheran efficacy supplement is eligible for priority review (128).

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Subsection (c) required FDA to designate an individualwho would be responsible for encouraging the prompt reviewof supplemental applications and working with applicants tofacilitate submissions. Finally, subsection (d) required theSecretary of HHS to develop programs and policies that willfoster collaboration between FDA, NIH, professional medicaland scientific societies, and others, to identify any studies thatmay support supplemental applications and to encourage spon-sors to make supplemental applications or conduct furtherresearch in support of a supplemental application based onsuch studies.

4.7. Product Classification

Section 416 of FDAMA added a new section 563 to the FDC Actto provide for classification of products (129). New section563(a) provides that a person submitting an application forapproval of a product under the FDC Act may request thatFDA classify the product as a drug, biologic, device, or combi-nation product. FDA must respond within 60 days, giving theclassification of the product and the reasons for the determina-tion. If FDA fails to respond in 60 days, the submitter’s recom-mendation for a classification will be deemed to be a finaldecision by FDA. In either case, FDA may not modify the clas-sification unless the submitter consents to the reclassificationin writing, or there is a public health reason for the reclassifica-tion that is based on scientific evidence.

FDA has yet to issue a proposed rule implementing thisprovision (130).

5. DRUG MANUFACTURING ANDCOMPOUNDING

5.1. Manufacturing Changes for Drugs

Section 116 of FDAMA, Manufacturing Changes, establishedrequirements for making and reporting manufacturing changesto an approved NDA or ANDA (131). For any ‘‘major’’



manufacturing change, prior to distributing the changed drug,the sponsor must (132):

Validate the effects of the change on the identity,strength, quality, purity, and potency of the drug asthose characteristics may relate to the safety oreffectiveness of the drug

Submit to FDA a supplemental application for suchchange and receive FDA approval for the supplement.The supplement must include the information thatvalidates the change.

A ‘‘major’’ change is one that has substantial potential to affectadversely the identity, strength, quality, purity, or potency ofthe drug with respect to the safety or effectiveness of a drug.Such a change fulfills one of the following (133):

Is made in the qualitative or quantitative formulation ofthe drug

Is determined by FDA, by regulation or guidance, torequire completion of an appropriate clinical studydemonstrating equivalence of the drug to the drug asmanufactured without the change

Is another type of change determined by the Secretary byregulation or guidance to have a substantial potential toadversely affect the safety or effectiveness of the drug

For any manufacturing change that is not ‘‘major,’’ priorto distributing the changed drug, the sponsor, as with ‘‘major’’changes, must validate the effects of the change on the identity,strength, quality, purity, and potency of the drug as thosecharacteristics may relate to the safety or effectiveness of thedrug (134). Section 116 sets out how FDA may regulate drugssubject to manufacturing changes that are not deemed‘‘major.’’ FDA may authorize the sponsor to distribute suchdrugs without submitting a supplemental application for suchchanges and may distinguish categories of changes that mustbe subject to a supplement prior to distribution from those thatneed not be subject to a supplement (135).

For any changes not requiring a supplemental application,the sponsor must submit a report to FDA, as the agency

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specifies. FDA may permit the sponsor to submit only onecumulative report for the year (136).

For changes that do require supplemental applications(but are not major changes, requiring prior approval), thesponsor may commence distribution of the changed drug 30days after FDA receives the supplemental application (137).If FDA disapproves the supplemental application, FDAmay order the sponsor to cease the distribution of thedrugs that have been made with the manufacturingchange (138).

In November 1999, FDA published a guideline implement-ing section 116, ‘Guidance for Industry—Changes to anApproved NDA or ANDA’ (139). As the guidance explains,section 116 provides the following reporting categories (140):

A major change has a substantial potential to have anadverse effect on the identity, strength, quality, purity,or potency of a product as they may relate to the safetyor effectiveness of the product. A major change requiresthe submission of a supplement and approval by FDAprior to distribution of the product made using thechange (506A(c)(1)). This type of supplement is called,and should be clearly labeled, a Prior Approval Supple-ment.

An applicant may ask FDA to expedite its review of a priorapproval supplement for public health reasons or if adelay in making the change described in it wouldimpose an extraordinary hardship on the applicant.This type of supplement is called, and should be clearlylabeled, a Prior Approval Supplement—ExpeditedReview Requested.

A moderate change is a change that has a moderatepotential to have an adverse effect on the identity,strength, quality, purity, or potency of the product asthey may relate to the safety or effectiveness of theproduct. One type of moderate change requires thesubmission of a supplement to FDA at least 30 daysbefore the distribution of the product made using thechange. This type of supplement is called, and should be



clearly labeled, a Supplement—Changes Being Effectedin 30 Days.

FDA may identify certain moderate changes for whichdistribution can occur when FDA receives the supple-ment. This type of supplement is called, and shouldbe clearly labeled, a Supplement—Changes BeingEffected.

A minor change is a change that has minimal potential tohave an adverse effect on the identity, strength, quality,purity, or potency of the product as they may relateto the safety or effectiveness of the product. The appli-cant must describe minor changes in its next AnnualReport.

5.1.1. Assessing the Effect of ManufacturingChanges

A drug to which the sponsor has made a manufacturing changemust validate the effects of the change on the identity,strength, quality, purity, and potency of the product as thesefactors may relate to the safety or effectiveness of the product.The validation should include a determination that the drugsubstance intermediates, drug substance, inprocess materials,and/or drug product affected by the change conform to thespecifications set out in the approved application. The assess-ment should also include, as appropriate, evaluation of anychanges in the chemical, physical, microbiological, biological,bioavailability, and/or stability profiles of the drug. The typeof additional testing that an applicant should perform woulddepend on the type of manufacturing change, the type of drugsubstance and/or drug product, and the effect of the change onthe quality of the product (141).

An important component of this validation of changes isestablishing equivalency. The sponsor should usually assessthe extent to which the manufacturing change has alteredthe drug by comparing test results from pre- and postchangematerial and determining if the test results are equivalent. Anexception to this general approach is that when bioequivalenceis redocumented for certain ANDA postapproval changes, the

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comparator should be the reference listed drug. If a manufac-turing change adversely affects the identity, strength, quality,purity, or potency of the drug product, the change must be filedin a prior approval supplement (142).

5.1.2. Changes in Components and Composition

Changes in the qualitative or quantitative formulation, includ-ing inactive ingredients, are considered major changes andshould be filed in a prior approval supplement, unlessexempted by regulation or guidance (506A(c)(2)(A)). The dele-tion or reduction of an ingredient intended to affect only thecolor of a product may be reported in an annual report.

5.1.3. Changes to Manufacturing Sites

CDER should be notified about a change to a different site to(a) manufacture or process drug products, in-process materials,drug substances, or drug substance intermediates; (b) packagedrug products; (c) label drug products; and (d) test compo-nents, drug product containers, closures, packaging materials,in-process materials, or drug products. A move to a differentmanufacturing site, when it is a type of site routinely subject toFDA inspection, should be filed as a prior approval supplementif the site does not have a satisfactory CGMP inspection for thetype of operation (143).

The guidance provides detailed descriptions of what typesof site changes should be reported to FDA and how they shouldbe reported. For example (144):

Moving to a different manufacturing site when FDA hasnever inspected the new site typically is major changethat must be subject to a prior approval supplement.

Moving to a different manufacturing site for the primarypackaging of a modified-release solid oral dosage formproducts is a moderate change that is subject to aSupplement—Changes Being Effected in 30 Days.

Moving to a different manufacturing site for the manu-facture for processing of the final intermediate is a



moderate change that is subject to a Supplement—Changes Being Effected.

A move to a different manufacturing site for labeling isa minor change that may be reported in the annualreport.

5.1.4. Changes to Manufacturing Processes

The guidance provides detailed descriptions of what types ofchanges to manufacturing processes should be reported toFDA, and how they should be reported. For example (145):

Any fundamental change in the manufacturing process ortechnology, such as changing the drug product manu-facture from dry to wet granulation is a majorchange that must be subject to a prior approvalsupplement.

For drug products and drug substances, most changes inthe process, process parameters, and/or equipment aremoderate changes subject to a Supplement—ChangesBeing Effected in 30 Days.

A change in methods or controls that provides increasedassurance that the drug substance or drug product willhave the characteristics of identity, strength, purity, orpotency that it purports or is represented to possess is amoderate change that is subject to a Supplement—Changes Being Effected.

A minor change in an existing code imprint for a dosageform such as changing from a numeric to alphanumericcode is a minor change that may be reported in theannual report.

5.1.5. Changes to Specifications

All changes in specifications from those in the approved appli-cation must be submitted in a prior approval supplementunless otherwise exempted by regulation or guidance. The gui-dance provides detailed descriptions of what types of changesto specifications should be reported to FDA and how they

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should be reported. For example (146):

Establishing a new regulatory analytical procedure (suchas are used to define a characteristic of the drugsubstance or drug product) is a major change that mustbe subject to a prior approval supplement.

Relaxing an in-process acceptance criterion associatedwith microbiological monitoring of the productionenvironment, materials, and components that areincluded in NDA and ANDA submissions is a moderatechange that is subject to a Supplement—ChangesBeing Effected in 30 Days.

An addition to a specification that provides increasedassurance that the drug substance or drug product willhave the characteristics of identity, strength, purity, orpotency that it purports to possess is a moderate changethat is subject to a Supplement—Changes BeingEffected.

Any change in a specification made to comply with anofficial compendium is a minor change that may bereported in the annual report.

5.1.6. Changes to Packaging

The guidance provides detailed descriptions of what types ofchanges to packaging should be reported to FDA and how theyshould be reported. For example (147):

A change in the primary packaging components for anyproduct when the primary packaging componentscontrol the dose delivered to the patient (e.g., thevalve or actuator of a metered-dose inhaler) is a majorchange that must be subject to a prior approvalsupplement.

Most changes to a container closure system are moderatechanges that are subject to a Supplement—ChangesBeing Effected in 30 Days.

A change in or addition or deletion of a desiccant is amoderate change that is subject to a Supplement—Changes Being Effected.



A change in the size and/or shape of a containercontaining the same number of dose units for anonsterile solid dosage form is a minor change thatmay be reported in the annual report.

5.1.7. Changes to Labeling

The guidance provides detailed descriptions of what types ofchanges to labeling should be reported to FDA, and how theyshould be reported. For example (148):

Changes based on postmarketing study results, including,but not limited to, labeling changes associated with newindications and usage are major changes that must besubject to a prior approval supplement.

Most changes to a container closure system are moderatechanges that are subject to a Supplement—ChangesBeing Effected in 30 Days.

A Supplement—Changes Being Effected should besubmitted for any labeling change that (a) adds orstrengthens a contraindication, warning, precaution, oradverse reaction; (b) adds or strengthens a statementabout drug abuse, dependence, psychological effect, oroverdosage; (c) adds or strengthens an instructionabout dosage and administration that is intended toincrease the safe use of the product; (d) deletes false,misleading, or unsupported indications for use or claimsfor effectiveness; or (e) is specifically requested by FDA.

Editorial changes and changes made to comply with anofficial compendium are minor changes that may bereported in the annual report.

5.2. Pilot and Small-Scale Manufacture

Section 124 of FDAMA, Pilot and Small-Scale Manufacture,amends section 505(c) of the FDC Act (149). The new languageof section 505(c) provides that a drug manufactured in a pilotor other small facility may be used to demonstrate the safetyand effectiveness of the drug and to obtain approval for the

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drug prior to manufacture of the drug in a larger facility,unless FDA makes a determination that a full-scale productionfacility is necessary to ensure the safety or effectiveness of thedrug (150). The same provision was added to the part of theFDC Act governing approval of animal drugs (151).

5.3. Registration of Foreign Establishments

Section 417 of FDAMA, Registration of ForeignEstablishments, amended § 510(i) of the FDC Act (152).Prior to FDAMA, foreign establishments could, but were notrequired to, register with the FDA. FDA, by regulation, didrequire foreign establishments to list their drug productsregardless of whether the foreign establishment was registered.Pursuant to § 417 of FDAMA, any foreign company engaged inthe manufacture, preparation, propagation, compounding, orprocessing of a drug or a device that is imported or offeredfor import into the United States must register with theSecretary the name and place of business of the establish-ment (153).

The establishment must also provide the informationrequired by the FDC Act for drug listing (154). Based uponregulations promulgated under FDAMA, an owner or operatorof an establishment is required to register a drug with FDAbefore beginning manufacture or processing if the drug is sub-ject to an NDA, ANDA, BLA, new animal drug application,abbreviated new animal drug application, or a medicated feedmill license application (155).

FDAMA also authorized FDA to enter into cooperativearrangements with officials of foreign countries (156). The pur-pose of these cooperative agreements is to ensure that ade-quate means are available for determining whether the drugsmanufactured or otherwise prepared by a foreign establish-ment should be refused admission into United States whenthey are imported or offered for import. No drug may beimported or offered for import into the United States unlessit is listed and manufactured or otherwise prepared at a regis-tered foreign drug establishment. This restriction doesnot apply to a drug imported or offered for import for



investigational use. Regulations implementing this section pro-vide that foreign establishments must submit all listing infor-mation, including labels and labeling and registrationinformation in English (157).

The establishment must also have a United States agentand identify the name and other business information for thatagent (158). ‘‘United States agent’’ means a person residing ormaintaining a place of business in the United States whom aforeign establishment designates as its agent. This definitionexcludes mailboxes, answering machines or services, or otherplaces where an individual acting as the foreign establish-ment’s agent is not physically present (159).

The owner or operator of an establishment entering intothe manufacture or processing of a drug or drugs shall registerthe establishment within 5 days after the beginning of theoperation and shall submit a list of every drug in commercialdistribution at that time. If the owner or operator of the estab-lishment has not previously entered into such an operation, theowner or operator shall register within 5 days after submittinga new drug application (such as an NDA, ANDA, etc.). Ownersor operators must renew their registration informationannually (160).

Foreign drug establishments whose drugs are imported oroffered for import into the United States must comply with theestablishment registration and drug listing requirementsunless the drugs enter a foreign trade zone and are reexportedfrom that foreign trade zone (161).

5.4. Mutual Recognition Agreements and GlobalHarmonization

Section 410 of FDAMA, Mutual Recognition Agreements andGlobal Harmonization, amends section 803 of the FDC Act(162). Section 410 directs FDA to take certain steps in supportof the Office of the United States Trade Representative and theSecretary of Commerce in furtherance of global harmonization.Section 410 requests that FDA (163):

Meet with representatives of other countries to discussmethods to reduce the burden of regulation and

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harmonize regulatory requirements, consistent withconsumer protection.

Engage in efforts to move toward acceptance of MutualRecognition Agreements (MRAs) relating to the regula-tion of devices and Good Manufacturing Practices(GMPs) between the European Union and the UnitedStates.

FDA shall participate regularly in meetings with represen-tatives of other foreign governments to discuss and reachagreement on methods and approaches to harmonize regula-tory requirements (164).

FDAMA required FDA to ‘‘make public a plan that estab-lishes a framework for achieving mutual recognition of goodmanufacturing practices inspections’’ (165). FDA issued thatframework on May 20, 1998, in ‘‘FDA Framework forAchieving Mutual Recognition of Good ManufacturingPractices Inspections—A Plan That Establishes a FrameworkFor Achieving Mutual Recognition of Good ManufacturingPractices Inspections’’ (166). This guidance establishes thatany foreign country must have in place regulatory require-ments for GMPs that are at least equivalent to FDA require-ments in order for FDA to recognize that country’s GMPstandards.

5.5. Pharmacy Compounding

On March 16, 1992, FDA issued a CPG, section 7132.16 (laterrenumbered as 460.200) to delineate FDA’s enforcement policyon pharmacy compounding. In section 127 of FDAMA,Congress essentially codified that CPG and added section503A to the FDC Act to clarify the status of pharmacy com-pounding under federal law (167). Under section 503A, drugproducts that were compounded by a pharmacist or physicianon a customized basis for an individual patient were entitled toexemptions from three key provisions of the FDC Act: (a) theadulteration provision of section 501(a)(2)(B) (concerning thegood manufacturing practice requirements); (b) the misbrand-ing provision of section 502(f )(l) (concerning the labeling ofdrugs with adequate directions for use); and (c) the new drug



provision of section 505 (concerning the approval of drugsunder new drug or abbreviated new drug applications). Toqualify for these statutory exemptions, a compounded drugproduct was required to satisfy several requirements, some ofwhich were to be the subject of FDA rulemaking or otheractions.

Among the restrictions set forth in section 127 of FDAMAwere certain prohibitions upon the advertising of compoundeddrugs. Several compounding pharmacies challenged theserestrictions. On February 6, 2001, the Ninth Circuit Court ofAppeals declared section 503A invalid in its entirety (168). TheU.S. Supreme Court affirmed the 9th Circuit Court of Appealsdecision that found section 503A of the Act invalid in itsentirety because it contained unconstitutional restrictions oncommercial speech (i.e., prohibitions on soliciting prescriptionsfor and advertising specific compounded drugs) (169). TheCourt did not rule on, and therefore left in place, the 9thCircuit’s holding that the unconstitutional restrictions on com-mercial speech could not be severed from the rest of section503A.

Accordingly, all of section 503A of FDAMA regardingpharmacy compounding is invalid. On June 7, 2002, FDA reis-sued its CPG 460.200 to eliminate what it deemed the uncon-stitutional requirements and to provide regulatory guidance onpharmacy compounding practice (170).

FDA recognizes that pharmacists traditionally havecompounded reasonable quantities of human drugs with avalid prescription for an individual patient from a licensedpractitioner. This activity is within the traditional practiceof pharmacy and not a matter of regulatory concern toFDA (171). However, FDA also believes that some retailpharmacies are engaged in manufacturing and distributingunapproved new drugs for human use in a manner that isclearly outside the bounds of this traditional pharmacy prac-tice and that these pharmacies are violating the FDC Act.The practices of many of these entities are more consistentwith those of drug manufacturers and wholesalers than withthose of retail pharmacies. Pharmacies engaged in activitiesanalogous to manufacturing and distributing drugs for

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human use may be held to the same standards as drugmanufacturers.

When the scope and nature of a pharmacy’s activities arelike those normally associated with a drug manufacturer, FDAstates that it will seriously consider enforcement action.In determining whether to initiate such an action, FDA willconsider whether the pharmacy engages in any of the followingacts:

Compounding of drugs in anticipation of receivingprescriptions, except in very limited quantities.

Compounding drugs that were withdrawn or removedfrom the market for safety reasons. [FDA has publisheda list of such drugs (172).]

Compounding finished drugs from bulk active ingredientsthat are not components of FDA-approved drugs with-out an FDA-sanctioned IND in accordance with 21U.S.C. § 355(i) and 21 CFR 312.

Receiving, storing, or using drug substances without firstobtaining written assurance from the supplier that eachlot of the drug substance has been made in an FDA-registered facility.

Receiving, storing, or using drug components not guar-anteed or otherwise determined to meet officialcompendia requirements.

Using commercial-scale manufacturing or testing equip-ment for compounding drug products.

Compounding drugs for third parties who resell toindividual patients or offering compounded drugproducts at wholesale to other state-licensed personsor commercial entities for resale.

Compounding drug products that are commerciallyavailable in the marketplace or that are essentiallycopies of commercially available FDA-approved drugproducts. In certain circumstances, it may be appro-priate for a pharmacist to compound a small quantity ofa drug that is only slightly different from an FDA-approved drug that is commercially available. In thesecircumstances, FDA will consider whether there is



documentation of the medical need for the particularvariation of the compound for the particular patient.

Failing to operate in conformance with applicable statelaw regulating the practice of pharmacy (173).

6. INFORMATION DISSEMINATION ANDLABELING

6.1. Health Care Economic Information

Section 114 of FDAMA, health care economic information,amended section 502(a) of the FDC Act (174). Section 114added the following (175):

Health care economic information provided to a formularycommittee, or other similar entity, in the course of thecommittee or the entity carrying out its responsibilities for theselection of drugs for managed care or other similar organiza-tions, shall not be considered to be false or misleading under thisparagraph if the health care economic information directlyrelates to an indication approved under section 505 or undersection 351(a) of the Public Health Service Act for such drug andis based on competent and reliable scientific evidence.

Information that is relevant to the substantiation of thehealth care economic information presented pursuant to thissection must be made available to FDA upon request (176).The statute defines ‘‘health care economic information’’ as‘‘any analysis that identifies, measures, or compares the eco-nomic consequences, including the costs of the representedhealth outcomes, of the use of a drug to the use of anotherdrug, to another health care intervention, or to no interven-tion’’ (177).

6.2. Elimination of Certain LabelingRequirements

Section 126 of FDAMA eliminated certain labeling require-ments for prescription drugs. Prior to the enactment ofFDAMA, the FDC Act stated that a prescription drug product

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would be deemed to be misbranded if, at any time prior todispensing, its label fails to bear the statement, ‘‘Caution:Federal law prohibits dispensing without prescription.’’Section 126 of FDAMA eliminated this requirement. Prior todispensing, the label of prescription products must contain thesymbol ‘‘Rx only’’ (178).

The ‘‘Rx only’’ statement should be prominent and con-spicuous. FDA prefers that the statement appear on the mainpanel of container labels and carton labeling. The ‘‘Rx only’’statement is not required for package insert labeling. However,if a manufacturer chooses to include the statement, the agencyprefers that it be placed in the ‘‘Title’’ section of the packageinsert. Manufacturers may exercise discretion as to whether toinclude the quotation marks and whether the word ‘‘only’’appears in upper or lower case letters (179).

Prior to FDAMA, section 502(d) of the FDC Act requiredthe labels of certain habit-forming drugs to bear the statement‘‘Warning—May be habit forming.’’ FDAMA eliminated thisrequirement as well.

In implementing regulations, FDA added new 21 C.F.R.§ 290.1 and § 290.2. Section 290.1 was added to make clear thata drug that is a controlled substance listed in schedule II, III,IV, or V of the Federal Controlled Substances Act (CSA) orimplementing regulations must, unless FDA otherwise deter-mines, be dispensed by prescription only (180). Section 290.2retains the exemption from the prescription-dispensing require-ment for small amounts of codeine in combination withother nonnarcotic active medicinal ingredients—these prod-ucts may continue to be dispensed over the counter, withouta prescription (181).

6.3. Notification of Discontinuance of aLifesaving Product

Section 131 of FDAMA, Notification of Discontinuance of aLifesaving Product, added a new section to the FDC Act(182). Section 131 provides that the sole manufacturer of adrug shall notify FDA of its intent to discontinue manufactureof the drug at least 6 months prior to the date of the



discontinuance (183). This 6-month notification requirementonly applies if the drug is life supporting, life sustaining, orintended for use in the prevention of a debilitating disease orcondition. The notice prior to discontinuance only applies if thedrug is subject to an application approved under section 505(b)of the FDC Act (an NDA) or 505( j) of the FDC Act (an ANDA).This means that the notification prior to discontinuance doesnot apply to drugs licensed under the PHS Act, such as bio-logics, including blood products, sera, toxins, and vaccines. Thenotification prior to discontinuance requirement does not applyto a product that was originally derived from human tissue andwas replaced by a recombinant product.

FDA may reduce the 6-month notification period if themanufacturer certifies that good cause exists for the reduction(184). Examples of situations where good cause exist include(185):

A public health problem may result from continuation ofmanufacturing for the 6-month period

A biomaterials shortage prevents the continuation ofmanufacturing for the 6-month period

A liability problem may exist for the manufacturer if themanufacturing is continued for the 6-month period

Continuation of the manufacturing for the 6-monthperiod may cause substantial economic hardship forthe manufacturer

The manufacturer has filed for bankruptcyThe manufacturer can stop making the product but

still distribute it to satisfy existing market need for6 months.

A manufacturer may also be able to show on some other basisthat good cause exists for a reduction in the 6-month notifica-tion period.

To the maximum extent practicable, FDA must distributeinformation on the discontinuation of the drugs describedabove to appropriate physician and patient organizations.

FDA proposed a regulation implementing section 131 onNovember 7, 2000 (186). That regulation is not yet final. Italso proposes additional procedures. The proposed 21 C.F.R.

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§ 314.91 would set out how a manufacturer would apply to theagency for a shortening of the 6-month notification period(187):

The applicant must certify in a written request that, in itsopinion and to the best of its knowledge, good causeexists for the reduction. The applicant must submit thefollowing certification: ‘‘The undersigned certifies thatgood cause exists for a reduction in the 6-monthnotification period required in Sec. 314.81(b)(3)(iii)(a)for discontinuing the manufacture of (name of the drugproduct). The following circumstances establish goodcause (one or more of the circumstances describedabove).’’

The certification must be signed by the applicant or theapplicant’s attorney, agents (representative), or otherauthorized official.

For drugs regulated by CDER, the certification must besubmitted to the director of the division that isresponsible for the drug application. One copy of thecertification must be sent to the Drug ShortageCoordinator, at the address of the Director of CDER,and one copy of the certification must be sent to theDrug Listing Branch. For drugs regulated by CBER, thecertification must be submitted to the Director ofCBER.

6.4. Dissemination of Information on New Uses

Prior to passage of FDAMA, FDA essentially had limited thedissemination of information on unapproved uses of medicaldevices, drugs, and biologics to responses to unsolicitedrequests for the information (188). Outside this narrow excep-tion, if a manufacturer disseminated information on an unap-proved use, FDA would consider the product adulterated ormisbranded. For years there had been heated debate amongvarious interest groups as to whether the restrictions on thedissemination of information on off-label uses should be loos-ened. Section 401 of FDAMA represented Congress’s attempts



to legislate a compromise of sorts among these competinginterests.

Section 401 added a new subchapter D to the FDC Act,consisting of new sections 551–557 authorizing manufac-turers to disseminate information about unapproved (‘‘off-label’’) uses of approved drugs, biological products, anddevices (189).

New section 551 permits a manufacturer to distributewritten information concerning a use not described in theapproved labeling under certain conditions described in thestatute (190). The information can be distributed to practi-tioners, pharmacy benefit managers, insurers, group healthplans, and governmental agencies. It cannot be distributeddirectly to patients. Section 551(b) sets forth requirementsfor distributing information under this section; these require-ments are quite restrictive and include requirements that theproduct be approved, that the information to be disseminatednot be derived from research conducted by another manufac-turer, except with its permission, and that the manufacturersubmit the information to FDA 60 days before beginning dis-tribution, together with safety and effectiveness informationfrom clinical trials and safety information from reports ofclinical experience. Further, the only information that a manu-facturer may distribute is (a) an unabridged reprint of a peer-reviewed article published in a scientific or medical journalabout a clinical investigation, which would be considered‘‘scientifically sound,’’ or (b) a reference publication containingsimilar information (191).

Under new section 553, a manufacturer must submit toFDA on a ‘‘biannual’’ basis a list of articles and referencepublications distributed under section 551 and a list identifyingthe categories of persons that received them (192). Under newsection 554, a manufacturer may disseminate informationabout an off-label use only if it has submitted to FDA a supple-mental application covering the new use, the manufacturercertifies that it will submit such a supplement, or it has anexemption from the supplement requirement (193). A manu-facturer may request an exemption from the supplementrequirement from FDA if it would be ‘‘economically

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prohibitive’’ or ‘‘unethical’’ to conduct the studies and submitthe supplement.

Under new section 555, FDA may, if it receives newinformation indicating that the new use may not be effectiveor may present a ‘‘significant risk to public health,’’ takeappropriate action, including ordering the manufacturerto cease dissemination (194). FDA may also order a manu-facturer to cease dissemination if there has been a failureto comply with the statutory requirements. FDA may alsoorder a manufacturer to correct information that has beendisseminated.

In July 1999, Judge Royce C. Lamberth of the UnitedStates District Court for the District of Columbia struckdown much of this provision (and the prior guidance docu-ment) as violative of the First Amendment free speech rightsof drug manufacturers (195). The court enjoined FDA frominterfering where a manufacturer wishes to disseminate to ahealthcare professional a reprint of an article published in a‘‘bona fide peer-reviewed journal’’ or an excerpt from a refer-ence textbook, if it (a) is published by a ‘‘bona fide independentpublisher’’ and (b) is otherwise generally available for sale inbookstores or other distribution channels, where similar booksare normally available (196).

The court’s injunction was based on a finding that theFDAMA provisions on the dissemination of informationabout off-label uses were flawed because they failed toadvance the government’s asserted interest in encouragingdrug manufacturers to obtain approval for on-label indica-tions for off-label use. Instead, the court found that almostall of the requirements were designed to force a ‘‘balanced’’presentation of information to physicians in order to preventthem from potentially being misled. Potentially misleadingspeech, however, is not proscribable under the FirstAmendment. The First Amendment could be overcome onlywhere speech is more likely than not to mislead. Moreover,the court found that the fact that physicians can freelyexchange articles amongst themselves, and the fact thatFDA permitted manufacturers to distribute the same infor-mation in response to a physician inquiry, cast doubt on the



validity of FDA’s professed concern over the ability of articlereprints to mislead physicians.

On February 11, 2000, the U.S. Court of Appeals for theDistrict of Columbia, ruling basically on procedural grounds,vacated the district court’s injunction as it related to FDAMA(197). The ruling was based on FDA’s position, enunciatedfor the first time during the appeal, that it did not claimauthority to regulate the dissemination of informationbased on FDAMA. According to FDA, FDAMA merely createdsafe harbors that could be followed without fear of govern-ment action. Moreover, while companies were free to tryother mechanisms, FDA stated that if the safe harborswere not followed, a company ran the risk that reprintscould be used as evidence in an enforcement action broughtagainst the company for shipping an unapproved drug. TheCourt of Appeals ruled, in effect, that the First Amendmentissue on which the district court had based its decision wasnot ripe for decision. Noteworthy, however, was the court’scomment in footnote 7 of the opinion that ‘‘we certainly donot criticize the reasoning or conclusions of the districtcourt’’ (198).

The end result is that a pharmaceutical, biological pro-duct, or medical device company has two options with regardto dissemination of ‘‘off-label’’ information. The more conser-vative approach is simply to refrain from disseminating ‘‘off-label’’ information except in the rare instances where it canbe done in accordance with the ‘‘safe harbor’’ set forth insection 401 and FDA’s implementing regulations. Second, acompany may consider continuing to disseminate, to health-care professionals, certain types of off-label information inaccordance with the district court opinion in theWashington Legal Foundation case. As noted, the Court ofAppeals did not question the substance of Judge Lamberth’sFirst Amendment analysis, and presumably it remains goodlaw. Importantly, however, if a company chooses to continuedisseminating information in accordance with the vacatedinjunction, FDA may consider the dissemination of off-labelinformation as evidence of a new ‘‘intended use’’ in a tradi-tional misbranding or distribution of an unapproved product

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enforcement action. Legal counsel should be consulted whensuch activity is planned.

7. FDA MANAGEMENT AND POLICIES

7.1. Scientific Advisory Panels

Section 120 of FDAMA, Scientific Advisory Panels, authorizesFDA to establish panels of experts to provide advice and recom-mendations regarding a drug’s clinical investigation and sub-sequent approval for marketing (199). FDA may both establishnew panels of experts and continue to use its existing advisorycommittees. In a guidance document implementing section120, FDA stated that its existing advisory committee regula-tions at 21 C.F.R. Part 14 do not need to be amended to complywith FDAMA (200).

As to membership requirements, FDA stated that existingadvisory committees need not amend their membership tocomply with the new FDAMA provisions. However, in theinterest of furthering the goals of the statutory amendments,CDER and CBER intend generally to modify current advisorycommittee membership on a meeting-by-meeting basis and torecharter committees, as needed, to reflect the representationdescribed in 21 U.S.C. § 355(n)(3) (201).

Under the new provision, a new advisory committee iscomprised of core members of the panel and other individualswho may be called upon to participate in a given meeting on anad hoc basis. The core members of the advisory committee areappointed by the Commissioner or his/her designee based ontheir scientific or technical expertise and serve for the durationof the committee or until their terms of appointment expire,they resign, or the Commissioner or his/her designee removesthem. The core membership of a committee may be supplemen-ted on an ad hoc basis to include (a) representation of consu-mer/patient interests; (b) representation from the interests ofthe drug manufacturing industry; and (c) at least two memberswho are specialists with expertise in the particular disease or



condition for which the drug under consideration is proposed tobe indicated (202).

Each panel member must disclose all conflicts of interestand may not vote on any matter where the member or theimmediate family of such member could gain financially fromthe matter. While the Commissioner (or his or her designee)may grant a waiver of any conflict of interest requirement ifthe waiver is necessary to the panel’s work, there are no waiv-ers where the panel is considering the member’s own scientificwork (203).

Ad hoc committee members who are representatives ofconsumer or patient interests, or who have expertise in theparticular disease or condition for which the drug under con-sideration is proposed to be indicated, may vote if (a) themember has the requisite scientific or technical expertise and(b) participation is not prevented by conflict of interest lawsand regulations. Because of inherent conflict-of-interest con-cerns, representatives of the drug manufacturing industrywill not be voting members of the committee. No regular,full-time employee of the United States government who isengaged in the administration of the FDC Act may be avoting member of an advisory committee (204).

Within 90 days after a scientific advisory panel makesrecommendations on any matter under its review, the FDAofficial responsible for the matter must review the conclusionsand recommendations of the panel and notify the affected per-sons of the final decision on the matter or of the reasons whyno such decision has been reached (205).

7.2. Modernization of Regulation

Section 123 of FDAMA was intended to ‘‘modernize’’ certainaspects of FDA regulation of drugs and biological products.Section 123 codified numerous practices that CBER hadalready required of biologics manufacturers. Section 123 alsosought to minimize the differences between FDA’s regulationof drugs approved under section 505(b)(1) of the FDC Act (206)and section 351 of the PHS Act (207).

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Prior to FDAMA, the PHSAct did not require specific FDA-approval or licensure of a biological drug product. FDAMAamended the PHS Act to clarify what FDA has long required.No person may introduce a biological product into commerceunless (208):

The product is covered by a biologics licenseEach package of the biological product is plainly marked

with (a) the proper name of the biological productcontained in the package; (b) the name, address, andapplicable license number of the manufacturer of thebiological product; and (c) the expiration date of thebiological product.

At one time, FDA had required two separate licensesfor the lawful marketing of a biological product—theEstablishment License Application (ELA) and the ProductLicense Application (PLA). In the regulation implementingsection 123, FDA eliminated the distinction and created asingle application, the Biologics License Application (BLA),which is intended to be analogous to the NDA for drugs (209).

Section 123 of FDAMA also charges FDA with approvingBLAs only for biological products that are safe, pure, andpotent and that are manufactured, processed, packed, andheld to standards that assure the biological product continuesto be safe, pure, and potent. The applicant must agree to aninspection of any facility that is the subject of the BLA (210). Inregulations implementing FDAMA, FDA explicitly extendedthe current good manufacturing practices (CGMP) require-ments applicable to drug products to biological products aswell (211).

FDAMA also explicitly extends the FDC Act to cover allbiological products licensed under the PHS Act, but does notrequire that such products also have approved drug applica-tions (212).

FDA regulations implementing FDAMA clarify proceduresfor submitting an application for marketing approval for aradioactive biological product in order to help ensure consis-tency with CBER and CDER policies. The regulation clarifiesthat when the biological component of a radioactive coupled



antibody determines the site of action, the sponsor shouldsubmit a BLA to CBER (213).

7.3. Dispute Resolution

Section 404 of FDAMA, dispute resolution, added a new section562 to the FDC Act (214). If there is a ‘‘scientific controversy’’under the FDCAct or section 351 of the PHS Act, and no specificprovision of the Act or a regulation provides a right to agencyreview of the matter, the sponsor, applicant, or manufacturermay request review under procedures established by FDA.

In the Federal Register of November 18, 1998, FDAamended 21 C.F.R. § 10.75 to state explicitly that a sponsor,applicant, or manufacturer of a drug or device may requestreview of a scientific controversy by an appropriate advisorycommittee (215). Should FDA deny such a request, FDA mustset forth the reasons for the denial request in writing to therequester (216). Persons who receive a CDER or CBER denialof their request for a 404 review by an advisory panel maysubmit a request for review of that denial to FDA’s ChiefMediator and Ombudsman (217).

Each Center within FDA is responsible for developing andadministering its own processes for handling requests forsection 404 reviews (218). CDER and CBER issued a joint gui-dance concerning dispute resolution in February 2000 (219).Generally, a drug sponsor should rely upon FDA’s existingregulations (220) and seek resolution of any scientific or pro-cedural dispute at the Division level using formal or informalmechanisms, as appropriate. The following is the path of anappeal through CDER or CBER (221):

Initial appeal to DivisionOffice DirectorDeputy Center DirectorCenter Director

Because all FDA decisions on a particular scientific mattermust be based on information in the matter’s administra-tive file, the sponsor may not submit new information as partof an appeal. If the sponsor has new information, it should

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submit that information first to the reviewing Division forconsideration (222).

At any point in the formal dispute resolution process, asponsor may request that an appropriate advisory committeereview the scientific dispute. The sponsor may make the requestas part of the original formal appeal or as an amendment to theformal appeal. FDA encourages sponsors to make the requestas early in the dispute resolution process as is feasible (223).

A sponsor interested in requesting formal dispute resolu-tion by an Office or Center should do so only if an attempt forresolution at the previous supervisory level was unsuccessful.The sponsor should submit a written request and supportingdocumentation to the appropriate CDER or CBER office.

The sponsor should also submit a copy of the appeal, as anamendment to the application, to the appropriate Divisiondocument room (224).

The request for dispute resolution should include thefollowing information (225):

Cover sheet that clearly identifies the submission asFORMAL DISPUTE RESOLUTION REQUEST inbold, uppercase letters.

Application number (IND, NDA, BLA, ANDA), if applic-able

Proprietary name and established name for a product inCDER; proper name and trade name for a product inCBER

Division or Office where the application is filedProposed indication(s), if applicableBrief, but comprehensive statement of each issue to be

resolved, including:Clearly describe the issue to be resolvedIdentify the issue as scientific, procedural, or bothState the steps that have been taken to resolve the

issue, including informal dispute resolutionIdentify possible solutions, including, for

scientific issues, whether an advisory committeereview is requested.

State expected outcome



Statement identifying the division that issued the originaldecision on the matter and, if applicable, the last agencyofficial who attempted to formally resolve the matter

List of documents previously submitted to the agency thatis deemed necessary for resolution of the issue(s) (If asponsor prefers, copies of such documents may beresubmitted to the agency.)

Statement that the previous supervisory level hasreceived and had the opportunity to review all of thematerial relied on for dispute resolution

Name, title, and telephone and fax numbers of companycontact for the appeal

On receiving the dispute resolution request, the DisputeResolution Project Manager (DRPM) will forward the requestto the appropriate CDER or CBER official (the Official). TheOfficial, on behalf of FDA, will generally provide a writtenresponse to a sponsor who requested formal dispute resolution.The written response will specifically agree or disagree withthe outcome desired by the sponsor, agree or disagree withparts of the proposed outcome, or indicate a resolution thatis different than that proposed by the sponsor. The responsewill include reasons for any disagreement and any actions thatthe sponsor can take to address issues FDA has raised (226).

If a PDUFA product is at issue in the dispute, the Officialshould complete the review and respond in writing or by tele-phone within 30 calendar days from the DRPM’s receipt of theformal request. The Official is required to follow a telephoneresponse with a written one within 14 days. If FDA is unable tocomplete the review and respond within 30 days, the Officialwill notify the sponsor, explain the reasons for the delay, anddiscuss the time frame for completing the review. Where addi-tional data or input from others are needed to reach a decisionon the appeal, the 30-day response should be a description ofthe plan for obtaining the information (e.g., requesting furtherinformation from the sponsor, deciding to schedule a meetingwith the sponsor, bringing the issue for discussion at an advi-sory committee). In such cases, once FDA receives the requiredinformation, the Official will again have 30 days to respond

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(227). For non-PDUFA products, the Official will ‘‘make allreasonable efforts to resolve the dispute as expeditiously aspossible’’ (228).

If a sponsor seeking resolution of a scientific disputerequests advisory committee review of the matter, theOfficial will determine whether such review is appropriateand would be helpful to the agency at that time in the formalappeal process. The Official will communicate this determina-tion to the sponsor following the procedures described above.Generally, in FDA’s view, an issue is appropriate for advisorycommittee review if it is related to matters of technical exper-tise that require some specialized education, training, orexperience to understand and resolve. Issues that generallyare not appropriate for advisory committee review includethose that involve (a) potential criminal activity (e.g., submis-sion of false information); (b) allegations of intellectual or regu-latory bias; (c) questions of inter-Center authority, such aswhich FDA Center will have lead regulatory responsibility fora particular matter and other matters in which regulatorypolicy or procedures are dominant; and (d) matters for whichthe Center Director has not been delegated authority (229).

If FDA agrees to the request and refers the matter to anadvisory committee, the matter will be brought to the nextscheduled advisory committee meeting for which there istime available on the agenda for adequate discussion of theissue. It may not be feasible to raise the matter at the nextscheduled meeting. The advice and recommendations of anadvisory committee concerning a scientific dispute will notbind the agency to a particular action or policy (230). Afterreceiving the committee’s advice, FDA will notify the sponsorof its determination on the matter within 30 days. Unlessotherwise provided by law, an FDA decision based on an advi-sory committee recommendation is not final agency actionsubject to judicial review (231).

If the reviewing Official does not grant advisory commit-tee review, the Official will notify the sponsor in writing of suchdecision, including the reason(s) for the denial. This notifica-tion may be included in the written response to the formaldispute resolution. The sponsor may appeal this denial up the



chain of command in the Center as part of any subsequentrequest for dispute resolution of the underlying matter. Afterexhausting the Center’s mechanisms for appealing a decisiondenying advisory committee review, a sponsor may requestreview of the Center’s decision through FDA’s supervisorychain of command to the Commissioner of Food and Drugs.Requests for such review should be submitted to the agency’sChief Mediator and Ombudsman (232).

7.4. Agency Guidances

Section 405 of FDAMA, Agency Guidances, codified certainparts of the agency’s current Good Guidance Practices(GGPs) and directed the agency to issue a regulation consistentwith the FDC Act that specifies FDA’s policies and proceduresfor the development, issuance, and use of guidance documents(233). The rule implementing this change, 21 C.F.R. § 10.115,became effective October 19, 2000. Section 405 and the regula-tion are intended to make the agency’s procedures for develop-ment, issuance, and use of guidance documents clear to thepublic.

The regulation defines a guidance document as a docu-ment prepared for FDA staff, applicants/sponsors, and thepublic that describes the agency’s interpretation of, or policyon, a regulatory issue. Guidances include, but are not limitedto, documents that relate to the design, production, labeling,promotion, manufacturing, and testing of regulated products;the processing, content, and evaluation or approval of submis-sions; and inspection and enforcement policies (234). Guidancedocuments do not include documents relating to internal FDAprocedures, agency reports, general information documentsprovided to consumers or health professionals, speeches, jour-nal articles and editorials media interviews, press materials,warning letters, memoranda of understanding, or other com-munications directed to individual persons or firms (235).

FDA is required to develop guidance documents withpublic participation and ensure that information identifyingthe existence of the guidances, and the guidances themselves,

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are publicly available in written and, if feasible, electronicformat (236).

Section 405 provides that guidances do not create orconfer any legally enforceable rights for or on any person.A regulated entity may choose an approach other than theone set forth in a guidance document. However, the alternativeapproach must comply with the relevant statutes and regula-tions (237). Section 405 also provides that guidances do notlegally bind FDA (238). However, guidances do present thecurrent views of the agency on a subject or issue, and theagency must ensure that its employees do not deviate fromsuch guidances ‘‘without appropriate justification and super-visory concurrence’’ (239). To ensure that employees complywith guidances, FDA will train all new and current employeesto follow the guidances. Additionally, FDA Centers and Officeswill monitor the development and issuance of guidances toassure that GGPs are followed (240).

There is to be a period for public participation and com-ment prior to implementation of a guidance if the guidance(a) sets forth initial interpretations of a statute or regulation,(b) changes an interpretation or policy that is of more than aminor nature, or (c) involves complex scientific or highly con-troversial issues (241). Guidances meeting one of these threecriteria are known as Level 1 guidance documents; all otherguidances are known as Level 2 guidance documents (242). Thepublic may comment upon Level 2 guidances, which set forthexisting practices or minor changes in policy, upon implemen-tation (243). An interested party may participate in the devel-opment and issuance of guidance documents by suggestingareas of guidance development to FDA and by commentingupon proposed guidance documents (244).

According to the guidance procedure, if FDA wishes tocommunicate new or different regulatory expectations to abroad public audience for the first time, it must use a guidancedocument and comply with FDAMA and the implementingregulations. FDA must follow the GGPs set out in the regula-tions ‘‘whenever regulatory expectations that are not readilyapparent from the statute or regulations are first communi-cated to a broad public audience’’ (245).



A standard guidance document (246):

Includes the term ‘‘guidance’’Identifies the center(s) or office(s) issuing the documentIdentifies the activity to which and the people to whom

the document appliesProminently displays a statement of the document’s

nonbinding effectIncludes the date of issuanceNotes if it is a revision to a previously issued guidance,

and identifies the document that it replacesContains the word ‘‘draft’’ if the document is a draft

guidanceMust not include mandatory language such as ‘‘shall,’’

‘‘must,’’ ‘‘required,’’ or ‘‘requirement,’’ unless FDA isusing these words to describe a statutory or regulatoryrequirement.

Section 405 included other ‘‘housekeeping’’ matters withregard to guidance practice within FDA (247):

In developing guidance documents, FDA shall ensureuniform nomenclature and uniform internal proceduresfor approval of such documents.

Guidance documents and revisions should be properlydated and should indicate the nonbinding nature of thedocuments.

FDA must periodically review all guidance documentsand, where appropriate, revise such documents.

FDA must maintain electronically and update and publishperiodically in the Federal Register a list of guidancedocuments.

Section 405 established that an effective appealsmechanism must be in place to address complaints thatFDA is not developing and using guidance documents inaccordance with FDAMA (248). FDA’s implementing regula-tion created such a process (249). Any aggrieved party isdirected to follow the FDA chain of command pursuant to21 C.F.R. 10.115(o) to address any issue concerning guidancedocuments.

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7.5. Environmental Impact Review

Section 411 of FDAMA, Environmental Impact Review, is a‘‘housekeeping’’ provision relating to the environmentalimpact of FDA actions and FDA-regulated activities.

The National Environmental Policy Act of 1969 (NEPA)requires that the laws, policies, and regulations of the UnitedStates be in accordance with NEPA policies. To comply withNEPA, many submissions that regulated entities and inter-ested parties make to FDA must be accompanied by an ‘‘envi-ronmental assessment’’ (250). The environmental assessmentmust provide sufficient information to enable FDA to deter-mine whether a particular proposed action (such as the manu-facture of a new drug) may significantly affect the quality ofthe human environment. As an example, NDA applicants mustaddress how their drug-manufacturing processes will affectsolid waste disposal, effluent discharges into waterways, andair emissions.

If FDA determines, based upon the applicant’s submittedenvironmental assessment, that the proposed action may sig-nificantly affect the quality of the human environment, FDAmay prepare an environmental impact statement (251). Section411 provides that any FDA-prepared environmental impactstatement conducted in accordance with FDA’s regula-tions also will be deemed to satisfy the ‘‘detailed statement’’requirements set out in NEPA (252).

7.6. National Uniformity for NonprescriptionDrugs and Cosmetics

Section 412 of FDAMA, national uniformity for nonprescrip-tion drugs and cosmetics, established national uniformity fornonprescription drugs (and cosmetics as well) (253). Undersection 412, a state or other political subdivision may notestablish or continue in effect any requirement for a nonpre-scription drug that is ‘‘different from or in addition to, or thatis otherwise not identical with’’ a requirement under the FDCAct, the Poison Prevention Packaging Act of 1970, or the FairPackaging and Labeling Act (254). Preemption of differingstate and local requirements applies to any requirement



relating to public information or any other form of public com-munication relating to a warning of any kind for a drug (255).

There are some exemptions to the uniformity require-ment. A state or political subdivision may make an applicationto FDA for an exemption by regulation. FDA must issue apublic notice of the application and provide an opportunityfor written and oral presentation of views. For FDA to issuean exemption from the requirement of national uniformity fornonprescription drugs, it must find that the proposed exemp-tion (a) would protect an important public interest that wouldotherwise be unprotected, including the health and safety ofchildren; (b) would not cause any drug to be in violation of anyapplicable requirement or prohibition under federal law; and(c) would not unduly burden interstate commerce (256). FDAmust make a decision on a requested exemption within 120days (257).

The national uniformity requirements do not apply to anystate or political subdivision requirement that relates to thepractice of pharmacy or that requires that a drug be dis-pensed only by prescription (258). Additionally, the nationaluniformity provisions are to have no effect upon State productliability law (259).

Further, section 412 mandated that all nonprescriptiondrug labels include the identification of all inactive ingredients,in alphabetical order, and the established name and quantity ofall active ingredients (260).

REFERENCES

1. 21 U.S.C. § 355a.

2. Guidance for Industry, ‘‘Qualifying for Pediatric ExclusivityUnder Section 505A of the Federal Food, Drug, and CosmeticAct,’’ (September 1999), available at

3. Pediatric Exclusivity Guidance at 2–3.

4. Pediatric Exclusivity Guidance at 3.

228 Tsien


http://www.fda.gov/cder/guidance/2891fnl.pdf.

http://www.fda.gov

http://www.fda.gov

5. See ‘‘Update of List of Approved Drugs for Which AdditionalPediatric Information May Product Health Benefits in thePediatric Population,’’ available at

6. See ‘‘The Pediatric Exclusivity Provision: January 2001 StatusReport to Congress,’’ available at

7. P.L.No. 107–109, January 4, 2002.

8. Regulations Requiring Manufacturers to Assess the Safetyand Effectiveness of New Drugs and Biological Productsin Pediatric Patients, 62 Fed. Reg. 43, 900 (proposed Aug 15,1997); 63 Fed Reg 66,632 (Dec. 2, 1998).

9. 21 C.F.R. § 314.55(c).

10. Status Report at ii.

11.

12. 42 U.S.C. § 282(j).

13. See 42 U.S.C. § 282(j)(3)(A).

14. Guidance for Industry, ‘‘Information Program on Clinical Trialsfor Serious or Life Threatening Diseases or Conditions’’

15.

16. 21 U.S.C. § 355.

17. 21 U.S.C. § 355(d).

18. Guidance for Industry, ‘‘Providing Clinical Evidence ofEffectiveness for Human Drugs and Biological Products,’’(May 1998), at 3, available at

19. 21 U.S.C. § 355(d).

20. See note 16, supra.

21. 21 U.S.C. § 355(b)(1).

22. Memorandum from Janet Woodcock, M.D., Director, Center forDrug Evaluation and Research, to Michael A. Friedman, M.D.,Acting Commissioner, (July 20, 1998), and accompanying



http://www.fda.gov/cder/


See FDA’s website at http://www.fda.gov/cder/pediatric.


(March 2002), available at http://www.clinicaltrials.gov.

http://www.fda.gov/cder/guidance/4856fnl.htm.

guidance/1397fnl.pdf.

pediatric/reportcong01.pdf (hereinafter ‘‘Status Report’’).

pediatric/peddrugsfinal.htm.

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.clinicaltrials.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

‘‘FDAMA Women and Minorities Working Group Report,’’

23. 21 U.S.C. § 355(i)(2).

24. 21 U.S.C. § 355(i)(3).

25. 21 U.S.C. § 355(i)(3).

26. Investigational New Drug Applications: Clinical Holds, 63 Fed.Reg. 68,676 (Dec. 14, 1998).

27. 21 U.S.C. § 355 (i)(3)(B).

28. 21 U.S.C. § 355(i)(4); 21 C.F.R. §§ 50.20, 50.23, 50.25.

29. 21 U.S.C. § 360bbb.

30. 21 C.F.R. § 312.36.

31. 21 C.F.R. § 312.35(b).

32. 21 U.S.C. § 356b.

33. 21 U.S.C. § 356b(a).

34. 21 U.S.C. § 356b(c).

35. 21 U.S.C. § 356b(b).

36. 62 Fed. Reg. 67,207 (Dec. 1, 1999).

37. 65 Fed. Reg. 64,607 (Oct. 30, 2000).

38. 66 Fed. Reg. 10,815 (Oct. 30, 2000).

39. 21 C.F.R. § 314.81(b)(vii).

40. 66 Fed. Reg. 17,912 (April 4, 2001).

41. Guidance for Industry, ‘‘Reports on the Status of Post-marketing Studies—Implementation of Section 130 of theFood and Drug Administration Modernization Act of 1997’’(April 2001), available at

42. 21 U.S.C. § 356b(b).

43. CBER, Report to Congress: Reports on Postmarketing Studies[FDAMA 130], available at

44. Id.

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available at http://www.fda.gov/cder/guidance/women.pdf.

http://www.fda.gov/cber/gdlns/

http://www.fda.gov/cber/fdama/

post040401.pdf.

pstmrktfdama130.htm.

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

45. 21 U.S.C. § 356.

46. 21 C.F.R. § 314.500 et seq.

47. 21 U.S.C. § 356(a).

48. 21 U.S.C. § 356(b).

49. The user fee deadlines, however, will be calculated based onthe date the application is complete.

50. 63 Fed. Reg. 64,094 (Nov. 18, 1998).

51. Guidance for Industry: ‘‘Fast Track Drug Development Pro-grams, Designation, Development and Application Review’’(September 1998), available at

52. Fast Track Guidance at 3.

53. Fast Track Guidance at 3–4.









62. 21 C.F.R. § 314.510; 21 C.F.R. § 601.41; Fast Track ApprovalGuidance at 15.

63. Fast Track Approval Guidance at 15.

64. Guidance for Industry, ‘‘Submission of Abbreviated Reportsand Synopses in Support of Marketing Application’’ (August1999), available at

65. Abbreviated Reports Guidance at 3.

66. Abbreviated Reports Guidance at 4–5.




http://www.fda.gov/cber/gdlns/fsttrk.pdf (hereinafter ‘‘Fast Track Guidance’’).

http://www.fda.gov/cder/guidance/2097fnl.pdf (hereinafter ‘‘Abbreviated Reports Guidance’’).

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov





72. Guidance for Industry, ‘‘Structure and Content of ClinicalStudy Reports’’ (July 1996), available at




76. 21 U.S.C. § 355(b).

77. 21 U.S.C. § 355(j).

78. 21 U.S.C. § 355(b)(4)(A).

79. See Implementation of the Food and Drug AdministrationModernization Act of 1997: Completed Items, available at

80. 21 U.S.C. § 355(b)(4)(B).

81. 21 U.S.C. § 355(b)(4)(C)–(D).

82. 21 U.S.C. § 355(b)(4)(C)(ii).

83.Meetings Guidance’’).

84. 21 U.S.C. § 379g(1); PDUFA Meetings Guidance at 1.

85. PDUFA Meetings Guidance at 2–4.

86. PDUFA Meetings Guidance at 5.






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http://www.fda.gov/cder/guidance/iche3.pdf.

http://www.fda.gov/po/modactchart/modact97fini.html.

http://www.fda.gov/cder/guidance/2125fnl.pdf (hereinafter ‘‘PDUFA

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

92. (hereinafter‘‘Special Protocol Guidance’’).

93. 21 U.S.C. § 379g(1).

94. Special Protocol Guidance at 2.

95. Special Protocol Guidance at 4–5.







102. 21 U.S.C. § 355(b)(4)(C); Special Protocol Guidance at 9.




106. 21 U.S.C. 355 note.

107. 63 Fed. Reg. 28,301 (May 22, 1998).

108. 64 Fed. Reg. 26,657 (May 17, 1999).

109. 21 C.F.R. § 315.2; 21 C.F.R. § 601.31.

110. 21 C.F.R. § 315.3; 21 C.F.R. § 601.32.

111. 21 C.F.R. § 315.4(a); 21 C.F.R. § 601.33(a).

112. 21 C.F.R. § 315.4(b); 21 C.F.R. § 601.33(b).

113. 21 C.F.R. § 315.5(a); 21 C.F.R. § 601.34(a).

114. 21 C.F.R. § 315.6(a); 21 C.F.R. § 601.35(a).

115. 21 C.F.R. § 315.6(c); 21 C.F.R. § 601.35(c).

116. 21 C.F.R. § 315.6(d); 21 C.F.R. § 601.35(d).

117. 63 Fed. Reg. 26,694 (May 13, 1998).

118. On January 5, 1999, FDA also issued a proposed rule toamend its regulations to remove references to the repealed



http://www.fda.gov/cder/guidance/3764fnl.htm

http://www.fda.gov

statutory provision of the FDC Act under which the agencycertified antibiotic drugs. The agency is also proposing toremove references to the repealed antibiotic monograph.64 Fed. Reg. 448 (Jan 5, 1999). This proposal has neverbeen finalized.

119. 21 U.S.C. § 355 note.

120. 65 Fed. Reg. 3,623 (Jan 24, 2000).

121. 21 U.S.C. § 382(i).

122. 21 U.S.C. § 371 note.

123. See H.R. Rep. No. 105–310 (1997).

124. 21 U.S.C. § 371 note.

125. Guidance for Industry, ‘‘Standards for the Prompt Review ofEfficacy Supplements, Including Priority Efficacy Supple-ments’’ (May 1998), available at

(hereinafter ‘‘Efficacy SupplementsGuidance’’).

126. Efficacy Supplement Guidance at 1.



129. 21 U.S.C. § 360bbb-2.

130. See, generally,

tation).

131. 21 U.S.C. § 356a.

132. 21 U.S.C. § 356a(a),(b),(c)(1).

133. 21 U.S.C. § 356a(c)(2).

134. 21 U.S.C. § 356a(a).

135. 21 U.S.C. § 356a(d).

136. 21 U.S.C. § 356a(d).

137. 21 U.S.C. § 356a(d).

138. 21 U.S.C. § 356a(d).

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http://www.fda.gov/cder/guidance/2423fnl.pdf

http://www.fda.gov/po/modactchart/modact97num.html (reviewing FDAMA items remaining for implemen-

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

139. Guidance for Industry—Changes to an Approved NDAor ANDA (November 1999), available for download at

(hereinafter‘‘Changes Guidance’’).

140. Changes Guidance at 2–3.

141. Changes Guidance at 5.








149. 21 U.S.C. § 355(c)(4).

150. 21 U.S.C. § 355(c)(4).

151. 21 U.S.C. § 360b(c)(4).

152. 21 U.S.C. § 360(i).

153. 21 U.S.C. § 360(i)(1); 21 C.F.R. § 207.20(a).

154. 21 U.S.C. § 360(i)(2); 21 C.F.R. § 207.20(a).

155. 21 C.F.R. § 207.20(c).

156. 21 U.S.C. § 360(i)(3).

157. 21 C.F.R. § 207.40(b).

158. 21 U.S.C. § 360(i)(1); 21 C.F.R. § 207.40(c).

159. 21 C.F.R. § 207.3(a)(11).

160. 21 C.F.R. § 207.21(a).

161. 21 C.F.R. § 207.40(a).

162. 21 U.S.C. § 383.

163. 21 U.S.C. § 383(c)(1)(2).

164. 21 U.S.C. § 383(c)(3).



http://www.fda.gov/cder/guidance/2766fnl.pdf)

http://www.fda.gov

165. 21 U.S.C. § 383(c)(4).

166.

167. 21 U.S.C. § 353a.

168. Western States Medical Center v. Shalala, 238 F.3rd 1090 (9thCir. 2001).

169. Thompson v. Western States Medical Center, 122 S. Ct. 1597(2002).

170. 67 Fed. Reg. 39,409 (June 7, 2002); CPG 460.200, availableat

171.

172. CPG 460.200, Appendix A.

173. CPG 460.200.

174. 21 U.S.C. § 352(a).

175. 21 U.S.C. § 352(a).

176. 21 U.S.C. § 352(a).

177. 21 U.S.C. § 352(a).

178. See 21 U.S.C. § 353(b)(4). See also 21 C.F.R. § 201.100(b)(1).

179. Guidance for Industry, ‘‘Implementation of Section 126 of theFood and Drug Administration Modernization Act of 1997—Elimination of Certain Labeling Requirements’’ (July 1998),

180. 21 C.F.R. § 290.1.

181. 21 C.F.R. § 290.2.

182. 21 U.S.C. § 346c.

183. 21 U.S.C. § 356c(a) (proposed 21 C.F.R. § 314.81(b)(3)(iii)(a),65 Fed. Reg. 66,665, 66,670 (Nov. 7, 2000)).

184. 21 U.S.C. § 356c(b).

185. 21 U.S.C. § 356c(b) (proposed 21 C.F.R. § 314.91(b),(d) 65Fed. Reg. 66,665, 66,670 (Nov. 7, 2000)).

186. 65 Fed. Reg. 66,665 (Nov. 7, 2000).

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Available at http://www.fda.gov/oc/fdama/fdamagmp.pdf.

http://www.fda.gov/OHRMS/DOCKETS/98fr/02D-0242_gdl

CPG 460.200.

0001.pdf.

available at http://www.fda.gov/cder/guidance/2496fnl.pdf.

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

187. Proposed 21 C.F.R. § 314.91(c), 65 Fed. Reg. 66,665, 66,670(Nov. 7, 2000).

188. 21 U.S.C. 360bbb. See also Guidance for Industry,‘‘Dissemination of Reprints of Certain Published OriginalData’’ (Oct. 1996), 61 Fed. Reg. 52,800 (Oct. 8, 1996).

189. 21 U.S.C. §§ 360aaa–360aaa-6.

190. 21 U.S.C. § 360aaa(b).

191. 21 U.S.C. § 360aaa(b).

192. 21 U.S.C. § 360aaa-2.

193. 21 U.S.C. § 360aaa-3.

194. 21 U.S.C. § 360aaa-4.

195. Washington Legal Foundation v. Henney, 56 F. Supp. 2d. 81(D.D.C. 1999).

196. Id.

197. Washington Legal Foundation v. Henney, 202 F.3d 331 (D.C.Cir. 2000).

198. Id. at 337.

199. 21 U.S.C. § 355(n)(1).

200. Guidance for Industry, ‘‘Advisory Committees: ImplementingSection 120 of the Food and Drug AdministrationModernization Act of 1997,’’ (October 1998), availableat (hereinafter‘‘Advisory Committee Guidance’’).

201. Advisory Committee Guidance at 2.

202. 21 U.S.C. § 355(n)(3); Advisory Committee Guidance at 2–3.

203. 21 U.S.C. § 355(n)(4).

204. 21 U.S.C. § 355(n)(3); Advisory Committee Guidance at 2–3.

205. 21 U.S.C. § 355(n)(8).

206. 21 U.S.C. § 355(b)(1).

207. 42 U.S.C. § 262.

208. 42 U.S.C. § 262(a).




http://www.fda.gov

209. 21 C.F.R. § 601.2(a); 64 Fed. Reg. 56,441, 56,450 (Oct. 20,1999).

210. 42 U.S.C. § 262(a)(2)(A).

211. 64 Fed. Reg. at 56,443; 21 C.F.R. § 601.2(d).

212. 42 U.S.C. § 262(j).

213. 64 Fed. Reg. at 56,443; 21 C.F.R. § 601.2(b).

214. 21 USC § 360bbb-1.

215. 63 Fed. Reg. 63,978 (Nov. 18, 1998); 21 C.F.R. § 10.75(b)(2).

216. Id.

217. 21 C.F.R. § 10.75(b)(2).

218. 63 Fed. Reg. at 63,979.

219. Guidance for Industry: ‘‘Formal Dispute Resolution: AppealsAbove The Division Level’’ (Feb. 2000), available at

(hereinafter ‘‘FDRGuidance’’).

220. 21 CFR §§ 10.75, 312.48, 314.103.

221. FDR Guidance at 3.

222. 21 C.F.R. § 10.75(d); FDR Guidance at 3.


224. FDR Guidance at 4–5.






230. 21 C.F.R. § 14.5(b).

231. FDR Guidance at 7–8.

232. FDR Guidance at 7–8; 21 C.F.R. § 10.75.

233. 21 U.S.C. § 371(h).

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http://www.fda.gov

http://www.fda.gov

234. 21 C.F.R. § 10.115(b)(1)–(2).

235. 21 C.F.R. § 10.115(b)(2).

236. 21 U.S.C. § 371(h)(1)(A); 21 C.F.R. § 10.115.

237. 21 C.F.R. § 10.115(d).

238. 21 U.S.C. § 371(h)(1)(A); 21 C.F.R. § 10.115(d).

239. 21 U.S.C. § 371(h)(1)(B); 21 C.F.R. § 10.115(d).

240. 21 C.F.R. § 10.115(l).

241. 21 U.S.C. § 371(h)(1)(C).

242. 21 C.F.R. § 10.115(c).

243. 21 U.S.C. § 371(h)(1)(D).

244. 21 C.F.R. § 10.115(g)–(h).

245. 21 C.F.R. § 10.115(e).

246. 21 C.F.R. § 10.115(i).

247. 21 U.S.C. § 371(h)(2)–(3).

248. 21 U.S.C. § 371(h)(4).

249. 21 C.F.R. § 10.115(o).

250. 21 C.F.R. § 25.15(a).

251. 21 C.F.R. § 25.15(b).

252. 42 U.S.C. § 4332(2)(C).

253. 21 U.S.C. § 379r.

254. 21 U.S.C. § 379r(a).

255. 21 U.S.C. § 379r(c)(2).

256. 21 U.S.C. § 379r(b)(1).

257. 21 U.S.C. § 379r(b)(2).

258. 21 U.S.C. § 379r(c)(1).

259. 21 U.S.C. § 379r(e).

260. 21 U.S.C. § 352(e)(1).



7

FDA Antibiotic Regulatory Scheme:Then and Now

IRVING L. WIESEN

Stamford, Connecticut, U.S.A.

1. INTRODUCTION

The history of antibiotic* regulation demonstrates the inter-play between regulatory schemes, which are artifacts of his-tory, and the scientific/regulatory constraints and marketingconditions in which they operate. Largely an outgrowth of anarrow legislative fix of a scientific and regulatory need, theantibiotic regulatory scheme grew to unwieldy proportions asthe market for such drugs increased. Accordingly, the U.S.

*Antibiotic: any drug containing any quantity of any chemical substanceproduced by a microorganism that has the capacity to inhibit or destroymicroorganisms in dilute solution (1).

241


Food and Drug Administration (FDA), within the statutorymandate, increasingly revised the regulatory requirementsgoverning antibiotic drugs, gradually eliminating them in suc-cessively more radical revampings of its drug approval require-ments. This window into FDA rule and policymaking finallyclosed in 1997, when Congress enacted the Food and DrugAdministration Modernization Act (FDAMA), which finallyand unambiguously put an end to the particular—and pecu-liar—requirements for antibiotic drugs.

2. ANTIBIOTIC REGULATION: A BRIEFHISTORY

In 1906 Congress passed the first comprehensive scheme offederal law to regulate the marketing of pharmaceutical prod-ucts. Lacking an approval requirement, however, the Foodand Drugs Act of 1906 merely proscribed the entry into inter-state commerce of drugs that were ‘‘misbranded’’ or ‘‘adulter-ated.’’ In 1938 Congress passed the Food, Drug and CosmeticAct (FDCA), which remains the overall federal drug regulatoryscheme to this day. The FDCA introduced for the first timea requirement that all drugs marketed in the United Statesafter enactment of the Act be reviewed prior to marketing.The criterion of such review, however, was merely for safety—no requirement of effectiveness existed until passage of theDrug Amendments of 1962.

Antibiotics and insulin-containing drugs were added tothe regulatory scheme beginning in a series of steps in1941 and culminating in 1945 (2) and were also containedin the 1962 amendments. However, the procedures for estab-lishing safety and efficacy applicable to other ‘‘new drug’’ anti-biotics were subject to a far different regulatory scheme. Thisscheme was two-pronged, requiring that antibiotics adhere toa drug monograph published by FDA and that each batch ofantibiotic be certified as conforming with established standardsof manufacture and conformity with specifications.

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Under the monograph system, FDA issues a set of rulesthat are given broad applicability to any prospective marketer.Any prospective marketer may market the product in confor-mity with the rules and specifications contained in the mono-graph without preclearance of the product per se. In the caseof antibiotics, the monographs were developed on the basisof the first product reviewed and approved in the antibioticclass. Thereafter, any prospective marketer merely needed toshow that it was bioequivalent to the first product for whichthe monograph was developed and that it followed the specifi-cations of the monograph.

In this way, the antibiotic-approval mechanism paralleledand prefigured the approval mechanism for generic drugs,by which subsequent versions of a drug are approvable basedupon standards developed in connection with the first approvedproduct. Like generic drugs prior to 1962, the first-approvedapplicant owned no proprietary rights in the information usedin approval of the product that could bar approval of subse-quent applicants who relied on the first approval.

Attendant to the monograph system, antibiotics were alsosubject to a batch certification requirement, which was insti-tuted due to the relative newness of antibiotic manufacturing.Thus, notwithstanding the existence of the monograph, anti-biotics were also subject to a requirement that served as acounterpart to the monograph system, which was the require-ment for ‘‘batch certification.’’ This requirement, enshrined inthe FDCA statute (3), required that each batch of antibioticbe certified to conform with regulations of identity, strength,quality, and purity. To meet this requirement, the antibioticmarketer provided a sample of each batch of the antibiotic toFDA prior to marketing for laboratory testing and certificationthat the requirements for marketing set forth by the statutewere met. Batches that were found by FDA to meet therequired standards were issued an Antibiotic Certificate, whichpermitted their shipment in interstate commerce, ‘‘Certified byFDA’’ (4).

Unsurprisingly, the batch certification requirement repre-sented a huge burden on both manufacturers and the FDA.As recounted by its Chief, Antibiotic Drug Review Branch of

FDA Antibiotic Regulatory Scheme 243


the FDA, the mechanism had long become expensive, time-consuming, and ultimately a bottleneck in drug distribution (5):

The law required the Government to charge fees to thosemanufacturers requesting the required certification tests. Feesin excess of $5 million dollars were collected annually on a user-cost basis to carry on the testing and certification program. Theregulated industry’s demands on the agency’s testing serviceincreased year by year as the market grew larger and larger.The agency’s testing services became slower and slower due topersonnel and facilities limitations imposed by the Office ofManagement Budget. As a result, during the late 1970’s largequantities of antibiotic products were being held in quarantinefor many weeks by industry while waiting for FDA’s clearanceat a time when interest rates were at an all time high.

As a result, FDA increasingly took advantage of its powerunder the statute (6) to exempt antibiotic products or manu-facturers from the batch certification requirement if the FDAdetermined that it was not needed to assure the safety andeffectiveness of the drug product. FDA took several increas-ingly significant steps: in October 1980, FDA indicated to theindustry that testing of topical antibiotics would no longerbe required. As described by the FDA, this small step wasnot effective, leading to a cascade of events: ‘‘Such limitedderegulation [topical antibiotic exemption] was not sufficientto relieve stock build-up. The Agency then tried selective test-ing where certain tests were skipped and certifications grantedon the basis of the manufacturer’s test results. With less test-ing, there was less income to support the laboratories’ costsand the program headed for a financial deficit’’ (7).

Finally, on September 7, 1982, FDA decided to eliminateentirely the batch certification program as unnecessary toassure the safety and effectiveness of antibiotics, whose manu-facturing by then had become well understood and whose con-sistency had proven itself over many years of practice. The newprogram was made effective on October 1, 1982. Instead of thebatch certification procedure, the industry and FDA would beguided by compendial and regulatory specifications—specifi-cally FDA’s monographs setting forth standards of identity,

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strength, quality and purity—and by FDA’s Good Manufactur-ing Practices regulations and policies applicable to production(8). In 1986 this exemption was extended to over-the-counterantibiotics that complied with the applicable monograph.

As a result of FDA’s revamping of its antibiotic-approvalprocess, the way was now cleared for significant new activityby manufacturers and enhanced delivery of antibiotic productsto the market. FDA described the effect of this ‘‘deregulatory’’effort shortly there after, in 1986 (9):

At the time batch-by-batch testing of antibiotic productswas terminated by FDA, a little over two years ago, there wereapproximately 65 domestic and 52 foregin manufacturers havingproducts tested for marketing. Since that phase of de-regulation25 additional domestic and 8 foreign companies have submittedone or more Form 5/6 applications to enter the U.S. Antibioticmarket for the first time.

The FDA analysis concluded, ‘‘[a]s deregulation occurs, growthand competition in the industry follows’’ (10).

The certification regulations remained in effect as a stan-dard of drug quality by which adulteration and misbrandingcould be gauged. Nevertheless, FDA retained the power to reim-pose the requirement for certification where it determined thata manufacturer or several manufacturers experience a problemthat is believed to pose a significant health risk. In such event,the requirement for certification would be reimposed only on thecompany or companies in which the problem was evident (11).

This process remained in effect until the recent repealof the entire antibiotic application scheme by Congress in theFood and Drug Modernization Act of 1997, discussed below.

3. THE CERTIFICATION PROCESS

At the time the antibiotic provisions were enacted in 1945, theonly antibiotic product then on the market was penicillin.In subsequent years, well over one hundred additional anti-biotic products were developed and approved by FDA. Mostof these approvals were under the 1945 regulatory scheme,



which utilized a monograph system in conjunction with batchcertification. To receive permission to market a product, theapplicant was required to address a request for certification ofa batch of an antibiotic drug to the Commissioner of the FDA.The application was required to contain information describingthe batch, including results of testing required by the regula-tions, and batch composition. Each batch shipped in interstatecommerce was required to adhere to stated standards of iden-tity, strength, quality, and purity. Additionally, batches wererequired to have results for tests and methods of assay, includ-ing sterility tests, biological tests, microbiological assays, chem-ical tests, and tests for certain antibiotic dosage forms.

In its application, the manufacturer was required tosubmit actual samples of each batch of antibiotic which FDAwould test in its own laboratories. Upon review and confirma-tion by FDA that the batch met appropriate requirements,FDA would certify the batch as safe and effective and fit fordistribution in interstate commerce. These certifications werecontained in an ‘‘Antibiotic Certificate’’ issued by FDA to theapplicant. Batches released prior to such FDA certificationwere deemed misbranded under Section 502(1) of the FDCAand were subject to seizure and other legal sanctions.

Certification was a creature of FDA discretion. FDA wasauthorized to withhold certification of any batches it deemedrequired a further demonstration of safety and effectiveness. Inthis respect, FDA could require any additional testing or otherinformation it deemed appropriate, and it did so in cases wherenew information or other changed circumstances indicatedthat the standard certification may no longer have been suffi-cient (12). Moreover, FDA had the power to suspend certifica-tion procedures for any person or company found to have usedfraud, misrepresentation, or concealment in the application forcertification or to otherwise have falsified records required bythe regulations to be maintained by the company.

The 1962 Drug Amendments added a requirement thatdrugs prove efficacy, in addition to safety, prior to distribu-tion—a requirement that was equally applicable to antibiotics.Prior to these amendments, FDA had been authorized to certifycertain antibiotics—penicillin, streptomycin, chlortetracycline,

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chloramphenicol, and bacitracin—as safe and effective. Otherantibiotics available at the time were either classified as safeand effective or generally recognized as safe (GRAS), and there-fore did not require a finding of effectiveness prior to marketing.As a result of the 1962 Amendments, which now required proofof effectiveness, FDA determined that antibiotics marketedunder a pre-1962 New Drug Application (NDA) would be certi-fied or released from certification under the pre-1962 regulatoryscheme, despite the fact that the pre-1962 regulatory schemedid not review drugs for efficacy. To address the new efficacyrequirements, FDA determined to proceed under the rubric ofits Drug Efficacy Study Implementation Program (DESI) toprovide appropriate regulations for these antibiotics.

As a result of the 1962 Amendments, FDA requiredthe submission for several antibiotics of scientific evidence of‘‘substantial well-controlled clinical studies’’ demonstratingthe effectiveness of the product. Those products that failedto provide such evidence had their certifications revoked, andthe regulations under which they were marketed were repealedby FDA. Legal challenges to this action failed (13). In addition,after review of submissions for other antibiotics, FDA with-drew certification and revoked approval of several antibioticand antibiotic combination products that did not meet FDA’sstandards of substantial scientific evidence (14).

4. EXEMPTIONS FROM CERTIFICATIONREQUIREMENTS

Under the FDCA, FDA was permitted to exempt certain prod-ucts from certification as a requirement for proving safety andefficacy. Accordingly, the FDA exempted antibiotic drugs fromthe requirements of certification (15). Promulgated by FDA torelieve the bottleneck in antibiotic approvals, this new regula-tion exempted from the certification requirements of the FDCAall antibiotic drugs provided there was an approved antibioticapplication for each product.



The antibiotic approval process had previously been con-tained in FDA’s Form FD-1675, rather than in a regulation.This form contained the information required to be submittedby the applicant for approval of the antibiotic and was alsoreferred to as a ‘‘Form 5’’ and ‘‘Form 6’’ application. Form 5applications were for antibiotics for which no standardshad previously been developed as shown in 21 CFR, Parts440–455; Form 6 applications were for products for whichsuch standards already existed and contained in the regulation.

In 1985 FDA published new regulations, known as the‘‘NDA Rewrite Regulations,’’ which entirely revamped theapplication procedures for drug products. In these regulationsthe FDA dispensed with the previous regulatory scheme ofForms 5 and 6 for antibiotics and replaced it with appellationsthat more closely mirrored those of nonantibiotic drugs.Accordingly, after May 23, 1985, antibiotic applications wereclassed as either ‘‘New Antibiotic Drug Applications’’ or‘‘Abbreviated Antibiotic Drug Applications’’ (16). Consonantwith the new regulatory framework, applicants and manu-facturers could now make certain changes in their productswithout requiring prior FDA approval (17).

5. FDAMA

In 1997 President Clinton signed into law the Food and DrugAdministration Modernization Act. This act, which wasdesigned in part to introduce legal mechanisms to permit thespeedier and broader introduction of pharmaceutical productsto consumers, also addressed a number of prevailing historicalanomalies in FDA’s review and approval process. Among theseanomalies was the approval mechanism for antibiotics, whosedistinction from the general class of pharmaceuticals had longlost any scientific rationale. Accordingly, Section 125 of Title Iof the Act repealed section 507 of the FDCA, which containedthe separate application scheme for antibiotics. Essentially, theimport of the repeal is that antibiotics would, with certainexceptions, be reviewed and approved on the same basis asany other pharmaceutical product.

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The Act specifically provided, moreover, that any fullapplication (NDA) approved under FDCA Section 597 beforethe signing into law of FDAMA would be deemed to have beensubmitted and filed under the general pharmaceutical provi-sions, section 505(b) of the FDCA, and approved for safetyand effectiveness under section 505(c) thereof. In addition, allabbreviated applications (ANDAs) approved under section 507would be deemed to have been filed and approved under section505( j) of the Act, applicable to ANDAs for general pharmaceu-tical products.

One consequence of the effective dating of the repeal, how-ever, was that antibiotic applications submitted to FDA beforethe date of FDAMA were not subject to the patent listing andnotification requirements, as well as the exclusivity attendantthereto.* The inevitable result was that post-FDAMA applica-tions for pre-FDAMA (‘‘old’’) antibiotics were not required toinclude patent information, and were not eligible for the exclu-sivities of Sections 505(c) or 505( j) of the FD&C Act. Thisincluded applications for a new dosage form or new indicationfor an old antibiotic.

6. FDA’S PROPOSED RULE

In the Federal Registers of May 12, 1998, (18) and January 5,1999, (19) FDA issued conforming amendments to its regula-tions to remove provisions which were made obsolete byFDAMA, specifically the provisions that governed certificationof antibiotic drugs (20).

*Under Section 505 of the FDCA, abbreviated new drug applications arerequired to certify the status of their product in relation to the patents claimedby the ‘‘listed’’ product in the Orange Book. These certifications indicatewhether the product infringes the listed product, whether the applicant claimsno patents of the listed product apply to the applicant’s product, whether listedpatents apply, or whether listed patents apply but the patents are invalid. Theapplication itself is deemed a legal infringement of any patents and thereforemay precipitate a patent infringement lawsuit by the owner of the listeddrug against the applicant who certifies that listed patents apply, but are invalid.The statute provides a period of exclusivity to the first to file such a certificationin the event of a patent infringement lawsuit by the listed product owner.



Under Section 125(d)(1), drugs that had been approvedpursuant to Section 507 of the Act were now to be deemedapproved under the standard new drug provisions of the Actand would be considered as NDA drugs. These drugs, havingbeen approved under the previous regulatory scheme, had notbeen subject to the patent and exclusivity provisions of the Actthat were enacted under the Drug Price Competition andPatent Restoration Law (Waxman-Hatch), enacted in 1984,which were contained in Section 505 of the Act. Accordingly,FDAMA also exempted antibiotic-related drug applicationsfrom the drug exclusivity and patent listing provisions ofWaxman-Hatch. As a result, Section 125 of FDAMA exemptedfrom the exclusivity and patent listing requirements all appli-cations that contained an antibiotic drug that was the subjectof a marketing application received by FDA under formerSection 507 of the Act and received by FDA prior to the enact-ment of FDAMA on November 21, 1997. This included applica-tions that were withdrawn, not filed, or even refused approvalunder Section 507.

In 2000 FDA published a proposed rulemaking notice inthe Federal Register in which it fleshed out its approach to itsregulatory stance on marketing exclusivity and patents forantibiotic drugs (21).

Notwithstanding the relatively bright-line distinctionscontained in FDAMA, an issue remained that was reminiscentof the original enactment of the Waxman-Hatch amendments,i.e., the definition of the type of drug product included in itsstrictures. In the case of FDAMA’s Section 125 exemption,therefore, it remained unclear what constituted an ‘‘antibiotic’’exempt from the requirements—and benefits—of drug exclu-sivities and patent listing.*

Accordingly, in the Federal Register of January 24,2000, FDA proposed regulations governing the exemption of

*The effect of ‘‘drug listing’’ in the Orange Book, for example, is to grant theowner of the Reference Listed Drug (‘‘RLD’’) an automatic thirty-month stayof approval in the event the RLD owner sued a generic applicant for patentinfringement following certification by the generic applicant that its productdid not infringe the patent of the RLD.

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antibiotic applications from regulatory provisions governingmarketing exclusivity and patents (22). In its Notice, FDAnoted that under the former Section 507 of the Act antibioticdrugs were not subject to the patent listing and exclusivityprovisions of Section 505. Under Section 125 of the Moderni-zation Act, however, this distinction is preserved ‘‘with anexpansive line’’ (23). Under Section 125, applications areexempted that contain an antibiotic drug that was the subjectof a marketing application received by FDA under formerSection 507 prior to the enactment of FDAMA on November21, 1997. Drugs approved and marketed under former Section507, as well as drugs that were the subject of applications‘‘which may have been withdrawn, not filed, or refusedapproval under section 507 of the act’’ were similarly excludedfrom the patent listing and exclusivity provisions of Section505 (24).

The term ‘‘antibiotic drug,’’ the FDA recounted, is definedin Section 125 of FDAMA as:

Any drug (except for drugs for use in animals other thanhumans) composed wholly or partly of any kind of penicillin,streptomycin, chlortetracycline, chloramphenicol, bacitracin, orany other drug intended for human use containing any quantityof any chemical substance which is produced by a micro-organism and which has the capacity to inhibit or destroy micro-organisms in dilute solution (including a chemically synthesizedequivalent of any such substance) or any derivative thereof.

From this definition, FDA concluded, the term ‘‘antibioticdrug’’ refers not only to the active chemical substance, but toany derivative of the substance, such as a salt or ester of thesubstance. Accordingly, FDA determined, Section 125’s appli-cability applied to any drug that is the subject of a marketingapplication containing an ‘‘active moiety’’ that could be foundin a drug application submitted to the agency prior to theenactment of FDAMA.*

*FDA defined an ‘‘active moiety’’ as the ‘‘molecule or ion responsible forphysiological or pharmacological action, excluding appended portions thatwould cause the drug to be an ester, salt, or other noncovalent derivativeof the molecule’’ (65 FR at 3625).



In defending its position, FDA noted that it had previouslytaken the same position with regard to nonantibiotic drugswith regard to patent listing and exclusivity:

In interpreting the exclusivity provisions in the Hatch-WaxmanAmendments, the agency concluded that Congress did notintend to confer significant periods of exclusivity on minorvariations of previously approved chemical compounds. . . .Therefore, the agency determined that it is appropriate toassess whether the drug seeking exclusivity is a new chemicalentity, that is, a drug that does not contain any previouslyapproved active moiety (25).

Having established that the congressional intent was toexempt from patent listing and exclusivity any applications forthe same ‘‘active moiety’’ of a prerepeal antibiotic drug, FDAwent on to propose a mechanism ‘‘[t]o help interested personsdetermine which drug products [are] exempt from the market-ing exclusivity and patent provisions’’ by maintaining in theCode of Federal Regulations (CFR) a list of the names of eachprerepeal active moiety, in Section 314.109(b) of the CFR. Thislist, FDA indicated, is intended to be comprehensive and toprovide interested persons a means of determining whether amarketing application would be for a drug that contains a pre-repeal antibiotic.* Included with its proposed rule was a list ofthese active moieties of pre-repeal antibiotics that the FDAconsidered exempt from patent listing and exclusivity provi-sions of Section 505 of the Act (26).

7. FDA’S GUIDANCE

In implementing the repeal, FDA issued a Guidance documentin which it outlined a new numbering system for applications

*Although intended to be comprehensive, FDA notably stressed its use as anaid to interested parties, but without legal effect. Thus, if any products wereinadvertently omitted from the list, such omissions would not affect theregulatory status of the application: the application would still be exemptfrom patent listing and exclusivity, notwithstanding inadvertent omissionfrom the list. 65 FR at 3625

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subject to the old and new regulatory schemes and, in addition,more clearly defined which applications were subject to therespective statutory frameworks (27). The Guidance indicatedthat the Section 125 exemption contained in the ModernizationAct applicable to ‘‘old’’ antibiotics applied to applicationsthat contained in whole, or in part (i.e., as part of a combina-tion product), an antiobiotic drug, as defined in the Act (28).Moreover, the Guidance made clear, the antibiotic contained inthe application would need to have been received by FDA priorto FDAMA, whether or not approved, marketed, marketed andwithdrawn by the Sponsor, for any reason, submitted and with-drawn by the Sponsor, and not further submitted. Action lettertemplates for Section 507 drugs would no longer be used, norwould monographs for antibiotics be published or maintained.

With respect to bulk drug applications, prior to FDAMAFDA had required that bulk antibiotic drug substances beeither batch certified or exempted from batch certificationvia an approved antibiotic drug application. FDA had used anapproval mechanism for bulk antibiotics that was similar to theapproval mechanism for finished antibiotic applications. Underthe new scheme, FDA indicated it would treat informationregarding bulk drug substances as DMFs, like their nonanti-biotic counterparts. Accordingly, this information would nolonger require specific approval, but rather, like DMFs, wouldmerely be filed with the Agency and considered as part of thedrug application. Like nonantibiotics, antibiotics could alsohenceforth contain drug substance information in the finishedproduct application itself (29).

As a result, all unapproved bulk applications pending atthe FDA were converted by FDA into DMFs and assigned DMFreference numbers.

8. CONCLUSION

The history and development of antibiotic regulation repre-sents a process of increasing evolution of a particular legisla-tive scheme which had, over time, increasingly outstripped thehistorical circumstances and needs that were its provenance.



Revised by FDA to take account of both changing scientificstandards and regulatory and marketplace realities, thescheme was finally abandoned entirely by Congress andfolded into the standard drug regulations, thereby putting anend to its unique approval mechanism and separate status.

REFERENCES

1. FDCA x 507(a); 21 U.S.C. 357(a).

2. Pub. L. No. 77-366, 55 Stat. 851 (1941); Pub. L. No. 79-139, 59Stat. 463 (1945); codified at 21 U.S.C. x 356.

3. Section 507 of the FDCA; 21 U.S.C. x 357.

4. John D. Harrision, Antibiotic application requirements, ClinRes Practices Drug Reg Affairs 4(4) 265, 267 (1986).

5. Id. at 267.

6. 21 U.S.C. x 357(a).

7. Harrison, id. at 267.

8. See FDA Proposal, 47 FR 19957, May 5, 1982; see also former21 CFR 314.50, 314.55.

9. Harrison, id. at 269.

10. Id.

11. FDA Order, 47 FR 39155, September 7, 1982.

12. See Barr Laboratories, Inc. v. Harris, 482 F. Supp. 1183 (DDC1980).

13. See Pfizer, Inc. v. Richardson, 434 F.2d 536 (2d Cir. 1970).

14. See In the Matter of Antibiotic Antifungal Drugs (FDA 1988),1988–89n FDC LRept Dev Trans Bind at 38,070.

15. 21 CFR 433.1(a) (repealed).

16. See former 21 CFR 314.

17. See former 21 CFR 314.70.

18. 63 FR 26066.

254 Wiesen


19. 64 FR 396; 64 FR 26657 (May 17, 1999).

20. 21 CFR parts 430 to 460.

21. Marketing exclusivity and patent provisions for certain anti-biotic drugs, 65 FR 3623 (January 24, 2000).

22. 65 FR 3623 (January 24, 2000).

23. Id. at 3624.

24. Id.

25. Id.

26. 65 FR at 3625.

27. Guidance for industry and reviewers: repeal of Section 507 ofthe Federal Food, Drug and Cosmetic Act, FDA Center forDrug Evaluation and Research (‘‘CDER’’), May 1998.

28. Section 201( jj) of the FDCA.

29. See Guidance for industry: drug master files for bulk antibioticdrug substances, FDA Center for Drug Evaluation andResearch (‘‘CDER’’), November, 1999.



8

Pioneer and Generic Drugs: BalanceBetween Product Life Cycle Extension

and Anticompetitive Behavior

ROBERT G. PINCO and BARBARA A. BINZAK

Buchanan Ingersoll Professional Corporation


1. INTRODUCTION

Consumers, although they may not realize it, live the effects ofthe Drug Price Competition and Patent Term Restoration Actof 1984, known commonly as the Hatch-Waxman Amendments(also known as the Waxman-Hatch Amendments, or simply theAmendments)(1) every day. The primary effect of the Amend-ments was to create the abbreviated new drug application(ANDA) process, which established an administrative mechan-ism for rapid clearance of generic drugs by allowing shortened

257


applications to be filed with the U.S. Food and Drug Adminis-tration (FDA). In these days of rapidly escalating health carecosts, especially medicines, the result has been to give consu-mers less expensive versions of the medications they need tomaintain their health. The passage of the Drug Price Competi-tion and Patent Term Restoration Act of 1984 signifiedCongress’s attempt to strike a balance between the need forpharmaceutical innovation and less expensive drugs. Thisbalance has not always been preserved, however.

This chapter builds on the previous discussions of Hatch-Waxman in this book and explores the ramifications ofthe Amendments almost 20 years after their enactment. Inparticular, the chapter examines the sophisticated regulatorystrategies that pioneer companies sometimes employ to maxi-mize the value of their products and the issues faced by genericcompanies as they seek to bring their generic drugs to market.While many of these ‘‘strategies’’ may be legal within thebounds of Hatch-Waxman, some have raised the interest andsubsequent involvement of the Federal Trade Commission(FTC), since such actions not only stretch and bend the con-tours of Hatch-Waxman, but also raise antitrust concerns. Thechapter also addresses some of the reform efforts that havebeen proposed from both a regulatory and a legislative stand-point. Given the high and ever-increasing cost of pioneer drugs,the public’s unyielding desire to have low-cost generic drugoptions when filling their prescriptions, and the government’sneed to lower health care costs, debate centered on reform ofHatch-Waxman is unlikely to disappear in the near future.

2. BRIEF OVERVIEW OF HATCH-WAXMAN

2.1. Purpose

The Hatch-Waxman Amendments were passed by Congresswith two goals in mind: balancing incentives for pioneer drugmanufacturers to continue bringing research-based products tomarket and providing opportunities for generic drug manufac-turers to enter the market in a timely manner with lower-cost

258 Pinco and Binzak


products (hereinafter ‘‘Study’’) (2). Since the enactment of theAmendments, generic drugs have moved from relative insignifi-cance to become a major factor in reducing U.S. health carecosts. While this figure was only 19% in 1984, the year Hatch-Waxman became law, it has increased to 47% (3). A Congres-sional Budget Office (CBO) study has estimated that, for drugssold by retail pharmacies, consumers saved $8–$10 billion byfilling their prescriptions with generic drugs during 1994 (4),and it is estimated that these savings have increased dramat-ically since the CBO study was carried out almost 10 years ago.Generic drugs clearly save the American public money; how-ever, the costs incurred by the pioneer drug manufacturerswho engage in the research and development of new pharma-ceutical compounds can be huge. The Boston Consulting Grouphas estimated that it can take more than 14 years and upwardsof $880 million to bring a new drug to market. While much ofthis amount can be attributed to failed research efforts alongthe way to achieving success with a single compound, suchsums must nevertheless be expended in order to bring a singleproduct to market (5). Therefore, while it is important tomake less expensive medicines available to the public, it isalso important for those companies engaging in research anddevelopment to be compensated for their costs and efforts. Thisis the delicate balance of objectives that Hatch-Waxman soughtto both establish and preserve.

2.2. The 30-Month Stay and 180-DayExclusivity Provisions

The Federal Food, Drug, and Cosmetic Act (FFDCA; ‘‘theAct’’) is the primary statutory authority for the regulation ofdrugs in the United States (6). The Hatch-Waxman Amend-ments amended the FFDCA in part by adding section 505( j)to the Act (codified at 21 U.S.C. x 355( j)), which established theabbreviated new drug application process.* As a result, generic

*FDA’s regulations governing the new drug approval process and the abbre-viated new drug approval process can be found at 21 C.F.R. Part 314 (appli-cations for FDA approval to market a new drug).

Pioneer and Generic Drugs 259


drug manufacturers can rely on FDA’s previous determinationthat the pioneer drug (also known as the innovator or listeddrug) on which the generic is based is safe and effective.* Itis the pioneer drug manufacturer that must submit a newdrug application (NDA) that contains not only safety andeffectiveness data, but patent information on the new drugcovered by the NDA as well (7). This patent information fromthe NDA is listed in an FDA publication, ‘‘Approved DrugProducts with Therapeutic Equivalence Evaluations,’’ knownas the Orange Book (8). When a generic drug manufacturerfiles an ANDA, the application must contain a certificationfor all of the patents that are found in the Orange Book forthe pioneer drug upon which the generic product is based.There are four possible certifications that the ANDA applicantmay make (9):

1. Patent information has not been filed (paragraph I).2. The patent has expired (paragraph II).3. The patent will expire on a given date (paragraph III).4. The patent is invalid or will not be infringed by the

manufacture, use, or sale of the generic drug forwhich the ANDA was filed (paragraph IV).

The filing effects of each of these certifications is different; fora paragraph IV certification, which is the provision at issue inthis chapter, the key determination that must be made iswhether or not the patent(s) on the pioneer drug are infringedby the filing of the ANDA for the generic drug.

When a paragraph IV certification is filed, a complex set ofevents are put into motion.y First, the ANDA applicant mustnotify the patent holder and the NDA holder for that patentlisted in the Orange Book that is referenced in the paragraphIV certification of the ANDA. This notification must indicatethat an application has been submitted ‘‘to obtain approval

*A list of the content requirements for an ANDA can be found at 21 U.S.C.Sect. 355( j)(2)(A).yThese procedures are detailed in 21 U.S.C. Sects. 355( j)(2)(B) and( j)(5)(A)-(B).



to engage in the commercial manufacture, use, or sale of suchdrug before the expiration of the patent referred to in thecertification’’ (10). Therefore, this filing of the ANDA, if thegeneric drug is going to be marketed before the pioneer patentexpires, constitutes an act of infringement.* As a result, theNDA holder or patent holder of the pioneer drug may choose tofile a lawsuit against the ANDA applicant for patent infringe-ment. This action must be taken, however, within 45 days ofreceiving notice from the ANDA applicant that the ANDA wasfiled. No declaratory judgment may be sought during the45-day period. Once the suit is filed, a 30-month stay provisionis triggered. In effect, the ANDA may not be approved by FDAfor 30 months from the date the NDA holder/patent holderreceived notice from the ANDA applicant. The 30-month timeperiod may be altered in length, however, if an earlier decisionis made by a court in the patent infringement suit or if a courtdecides on some shorter or longer period than 30 months forthe stay to be in effect. It is important to also note that if apioneer manufacturer later obtains patent(s) on the pioneerdrug that is the subject of an earlier-filed ANDA, the ANDAapplicant must certify as to the new patent(s) listed after filingthe ANDA, if the patent was listed within 30 days of issuance(11). It is this later listing of patents, and the triggering ofsubsequent 30-month stay periods, that has led to certainabuses, which will be addressed in this chapter.

Second, since the first generic drug manufacturer to filean ANDA with a paragraph IV certification takes the risk thatit may be sued for patent infringement, the generic companyis awarded a 180-day exclusivity period to market its genericdrug, which is also provided for in the Amendments. The begin-ning of this 180-day period is triggered by the first of twopossible events to occur. The period may begin on the date

*Note, however, that it is not an infringing act ‘‘to make, use, offer to sell, orsell within the United States or import into the United States a patentedinvention . . . solely for uses reasonably related to the development and sub-mission of information under a Federal law which regulates the manufac-ture, use, or sale of drugs or veterinary biological products’’ (35 U.S.C. Sect.271(e)(1)).



the generic drug is first commercially marketed. Alternatively,the period may begin on the date a court decides the pioneerpatent is invalid or not infringed. Only when this 180-dayperiod has expired can FDA approve other ANDAs it receivesfor the same drug (12).

As is apparent, these time periods are consideredextremely valuable to drug manufacturers, both pioneer andgeneric. A pioneer manufacturer will want to invoke the 30-month stay provision, when possible, to extend the life of itspatents as long as it can before generic competitors can enterthe market and begin to compete. On the other hand, a genericdrug manufacturer will utilize the 180-day exclusivity periodto its advantage, so that other generic competitors are forcedto wait to enter the market as long as possible. This tensionis illustrated in Sec. 3 which highlights recent consent ordersthat have been issued by the FTC against various drug manu-facturers in response to allegations of anticompetitive behavior.

3. PRACTICES RAISING ANTITRUSTCONCERNS

The FTC has become involved in enforcement of the Hatch-Waxman Amendments because of the antitrust implicationsraised when drug manufacturers, individually or in agreementwith each other, attempt to side-step the legal effects of theAmendments. These activities and agreements appear to fallinto two general categories: (a) agreements between a pioneerand a generic drug manufacturer or two generic drug manu-facturers, and (b) activities solely of pioneer drug manufac-turers. Agreements coming within the former category ofteninclude payments to a potential generic drug manufacturerto stay off the market and not compete with a product thatis already on the market, at times affecting the tolling of the180-day period of generic drug exclusivity. Actions fallingwithin the latter category include strategies to list additionalpatents covering a pioneer drug in the Orange Book just priorto patent expiration, in an attempt to generate an additional30-month stay period. While some of the activities these



companies have engaged in may be technically legal within thebounds of the Amendments, it is questionable whether suchpractices defeat the spirit of Hatch-Waxman, and the balancebetween rewarding innovation and encouraging generic compe-tition, that the legislation attempted to strike.

3.1. FTC’s ‘‘First-Generation’’ Activities:Bilateral Agreements Raising Antitrust ConcernsUnder Hatch-Waxman

According to the FTC, the Commission’s ‘‘first-generation’’activities involved settlement agreements arrived at duringpatent litigation, entered into between the pioneer drug man-ufacturer and the generic drug manufacturer, which allegedlydelayed market entry of the generic product (13). This sectionfirst examines two such agreements, each involving a pioneerand a generic manufacturer, which resulted in FTC action. Itwill then turn to a third example involving a different scenario:an agreement entered into between two generic manufacturersto limit the number of generic versions of a pioneer drugintroduced on the market.

3.1.1. Agreements Between Pioneer and GenericManufacturers

Hoechst Marion Roussel, Inc./Carderm Capital L.P./AndrxCorporation

In a March 16, 2000, complaint against Hoechst MarionRoussel, Inc. (‘‘HMR,’’ now Aventis Pharmaceuticals, Inc.),*Carderm Capital L.P. (‘‘Carderm’’), and Andrx Corporation(‘‘Andrx’’), the FTC made allegations related to payinga generic drug manufacturer to keep its generic version of adrug off the market (14). The agreement entered into involvedthe drug known as Cardizem CD, a once-a-day diltiazem drug,which is used in the treatment of hypertension and angina (15).HMR was the leading manufacturer of Cardizem CD, whichaccounted for more than 70% of the total sales of once-a-day

*This section will continue to refer to the party as ‘‘HMR,’’ as opposed toAventis.



diltiazem (16). In late 1995, Andrx (the generic drug manufac-turer) filed the first ANDA for its generic version of CardizemCD, which included a paragraph IV certification (stating theproduct in the ANDA did not infringe any CardizemCD patents)(17). In January 1996 HMR and Carderm (Carderm as theholder of the rights to three patents for Cardizem CD)(18) fileda patent infringement suit against Andrx, which triggered the30-month stay provision of Hatch-Waxman until July 1998 (19).

On September 24, 1997, HMR, Carderm, and Andrxentered into a Stipulation and Agreement (‘‘Agreement’’),whereby the parties agreed that Andrx would not bring itsgeneric version of Cardizem CD (covered in the ANDA inissue) to market until the earliest of (a) an entry of final judg-ment in the lawsuit that had been filed against Andrx,(b) Andrx obtaining a license from HMR per the Agreement,or (c) HMR providing notice that it would sell its own bioequiv-alent or generic version of Cardizem CD or would license athird party to do so* (20). In this Agreement, Andrx alsoagreed that it would not sell any other bioequivalent or genericversion of Cardizem CD, even if it would not infringe HMR’sor Carderm’s patents (21). In exchange, HMR agreed to payAndrx $10 million per quarter, to begin when Andrx’s ANDAwas finally approved by FDA; this payment would continueuntil one of the three events listed above occurred. Andrxwould also receive $60 million per year during this same timeperiod if HMR were to lose the infringement suit it had filed(22). In addition, Andrx would have an option to get a licensefrom HMR for HMR’s Cardizem CD intellectual property (23).If Andrx breached the Agreement, it would have to repay themoney it received (24).

FDA granted Andrx final approval for its generic versionof Cardizem CD on July 9, 1998; however, per the Agreement,Andrx did not begin selling its product. Rather, Andrx beganreceiving payments from HMR (25). In mid-1999, HMR and

*This was not an agreement to settle litigation; the parties agreed to con-tinue the lawsuit. In the Matter of Hoechst Marion Roussel, Inc., CardermCapital L.P., and Andrx Corporation. Docket No. 9293. Complaint. March 16,



2000. http://www.ftc.gov/os/2000/03/hoechstandrxcomplaint.htm. �23.

http://www.ftc.gov

Andrx entered into another agreement whereby Andrx beganmarketing a generic version of Cardizem CD (26).

The FTC’s complaint further alleged that the activities ofthe companies ‘‘had the purpose or effect, or the tendency orcapacity, to restrain competition unreasonably and to injurecompetition and consumers by preventing or discouraging theentry of competition in the form of generic versions of CardizemCD into the relevant market’’ (27). Furthermore, the ‘‘purposeand intended effect’’ of the quarterly payments ‘‘was to providean incentive for Andrx to refrain both from entering the rele-vant market, and from taking any steps, including relinquish-ing its right to a 180-day Exclusivity Period, to permit orfacilitate the entry of any other generic manufacturer’’ (28).Finally, the FTC alleged that the Agreement entered into con-stituted an unreasonable restraint of trade and that the activ-ities engaged in constituted unfair methods of competition,both in violation of Section 5 of the Federal Trade CommissionAct, as amended (29).

The FTC issued its consent order against HMR, Carderm,and Andrx in May 2001* (30). The order states that the partiesmust cease and desist from entering into any agreementbetween a pioneer company and a generic company that putsrestrictions on relinquishing 180-day exclusivity rights andthat restricts entering the market with a noninfringing prod-uct, subject to certain exceptions (31). Furthermore, if any ofthese three companies are the NDA holder or the allegedinfringer in a patent infringement case, they are to cease anddesist from entering into an agreement in which the parties donot agree to dismiss the litigation, the NDA holder provides‘‘anything of value’’ to the alleged infringer, and the allegedinfringer agrees not to sell the product at issue or anotherproduct containing the same active chemical ingredient duringlitigation, subject to certain exceptions (32). The consent orderwill last for 10 years, terminating on May 8, 2011 (33).

*Note that two separate consent agreements were reached, one by HMR andCarderm, the other by Andrx. The one consent order issued, however, isidentical for all parties.



As is apparent, this ‘‘Agreement’’ between the partiesserves as an example of how companies may financially com-pensate one another to remain off of the market and, in effect,‘‘park’’ the 180-exclusivity period so that no other generic drugmanufacturer can enter the market, either.* The pioneer drugmanufacturer benefits, because its ‘‘monopoly’’ remains intactfor a longer period of time; the generic drug manufacturerbenefits because it receives financial compensation that itwould otherwise have received had it brought the generic ver-sion of the drug to market. While these companies initially mayhave thought they had found a way to ‘‘game’’ the system, it isclear, in the end, that they did not. Ultimately, in such situa-tions, the American consumer is the party that is harmed, sinceit is the consumer who benefits from the timely introduction ofgeneric drugs to the market.

Abbott Laboratories/Geneva Pharmaceuticals, Inc.

A second example involving Abbott Laboratories (‘‘Abbott’’)and Geneva Pharmaceuticals, Inc. (‘‘Geneva’’) raises many ofthe same issues. Terazosin hydrochloride (terazosin HCl) is adrug primarily used to treat hypertension and benign prostatichyperplasia (BTH) or enlarged prostate (34). Abbott was themanufacturer of the pioneer drug Hytrin, first introducedin tablet form in 1987 and later in capsule form in 1995 (35).In the first half of 1999, Abbott reported that its U.S. salesof Hytrin represented more than 20% of the net sales for itspharmaceutical division (36). Geneva was the first generic drugmanufacturer to file an ANDA for both the tablet and capsuleforms of Hytrin, in early 1993 and late 1995, respectively (37).In early 1996, Abbott listed a new patent covering Hytrin inthe Orange Book; Geneva subsequently filed a paragraph IV

*It should be noted that two other generic drug manufacturers submittedANDAs as well. In January 1997, Purepac Pharmaceutical Co. filed anANDA, and in June 1997 Biovail Corporation International filed an ANDA.These companies did not receive FDA approval on their ANDAs until Andrx’s180-day exclusivity period expired, in December 1999. (In the Matter ofHoechst Marion Roussel, Inc., Carderm Capital L.P., and Andrx Corporation,



Docket No. 9293, Complaint, March 16, 2000, http://www.ftc.gov/os/2000/03/hoechstandrxcomplaint.htm, �� 16, 19, 20.)

http://www.ftc.gov

http://www.ftc.gov

certification (38). Abbott then sued Geneva, claiming thatGeneva infringed the Hytrin tablet product. However, noinfringement claim was made against Geneva regarding thecapsule product (39). As a result, FDA was prohibited fromapproving Geneva’s tablet product ANDA for 30 months, butthe capsule product could be approved right away (40). Thisapproval of the capsule product ANDA was granted on March30, 1998 (41).

The agreement entered into between the parties resemblesthat entered into by HMR and Andrx. The day FDA grantedGeneva approval of the ANDA covering its generic capsule prod-uct, Geneva contacted Abbott and indicated it would marketthis product unless Abbott paid Geneva not to do so (42). Abbottestimated that Geneva would earn revenues of $1–$1.5 millionper month once it began marketing its generic version (43);Abbott further estimated that generic entry would eliminatemore than $185 million in sales of Hytrin in 6 months (44).As a result, the FTC’s complaint alleges that Abbott ‘‘waswilling to pay Geneva a ‘premium’ over that [$1–$1.5 millionper month] not to compete’’ (45). In the end, Abbott agreed topay Geneva $4.5 million per month in nonrefundable paymentsuntil a decision was reached in the patent litigation (46). Inexchange for these payments, Geneva agreed not to enter themarket with its generic version, either capsule or tablet, untileither (a) final resolution of the patent litigation or (b) entry ofanother generic version of Hytrin, whichever occurred first.Abbott further insisted that Geneva agree not to transfer,assign, or relinquish the 180-day exclusivity period to whichit would be entitled (47).

Once the parties became aware that the FTC was investi-gating their arrangement, the agreement was canceled; Genevaintroduced its generic capsule onto the market in August 1999(48). The FTC alleged in its complaint that (a) the parties’agreement was an unreasonable restraint on trade, (b) theparties acted with specific intent that Abbott would monopolizethe relevant market, (c) Abbott had monopoly power and mono-polized the market, and (d) the activities had an anticom-petitive effect and constituted unfair methods of competition,all in violation of Section 5 of the Federal Trade Commission



Act, as amended (49). The FTC issued a consent order againsteach party, which were substantially similar to each otherin many respects. Both included a prohibition against enteringinto certain types of agreements in the future (50), andboth banned private agreements regarding payments to keepa generic version of a drug off the market during patentlitigation (51). Furthermore, Geneva agreed to relinquish itseligibility for the 180-day exclusivity period for the terazosintablets (52).

It is clear from both of these examples that drug manu-facturers have discovered ways to keep generic products offthe market. These are also illustrations of how the 180-dayexclusivity provision can be ‘‘parked,’’ since the company agree-ments in both cases involved generic companies agreeing notto assign their rights to the 180-day exclusivity period. Thisultimately meant that, even though the generic manufacturershad received ANDA approvals for their generic products, thegenerics would not be marketed. As a result, no other genericdrug could be approved by FDA, either. The tolling of the180-day clock had simply been forestalled. It is this type ofscenario that those wishing to reform Hatch-Waxman wouldlike to preclude in the future.

3.1.2. Agreements Between Generic DrugManufacturers: Biovail Corporation/ElanCorporation, PLC

While agreements between pioneer and generic drug manufac-turers to side-step the legal effects of Hatch-Waxman may makeintuitive sense, since both parties can ultimately profit fromkeeping a generic drug off the market entirely, it is not unheardof for two generic drug manufacturers to enter into agreementsas well. In the case of Biovail Corporation (‘‘Biovail’’) and ElanCorporation, PLC (‘‘Elan’’), two generic drug manufacturersagreed not to compete with one another, thus limiting thenumber of generic versions of a pioneer drug that were on themarket. Prior to the issuance of the consent order againstthe two companies, the FTC called the proposed consent order‘‘the Commission’s first enforcement action regarding an



allegedly anticompetitive agreement between two competinggeneric drug manufacturers’’ (53).

In its complaint, the FTC described that nature of theagreement entered into by Biovail and Elan (54). The agree-ment involved the pioneer drug known as Adalat CC (‘‘Adalat’’),which is used to treat hypertension (55). In 1993, Bayer AGfirst introduced this product, which is available in the UnitedStates in dosages of 30, 60, and 90mg (56). Elan filed the firstANDA for a 30mg generic Adalat product in April 1997; Biovailwas the second company to file an ANDA for this strength inDecember 1997. Final FDA approval for Elan’s 30mg genericproduct was granted in March 2000, and Elan entered themarket that same month. Biovail, being the second genericmanufacturer to file an ANDA for the 30mg product, receivedFDA approval in December 2000, but has never entered themarket (57). The two companies were in the opposite positionsregarding the 60mg product: Biovail filed the first ANDA inApril 1998, which was both FDA approved and marketed byBiovail in December 2000. Elan was the second company to filean ANDA on the 60mg product in June 1999. The ANDA wasapproved in October 2001, but Elan has never marketed the60mg generic version of Adalat (58).

Before either Elan or Biovail received final FDA approvalof their ANDAs for the 30mg and 60mg generic Adalat ver-sions, respectively, the two companies entered into an agree-ment in October 1999 (59). Under the agreement, which had aminimum lifetime of 15 years, Biovail was made the exclusivedistributor of Elan’s 30mg and 60mg generic Adalat prod-ucts (60). Since neither Elan nor Biovail distributed productsthemselves in the United States, a third party, Teva Pharma-ceuticals, Inc. (‘‘Teva’’), became the subdistributor, underBiovail, of Elan’s 30mg product (Teva was already Biovail’sdistributor). Whenever Elan notified Biovail that the 60mgproduct was ready for marketing, Biovail further agreed toappoint either Teva, or some other company, to be the sub-distributor (under Biovail) for the 60mg product as well (61).

Although the agreement had been twice modified, theFTC’s complaint alleged that ‘‘these modifications did notlessen any of the agreement’s anticompetitive features’’ (62).



At the time the complaint was filed, Biovail had paid Elanapproximately $33 million related to the distribution of Elan’s30mg product by Teva; Biovail had also paid Elan $12.75million to be able to distribute Elan’s 60mg product (63).

The results of this agreement meant that (a) Teva coulddistribute Biovail’s 60mg product and Elan’s 30mg product,(b) some other company could distribute Biovail’s 30mg prod-uct and Elan’s 60mg product, and (c) Biovail would receiveprofits on all of the products (64). The net effect upon theAmerican public, however, was that even though FDA hadapproved two ANDAs for generic versions of 30mg Adalatand two ANDAs for generic versions of 60mg Adalat, Biovailand Elan agreed to market only one 30mg and one 60mggeneric version (65). However, according to the complaint,even if both companies marketed 30mg and 60mg versionsof Adalat, ‘‘the agreement allows Biovail to control or influencepricing and other competitive features of both its and Elan’s30mg and 60mg generic Adalat products’’ (66). Furthermore,the FTC alleged that the agreement restrained competition andinjured consumers by (a) denying consumers, and other partiessuch as pharmacies and hospitals, the benefits of having accessto multiple versions of Adalat, (b) forcing pharmacies, hos-pitals, and other parties to pay ‘‘artificially high prices’’ forgeneric Adalat, and (c) forcing consumers either to pay ‘‘artifi-cially high prices’’ for generic Adalat, or not to buy the productat all because of not being able to pay for it (67).

In August 2002, a consent order was issued by the FTCagainst both Biovail and Elan* (68). According to the order,which will last for 10 years (69), the parties must terminatetheir agreement and not engage in such conduct in the future(70). Furthermore, Elan ‘‘shall use best efforts’’ to manufac-ture and market its own 30 and 60mg generic Adalat productsthrough a distributor other than either Biovail or Teva (71).In addition, Biovail is also required to use such ‘‘best efforts’’to manufacture and market its own 30 and 60mg genericAdalat products through a party other than Elan’s generic

*Note that Teva was not a party.



Adalat distributor (72). In order to prevent any disruption inthe availability of generic Adalat products during this period ofdissolution of the agreement and product launch by both par-ties, the order attempts to ‘‘maintain[] commercial suppl[ies]’’of the products presently on the market, and ‘‘eliminates theanticompetitive obstacles to entry’’ of additional generic ver-sions of Adalat (73).

This example illustrates yet another type of agreementthat drug manufacturers may enter into in order to extendthe market life for their products. In the Biovail/Elan situation,the arrangement entered into by the parties involved puttinga hold on introducing additional generic versions of a pioneerdrug product. Thus, although one generic version was on themarket, the agreement between the parties limited the compe-tition, and likely any further price reduction, that additionalgenerics would offer to the American public. In general, ageneric drug may cost 25–50% less than a pioneer drug, withthe price dropping further as more generic competitors enterthemarket. This agreement had prevented further reductions inprice, as normally occurs. While this scenario did not involveHatch-Waxman in a direct manner, as did the HRM/Andrxor Abbott/Geneva situations outlined above, the agreemententered into between the companies was still, arguably, madein violation of the spirit of Hatch-Waxman, which was meant topromote competition of generic and pioneer drugs.

3.2. FTC’s ‘‘Second-Generation’’ Activities:Unilateral Hatch-Waxman Abuse ThroughImproper Orange Book Listings

The FTC has recently been active in another area of antitrustenforcement: improper listing of patents in FDA’s OrangeBook. The agency has called its efforts on this front ‘‘second-generation activities’’ (74). In this section, the chapteraddresses two recent allegations made by generic drug manu-facturers of improper Orange Book listings by pioneer drugmanufacturers, both listings made in efforts to extend thelives of the drug patents beyond the 30-month stay provided



for by the Hatch-Waxman Amendments. This section also sur-veys the FTC’s actions in curtailing such efforts.

3.2.1. Andrx Pharmaceuticals, Inc./BiovailCorporation

In recent years, Andrx Pharmaceuticals, Inc. (‘‘Andrx’’) andBiovail Corporation (‘‘Biovail’’) have become involved in litiga-tion involving the ‘‘delisting’’ of a patent in the Orange Book.The FTC has also taken action, since the agency alleged thatBiovail, the pioneer drug manufacturer, illegally acquired anexclusive patent license to a product it subsequently wrongfullylisted in the Orange Book (75). According to the FTC, this wasits first complaint and proposed consent order with a drugmanufacturer for such actions (76). Diltiazem hydrochloride(‘‘diltiazem’’) is the active ingredient in the drug Tiazac, man-ufactured by Biovail. Biovail had sales of Tiazac, which is usedin the treatment of angina and high blood pressure* (77), ofalmost $200 million in 2000, which accounted for 38% of grosssales for the company (78). Biovail received NDA approval forTiazac (covering aspects of the extended-release formulation)on September 11, 1995, and certified to FDA that U.S. PatentNo. 5,529,791 (‘‘ ’791’’) claimed the drug that was the subjectof this NDA. The ’791 patent issued on June 25, 1996, and waslisted in the Orange Book (79).

After Andrx filed an ANDA containing a paragraph IVcertification on June 22, 1998, Biovail sued Andrx for patentinfringement, triggering a 30-month stay. Andrx won theinfringement suit in district court, and the decision wasaffirmed in the U.S. Court of Appeals for the Federal Circuiton February 13, 2001 (80). Andrx’s ANDA for the genericversion had been tentatively approved on September 29, 2000,with final approval pending the expiration of the 30-monthstay that was triggered by Biovail’s lawsuit against Andrx.This time period ended around February 13, 2001 (the dateof the decision of the appellate court in the infringement

*Note that the complaint refers to ‘‘angina’’ as ‘‘chronic chest pain.’’



lawsuit) (81). However, other events prior to February 2001prevented the immediate marketing of the approved genericversion upon resolution of the patent dispute in the courts.

After the ’791 patent issued in 1996, another patent, U.S.Patent No. 6,162,463 (‘‘ ’463’’) was issued on December 19, 2000to Dr. Arnold Lippa, founder and CEO of DOV Pharmaceu-ticals, Inc. (‘‘DOV’’) (82). This patent covered an extended-release form of the drug, comprising both quick-release andslow-release preparations of the drug (83). In January 2001,Biovail acquired an exclusive license from DOV for the ’463patent (84). Biovail subsequently filed a certification whichsupported the Orange Book listing of the ’463 patent. Andrxargued that this ’463 patent did not claim Tiazac, andrequested delisting of the patent by FDA (85). However, Biovailagain certified that the ’463 patent claimed the drug for whichthe NDA on Tiazac had originally been submitted (86). There-fore Andrx, in addition to filing suit against Biovail to delist the’463, filed a paragraph IV certification for this second patent(87). Andrx sought to have this second 30-month stay periodshortened under the authority of the Act (88). The Act statesthat the 30-month stay provision may be modified in length to‘‘such shorter or longer period as the court may order becauseeither party to the action failed to reasonably cooperate inexpediting the action’’ (89).

After the ’463 patent issued, Biovail changed its processfor Tiazac production and sought approval to market theformulation covered by the ’463 patent. However, FDA indi-cated that it would require a supplement to Biovail’s NDA inorder for Biovail to make such a change (90). Andrx claimedthat Biovail had changed the formulation of Tiazac to fallwithin the scope of the ’463 patent for purposes of receivingan additional 30-month stay period from FDA (91). The districtcourt ruled in favor of Andrx, stating that

its [Biovail’s] overall conduct in listing the ’463 patent basedupon a manufacturing change that the FDA has concluded isa ‘‘major’’ change requiring a supplement to Biovail’s New DrugApplication, and that with this change, Biovail’s Tiazac drugis not an approved drug, was not done to reasonably cooperate



in expediting the action. . . . it is clear that Biovail’s actions withregard to obtaining the ’463 patent after tentative approval ofAndrx’s generic drug and changing the formulation of its ownapproved drug, Tiazac, to come within the newly obtained patentwere done to impede or delay the expeditious resolution ofthe patent actions between Biovail and Andrx over approval ofAndrx’s generic equivalent to Tiazac (emphasis in original) (92).

Furthermore, the district court ordered that the stay providedfor by the Act should end on September 27, 2001, much earlierthan August 8, 2003, when a second 30-month stay would haveended (93).

On appeal, the appellate court vacated the district court’sdecision as being an overly broad reading of the Act andremanded the case to the district court for further proceedings(94). While the district court apparently concluded it couldshorten the 30-month period because of the delay in the ‘‘over-all’’ patent dispute between the two companies, the appellatecourt concluded ‘‘[w]e find no such authority in the statute,which is addressed only to delay related to the particularinfringement action’’ (95). Furthermore, the appellate courtstated that, per its decision in Mylan Pharmaceuticals v.Thompson (96) a district court has no authority in an infringe-ment action to shorten the stay period because of ‘‘allegedlyimproper conduct’’ before FDA (97). Finally, the appellatecourt reiterated that while its Mylan decision held that theAct did not provide a private cause of action for delisting,Mylan did not stand for the proposition that an ANDA applicantcould not sue FDA directly for improper actions. In otherwords, under the Administrative Procedures Act (APA), anANDA applicant may sue FDA to force the agency to approvean ANDA if FDA’s actions were arbitrary, capricious, or nototherwise made in accordance with the law (98).

The FTC decided to take its own action against Biovail forallegedly anticompetitive behavior in its dealings with Andrxand FDA. The FTC focused its allegations on the exclusivelicense arrangement Biovail had entered into with DOV andthe listing of the ’463 patent in the Orange Book. Accordingto the FTC’s complaint, at the time the ’463 patent was listedin the Orange Book, Biovail was aware that it did not cover



the formulation of Tiazac that was on the market and thatwithout the exclusive license from DOV, Biovail could nothave listed the ’463 patent at all (99). When Andrx inquiredabout getting a license from DOV in early 2001, DOV indicatedto Andrx that it had made an exclusive license arrangementwith Biovail (100).

The FTC alleged that Biovail’s actions violated the lawin two ways. First, the FTC alleged that the exclusive licenseconstituted an asset acquisition as defined in the Clayton Act,codified at 15 U.S.C. x 18 (101). The agency stated that Biovaildid not need any license to market the Tiazac product that hadalready been approved by FDA and that was on the market.The exclusive license ‘‘raised substantial barriers’’ for anotherparty to enter the market, in violation of the Clayton Act andthe FTC Act (102). Second, the FTC alleged that Biovail‘‘engaged in acts to willfully maintain its Tiazac monopoly,’’including acquisition of the exclusive license to the ’463 patent,wrongfully listing the patent in the Orange Book as claimingTiazac so that the company could gain another 30-month stay,and ‘‘giving non-responsive answers to questions raised bythe FDA about the propriety of listing the ’463 patent in theOrange Book so as to avoid de-listing’’ (103). According to theagency, Biovail’s March 26, 2001, declaration to FDA, whichcertified that Biovail believed the ’463 patent was eligible forlisting with respect to Tiazac, did not clarify if ‘‘Tiazac,’’ asBiovail intended it to be understood by FDA, meant the FDA-approved form of Tiazac on the market or the modified form ofTiazac covered by the ’463 patent (104). The complaint furtherstated that, as was determined in the lawsuit that had beenfiled by Andrx to delist the ’463 patent, FDA understood thatBiovail had meant this declaration to refer to the ‘‘Tiazac’’product that was currently approved (105).

The FTC issued a consent order against Biovail on October2, 2002, which will last for 10 years (106). According to itsterms, Biovail is required to divest ‘‘absolutely, in good faith,and only in a manner that receives the proper approval of theCommission,’’ all exclusive licenses to the ’463 patent ownedby DOV (107). Biovail shall not place restrictions on DOV’suse of this patent, and Biovail shall not ‘‘initiate, maintain,



or be a party to’’ legal action to enforce the ’463 patent (108).Furthermore, if Biovail does not divest within the specifiedtime period and in the manner dictated by the order, theFTC may appoint a trustee to divest the assets to DOV (109).Biovail shall not take action that furthers the listing of anyOrange Book patent that violates the law, and Biovail maynot acquire a patent or exclusive license to a patent if thecompany seeks or secures listing of the patent in the OrangeBook for an NDA that has been approved by FDA withoutproviding a notification to the FTC (110).

3.2.2. Bristol-Myers Squibb

A recent consent order issued by the FTC against Bristol-MyersSquibb (‘‘BMS’’) provides a final illustration of anticompetitivebehavior in the pharmaceutical industry. The FTC wrote alengthy complaint alleging anticompetitive behavior over thecourse of a decade by BMS with respect to its three drugsBuSpar, Taxol, and Cisplatin (111). BMS first received FDAapproval for BuSpar in 1986. The drug contains buspironehydrochloride (‘‘buspirone’’) as the active ingredient and isused to treat symptoms of anxiety and anxiety disorders (112).When the product was first approved by FDA, two patentscovered the product: U.S. Patent Nos. 3,976,776 (‘‘ ’776’’) and4,182,763 (‘‘ ’763’’). In August 1992, Schein Pharmaceutical,Inc. (‘‘Schein’’) filed an ANDAwith a paragraph IV certificationfor a generic version of BuSpar, arguing that the ’763 patentclaimed a use that was anticipated by the ’776 (113). BMS sub-sequently filed suit (114). The district court granted Schein’ssummary judgment motion, finding the ’763 to be invalid, butthe appellate court vacated and remanded for trial (115). There-fore, BMS and Schein entered into a settlement agreement.BMS paid Schein $72.5 million in yearly installments between1995 and 1998, and Schein agreed not to compete with anygeneric bioequivalent version of BuSpar until the ’763 patentexpired (116). The agreement also demanded other actions ofSchein, including the company’s acknowledgement that the’763 was valid and enforceable (even though this determinationhad not been reached yet by the courts) and to withdraw



the paragraph IV certification Schein had submitted to FDA,replacing it with a paragraph III certification (117).

BMS also allegedly engaged in other anticompetitiveactivities, according to the FTC complaint. By the day the’763 patent was to expire, November 21, 2000, FDA hadalready granted tentative ANDA approval to more than 10manufacturers to market a generic version of BuSpar (118).Only hours before the expiration of the ’763 patent, however,the PTO issued to BMS U.S. Patent No. 6,150,365 (‘‘ ’365’’),which claimed only a metabolite of the active ingredientbuspirone, and not the use of buspirone (119). Hours afterthe ’365 was issued, BMS in turn submitted the informationto FDA so that the ’365 could be included in the OrangeBook. Even though BMS knew that the ’365 covered ametabolite of the active ingredient only, BMS stated to FDAthat the ’365 was a method-use patent that covered, in part,a method of using BuSpar (the drug, not the metabolite) (120).According to the FTC, this listing of the ’365 was improperbecause it did not satisfy the two-prong approach set forthin the Act: the patent did not claim BuSpar or a methodof using BuSpar, and it is not a patent with respect to whicha claim of infringement could reasonably be asserted against aseller of BuSpar (121). BMS allegedly lied to FDA furtherwhen, on December 4, 2000, BMS provided another declara-tion that the ’365 covered buspirone hydrochloride, notthe metabolite (122). According to the complaint, ‘‘BMS’sstatements to the PTO are irreconcilable with BMS’s sworndeclaration to the FDA . . . that the ’365 patent ‘contains aclaim for the approved uses of buspirone hydrochloride’ ’’(123). Furthermore, once the ’365 was listed in the OrangeBook, infringement suits were filed against ANDA applicantswhich ‘‘were objectively baseless because . . . the ’365 patentcould not be both valid and infringed’’ (124). In a districtcourt case brought by Mylan Pharmaceuticals (125) in aneffort to have the ’365 delisted, BMS was ordered to seek delist-ing of the patent, which eventually occurred; even though thedistrict court holding was later overturned (126), BMS did notseek relisting of the ’365 (as the generic version was alreadyon the market by that time) (127).



In total, the FTC’s complaint alleged five violations, includ-ing an agreement in restraint of trade on BuSpar and themonopolization of BuSpar, plus allegations related to actionstaken by Bristol-Myers Squibb with respect to Taxol andPlatinol (128). The FTC complaint asserted the agency’sposition that BMS is not immune from liability under the anti-trust laws under the Noerr-Pennington doctrine as both amatter of law and a matter of fact (129). This doctrine givesantitrust immunity to those individuals who ‘‘petition’’ govern-ment (130). The agency stated that BMS was not protected bythis doctrine for several reasons, including (a) many of theactions taken by BMS do not qualify as ‘‘petitioning’’ behavior,(b) BMS engaged in ‘‘objectively baseless ‘sham’ litigationagainst its generic competitors,’’ and (c) BMS made false andmisleading statements or misrepresentations to the PTO andFDA (131). The FTC concluded that ‘‘the course of conductalleged herein constitutes a pattern of abusive filings madewithout regard to the merits that used administrative and judi-cial processes (as opposed to the outcome of those processes) asan anticompetitive weapon’’ (132).

The consent order addressed specific actions BMS musttake with respect to its alleged anticompetitive behaviors involv-ing all three products. For its drug BuSpar, BMS may not listthe ’365 patent in the Orange Book with regard to any NDAthat has buspirone as the active ingredient (133). Furthermore,BMS may not seek to enforce the ’365 patent against a drugproduct or use of a drug product containing the active ingre-dient buspirone; however, enforcement would be allowed if thedrug product also contains the metabolite claimed in the ’365patent and the lawsuit is based on that metabolite (134). BMSalso may not act or encourage another party to act by initiatingor maintaining a 30-month stay of an ANDA that referencesthe NDA for BuSpar (or Taxol) (135). BMS is also barred fromlisting patents in the Orange Book that would violate the law(136). The agreement also generally bars a 30-month stayif BMS engages in certain types of misconduct, regardless ofwhether the patent is listed, including inequitable conduct indealing with the PTO or making false or misleading statementsto FDA (137). BMS is prohibited from asserting fraudulent or



‘‘objectively baseless’’ claims in patent infringement litigationand shall not enforce a patent it knows is not infringed, invalid,or not enforceable (138). Other provisions that appear in theconsent order also aim to deter BMS from engaging in thecourse of conduct it pursued with regard to the three drugsat issue here.

The FTC has also indicated that several state attorneysgeneral have filed antitrust suits in federal court, and thatthe FTC ‘‘assumed the lead in negotiating the conduct limita-tion provisions contained in the proposed order’’ (139). Theagency further notes that ‘‘in principle’’ the states havereached agreements to settle, and that ‘‘[t]he states will enteressentially the same injunctive terms in their orders’’ (140).However, ‘‘the states will recover substantial monetaryrelief ’’ (141).

These examples have been provided to illustrate some ofthe mechanisms both pioneer and generic drug manufacturershave employed to try to circumvent the 180-day and 30-monthprovisions provided for by Hatch-Waxman. Because of theenormous profits that can be earned in the pharmaceuticalindustry, it is not surprising that gaining even a short periodof time beyond these two prescribed time frames can meansubstantial money earned by a pioneer or generic drug com-pany. Trade associations and legislators would like to stop this‘‘abuse’’ of the Amendments through reform efforts.

4. HATCH-WAXMAN REFORM ATTEMPTS

In light of this recent litigation and issuance of consent ordersby the FTC, there has been debate about how to curtail suchscenarios in the future. How can the objectives that Hatch-Waxman was designed to meet—rewarding pioneer drug com-panies, which take the financial risks in bringing new drugsto market, and encouraging generic drug companies, whichtake the litigation risks in order to enter the market as soonas possible to provide Americans with lower-priced drugs—be balanced? This section of the chapter addresses severalproposals that have been advanced which attempt to restore



this balance, including both regulatory and legislative reformefforts. The focus of this section will be on FDA’s recent pro-posed rule* to eliminate, or at least limit, such ‘‘gaming,’’ withsome of the responses from different sectors of the industry,

*Following the writing of this chapter, FDA’s proposed rule was finalized.The final rule was published in the Federal Register of June 18, 2003.Applications for FDA Approval to Market a New Drug: Patent Submissionand Listing Requirements and Application of 30-Month Stays on Approval ofAbbreviated New Drug Applications Certifying That a Patent Claiming aDrug is Invalid or Will Not be Infringed; Final Rule. 68 Fed. Reg. 36675(June 18, 2003). The effective date for the final rule is August 18, 2003,with a compliance date of December 18, 2003, for submission of informationon polymorph patents. Id. at 36676. According to FDA’s Question andAnswers on the final rule, ‘‘[t]he final rule requires information concerningcertain polymorph patents to be submitted if they claim the same activeingredient as the approved product. The polymorph patents must be sub-mitted if the NDA holder has test data demonstrating that the drug productcontaining the polymorph will perform the same as the drug productdescribed in the NDA. The information on polymorph patents must not besubmitted if the NDA holder does not have the test data demonstrating thatthe drug product containing the polymorph will perform the same as the drugproduct described in the NDA.’’ Food and Drug Administration. FDA

ments and Application of 30-Month Stays on Approval of Abbreviated NewDrug Applications Certifying That a Patent Claiming a Drug is Invalid orWill Not be Infringed; Final Rule. 68 Fed. Reg. 36675, pp. 36678–36679 (June18, 2003). The other key features of the proposed rule were adopted in thefinal rule as well, including restrictions on the types of patents that may andmay not be listed in the Orange Book, and limitations on the number of 30-month stays to one per ANDA or 505(b)(2) application, provided a full oppor-tunity for a 30-month stay has been afforded. ‘‘One full opportunity for a 30-month stay’’ means ‘‘a notice of a paragraph IV certification followed byeither the full 45 day period, or notice followed by the initiation of patentlitigation before the 45 days expire.’’ Id. at 36689. One change made from theproposed rule was FDA’s decision to not require submission of a claim-by-claim declaration for all patents. According to FDA, ‘‘[s]uch detailed infor-mation is not explicitly required by the act and is not necessary for a patentto be listed in the Orange Book. . . . Individual patent claims are relevant forpurposes of the Orange Book only in the context of method-of-use patents.’’Id. at 36685. In a Question and Answer piece provided by FDA on the finalrule, the Agency makes clear that a pioneer company could still obtain morethan one 30-month stay, but not on one application. This could occur sincethe 30-month stay applies to each ANDA, and there might be more than oneANDA applicant for one listed drug. Food and Drug Administration.FDA Generic Drugs Final Rule Questions and Answers. June 12, 2003.



Generic Drugs Final Rule Questions and Answers. June 12, 2003. http://

Approval to Market a New Drug: Patent Submission and Listing Require-www.fda.gov/oc/initiatives/generics/qna.html. See also Applications for FDA

http://www.fda.gov

http://www.fda.gov

including the FTC, provided. Several legislative reform effortswill also be briefly summarized.y

4.1. Regulatory Approaches

In October 2002, FDA proposed a rule that would essentiallyreinterpret Hatch-Waxman as allowing only one 30-month stayperiod per ANDA and would clarify which types of patents canbe listed in the Orange Book (142). Prior to FDA’s issuanceof its proposed rule, however, the FTC issued its 2002 Studycovering the pharmaceutical industry and issues related toHatch-Waxman; the Study listed suggestions for reinterpretingHatch-Waxman that the agency claims would help eliminatethe sort of industry behavior discussed in the previous sectionof this chapter (143). While the FTC’s Study carries little legalweight, it does provide additional evidence of the Commission’scurrent thinking on this topic, and reflects how that agencymay proceed in similar circumstances in the future.

4.1.1. FDA Proposed Rule

On October 21, 2002, President Bush announced during aWhite House ceremony that FDA was issuing a proposed ruleto modify FDA’s interpretation of the Hatch-Waxman Amend-ments. The president cited the FTC’s Study of delays in bring-ing generic drugs to market and stated, ‘‘I have reviewed theFTC findings and I am taking immediate action to ensure

FDA announced it had finalized the rule described above, the Agencyalso announced its initiative on ‘‘Improving Access to Generic Drugs.’’This significant effort includes several major efforts, including (a) a proposedincrease of $13 million in FDA’s budget for generic drug program spending,(b) new regulatory processes aimed to reduce time and costs involved ingeneric drug approvals, and (c) enhanced public education, as well as scien-tific study of generic drugs. Food and Drug Administration. FDA WhitePaper. ‘‘New FDA Initiative on ‘Improving Access to Generic Drugs.’ ’’

yThis chapter was drafted prior to passage of Pub. L. No. 108–173, 117 Stat.2066 (Dec. 8, 2003), the Medicare Prescription Drug, Improvement, andModernization Act of 2003, which significantly changed important aspectsof the patent notification and 30-month stay provisions of Hatch-Waxman.



http://www.fda.gov/oc/initiatives/generics/qna.html. Finally, on the same date

June 12, 2003. http://www.fda.gov/oc/initiatives/generics/whitepaper.html.

http://www.fda.gov

http://www.fda.gov

that lower cost, effective generic drugs become available toAmericans without any improper delays’’ (144). FDA’s pro-posed rule was published in the October 24, 2002, issue ofthe Federal Register (145). The two major goals of the ruleinclude (a) clarifying the types of patents that must and mustnot be listed in the Orange Book, along with revising the typeof information an NDA applicant must include in its patentdeclaration, and (b) providing for only one 30-month stayperiod for each ANDA* (146). As of the writing of this chapter,this rule has not yet been finalized.y

The first of the goals advanced in FDA’s proposed rule,clarification of the types of patents to list in the Orange Book,has its roots in the types of recent industry practice discussedearlier in this chapter. Not all patents are eligible for OrangeBook listing; according to current regulations, patent informa-tion is required when ‘‘such patents consist of drug substance(ingredient) patents, drug product (formulation and composi-tion) patents, and method of use patents. Process patents arenot covered by this section and information on process patentsmay not be submitted to FDA’’ (emphasis added) (147). Inaddition, FDA notes that

both the act and our regulations establish two distinct criteriafor a patent intended for listing in the Orange Book: (1) Thepatent must claim the approved drug product or a methodof using the approved drug product; and (2) the patent mustbe one with respect to which a claim of patent infringement

*The proposed rule also addresses changes to Sect. 505(b)(2) of the Act, codi-fied at Sect. 355(b) of the U.S. Code. Section 505(b)(2) refers to the submissionof NDAs that rely on safety and effectiveness data ‘‘not conducted by or for theapplicant and for which the applicant has not obtained a right of reference oruse from the person by or for whom the investigations were conducted.’’ 21U.S.C. Sect. 355(b)(2). In such a case, an NDA applicant must also file one ofthe same four certifications described with respect to ANDA applicants. 21U.S.C. Sect. 355(b)(2)(A). The same 30-month stay that is triggered whenfiling a paragraph IV certification in an ANDA is also triggered when filinga paragraph IV certification as part of a Sect. 505(b)(2) application. However,because the focus of this chapter is on ANDA/generic drug applicants, theproposed rule will only be discussed in terms of ANDAs.yThis rule was finalized following the writing of this chapter.



See the foot-note beginning on p. 280.

could reasonably be asserted if a person not licensed by thepatent owner sought to engage in the drug’s manufacture, use,or sale (148).

By applying this test, FDA has decided to clarify which types ofpatents can be listed in the Orange Book.

In addition to process patents, which are already excludedfromOrangeBook listing, FDA’s proposal would exclude patentsclaiming packaging, metabolites, and intermediates (149). FDAreasons that, since the Agency does not specifically approveof product packaging or the container per se (even thoughsuch information must appear in an NDA), this material is‘‘distinct from the approved drug product’’ (150). Likewise,metabolites would not be eligible for Orange Book listingbecause a metabolite does not exist prior to ingestion andsubsequent breaking-down in the body (151). Finally, an inter-mediate is a material produced while an active drug ingredientis being processed, but which is not a component of the finaldrug product (152). FDA concluded that all three categories ofpatents fail the first part of the test, since neither a drug nor amethod of using a drug is claimed in any instance (153). ShouldFDA’s proposed rule become final, all three of these categoriesof claims would be excluded from Orange Book listing.

FDA further clarifies two other issues related to patentlisting. First, by proposing new language to the current regula-tion, FDA indicates that product-by-process patents shouldbe listed, since they are product patents. A product-by-processpatent is one that covers the final product, when the finalproduct can only be adequately described through the processof making the final product; on the other hand, a processpatent claims the process that is used to create a final product,but not the product itself (154). Second, FDA addresses listingpatents that claim a different form of a drug substance. FDAwould interpret its proposed language to mean that ‘‘an appli-cant would be able to submit patent information on a drugsubstance even when the patented drug substance was adifferent form than the drug substance that is the subject ofthe pending or approved NDA as long as the drug substancesare the ‘same’ active ingredient under section 505( j)(2)(A)(ii) of



the act’’ (155). A determination of what constitutes the ‘‘same’’active ingredient would be based on whether two drug sub-stances are likely to have the same characteristics with respectto dissolution, solubility, and bioavailability (156). The key toFDA’s logic appears to be its position that products can betherapeutically equivalent, meaning they are pharmaceuticallyequivalent plus both safe and effective, even if the genericdrug’s active ingredient is not in the same exact physicalform as the pioneer drug’s active ingredient (157).

In addition to clarifying the types of patents that must notbe submitted for Orange Book listing, FDA proposes to amendthe requirements for the declaration that an NDA applicantmust file in an attempt to ensure that only ‘‘appropriate’’patents are listed. The current regulations require that aperson submitting an NDA, an amendment to an ANDA, oran NDA supplement submit a signed declaration if the patentis a formulation, composition, or method of use patent (158).FDA ‘‘designed this declaration to help ensure that appropriatepatents are listed and to preclude any need on our part todecide patent issues because we lack the patent expertise,resources, and statutory mandate to scrutinize patent listings’’(159). FDA’s proposed rule would revise the patent declarationrequirements by creating a ‘‘checklist’’ to ‘‘ensure that app-licants submit only appropriate patent information and standbehind the accuracy of that information’’ (160). AlthoughFDA acknowledges that it does not have the ability to examinepatent issues, the agency is advocating for these changes inthe regulations so that NDA applicants will accurately andthoughtfully include proper patent information in the applica-tion, hopefully resulting in improved compliance with therequirements for listing patents in the Orange Book (161).

The second major goal of FDA’s proposed rule is to alterthe Agency’s interpretation of how many 30-month staysan ANDA applicant may receive. FDA has consistently inter-preted section 505( j)(5)(B)(iii) of the act as allowing multiple30-month stay periods if a patent that was not part ofthe original NDA is later listed in the Orange Book (162).However, both FDA and the FTC have found that, over time,the number of 30-month stays allowed for a given drug product



has increased (163). According to the FTC’s Study, the listingof later-issued patents has resulted in FDA approval delaysfor ANDAs of 4–40 months beyond the original 30-monthstay period (164). As a result of this trend, FDA proposes tochange its interpretation of the relevant statutory provisionsgoverning the granting of the 30-month stay.

Relying heavily on strict statutory interpretation ofthe Hatch-Waxman Amendments, FDA proposes to alter itsinterpretation of the statute by indicating that

the addition of a second paragraph IV certification to an ANDAor a 505(b)(2) application that had already contained at leastone paragraph IV certification would not trigger an obligationto provide a second notice to the NDA holder or to thepatent owner and would not result in another opportunity fora 30-month stay. . . . the subsequent paragraph IV certificationwould allow us to approve the ANDA or 505(b)(2) applicationimmediately if the Act would otherwise permit us to do so (165).

Therefore, only if an ANDA did not contain a paragraph IVcertification to begin with would an ANDA applicant, whoamends their application to include a paragraph IV certifi-cation to a later-listed patent by the NDA holder/patentholder, be required to provide the NDA holder/patent holderwith notice of this paragraph IV certification* (166).

FDA notes that their amended interpretation of the 30-month stay provision would not affect the parties’ ability to sueand be sued for patent infringement. Rather, an NDA holder/patent holder would still be able to protect the later-filedpatent (which was not included in the original NDA) becausethey would already have received the required notice from theANDA applicant that an ANDA containing a paragraph IVcertification had been filed (167). FDA further claims that the

*In the final rule, FDA provides three examples of situations that mightbe confusing as to whether or not notice is required, and what the resultswould be. Applications for FDA Approval to Market a New Drug: PatentSubmission and Listing Requirements and Application of 30-Month Stayson Approval of Abbreviated New Drug Applications Certifying That a PatentClaiming a Drug is Invalid or Will Not be Infringed; Final Rule. 68 Fed. Reg.36675, pp. 36688–36689 (June 18, 2003).



NDA holder/patent holder would not have to rely on any secondnotice (from the ANDA applicant filing a second paragraph IVcertification) in order for them to be able to defend the later-listed patent(s) (168).

Finally, FDA asserts that this change in interpretation ofthe 30-month stay provision will not affect how the 180-dayexclusivity period will be applied. This would be expectedbecause the 180-day exclusivity period is awarded to the firstgeneric manufacturer filing an ANDA with a paragraph IVcertification regardless of whether that certification wouldresult in a requirement to notify the NDA holder/patentholder or whether the applicant would be subject to being suedfor patent infringement (169).

4.1.2. FTC Proposals

In its 2002 Study, the FTC makes several recommendationsregarding these pioneer drug/generic drug issues that the agencybelieves would reduce the number of situations of abuse thathave been uncovered. The FTC’s first recommendation, similarto FDA’s proposed rule, is to limit the number of automatic30-month stays to just one per drug per ANDA. However, theFTC’s proposal would go further: the Commission would allowsuch a stay to be granted only if the paragraph IV certificationfiled by the ANDA applicant was filed on an existing OrangeBook patent (i.e., a 30-month stay would not be granted if thecertification was made to a later-listed patent, after the ANDAwas filed) (170). The FTC believes that allowing one 30-monthstay per ANDA ‘‘should eliminate most of the potentialfor improper Orange Book listings to generate unwarranted30-month stays’’ (171). The Commission addressed severalissues in arriving at this recommendation.

The first issue the agency looked at regarded the fact thatthose patents that are later-listed may not meet the require-ments FDA has set forth with respect to listing a patent in theOrange Book. FDA has attempted to remedy this problem inpart by proposing to amend its regulations for Orange Booklisting, as discussed above. The problem of improper OrangeBook listings may not be entirely remediable, however. First,



FDA has repeatedly stated that it does not have the expertisenecessary to review every patent that is submitted for OrangeBook listing (172). In FDA’s final rule adopting regulationsimplementing Hatch-Waxman, FDA noted that ‘‘[t]he agencybelieves that its scarce resources would be better utilized inreviewing applications rather than reviewing patent claims’’(173). Only if a pioneer drug manufacturer amends or volunta-rily withdraws an Orange Book listing will FDA change patentinformation listed in the Orange Book (174). Second, recentlitigation has determined that Hatch-Waxman does not providea private cause of action which ANDA applicants may use tochallenge an allegedly improper Orange Book listing. This deci-sion was reached in Mylan Pharmaceuticals, Inc. v. Thompson,discussed previously (175).

The second point the agency noted in arriving at itsrecommendation to limit the 30-month stay period was thatby limiting the number of 30-month stays to one, the timeperiod is not out of line with the length of time it takes FDAto approve an ANDA. For example, the FTC reported that thecurrent 30-month time period was not very different fromthe length of time it took FDA to approve an ANDA containinga paragraph IV certification when the generic drug manufac-turer was not sued (25 months and 15 days from filing date)(176). Therefore, the FTC concluded that a single 30-monthstay provision would not delay the entry of generic drugsonto the market (177). However, in the future, ‘‘[g]enericapplicants may rely on expiration of the 30-month staymore frequently as the first point at which they may decidewhether to enter the market, rather than to wait for a courtdecision on ANDA-related patent litigation that may takelonger than 30 months’’ (178).

The second recommendation the FTC made in its Studywas that legislation should be passed to require pioneer compa-nies and first generic drug applicants to provide copies ofsome agreements to the FTC and the Department of Justice(DOJ) (179). Such submitted agreements would encompassthose situations where a pioneer and a generic manufacturerattempt to ‘‘alter’’ the 180-day exclusivity period, as discussedin previous sections of this chapter. As a result, the FTC



supports the Drug Competition Act of 2002, a bill that wasintroduced in (and passed by) the Senate (180). This billwould require both parties to an agreement relating to the180-day exclusivity period or concerning the manufacture,marketing, or sale of either the pioneer or generic drug tofile a copy of the agreement with the FTC and the DOJ(181). This bill, S.754, represents one legislative attempt toeliminate the Hatch-Waxman abuses that have recently beenuncovered. The key features of this and other recent legislationare discussed next in an attempt to illustrate that Hatch-Waxman reform may come either at the agency (regulatory)level, or at the congressional (legislative) level.

4.2. Legislative Approaches

In addition to possible regulatory changes in how Hatch-Waxman is interpreted, several bills have been introduced inCongress that would make legislative changes affecting Hatch-Waxman.y While none of these have been enacted into law,they do reflect congressional thinking on how the recentproblems highlighted so far in this chapter pertaining to distor-tion of the original goals of the Amendments can be rectified.

One of these attempts to limit abuses was the introductionof S.754 (the ‘‘Drug Competition Act of 2001’’) in the Senateon April 6, 2001, by Sen. Patrick Leahy (D-VT)* (182). The billpassed the Senate and was referred to committee in the House(183). The purposes of the bill are to provide ‘‘timely notice’’ tothe FTC and the DOJ about agreements that pioneer and gen-eric drug companies may enter into, which will ‘‘enhance theeffectiveness and efficiency of the enforcement of the antitrustand competition laws of the United States’’ (184). Each partyto such an agreement (a generic drug manufacturer whohas submitted a paragraph IV certification in an ANDA and a

*As introduced, the bill was entitled ‘‘Drug Competition Act of 2001,’’ but asit passed the Senate, the year was changed to ‘‘2002.’’yThis chapter was drafted prior to passage of Pub. L. No. 108–173, 117 Stat.2066 (Dec. 8, 2003), the Medicare Prescription Drug, Improvement, andModernization Act of 2003, which significantly changed important aspectsof the patent notification and 30-month stay provisions of Hatch-Waxman.



pioneer drug manufacturer), where the agreement refers to (a)the manufacture, marketing, or sale of a pioneer drug or ageneric drug that is the subject of the ANDA for the genericdrug, or (b) the 180-day exclusivity period as it applies to theANDA or other ANDA based on the same brand name drug,would be required to file the text of the written agreement(or a written description of a nontextual agreement) with theFTC and the DOJ not later than 10 business days afterthe execution of the agreement (185). An agreement wouldnot have to be filed that ‘‘solely concerns’’ purchase orders forrawmaterial supplies, equipment and facility contracts, employ-ment or consulting contracts, or packaging and labeling con-tracts (186). Any party that does not comply would be subjectto a civil penalty not greater than $11,000 for each day duringwhich the party is in violation of the act (187).

In January 2003, the ‘‘Greater Access to AffordablePharmaceuticals Act of 2003’’ was introduced by Sen. CharlesSchumer (D-NY) (188). This bill is nearly identical to a billthat Sen. Schumer introduced in the last Congress* (189). S.54attempts to accomplish several reforms, including (a) prohibit-ing an extension of the 30-month stay period for a new drugwhere the ANDA or NDA contains a paragraph IV certificationand a patent(s) is subsequently issued (190), (b) requiring thefirst generic applicant who files a paragraph IV certificationto forfeit their right to 180-day marketing exclusivity to alater generic applicant if the first applicant acts in a mannerpreventing the generic drug from being brought to market in atimely manner (191), and (c) allowing a private cause of actionwhen needed to correct information contained in the OrangeBooky (192). S.54 has been referred to committee (193). It isclear that, despite resistance by some to use legislative means

*S.812 passed the Senate in July 2002. (S.812, Bill Summary and Status,

not passed; a floor vote was forced despite a lack of favorable committee action.

and Richard Smith, ‘‘Legislative Proposals to Change the Hatch-Waxman Act:Misguided and Unnecessary,’’ FDLI Update, March/April 2003, 22–24, p. 22.yThe Berman article contains a summary of the key features of S.54, whilethe Kuhlik and Smith article provides a summary of S.812.



http://thomas.loc.gov/). However, the House version of S.812 (H.R.1862) was

S.812, Bill Summary and Status, http://thomas.loc.gov/. See also Bruce Kuhlik

http://thomas.loc.gov


to address Hatch-Waxman abuses, this is not an issue that willleave the halls of Congress in the near future.

4.3. Government and Industry Responses

4.3.1. FTC’s Comments on FDA’s Proposed Rule*

The FTC has submitted comments to FDA on FDA’s proposedrule for reinterpretation of the regulations related to Hatch-Waxman (194). Not surprisingly, the FTC advocates changes toFDA’s regulations that are more in line with the Commission’sown 2002 Study. First, while the FTC believes that limitingpioneer drug manufacturers to only one 30-month stay wouldbe beneficial, it will not completely limit the possibility of‘‘gaming’’ the system to delay generic drug entry onto themarket (195). Therefore, the FTC suggests that FDA shouldadopt even stricter regulations than it sets forth in its proposedrule. This would include adoption of the FTC’s approach tothe 30-month stay issue: a pioneer drug company would beeligible for the stay only if the patent(s) at issue was listed inthe Orange Book before the ANDA was filed (196).

Second, the FTC makes several suggestions for ways FDAshould change the proposed rule with respect to listing ofpatents in the Orange Book. The FTC supports FDA’s proposalof not allowing NDA applicants to list patents in the OrangeBook that claim packaging, metabolites, or intermediates(197). The FTC also suggests that FDA ‘‘refine its approach’’in requiring the listing of product-by-process patents in theOrange Book in order to prohibit pioneer drug manu-facturers from disguising process patents (which are prohi-bited from listing) as product-by-process patents (which arerequired) (198). Towards this end, the FTC suggests thatFDA specifically require, in the patent declaration that FDA

*In recent testimony to the U.S. Senate Judiciary Committee on June 17,2003, FTC Chairman Timothy Muris ‘‘generally praised’’ the new rule, eventhough it is not identical to the one the FTC recommended in its study.According to Muris, ‘‘it is an important reform that would eliminate mostof the potential for unwarranted delay of FDA approval for generic drugsthe FTC study identified.’’ FDA Webview. FDA Balancing Innovation and



Generic Approvals: Troy. June 18, 2003. http://www.fdaweb.com.

http://www.fdaweb.com

seeks to amend through this same rule, that there be a ques-tion on product-by-process patents that would provide certifi-cation that it is the product that is claimed in the patent, nota process (199). The FTC also suggests that FDA should revisethe language of the regulation, as proposed, to state that onlyproduct-by-process claims in which the product is novel shouldbe listed (200). In addition, the FTC takes a different stancethan FDA does on the listing of patents that claim a differentform of a drug substance from what was approved in the NDA.Whereas FDA’s proposal would amend the listing regulationsso that listing these patents in the Orange Book would berequired, the FTC argues that the ‘‘plain language’’ of the list-ing statute and the purpose of Hatch-Waxman do not supportthe change FDA has proposed (201). Finally, with respect toOrange Book listings, the FTC would also include a require-ment in the proposed regulation that ‘‘double patenting,’’ orobtaining a second patent that claims subject matter that is thesame as or obvious in light of the claims of an earlier patentgranted to the same applicant, should be prohibited (202).

Third, regarding the patent declaration provision, theFTC supports a redesign of the information the NDA appli-cant is required to submit; however, they would suggest‘‘even more stringent certification requirements’’ (203). Suchadditional requirements would include that the person whoattests to the certification specifically be a patent attorney—someone who has knowledge of and familiarity with patentissues. The Commission would include an attestation require-ment that the person submitting the information is familiarwith the relevant regulations and the scope of the claims forthe patent in issue, and would also require two other declara-tions on product-by-process claims and terminal disclaimers(204). Importantly, the FTC stresses that FDA has causedpotential confusion by its proposed changes to the regula-tions governing the patent declaration: while FDA puts ‘‘newemphasis’’ on individual claims of a patent and not on thepatent in its entirety, it is ‘‘unclear whether the FDA’s regu-lation now treats individual claims of the patent to be listable,or whether the patent itself is listable given the presence ofa single listable claim’’ (205).



4.3.2. GPhA’s Response*

The Generic Pharmaceutical Association (GPhA) is the indus-try trade association for manufacturers and distributors ofgeneric drugs, manufacturers and distributors of bulk activedrug ingredients, and suppliers of goods and services to thegeneric drug industry.y Not surprisingly, GPhA has beenvocal in expressing the generic drug industry’s position relativeto these suggested changes to Hatch-Waxman and to FDA’sinterpretation of the Amendments. In materials submitted toFDA for a January 30, 2002, meeting with the agency, GPhAoutlined in detail its position on Hatch-Waxman regulatory andlegislative reform (206). In setting forth its views, GPhA madeit clear that ‘‘[b]oth legislative and regulatory action is urgentlyneeded to restore the balance of the Hatch-Waxman Act andthe policy objectives behind it’’ (emphasis in original) (207).

First, GPhA supports only one 30-month stay period perANDA. As a legislative approach, GPhA backs S.812 and backsFDA’s interpretation of Hatch-Waxman to limit the number of30-month stays to just one (208). GPhA notes that

[i]n 1984, the supporters of the 30-month stay argued thatbecause generic drug companies were small and essentiallyjudgment-proof, the prospect of damages in a patent infrin-gement action would not deter infringement by these com-panies. S.812 recognizes, however, that the generic industryhas matured considerably since 1984 and that, because genericcompanies are substantial enterprises, traditional patent lawremedies are generally a significant and sufficient deterrent toinfringement (209).

The group further comments that other patents have neverbeen subject to a 30-month stay and that there is no need to

*GPhA has noted that the final rule’s patent listing clarification and patentcertification requirements are important, but that additional measuresthat are beyond the authority of the Agency will be necessary to ensurethat consumers have access to generic drugs in a timely manner. FDAWebview. Polymorph Listings Tougher in Generics Final Rule. June 12,

yFor additional information on GPhA, visit



2003. http://www.fdaweb.com.

index.phtml.http://www.gphaonline.org/


http://www.gphaonline.org

http://www.gphaonline.org

treat pharmaceutical patents differently. The group cites bothstatutory and regulatory language in support of its inter-pretation of Hatch-Waxman as allowing only one 30-monthstay (210). Since the submission of these comments to FDA(prior to the publication of FDA’s proposed rule), FDA hasessentially adopted similar reasoning by way of its 2002proposed rule.

GPhA also supports FDA regulatory change in how OrangeBook listings are treated. The group’s two-step approachinvolves, first of all, placing the burden of establishing thata patent is eligible to be listed in the Orange Book on theNDA applicant. Second, FDA must review the informationthe NDA applicant submits, but FDA would not have to inde-pendently review the patent (211). To these ends, GPhA wouldstrengthen the requirements for the information included inthe patent listing declaration, which would include informationon the type of patent claim that is being submitted (to elimi-nate the possibility of process patents, which are not allowedto be listed in the Orange Book, masquerading as product-by-process patents, which are required to be listed). The declara-tion would also include a certification that the information issubmitted under penalty of perjury. As a result, ‘‘it would nolonger be possible for a proponent of an Orange Book listing tostate in a conclusory manner that the patent meets the Hatch-Waxman criteria. Rather, the proponent would have to demon-strate that this is so . . .’’ (212). FDA’s proposed rule has sinceaddressed some of these issues. GPhA has responded to FDA’sproposed rule positively, stating that it ‘‘applauded the intent’’of FDA to close loopholes in the Amendments (213). But‘‘GPhA believes that FDA’s proposal to limit brand companiesto a single 30-month stay per generic drug application couldcause further imbalance in the Hatch-Waxman system byimpeding the ability of generic companies to obtain timely reso-lution of legitimate patent disputes’’ (214). As a result, GPhAbelieves that by preventing ‘‘gaming’’ of the system, the partialremoval of the 30-month stay inhibits the timely resolution ofpatent disputes. Thus, as GPhA sees it, the two fundamentalpurposes of Hatch-Waxman would still be unbalanced shouldFDA’s proposed rule become finalized.



4.3.3. PhRMA’s Response*

Like the FTC, the Pharmaceutical Research and Manufac-turers of America (PhRMA) submitted comments in responseto the publication of FDA’s proposed rule (215). PhRMA isthe industry trade group for research-based pharmaceuticaland biotechnology companies.y PhRMA’s comments addresseach of the major points covered in FDA’s proposed rule.

First of all, PhRMA focuses on the fact that NDA holders/patent holders should have ‘‘one meaningful opportunity’’to receive the benefit of a 30-month stay (216). The groupprovides several examples of ways in which the generic drugmanufacturer could ‘‘game’’ the system to its advantage if theproposed rule is finalized. For example, PhRMA suggests asituation in which an ANDA applicant files both paragraphIII and IV certifications in its application (217). If the NDAholder/patent holder decides that it cannot sue on the para-graph IV certification, there would be nothing to stop theANDA applicant from then converting the paragraph III certi-fication to a paragraph IV certification. If this were to occur,then, according to FDA’s proposed rule, the ANDA applicantwould not have to provide notification to the NDA holder/patent holder that it had made this change, since the NDAholder/patent holder had already been notified once that aparagraph IV certification in an ANDA had been filed.Therefore, there would not even be a single 30-month stay inthis situation. PhRMA suggests that any amendments that aremade to an ANDA to change a patent certification shouldrelate back to (and should substitute for) the original certifica-tion, thus triggering a new notice obligation (218). As FDA’sproposal stands, PhRMA believes that ‘‘[t]his potential forabuse is real. Under FDA’s proposal, there would be little

*Alan Holmer, the President of PhRMA, has stated, with respect to the finalrule, that ‘‘[t]he new FDA rule revising Hatch-Waxman requirements is lengthyand complex, and we are studying it closely. We need to be sure that the ruleclarifies current law in a way that supports continued development of new andbetter medicines that patients need.’’ FDA Webview. Polymorph Listings

y



Tougher in Generics Final Rule. June 12, 2003. http://www.fdaweb.com.

For additional information on PhRMA, visit http://www.phrma.org/.


http://www.phrma.org

reason for an ANDA or 505(b)(2) applicant ever to make morethan one paragraph IV certification in an initial application’’(219). With the changes PhRMA recommends, however, NDAholders would not be able to abuse the system; the ANDAapplicant would ultimately be the party to determine whetheror not to change a prior certification (220).

Related to the 30-month stay provision, PhRMA also advo-cates for NDA holders/patent holders to be notified about aparagraph IV certification made in an amended ANDA, eventhough the NDA holder/patent holder had been notified pre-viously about a paragraph IV certification and even though anew 30-month stay would not be triggered (221). PhRMA takesissue with FDA’s assumption that NDA holders/patent holders‘‘will somehow learn about’’ these subsequent paragraph IVcertifications so that they can enforce the statutory patentrights afforded to them (and to all patent holders). PhRMAwould resolve this issue by having FDA post these certifica-tions on the FDA website, or by making the informationotherwise public (222).

Second, PhRMA addresses the issues in the FDA proposedrule related to Orange Book listings. Not surprisingly, PhRMA(unlike GPhA) believes that FDA’s requirement for listingpatents that claim a form of a drug substance that is thesame as the active ingredient in an NDA is entirely appropriateand consistent with the statute: ‘‘it would be improper for FDAto consider different forms of a drug substance to be the ‘same’active ingredient under the ANDA approval provisions of theAct, and yet somehow not to be the same for determiningwhether a patent may be listed under the Act’s closely relatedpatent listing provisions’’ (223). In addition, PhRMA does notbelieve that FDA has to outline any new methods of determin-ing what is a process patent, which is not listable, and what isa product-by-process patent, which is listable. If FDA did so,it might ‘‘plunge the agency inappropriately into complicatedissues of patent law and introduce listing criteria alien to thestatute’’ (224).

Finally, PhRMA addresses the proposed changes to thepatent declaration of an NDA by focusing on FDA’s proposedchange to require a submission of a claim-by-claim declaration.



While FDA argues that such a measure will aid in the listing ofonly proper patents, PhRMA argues that FDA provides no sup-port for its position (225). Furthermore, according to PhRMA,FDA’s claim that such listing may reduce the number of patentinfringement cases ‘‘reflects an inappropriate attempt by theagency to influence patent infringement litigation, and is unre-lated to the role assigned the agency under law with respect topatent listing’’ (226).

5. CONCLUSIONS

This chapter has attempted to accomplish several objectives.First, it has provided a brief overview of some of the key provi-sions of the Hatch-Waxman Amendments, particularly the180-day exclusivity and 30-month stay provisions, that havebeen the subject of recent industry abuse. Second, the chapterhighlighted some of the recent court cases and FTC-issuedconsent orders related to allegedly anticompetitive behaviorby both pioneer and generic drug manufacturers. Finally,it has outlined some of the recently proposed attempts atreform, including FDA’s 2002 proposed rule to reinterpretHatch-Waxman and the responses of various segments ofthe industry to this proposed rule. In doing so, this chapterhas hopefully illustrated the complexity of the issues relatedto maintaining the balance that Hatch-Waxman sought toestablish: the balance between pioneer drug manufacturerinnovation and generic drug manufacturer ability to enterthe market in a timely manner to provide American consumerswith less expensive drug options. Given the recent activityin this area by many sectors—FDA, the FTC, Congress, andthe drug manufacturers themselves—it is very likely that thedebate on how to reform Hatch-Waxman, if at all, will continuefor some time.

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76. Federal Trade Commission. News Release. ‘‘Wrongful ‘OrangeBook’ Listing Raises Red Flag with FTC; Leads to ConsentOrder with Biovail Corp. Concerning its Drug Tiazac.’’ April

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1996. http://www.uspto.gov/patft/index.html.

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89. 21 U.S.C. Sect. 355( j)(5)(B)(iii).



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94. Andrx Pharmaceuticals, Inc. v. Biovail Corporation. 276 F.3d1368 (Ct. App. Fed. Cir. 2002). p. 1376, 1380.


96. Mylan Pharmaceuticals, Inc. v. Thompson. 268 F.3d 1323 (Ct.App. Fed. Cir. 2001).




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http://www.fda.gov

http://www.fda.gov

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be Infringed. Docket No. 02N-0417. Dec. 23, 2002.

224. Comments of the Pharmaceutical Research and Manufactur-ers of America (PhRMA) on FDA’s Proposed Rule: Applica-tions for FDA Approval to Market a New Drug: Patent ListingRequirements and Application of 30-Month Stays on Approvalof Abbreviated New Drug Applications Certifying that a PatentClaiming a Drug is Invalid or Will not be Infringed. DocketNo. 02N-0417. Dec. 23, 2002.

225. Comments of the Pharmaceutical Research and Manufac-turers of America (PhRMA) on FDA’s Proposed Rule: Appli-cations for FDA Approval to Market a New Drug: PatentListing Requirements and Application of 30-Month Stays onApproval of Abbreviated Drug Applications Certifyingthat a Patent Claiming a Drug is Invalid or Will notbe Infringed. Docket No. 02N-0417. Dec. 23, 2002.

226. Comments of the Pharmaceutical Research and Manufac-turers of America (PhRMA) on FDA’s Proposed Rule: Appli-cations for FDA Approval to Market a New Drug: PatentListing Requirements and Application of 30-Month Stays onApproval of Abbreviated New Drug Applications Certifyingthat a Patent Claiming a Drug is Invalid or Willnot be Infringed. No. 02N-0417. Dec. 23, 2002.




http://www.fda.gov/ohrms/

c000027-vol1.pdf. p. 13–14.

dockets/dockets/02n0417/02n-0417-c000027-vol1.pdf. p. 16.



c000027-vol1.pdf. p. 17–18.

Docket

New

c000027-vol1.pdf. p. 18.

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9

The Influence of the PrescriptionDrug User Fee Act on the

Approval Process

MARC J. SCHEINESON

Alston & Bird LLP


1. SUMMARY OF THE PRESCRIPTION DRUGUSER FEE ACT OF 1992 (PDUFA I)(OCTOBER 1, 1993–SEPTEMBER 30, 1997)

1.1. Nature of the Deal

In 1991, when Dr. David Kessler sat in his new desk chair in hisdowntown Washington, D.C., office, shortly after being nomi-nated and confirmed as the Commissioner of Food and Drugs,he asked himself the recurring question, ‘‘How can so few

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employees with such a limited federal budget perform all theresponsibilities expected of us?’’ At that time, the U.S. Foodand Drug Administration (FDA) had fewer than 8,000 employ-ees in 25 districts across the United States. Its budget was justover $850 million. Its jurisdiction included inspecting theentire domestic processed food supply, sampling and inspectingimported products under its jurisdiction, reviewing and approv-ing the export of regulated products to foreign countries,inspecting every product manufacturing establishment every2 years and the country’s entire blood supply, reviewing andapproving applications and labeling and promotion for newprescription drugs, generic drugs, animal drugs, biologics, vac-cines, medical devices, completing over-the-counter drug regu-lations, conducting surveillance on those approved products,soliciting and investigating adverse reaction reports, supervis-ing the labeling and sale of medical foods, infant formulas, teas,dietary supplements, cosmetics, regulating every productthat emits radiation (including light bulbs, cellular telephones,lasers, microwave ovens, television sets), inspecting the kitch-ens of commercial aircraft and cruise ships, and, with whatevertime was left, making sure that product advertising was truth-ful, fairly balanced, and not false or misleading. This was arelatively paltry budget, especially when compared to the $2billion budget of the U.S. Department of Agriculture to supporthundreds of thousands of employees with a tenth of the juris-diction. FDA states that it regulates products that comprise$.25 of every consumer dollar spent. In reality, it regulatesnearly one quarter of the American economy. On top of allthis pressure, Dr. Kessler was bombarded with industry andcongressional pressure to streamline and expedite the review ofpromising new life-saving prescription drugs and biologics.Those approvals were averaging 2–3 years following sub-mission of complete new drug applications (NDAs) and whatare now called Biologics Licensing Applications (BLAs). Non-priority applications for ‘‘me-too’’ drugs could take 5 years ormore to preview and approve.

Dr. Kessler convened his policy, legal, and legislative team.Viewing proposals by other agencies to adopt ‘‘user fees’’ topay the cost of specialized government services that benefited

324 Scheineson


identified categories of Americans, the terms of his offer toindustry soon became clear. Would companies be willing topay for the review of their product applications if it meantfaster review? Those additional resources would, in turn, bededicated to paying the salaries of additional productreviewers. All applications would be assigned to expandedagency personnel immediately. They would not wait formonths, and sometimes years, until a reviewer was availableto pick it up and read it.

Gerald Mossinghoff, president of what was then the Phar-maceutical Manufacturers Association and is now PhRMA,was called in by the Commissioner and his team. Mossinghoff,a former commissioner of the Patent and Trademark Office(PTO), was initially skeptical. PTO had made a similarproposal to expedite review of patent applications. Applicantsopposed the measure. Then when a nominal fee structure wasadopted, all the new money flowed directly into the generalfederal treasury; it had not been dedicated to supplementingPTO resources. Even if money could be so dedicated, wouldn’tHHS budget cutters just reduce FDA’s appropriated funds bythe amount of revenue from private sources. This would be azero-sum gain. He also didn’t believe that companies shouldhave to pay the government to do its job. Wasn’t that whattaxes were for? Finally, an industry committee was formed towork with FDA and the Congress. A creative new proposal wasworked out. PhRMA and the Industrial Biotechnology Associa-tion (a predecessor of the Biotechnology Industry Association)agreed on behalf of its member companies to support signifi-cant fees in the hundreds of thousands of dollars for NDAs,BLAs, and establishment registrations if the fees met thefollowing criteria. They had to be (a) additive to existing FDAbaseline appropriations; (b) fully dedicated to the approvalof new drugs and biologics; (c) reasonable amounts; (d) basedon a long-term government commitment to specific improve-ments in the approval process; and (e) part of performancegoals that should be established by the Center for Drug Eval-uation and Research (CDER) and the Center for BiologicsEvaluation and Research (CBER) to evaluate improvementsin the review and approval process.

Influence of PDUFA on Approval 325


These parameters were creatively hammered out intospecific legislative language in a series of painstakingly longdrafting sessions. Meetings were held in the office of theHouse Legislative Counsel, David Meade, between representa-tives of FDA’s Office of Legislative Affairs, the PhRMA/IBCworking group, the Department of Health and HumanServices Assistant Secretary for Legislation, Bill Schultz(Rep. Henry Waxman), Mark Childress (Sen. EdwardKennedy), and Anne LaBelle (Sen. Orrin Hatch). Innovativenew provisions insured that the industry’s fees did not disap-pear into general government coffers or that direct FDA appro-priations were not reduced by the amount of private fundsreceived. FDA’s existing fiscal 1992 appropriations became abaseline that had to increase by at least an established cost-of-living adjustment every year or the authority to assess privateuser fees would terminate. Legal commitments were madethat the fees would supplement FDA’s direct appropriations.CDER and CBER developed specific plans to hire 600 newfull-time equivalent employees. FDA refused to commit tostatutory language requiring specific time frames for appli-cation review. It agreed, however, to issue a side letter tocongressional committee chairmen containing nonbinding‘‘performance goals.’’ These goals would include a designatedpercentage of applications that would be reviewed and actedupon within one year of submission for standard applicationsand within 6 months of submission for priority applications(involving drugs to treat serious and life-threatening illnessesfor which no comparable therapy was currently available). Thelaw would expire in 5 years. It would require periodic con-gressional reauthorization as a mechanism to force FDA tobe accountable for these performance goals or risk losing hun-dreds of millions of user fee funds that would support hundredsof new employees and infrastructure improvements.

Once the deal was reached behind the scenes betweenindustry, FDA, and the Democratic and Republican Committeeleadership, legislation was introduced. It was reviewed incursory hearings and passed in Congress with remarkablespeed. On October 29, 1992, the President signed the Prescrip-tion Drug User Fee Act of 1992 in the Rose Garden of the White

326 Scheineson


House amid great fanfare and celebration. If CDER and CBER’sdetailed action plans could be administered properly, the newlaw would revolutionize the American drug review process. Itwould push the industry, and the quality of American healthcare, ahead of our European counterparts. Drug applicationswould be reviewed immediately upon completion and filing.Review time would be cut in half. An efficient new systemwould restore resources and accountability to FDA. Phar-maceutical manufacturers were not buying approvals. Theinsular FDA Center review structure would not allow that tohappen. They were, however, dedicating large sums of moneyin fees for the opportunity to participate in a more interactiveprocess potentially marketing their new drugs years in advanceof the prior system. Patients would no longer be required towait additional years to gain access to life-saving new thera-pies. FDA would quantify its progress through written reportsto congressional oversight authorities on an annual basis. Ifthe experiment didn’t work, the parities would pull the plugafter the initial 5 year term. The authorization bill creating theuser fee program still required separate appropriations legisla-tion to allow the government to fund FDA and collect theprivate funds. On July 2, 1993, the President signed a supple-mental appropriation bill allowing FDA to collect user feesdue from October 1, 1992, through September 31, 1993, thegovernment fiscal year (FY).

1.2. Type of User Fees

In order for these fees not to be viewed as taxes (and therebyincur the jurisdiction of the congressional taxing committeeswhich did not support the concept of dedicated user fees), thenew law was intended to divide the fee burden across existingmanufacturers. Segments were created which relied directlyon the payment for real FDA services, including (a) thereview of drug/biologic applications (application fee), (b) insur-ing safe manufacturing processes (establishment fees), and(c) monitoring adverse reports, recalls, labeling, etc. (productfees). These three segments insured that a company with alot of product applications but few products on the market



currently or with no existing manufacturing facility wouldnot bear the entire burden of funding FDA review operations.Likewise, if a company marketed many products or maintainednumerous facilities, it could afford to sustain FDA CDER andCBER operations more easily than a new company with fewproducts. Therefore, the fees were divided into three segments,as summarized below.

1.2.1. Application Fees

Who Pays?

Fees are assessed for the submission of certain human drugor biological applications. Human drug applications include:new drug applications (NDAs), Pre-Licensing Applicationsand Establishment Licensing Applications for biologics whichhave been consolidated into Biological Licensing Applications(BLAs), and initial certification of antibiotic drugs (whichbecame NDAs in the FDA Modernization Act in 1997). Alsoincluded are product efficacy and manufacturing supplements.Expressly excluded from application fees, and also from FDAperformance commitments, were (a) over-the-counter drugs,which commonly do not require advance FDA approval (exceptfor Rx-to-OTC switches, which do commonly contain clinicalinformation and are included), (b) generic drug applications(ANDAs), (c) animal drug applications (NADAs), (d) bloodproducts, (e) allergenic extracts, (f) in vitro diagnostics, and(g) large-volume parenterals.

Fee Schedule

One third of the total annual revenue was required tocome from each fee. For the term covered by PDUFA I, thesefees, which were calculated to meet the total designated incomerequired to hire 600 additional reviewers based on the numberof applications actually filed, as well as support staff and com-puter back-up, included $100,000 per application (FY 1993),$162,000 (FY 1994), $208,000 (FY 1995), $204,000 (FY 1996),and $223,000 (FY 1997). For applications not requiring reviewof clinical data, fees were reduced by one half.

328 Scheineson


Payment Terms

One half of the fee was due on submission. One half of theamount submitted was returned if the application was notaccepted for filing by FDA. The remaining payment was duewithin 30 days of when FDA sent its action letter, or when theapplicant withdrew its application.

1.2.2. Drug Establishment Fees

Who Pays?

A Rx drug user fee was due from each person (corporation)that owned an establishment in which at least one Rx drug (orbiologic) was manufactured during the relevant fiscal year. Ifthe drugs made in the establishment are all subject to genericcompetition, no fee would accrue. So that the user fee wouldnot be deemed a tax, the payor had to have at least one appli-cation pending for FDA review after September 1, 1992. FDAlater interpreted this requirement to mean that if the otherestablishment fee criteria were met, an original application orsupplement (with or without clinical data) that was pendingafter that date would trigger establishment fees for all qualify-ing establishments. Contract manufacturers that were notregistrants on a FDA application were exempt from this fee.

Prescription Drug Establishment

A separate fee was due on each establishment maintainedby the applicant. Both foreign and domestic establishmentswere subject to a fee if the products they made were marketedin the United States (1). One or more buildings located within5 miles of each other were classified as one establishment. Thefacility had to make one or more Rx drugs manufactured in‘‘finished dosage form,’’ interpreted by FDA to mean in a formapproved for administration to a patient without furthermanufacturing (2). Finally, it had to be under the managementof the applicant listed on the NDA or BLA. FDA later inter-preted this to mean that the applicant need not be the holder ofthe approved NDA or BLA for the product manufactured atthe establishment.



Fee Schedule

Payment was due annually on each Rx drug establishment,as billed by FDA based on its establishment registration list, asadjusted at the end of the previous year based on the feesneeded to reach the total income amount required by this seg-ment of the user fee. Those amounts were $60,000 (FY 1993),$88,000 (FY 1994), $129,000 (FY 1995), $135,300 (FY 1996),and $138,000 (FY 1997).

Payment Terms

The establishment fee is due on or before January 31 ofeach calendar year. FDA routinely sends out an invoicebased on establishments contained in its establishment regis-tration list. Many of those establishments listed and billedmay not conform to the requirements of PDUFA. The initialFDA mailings were overly broad. Therefore, manufacturersshould have notified FDA regarding incorrect or unauthorizedbilling.

1.2.3. Drug Product Fees

A separate annual fee was assessed to each manufacturer basedon the number of Rx drug products listed in FDA’s productregistry.

Who Pays?

The fee is assessed to ‘‘each person named as an applicanton a human drug application’’ for each Rx drug (or biologic)listed on FDA’s product registration list. The applicant isrequired to have at least one application or supplement pend-ing agency review in the year the product fee was assessed(beginning after Sept. 1, 1992). A listed product is exemptfrom the fee once it has generic competition (3). Innovatorantibiotic drug products (approved under x507) are subject toproduct fees. Generic antibiotic drug products (those that arenot the first approval of a particular antibiotic drug) are notsubject to product fees (4).

330 Scheineson


Fee Schedule

The fee for each listed drug included: $6,000 (FY 1993);$9,400 (FY 1994); $12,200 (FY 1995); $12,600 (FY 1996);$14,000 (FY 1997).

Payment Terms

Product fees were due at the time of the first productlisting in each calendar year. The product must be listed asrequired by x510 to be subject to the product fee. FDA consid-ers a product to be listed on the date of receipt of the initialsubmission of information, whether or not the agency findsthat the information submitted was complete or requests addi-tional information (5). A product is considered delisted, and nolonger assessed a fee, on the date of the agency’s receipt of thesubmission deleting the product from the Drug Listing.A product is subject to the fee if it is listed under x510 whetheror not it is actually marketed or even if it is only marketedabroad. If a product is transferred from one NDA/BLA holderto another during a fiscal year, the first holder will be assessedthe product fee in that fiscal year.

1.3. Performance Goals

In negotiating the user fee program, FDA was determined toinformally offer nonbinding goals. It refused to include inflex-ible standards in the language of the statute. In a compromise,industry acquiesced to a side letter sent to the Chairman andthe Ranking Member of the House Committee on Energy andCommerce, Rep. John Dingell (D-MI) and Rep. Norman Lent(R-NY). These goals provided the expectations of regulatedindustry and the Congress concerning review times thatwould deem the program successful and allow its reauthoriza-tion for successive 5 year terms. PhRMA and BIO reportedlybelieved that if the resources of its member companies failed toshorten review times in accordance with the written goalsincluded in the letter, it could successfully persuade theCongress to shut down the program.



The letter to the Congress stated the following:

1. The additional user fee revenues would be dedi-cated to expediting the drug review and approvalprocess.

2. Priority NDAs and BLAs that were complete wouldbe reviewed and acted on (through the issuance of anaction letter) within 6 months of submission.

3. Standard NDAs and BLAs that were complete wouldbe reviewed and acted on within 12 months ofsubmission.

4. Priority supplements and amendments (or those notrequiring review of clinical data) would be reviewedand acted on within 6 months of submission.

5. Standard supplements and amendments would bereviewed and acted on within 6 months of submission.

6. Applications resubmitted following the receipt of a non-approval letter would be acted on within 6 months ofsubmission.

7. Application backlogs were to be eliminated within18 months to 2 years.

8. The goals were to be achieved based on a stag-gered schedule with 55% compliance with applica-tions received in 1994 moving to 90% compliance in1997.

1.4. Small Business Exception

The law allowed a company to pay one half of the prescribedapplication fee, not payable until one year following the sub-mission (6), if it maintained fewer than 500 employees (includ-ing affiliates) and had no Rx or biologic drug product on themarket (7). An affiliate was defined as one business with director indirect control of another, one business with the powerto control another, or a third party that controls or has thepower to control both businesses (8). For these qualifying smallbusinesses, FDA sends an invoice one year following sub-mission for the first installment of the fee, whether or not anaction letter was issued. The second installment is due at the

332 Scheineson


same time if an action letter was already issued. The numberof an applicant’s employees is calculated using the proceduresof the Small Business Administration contained in 13 C.F.R.Part 121. The suggested procedure to request the exemptionis to submit an application to FDA’s Office of the Ombudsman.The written request must contain the details of the appli-cant and fee for which a waiver or reduction is requested. Itmust also contain information and analysis showing thatthe statutory criteria for the waiver or reduction have beenmet (9). The request for the small business exemption shouldbe submitted approximately 90 days before the applicationis submitted. It must also contain a statement from a respon-sible officer of the company that it has fewer than 500 employ-ees, has no Rx drugs on the market and does not intendto introduce any within the next 12 months, and expects tosubmit an application within 90 days (10). The Office ofOmbudsman as waiver officer will review the request, reviewproduct listings, and refer the small business criteria con-sideration to the SBA. A written acknowledgement of thedecision will be made. If the request for exemption is denied,an approval process is available as summarized in FDA’s draftinterim guidance.

1.5. Fee Waiver or Reduction

A fee may be waived or reduced if (a) FDA did not spend sub-stantial time or resources in reviewing the application before itwas withdrawn, (b) it is necessary to protect the public health,(c) the fee would present a significant barrier to innovation,(d) the fee would exceed the cost incurred in reviewing theapplication, (e) a competing copy of the drug is not subject tothe fee, or (f) the fee was paid previously and the applicantis resubmitting the application (11). These provisions allowFDA to consider the limited resources of the entity when eval-uating requests for a fee waiver or reduction. It requestsa range of information to evaluate whether user fees presenta barrier to an entity’s ability to develop or market specificproducts or otherwise continue to pursue innovative technol-ogy. The criteria used by FDA include the following:



1.5.1. Protect Public Health; Significant Barrierto Innovation

FDA believes that the annual establishment fee is the greatestbarrier under this category. Therefore,most of the fee waivers orreductions granted for public health or innovation reasons relateto small entities where annual establishment fees would be dis-proportionate in relation to revenues. FDA requests a certifiedstatement from the entity and its affiliates concerning annualrevenues both domestic and foreign. Commercial and financialinformation is not releasable to the public under the Freedom ofInformation Act (12). FDA evaluates the annual cost of userfees v. the entity’s gross annual revenues, the resources of theentity’s parent and other major funding sources. Lack of profit-ability is not considered evidence of limited resources.

1.5.2. Fees Paid Would Exceed Cost ofFDA Review

In order for a government assessment to constitute a true feefor the use of services and not a tax, the law insures that thecost of those services approximate the level of the fee. There-fore, FDA may waive all or a portion of the user fee amount ifthe fee exceeds the anticipated cost of rendering applicationreview and related services (13). FDA was attempting to quan-tify the cost of the major elements associated with its reviewof common applications and supplements (14). Few if any feereductions have been based on this provision, in part becauseFDA interpreted the provision to determine not just the agencycost of reviewing the one application for which the fee wasassessed, but also the cost of reviewing all active applicationsof that person, including INDs, NDAs, BLAs, supplements, andamendments (15). The agency made it clear, however, that anapplicant can apply for such a fee reduction if its applicationwas not accepted for filing and the fee was paid (16).

1.5.3. Reduction because of Paper NDA forSame Product

A fee waiver or reduction request can be made by anNDA sponsor who submitted an application under x505(b)(1)

334 Scheineson


(full-NDA) if assessing such fee would be inequitable becausean application or supplement for a product containing the sameactive ingredient was filed by another person under x505(b)(2)(paper NDA) of the Act (17).

1.6. Increases and Adjustments

The law provides an annual total amount of user fees that areestablished each fiscal year by congressional appropriationcommittees. FDA then sets the level of its specific applica-tion, establishment, and product fees in November for thenext fiscal year to raise the annual user fee level appropri-ated by the Congress. FDA’s scheduled fee rates areannounced by a notice in the Federal Register. The applicationfee rates were set by statute, but are to be adjusted annuallyfor cumulative inflation. Total application fee revenues arestructured to increase or decrease each year as the numberof fee-paying applications to FDA increases or decreases.Each year, FDA is required to set establishment fees and prod-uct fees so that the estimated total fee revenue from each ofthese two categories will equal the total revenue FDA expectsto collect from application fees that year. This procedurecontinues the arrangement under which one third of the totaluser fee revenue is projected to come from each of the threetypes of fees.

1.7. Appropriated Fee Amounts

Each year that user fees are authorized, they must be con-tained in the annual appropriations legislation for FDA (appro-priated by the Agriculture, Rural Development and RelatedAgencies Subcommittees of Appropriations). In PDUFA I(for the fiscal years October 1, 1993, through September 30,1997), the appropriated amounts for total Rx drug user fees, asadjusted for the number of applications actually filed, wereas follows: $36 million (FY 1993), $56,284,200 (FY 1994),$77,415,000 (FY 195), $79,981,200 (FY 1996), and $84 million(FY 1997).



1.8. Effect of Failure to Pay Fees

Under the initial user fee legislation, unless fees were paidtimely when assessed, applications would not be accepted forfiling or review would be discontinued.

1.9. Annual Reports

Two annual reports were required to be prepared by FDA andsubmitted to the House Energy and Commerce Committee andto the Senate Labor and Human Resources Committee. Thefirst report would quantify FDA’s progress in achieving itsperformance goals and would be filed within 60 days followingthe end of the first fiscal year (by November 29, 1993). Thisbecame known as the ‘‘Performance Report’’ and has been filedannually since. A second report was required to review imple-mentation of FDA’s new authorities under the Act and how itused fees collected. This became known as the ‘‘FinancialReport’’ and has been filed annually since. This report wasdue within 120 days after the end of the fiscal year (by March29, 1994). Annual FDA PDUFA reports are available at

1.10. Five-Year Sunset

The Act was terminated after 5 years, effective on September 30,1997. The purpose of this ‘‘sunset’’ was to provide an opportu-nity for Congress and industry to meet with FDA to assess theprogram and FDA’s progress in expediting application review.Since FDA hired more than 600 FTEs, the agency has enormouspressure to meet its obligations or risk losing significant fund-ing, which sustained that increased workforce. If the programwas not reauthorized at the end of that term, FDA would likelybe forced to fire its new reviewer workforce. Since enactment ofthis FDA legislation was consideredmandatory every 5 years, itsreenactment for two successive 5 year periods has been used asa vehicle to pass other FDA and health-related reforms.

1.11. Animal Drug Study

Finally, since manufacturers of animal drugs were not invitedto participate in the PDUFA program, the legislative drafters

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www.fda.gov/cder/pdufa/mainpduf.htm.

http://www.fda.gov

agreed, at the request of industry, to require FDA to prepare astudy evaluating whether to impose user fees on new animaldrug applications to improve existing review processes. Thereport was due to Congress by January 4, 1994.

2. SUMMARY OF FDA MODERNIZATION ACTOF 1997 (PDUFA II) (OCTOBER 1, 1997 TOSEPTEMBER 30, 2002)

2.1. Modifications of Prior Law

Based on FDA’s significant progress to reform its review of Rxdrug and biologics applications, Congress reauthorized PDUFAas part of broader FDA Reform Act legislation (FDAMA). Thisnew Title 1 of FDAMA (called PDUFA II) amended PDUFA Iand extended it through September 30, 2002. In July 1998,FDA released a Five-Year Plan for PDUFA II that presentedthe major assumptions FDA was making and how it intendedto use its additional resources in order to achieve the new goalsassociated with the amended Act.

2.2. New Fee Amounts

1. Application Fees: $256,846 (applications includingdata), $128,423 (applications without data and sup-plements with data) (FY 1998); $272,282 (applica-tions including data), $136,141 (applications withoutdata and supplements with data) (FY 1999); $285,740(applications including data), $142,870 (applicationswithout data and supplements with data) (FY 2000);$309,647 (applications including data), $154,823(applications without data and supplements withdata) (FY 2001); $313,320 (applications includingdata), $156,600 (applications without data and sup-plements with data) (FY 2002).

2. Establishment Fees: $141,966 (FY 1998), $128,435(FY 1999), $141,971 (FY 2000), $145,989 (FY 2001),$140,199 (FY 2002).



3. Product Fees: $18,591 (FY 1998), $18,364 (FY 1999),$19,959 (FY 2000), $21,892 (FY 2001), $21,630 (FY2002).


As part of the consideration of PDUFA II, FDA again agreed toa series of performance goals against which its performancewould be measured when reauthorization of a successive 5year term was considered in 2002. Those goals for CDER andCBER review included:

Original NDAs, BLAs, andefficacy supplements Standard application Priority application

FY 1998 90% in 12 months 90% in 6 months

FY 1999 30% in 10 months 90% in 6 months90% in 12 months



FY 2002 90% in 10 months 90% in 6 months

Ninety percent of manufacturing supplements requiringapproval were to be reviewed in 6 months, with a sliding scaleto be reviewed in 4 months (30% in FY 1999, 50% in FY 2000,40% in FY 2001, and 90% in FY 2002). Resubmission of origi-nal NDAs/BLAs were to be considered in 6 months, with asliding scale to be considered in 4 months and then 2 months.

Other performance goals unrelated to application reviewswere built into the PDUFA II regime. FDA was required tomonitor responses to requests for meetings (70% of requestswere to be responded to within 14 days moving to 90% by 2001).Type A meetings were to occur within 30 calendar days of theagency receiving the meeting request, Type B meetings within60 calendar days, and Type C meetings within 75 calendardays. FDA meeting minutes were to be available to the sponsorwithin 30 calendar days after the meeting. They would clearly

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outline the important agreements, disagreements, issues forfurther discussion, and action items from the meeting inbulleted form, and need not be in great detail (18).

Procedures for clinical holds were also carefully delineated.FDA Centers would respond to a sponsor’s complete responseto a clinical hold within 30 days of the agency’s receipt ofa sponsor’s response. Ninety percent of such responses mustbe timely after FY 1999.

Procedures for major dispute resolution were also quanti-fied. By 2001, 90% of procedural and scientific matters wouldbe responded to within 30 days, which involved drug reviewsthat could not be resolved at the divisional level and for whicha formal dispute resolution petition was filed. A series of con-ditions was provided, which included (a) disputes should firstbe worked through the review chain from the reviewer to theDivision Director, (b) FDA-timed responses to grant or denythe appeal could be oral (followed by written confirmationwithin 14 days) or written, and (c) reasons for a denial mustbe provided. Many of these conditions conform to FDA guidancefor formal dispute resolution.

Sponsors frequently consult review staff seeking commentson protocol design. The PDUFA II performance standardscontain a 45-day time frame and procedural outline for this feed-back process. Miscellaneous issues also include using user feeresources to update FDA’s information management infrastruc-ture to allow for paperless INDs and human drug applications,use of complete response letters in lieu of action letters, separateinformation request letters from each discipline reviewing anapplication, and a definition of terms used in this document.

3. SUMMARY OF PRESCRIPTION DRUG USERFEE AMENDMENTS OF 2002 (PDUFA III)(OCTOBER 1, 2002–SEPTEMBER 30, 2007)

3.1. Modifications of Prior Law

In 2002, the Prescription Drug User Fee Amendments of 2002were included as Title 5 of the Public Health Security and



Bioterrorism Preparedness and Response Act of 2002. Rx druguser fees were reauthorized for another 5 years until Septem-ber 30, 2007. The level of fees increased to reflect a decline inthe number of applications filed with the agency. In addition, adetailed letter dated June 4, 2002, was prepared for the regu-lated industry and the Congress under the signature of HHSSecretary Thompson (19). The letter transmitted detailed newperformance goals and procedures prepared by the agency (20).

3.2. New Fee Amounts

1. Application fees: $533,400 (applications includingdata), $266,700 (applications without data and sup-plements with data)(FY 2000) (FY 2001) (FY 2003)

2. Establishment fees: $209,900 (FY 2003)3. Product fees: $32,400 (FY 2003)


Application review times maintained the final schedule pro-posed as part of PDUFA II: original standard applicationsand efficacy supplements with data—90% within 10 months;original priority applications and efficacy supplementswith data—90% within 6 months; class 1 resubmissions—90%within 2 months; class 2 resubmissions—90% within 6 months;and resubmitted efficacy supplements (class 1) reduced from6 to 2 months for review.

Meeting management goals were refined in the PDUFAIII document. CDER and CBER committed to notifyingparties requesting meetings, teleconferences, or videoconfer-ences within 14 calendar days of receiving an industry requestfor a formal meeting with the date, time, place, and expectedFDA attendees. Meetings continued to be classified as Type A,B, or C, and detailed procedures for requesting the meetingswere provided.

Procedures similar to PDUFA II were provided for clinicalhold responses, major dispute resolution, and protocol designreview. FDA also agreed to conduct two pilot programs to eval-uate the development of a continuous marketing application.

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3.4. Impact of User Fees on Rx Drug Approvals

There is no question that the enactment and implementationof PDUFA led to the dramatic restructuring of the agency andits industry relationship. Reviewers and their superiors withinthe FDA product centers were accountable for the pace of theirwork for the first time. Review time decreased from a mediantime in excess of 2 years or more to within 1 year for standardapplications and 6 months for priority applications. Hundredsof new employees were retained to review data and to interactwith the regulatory officials of constituent product sponsors.FDA has consistently reported to the Congress in its annualPerformance and Financial Reports that it met and exceededall its performance goals under PDUFA I, II, and III (for drugsbut not biologics). It has noted a trend, however, of fewer ori-ginal applications and efficacy supplements that pay the largestcomponent of application fees under the Act. The number oforiginal new product applications submitted and filed each yearincreased steadily in the early years, from 88 in FY 1993 to 133in FY 1997. From FY 1997 to FY 2000, the growth reportedlyleveled off, and in FYs 2001 and 2002 application submissionsand filings dropped substantially (21). Twenty-five percentfewer applications were filed with FDA in 2001 than in 2000.The number of priority applications was down more than 60%in 2001 from the previous year and was less than half the levelof any year since FY 1997 (22). Since priority applications oftenrepresent significant therapeutic gains, the Congress commis-sioned a report by the General Accounting Office (GAO) toevaluate the cause of this decline.

At the same time, FDA continued to report increasedproductivity. In recent congressional testimony, FDA DeputyCommissioner Lester Crawford reported approval of 66new drugs in 2001, 24 of which were new molecular entities(23). Ten of the 66 new drugs (7 of the new molecular enti-ties) received priority review and were reportedly reviewedand approved in the median time of 6 months. CBERreviewed a total of 16 complex BLAs in the median time of13.8 months and approved them in the median time of 20.3months. Two priority BLAs were reviewed in the median time



of 11.5 months and approved in the median time of 13.2months.

Finally, FDA reported that in recent years 50% of allnew drugs worldwide were launched in the United States,and American patients have access to 78% of the world’s newdrugs within the first few years of their introduction (24). Theagency advocated a need to use some PDUFA resources forrigorous safety monitoring of newly approved drugs in the firstfew years after a product is on the market to quickly detectunanticipated problems.

4. EVALUATION OF THE PROGRAM BY THEGENERAL ACCOUNTING OFFICE

In September 2002, the GAO issued a report entitled ‘‘Effect ofUser Fees on Drug Approval Times, Withdrawals, and otherAgency Activities’’ (25). The report concluded that PDUFA hasbeen successful in providing FDA with the funding necessaryto hire additional drug reviewers, thereby making new drugsavailable in the United States more quickly. But while themedian approval time for NDAs for standard drugs droppedfrom 27 months to 14 months from 1993 to 2001, the newpriority time for priority drugs remained stable at 6 monthsafter 1997. The median approval times for standard newmolecular entities (drugs containing active ingredients thathave never been marketed in the United States in any form)increased from 1998 from about 13 months to 20 months. Incontrast, median approval times for BLAs have fluctuated since1993, ranging from a low of 12 months in 1997 to a high ofabout 32 months in 1995. In 2001 that time had slipped toabout 22 months.

FDA reportedly had to increase the amount of its appro-priated funds, outside of user fees, to drug and biologicsreviews to compensate for the minimum allocation of fundsrequired by PDUFA. FDA also reportedly used user feeproceeds to fund employee pay raises that were generallynot covered by annual appropriations. PDUFA II increasedreviewer workload by shortening review times and establishing

342 Scheineson


new performance goals to reduce overall drug developmenttimes. This resulted in higher attrition rates for drug reviewersthan comparable occupations in the federal workforce.

Finally, GAO reported that a higher percentage of drugapplications had been withdrawn from the market for safety-related reasons during the most recent term of PDUFA (5.3%from 1997 to 2000) compared to 1.6% in the period immedi-ately after PDUFA implementation (1993–1996). Using 8 yearperiods before and after enactment of PDUFA, the rate ofpostapproval drug withdrawals increased from 3.1 to 3.5%.Some drugs were withdrawn because doctors and patients didnot use them according to approved labeling, while others werefound to have rare side effects that were not detected in clinicaltrials. GAO recommended that FDA strengthen its postmarketsurveillance activities. It plans to spend approximately $71million in user fees over the next 5 years to better monitorsafety and track adverse events. Under PDUFA III, FDA wasgiven the authority for the first time to utilize user fees forthese postmarket surveillance and compliance activities. Theindustry had aggressively resisted use of its own proceeds topay for agency compliance activities.

5. STRATEGIES TO USE PDUFA TO EXPEDITEREVIEW AND APPROVAL

5.1. Evaluate Whether the Application Will BeSubject to Rx Drug User Fees

These fees, and the performance standards associated withthem, generally apply only to original NDAs and BLAs andsupplements to those filings. Remember, these are user feesand not taxes for government services. Therefore, FDA has tojustify its imposition by utilizing the services of data reviewershired with the fee proceeds.

5.2. Attempt to Negotiate the LowestPossible Fee

User fees are substantial. They include a $533,400 applicationfee in FY 2003, a $209,900 fee permanufacturing establishment,



and a $32,400 fee per listed product. One half of the applicationfee is due on submission of the application, and one half isdue within 30 days of the date of the action letter (which hasbecome a complete response letter). If the applicant is a smallbusiness (fewer than 500 employees with no Rx or biologicproduct on the market), only half of the fee is owed, and notuntil one year following the date of submission (and only ifthe application is accepted for filing). A major manufacturershould consider allowing a smaller entity from which it is licens-ing the product to become the sponsor of the application.Corporate structuring might be possible to save a significantportion of this fee.

An application for fee waiver or reduction might be avail-able under the criteria included in Sec.1.5. Specifically, if thefee precludes the application because of an orphan or smallmarket or fewer agency resources are required for a narrowreview, the fee might be reduced. In the current budget climate,and with fewer applications, FDA may not give in easily in thisregard, but the law might be on your side. Also remember thatonce a drug has generic competition, or even if a paper NDA ison the horizon, the fee might not be due.

Likewise, the definition of an establishment might bereduced for purposes of the fee. Buildings making multipledrugs might count as a single establishment if they are locatedwithin a 5-mile radius. The plant must make finished dosageforms to count. Contract manufacturers or makers of ingredi-ents do not count. Foreign plants only count if their product isimported into the United States.

Finally, product fees can be reduced if a manufacturerlimited or aggregated the product listing of multiple dosagesor dosage forms of its products. These might be included inone product listing. Antibiotics do not count if they were notapproved by NDAs. Once a generic competitor is approved, theinnovator product no longer has the fee assessed. Finally, sincea drug-maker must use the product review services of theagency to owe a fee (remember the law created a user fee andnot a product tax), no fee is owed unless the company has atleast one application or supplement pending for agency reviewin the year of the fee assessment.

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5.3. Create a Priority Application

Performance goals are not legally binding on FDA, but theagency is under great pressure from industry and the Congressto review most priority applications within 6 months of filing.The review divisions have discretion about how they classifynew applications. Seek priority designation wherever possible(separate and apart from fast-track review for drugs treatingserious or life-threatening illness). This discussion should occurin pre-NDA/BLA meetings with the review staff. If the drug isa new chemical compound, meets an unmet medical need, ortreats a debilitating disease, the sponsor should create an orga-nized presentation to the agency to request this designation.

5.4. Refer to Agency Performance Goals Duringthe Product Review

The sponsor must create a complete application as quicklyin the process as possible so it is accepted for filing and theFDA clock begins to run. Experienced regulatory lawyers orprofessionals maintain constant contact and interaction withproduct reviewers so that reviews progress efficiently. FDA haspreserved considerable flexibility to meet its statistical user feegoals while stopping its review clock with informationalrequests to the sponsor. In order to obtain an approvableletter and avoid a delaying complete response letter thatrequests additional information, this interaction must be main-tained. The company must be responsive and anticipate theneed for additional data, analyses, or clarification. The quickerand more lucidly this information is provided, the better thechance of making it under the review goal. FDA must accountfor meeting its PDUFA goals in annual performance reports tothe Congress. Once the FDA clock has shifted back to thesponsor and the performance goal has been met in the first-review cycle, many of the benefits of PDUFA have been lostto the product sponsor. Multiple review cycles delay productapproval significantly. Prepare quality applications, anticipatequestions or information requests, and do not file the applica-tion until ‘‘all your ducks are in a row.’’



5.5. Employ Formal Dispute Resolutionor Congressional Oversight inAppropriate Circumstances

PDUFA is the product of a delicate compromise between theCongress on behalf of industry and the agency. FDA has becomemuch more interactive in order to relieve last-minute pressuresto meet tighter PDUFA performance goals. If scientific differ-ences arise, use the formal dispute resolution guidance thatFDA has provided. If policy differences arise, seek congres-sional oversight and support as appropriate.

REFERENCES

1. If an Rx drug, as defined in PDUFA, was made in a foreignplant for foreign marketing under an approved NDA, the foreignestablishment was subject to establishment fees if it wasowned by an NDA/BLA holder that had a pending NDA/BLAor supplement after Sept. 1, 1992.

2. Thus, for example, if a product is sterilized by filtration andplaced into vials by a ‘‘contract manufacturer’’ that has nopending NDAs, BLAs, or supplements after September 1, 1992,then no establishment fee was due for either the contractmanufacturer or the facility that performed the rest of themanufacturing steps. Attachment D, ‘‘Application, Product, andEstablishment Fees, Common Issues and their Resolution,’’revised as of Dec. 16, 1994.

3. FDA has interpreted the generic exemption narrowly. Therefore,me-too products that are the same as a listed Rx product butwere approved under the NDA provision of x505(b)(1) do not qual-ify for the exclusion. If a listed product has a competitor approvedunder x505(b)(2)(paper NDA) or ( j)(ANDA), that drug is exempt.If the x505(b)(2) or ( j) applications have been approved andnot withdrawn, the first approved product is excluded from feeseven if the generic product is not presently marketed. Tentativeapprovals of a 505( j) application are not considered approvals.Finally, according to FDA, products listed that were approvedby a paper NDA before 1984 when x505(b)(2) was added to theFDCA are not eligible for exclusion from product fees.

346 Scheineson


4. FDA’s interpretation of PDUFA did not allow innovator anti-biotic drug products to become exempt from the product feeeven after subsequent generic antibiotic drug products wereapproved, when they were approved under x507. However,since 1997 generic antibiotics have been approved underx505( j), and should therefore trigger the exemption of theinnovator product. Likewise, bulk antibiotic drugs should notbe subject to product fees because they are not products infinished dosage form.

5. Id.

6. The date of submission, according to FDA, is the date theapplication is received by FDA and stamped as received inthe CDER or CBER central document control center. Attach-ment G, ‘‘Draft Interim Guidance Document for Waivers of andReductions in User Fees,’’ July 16, 1993, p. 11. This is distin-guished from ‘‘filing,’’ which occurs after FDA determines thatthe application is sufficiently complete to permit a substantivereview. See 21 C.F.R. x314.101.

7. 21 U.S.C. x379h(b)(2). The Act did not provide a small businessexception for supplement applications.

8. Id.

9. Id. at 24–32. This draft guidance document is available at

10. Id. at 28.

11. x379h(d).

12. See 5 U.S.C. x552, and FDA implementing regulations at 21C.F.R. Part 20. Supra note 6 at 15.

13. x379(h)(d).

14. Supra note 6 at 18–19.

15. Id.

16. Under x379h(a)(1)(D), FDA refunds 50% of the application feepaid for any application and supplement refused for filing.That amount actually represents only 25% of the total applica-tion fee since only 50% of the total fee is due upon submission.Id. at 19.



www.fda.gov/cder/pudfa/mainpduf.htm.

http://www.fda.gov

17. x379h(d)(4).

18. PDUFA Reauthorization Performance Goals and Procedures;

19.

20.

21. FY 2001 and FY 2002 Performance Reports to Congress, p. 4.

22. Id.

23. Statement of FDA Deputy Commissioner before the HouseAppropriations Subcommittee on Agriculture RuralDevelopment, FDA and Related Agencies, March 21, 2002,

24. Id. at 20.

25. GAO Report No. 02-958, Report to the Chairman of the SenateCommittee on Health, Education, Labor and Pensions, ‘‘FDA –Effect of User Fees on Drug Approval Times, Withdrawals, andOther Agency Activities,’’ September 2002.

348 Scheineson


III. C., www.fda.gov/cder/news/pdufagoals.htm.

See www.fda.gov/oc/pdufa/transltr.html.

See www.fda.gov/oc/pdufa/pdufaIIIgoals.html.

p. 10, www.fda.gov/ola/2002/fy2003.html.

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

10

Clinical Research Requirements forNew Drug Applications

GARY YINGLING and ANN BEGLEY

Kirkpatrick and Lockhart LLP


1. INTRODUCTION

The U.S. Food and Drug Administration (FDA) has as its leg-islative mandate the regulation of all drugs manufacturedor marketed in the United States. When the agency uses theterm ‘‘drug,’’ it includes within that definition biologics. Theregulation of drugs is basically separated into two categories:those for which preapproval is not required, which includesthose that are considered generally recognized as safe andeffective (GRASE), and those that require preapproval in theform of the submission of a New Drug Application (NDA) or an

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Abbreviated New Drug Application (ANDA) (1). For those thatfall into the category of being under review or GRASE, includ-ing all those subject to the over-the-counter (OTC) Monographsystem, there is no preapproval requirement and, therefore,no submission of information required for the product toenter the marketplace. For those drugs that require the sub-mission of a drug application, it is highly likely that the appli-cation will be dependent on the submission of clinical dataor bioequivalence studies to demonstrate that the productis safe and effective. Just as the submission of the applicationis subject to various statutory and regulatory requirements,the clinical or bioequivalence testing necessary for obtainingapproval of an NDA or ANDA is covered by a number of stat-utory and regulatory provisions.

To fully appreciate the clinical requirements, one needsto recognize that, for a drug requiring preapproval, it is a vio-lation of the Federal Food, Drug, and Cosmetic Act (FFDCA)to ship an unapproved new drug in interstate commerce, unlessit is the subject of an Investigational New Drug (IND) applica-tion (2). The statute states that, in order to obtain approval,the sponsor or the applicant must submit a drug applicationunder xx 505(b)(1), 505(b)(2), or 505(j) of the FFDCA.

When one considers the filing of a 505(b)(1) application,one is looking at submitting an application for a new chemicalentity, a novel dosage form, or a very significant labeling changethat will require preclinical animal data and clinical studies.The clinical studies will probably be organized into threephases: phase 1 being basic toxicology studies, phase 2 beingdose-range studies, and phase 3 being the pivotal clinical studyor studies that allow that agency to approve the application.

A 505(b)(2) application will, in all likelihood, require lessclinical data and could be approved based on a single phase 3study or even a bioequivalence study. This is because the505(b)(2) application relies on the fact that the active pharma-ceutical ingredient that is the subject of an approved drugapplication is well known to the agency so that it is not neces-sary to obtain the detailed data (e.g., animal studies, phase 1and phase 2 studies) that would be required for a 505(b)(1)application.

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If the application is a 505(j), or what is called an Abbre-viated New Drug Application (ANDA), the required data willconsist of a bioequivalence study to demonstrate that the appli-cant’s drug is equivalent to the product already marketed.Under the ANDA regulations, it is possible for the bioequiva-lence study to be a single-dose, crossover, limited patient studylooking at blood levels or a 500- or 600-patient clinical studycomparing the referenced listed NDA to the proposed abbre-viated application. Whatever the form of the application, inall likelihood there will be the necessity to do clinical research,and FDA has set forth detailed regulations and guidancescontrolling clinical and bioequivalence studies that supportnew drug applications.

2. SPONSORS

The firm or organization that bears the responsibility for theclinical study is called the sponsor. The sponsor is the organi-zation that will file the drug application, whether it is acomplete 505(b)(1), a 505(b)(2), or an ANDA. As the sponsor,the organization will be charged with obtaining the data tosubmit in the NDA or ANDA for the purpose of gaining FDAapproval. This undertaking becomes a multistep process, fromdeciding what drug the firm will file an application on, to gath-ering the supporting scientific data to submit to the agency forthe purpose of obtaining approval. For a firm filing a 505(b)(1)application, usually for a new chemical entity, the initial ques-tion is what amount of basic research needs to be done beforetests can be conducted in humans. This pre-submission datastage involves in vitro and animal testing and is normallycharacterized as pre-IND data. The sponsor does not need tonotify FDA of its interest in working on the chemical entityand is under no obligation to update the agency on its devel-opment plan at the pre-IND stage. However, once a sponsordecides that it has obtained enough in vitro and animal datato believe there is benefit in conducting human testing, itbecomes necessary for a firm to submit an IND application.The IND application is the submission that allows a firm to

Clinical Research Requirements for New Drug Applications 351


ship an investigational new drug for the purpose of conductingresearch. As noted earlier, it is illegal to ship a drug that hasnot been approved unless it is the subject of an IND application(3). The statute specifically provides that the Secretary willpromulgate regulations to allow sponsors to conduct studiesfor the purpose of gathering data so that applications can besubmitted for approval.

FDA’s Code of Federal Regulations (CFR) (4) sets forththe basic requirements for the submission of an IND appli-cation and the various requirements that arise from thatsubmission. The sponsor will need to prepare an actual INDapplication, which will include the animal studies that havebeen conducted, any data of which the sponsor may be awareconcerning studies outside of the United States, and theprotocol (study plan) for the first studies which the sponsorintends to conduct.

Under the current user fee program, which is designed tocreate a cooperative working relationship between the agencyand the sponsor, often a sponsor will request, or the agencymay seek, a pre-IND meeting to discuss the nonclinical datathat have been collected to date, the ingredients being usedin the proposed product, and the clinical testing, particularlythe studies involved in phase 1 and phase 2 development. Ifthe sponsor and the agency engage in a pre-IND meeting, it willbe necessary for the sponsor to prepare a summary of theinformation that it would submit in the IND application. It isto the sponsor’s advantage to provide FDA with a very detailedsummary, so that the agency does not require testing that maybe unnecessary or fail to appreciate if there are data that willsuggest an issue. If a pre-IND meeting is held, there is usuallya fairly substantial level of agreement between the agencyand the sponsor before the actual IND application is submitted.However, it is not necessary to request a pre-IND meeting,and it is not unusual for firms, particularly if they are seeking505(b)(2) applications, not to request a pre-IND meeting.

After receiving an IND application, the agency then has30 days to review the IND application to determine whetherthere is enough preclinical data to assure that the product issafe enough to allow the conduct of human clinical studies.



There is also a careful review of the clinical studies, whether it beone or more studies, to determine if the study design will resultin data that will allow the drug development to move forward.If the proposed phase 1 study fails to provide enough data andinformation in its design to move to phase 2 studies, there isno benefit to subjecting human patients to the drug. Therefore,the agency will carefully look at the proposed protocol. If it isnot satisfied with the study design, FDA may notify the spon-sor of a clinical hold. A clinical hold means that the sponsorcannot go forward with the studies. Clinical holds seldom occurwhen there have been pre-IND meetings where the agency andsponsor have worked out the study design. Again, it behoovesthe sponsor to be as detailed as possible regarding the firststudies so that the agency has a complete understanding ofthe pre-clinical data and proposed design of the studies.

For those sponsors that find themselves in a clinical hold,the agency has created a fairly elaborate review process toassure that the agency’s clinical hold decision can be reviewedand that the sponsor will have an adequate opportunity toexplain why the proposed protocol is adequate. However, oneneeds to recognize that FDA’s review process is inherently slowand that every effort should be made to avoid this detour byassuring that the protocol design is one that the agency willaccept.

After submitting the IND application, a sponsor mustcomply with a 30-day waiting period before it can initiate thestudy. If, at the end of the 30 days, the sponsor has not heardfrom the agency, in theory the sponsor may go forward withthe clinical study. However, the sponsor should be very reluc-tant to go forward with a clinical study at the end of the 30days if it has not heard from the agency. Under these circum-stances, there is a possibility that the agency has some concernthat it has not been able to articulate within the 30-day period,and that shortly after the 30-day period expires the agencywill notify the sponsor that the study is on clinical hold.If the sponsor has already started the study, both the sponsorand the agency face major problems in that the agency isunhappy with the study design and the sponsor has alreadyentered patients. This can be avoided by making contact with



the agency shortly after the IND application is submitted to beabsolutely sure the agency has received the IND applicationand that it is being reviewed. Then the sponsor should makecontact again, as the 30-day period is winding down, to con-firm that the agency will not have problems such that it willconsider placing the study on a clinical hold.

While sponsors often identify the clinical investigatorsat the time they are preparing the studies and will often havethe major clinical investigator accompany them if they have apre-IND meeting with the agency, it is not necessary to identifyup front any or all of the investigators who will participate inthe clinical studies. The sponsor does bear the responsibilityfor the eventual selection of the clinical investigators who willactually do the studies. It is unusual in today’s marketplace fora sponsor to have a medical staff capable of doing the studies orthat will even play a major role in overseeing the actual conductof the study. However, it is not unusual for a sponsor to havenumerous contacts in the clinical community and to have iden-tified any number of individuals they believe are appropriatefor the purpose of being clinical investigators in the study.

In today’s clinical research environment, sponsors typi-cally have a small, specialized medical staff for the purpose ofassisting in study design, reviewing study results, and playingan active role in planning. The actual protocol for the studywill probably be prepared by a contract research organization(CRO) or a clinical investigator working with a CRO. There area number of very large CROs as well as a number of mid-sizedand small CRO firms that specialize in clinical studies, as wellas highly specialized firms that conduct studies on particularorgans or disease conditions or patient populations. Therefore,the sponsor often has many options from selecting either asingle large CRO, which may have multiple sites at which astudy can be done and can therefore increase potential enroll-ment, to selecting a small CRO for the purpose of going to par-ticular parts of the country or identifying specialized practices.

The sponsor can actually transfer its responsibilities fora study over to a CRO. FDA regulations (5) specifically pro-vide for the authority of the sponsor to transfer responsibility.The transfer must be in writing, and it is to the sponsor’s



advantage to delineate exactly what activities have beentransferred. While the sponsor can transfer the activities, itis not able to transfer its responsibility for the clinical trials.Therefore, it needs to assure itself that the selected CROunderstands the importance of having good investigators, offollowing the protocol, and of conducting the study in amanner that FDA will find satisfactory.

The agency requires that the sponsor monitor the investi-gators to be sure that the investigators and their staff areconducting the study in accordance with the protocol and withthe sponsor’s and the agency’s expectations. Again, the sponsorcan contract with a CRO or a third party for the purpose ofmonitoring, or it may have monitors of its own. The monitor’srole is very important in a clinical study, because it is themonitor who visits the study site to determine whether or notthe clinical investigator fully understands the protocol andwhether the investigator and the investigator’s staff are con-ducting the study in accordance with the sponsor’s and theagency’s expectations.

In the past it was not uncommon for the monitor to func-tion mostly as a study promoter, making sure the investigatorwas actively involved in enrolling patients and in correctingrecord-keeping errors and oversights of the staff. While moni-tors today may fulfill some of those roles, FDA’s heightenedexpectations for monitoring to assure quality of data haveresulted in monitoring being a much more important activity.The monitor is the person who is able to identify investigatorsites where patients are being entered who fail to meet thestudy criteria, to identify staff errors and/or malfeasance, andto correct staff and investigator misunderstandings with regardto the protocol and the way the study is being conducted.More and more, when it finds problems at a study site, theagency asks why monitoring did not identify and correct theproblem or discontinue the investigation. As the agency becomesmore resource conscious, it will turn increasingly to using itsenforcement tools to ensure sponsor compliance with all of therequirements within the IND regulations.

In addition to the monitoring activity required of the spon-sor or CRO, there is an expectation that all of the information



required to be reported in the Case Report Forms (CRF) orpatient medical records (source documents) will be properlyrecorded (i.e., written down or entered in the computersystem). Only information that is actually reported can beused by FDA in its evaluation of the clinical data. The popu-lar phrase is, ‘‘If it isn’t written down, it didn’t happen.’’The agency is extremely strict with reporting requirements.Efforts by investigators to explain a particular set of eventsor activities at a later date will be dismissed because therewas a failure to record the information properly at the timeit should have been recorded. As with all statements thatappear to be absolutes, there is a certain level of flexibilityin relationship to written records, as long as the reporting isdone in the manner required and is corrected in the mannerthat is appropriate. For instance, a study nurse records thepatient’s blood pressure as 120/80 in the patient’s chart andas 80/140 in the CRF records. Some days later, in reviewingthe records, the study coordinator notes the error and, at thattime, the incorrect record may be corrected if a single line isdrawn through it, the correction is recorded, it is initialed,dated, and there is an explanation either on the CRF or on aseparate memorandum that explains what has occurred andwhy the correction was made. While the agency will acceptsuch corrections, there is an expectation that they will be mini-mal and that they will be properly recorded, dated, and signed.

It is understood that neither the sponsor nor the CRO willbe doing the actual writing in the patient records or CRF andthat, in fact, most of the time the clinical investigator will notbe making those recordings either. This task will often be doneby staff. Therefore, monitoring mandates a review of the site’scompliance with record-keeping and record-retention require-ments. Review of the record is for the purpose of catchingthe type of error described above or to look for patterns orproblems in a clinical study. The review may be done by theclinical investigator or staff, the CRO, or the sponsor. Today,with many records created and transferred electronically, itis possible for the sponsor or CRO staff to do an almost instan-taneous review of records for completeness and to ensurethat there are no apparent discrepancies. It is the agency’s



expectation that the records have been reviewed and moni-tored to assure that the required information is recorded.There is also a record-keeping requirement that the retainerof the records, whether the clinical investigator or the CRO orperhaps even the sponsor, will retain the records for a period of2 years after the drug is approved or 2 years after the study iscompleted if there has been a decision that the drug will notbe the subject of an application and FDA has been notified.FDA regulations outline record-retention time frames (6). Thesponsor or CRO must be extremely vigilant in relationship tothe record-keeping and record-retention requirements.

In addition to the monitoring, the reporting requirements,and the record review, there is a need to keep track of theactual study drug. The sponsor provides the study drug forthe purpose of the study. In addition to the drug itself, it willoften be necessary to provide a placebo that is indistinguish-able from the drug so that the study can be blinded. To ensurethat the study is properly blinded, it must be coded, and codingmay be the sponsor’s responsibility or that of the CRO. Oncethe drug is sent to the clinical investigator, the responsibilityfor keeping track of the drug falls to the investigator. Thatwhich is not dispensed at the end of the study should be sentback to the sponsor so that it can make records of the drug thatwas manufactured, dispensed, used, and returned. There isone quirk in the process: for those manufacturers involved inANDAs, even if they are ‘‘biostudies’’ that are basically clinicalstudies in design and length, the retention samples cannot besent back to the sponsor but must be retained by the clinicalinvestigator, the CRO, or an independent third party (7).Failure of the retention samples to be in the possession ofan independent third party can and has resulted in clinicalstudies being called into question by the agency.

3. CLINICAL INVESTIGATORS

While sponsors are responsible for the development, monitor-ing, and submission of clinical studies in an NDA or ANDA,the clinical investigators are responsible for the actual conduct



of the study. Prior to allowing the clinical investigator to par-ticipate in the clinical study, the sponsor or CRO must obtain asigned Form FDA 1572, in which the clinical investigator com-mits to performance of a number of study-related responsibil-ities. The clinical investigator is responsible for understandingand complying with the investigational plan, obtaining Insti-tutional Review Board (IRB) approval before beginning thestudy, protecting the rights and welfare of the participatingresearch subjects, and assuring that legally effective informedconsent is obtained from each subject. In addition, prior tocommencing the study, the clinical investigator must providethe sponsor with sufficient financial information to allow thesponsor to make complete and accurate certification or disclos-ure statements under 21 C.F.R. part 54 concerning potentialfinancial conflicts of interest. The clinical investigator mustalso commit to update this financial information if relevantchanges occur during the course of the study and one yearfollowing the completion of the study.

The lead clinical investigator is usually referred to asthe principal investigator (PI), and those clinical investigatorswho work under the PI’s supervision, if any, are referred toas subinvestigators. PIs with significant research practiceswill likely have a clinical research team composed of a clinicalresearch coordinator (CRC), who is generally responsible formanaging the research team, one or more subinvestigators,and one or more study nurses to assist in the conduct ofthe research. While the PI can delegate appropriate researchresponsibilities to the team members, ultimately the PI isresponsible for supervising all members of the research teamand for assuring that they understand their obligations inconducting the research. For example, research nurses maybe responsible for recruiting research subjects, obtaininginformed consent, providing the study drug, and maintain-ing appropriate documentation, while subinvestigators maybe responsible for conducting the physical exam necessaryto determine the potential subject’s eligibility for the study.However, it is the PI who commits to personally conductingor supervising the clinical study in signing a Form FDA-1572,and so it behooves the PI to maintain a level of involvement



in the study that assures sufficient supervision of the teammembers.

One traditionally thinks of informed consent in terms ofthe document, signed and dated by the participant, settingforth the purpose, benefits, risks, and other study informa-tion necessary to allow the participant to make an informedand voluntary decision to participate in the clinical study.In reality, informed consent is a process that applies to eachcommunication with the participant, commencing with thesubject recruitment material and the initial telephone screen-ing of potential subjects, through the conclusion of the study.If new information that may affect a participant’s willingnessto continue in the study arises during the conduct of the study,clinical investigators have a responsibility to inform the partic-ipant of the new information. As to the informed consentdocument itself, clinical investigators must assure that it com-plies not only with the content requirements set forth in 21C.F.R. part 50, but also with applicable state law requirements.For example, California requires, in addition to the informedconsent document, that clinical investigators provide allresearch participants with an Experimental Subject’s Bill ofRights.

The clinical investigator also has significant record-keeping and reporting responsibilities. As briefly discussedabove, clinical investigators are responsible for controllingdistribution of the study drug through the maintenance ofadequate records identifying dates, quantity, and use by theresearch subjects. The PI must create and maintain recordsto document receipt of the drug and will need to have appro-priate storage facilities so the drug can be secured and notaccidentally dispensed to a patient outside the study. Duringthe study, the drug must be tracked so that records willaccurately reflect how much of the drug was taken by thepatient. Part of the study protocol may require questioningthe subject about taking the drug. Any drug not taken bythe patient should be returned to the PI and accounted for.At the conclusion of the investigator’s participation, anyunused study drug must be returned to the sponsor or disposedof as directed by the sponsor.



In addition to study drug accountability records, the clin-ical investigator must prepare and maintain adequate andaccurate documentation reporting all observations and otherdata of significance for each research participant in the clini-cal study. Such documentation includes, but is not limitedto, informed consent, CRFs, medical records, and laboratoryresults. The sponsor must collect CRFs at the conclusion ofthe study. However, the investigator must maintain other doc-umentation for 2 years following the date of the application’sapproval or, if the application was not filed or there was nosuch approval, 2 years after the conclusion of the study andafter FDA has been notified.

The clinical investigator should submit progress reportsto the sponsor as specified in the investigational plan. Inaddition, the clinical investigator must report such adverseexperiences to the sponsor that may reasonably be regardedas caused by, or probably caused by, the study drug. At theconclusion of the study, the investigator must issue a reportto the sponsor discussing the investigator’s participation inthe study.

Finally, the clinical investigator has reporting respon-sibilities in relationship to the Institutional Review Board(IRB, or Board). The investigator must promptly report allchanges in the research activity and all unanticipated prob-lems involving risk to human subjects or others. Thus, theclinical investigator must provide the IRB with adverse experi-ence information that occurs at the clinical investigator’s site.The clinical investigator would also generally be expectedto report to the IRB adverse experience information thatoccurs at other sites in a multi-site study. Changes in thestudy such as a change in protocol must be reported to, andapproved by, the IRB before making the change unless thechange is necessary to eliminate apparent immediate hazardsto human subjects (8). The clinical investigator must alsocomply with other IRB-specific reporting requirements. Thesemay include intermittent progress reports, continuing reviewreports, and study close-out reports. Failure to comply withIRB reporting requirements can result in termination orsuspension of the IRB approval.



4. INSTITUTIONAL REVIEW BOARD

In the process of setting up the clinical study and arrangingfor manufacture of the drug, creation of the protocol, identi-fication of the PI, and creation of the informed consent, it willbe necessary for the sponsor, CRO, or PI to seek the servicesand oversight of an IRB. Under 21 CFR part 56 of the agency’sregulations, five subparts set out the requirements for IRBs.In 21 CFR x 56.102 of the definitions section, the agency dis-cusses what a clinical investigation is and defines an IRB.It notes that the primary purpose of such a review by a Boardis to ensure the protection of the rights and welfare of thehuman subjects. The agency specifies the composition of theIRB membership under 21 CFR x 56.107 and states that eachIRB shall have at least five members with various backgroundsto evaluate different aspects of the proposed study. The Boardreviews the protocol for the clinical study and the informedconsent to determine whether the protocol is appropriateas to gathering clinical data and whether subjects are properlyinformed of the risks they are being asked to undertake aspart of the clinical investigation.

In theory, the IRB has a direct working relationship withthe PI, and in practice that is largely true. An often-overlookedfact is that the protocol and informed consent have beencreated by the sponsor or CRO who has been in contact withthe IRB and therefore the relationship between the PI and theIRB occurs because of the work of the sponsor/CRO. Whilethe agency recognizes the relationship between the IRB andthe PI, it often ignores the IRB’s relationship with the CRO/sponsor. Usually, a good working relationship between all ofthe parties exists to ensure that any information the IRB needsto review will be received. In addition to approving the studyinitially and looking at the informed consent, all of the serious,unexpected adverse events that the clinical site identifies aresupposed to be immediately reported to the IRB.

Because the IRB has as its primary mandate the protec-tion of the human subjects, it is necessary for the IRB to recog-nize when assumptions made in relationship to the safety ofthe study turn out not to be accurate and the risk-benefit ratio



changes such that the informed consent is no longer valid.A case in point would be a clinical study that envisioned thelikelihood of a serious adverse event as extremely rare butwhen the study is performed, the study has two patient adverseevents, both of them life threatening. Suddenly the informedconsent is no longer accurate and all of the study sites involvedin the study need to be informed of the fact that the studyneeds to be immediately stopped until new information canbe reviewed and evaluated to determine whether the clinicalstudy can go forward. Clearly, the PI would be reporting theinformation to the IRB as required by the agency’s regulation,but also to the sponsor, because the sponsor or CRO is equallyconcerned about the patients involved in the clinical study.

Like the clinical site, the IRB has a record-keeping andrecord-reporting requirement. First of all, it must documentthat it has reviewed the protocol and informed consent. Inthe minutes of the IRB meeting, to the extent there are issuesdiscussed, the minutes should reflect that discussion. The IRBis also required to review, at least yearly, any studies that arecontinuing to be sure that nothing has changed in the specifiedperiod of time that would impact continued approval. The fre-quency of this continuing review is based on the study risks.To make sure the IRB fully understands the status of the study,it needs a report from the clinical site. To the extent the clinicalsite does not provide that report, the IRB may be forced towithdraw its approval. If it withdraws its approval from thesite, it must notify FDA so that the agency is aware of the factthat the IRB of record no longer approves the clinical site.

To be sure that the IRB has proper procedures in place,FDA regulations require it to develop standard operating pro-cedures, or SOPs. These SOPs will outline the IRB meetingprocedures, preparation of the minutes, how the minutes willbe developed, reviewed, and stored, the procedure for notifyingsites if the IRB has questions, methods for reviewing adverseevents, methods of seeking continuing review and researchchange information from the clinical investigational sites,procedures for doing the continuing reviews, and proceduresfor withdrawing approval of the IRB in relationship to a clini-cal investigational site.



Because FDA has recognized the need for the IRB in itsregulations, and to the extent that it has created the entitywithin the context of the regulations, it will inspect the IRBto look at its method of reviewing clinical studies to determinewhether or not the Board is meeting the agency’s expectations.Failure to allow the FDA to inspect or to follow FDA’s regu-lations could result in an FDA refusal to accept the studiesapproved by that IRB in support of an application. As witha clinical site, this will be, for the most part, a record reviewlooking at the IRB’s meeting minutes, correspondence withclinical sites, and whether the IRB has taken appropriateaction in response to problems or issues that have arisen.

5. FDA OVERSIGHT/MONITORING

The FFDCA and its implementing regulations provide FDAwith the authority to inspect sponsors, CROs, clinical investi-gators, and IRBs (9). Where FDA identifies violations of clinicalresearch regulations, it has a number of statutory and regula-tory remedies at its disposal—from letters requiring correctiveaction to criminal proceedings resulting in jail time and signif-icant fines.

FDA inspections in the clinical research area are coordi-nated under the Bioresearch Monitoring Program (BIMO), anagency-wide program coordinated by both the FDA Commis-sioner’s Good Clinical Practice Program and the Office ofRegulatory Affairs. Under BIMO, inspectional guidances areavailable to assist FDA field investigators in their inspectionof sponsors, monitors, CROs, investigators, and IRBs (10).In addition, each FDA Center has its own bioresearch monitor-ing branch, which, in cooperation with BIMO, evaluates theresults of inspectional investigations of sponsors, CROs, inves-tigators, and IRBs, and reviews data submitted in support of anapplication. For drug studies, the Center for Drug Evaluationand Research’s (CDER) bioresearch division, the Divisionof Scientific Investigation (DSI), is responsible for directinginspection requests to the field, conducting inspections withinvestigators from the appropriate field office, reviewing the



inspection reports, assigning classifications to the inspec-tion reports, and initiating appropriate regulatory action, asnecessary.

Following the conclusion of an inspection, a field officermay issue the site a form FDA-483, which lists inspectionalobservations that the field officer believes rise to the levelof a violation of clinical research requirements. In addition,the field officer writes a much more lengthy EstablishmentInspection Report (EIR) and submits this to DSI for review.DSI then assigns a final classification to the report, which isused to determine whether regulatory action must be takenagainst the site. There are three possible classifications:

1. No Action Indicated (NAI) means that no objectionableconditions were found during the inspection. While anNAI classification may result in an FDA letter tothe site, it will not rise to the level of a WarningLetter, and no response is required from the site.

2. Voluntary Action Indicated (VAI) means that theinspection disclosed objectionable conditions thatdeparted from the regulations. A VAI classification ismore likely to result in an untitled FDA letter. Unlessthe written response to the FDA-483 has left nomatter requiring a comment, a response to such anuntitled letter is generally required.

3. Official Action Indicated (OAI) means objectionableconditions or practices that represent serious depar-tures from the regulations were discovered. In thiscase, the imposition of administrative/regulatory sanc-tions may be required. An OAI classification is muchmore likely to result in an FDA Warning Letterand additional enforcement action if FDA deems itappropriate.

6. FDA ACTIONS

FDA has a number of administrative and regulatory remediesat its disposal when it determines that a sponsor, CRO, inves-tigator, or IRB is failing to act in accord with requirements



under the FFDCA and its implementing regulations. An FDAWarning Letter can be issued, demanding immediate correctiveaction. If the violation is serious enough, criminal prose-cution can be pursued by recommending the matter to theDepartment of Justice for violations of the FFDCA, its imple-menting regulations, and possibly violations under Title 18 ofthe U.S. Code (USC). In addition, several remedies are specificto the parties involved.

As to sponsors, FDA can impose a clinical hold, whicheither delays commencement of a clinical investigation or sus-pends an ongoing investigation. When a clinical hold is ordered,research participants cannot be enrolled in the study or giventhe study drug, and patients already in the study must be takenoff the study drug unless FDA specifically permits continuationof the therapy for patient safety reasons. Among other factors,FDA can impose a clinical hold whenever human subjects areor would be exposed to an unreasonable and significant riskof illness or injury. The clinical hold can be complete or partial.If all investigations under an IND are subject to the clinicalhold, it is deemed a ‘‘complete clinical hold,’’ whereas if onlyspecific study sites in a multi-site investigation are subject tothe clinical hold, the hold is deemed partial. Serious sponsor orCRO monitoring failures could result in a complete hold. Inves-tigator misconduct is more likely to result in a partial holdspecific to that investigator’s research site. An investigationmay only resume after FDA has notified the sponsor that theinvestigation can proceed, which will only occur after FDA issatisfied that the reason for the clinical hold no longer exists.

Sponsors can also be subject to an IND termination if FDAdetermines that the IND is deficient or the conduct of thestudy is deficient. Except where FDA concludes that an imme-diate and substantial danger to the health of individuals exists,it must first provide the sponsor with a proposal to terminatethe study and give the sponsor an opportunity to dispute theneed to terminate. Termination is only pursued by FDA ifthe clinical hold procedures are insufficient to address theserious deficiencies identified by FDA.

If FDA determines that sponsor or CRO failures in theiroversight or monitoring duties result in the submission of



new drug applications containing false data, the agency couldinvoke the Application Integrity Policy (AIP). The drug appli-cation system is based on a system of trust, in that FDA willaccept the truthfulness and accuracy of the data presented ina new drug application unless FDA is given reason not to havesuch trust. When that trust is broken, and FDA subjects asponsor to the AIP, it treats the data and information in allnew drug applications submitted by the sponsor as suspect,and thus, FDA first assesses the validity of data and informa-tion contained in a drug application prior to conducting thesubstantive scientific review. In addition, if FDA investigationsidentify deficiencies in previously approved drug applications,FDA can proceed to withdraw drug approval, require new test-ing, and/or seek recalls of marketed products.

An FDA invocation of the AIP can be financially cripplingto a company because it brings the drug approval process to astop and may affect the marketing of approved drugs. A recentcase in point concerns a medical device firm. During a 3-monthinspection of the firm, FDA determined that the firm hadimproperly substituted reread data for original data withoutnotification to FDA in an application to support the efficacyof its antiadhesion gel. In issuing an AIP letter, FDA sus-pended review of three premarket approval submissions.Further, re-launch of the firm’s only U.S. product was madecontingent on submission and approval of an AIP correctiveaction plan. After the firm submitted a corrective action plan,FDA did not accept it until a year later. In light of the AIPand other FDA actions against the company, the firm was

Debarment is another enforcement option for FDA if acompany or person has been convicted for misconduct relatedto the development or approval of a drug application (11). Whena person or company is debarred, they are essentially barredfrom participating in the pharmaceutical industry. Debarredcompanies cannot submit, or assist in the submission of,an ANDA, and debarred persons cannot provide services inany capacity to a person that has an approved or pendingdrug application. Each time a drug company applies forapproval of a drug, it must submit to FDA a signed statement



forced to file for chapter 11 bankruptcy.

that no debarred persons worked on the application. Drug com-panies that use debarred persons can be subject to stiff civilpenalties (12). As required by the FFDCA, FDA publishes a listof debarred persons on its website at

As a practical matter, FDA has never debarred a company,instead focusing its enforcement resources on debarring per-sons within a company who were convicted for conduct relatedto the development, approval, or regulation of a drug product.The statutory debarment provisions historically were usedto debar pharmaceutical industry personnel, particularlythose connected with the generic drug industry. However,in recent years debarment of clinical investigators, as well asclinical research staff, has been more common. For example,a California doctor and three members of his research staffwere debarred following criminal convictions associated withthe fabrication of research data. The physician was president ofa research company in California that, beginning in the 1990s,conducted more than 200 studies for as many as 47 drug com-panies. FDA inspection of his research facility revealed exten-sive deficiencies, including the use of fictitious patients,fabrication of data by substituting lab specimens and manipu-lating lab instrumentation, and the prescription of prohibitedmedications to manipulate data.

Investigator disqualification is another enforcement rem-edy that can be pursued by FDA if it has information that aclinical investigator has repeatedly or deliberately failed tocomply with the requirements set forth in 21 C.F.R. parts 312,50, or 56, or has submitted to FDA or the sponsor false informa-tion in any required report (13). A disqualified investigator isineligible to receive investigational drugs. When pursuing thisremedy, FDA must provide the investigator with written noticeof the basis for seeking disqualification and give the investigatoran opportunity to respond in writing or, if requested by theinvestigator, at an informal hearing. If FDA does not acceptthe investigator’s explanation, the investigator will be offeredthe opportunity to pursue an administrative hearing under21 C.F.R. part 16. At the conclusion of FDA’s investigation, ifit determines that disqualification is appropriate, it will notify



www.fda.gov/ora/com-pliance_ref/debar/default.htm.

http://www.fda.gov

http://www.fda.gov

the investigator and the sponsor of any investigation in whichthe investigator has been named as a participant that theinvestigator is not entitled to receive investigational drugs.

As to FDA actions against IRBs, FDA may limit an IRB’sability to continue to operate by withholding the IRB’s author-ity to approve new studies, directing that no new subjects beadded to ongoing studies subject to the IRB’s review, terminat-ing studies subject to the IRB’s review, and notifying state andfederal regulatory parties and others with a direct interest inthe matter about concerns with the IRB’s operations. Suchremedies must be presented in a letter to the IRB and to theparent institution, and a response describing corrective actionsmust be provided to FDA within a specified period of time.While it has never pursued this regulatory enforcementoption, if the IRB fails to provide FDA with an appropriateresponse letter and its corrective actions are insufficient,FDA can pursue disqualification proceedings. Such proceedingswill be instituted in accordance with FDA’s requirements forregulatory hearings under 21 C.F.R. part 16. The IRB can thenbe disqualified if FDA determines that the IRB has refused orrepeatedly failed to comply with any of the regulations set forthin 21 C.F.R. part 56, and that this noncompliance adverselyaffects the rights or welfare of the human subjects in a clinicalinvestigation. FDA will notify the IRB, the parent institution,and other affected parties, such as sponsors and clinical inves-tigators, of the disqualification. In addition, it may publish theIRB disqualification in the Federal Register. FDA will notapprove an IND for a clinical investigation that is under thereview of the disqualified IRB, and it may refuse to accept datain support of a drug application from a clinical investigationthat was subject to the disqualified IRB’s jurisdiction.

7. OTHER OVERSIGHT BODIES

In addition to FDA oversight, clinical studies may also be sub-ject to oversight by the Department of Health and Human



gov/ora/compliance_ref/bimo/dis_res_assur.htm.FDA publishes a list of disqualified investigators at www.fda.

http://www.fda.gov

http://www.fda.gov

Services’ (HHS) Office for Human Research Protections(OHRP), particularly if the studies are conducted at insti-tutions that receive funding from the HHS. OHRP has compli-ance oversight authority over all institutions that conductHHS-funded research. In order to participate in HHS-fundedresearch, an institution must obtain an approved Assurancefrom the OHRP. The Assurance formalizes the institution’scommitment to protect human subjects and generally containsa voluntary agreement that all research conducted at thesite, regardless of funding, is subject to OHRP oversight andresearch regulations set forth at 45 C.F.R. part 46. Thus, a drugstudy sponsored by a pharmaceutical company may be subjectto OHRP oversight even if there is no government funding.

When OHRP initiates an investigation, it is usually inresponse to an allegation or indication of noncompliance.However, investigations can also occur in the absence ofnoncompliance. Generally, OHRP notifies the institution inwriting of the investigation and provides it with an opportunityto respond. The investigation may occur completely by letteror telephone correspondence, or an on-site evaluation maybe involved. At the conclusion of the investigation, no matterwhat the outcome, the OHRP issues a determination letter.Thus, even where full compliance is determined, the institutionwill receive a determination letter. If less than full complianceis found, OHRP’s determination letter may cite remedies thatcan range from requiring improvements at the institutionalsite to withdrawal of the institution’s Assurance. OHRP canalso recommend debarment of the institution or individualinvestigators, rendering them ineligible to receive any govern-ment funding.

Sponsors and investigators conducting clinical researchconcerning recombinant DNA human gene transfer should alsobe aware of their responsibilities under the National Institutesof Health’s Guidelines for Research Involving RecombinantDNA Molecules (NIH Guidelines) (14). The NIH Guidelinesarticulate standards for investigators and institutions to followto ensure the safe handling and containment of recombinantDNA and products derived from recombinant DNA. Theyoutline requirements for institutional oversight, including



Institutional Biosafety Committees (IBCs), and describe theprocedures of the Recombinant DNA Advisory Committee.Even where the study is privately funded, it may be subjectto the NIH Guidelines if the site at which the research isconducted receives any NIH funding.

The sponsor, CRO, investigator, and IRB should alsobe aware of state laws and regulations concerning the conductof clinical research. While most states exempt research thatis subject to and in compliance with federal research require-ments from state laws and regulations, several states have anumber of clinical research requirements that exceed federalrequirements. For example, California requires that all infor-med consent documents be signed by a witness. In addition,some states require state approval of research occurring withcertain patient populations. Also, certain issues affecting infor-med consent are state specific. Age of consent varies from stateto state ranging from 14 years in Alabama to 21 years in PuertoRico. Where a patient is unable to provide informed consentdue to mental or physical incapacity, legally authorized repre-sentatives must be utilized, and it is imperative that the inves-tigator understand the order of priority with regard to who canact as a legally authorized representative. Investigators mustalso comply with state medical record privacy requirementsand sexually transmitted disease-reporting requirements.

8. THE HEALTH INSURANCE PORTABILITYAND ACCOUNTABILITY ACT OF 1996

As to medical records privacy, it is important for the sponsor,CRO, clinical investigator, and IRB to be aware of privacyrequirements under the Health Insurance Portability andAccountability Act of 1996 (HIPAA) (15). HIPAA was imple-mented to improve the efficiency and effectiveness of the health-care system by requiring HHS to adopt national standards forelectronic health-care transactions. However, in order to assurethe continued privacy of health information, HIPAA includeda provision that required HHS to adopt federal privacy



protections for individually identifiable health information.Regulations adopted by HHS, which became effective on April14, 2003, require covered entities (i.e., health plans, health-careclearinghouses, and health-care providers who conduct certainfinancial and administrative health-care transactions electron-ically) to implement standards to protect and guard againstthe misuse of individually identifiable health information. Indi-vidually identifiable health information (‘‘protected healthinformation’’) is health information that is collected from anindividual patient that either specifically identifies the patient(e.g., name, address, social security number) or that couldreasonably be used to identify an individual (e.g., gender andage information in connection with an unusual diseasecondition) (16).

Because filing for insurance reimbursement is the type ofelectronic transaction that triggers the applicability of HIPAA,most health-care providers are considered covered entitiesand thus subject to HIPAA requirements. For the purposeof research, if a clinical investigator is a covered entity, theclinical investigator must (17):

1. Provide all patients with a written notification ofthe office’s privacy practices and the patient’s privacyrights (while not required, clinical investigators areencouraged to obtain the signature of all patientsacknowledging receipt of the privacy notice);

2. Unless an IRB or privacy board waiver is approved,obtain written authorization from all research par-ticipants (i.e., a subcategory of patients) before dis-closing information for research purposes;

3. Have written agreements with all parties to whomit releases confidential information (Business Asso-ciates) that satisfactorily document that theBusiness Associate will appropriately safeguard theprotected health information.

Because it is possible that sponsors or IRBs may receiveprotected health information, it is likely that clinical investi-gators could require them to sign a Business Associate agree-ment. If the investigator learns that a Business Associate fails



to comply with the written agreement, the investigator musttake reasonable steps to cure the breach or end the violation.If such steps are unsuccessful, the clinical investigator mustterminate the Business Associate contract or, if termination isnot viable, report the problem to the HHS (18).

9. INTERNATIONAL GOOD CLINICALPRACTICE

Going back a number of years, FDA had as a policy that allclinical investigations that were submitted in an NDA neededto be conducted on patients in the United States. Foreign datafrom sites outside of the United States were not consideredacceptable. The concern was that patient populations weredifferent, and that use of the drug could be different, and dietand other environmental factors were such that informationobtained on subjects outside of the United States might notbe valid for the U.S. population. Such an approach to clinicalresearch has been set aside, and clinical data from all over theworld are now used to obtain approval of drugs in the UnitedStates. While the data may come from Europe, Russia, China,South America, and Africa, the standards used in obtaining thedata are the same as to the need for a protocol, informed con-sent, and proper record-keeping. Much of the internationalagreement on standards is the result of most of the countriesin the world establishing policies that are consistent withthe clinical standards recognized in the United States. Whileit is clearly possible to conduct a study almost anywhere in theworld and submit the data for approval to the U.S. FDA basedon agreements with the clinical sites in the countries in whichthe studies are being performed, many countries are lookingto the establishment of international standards.

The leading body in creating international clinicalstandards is the International Conference on Harmonization(ICH). ICH was organized in April 1990 and has as its soleand primary purpose the creation of international standardsfor the purpose of pharmaceutical research. The main bodies



participating in the creation of ICH standards are the UnitedStates, the European Union, and Japan. In addition to thesecountries and their government delegates, ICH is heavilysupported by the pharmaceutical industry [in particularthe Pharmaceutical Research and Manufacturers of America(PhRMA)] in the United States, the European Federationof Pharmaceutical Industries and Associations (EFPIA) inEurope, and the Japan Pharmaceutical Manufacturers Asso-ciation (JPMA) in Japan. Further, the World Health Organiza-tion (WHO), the European Free Trade Area (EFTA), andCanada hold observer status in the ICH. The creation of ICHis a recognition of the fact that the pharmaceutical industryis an international business and that diseases and conditionsbeing treated in the United States are not significantly differ-ent from those being treated in other parts of the world.Though clear differences in disease patterns exist (i.e., thereare few tropical diseases in the United States), given themodern scale of human interaction through travel and com-merce, the need for and use of pharmaceuticals is recognizablyglobal. There is no practical reason to do the same clinicalstudy on a Japanese population, a European population, anda U.S. population. If there are adequate clinical data to showthat the drug works in the patient population for whom thedrug can be prescribed, the quickest and most expeditious wayof conducting the research will benefit the pharmaceuticalindustry, the governments, and the populations that theyserve.

While only a small part of this chapter is devoted to inter-national clinical research issues, the reader should understandthat there has been an increasing demand for internationalharmonization of clinical research and drug developmentpractices. Already, FDA has adopted a number of the ICHGuidelines as FDA Guidance documents, including the ICHGuideline for Good Clinical Practice. Thus, although we expectthat FDA will maintain its deep involvement in the develop-ment of new international standards, we also expect thatthe future of clinical research will be largely driven by inter-national standards and expectations, as opposed to nationalstandards alone.



REFERENCES

1. There is a group of drugs that, in FDA’s view, do not qualify asGRASE, but which continue to be marketed in the absenceof an NDA or an ANDA as a result of an FDA enforcementdiscretion policy. Compliance Policy Guide 7132c.02. Thesedrugs are part of FDA’s Drug Efficacy StudyImplementation (DESI) and its Prescription Drug Wrap-up(DESI II) programs, and FDA will take appropriate action inconnection with these products as it determines their status.

2. Federal Food, Drug, and Cosmetic Act (FFDCA) xx505(a) and505(i), 21 U.S.C. x355 (2000). FDA, by regulation, has waivedthe requirement to submit an IND application for certainbioequivalence studies. 21 C.F.R. x320.32.

3. FFDCA x505(i), 21 U.S.C. x355 (2000).

4. Investigational New Drug Application, 21 C.F.R. part 312(2002).

5. 21 C.F.R. x312.52 (2002).

6. 21 C.F.R. xx312.57 and 312.62 (2002).

7.(last modified March 8,

2001).

8. Institutional Review Boards, 21 C.F.R. part 56 (2002).

9. FFDCA xx505(i) and 505(j), 21 U.S.C. x355 (2000).

10. Bioresearch Monitoring (BIMO) Compliance ProgramGuidance Manual available at

11.

12. FFDCA x307, 21 U.S.C. x335b (2000).

13. 21 C.F.R. x312.70 (2002).

14. National Institutes of Health, NIH Guidelines for ResearchInvolving Recombinant DNA Molecules, available at



FDA Policy on Retention Samples, available at http://www.fda.gov/cder/ogd/retention_samples.htm

default.htm#bimo (last updated April 26, 2002).http://www.fda.gov/ora/cpgm/

FFDCA x306, 21 U.S.C. x335a (2000).

http://www4.od.nih.gov/oba/rac/guidelines_02/NIH_Gdlnes_lnk_2002z.pdf (updated April 2002).

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www4.od.nih.gov

http://www4.od.nih.gov

15. Health Insurance Portability and Accountability Act of 1996,Pub. L. No. 104–191, 110 Stat. 1936 (1996).

16. 45 C.F.R. x164.501 (2002).

17. 45 C.F.R. parts 160, 164 (2002).

18. 45 C.F.R. x164.504(e)(1) (2002).



11

Active Pharmaceutical Ingredients

MAX S. LAZAR

FDA Regulatory Compliance Consulting

Surprise, Arizona, U.S.A.

1. INTRODUCTION

Active pharmaceutical ingredients (APIs), which have beenrefered to under a number of different names over the years,play a critical role in the review and approval process usedaround the world for pharmaceutical dosage (galenic) forms.APIs have been called bulk actives, bulk pharmaceuticalchemicals, and even bulk chemicals.

No matter what they are called, these materials are criti-cal to the drug approval process in all regions of the world.Since APIs are the compounds that actually provide the activ-ity and effectiveness of all drugs, they are subject to a signifi-cant amount of review during the filing and approval processes.

377


In addition, unlike inactive ingredients, APIs are subjectedto ongoing Good Manufacturing Practice (GMP) examinationsand inspections during a drug product’s life cycle.

To simplify the discussion in this chapter, we will focus onterms and approaches that are common in the United States.Where appropriate, other terms or practices may be identifiedto help understand how API practices used by other countriesor regions may differ from that of the United States.

2. APIs IN THE UNITED STATES

While there are no specific regulations that apply exclusivelyto APIs in the United States, API manufacturing sites havebeen expected to meet the spirit or intent of the Drug GMP(21 CFR Part 211). FDA authority over APIs comes directlyfrom the U.S. Food, Drug and Cosmetic (FD&C) Act, and regu-lators always cite the FD&C Act during inspections.

In November 2000, the International Conference on Har-monization issued Q7A, which is a guidance addressing APIGMP. FDA as one of the members of ICH has now adoptedthese GMPs as official guidance for the United States. There-fore, FDA is now expecting to observe compliance with Q7Aduring any inspections of API facilities.

FDA has for many years reviewed API manufacturingand control issues during the review process. Specific APIfiling issues were identified in the 1987 guidance issued byFDA. The agency has continued to refine its expectations andis working on new guidances on this subject, including ICHguidance on the Common Technical Document (CTD).

3. APIs IN OTHER PARTS OF THE WORLD

Other countries and regions of the world have either developedtheir own review processes or adopted systems similar to thatof the United States. Although terms may differ, the basicsremain very similar.

378 Lazar


No matter what specific system has been established inany one country or region, the information normally containedin a DMF, NDA, or ANDA (see below) is usually expectedfor regulatory submissions around the world. Whether priorapprovals or actual reviews take place is dependent on eachindividual country or region. In some cases, the approval ofone country or the API’s presence in a compendium isenough to permit regulatory approval in a country.

4. REGULATORY ISSUES

4.1. Filings

Numerous regulatory and pseudo-regulatory issues impactAPI and, more importantly, impact the drug developmentand approval process. Among the various issues are that regu-latory filings can have a long-term impact upon firms becauseof the inspectional reviews that take place at the manufactur-ing sites producing APIs. All drug filings include API informa-tion. This information is usually included in documents thatare referred to under different names. These can include:

Drug Master Files (DMF)New Drug Applications (NDA)Abbreviated New Drug Applications (ANDA)New Animal Drug Applications (NADA)Dossiers

4.2. Compendia

In addition to government-required filings, API standards ofquality are frequently included in publications called Compen-dia. In the United States the U.S. Pharmacopoeia (USP), inEurope the European Pharmacopoeia (EP), and in Japan theJapanese Pharmacopoeia (JP) all publish drug product andAPI standards of quality. Other pharmacopoeias are publishedby countries around the world. What is important for industryis that doing business in countries with a pharmacopoeiausually means that their products must comply with that

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country’s compendia in addition to other requirements. Meet-ing the requirements of the different regulatory authorities hasbeen one of the greatest challenges facing API developers andmanufacturers.

4.3. GMP

While there are no regulations covering GMP for APIs in theUnited States, FDA does expect GMP compliance with Q7A.This expectation will become more apparent as investigatorsare trained in the guidance and FDA issues more FDA-483 andWarning Letters to API producers.

The majority of API producers for the U.S. market arefrom countries outside of the United States (1). Many APImanufacturers are in Europe, where there has been an antici-pation of a United States–European Union Mutual RecognitionAgreement (MRA). While work continues on this MRA, itsactual implementation appears in doubt. If in fact an MRA doesnot become a reality, Europe will continue to see FDA inves-tigators using Q7A as a GMP expectation.

FDA has influenced European and world GMP standardsover the years. Its investigators’ positions and expectations willcontinue to impact world behavior in API GMP.

Although the Pharmaceutical Inspection Convention (PIC)and the World Health Organization (WHO) continue to haveGood Manufacturing Practice documents, the expectationsestablished by Q7A will become the primary driver for APIGMP. It is important that the expectations established bythe ICH Expert Work Group that developed the API GMP beremembered and understood. Without that understanding,actual GMP can vary significantly due to misinterpretation byindividual investigators from different countries. What is alsocritical is that expectations normally appropriate for drug prod-ucts not be misapplied to APIs. All parties must rememberthat unlike dosage forms, API manufacturing usually includespurification steps that can allow for flexibility that is notpossible for dosage form manufacturing.

API manufacturers will need to be flexible in thereview processes that will be applied to them by regulators

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and customers. Provision of data that can support processesand controls will be expected. These data would normally beexamined during both filing and inspectional reviews.

5. APIs AND DRUG MASTER FILES ORNEW DRUG APPLICATIONS

In the last 50 years, the majority of APIs have moved frombeing manufactured by the original developing companies tobeing outsourced from third-party manufacturers from aroundthe world. According to FDA, the vast majority of APIs comefrom manufacturing sites outside of the United States. Withthe major growth of the generic industry, sources of APIs haveshifted from innovator firms to new third-party manufacturersand developers.

API materials that are the active for new drugs arecovered by NDA documentation. Details of requirementsare aptly covered by numerous FDA guidances, including theFebruary 1987 ‘‘Guideline for Submitting Supporting Docu-mentation in Drug Applications for the Manufacture of DrugSubstances’’ (2).

Innovator companies would use their IND or NDA filingsto provide the expected details covering an API, while allothers would establish and submit a DMF with the FDA orother appropriate country authority, such as EMEA in Europe.DMFs have no legal or regulatory basis in the United States;however, they do provide companies a relatively easy andconfidential way to provide confidential information about aprocess without making it available to other commercial com-panies. The DMF should contain all of the detailed informationexpected by the regulatory authorities so that a DMF referencein an NDA or ANDA can be used to complete an agency reviewprocess (3–6).

In addition to physical characteristics of an API, whichcan affect the performance of a dosage form, regulators arealways concerned with potential impurities and impurity pro-files associated with an API and its mode of manufacturing.



Since this issue can significantly impact the review andapproval process of a drug, it is strongly suggested that filerscomply with agency guidance on this subject (7). FDA refersapplicants and submitters of a DMF to the ICH Q3A guidancefor an understanding of impurity issues (8).

DMFs are an essential element in the drug review andapproval process. What is important to understand is that eachregion of the world has a different approach to writing andfiling of a DMF. In the United States there is no approvalprocess for a DMF. In fact, DMFs are only examined whenreferenced in other regulatory filings, such as an NDA orANDA; only then is the content of a DMF reviewed. Ifrequested by FDA headquarters, an FDA inspection may takeplace at an API manufacturing site after a review of the DMF.

Similar practices may or may not exist in other regions ofthe world. For example, it is only in the last 10 years that anysignificant API inspection activities took place in Europe byregulatory agencies other than the FDA. While certain coun-tries around the world may be exceptions, the U.S. FDA hasbeen the most assertive in performing such inspections as partof the approval process for drug products.

Firms that reference a DMF should be sure that the com-pany and the manufacturing site being used as a supply havean approved FDA GMP review. If not, the DMF holder is likelyto be inspected by FDA prior to an approval of any application.DMF and application holders need to be sure they understandand comply with FDA expectations before initiating anychanges to their suppliers or processes used to make APIs (9).

Another area for careful focus includes changes to exist-ing, already approved API processes. For a number of years,FDA has been working on establishing guidelines that moreclearly identify what changes can and cannot be initiated bya manufacturer without prior approval from FDA. Althoughindustry has pressed for definitions, which would includechanges up to the final API, FDA has only been willing toestablish a guidance that discusses intermediates in drug sub-stances (10). This guidance has been referred to as BACPAC I.It can also be used by DMF holders for guidance on the subjectof postapproval changes.

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While API producers tend to experience less frequentinspections of their facilities than drug product manufacturers,some of the more significant violations occur when it is deter-mined that a DMF holder is violating its submission. Theseviolations include having modified operations without priornotification or approval as expected by FDA. Such actions bythe API producer can have significant negative impact on thedrug product NDA or ANDA holder. Serious deviations caneven result in the FDA expecting the company to conduct amajor recall. For this reason, care must be exercised to assurecompliance with change control and filing requirements. If not,significant liability exposure could surface.

6. THE DMF

Since the DMF plays such an important role in the APIapproval process, we need to examine it more closely. A DrugMaster File is a submission to FDA of information concerningthe chemistry, manufacturing, and controls (CMC) of a drugproduct or a component of a drug product to permit the FDA toreview this information in support of a third party’s submis-sion (11). While there were originally five types of DMFs, cur-rently only four are active. FDA no longer requests a Type IDMF (which provided plant information) since investigators inthe field easily obtain all appropriate facility information.

We will focus here on the Type II DMF that covers APIand CMC issues. According to FDA (11), of the more than 6000active DMF, almost 4000 are Type II. What is important tounderstand is that there is no requirement in the UnitedStates for submitting a DMF to FDA. Such submissions arecommonly done to permit review of third-party informationduring an NDA or ANDA examination. It is the simplest wayto provide this information in a confidential way to regulatorsin the United States.

Submission of a DMF does not mean FDA will ever reviewit. Such a review usually only occurs when it is referenced inother applications for drug approval. Many over-the-counter(OTC) products are not reviewed, and therefore the API



referenced in a DMF may never be examined under normalcircumstances.

Applicants filing an NDA or ANDA will usually reference aDMF as the authorized party if they themselves do not producethe API. The company that submits the DMF usually is theproducer of the API and may or may not have a local agentto represent them in the United States. Since API manufac-turers may be producing APIs for several users, the DMF pro-vides a way for multiple applicants to reference the same DMFwhile keeping proprietary information confidential. (For theconvenience of the reader, the references included at the endof this chapter can be used to obtain detailed filing information.)

The DMF should contain a cover letter and the expectedadministrative and technical information. Two copies shouldbe submitted to the DMF staff at FDA. Be sure to include aclear statement of commitment as discussed in the referencedguidances. Absence of such a statement will delay accept-ance by FDA. Once accepted, the DMF is entered into theagency database and the holder or its agent should receive anacknowledgment letter.

The acknowledgment letter will provide the assignednumber and will remind the holder to:

� Submit changes as amendments� Notify FDA of changes in (a) holder name/address or

(b) agent� Submit letter of authorization for each customer

authorized� Submit an annual report

Review of the DMF will only occur once it is referencedin an official application that contains the letter of authoriza-tion from the DMF holder. Reviewing chemists must requestthe DMF from the FDA central document room, whereasan NDA, ANDA, or IND goes directly to the reviewing staff.Any deficiency in a DMF that is found during a review initiatedby an application is communicated to the DMF holder.

An agent for a DMF is not a requirement, but is sug-gested since it can facilitate and improve communication withcompanies not located in the United States. It is important to

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understand that this agent is not the same as an agentrequired for drug registration and listing.

For postapproval changes, BACPAC guidances shouldbe followed as they are issued. Currently, BACPAC onlyexists for intermediates. Be sure to specify, where appropriate,the API starting material(s) as defined in ICH Q7A, since ithas significant future impact on GMP operations of an APIfacility. This does not mean that a company does not need toprovide chemistry information for materials in early stages ofmanufacturing. It just helps identify a GMP starting point inprocesses.

7. ADDITIONAL IMPACT ON APIs

Both the new Q7A API GMP and the work being conductedby ICH for the Common Technical Document will impact APIapprovals and filings around the world. API manufacturersand developers will need to prepare appropriate documentationof all development activities and decisions made during devel-opment while also preparing full documentation of the estab-lished manufacturing and control procedures established forthe filed processes.

All development activities and processes evaluated needto be documented in development reports. These reportsdocument the API starting materials as defined in the Q7AGuidance and define all critical controls, steps, and conditions.

All critical items defined in the development report playa significant role in the level of GMP applied by a firm to theirprocess. Companies must be sure to apply full GMP require-ments to all activities defined as critical. This is explicitlyexpected for compliance with API GMP. For this reason, caremust be taken when defining such critical steps, control, orconditions. The amount of extra documentation expected forsuch steps can be extensive. The more important issue is thatregulators will expect to see evidence of the extensive documen-tation during either preapproval or postapproval inspections.

Whether an API is manufactured under an NDA or a DMF,the level of documentation and control procedures should be



similar for critical items. From a regulatory perspective,governments are beginning to examine manufacturers ina similar manner no matter what type of API filing is made.Governments have become increasingly aware of the impor-tance of the API and its impact on dosage form effectivenessand characteristics.

8. WHAT DOES A FIRM NEED TO INCLUDE INAN API FILING?

Some of the most important information includes the following:

� Facility and process train description� Full description of the synthesis or process used show-

ing reactions and flow diagrams� All raw materials, solvents, catalysts� API starting materials as defined in Q7A� Critical steps, materials, control or operating condi-

tions� Impurity profile� Reprocessing steps� Description of special rework procedure (if it exists)

and conditions in which it is to be used� Key specifications for all materials� Quality of water to be used for processing and/or

cleaning� Supplier information where appropriate or required� Sample batch record

9. OTHER ISSUES FOR API PRODUCERS

Like APIs, nonactive ingredients are also part of most dosageforms. While this is not an issue for the API producer, dosageform manufacturers need to determine whether suppliers ofnonactive ingredients are supplying reliable materials.

Pharmaceutical firms need to establish appropriate qual-ity programs to review and, where appropriate, audit not only

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APIs, but also non-API materials. For the API producer, Q7Aestablishes expectations for the quality unit’s responsibility.

It is expected that API manufacturers have both internaland external auditing programs. Specifically who must conductsuch audits can be established by an individual firm, but thereview and approval of the firm’s independent quality unit isalways required.

API manufacturing and development companies need tohave appropriate written procedures for the manufacturing,control, and distribution of the materials they produce anddistribute. This includes written recall procedures. Appropriatechange control and supplier procedures should be establishedin writing and approved by the company’s quality unit.

Agents and suppliers should understand their contractualresponsibilities and be in conformance with the requirementsof ICH Q7A for agents, etc. Manufacturers must know thesource of their materials, including the company and locationof the manufacturing sites.

Aside from prospective validation packages, firms shouldhave established written procedures for how to treat and pro-cess out-of-specification materials. Having such procedures willreduce regulatory conflict during preapproval and postapprovalinspections. Establishing a written procedure for the notifi-cation of customers using an API is extremely important andexpected under DMF guidances. Failure to provide propernotification or to restrict changes until approved by the drugproduct applicant could result in significant legal exposure.

10. HARMONIZATION

Harmonization activities have been underway for years primar-ily under the guidance of the ICH. Progress has been slowprimarily because each partner in the process has some uniqueinterests and expectations, making it difficult to arrive ata harmonized guidance. Even with this slow progress, it canbe expected that eventually there will be a uniform approach todrug filings. ICH Q7A stands as an example of why, when theneed for harmonization becomes strong enough, rapid progress



will occur. This same driver will eventually lead to worldwidefiling formats. It is, however, more doubtful that worldwideapprovals will happen given the nature of humankind.

On the compendia side of API standards, there exists agreater probability for eventual harmonization. Commercialinterests within any given compendia provide the primary con-straint in this arena. If economic drivers can be limited, thereis a high probability of harmonization within these API stan-dards. Agreement between scientific and regulatory functionsis not always easy to obtain. What one considers importantis not important to others. Of course, the reverse is also true.This is a primary reason why drugs are approved more quicklyin one region as opposed to another area of the world. Techni-cal expertise is similar. What is different is the cultural or localdriver in all systems.

11. REGULATORY UNIFORMITY

The most difficult issue, aside from technical developmentactivities that can affect API manufacturers and developers,is being able to address the different expectations and require-ments that are likely to exist between countries and regionsaround the world. Obtaining true harmonization with the drugregulatory system is indeed challenging and very difficult.Human differences, expectations, and cultural issues drivemost of the problems. Scientific and technical reviewers haveexpectations that are culturally and economically impacted bylocal conditions. These differences between people and culturesare very evident when a manufacturer experiences an on-siteinspection by foreign investigators. What is expected duringsuch inspections will usually vary significantly from inspec-tions conducted by local country inspectors. While MutualRecognition Agreements can prevent possible cultural pro-blems in the inspectional area, such MRAs need to exist inthe first place. Such an agreement currently does not existbetween the United States and Europe and Japan coveringAPI inspections. While MRAs exist between many countries,

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Table 1 Application of ICH Q7A API Manufacturing*

Type of manufacturing Application of ICH Q7A to (shown in bold type) steps used in this type of manufacturing

Chemicalmanufacturing

Production ofAPI startingmaterial

Introduction ofAPI startingmaterial intoprocess

Production ofintermediate(s)

Isolation andpurification

Physicalprocessingand packaging

APIs derived fromanimal sources

Collection of organ,fluid, or tissue

Cutting, mixing,and/or initialprocessing




APIs extractedfrom plantsources

Collection ofplants

Cutting and initialextraction(s)




Herbal extractsused as APIs

Collection ofplants

Cutting and initialextraction

Furtherextraction


APIs consisting ofcomminuted orpowdered herbs

Collection of plantsand/or cultiva-tion andharvesting

Cutting/comminuting


Biotechnology;fermentation/cell culture

Establishment ofmaster cell bankand workingcell bank

Maintenance ofworking cellbank

Cell cultureand/orfermentation



‘‘Classical’’fermentation toproduce an API

Establishment ofcell bank

Maintenance ofcell bank

Introduction ofcells intofermentation



*Application (as indicated by bold type) increases as one proceeds from left to right.

Active

Pharm

aceutical

Ingred

ients

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Source: Ref. 12.

these major players have yet to finalize any real agreement inthis area. Therefore, manufacturers can expect to be subjectedto the problems associated with multinational reviews andinspections until such agreements can be established in thefuture.

As ICH agreements increase in the areas covering filings,it will become easier for firms to standardize what they filewith regulators. ICH Q7A has helped level the field of expecta-

needs to be applied internationally.Similar help can be expected as the filing issues are stan-

dardized around the world. Then firms will only need toface the normal challenges presented by different individualsinterpreting requirements in their own unique way.

12. CONCLUSIONS

Active Pharmaceutical Ingredients are not only the heart andbrain of drug products, but are also crucial to the regulatoryfiling success of drug applications. This is true whether or notthe API is described in an NDA, ANDA, IND, or DMF.

While current U.S. practices do not require prospectivereviews and approvals of a DMF, the reliability and quality ofa DMF can have a significant impact on the approval and reg-ulatory conformance of drug products. The worldwide regula-tory climate is constantly changing, and companies need tobe prepared to satisfy government requirements if theywant to stay in business and meet the needs of their custo-mers. Following the procedures described in this chapter willhelp meet those requirements no matter how individualexpectations change in the future.

REFERENCES

1. Various FDA Presentation by Edwin Rivera, CDER, Office ofCompliance.

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tions for API GMP. Table 1 helps identify where API GMP


2. Guideline for Submitting Supporting Documentation inDrug Applications for the Manufacture of Drug Substances;February 1987; Food and Drug Administration, Center forDrug Evaluation and Research, Office of Drug Evaluation I(HFD-100).

3. EMEA Note for Guidance, European Drug Master FileProcedure for Active Ingredients (III/5370/93).

4. Guideline for Drug Master Files, September 1989;Food and Drug Administration, Center for Drug Evaluationand Research, Office of Drug Evaluation I (HFD-100).

5. Guidance for Industry, Drug Master Files for Bulk AntibioticDrug Substances, November 1999; U.S. Department of Healthand Human Services, Food and Drug Administration, Centerfor Drug Evaluation and Research (CDER).

6. Guidance for Industry, ANDAs: Impurities in Drug Sub-stances, November 1999; U.S. Department of Health andHuman Services, Food and Drug Administration, Center forDrug Evaluation and Research (CDER).

7. Guidance for Industry, NDAs: Impurities in New Drug Sub-stances, February 2000; U.S. Department of Health andHuman Services, Food and Drug Administration, Center forDrug Evaluation and Research (CDER).

8. Guideline for Industry, Impurities in New Drug Substances,January 1996; U.S. Department of Health and Human Ser-vices, Food and Drug Administration, Center for DrugEvaluation and Research (CDER). Reprint of ICH Q3AStep 4 Document approved by ICH Steering Committee March1995.

9. Guidance for Industry, Changes to an Approved NDAor ANDA, Questions and Answers, January 2001; U.S. Depart-ment of Health and Human Services, Food and DrugAdministration, Center for Drug Evaluation and Research(CDER).

10. Guidance for Industry, BACPAC I: Intermediates in DrugSubstance Synthesis, Bulk Actives Postapproval Changes:Chemistry, Manufacturing, and Controls Documentation,February 2001; U.S. Department of Health and HumanServices, Food and Drug Administration, Center for Drug



Evaluation and Research (CDER), Center for VeterinaryMedicine (CVM).

11. DMF Workshop, Arthur Shaw of FDA, March 25, 2002.

12. International Conference on Harmonization, Guidance forIndustry, Q7A Good Manufacturing Practice Guidance forActive Pharmaceutical Ingredients, November 2000.

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12

Obtaining Approval of New DrugApplications and AbbreviatedNew Drug Applications froma Chemistry, Manufacturing,

and Controls Perspective

DHIREN N. SHAH

Aventis Pharmaceuticals

Kansas City, Missouri, U.S.A.

1. INTRODUCTION

Chemistry, Manufacturing, and Controls (CMC) is a relativelysmall section (approximately 15–20%) of a typical New DrugApplication (NDA), but it often becomes a reason for delay inthe approval of NDA/Biologics Licensing Applications (BLAs).For Abbreviated New Drug Applications (ANDAs), however,

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the CMC section is significant (around 80–90%). This sectionalso becomes quite important in the postapproval life-cyclemanagement of the products. It should be noted that theCMC section is made up of three distinctly different but over-lapping disciplines/sciences: synthetic/fermentation chemistry,analytical chemistry, and formulation chemistry. Also, the CMCsection continuously changes with clinical phases. Typicallyduring clinical phase 1 trials, the CMC section is quite smalland contains laboratory-scale manufacturing experience forthe drug substance and the drug products with quite simpleanalytical methodologies. During clinical phase 2 trials, theCMC section evolves to pilot-scale manufacturing of the drugsubstance and the drug products, and the specifications andanalytical methodologies become more sophisticated. End ofphase 2 (EOP2) usually becomes a pivotal point in the drugdevelopment since at this point decisions and major commit-ments are made to as to whether to go forward with the phase 3clinical development and marketing authorization applica-tion (NDA/BLA). EOP2 means for the CMC section a majorshift in planning and execution. The drug substance anddrug product manufacture typically need to be moved to com-mercial site at a commercial scale, and the specifications andthe analytical methodologies need to be upgraded and finalized.So, one can see that the CMC section is a ‘‘moving target.’’After the completion of clinical phase 3 studies, an NDA/BLA issubmitted to the U.S. Food and Drug Administration (FDA) forreview and approval. The CMC section of an NDA/BLA shouldcontain all the relevant developmental information that bridgesphase 1 through 3 leading up to the NDA/BLA submission.

This chapter will systematically analyze and describe theFDA organization, its various regulations and guidances,the industry process by which CMC information is generatedand submitted, and various ways to compress timelines andsecure timely approvals of NDA/BLAs and ANDAs. As thischapter is being written, it is expected that the CMC reviewand approval process for new chemical entities and possiblybiotechnologically produced drugs and generic drugs at theFDA may undergo a paradigm change. However, the basicprinciples behind obtaining approval of NDAs/BLAs/ANDAs

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in a timely manner remain the same. It is anticipated thatICH Q8 (Development Pharmaceutics) and ICH Q9 (RiskAssessments) will reflect the paradigm shift at the agency.

2. CURRENT U.S. FDA ORGANIZATION

The U.S. Food and Drug Administration is one of the mostimportant customers for pharmaceutical companies. In orderto understand the review and approval process for the CMCsection of NDAs and ANDAs, one should be familiar with theregulatory authority and the process in the United States.The U.S. FDA is an agency within the Department of Healthand Human Services, and it regulates biologics, drugs, food,devices, and veterinary products. It is made up of eight cen-ters/offices. The biologics such as vaccines and blood productsare regulated by the Center for Biologics Evaluation andResearch (CBER). The Center for Drug Evaluation andResearch (CDER), which is the largest of the five centers inthe FDA, regulates drugs that include NDAs and ANDAs. Thedevices are regulated by the Center for Device and RadiologicalHealth (CDRH). Animal products are regulated by the Centerfor Veterinary Medicines (CVM). The Center for Food Safetyand Applied Nutrition (CFSAN) regulates foods and nutritionalproducts. The National Center for Toxicological Research(NCTR) regulates all types of toxicological research. The Officeof the Commissioner (OC) and the Office of Regulatory Affairs(ORA) provide administrative and management support.

The CDER organization consists of therapeutic area–based review divisions. Each review division has the primaryresponsibility of reviewing submissions and provides an actionthat could involve approval, approvable, nonapproval, requestfor more information, etc. The review divisions are staffedby the division director, medical reviewers, pharmacologists,chemists, bio-statisticians, bio-pharm reviewers, project man-ager staff, etc. The chemistry and bio-pharm reviewers reportto the Office of Pharmaceutical Sciences (OPS). The Office ofGeneric Drugs (OGD) also reports to OPS. The OGD has two

Obtaining Approval of a New Drug 395


divisions of chemistry, each made up of five teams. This divisionof OGD is based on major therapeutic classes. As this chapter isbeing written, by the middle of 2005 the chemists from reviewdivisions will be combined into one new drug chemistry groupunder the Office of New Drug Chemistry. The objective behindthis change is consistency in reviews and better time manage-ment. This step is a predecessor to other CMC review andapproval practices changes being planned at the agency.

Various regulations as published in the 21 Code of FederalRegulations (CFR), guidances and points to consider (PTC)published by FDA, the Manual of Practices and Procedures(MaPP) published by FDA, and guidelines published by theInternational Committee on Harmonization (ICH) are impor-tant documents that become the foundation of scientificallyand regulatorily sound CMC submission documents.

3. FDA AND ICH CMC/QUALITYREGULATIONS AND GUIDANCES

FDA regulates new drugs as well as generic drugs under theFederal Food, Drug, and Cosmetic Act enacted by the U.S.Congress. The law, among other things, ensures that drugsand devices are safe and effective for their intended uses andall labeling used is truthful, accurate, informative, and notdeceptive. Chapter five and specifically subchapter A of the Actprovides for Drugs and Devices. The interpretation of the Actis provided in the Code of Federal Regulations (CFR), which ispublished annually. There are 50 titles/sections in CFR, andtitle 21 specifically provides interpretation of the Federal Food,Drug, and Cosmetic Act. Typically the regulations are brief andoften difficult to fully interpret for actual implementation. FDAissues guidances and PTCs, which provide further interpreta-tion of the regulations. FDA also publishes MaPPs, whichare approved detailed instructions to FDA reviewers in orderto standardize reviews of submissions.

The reader is encouraged to make use of all FDA guid-ances and manuals. If properly used, they will ensure the

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quality of CMC submission, which should result in approvalby FDA.

4. FDA’S QUALITY BY DESIGN (QbD) ANDPAT INITIATIVE AS PART OF CENTURYGOOD MANUFACTURING PRACTICES

FDA, in its latest initiative for the Twenty-First Century GoodManufacturing Practices has, among other things, two initia-tives named Quality-by-Design (QbD) and Process AnalyticalTechnologies (PAT). PAT should not be considered as ‘‘infinitetesting,’’ but it is a part of the QbD. Both of these initiativesgo to the basics of product development, whether it is for a newdrug or a generic product. By employing basic principles ofscience-based drug substance and drug product development,one can achieve QbD. The whole idea behind QbD and PAT isto build quality into the drug product from the very beginningof the manufacturing process so that testing for quality at theend may not be that critical. For example, a thorough physical,chemical, and biological (as necessary) understanding of all thecomponents of the dosage form and a complete analysis andknowledge of all the critical manufacturing processes shouldresult in a product in which the quality is built in and theremay be limited need for final testing for quality. Properly selec-ted in-process testing and controls should provide the basis forQbD. Process analytical technologies embrace the principlesof QbD and include at-line, on-line, off-line, and in-line testingof in-process materials at critical stages of manufacturing. PATprovides for continuous manufacturing and real-time releaseof the product and the possibility of replacing the conventionalvalidation batches. The reader is encouraged to read and followFDA’s draft guidance on PAT. One of the ways to success-fully obtain approval of NDAs is to ‘‘retro-engineer’’ the drugsubstance and drug product. Once the sponsor identifiesthe final characteristics of the drug product to be marketed(dose, dosage type, shape, color, marking, packaging, etc.),a development and regulatory plan should be generated that



will determine what kind of CMC information needs to begenerated—and when—to secure an approval by the agency.Figure 1 summarizes the QbD and PAT intiatives. Aspects ofQbD and PAT will be discussed later in this chapter.

5. SPONSOR COMPANY AND AGENCYPROCESSES TO SUCCESSFULLY DEVELOPTHE CMC SECTION OF NDAs ANDANDAs BASED ON QbD AND ICH/FDAREGULATIONS

The activities at the sponsor company in regards to CMC devel-opment from pre-IND through various phases of INDs leadingup to the NDA and, in the case of generic drugs, the processleading up to ANDA determine one’s success or failure. Theproduct one delivers to FDA is the CMC submission, andits scientific quality determines its successful approval by theagency.

Figure 1 Quality-by-Design and Process Analytical Technologiesinitiatives.

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5.1. Pre-IND Phase

In this very early phase of drug development some basic workis performed. Preliminary solubility in various solvents, stabil-ity, and other important structural elucidations and charac-terizations are typically determined, which become the basisfor future development of the new molecular entity. Of course,limited work is done at this stage, since the failure rate for newmolecular entities (NMEs) is quite high. The CMC informationfrom this stage typically becomes the basis for developmentpharmaceutics, and as the drug development progresses,additional tests and information are carried out.

5.2. IND Phase 1

This phase is still an early phase of product development anda limited and necessary effort is typically made. Since CMC isa multi-functional section, it will be highly beneficial to puttogether multi-functional teams consisting of scientists fromdrug substance synthesis, formulation, analytical, regulatory,writing group, etc. This team of people becomes responsibleand accountable for putting together the CMC section of theIND and following the new drug’s progress through phases 2and 3 and making sure an NDA is filed on a quality submission.In some instances, a sponsor may want to request a pre-IND meeting, which could be in the form of a teleconference,with the agency to seek advice and/or clarification. The agencyrequires that a briefing document be submitted by the spon-sor at least 4–6 weeks prior to the meeting. The briefingdocument should contain relevant information on the drugsubstance and drug product and concise questions about whichthe sponsor seeks advice from the agency. FDA requires limitedCMC information in a phase 1 IND. The main emphasis is onthe safety of the volunteers and patients, and hence the spon-sor is required to make a connection between preclinical mate-rial and the proposed clinical material from impurity andbioavailability points of view. (It is conceivable that the mate-rial used in the preclinical safety studies was not as bioavail-able as the clinical material posing a safety risk to thepatients.) Also, if the clinical material has any impurity with



safety implications, the agency will want to know more aboutit. At the time of submitting an original IND, very limited stabil-ity information is required. A commitment to generate con-current stability data during the course of a clinical trial andreporting the data in most cases should suffice. It is the spon-sor’s responsibility to make sure that the NME is stable in thedosage form when given to patients. During this early phaseof clinical development, the analytical methods should be capa-ble of determining the assay, impurities, etc., with specifi-city, accuracy, and precision. A formal validation of methodstypically is not required at this early stage of development.Of course, as the drug development progresses, the analyticalmethods should be progressively validated so that they ensurestrength, identity, purity, potency, and quality (SIPPQ) of theproduct. The sponsor must wait for a period of 30 days beforeinitiating studies on human volunteers and patients. Duringthis period the agency determines whether the sponsor couldproceed with proposed studies, and if it has any objection it willinstruct the sponsor not to initiate the study (known as clinicalhold) until the deficiencies are satisfactorily addressed. Theagency has issued a guidance as to the format and the contentof the CMC section of IND, and the reader is encouraged toread and apply it to fullest extent as possible.

5.3. IND Phases 2 and 3

IND phases 2 and 3 are pivotal and become the basis forsuccessfully obtaining approval of NDAs, because under thesephases critical CMC information that supports SIPPQ is gen-erated, drug substance and drug product manufacturing areoptimized, bioavailability of the drug product is established,and primary stability data for the drug substance and the drugproduct are generated. The multifunctional team plays a criti-cal role in advancing the NME through phases 2 and 3 leadingup to NDA submission. Based on input from the clinical stud-ies through phase 2, the safe and effective dose of the drug ischosen and various QbD parameters for the drug substanceand drug product are introduced in the product development.The agency requires that during phases 2 and 3 the sponsor

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inform the agency of any new patient safety–related informa-tion in the form of IND amendments. These amendments tothe IND typically do not require a waiting period; however, ifthe new information is significantly different from the originaland if it affects the safety of the patients in the clinical trials,then the agency may advise the sponsor not to implementthe change. The usual changes to the CMC, such as optimiza-tion to synthesis/manufacture of the drug substance, analyticalmethods, the drug product, new stability data, etc., could besubmitted in IND annual reports to the agency. The sponsorcould take advantage of the IND amendments to update theagency on the progress in the CMC and identification of criti-cal issues and proposed/planned solutions to the issues. Duringphase 2, typically the drug substance and the drug product areproduced in a large laboratory to pilot scale. At this phase, thedrug substance synthesis/manufacturing, drug product formu-lation/process, analytical test methods, etc. are fine-tunedand the principles of QbD and PAT may be introduced andimplemented. The end of phase 2 or the beginning of phase 3becomes a pivotal point in the overall drug developmentprocess. At this point the NME has shown a certain thresholdfor safety and desired efficacy and the drug development picksup the speed with which confirmation of clinical results fromphases 1 and 2 are reached in a larger patient populationin phase 3. The CMC has to match the increased clinicalactivity of phase 3 by gearing up all three disciplines: drugsubstance synthesis and manufacturing, drug product formula-tion and manufacturing, and analytical testing. Typicallyphase 3 clinical trials are conducted on many hundreds tothousands of patients, leading to marketing application. Inthis phase the CMC section has to match the expanded clinicaltrials leading towards commercial distribution. In phase 3, theCMC section should focus on two important aspects of devel-opment: combining information and data from all three phasesand bridging those with the future commercial product. FDAhas issued a guidance for CMC information requirements forphases 2 and 3. The bridging study will be discussed in thenext section.



5.4. Successful Bridging of Pre-IND, Phase 1,Phase 2, and Phase 3 with Commercial Product

One of the secrets of obtaining approval of NDAs and BLAsfrom a CMC perspective is successfully bridging the CMC infor-mation and data from preclinical through the three phases ofIND and the commercial product. Bridging of critical informa-tion on strength, identity, purity, potency, and quality startingfrom the preclinical phase leading up to commercial product isof utmost importance. Some important characteristics of thedrug substance and the drug product are as follows:

Drug substance

Structural elucidationImpurity/Related substances

SolubilityCritical relevant characteristicsCritical manufacturing informationStability (RT and accelerated)

Drug productDescriptionDegradation productsDissolution

All relevant drug substance and drug product character-ization information from all phases of development should bebridged to come up with a complete picture of strengths andweaknesses of the drug substance and the drug product. Keycharacteristics such as impurity profile, solubility of thedrug substance, dissolution-friability balance (DFB) for SODF,accelerated/forced degradation to understand the mechanis-tic aspects of degradation, design of experiments, etc., shouldbe bridged to get a complete picture of the drug product.The aforementioned information on the drug substance andthe drug product from investigational phases is bridged tothe planned commercial drug product. All of this bridginginformation, along with design of experimental data in whichthe boundaries of success and failures of all critical param-eters (drug substance manufacturing processing parameters,formulation components, composition, processing equipment

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and parameters, in-process controls, specifications, etc.) aredetermined, become part of developmental pharmaceutics andshould be included in a New Drug Application. It should beemphasized that bridging in the form of evolution of analyticalprocedures starting from preclinical phase to phase 3 andcommercial product testing should be thoroughly discussed indevelopmental pharmaceutics.

5.5. Developmental Pharmaceutics andIts Importance to CMC

As discussed above, Design of Experiments, Quality-by-Design,Process Analytical Technologies, bridging of all the phases ofINDs, technology transfer, etc., become the basis for develop-mental pharmaceutics, which becomes the foundation of a goodCMC section of NDAs and ANDAs. It provides an overview ofthe thoughts and rationale behind the product development andcommercial product to the CMC reviewing staff at the agencyand becomes an important tool in the review and approvalprocess. The ICH CTD format also provides for a sectionfor Development Pharmaceutics. ICH Q8 is on developmentalpharmaceutics, and once this guidance (which is at early stagesof its development at this time) is finalized, it should provideappropriate guidance to the industry.

5.6. Technology Transfer to Manufacturing

It is obvious that at the end of phase 3 clinical trials, the mostcritical and important step is to make sure that the drugproduct is ‘‘manufacturable,’’ because without it the new drugcould not be commercialized. Over the past 30 years, majorpharmaceutical and generic companies have often failed toproduce commercial products immediately upon approval ofNDAs/ANDAs because companies failed to perform timelytechnology transfer. Technology transfer involves transferringof information and experience from lab and pilot scales toa commercial level for the drug substance, drug product, andassociated analytical testing procedures. All these become thebasis for seamless and sound manufacturing of the new drugon a commercial scale.



5.7. Quality-by-Design and Process AnalyticalTechnologies

As this chapter is being written, the Office of PharmaceuticalSciences (OPS) under CDER is in the process of redesigningand introducing a paradigm shift in the CMC reviews and com-pliance investigations. It is expected that by the end of 2005the Agency would have implemented the planned changes inCMC reviews and compliance investigations. The ICH throughinitiation of Q8 (Pharmaceutical Development) and Q9 (RiskAssessment) is also gearing up towards the same goal of OPS.Both ICH Q8 and Q9 will involve the concept of QbD. Quality-by-Design, which encompasses Process Analytical Technologiesand embraces building quality in the process and productthroughout the manufacturing process, may be summarizedas follows:

QbD ¼ Preprocess controls ðPPCsÞ

þ in-process controls ðIPCsÞ

þ Postprocess controls ðPOPCsÞ

PPCs: Preprocess controls (throughout the preclinical,the three phases of INDs, and for commercial produc-tion) such as thorough physical-chemical-biologicalcharacterization of the (a) drug substance and allits manufacturing/synthesis components and (b) exci-pients. The drug substance starting materials, itsother components (catalysts, solvents, etc.), key andpivotal intermediates, etc., should be thoroughlycharacterized. The pharmacopoeias provide fairlygood chemical characterization, but do not providethorough functional physical characterization, and it isup to the sponsor to develop that characterization. Thedrug substance physical and chemical characteriza-tion is of critical importance to successful Quality-by-Design. Some examples of PPCs are chemicalpurity of starting materials and intermediates, purifica-tion steps, drug substance particle size and specific

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surface area, density, excipient particle size and shape,density, etc.

IPCs: In-process controls is the heart of process analyt-ical technologies. IPCs such as assay, purity, residualsolvents, particle size, specific surface area, polymor-phism, etc., are critical in the manufacturing of drugsubstance. For drug products, in-process controlssuch as granulation endpoints, moisture level, contentuniformity, etc., are critical. Process analytical technol-ogies could involve off-line, at-line, in-line, on-linetesting of in-process parameters for drug substanceand drug product. Carefully and strategically chosenin-process controls, if done in-line or on-line, mayobviate final testing because of the large sample size.

PoPCs: Postprocess controls play an important role inQbD. Testing of final drug product per specifications,storage conditions, long-term and accelerated stabilitystudies are components of PoPCs.

5.8. Sponsor-FDA Meetings

FDA allows several kinds of meetings with sponsors in orderto assist and gather information. Meetings such as pre-INDtypically are clinical oriented. For CMC section, end-of phase 2and pre-NDA meetings are important for the CMC section ofNDAs and BLAs. (FDA has issued a guidance on sponsor-FDAmeetings.) The sponsor should submit a briefing document tothe agency at least 6 weeks prior to the requested meeting, andthe briefing document should contain relevant backgroundinformation and questions on which the sponsor is seekingadvice. The briefing document should not be voluminous. Itshould be a focused document that contains specific questions/issues. The sponsor can easily enhance its NDA/BLA/ANDAsubmissions by taking advantage of these meetings.

5.9. NDA Submissions

NDA submission on a new drug should follow the FDA andICH guidance. From a technical regulatory perspective, if all



the work is done properly as described in sections a through h,the NDA submission should become fairly easy and result inapproval in a timely manner. The submission should follow theFDA and ICH guidances, and moreover it should be reviewer-friendly. The data should be presented in a clear-cut manner.One should remember that the product that the FDA seesfrom an applicant is the NDA/ANDA submission. The chem-istry reviewers have a responsibility to make sure that theproduct they approve meets the regulatory requirements asprescribed in the Code of Federal Regulations. Submissionsto the FDA should be accurate and of high quality.

All submissions to the FDA must meet four importantcriteria in order to secure approval the first time: (a) Adher-ence to Regulations and Guidances—strict adherence to FDACMC regulations and guidances for format and content, whichinclude those ICH quality guidelines that have reached step 5.It is possible to adopt an approach other than that provided bythe FDA guidances; however, it is the applicant’s responsibilityto secure approval on the alternative approach from the FDAreviewing staff (for example, at EOP2 and/or Pre-NDA meet-ing). Careful and strategic implementation of guidance shouldbe received from the reviewing staff at the FDA; (b) Introduc-tion—submissions should have an introductory section thatclearly provides the purpose, scope, and context of the submis-sion that helps the reviewing team. This introduction shouldhave a clear delineation of any agreement made prior to thesubmission. The introductory section should provide a higherlevel overview of the submission, which will lead into the nextsection, where the nuts and bolts of the submission are pro-vided. This section should end with a summary of the submis-sion; (c) Body of the submission—this part of a submission isof utmost importance since it provides the main basis forapproval. The chemistry review staff has to provide a rationalefor their action (approval, nonapproval, approvable, etc.) anda good introduction and summary aids them in making theirdecision. The information provided in submissions must befocused, relevant, precise, accurate, complete, and of quality.When it comes to quality of the submission, one should adoptthe philosophy of ‘‘quality always.’’ In this main body of the

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submission, one should pay special attention not to provideredundant and unrelated information, because it takes awayfrom the reviewers’ attention and wastes their precious time.The submission should have a logical flow of informationand justified decisions based on scientific rationales. The logi-cal flow of information and justified decisions along with clearobjectives and findings that lead to clear conclusions provide acoherent submission. The main body of the submission shouldfollow the time-tested organizational characteristics of a soundbeginning, experimental details, organized results, discussionof results, and conclusions. Information should be providedwith an appropriate combination of text, figures, tables,etc., which will provide a clear picture of the submission. Theinformation should convey a clear message and conclusion andshould follow the usual standards of quality (free of typo-graphical and grammatical errors, clear legends, footnotes asnecessary for clarity, etc.); (d) A summary and conclusionsection should be provided, including any short- or long-termcommitments (such as placing batch(es) of drug product onlong-term stability and reporting the data to the agency at alater date, etc.).

5.10. ANDA (505b2) Submissions

The ANDA submission on a generic drug should follow the FDAguidance. FDA has provided a clear-cut format and contentguidance on the organization of an ANDA. Section VII of theguidance provides for detailed CMC requirements. The appli-cant should provide a statement on the components andcomposition of the product. This should be followed by infor-mation on raw materials (active ingredient and inactive ingre-dients), description of manufacturing facility, information onthe outside/contract firms, manufacturing process and packag-ing instructions, in-process information, packaging materialcontrols, controls for finished dosage form, analytical methodsfor the drug substance and drug product, stability of finisheddosage form, and availability of samples. If the generic productis a parenteral product, the applicant must provide steriliza-tion assurance information and data package. The above CMC



section is somewhat similar to the NDA requirements, and ifit follows the above recommendations, obtaining approval foran ANDA should be easy. The CMC section should be precededby information on the bioavailability/bioequivlaence of thedosage form in relation to the reference listed drug.

5.11. Quick and Complete Response (QCR)Team Approach to FDA Questions/Comments

Once an NDA or ANDA has been submitted by an applicantand filed (meaning accepted) by FDA, during and/or after thecompletion of the review, FDA might have questions/commentson the submission. The questions/comments may come verballyor in writing. In either case it is very important for the appli-cant to respond to the questions/comments in a timely,thorough, and accurate fashion. Often applicants form a team(such as QCR) that develops complete and timely responsesthat aide the agency’s review process. The QCR team, if prop-erly organized, could play an important role in obtaining theapproval of NDAs in a timely manner.

6. UNDERSTANDING THE CMC REVIEWPROCESS

The CMC review process at FDA is quite transparent. Theagency publishes its most current ONDC organization chartand several MaPPs. The primary CMC review chemistsreview the submissions and share their reviews with thechemistry team leaders. Based on their reviews, they mayissue information request letters. Alternatively, CMC reviewsare further reviewed by CMC division directors and then ulti-mately by the director of ONDC. Once the reviews are finalizedby the CMC reviewers and ONDC management, the reviewdivision director will issue appropriate letters (approval, non-approvals, approvable, etc.). The CMC reviewers issue a reviewreport, which includes their assessment and reasons for theirrecommendations. As stated earlier, the overall CMC reviewand approval processes may change in 2005 as a result of

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ICH Q8 and Q9. However, it should be remembered thatthe basics and fundamentals of CMC reviews (and complianceinspections) will focus on strength, identity, purity, potency, andquality, which are surrogates of safety and efficacy of drugs.The OGD follows a similar review process. Of course, forANDAs the final reviews stop at the OGD head level. The CMCreviewers have a legal responsibility to review and assess CMCsubmissions and to make sure that the submissions meet thelaw and regulations and the product meets the strength, iden-tity, purity, potency, and quality requirements. If for somereason a product is recalled because of SIPPQ, then the review-ing staff that approved the product is in part responsible. Thus,understanding the review process and the responsibility of thereviewing staff is important in obtaining approval of NDAs/BLAs.

As this chapter is being written, the Office of Pharmaceu-tical Sciences is planning for a paradigm change in the CMCreviews and compliance. The ICH through Q8 (PharmaceuticalDevelopment) and Q9 (Risk Assessment) is also gearing uptowards the same goal of OPS.

7. PROBLEMS AND CHALLENGES INVOLVEDIN SECURING TIMELY APPROVALS ANDPOTENTIAL SOLUTIONS

Most delayed approvals are due to poor science contained in thesubmission and poor submission strategy. The poor sciencemay be reflected in instability of the product or unacceptablelevels of impurities or poor product bioavailability as measuredby tablet dissolution, etc. A good product developmentplan based on the principles of QbD (see above) should resultin an approvable submission. Judicial use of contacts with theagency and maximizing various FDA-sponsor meetings shouldavoid delays in the approvals of applications. Agency reviewersare available to assist the industry as long as it is done ina professional manner. The Agency is pushing for science-based regulations and review practices. Applicants should take



advantage of this new paradigm to secure approvals in a timelymanner. As described in Sec. 5.9, the quality of submissionis critical in securing approval of applications in a timelymanner.

8. SUMMARY AND CONCLUSIONS

This chapter has offered some practical ways to develop ascience-based, regulatory-friendly application that should beapproved at first submission. By focusing on the fundamentalscientific principles and FDA and ICH guidances, it is quitefeasible to obtain approval of NDAs and ANDAs. In orderto obtain approval of NDAs/ANDAs in a timely manner, oneshould focus on four pillars: (a) development of CMC basedon QbD/PAT, (b) application of FDA and ICH CMC regulationsand guidances, (c) bridging of phases 1 through 3 to a success-ful NDA, and (d) preparing sound CMC scientific and regula-tory submissions.

REFERENCES

1. Federal Register, Vol. 69, No. 68, April 8, 2004, Code of FederalRegulations, Title 21, Part 314.70.

2. FDA, Center for Drug Evaluation and Research, ‘‘Changes to anApproved NDA or ANDA,’’ Guidance Document, (April 2004).

3. FDA, Center for Drug Evaluation and Research, ‘‘ImmediateRelease Solid Oral Dosage Forms: Scale-up And Post-ApprovalChanges: Chemistry, Manufacturing and Controls; In VitroDissolution Testing; In Vivo Bioequivalence Documentation,’’Guidance Document (November 1995).

4. FDA, Center for Drug Evaluation and Research, ‘‘SterilizationProcess Validation in Applications for Human and VeterinaryDrug Products,’’ Guidance Document, (November 1994).

5. FDA, Center for Drug Evaluation and Research, ‘‘SUPAC-IRQuestions and Answers,’’ Guidance Document, (February 1997).

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6. FDA, Center for Drug Evaluation and Research, ‘‘SUPAC-SS—Nonsterile Semisolid Dosage Forms; Scale-Up and Post-approval Changes: Chemistry, Manufacturing, and Controls;In Vitro Release Testing and In Vivo Bioequivalence Documen-tation,’’ Guidance Document, (June 1997).

7. FDA, Center for Drug Evaluation and Research, ‘‘DissolutionTesting of Immediate Release Solid Oral Dosage Forms,’’Guidance Document, (August 1997).

8. FDA, Center for Drug Evaluation and Research, ‘‘ExtendedRelease Oral Dosage Forms: Development, Evaluation, andApplication of In Vitro/In Vivo Correlations,’’ GuidanceDocument, (September 1997).

9. FDA, Center for Drug Evaluation and Research, ‘‘SUPAC-MR:Modified Release Solid Oral Dosage Forms: Scale-Up and Post-approval Changes: Chemistry, Manufacturing, and Controls,In Vitro Dissolution Testing, and In Vivo BioequivalenceDocumentation,’’ Guidance Document, (October 1997).

10. FDA, Center for Drug Evaluation and Research, ‘‘PAC-ALTS:Postapproval Changes-Analytical Testing Laboratory Sites,’’Guidance Document, (April 1998).

11. FDA, Center for Drug Evaluation and Research, ‘‘StabilityTesting of Drug Substances and Drug Products,’’ DraftGuidance Document, (June 1998).

12. FDA, Center for Drug Evaluation and Research, ‘‘MeteredDose Inhalers (MDI) and Dry Powder Inhalers (DPI) DrugProducts: Chemistry, Manufacturing, and Controls Documen-tation,’’ Draft Guidance Document, (November 1998).

13. FDA, Center for Drug Evaluation and Research, ‘‘SUPAC-SS:Nonsterile Semisolid Dosage Forms Manufacturing EquipmentAddendum,’’ Draft Guidance Document, (January 1999).

14. FDA, Center for Drug Evaluation and Research, ‘‘SUPAC IR/MR: Immediate Release and Modified Release Solid OralDosage Forms, Manufacturing Equipment Addendum,’’Guidance Document, (February 1999).

15. FDA, Center for Drug Evaluation and Research, ‘‘Bioavail-ability and Bioequivalence Studies for Nasal Aerosols andNasal Sprays for Local Action,’’ Draft Guidance Document,(June 1999).



16. FDA, Center for Drug Evaluation and Research, ‘‘ContainerClosure Systems for Packaging Human Drugs and Biologics,’’Guidance Document, (July 1999).

17. FDA, Center for Drug Evaluation and Research, ‘‘NDAs: Impu-rities in Drug Substances,’’ Guidance Document, (February2000).

18. FDA, Center for Drug Evaluation and Research, ‘‘AnalyticalProcedures and Methods Validation: Chemistry, Manufactur-ing, and Controls Documentation’’ Draft Guidance Document,(August 2000).

19. FDA, Center for Drug Evaluation and Research, ‘‘Waiver ofIn Vivo Bioavailability and Bioequivalence Studies for ImediateRelease Solid Oral Dosage Forms Based on a BiopharmaceuticsClassification System,’’ Guidance Document, (August 2000).

20. FDA, Center for Drug Evaluation and Research, ‘‘Changesto an Approved NDA or ANDA: Questions and Answers,’’Guidance Document, (January 2001).

21. FDA, Center for Drug Evaluation and Research, ‘‘BACPAC I:Intermediates in Drug Substance Synthesis: Bulk Actives Post-approval Changes: Chemistry, Manufacturing, and ControlsDocumentation,’’ Guidance Document, (February 2001).

22. FDA, Center for Drug Evaluation and Research, ‘‘StatisticalApproaches to Establishing Bioequivalence,’’ Guidance Docu-ment, (February 2001).

23. FDA, Center for Drug Evaluation and Research, ‘‘Nasal Sprayand Inhalation Solution, Suspension, and Spray Drug Prod-ucts—Chemistry, Manufacturing, and Controls Documenta-tion,’’ Guidance Document, (July 2002).

24. FDA, Center for Drug Evaluation and Research, ‘‘Compar-ability Protocols—Chemistry, Manufacturing, and ControlsInformation,’’ Guidance Document, (February 2003).

25. FDA, Center for Drug Evaluation and Research, ‘‘Bioavail-ability and Bioequivalence Studies for Orally AdministeredDrug Products—General Considerations,’’ Guidance Docu-ment, (March 2003).

26. FDA, Center for Drug Evaluation and Research, ‘‘Requests forExpedited Review of NDA Chemistry Supplements,’’ Manualof Policies and Procedures MAPP 5310.3 (June 1999).

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27. FDA, Center for Drug Evaluation and Research, ‘‘DrugShortage Management,’’ Manual of Policies and ProceduresMAPP 4730.1 (November 1995).

28. Code of Federal Regulations, Title 21, Part 314.81(2). Otherpostmarketing reports—Annual Reports.

29. Code of Federal Regulations, Title 21, Part 211.180. Currentgood manufacturing practice for finished pharmaceuticals—Records and Reports—General Requirements.

30. Code of Federal Regulations, Title 21, Part 211.100. Currentgood manufacturing practice for finished pharmaceuticals—Production and Process Controls—Written procedures,deviations.

31. Code of Federal Regulations, Title 21, Part 211.160(e). Currentgood manufacturing practice for finished pharmaceuticals—Laboratory Controls—General Requirements.

32. Code of Federal Regulations, Title 21, Part 314.3(b). GeneralProvisions—Definitions.

33. FDA, Center for Drug Evaluation and Research, ‘‘Format andContent for the CMC Section of an Annual Report,’’ GuidanceDocument, (September 1994).

34. FDA, Center for Drug Evaluation and Research and Center forBiologics Evaluation and Research, ‘‘Formal Meetings withSponsors and Applicants for PDUFA Products,’’ GuidanceDocument (February 2000).

35. Code of Federal Regulations, Title 21, Part 314.50(a)5. Contentand format of an application—ccApplication form.

36. Pharmaceutical Research and Manufacturers of America, 2002Industry Profile, PhRMA, Washington, DC, 2003.

37. J.A. DiMasi, R.W. Hansen, and H.G. Grabowski, ‘‘The Priceof Innovation: New Estimates of Drug Development Costs,’’Journal of Health Economics 22 (2003): 151–185.

38. H. Grabowski, J. Vernon, and J. DiMasi, ‘‘Returns on Researchand Development for 1990s New Drug Introductions,’’Pharmacoeconomics 20 (2002): suppl. 3, 11–29.

39. FDA, Center for Drug Evaluation and Research, ‘‘A Frame-work for Innovative Pharmaceutical Manufacturing andQuality Assurance,’’ Draft Guidance Document, (August 2003).



40. ‘‘GSK Announces FDA Approval of Their First PATSubmission,’’ AAPS News Magazine (April 2004): 10.

41. FDA, Center for Drug Evaluation and Research, ‘‘M2 eCTD:Electronic Common Technical Document Specifications,’’Guidance Document, (April 2003).

42. FDA, Center for Drug Evaluation and Research, ‘‘M4 Organi-zation of the CTD,’’ Guidance Document, (August 2001).

43. FDA, Center for Drug Evaluation and Research, ‘‘M4 The CTD- Quality,’’ Guidance Document, (August 2001).

44. FDA, Center for Drug Evaluation and Research, ‘‘ProvidingRegulatory Submissions in Electronic Format—NDAs,’’Guidance Document, (January 1999).

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13

Obtaining Approval of a Generic Drug

LOREN GELBER

Andrx Corporation

Davie, Florida, U.S.A.

1. INTRODUCTION

In order to obtain approval of a generic drug product, a sponsormust submit an Abbreviated New Drug Application (ANDA)to the FDA’s Center for Drug Evaluation and Research(CDER), Office of Generic Drugs (OGD). The sponsor can bea drug company that intends to manufacture the generic drugitself and has performed the necessary research to obtain thedata required for submission, which will be described in thischapter. Alternatively, the sponsor could be some individualor group that has done the research or obtained the rights tothe research performed by others, even if the sponsor does notintend to manufacture the product itself. For simplicity in thischapter, we will refer to the sponsor as the applicant.

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The goal of the applicant is to receive FDA approval of theproposed product with a rating that means that FDA considersthe generic drug bioequivalent to the brand drug. If a genericproduct has such a rating, pharmacists may substitute thatgeneric for the brand product or one bioequivalent genericproduct for another. In FDA language, this innovator productis called the reference listed drug. Since the generic drug is‘‘equivalent’’ to the brand, the former does not have to repeatthe preclinical animal studies or the clinical human studiesthat were performed on the brand in order to prove that thebrand product is both safe and effective.

In this chapter we will cover several aspects of getting ageneric drug product approved. There are a number of essen-tial parts of the process of getting a generic drug approved.First, the applicant must select a product to work on. Second,a formulation and manufacturing process for the generic drugproduct must be developed that shows promise of producing aproduct that will be bioequivalent to the reference listeddrug. Then one or more batches of generic product must bemanufactured. In most cases one or more human bioequiva-lence trials (biostudies) must be performed on the productmanufactured. Various chemical and physical tests mustalso be performed on this product. When sufficient informationhas been obtained, an ANDA is prepared and filed withthe FDA.

We will discuss some general principles related to how todecide what product to pursue, how to develop a formulation,how to perform a biostudy, and how to prepare an ANDA.The information needed to submit the application will beconsidered in the ANDA preparation section. We will end thischapter with a short discussion of applicant activities betweensubmission of the ANDA and its approval.

2. DECIDE WHAT PRODUCT TO PURSUE

The first step in obtaining approval of a generic drug is select-ing the product to work on. Each generic drug product is

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declared by FDA to be a form of an innovator product thatwas originally approved via a full New Drug Application(NDA). Selection of the proper reference listed drug is criticalto market success.

Depending on the strategy of the firm involved, one maychoose the easy route or the hard route. The easy route is towork on a product for which there are already generic equiva-lents. One of the reasons this is the easy route is because therewill be a body of information available from FDA and possiblyalso in the literature about the product. This information canbe very valuable during product development and biostudytesting. FDA will also be familiar with the product and whatis required for it to be approved. The hard route is to work ona product for which there are no generic equivalents, usuallybecause the product is still under patent or because it isdifficult to formulate a product that is bioequivalent to theinnovator product.

When considering which product to pursue, one of the firstplaces to look for product information is the FDA Orange Book(1). Fortunately, this is available at the FDA web site, fda.gov,with a link on the Center for Drugs home page, fda.gov/cder/.By searching the Orange Book, one can determine how manygeneric equivalents of a product are approved and the names ofthe holders of the approved applications. The patent numbersand expiration dates of all patents that have been listed withthe FDA for the product can also be found.

If generic equivalents already exist, the Orange Bookwill indicate what their equivalence rating is to the innovatorproduct. The Orange Book uses two-letter codes for this pur-pose. If the first letter of the code is A, the products withthis code are considered bioequivalent. The second letter ofthe code represents different dosage forms. Products codedAA, AN, AO, AP, and AT do not require biostudies in orderto be approved, because there is no evidence that they have anybioequivalence problems. These products are less expensive topursue, but there are almost always many competitors forthem. Products rated AB require biostudies that demonstratebioequivalence of the applicant’s product to the innovatorfor approval.

Obtaining Approval of a Generic Drug 417


http://www.fda.gov

http://www.fda.gov

If the first letter of the code is B, the products are not bio-equivalent to each other. FDA is in general unwilling to app-rove any generic products with these ratings and is attemptingto upgrade them to AB status if possible. For further discussionof this rather complex topic, see the Preface to the OrangeBook.

While the issue of pharmaceutical patents is coveredin Chapter 5, a discussion of practical aspects will be includedin this chapter. The Orange Book listing of patent numbers isprovided by the holders of the NDA for the innovator product.Patent lists were established by the Hatch-Waxman Act, passedin 1984 (2). If an applicant has decided to submit an applicationfor a product that has one or more patents listed in the OrangeBook, the applicant needs to research the patents and decidewhether it wants to, and can, invalidate some or all of thepatents or develop a formulation that does not infringe on anyof the claims in the patents. There are several ways in which theapplicant can approach these patents and deal with, or certify,them in its application. A short discussion of the types of patentcertifications appears later in this chapter.

One of the reasons that research is needed is that thereare several different types of patents listed in the Orange Book.It is the opinion of this author that a patent covering the mole-cular structure of the drug can only rarely be successfully chal-lenged by generic competitors. The original use for which theproduct was approved may be in the same patent or a differentone. A firm must usually wait for all of these to expire beforeit can receive final approval of an ANDA that refers to thereference listed drug included in the patent. It often seems tothe layman that more than one patent is granted for the samething; this requires clarification from patent attorneys.

Patents for other uses can be overcome by submitting,in the patent certification section of the abbreviated newdrug application, a statement that the generic drug applicationis not requesting approval for the other patented indicationor indications. This statement is called a Section (viii) notice.In this case, all references to the patented indication or indica-tions being certified must be removed from the labelingincluded in the application.

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Formulation patents require analysis by both chemistsand attorneys who are experts in pharmaceutical patents.Skilled formulators often devise products that are intendedto ‘‘engineer around’’ restrictions in formulation patents. Inmany cases, applications that certify that they do not infringeformulation patents result in litigation. The litigationmay hingeon the judge’s interpretation of a few words in the patent beingchallenged. One must also consider the doctrine of equivalents,discussion of which is beyond the scope of this chapter.

To add to the complex situation described above, startingin the 1990s innovator firms began to list patents that have onlya tenuous connection to the reference listed drug. These includepatents for other crystal forms, isomers and metabolites. Inno-vator firms have maintained that they interpret the Hatch-Waxman Act to require them to list any patent connected tothe active ingredient in their product, even when the patentdoes not cover the final dosage form. Generic drug companieshave attacked this position both in court and via attempts torevise the Act. As of this writing these attacks have met withsome success, but the problem has not been resolved.

When the generic drug application contains a certifica-tion that a patent listed in the Orange Book is invalid or willnot be infringed, there is a requirement that the ANDA appli-cant notify the patent holder as well as the holder of the appro-ved NDA if they are different (4). The rules for this notificationare very complex, and discussion of them is beyond the scope ofthis chapter.

In the majority of cases the ANDA applicant will be suedfor patent infringement if the application contains a certifi-cation that a patent is invalid or will not be infringed. If thisoccurs, FDA may not approve the ANDA for ‘‘30 months afterthe date of the receipt of the notice of certification by thepatent owner or by the exclusive licensee (or their representa-tives) unless the court has extended or reduced the periodbecause of a failure of either the plaintiff or defendant to coop-erate reasonably in expediting the action’’(5). This provision isusually referred to as the 30-month stay of approval.

In October 2002, FDA proposed a rule amending its patentlisting requirements to, among other things, allow only one



30-month stay of approval for each ANDA filed (6). Most of thisrule was included in the Greater Access to Affordable Pharma-ceuticals Act which became law inmore details.

One can see that filing an ANDA citing a reference listeddrug that does not have any approved generic equivalents posessome risk. In an attempt to partially counterbalance this risk,the Hatch-Waxman Act provides a 180-day exclusivity forthe first applicant to file a substantially complete applicationcontaining the required biostudies. This exclusivity starts whenthe holder of the exclusivity starts marketing the drug or whenthe final court decision in a patent challenge is rendered.

In addition to the patents listed in the Orange Book at thetime the ANDA is filed, the applicant for an ANDA must file acertification amendment if a new patent is listed in the OrangeBook before the ANDA is approved. If the NDA holder submitsthe patent for listing in the Orange Book within 30 days of itsissuance by the Patent and Trademark Office and the applicantis sued for infringement of these later listed patents, a new30-month stay of approval begins. In several cases this hasoccurred the day before the ANDA was due to be approvedby FDA. Even if the original application contained a certifica-tion that all patents have expired or that approval is requestedwhen the last patent listed in the Orange Book expires, it isalways possible that a new patent will be listed in the OrangeBook at any time before approval. When a new patent is listedbefore an ANDA is approved, the applicant has to file a newpatent certification. In most cases, the patent and/or NDAholder will sue for infringement, starting a new 30-month stay.

It is not required that the holder of exclusivity market theproduct; there have been cases where the holder of exclusivitychooses not to market and all other applicants are blocked andcannot market. The FDA rules governing 180-day exclusivityare very complex and have changed several times since 1984,when the Hatch-Waxman Act became effective.

There are also economic considerations involved. Whenpatents for a brand product with high sales are due to expire,many other firms are likely to prepare and submit ANDAs.If there is a potential for 180-day exclusivity, one firm may

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2003. See Chapter 5 for


make a great deal of money for this period. At the end of thisperiod, or if there are no other patents to challenge andthus no potential for exclusivity, many ANDAs will probablybe approved on the first possible day. Having 13 or more enterthe market at the same time is possible. In this case competi-tion is fierce and the price drops quickly. The product becomesa commodity, and no one makes very much money. The lowerthe sales of the brand product, the less likely this is to happen.These ‘‘niche’’ products can paradoxically produce much betterprofits than the ‘‘blockbusters.’’

Another possible strategy is to submit a citizen’s petitionto FDA requesting approval of one of the permitted variationsfrom a reference listed drug. One variation is an additionalstrength within those supported by the safety and efficacydata pertinent to the reference listed drug. This is also acomplex area, discussion of which is beyond the scope of thischapter, and appropriate experts should be consulted.

As if this situation were not complicated enough, theHatch-Waxman Act also granted various types of exclusivityto holders of new drug applications. The most important typeof exclusivity is new chemical entity (NCE) exclusivity, becauseFDA is not allowed to accept an ANDA citing a referencelisted drug with NCE exclusivity in force (3). NCE exclusivityis awarded if the active ingredient in a new drug product hasnever before been approved in the United States. NCE exclu-sivity is not awarded if another salt or ester of the active ingre-dient is already approved. NCE exclusivity is granted for 5years from the date the NDA is approved.

There are several other types of exclusivity. For these,FDA may accept an ANDA but may not make its approvaleffective until the exclusivity expires. Orphan drug exclusivityis granted for 7 years. New indication, new combination, newdosing schedule, new dosage form, new ester or salt of theactive ingredient, new product, new patient population, newroute, and new strength exclusivities are granted for 3 years.For many of the exclusivities listed in the previous sentence,an applicant can carefully craft the submission not to includethe matter subject to the exclusivity. However, occasionally theowner of the reference listed product will sue and/or submit



a citizen’s petition to FDA, arguing that the exclusivity shouldapply to the ANDA so crafted.

A newer type of exclusivity is pediatric exclusivity. This isgranted if the owner of an NDA obtains certain new informa-tion about the use of the product in children via new clinicaltrials. Pediatric exclusivity is an extension of a previous patentor exclusivity for 6 more months. It is usually granted shortlybefore expiration of the patent or exclusivity being extended.The prudent applicant checks the exclusivity listings in theOrange Book every month, when updates and supplementsare published.

The rules for granting exclusivity are, of course, very com-plex and beyond the scope of this chapter. The main thing theapplicant needs to know is what the exclusivity is for and whenit expires. This information can be found in the Orange Book.

From the above discussion, it is clear that many uncer-tainties are involved in deciding which product to pursue. Eachfirm must consider its overall strategy when deciding whetherthe rewards are commensurate with the risks.

3. DEVELOP A FORMULA

Once a firm has picked a candidate product to develop, the nextstep is to develop a formulation that can pass the bioequi-valence studies. The requirements for such studies are descri-bed in the next section of this chapter.

Patent issues aside, there are many techniques for devel-oping a bioequivalent formulation. Among them are twocommonly used approaches: reverse engineering the referencelisted drug to better understand its characteristics, or buildingon a previous formulation or technology for a similar product.These approaches can also be used together.

FDA regulations declare, ‘‘For certain drug products,the in vivo bioavailability or bioequivalence of the drug productmay be self-evident.’’ These include liquid dosage forms thatare true solutions, contain the same inactive and active ingre-dients in the same concentrations as the reference listed drug,

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and are used in parenteral, ophthalmic, or otic applications.Products administered by inhalation that contain the sameactive ingredients as the reference listed drug are included.Topical products and oral solutions (including elixirs, syrups,and tinctures) that contain the same active ingredients as thereference listed drug and do not contain any inactive ingredientthat differs from those in the reference listed drug that maysignificantly affect drug absorption are also considered self-evi-dently equivalent. All of these products can qualify for a waiverthat allows them to be approved without a bioequivalencestudy (3).

Parenteral products are required by FDA to include theirqualitative and quantitative compositions in their labeling,so the formulator needs only to follow the labeling to makea product FDA will accept. Ophthalmics or otics will list theconcentration of any preservative present in the labeling, andoften the osmolality and/or pH, but other ingredients are givenonly qualitatively.

In the reverse engineering approach, simple and sophis-ticated chemical and physical tests are applied to the referencelisted drug product to determine its exact qualitative and quan-titative composition. While listing of inactive ingredients inlabeling of solid dosage forms is voluntary, almost all innovatorfirms do it, and this can be a big help when trying to copy itexactly. There is a loophole, however. If the innovator contendsthat the reference listed drug contains ingredients that aretrade secrets, these may be listed as ‘‘other ingredients.’’ Ofcourse, the most important and unusual ones are listed this way.

In the late 1980s, just after the Hatch-Waxman Act passed,several firms tried to use reverse engineering to guide theirformulators. It is interesting that solid dosage form productsproduced in this way failed bioequivalence studies more oftenthan would be expected. As a result, formulators are morelikely to use variations on known formulas. If the firm wishingto develop a generic drug already has a successful product thatis similar, using a similar formulation for the new product isoften a very good starting point. Basic physical pharmacy text-books and research articles in journals like PharmaceuticalTechnology can be good sources for basic formulas as well.



If the formulator chooses to be creative and use an origi-nal formulation, he or she must be aware of FDA’s safety rulesfor generic drug formulations. FDA will not question the safetyof an inactive ingredient if it has been used in an approvedproduct and the level in the proposed generic drug productis not higher than the highest level ever approved for patientconsumption in that route of administration. Since this infor-mation is generally part of the proprietary secrets in manyapplications, FDA published an Inactive Ingredient Guide,which may be accessed from the FDA web site. This guidewas recently revised. While it is not perfect, it is a valuableresource for formulators.

How does the formulator know when he has developed apromising formulation? First, the product must be suitable formanufacture on a commercial scale. Extremely fragile tablets,called friable tablets, ingredients that are very hard to blend,blends that do not flow well in manufacturing machinery, orprocesses that use toxic solvents are the sorts of things theformulator must avoid. Second, one must obtain some informa-tion on the nature of the bioequivalence requirements. Then, ifa biostudy is required, an in vitro test that can serve as asurrogate for it is highly desirable.

The most common surrogate for bioequivalence is thecomparative dissolution profile. Typical results obtained for acomparative dissolution profile are shown in Figure 1, in which

Figure 1 Graph of a typical comparative dissolution profile, obtai-ned by measuring the dissolution of the proposed generic product andthe reference listed drug every hour for 5 hours.

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the generic drug is the test and the reference listed drug isthe reference. A dissolution test measures how much drug dis-solves in a specific time using diluents and apparatus definedby the United States Pharmacopoeia (USP) (7). A dissolutionprofile is a group of measurements on the same dosage unitat various times. Comparative dissolution profiles comparethe dissolution profiles for the average of 6 or 12 units of twodifferent products or two different lots or versions of the sameproduct.

If a dissolution test method exists in USP or the EuropeanPharmacopoeia (EP) or if the test approved for the referencelisted drug can be obtained from FDA via a Freedom of Infor-mation request, then dissolution profiles using these conditionsare a good place to start developing a predictive test. It is notunusual to find that different conditions are more predictive,in which case profiles under both sets of conditions must beincluded in the ANDA, using 12 dosage units of each of thelots used in the bioequivalence trials. If there is no establisheddissolution test, FDA recommends submitting data using USPmedia at pH 1.2, 4.5, and 6.8 (8). FDA has defined a differencefactor and a similarity factor that can be calculated when com-paring two dissolution profiles (9).

Unfortunately, dissolution is not always predictive of bio-availability or bioequivalence. If it were, there would be no needto ever perform bioequivalence studies.

4. DO A BIOSTUDY

Before considering even a pilot biostudy, those involved in thedesign of the study protocol must find out everything they canabout the pharmacokinetics of the drug substance and the drugproduct. For example, if the drug substance has three charac-teristics—(a) the drug substance is highly soluble in water,(b) biological membranes are likely to be highly permeable tothe drug substance, (c) the dissolution of the drug product ishigh—then absorption of the product from the gut is unlikelyto be the rate-limiting step in distribution of the productthroughout the body (10). If these conditions are met, any



formulation that gives adequate dissolution should be bioequi-valent to any other formulation. While it is relatively easy todetermine drug solubility and product dissolution, it is moredifficult to determine membrane permeability. Methods fordetermining membrane permeability are beyond the scope ofthis chapter. If an applicant can determine permeability, a bio-study waiver can be requested. If this waiver is approved,the applicant does not need to do any biostudies. Even if thepermeability cannot be determined to a degree that will satisfyFDA, such products are very likely to be bioequivalent, andtherefore a pilot biostudy may not be necessary. In 2002,OGD declared their intention to provide more details in theBiopharmaceutics Classification Guidance and to look at con-cerns that it is overly conservative (11).

The standard design of a bioequivalence study is a two-way crossover. The subjects are divided into two equal, ran-domly assigned groups. The first group receives the testproduct, while the second receives the reference. Blood samplesare taken at appropriate intervals and frozen for measurementof the concentration of drug in the sample. If there are impor-tant active metabolites, these will be measured as well. Aftera suitable time period following the first part of the biostudy,called the washout period, the first group receives the referenceproduct and the second receives the test product. When allsamples for each subject are collected, the analysis of eachperson’s samples from both periods is done sequentially, tominimize the affect of analytical variability. The results foreach subject obtained during the two periods are compared.

In order to properly design a biostudy, one must havea good estimate of the expected time of maximum absorption,tmax, and the elimination half-life, t1=2. The maximum time isneeded to make sure that enough blood samples are takenbefore and around tmax. This is needed to ensure adequatedata for determination of the maximum blood concentrationachieved, cmax. The elimination half-life is needed to decidehow long to take blood samples in order to get a good measure-ment of the area under the blood concentration curve, AUC. Agood estimate of cmax is also needed so that the method used toanalyze the blood samples can be validated in the proper

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range. Figure 2 provides a graphic illustration of tmax, cmax,and AUC.

Values for tmax and t1=2 can sometimes be obtained fromthe labeling of the reference listed drug product and/or fromthe scientific literature. However, it is not infrequent for thesevalues to differ from those obtained in the specific populationto be used for the bioequivalence trials. Unless one has confi-dence in the data available, or if no data can be obtained, itis quite prudent to run a small bioequivalence study on thereference listed drug in about 4 subjects representative ofthe population to be used for the studies.

Very few generic drug firms do their own biostudies,especially not the clinical portion, because it takes a verylarge product development program to keep an in-house bio-study clinic busy full time. Instead, these studies are done byseparate firms called contract research organizations (CROs).At times the CRO may choose to perform the study neededto get an estimate of tmax and t1=2 in its population underits own auspices, rather than having a customer pay for it.

Figure 2 Graph illustrating the results of a typical biostudy. Druglevel in blood is measured at various times, and the cmax, tmax, andAUC of the test and reference products obtained are compared.



Be forewarned, however, that this usually means the CROanticipates having many customers for its services involvingthe drug product.

Pilot biostudies are conducted on a small number ofsubjects. More subjects are used when the expected variabilitybetween subjects is higher. If an insufficient number ofsubjects is used, there is a large risk that the conclusionsdrawn from the results of the pilot study will not agree withthe results of the full-size study. The purpose of a pilot studyis to obtain a relatively quick and inexpensive estimation ofhow close the bioavailability of the generic drug productunder development is to its reference listed drug.

It is advisable to perform a pilot biostudy for all butthe simplest and most bioavailable products. It is imperativeto perform a pilot study when there is any possibility thatthe dissolution profile does not reflect the actual bioavailabilityof the product and for all modified release products.

There are three types of bioequivalence studies: fastingsingle-dose, fed, and multiple dose studies. At least one fast-ing single-dose study is required for every ANDA, except forproducts that are self-evidently bioequivalent, as discussed inthe previous section, or products whose Orange Book ratingis AA rather than AB. An AA rating means that the productsare not regarded as having actual or potential bioequi-valence issues as long as they meet the appropriate dissolutionspecifications. Most if not all AA products that are solid dosageforms were originally approved before 1984.

The standard for determining whether a biostudypasses is average bioequivalence. This means that, for thefasting single-dose biostudy, the average cmax, measured AUCto the last sample time, and AUC extrapolated to infinityfor the test and reference are compared. These values arecompared as log transforms. The 90% confidence interval(CI) of the ratio of test to reference must fall between 0.800and 1.250.

Fed bioequivalence studies are required for most oraldosage forms that require biostudies. FDA has released adraft guidance (12), which proposes that three types of imme-diate release oral products be exempt from the requirement

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for fed studies. The first is products that are exempt fromthe requirement for fasting studies based on solubility andpermeability, as discussed above. The second is a product forwhich the labeling of the reference listed drug requires thatit be taken on a empty stomach. Both of these exemptionsare accepted by OGD today. The third, a product for whichthe labeling of the reference listed drug ‘‘does not make anystatements about the effect of food on absorption or admini-stration,’’ has historically not been accepted by OGD inmany cases as a good reason for exempting a product fromrequirements for a fed bioequivalence trial.

There are additional complexities in this area. For exam-ple, if the reference listed drug is labeled that it may be admi-nistered by sprinkling it on food, the generic applicant mustdemonstrate bioequivalence under these conditions in additionto all the other requirements.

Current policy at OGD is that the cmax and AUCs for testand reference under fed conditions must be comparable. Thedraft guidance proposes the use of the same confidence intervalapproach used for the single-dose fasting study. If this proposalis adopted, the number of subjects used in fed studies willincrease.

Multidose studies have in the past been required formodified release products. The General Considerations DraftGuidance recommends single-dose studies for both immediate-release and sustained-release products.

All of the above presumes that the level of the drug or itsmajor active metabolite can be measured in plasma, serum, orurine. While this measurement is possible for the majority oforal dosage forms, there are quite a few products for which itis not. Among these are endogenous substances such as hor-mones and products that are not systemically absorbed.Topical, nasal, and inhalation products generally require spe-cial approaches. While conventional biostudies can be perfor-med for many transdermal products, adhesion studies as wellas skin irritation and sensitization studies are also required.

If measurement of the drug or metabolites is not possible,bioequivalence can sometimes be demonstrated using a clinicalendpoint. An example would be a product intended to treat



hair lice. The endpoint must be one that can be clearly relatedto the function of the product under test. Its evaluation, espe-cially if somewhat subjective, must be performed by a clinicalteam that is blinded to the identification of the test versusreference product and well qualified to evaluate the endpoint.Both active treatments, test and reference, must demonstratesuperiority over vehicle and/or placebo. These types of studiesoften require larger numbers of subjects than conventionalbiostudies. As the number of subjects and the length oftreatment needed to observe an effect increase, these studiesbegin to approach clinical trials in cost and complexity. Whenthis happens it is often not practical or cost-effective to performsuch studies. Further discussion of this area is beyond thescope of this chapter.

When an ANDA is submitted for multiple dosage strengthsof the same product, it is usually not necessary to do all studiesfor each strength. Waivers are available for some strengths ofa product line. FDA regulations permit waivers to be granted ifthe drug product for which the waiver is being requested meetsthree criteria. First, it must be the same dosage form as thestrength on which the biostudy was performed. In other words,a tablet cannot be granted a waiver based on a study done ona capsule and vice versa. Second, the two strengths of theproduct must be proportionally similar in their active andinactive ingredients. Third, the strength for which the waiveris being requested must meet appropriate in vitro dissolutionrequirements (13).

The General Considerations Draft Guidance gives threeways in which two strengths of a product can be proportionallysimilar. The first is when the ingredients are present in exactlythe same proportions. In this case, a 20 mg formulation wouldcontain exactly twice the amount of all ingredients as a 10 mgformulation. This is called dose proportional. The second caseis when the two formulations differ from dose proportionalityby no more than the amounts permitted by the postapprovalchanges guidances up to level II (14). The third case is limitedto low-strength drugs. In this case the total weight of the dosageunit stays the same, and the amount of one or more inactiveingredients is decreased by the same amount as the active

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ingredient is increased. The change in the amount of anyinactive ingredient may not be more than that permitted bythe postapproval changes guidances up to level II.

There are several more details that must be controlledand rules that must be followed in order to achieve an accept-able set of biostudies for an ANDA submission. The reader isreferred to the appropriate FDA guidance.

5. PREPARE A SUBMISSION

The current OGD Guidance for Industry on Organization of anANDA became official in February 1999 (15) (available on theFDA web site). The Guidance describes how OGD has pre-ferred to receive ANDAs for many years.

The text below describes the contents of an ANDA as ithas been developed since 1985. However, changes may occurbecause of an initiative of the International Committee on Har-monization (ICH). The ICH is a joint venture between the drugregulatory authorities and pharmaceutical innovator tradeassociations of the United States, the European Union, andJapan. As of this writing, the ICH initiative for a commontechnical document has not had any impact on ANDA prepara-tion, but in January 2003, FDA published a draft guidance forIndustry called Drug Product Chemistry, Manufacturing andControls Information, which incorporates the common techni-cal document approach. The introduction to this guidancestates that it will apply to both NDAs and ANDAs. While theinformation described below is generally also included inthe draft guidance, the order is different. The reader is advisedto check the FDA web site before commencing preparation ofthe documentation.

5.1. Cover Letter

The first page or two of every ANDA should be a cover letter.This letter must make clear to FDA who is submitting theapplication and what they are submitting.

Regarding who is submitting the application, the letter-head used and signature of the applicant should match the



corresponding fields on the 356h form described below. Allsubsequent submissions must use the same letterhead and befrom the same firm at the same address. If the name or addressof the firm changes, FDA must be provided with adequatedocumentation. In a merger or sale, the Agency usually wantsdocumentation from both parties and a clear indication of whonow owns the application.

The person whose signature is on the application coverletter and the 356h form will be the one to whom FDA willaddress all communications regarding the application. It is mostuseful for this to be the employee who has the primary respon-sibility to prepare responses to FDA communications forthis application. This is often the director of regulatory affairs.Be sure to provide phone and fax numbers so that FDA com-munications can be received expeditiously.

5.2. 356h Form

The signed application form goes directly after the cover letter,in the first section of the application.

Fill in the Applicant Information section of the formto exactly match the information in the cover letter. If thefirm submitting the application is located outside the UnitedStates, it is required that the firm appoint an agent withan office in the United States. The information about thisagent should be placed in the appropriate box in this section.U.S. firms should leave this box blank or fill it in as notapplicable (N/A).

The first line of the product description section is leftblank for a new ANDA submission. If a previously withdrawnapplication is being resubmitted, the number of the withdrawnapplication goes in this box. The generic name of the productgoes in the box marked Established Name. If a trade name hasbeen chosen, this name goes in the Proprietary Name box.(Trade names require clearance from FDA in order to try tominimize the chances for errors due to similar names.)

The chemical name of the drug goes in the box markedChemical/Biochemical/Blood Product Name. FDA usuallyprefers the official Chemical Abstracts name. For example,

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USP lists three names for ibuprofen in the active ingredientsmonograph:

Benzeneacetic acid, �-methyl-4-(2-methylpropyl), (�)(�)-p-Isobutylhydratropic acid(�)-2-( p-Isobutylphenyl)propionic acid [15687-27-1]

The third name is followed by a number in brackets. This isthe Chemical Abstracts number, which can be used to searchChemical Abstracts for information about the compound. OGDhas traditionally asked that the name before the ChemicalAbstracts number be the name used in the labeling and onthe 356h form.

Dosage form, strengths, and route of administration shouldbe self-evident. The contents of the Indications for Use boxshould match the indication section of the labeling but maybe paraphrased if this section is too long to fit. Be sure notto include any indications protected by exclusivity, unless youare requesting that your approval be made effective after theexclusivity expires. Refer to the Orange Book to be sure. If youinclude indications protected by patent but not exclusivity, apatent certification regarding them will be required.

In the first box in the Application Information section, thebox next to Abbreviated New Drug Application (ANDA, 21CFR314.94) should be checked. The next box is for NDAs only.In the next box, the trade or brand name of the referencelisted drug should be entered, as well as the name of the com-pany that owns the NDA for this product. This entry shouldmatch the company listed in the FDA Orange Book as theowner of the application, regardless of who actually marketsthe product.

Since we are discussing a new ANDA submission, OriginalApplication should be checked in the Type of Submission box.Partial submissions are not used for ANDAs, so the next boxshould be left blank. The box labeled If a Supplement is alsonot applicable to original applications. The reason for sub-mission is Original Application in this case. ProposedMarketing Status must be the same as that of the referencelisted drug. Number of Volumes and Paper and/or Electronicshould be self-evident.



For the last two sections on the first page of the 356h, it isalmost always necessary to attach one or more continuationsheets. In the Establishment Information section the appli-cation must list all sites to be used to manufacture, package,and or test both the bulk active pharmaceutical ingredient andthe finished product. Even an outside laboratory used to do onetest must be listed here. The address, phone number, and nameof a contact for FDA to call must be given. For firms in theUnited States, the registration (CFN, central file number)number must be included. Just to make things even more com-plicated, FDA is currently in the process of changing CFNs toFEI numbers. For firms that have Drug Master Files (DMFs),the DMF number must be provided. Finally, for every firmlisted, the applicant must state whether the firm is ready tobe inspected or, if not, the date on which it will be ready.

A DMF is a separate submission made to the FDA in whicha firm other than the applicant can disclose information to theFDA that they do not want to disclose to the applicant becauseit is proprietary or a trade secret. FDA only reviews DMFsin connection with the review of an application; they are notindependently reviewed.

Do not state that a firm is ready in the hope that it willbe ready by the time FDA calls. It is always possible that thefirm’s district FDA office might call to schedule a preapprovalinspection shortly after the application is filed by FDA.

The last section on the first page of the 356h form is CrossReferences. For ANDAs, this is a list of all DMFs referencedthroughout the application. In addition to the DMFs listedin the previous section, packaging components suppliers andsometimes suppliers of inactive ingredients have DMFs. It isadvisable to carefully review the assembled submission toensure that all DMFs mentioned anywhere in the applicationare listed here. For every DMF mentioned, the holder of theDMF must send a letter to FDA for filing in the DMF, autho-rizing the FDA to refer to the DMF on behalf of the ANDAapplicant. A copy of each letter must be included in theappropriate section of the application.

The second page of the 356h form contains a list of varioussections that might be included in an application. An initial

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ANDA submission normally contains item 2, labeling; items4.A and 4.C, the chemistry section; item 6, the bioequivalencesection; item 14, the patent certification section; item 16, thedebarment certification; item 17, the field copy certification; anditem 19, financial information for those who conducted thebiostudies. Items 16 and 17 are briefly discussed in the nextsection; item 19 is normally provided by those who conduct thebiostudies.

Make sure that the original 356h with the original signa-ture is placed in the archival copy of the ANDA; this is the copythat is submitted with the blue plastic covers and that containsall sections of the application. Also make sure that the addressand telephone number on the second page match those on thefirst page.

5.3. Organization of Application

It is strongly suggested by OGD that the application be organi-zed according to Attachment C of OGD Guidance for Industryon Organization of an ANDA, February 1999. Each volume ofthe submission must contain a copy of the table of contents.Page numbers in the table of contents are filled in after theentire application has been numbered as required in theGuidance.

Section I of the application contains the completed 356hform discussed in the previous section. Section II is called Basisfor ANDA Submission. In this section the applicant states thatthe submission is based on the reference listed drug. This is thesame information that is in the third box of the ApplicationInformation section of the 356h. Make sure it matches exactly.It is advisable to include a printout from the electronic OrangeBook in this section, so there is no doubt as to the status ofthe reference listed drug chosen. If the application is based onan approved Citizen’s Petition, this section must make an affir-mative declaration to that effect. A copy of the petition and itsFDA approval should be included.

Section III includes the patent certification and the exclu-sivity statement. If no patents for the reference listed drugwere listed in the Orange Book, then the applicant should



submit a Paragraph I certification. Suitable language would be‘‘Paragraph I Certification: Company X (the applicant) certifiesthat patent information for product Y has not been submittedto FDA. In the opinion and to the best knowledge of (nameof applicant), there are no patents that claim the listed drugreferred to in this application or that claim a use of the listeddrug.’’ If patents were listed in the Orange Book but they haveall expired on the date the submission is sent to FDA, then aParagraph II Certification is required. For example, ‘‘Para-graph II Certification: Company X (the applicant) certifiesthat all patents submitted to FDA for product Y have expired.’’If there are patents still in force on the day of submission andthe applicant does not intend to market their product untilthey expire, a Paragraph III Certification is appropriate. Typi-cal language would be ‘‘Paragraph III Certification: CompanyX (the applicant) certifies that Patent No. ZZZZZ will expireon QQ (date). Applicant requests that final approval of thisapplication be made effective on that date.’’

Paragraph IV certifications are submitted when the appli-cant is challenging the patent. FDA regulations (21CFRx314.94(a)(12)(4) give language to be used: I, (name of applicant), cer-tify that Patent No. ZZZZZ (is invalid, unenforceable, or willnot be infringed by the manufacture, use, or sale of ) (name ofproposed drug product) for which this application is submitted.Following the certification must be a statement that the appli-cant will comply with the requirements under Sec. 314.95(a)with respect to providing a notice to each owner of the patentor their representatives and to the holder of the approvedapplication for the listed drug, and with the requirementsunder Sec. 314.95(c) with respect to the content of the notice.

Section IV of an ANDA, entitled Comparison betweenGeneric Drug and Reference Listed Drug, is usually submitted

exception of permitted variations in ingredients, the informa-tion for the reference listed drug and that for the proposedgeneric drug should be the same.

Section V contains the proposed labeling for the genericdrug. The first pages of this section may be a copy of the refer-ence listed drug labeling or a side-by-side comparison of the

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as a table. (See Table 1 for a guide to preparing this.) With the


proposed labeling to that of the reference listed drug, boththe insert and the container labels. If the reference listed druglabeling is first, a side-by-side comparison is included with thecopies of the applicant’s proposed labeling.

In the side-by-side comparison of the proposed labeling tothat of the reference listed drug, every difference between thetwo must be highlighted and explained. In all cases, the brandname in the reference labeling must be changed to the genericname. It is not always easy to decide exactly how to do this,especially when the drug is a salt. The name of the productwith its dosage form is used in the description of the product,the Dosage and Administration section of the labeling, and inthe How Supplied section. When discussing the drug after ithas been absorbed into the circulation, the counterion is notincluded, since dissociation will have occurred in solution.After the side-by-side comparison, four copies of the proposedlabeling in draft must be presented. It is rarely appropriate to

Table 1 Guide to Preparing Table for Section IV of an ANDA

NDA holder’s brandname of reference

listed drug

Applicant’s name ofproposed generic

drug

Conditions of use e.g., Pain (exactly as inlabeling)

e.g., Pain

Active ingredient(s) Generic name ofactive(s)

Generic name ofactive(s)

Inactive ingredients(for productsrequired to have thesame inactive ingre-dients only, such asparenterals)

List all ingredientsincluded in brandlabeling

List all ingredientsincluded inproposed product

Route ofadministration

Oral, parenteral, etc. Oral, parenteral, etc.

Dosage form Tablet, capsule,injection,ointment, etc.

Tablet, capsule,injection,ointment, etc.

Strength X mg X mgLabeling See Section V See Section V.



submit final printed labeling in an initial submission. However,should the applicant choose to do so, 12 copies must bepresented.

Section VI is quite long for those submissions that requireone or more biostudies. Therefore, it is recommended thatthe order of information not follow that given in the guidance.The beginning of Section VI should contain a summary of thesection contents, a list of all biostudies included in the applica-tion, any necessary requests for in vivo biostudy waivers,and all dissolution profile data required. Immediately afterthe dissolution profile data, it is advisable to include a copyof the method used to obtain the results. The reason for placingthe method here, even though it will be repeated in Section XV,is that the bioequivalence review copy does not contain SectionXV. The bioequivalence reviewer needs to see the method usedto obtain the dissolution results.

For applications requesting biostudy waivers, a compari-son of the formulation for the strengths on which biostudieswere performed to the formulations of the strengths for whichwaivers are requested is required. This comparison should alsobe in the beginning of Section VI. The comparison is used by thereviewer to determine if the products meet the requirementsfor proportional similarity of formulations. These requirementsare discussed earlier in this chapter.

In addition to the items listed in Attachment C of OGDGuidance for Industry on Organization of an ANDA forSection VI, it is advisable to include the actual yields of allbatches used for biostudies or dissolution profile testing. Whileit is true that these data can be found in Section XII in theexecuted batch records for these batches, Section XII is nota part of the bioequivalence review copy, so this informationis not readily available to the bioequivalence reviewer.

We have now finished the information that should bein the beginning of Section VI. The remaining informationincludes the Financial Certification/Disclosure Statements(Forms 3454 or 3455) and the biostudies themselves, togetherwith their protocols. Firms may choose to number these manypages sequentially after the page numbers of the informationalready included in the Section or may choose to put the

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studies in Appendices, numbering them at the end of thesubmission or with their own appendix numbers. The formerallows the information to remain in the order specified by theOGD Guidance, while the latter is much easier to perform andallows the rest of the pages to be numbered before the biostudyfinal reports are received.

Section VII is entitled the Components and CompositionStatements. One would think that this section should be oneof the easiest to complete in the entire ANDA, as it is oftenonly one or two pages. Nevertheless, this section garners adisproportionate number of comments from OGD reviewers.There are several pitfalls that one should attempt to avoid.

The Components statement is a qualitative list of all theingredients in the product; the Composition statement includesthe same ingredients in a quantitative manner. The amount ofeach ingredient per dosage unit must be in the Compositionstatement. Firms often include the amount per batch and/or therelative percentage of each ingredient. These statements mustmatch exactly the equivalent statements in the manufacturingand processing instructions and the executed batch records. Adifference of one digit in the last decimal place between thesedocuments and the lists will likely elicit a comment from theOGD reviewer. Manufacturing aids such as solvents that areremoved during processing must also be included. They shouldbe annotated to indicate that they are removed during proces-sing. Inactive ingredients that are mixtures, such as commer-cial tablet coatings, must have their individual ingredientslisted. The Components statement must also match the inac-tive ingredients statement in the labeling, except that thoseingredients removed during processing are not included inthe labeling and the order of ingredients may differ.

Section VIII covers the raw materials used to manufac-ture the dosage form. The first subsection of this section con-cerns the active ingredients. Start with a list of each activeingredient and the name and address of the facility at whichit will be manufactured. This is often not the address of theadministrative office, so research it carefully. Foreign addressesare often less complete than those for American firms, but tryto get at least the name of the street on which the factory is



located, even if there is no equivalent to the American streetaddress.

If possible, try to include the facility’s FDA CentralFile Number (CFN). The CFN is a number used by the FDADistricts and the Foreign Inspections Branch to organize theirrecords. There is a space for the CFN on the FDA 483 form;this is the form where the FDA Investigator reports his or herobservations during the inspection to the inspected firm. TheCFN is also usually included in the Establishment Investiga-tion Report (EIR) that the investigator writes reporting hisor her observations to FDA management. If neither of thesesources provides the CFN, a telephone call to the appropriateFDA District Office or the Foreign Inspections Branch shouldsuffice.

For most ANDAs the required information about howthe active ingredients are produced is contained in the relevantDMFs held by the manufacturers of these materials. Copies ofall letters of authorization from the holders of these DMFsshould be placed here. If the manufacturer has authorizedtheir U.S. agent and/or supplier to issue DMF authorizationletters, a copy of that authorization letter should follow theDMF authorization letter from the agent or supplier.

If the product contains more than one active ingredient,an introductory page listing which manufacturer and whichsupplier are used for each will help the reviewer avoid confu-sion. It is not a bad idea to do this even when only one activeingredient is involved.

If the ANDA applicant is going to synthesize the activeingredients, all the information usually included in a DMF maybe included in Section VII of an ANDA. A discussion of thisinformation is outside the scope of this chapter. Those firmsthat synthesize their own active ingredients should be sophis-ticated and knowledgeable enough to prepare this information.

The next pages of this section are certificates of analysis(CoA) from the manufacturers of the active ingredients. Thesecertificates should contain both the specifications and thetest results for all appropriate tests. At times the letterheadof the DMF authorization letter or U.S. agent authorizationletter contains a different address than the address on the

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CoA. This may be caused by the headquarters of a manu-facturer issuing the letters while the manufacturing siteissues the CoA. Be careful to explain any such circumstancesto the reviewer. It is usually advisable that this information befor the batches actually used to produce the exhibit or biostudybatches.

After the manufacturers’ CoAs come the CoAs fromthe firm that will be manufacturing the finished dosage form.Include the same batches as those for which manufacturerCoAs are submitted. Any large discrepancy between the twodata sets must be investigated and explained.

Following the CoAs, examples of spectra and chromato-grams are required. For each test, include both standard andsample examples, clearly labeled so the reviewer can tell whichis which. Include the source and lot numbers of the standards.If any standard was not USP, the FDA reviewer will wantto know how it was qualified. There is no mention of whereto place this information in the OGD Guidance, so many firmsput it directly after the spectra and chromatograms. Be sureto include every test that produces a spectrum or a chroma-togram, including thin layer chromatography photographs.

The last requirement for this subsection is a statement ofthe retesting period that will be used for the drug substances.If a subset of the original tests will be used for retesting, thatsubset should be described at this point in the application.

The second subsection of Section VIII covers inactiveingredients. For each ingredient the applicant must includethe specifications the applicant will apply to the ingredient, acopy of the supplier’s CoA with specification and test results,and a discussion of the retesting schedule. It is appropriate toinclude a general discussion of any reduced testing programused at this point in the application. The applicant wouldbe well advised to compare the contents of this section tothe components and composition statements in Section VII.Failure to include all ingredients, especially solvents removedduring processing, is a frequent observation made by OGDreview chemists.

Section IX is much shorter than Section VIII. It starts witha list of every facility used to manufacture, package or test the



product, including the address and Central File Number (CFN)of each. A brief description of the facility is listed next inthe OGD Guidance. Inclusion of this description is voluntarybecause facility issues are handled by the FDA District Officesand not OGD. The Quality Unit of each facility described in thissection must provide a signed certification that FDA CurrentGood Manufacturing Practice regulations are being followed atthe facility. A copy of each certification is placed in Section IX.

Section X covers outside firms, including contract test-ing laboratories. Admittedly, whether a firm is considered‘‘outside’’ or not is somewhat arbitrary, particularly for firmsthat use contract manufacturers or packagers. As long asevery firm is listed in either Section IX or X, the reviewershould be satisfied. It is important to make it very clear whateach facility or firm will do and how they will be involved in theproduct that is the subject of the application. Include the CFNof each firm. Each outside firm is also required to provide asigned certification that FDA Current Good ManufacturingPractice regulations are being followed at the firm; copies goin Section X.

Section XI covers manufacturing and processing instruc-tions. It starts with a description of the manufacturing process.A flow chart of the process is often a useful tool to assist thereviewer in understanding the methods and procedures used.Each stage should be labeled clearly and in a manner consis-tent with the manufacturing instructions, which come next.Manufacturing instructions can also be called masters, masterbatch records, or blank batch records. Whatever they are called,the blank batch records for the largest intended commercialbatch size planned are included here. These records are inclu-ded for each product strength covered by the application.All equipment to be used must be specified. Be aware that ifa firm has not yet received the equipment specified in thissection of the ANDA at the time of a preapproval inspection,FDA will classify the inspection as ‘‘firm not ready’’ and willnot grant approval. Further scale-up is permitted after appro-val. It is prudent to restrict the equipment specified to thatalready in the plant. Do not forget to include blank batchrecords for the packaging operations.

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For sterile dosage forms, there are some special require-ments for Section XI. Microbiological Validation should beincluded in the description of the manufacturing process, if itis applicable. The applicant should explain whether the productis prepared using aseptic fill techniques or if it is terminallysterilized. If aseptic fill is used, filter validation should be pro-vided. If terminal sterilization will be used, explain the methodand its validation.

The OGD Guidance lists the reprocessing statement ascoming after the blank batch records. Since the blank batchrecords are long, while the reprocessing statement is short, it isusually advisable to reverse this order. The reprocessing state-ment is basically an acknowledgment that the applicant isaware that reprocessing procedures require prior approvalfrom FDA. FDA will only grant this approval based on datashowing that the reprocessing does not affect the performanceor quality of the drug product. If a firm has such data, it ispermissible to include the procedure and its supporting dataat this point in the application. However, most firms will not dothis for fear that such a procedure might delay applicationapproval.

Section XII is designated In-Process Information. The pri-mary contents of this section are the executed batch records forthe batches on which biostudies or dissolution profile testingwere performed. The records must specify the equipment usedand the results of yield reconciliation at each stage. Packagingrecords with label reconciliation must also be included. As arule, only one batch for each strength of the product isrequired. However, for antibiotics manufactured by fermenta-tion, three batches are required.

Inevitably, there will be some differences between the exe-cuted records in Section XII and the blank records in SectionXI. Each such difference must be explained. For example, if theequipment used to make the executed batch differs from thatplanned for the commercial batches, the firm could use the FDAGuidance for Industry SUPAC-IR/MR: Immediate Release andModified Release Solid Oral Dosage Forms, ManufacturingEquipment Addendum (16), to demonstrate that they areequivalent.



Executed batch records contain information not includedin the blank batch records, such as temperature chart record-ings, forms from Standard Operating Procedures, and labelsthat were removed from drums being used. Keep in mind thatwhile these items may seem obvious to those preparing thesubmission, they will not be so obvious to the reviewer. Carefullabeling and explanation of the forms can avoid unnecessaryreviewer questions and observations.

After the executed batch records there is a subsection forthe in-process controls used during manufacturing and packa-ging. The test procedures, specifications, and data obtainedfrom the exhibit batches must be provided. OGD reviewersoften ask for tighter control specifications than those proposedby applicants. They will accept only specifications that can bejustified by real data. If the specifications are based on dataobtained during product development or on data from batchesnot included in the submission, a report justifying the specifi-cation with the associated data can avoid reviewer comments.

Section XIII includes Packaging Materials Controls. Startthis section with a summary of the packaging system, usually alist of each package size and the components that go into it.Make sure that this list matches the sizes listed in the productlabeling and the information in the packaging records inSections XI and XII. Include in the list the source of each com-ponent—both the name of the firm and the address where thecomponent is manufactured.

After this list include a subsection for each component.Instead of attempting a physical description, an engineeringdiagram from the component manufacturer is usually included.Provide information about the source of the component, thematerials used to manufacture the component, the sourcesof these materials, and the testing performed to ensure thatthe component complies with appropriate specifications. Forthose components, like bottles, that have USP specifications,make sure that there are provisions for ensuring that theserequirements are met. GMPs require that a firm performperiodic testing to confirm the acceptability of their vendors;information about how this is done for packaging componentsmust be included in this section. Also include the acceptance

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tests done by the packaging facility when they receive thecomponents and the retest requirements for components thathave remained at the facility for some time.

Section XIV, entitled Controls for the Finished DosageForm, contains the test procedures the laboratory will useto test the finished product and the specifications that theproduct must meet. The results of the testing of the submissionbatches are also presented in this section. Most firms use pre-printed specification and report forms, but these are sometimesnot available at the time the testing of the submission batchesis performed. Many firms will transcribe the data onto the formfor the submission. This is acceptable provided the fact thatthis is a transcription after the fact is clearly indicated on theform. This transcription must be carefully checked and signedfollowing GMPs.

Section XV is for Analytical Methods. There should be twosubsections: one for the drug substance (the active pharmaceu-tical ingredient) and one for the finished product. If the drugsubstance is listed in USP, it is not necessary to include acopy of the USP monograph. The applicant simply states thattesting will be performed as directed in the current USP. Nomethod validation is required for USP monographs that applyto drug substances. If the drug substance is not listed in theUSP, a copy of the test procedure and its validation must beincluded at this point.

In many cases, additional tests must be added to a USPmonograph for a drug substance to control impurities such asprocess intermediates, side products, and residual solvents.The Guidance for Industry ANDAs: Impurities in Drug Sub-stances [U.S. Department of Health and Human Services, Foodand Drug Administration, Center for Drug Evaluation andResearch (CDER), November 1999] explains that no unidenti-fied impurity may be present in a drug substance at a levelgreater than 0.1%. The Guidance for Industry, Q3C Impurities:Residual Solvents [U.S. Department of Health and HumanServices, Food and Drug Administration, Center for Drug Eva-luation and Research (CDER), Center for Biologics Evaluationand Research (CBER), ICH, December 1997] gives permittedlevels of solvents. These tests must be validated. Recovery and



limit of quantitation are particularly important for limit testsof this type. The applicant must include the methods for thesetests and their validation at this point in the ANDA.

The FDA Guidance lists drug substance test specificationsand data as being the next item in this section. However, thisinformation has already been included in Section VII under theactive ingredients subsection. Some firms choose to repeat theinformation at this point, while others will include a referenceto Section VII. Both approaches have been accepted by OGD.

The next subsection concerns the methods for the drugproduct. The methods themselves are included in Section XIVand need not be repeated in Section XV. Method validation isalways required. Even if the drug product is listed in the USP,the applicant must demonstrate that the methods are suitablefor the product being submitted. Recovery and specificity stud-ies are the most common ways that suitability is demonstrated.

Similarly to the drug substance requirements, the FDAGuidance lists drug product test specifications and data asbeing the next item in this section. However, this informationhas already been included in Section XIV Controls for theFinished Dosage Form. Some firms choose to repeat the infor-mation at this point, while others will include a reference toSection XIV. Both approaches have been accepted by OGD.

If the drug product and/or the drug substance are not USParticles, two separately bound copies of Section XVmust be sub-mitted. These are supposed to be sent by the review chemist tothe testing laboratory. If Section XV refers to Sections XIV andVII, include the appropriate information from those sectionsas well. It is prudent to make another copy of this informationand include it with the samples when FDA requests them.

In the most recent ANDA Checklist for Completeness andAcceptability of an Application, there is no section for Analy-tical Methods. It is possible that the intent is for the informa-tion described above for this section to be included only inthe Methods Validation Package. Because of this difference,the numbering of Sections XV and higher is different in theChecklist and in the Guidance.

Section XVI covers Stability of the Finished Dosage Form.Five items must be included in this section. First, the applicant

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must include a stability protocol. This document is specific tothe product covered by the application, but it may be derivedfrom the firm’s Stability Standard Operating Procedure. Theprotocol defines which samples will be included in the stabilitytesting program, how often and when they will be tested, andwhich tests will be performed. It should also include informa-tion about how the data obtained will be used to extend theexpiration period of the product, if appropriate.

The second item in this section is postapproval commit-ments. This is a statement by the applicant that the first threepostapproval batches and at least one batch per year will beincluded in the stability testing program and that any batch forwhich any parameter goes out of specification on stability willbe removed from the market. The applicant also promises tonotify OGD of any stability recall conducted on the productcovered by the application. This commitment is usually signedby the firm’s director of quality or the employee responsible forensuring that the commitments are followed.

Third on the list of things for the stability section isa statement of the expiration period that the applicant plansto use for the product. If a solid dosage form continues to meetall specifications after testing for 3 months under acceleratedconditions (17), the applicant may request a 24-month expira-tion period. If the product is packed in blisters, an 18-monthperiod may be requested. If the product does not stay withinspecifications on accelerated stability, at this time OGD requiresreal-time stability at controlled room temperature up to therequested expiration period and does not accept intermediatecondition data as defined in the draft stability guidance.

The stability data available at the time of submission arepresented next. OGD requires extensive information about thebatch to be part of the stability record. For example, the sourceof the active ingredient and all packaging components, thelocation where the finished product was manufactured, thebatch size, and the formulation must be included. Several com-mercial computer programs are available that make the task ofpreparing acceptable stability reports somewhat easier.

The last item listed for this section is stability—indicatingtest data of samples under various stress conditions. The data



are almost always included in the method validation reportin Section XV. The firm may choose to reproduce the data inthis section or include a reference to Section XV.

There is no Section XVII. This number is annotated as‘‘reserved’’ in the FDA Guidance.

Section XVIII covers Samples. Do not submit sampleswith the application. FDA will send a letter telling you whenand where to send them. However, you do need to submit a listof available samples. List the active ingredient lot used to makethe exhibit batches and all exhibit batches. If any standardsneeded to test these samples are not compendial, list thoseas well.

Section XIX is Environmental Considerations. For mostANDAs this section is a claim of a categorical exclusion fromthe requirements to submit an environmental assessment,because approval of the application will not increase theuse of the active moiety. The applicant should refer to 21CFRx25.31(a).

Section XX contains information required by the GenericDrug Enforcement Act and U.S. agent letters of authoriza-tion. All firms mentioned in Sections IX and X of the applica-tion must provide certifications required by the Generic DrugEnforcement Act, often called debarment certifications. In thedebarment certification the applicant must certify that no onewho was in any way involved with the ANDA being submittedis on the current FDA debarment list. The current list is postedin the Office of Regulatory Affairs section of the FDA web site,under compliance references.

In addition, all foreign firms are now required by FDA toappoint a U.S. agent. A copy of the letter from the foreign firmto FDA, usually part of the DMF, which appoints this agentshould be included in Section XX. FDA will send all correspon-dence, such as DMF deficiency letters, to the U.S. agent.

Section XXI is a catch-all section for information that isnot included in the previous sections. References to previouslysubmitted information and copies of literature publicationsfor which English translations are submitted are included inSection XXI. If some or all of this information is not needed,the applicant should so state. For example, state references to

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previously submitted information—none. Even though lettersof authorization for FDA to refer to a DMF on behalf of anapplicantwere submitted in various previous sections, two copiesof each letter are to be included in Section XXI. The applicantmust also certify in Section XXI that a copy of the applicationis being sent to the FDA District Office responsible for thegeographical location in which the applicant is located. ThisField Copy is required to contain all sections of the ANDAexcept the bioequivalence and labeling sections.

Section XXII covers Sterilization Assurance for sterileproduct only. For all other products, Section XXII should say‘‘sterilization assurance not applicable.’’ If the application isfor a sterile product, the review copy of Section XXII shouldbe bound separately from the chemistry review volumes. Thissection will be reviewed by the microbiologists. FDA recom-mends including a copy of the cover letter, package insert label-ing, a summary of the manufacturing process includingthe components and composition statement, and copies of theexecuted batch record containing holding times, filter inte-grity testing, and sterilization records. FDA also recommendsthat the application follow the portions of the Guidance forIndustry on Submission of Documentation for SterilizationProcess Validation in Applications for Human and VeterinaryDrug Products that apply to the process in the application.

5.4. Electronic Submissions

As of July 15, 2000, one may now submit ANDAs in electronicformat in place of paper. OGD placed the ANDA on publicdocket 92S-0251 as a submission acceptable in electronicformat as allowed under 21 CFR Part 11. It should be notedthat Part 11 requires that datasets provided in electronicformat and used in the review process meet the requirementsfor archiving, i.e., protection of those records to enable theiraccurate and ready retrieval throughout the records retentionperiod. It is highly recommended that the applicant discussthe format they plan to use with appropriate OGD staffbefore making a financial commitment to a given electronicsubmission system.



In June 2002 a guidance for industry entitled ProvidingRegulatory Submissions in Electronic Format—ANDAs (18)was implemented by OGD. This guidance indicates that mostfiles should be images in PDF format. It also gives a folderstructure that the applicant should use and other importantdetails. The applicant should be aware that electronic datasets,including those accompanying a paper submission, cannot beconsidered as official and used to support the application if theyare submitted in a file format that is not archivable. In thefuture, as FDA and industry progress in meeting the goalsof use of electronic submissions, compliance with electronicsubmission regulations will be required.

Even if the rest of the application is paper, electronic data-sets must accompany an ANDA application to support thereview of bioequivalence studies. At this time the archival data-set format is SAS Transport. Applicants typically rely on theirbiostudy contract laboratories to create the electronic datasetsin a way that is pleasing to the FDA reviewers.

5.5. Making the Submission User-Friendly

An ANDA, even though it is abbreviated in comparison to anNDA, is not a short document. If the applicant makes it easierfor the FDA reviewer to find the information in the document,the review will go more smoothly. A table of contents for theentire document is required, a copy of which must be in thefront of each volume. Any section that is more than four or fivepages long should have its own table of contents. Make liberaluse of dividers between sections and colored paper or othermarkers between subsections. Do not hide short subsectionsof required information behind longer subsections, even ifthis means you deviate from the order of section informationlisted in the FDA Guidance.

Make your submission easy to read. Use clear language.All information authored by those whose first language is notEnglish should be carefully reviewed by good editors whose firstlanguage is American English. All sections should be reviewedby several editors, as well as those who are responsible for the

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technical contents. Use a clear font and do not make the typesize too small.

Inevitably, your submission will contain some photocopiesof documentation, such as manufacturer’s certificates of ana-lysis. Make sure that every copy you submit is completelylegible. Beware of American copies of European documents.Europeans use paper that is slightly longer, and if copies arenot reduced, information on the bottom will be cut off.

6. RESPONSE TO FDA COMMENTS

One to 3 months after the OGD receives the ANDA, theapplicant can anticipate a letter indicating that the applicationhas been accepted for filing and providing the ANDA number.If there is a relatively small matter preventing OGD fromaccepting an application, the usual procedure is for the projectmanager to call the person who signed the application andexplain what is needed. A very quick response is required. Ifthe application has a serious flaw or if one does not respondquickly to the telephone call, the applicant will receive arefuse-to-file letter.

About 120 days after OGD receives the application, theapplicant should anticipate receiving the first FDA bioequiva-lence comment letter, followed by the chemistry and labelingcomment letter at about 180 days. If the applicant has done agood job of preparing a complete and reviewer-friendly sub-mission, and if there are no difficult scientific issues involved,one might anticipate that the bioequivalence letter might saythat the Division of Bioequivalence has no comments, while thechemistry and labeling letter will require a minor amendment,rather than a major amendment.

In OGD, each reviewer has a computer-controlledwork queue. New applications and major amendments goto the bottom of the queue. Minor amendments go after allother minors already in the queue but ahead of majors andnew applications. The difference is usually about 4 months inturnaround time.



How an applicant responds to the FDA reviewer’s obser-vations is critical to how quickly the application can be appro-ved. Read the observation very carefully. Make sure that yourresponse addresses what the reviewer is asking for. Watch outfor observations that require more than one item in response.Include as much supporting data, as attachments or exhibitsto your response, as is necessary to prove to the reviewer thatyour response is correct.

Sometimes the reviewer will ask for something that wasalready in your original submission. The applicant should con-sider these observations as an indication that the applicationwas not as reviewer friendly as it could have been. Politelypoint out in your response the page number where the infor-mation was located in the original application. It is a good ideato provide another copy as an attachment to the responsefor the reviewer’s convenience.

7. APPROVAL

At this point the applicant who has prepared a complete andreviewer-friendly application and responded carefully andcompletely to all FDA requests for additional information cananticipate a speedy approval. As of this writing the mediantime from submission to approval is 18–24 months. When youare close to approval you may inquire with the OGD ProjectOfficers as to the status of the approval package for yoursubmission. This can help in planning scale-up, validation,and commercial marketing. The latter is, of course, the objec-tive of the entire exercise, a commercial product that canproduce profits for its sponsor.

REFERENCES

1. Approved Drug Products with Therapeutic EquivalenceEvaluations. U.S. Food and Drug Administration, Publishedyearly and updated monthly.

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2. The Drug Price Competition and Patent Term Restoration Actof 1984. United States Congress.

3. Food Drug and Cosmetic (FC&D) Act, United States Congress,section 505(3)(D)(ii).

4. United States Code of Federal Regulations, 21CFR 314.95.

5. 21CFR 313.107(b)(3).

6. Federal Register Vol. 67, No. 206, October 24, 2002, pages65448–65465.

7. USP 26—NF 21, United States Pharmacopeial Convention,2002, section <711>.

8. Guidance for Industry; Bioavailability and Bioequivalence forOrally Administered Drug Products—General Considerations,Draft, U.S. Food and Drug Administration, July 2002.

9. Guidance for Industry; Dissolution Testing of ImmediateRelease Solid Oral Dosage Forms, U.S. Food and DrugAdministration, August 1997.

10. Guidance for Industry; Waiver of the In Vivo Bioavailabilityand Bioequivalence Studies for Immediate-Release Solid OralDosage Forms Based on a Biopharmaceutics ClassificationSystem, U.S. Food and Drug Administration, August 2000.

11. The Pink Sheet, F-D-C Reports, July 15, 2002

12. Guidance for Industry; Food-Effect Bioavailability and FedBioequivalence Studies: Study Design, Data Analysis, andLabeling, Draft, U.S. Food and Drug Administration, October2001.

13. 21CFR 320.22.

14. Guidance for Industry; Immediate Release Solid Oral DosageForms—Scale Up and Post Approval Changes: Chemistry,Manufacturing and Controls, In Vitro Dissolution Testingand In Vivo Bioequivalence Documentation (SUPAC-IR), U.S.Food and Drug Administration, November1995; and Guidancefor Industry; SUPAC-MR: Modified Release Solid Oral DosageForms—Scale Up and Post Approval Changes: Chemistry,Manufacturing and Controls, In Vitro Dissolution Testingand In Vivo Bioequivalence Documentation, U.S. Food andDrug Administration, October 1997.



15. Guidance for Industry; Organization of an ANDA, U.S. Foodand Drug Administration, February 1999, OGD #1 Revision1.

16. Guidance for Industry; SUPAC-IR/MR: Immediate Release andModified Release Solid Oral Dosage Forms, ManufacturingEquipment Addendum CMC 9, Revision 1, U.S. Food andDrug Administration, January 1999.

17. Guidance for Industry, Stability Testing of Drug Substancesand Drug Products, Draft, U.S. Food and Drug Administration,June 1998.

18. Guidance for Industry, Providing Regulatory Submissions inElectronic Format—ANDAs, U.S. Food and Drug Administra-tion, June 2002.

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14

Current Good Manufacturing Practiceand the Drug Approval Process

NICHOLAS BUHAY


Rockville, Maryland, U.S.A.

Employment of current good manufacturing practice (CGMP)and approval of a new drug application (NDA) are two pillarsof federal law providing support of manufacturing quality forpharmaceutical drug products offered to American consumersin the United States marketplace. These requirements areestablished in the Federal Food, Drug and Cosmetic Act(FDCA). In this chapter we will discuss these two requirementsand how they interface with each other in the FDA programsdesigned to execute the mandates of the law.

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The CGMP requirement focuses on manufacturing qualityfor the purpose of assuring that each pharmaceutical drug prod-uct is as safe as the law requires it to be and that it has theidentity, strength, quality, and purity characteristics by whichit is defined in large part. Under FDCA Section 501(a)(2)(B),activities that amount to ‘‘manufacture, processing, packing,or holding’’ of a drug must be performed in conformance withthis current good manufacturing practice. Very explicitly, theCGMP requirement applies to the methods used in performingthe above regulated activities and to the facilities and thecontrols used for these activities in producing a drug.

Pharmaceutical drugs resulting from manufacturingmethods, facilities, and controls that are not operated oradministered in conformance with CGMP are considered tobe adulterated. In essence, their manufacturing quality is notassured to a legally minimum level. They are in violation ofthe law, and they are subject to regulatory actions by theU.S. Food and Drug Administration (FDA).

Section 505(a) of FDCA prohibits in U.S. commerceany ‘‘new drug’’ unless that product is the subject of a properlyfiled application with FDA to place it in commerce and an FDAapproval of the application is effective. A new drug applica-tion (NDA) filed with FDA to meet the requirement to acquireapproval may be disapproved if a number of conditions arenot met. The full list can be found in Sections 505(d)(3) fornew drug applications and 505( j)(4) for abbreviated new drugapplications (ANDAs). Both sections contain the conditions forapproval that the methods used in, and the facilities and con-trols used for, the manufacture are adequate to preserve itsidentity, strength, quality, and purity. It should be noted thatthis is essentially the same expression as the statement of theCGMP requirement. The CGMP requirement assures thatlegally acceptable product attributes result from manufactur-ing operations; all manufacturing-related proposals in the appli-cation for the product must maintain these same attributes.

A new drug application may not be approved if FDAfinds the CGMP to be employed in its production is inadequate.FDA programs for assessment of conformance with the CGMPrequirement use an approach that includes a number of

456 Buhay


variations in inspection action. The variations have beendevised and put into use to satisfy a number of regulatorypurposes as well as management efficiency purposes.

There is no such thing as virtual manufacturing ofpharmaceutical drugs. They are real products fashioned in areal environment with real resources. It is a fundamentalaxiom of the regulatory scheme that this environment, bothphysical and operational, in large part determines the quality,identity, purity, and strength characteristics that have beenestablished for drug products. Conditions and practices inthis manufacturing venue are complex, involving many steps,sophisticated equipment, and many people. This complexityprovides the potential or the occasion for variation or contam-ination that raises concern that the desired fundamental char-acteristics have been put into output products. An inspectionoperation directed at evaluating the ongoing conditions andpractices in the site addresses this concern. Besides the con-cerns for manufacturing in an environment free from obviousconditions like insanitation, there are additional conditions andpractices unique to the industry. Pharmaceutical drug manu-facture is a part of the chemical industry; products are appliedto the living individual. Most pharmaceutical manufacturingoccurs in multiproduct facilities.

Manufacturing operations may create conditions resultingin cross-contamination. An example is chemical ingredientdust generated by equipment operations. Many white powdersare used to produce different products. Each may have avastly different toxicity profile and treatment application.Wrong selection of materials and incorporation in a manu-facturing process has occurred. Manufacturing processes arecomplex, employing many steps and ordered activities to real-ize the object product. Written procedures, preparation ofrecords of actions, and training decrease or eliminate mistakesor variations that have an impact on product attributes. Toensure against manufacturing quality problems resulting fromthis situation, Congress has recognized the value and impor-tance of inspection and established it as a required operationfor the assessment of conformance with the CGMP requirementfor manufacture of pharmaceuticals.

CGMP and Drug Approval Process 457


Periodic inspection of a pharmaceutical manufacturing fac-tory is a specific requirement in the Food, Drug, and CosmeticAct. Section 510(h) requires ‘‘every such establishment engagedin the manufacture, propagation, compounding or processingof a drug or drugs . . . shall be so inspected at least once inevery . . . two-year period.’’ Section 704 of the law discussessome purposes of the inspection and indicates both specific andgeneral items of interest for the inspection. Those items include‘‘processes, controls, facilities, equipment, finished and unfin-ished materials, containers, labeling and records and files.’’

Mandated periodic inspections are performed to assessthe conformance of the factory site to the requirement formanufacture within current good manufacturing practice.The inspections are performed according to instructions pro-vided by an FDA operating procedure called the Drug Manu-facturing Inspections Compliance Program. This complianceprogram is one of a set of such programs established and main-tained to allocate resources for and to guide the performanceof investigative operations for compliance assessment in iden-tified priority regulatory areas. The need for compliance pro-grams is reviewed each year. Compliance programs may beestablished and retired in response to emerging developmentsin the regulated industry.

Because of the enduring priority of assurance againstmanufacturing error and of controlled manufacturing practice,the Drug Manufacturing Inspection Compliance Programhas been and will continue to be a fixture in the overall drugregulatory program of the Center for Drug Evaluation andResearch (CDER).

The outcomes of these inspections are available for use inthe drug approval decision. Pharmaceutical factory sites foundby the inspection to be in acceptable conformance with theCGMP requirement means that manufacturing methods, facili-ties, and controls are operated or administered satisfactorily inthat site. This general conclusion may be applied to the caseof a specific new drug application pending approval, recallingthat one of the approval requirements is that methods used in,and the facilities and controls used for, the manufacture areadequate to preserve its identity strength, quality, and purity.

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It is evident that some extrapolation is done in applying aCGMP inspection conformance assessment to an approval deci-sion for an application. The inspection observes and assessesconditions and practices at a period in the past; a new drugapplication proposes future manufacture. The inspection eval-uates manufacturing operations for products that are differentfrom the product that is the subject of the application. Theproposed product may involve for commercial production somemanufacturing technology not yet in operation at the time ofthe CGMP inspection.

Judgments are made, indirect information is considered;a risk management approach is used. Similarities between themanufacturing experience in place and the proposed productmanufacturing requirements, the complexity of the manufac-turing process and the process controls, the CGMP compliancehistory of the factory site proposed, the physical and toxicolog-ical properties of the materials that may be processed in a site,the completeness of information available supporting a factorysite conformance with the CGMP requirement—all may be usedto decide upon the use and extent of application of a CGMPinspection.

Where an existing report of CGMP inspection is judgedinsufficient for supporting an application approval decision,a special inspection will be scheduled. This is known as thepreapproval inspection. As with CGMP conformance assess-ment inspections, performance of FDA preapproval inspec-tions are organized in a compliance program. This program iscalled the Preapproval Inspections/Investigations ComplianceProgram. The program was established in August 1994,largely in response to the discovery that a number of applicantfirms provided in new drug applications to the FDA unreliable,misleading, and false information. In an investigation thatspanned about 8 years, about 20 companies and 75 individualswere prosecuted for various violations of requirements forsubmission of invalid, incomplete information related to newdrug applications. Such information is essentially worthless forthe process of evaluating the safety and efficacy of a proposednew drug before it is introduced to the marketplace. The pre-approval inspection (PAI) was designed to provide assurances



that the data and information submitted in new drug appli-cations are reliable and that actual conditions and practicesin a given manufacturing facility were adequate to incorporatethe production of a new product.

Since FDA does not have the enough inspection resourcesto perform a PAI for every application received, risk manage-ment principles were incorporated into the program rules forselection of facilities for inspection. Considering the products,PAIs are scheduled for applications proposing products withnew chemical entities, with narrow therapeutic ranges, withthe first generic version of a brand name product, andwith generic versions of the most prescribed drug products.Considering producer firms, PAIs are scheduled when theapplication is the producer’s first and when the producerhas a CGMP compliance history that has been inconsistent,trending down, or noncompliant. Any apparent discrepancy inan application may result in a PAI to investigate the matterthoroughly.

Data and information universally required to be includedin a new drug application document trial manufacture ofthe proposed product and summarize results of various testson samples from the trial manufacture. Trial manufacturemay include one or more batches of the proposed product.Tests include those assessing conformance with the productspecifications, those assessing the manufacturing process, andthose assessing stability of the product in a container-closurepresentation.

PAIs may be performed at any facility providing manu-facturing or control services for and associated data and infor-mation on production of the proposed product. These facilitiesinclude the site where the dosage form is realized, but alsoat contract packagers and labelers, contract test laboratories,contract processors like sterilizers or micronizers, and at pro-ducers of the active pharmaceutical substance chemical andother ingredient chemicals.

A major objective of the PAI was to develop an assur-ance that application data and information are authentic andaccurate. The PAI could include examination of any and allsystems and records used to generate the data and information

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submitted to FDA. Trial manufacture is verified. Investigationof the industry has shown that trial manufacture was not done,that it was done on a much smaller scale than reported, or thatit was done using different procedures than reported. The PAIwill determine if resources were available at the time and placeof the manufacture trial reported. The inspection will look forconsistent and mutually supportive documentation of the man-ufacture. Reported test results are verified. The investigationof the industry has shown that reported tests were not done,the tests were not done on approprite samples, or that resultswere not reported accurately. The PAI determines if testdocumentation supports the test results reported and if testmethods had been developed, validated, and applied correctly.Application data and information from trial manufacture andtests are not all-inclusive; data showing support of the pro-posed product have been reported, while data not supportingthe product have not been included in the application. ThePAI inspection determines if development data not submittedwas properly excluded. Reports of findings in a PAI arereported to the application review division.

PAI findings of data unreliability could cause review ofthe pending application to be suspended; findings of a patternor practice of submission of unreliable data by an applicantcould result in a broad-scope evaluation of many, or even all,of the applicant’s approved new drug applications to determineif those also contained unreliable data. Suspension of review ofany submission by the applicant could be put in place until theapplicant has carried out an adequate corrective action operat-ing plan. Experience has shown that it can take years to clearup the concerns raised by an applicant’s submission of unreli-able data.

These regulatory procedures are implemented under FDACompliance Policy Guide 7150.09 Fraud, Untrue Statements ofMaterial Facts, Bribery and Illegal Gratuities published in theFederal Register on September 10, 1991. Also published withthe policy was another document called ‘‘Points to Considerfor Internal Reviews and Corrective Action Operating Plans.’’This document provides detailed discussion of elements of anadequate plan.



PAI findings may result in the withholding of approval ofa pending application if the findings show that preapprovalbatches were not made in compliance with current good manu-facturing practice or that noncompliance with CGMP mayadversely impact the product that is the subject of the pendingapplication. Drug product dosage form units resulting fromtrial manufacture using the proposed manufacturing procedureare those tested for data and information that will be usedto determine if the product is safe and effective. The dataand information could be difficult or impossible to interpret ifthe tests are made on units that are not uniform or thatinclude an unknown contaminant. Manufacture in compliancewith CGMP assures the quality, identity, purity, and strengthin the products to be tested. Trial manufacturing performed incompliance with CGMP assures that the data and informationused to evaluate the safety and efficacy of the proposed productare interpreted scientifically.

Likewise, PAI findings that indicate that CGMP wouldbe incorrectly applied to the manufacture of the proposedproduct after approval would have to be resolved. Again, theapproval of the application may be withheld until such resolu-tion is achieved. Manufacture in compliance with CGMPassures quality, identity, purity, and strength in the productsto be distributed to the marketplace after approval. Commer-cialmanufacturingperformed in compliancewithCGMPassuresthat the untested units of products sold and used in themarketplace perform in an equivalent manner to the productstested and evaluated for approval.

The CGMP requirement provides support for reduction ofinformation required to be submitted to FDA in a new drugapplication. From the earliest days of the use of the new drugapplication for assuring the safety and efficacy of new drugs,there has been lively debate about the type and amount of dataand information needed for FDA to agree with the applicantproposer that the product may be introduced to the market-place for use by patients. FDA reviewers of applications havebefore them the need to decide on product questions thatwill impact the life and health of patients using them, begin-ning with the very first dosage unit sold. Having no other data

462 Buhay


and information except that before them in an application, anFDA reviewer is encouraged to be sure that all important attri-butes of the proposed product are supported. The producers ofthe proposed product have before them as a matter of presenceand experience vast amounts of data and information about theconditions, practices, and resources used, available, or plannedfor the new product. With this as background, they are encour-aged to interpret differently the needs for the collection,arrangement, and presentation of data and information theyregard as routine or usual.

Reducing required data and information in applicationshas been part of an ongoing FDA process to make the appli-cation process and the review of applications as efficient aspossible while maintaining the high level of public health pro-tection the drug approval process provides. This process hasincluded recognition of an existing CGMP requirement as ade-quate regulatory oversight of an issue being considered for anapplication requirement.

In October 1982, FDA proposed a significant revision tothe regulations that govern the approval process. A major fea-ture of that revision, finalized in February 1985, eliminatedfrom applications substantial information about manufactur-ing practices that had been included in the September 1978revision of the current good manufacturing practice regu-lations. It was recognized that the updated CGMP regulationsset comprehensive standards for drug manufacturing condi-tions and practices that were enforced by required on-siteinspections of manufacturing facilities. The CGMP regulationseliminated the need for application-by-application review ofsome drug manufacturing information.

The same revision cut new drug application recordkeepingrequirements formanufacturing and control data resulting frompostapproval manufacturing of the application product. Thiswas done because adequate record retention requirementsare imposed on manufacturers of drug products under theCGMP regulations.

In April 1992, FDA published final regulations detailingrequirements for abbreviated new drug applications. Duringthe regulation-writing process there had been a proposal for



ANDA applicants to obtain samples and to retain them in theirstability containers for all lots of a finished generic drug pro-duct. This proposal did not need to be accepted because man-ufacturers are already required to retain samples of each lot byexisting CGMP regulations.

In March 1987, FDA published final regulations governingthe submission and review of investigational new drug applica-tions (INDs). That new regulation allowed a sponsor of a newdrug under investigation to perform stability testing concur-rently with clinical investigations of the product because con-current testing was consistent with existing requirements forstability testing in the CGMP regulation. It was noted thatpermitting concurrent stability testing furthers the FDAobjective of speeding up the drug development and approvalprocess.

The application reduction program also includes a largeeffort in publishing guidance documents specifying the formatand content of sections of applications and recommending typesof data and information that will be useful in an efficient reviewof chemistry, manufacturing, and control issues. The latterguidances especially serve to inform the expression of CGMPrequirements as they are applied to the manufacture of theapplication product or products using similar manufacturingprocesses. Most often the application requirement is the sameas the CGMP requirement. Where they are different, the differ-ences are usually in extent of use rather than in the nature of thecompliance expected. An example would be that more frequenttesting might be needed to meet a CGMP requirement than tomeet the requirement for submission of data for the application.

Application guidances and CGMP guidances are developedusing a process that includes cross-program participation.CGMP program representatives sit on work groups developingapplication guidance documents and attend application reviewcoordinating committee meetings that monitor the develop-ment of guidance projects. Draft guidances are distributedto the CGMP program for review and comment at later stagesof preparation. The development of CGMP guidances occurswith representatives of the application review program asparticipants.

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The relationship between the GMP requirement and theapplication approval process continues to develop. In August2002, FDA announced a formal management initiative toupdate the agency’s approach to ensuring manufacturingquality. The initiative, titled ‘‘Pharmaceutical CGMPs for the21st Century: A Risk-Based Approach,’’ will examine closelythe currency of both the CGMP program and the premarketreview of chemistry and manufacturing issues. With a viewtoward the industry, goals identified include incorporationof modern concepts of risk-management, quality systems, andadvances in electronic technology into pharmaceutical manu-facturing control. Specific attention will be given to fashioninga drug regulatory program that will encourage innovation inmanufacturing to enhance efficiency and quality management.From the FDA view, coordination of the application reviewprogram with the CGMP inspection program is to be soughtfor effective, efficient, and consistent application of regulatoryrequirements. The two-year CGMP initiative concluded inSeptember 2004. A full report of findings and goals is publishedon the FDA/Center for Drug Evaluation and Research web site.Many of the goals provide for closer coordination of the CGMPprogram operations and application review activities.

Under certain conditions, FDCA permits exportationof unapproved drug products ordinarily requiring approvalfor interstate commerce. One of the conditions to allow unap-proved products to be shipped out of the United States is thatsuch products are manufactured, processed, packaged, andstored under conditions and practices substantially in confor-mance with the current good manufacturing practice require-ment. This allows manufacture in U.S. factories of productsthat do not meet U.S. requirements for approval but meet aforeign country’s requirements. Of course, they must beintended for use only in the identified foreign country. TheCGMP provision provides basic protections against low-qualityproducts being distributed from a U.S. base and assists foreigngovernments in establishing a level of acceptability for the pro-ducts to be used in their country without conducting expensiveregulatory programs and operations of their own.



Approval of a new drug application does not insulate theproduct that is the subject of the application from the currentgood manufacturing practice requirement. When the new drugapplication requirements were being established, some holdersof applications had contended that the approval process andrequirements made withdrawal of the application the exclusivemethod available to FDA for regulating application products.FDA rejected that contention and established a specific regu-lation explicitly stating the full applicability of the CGMPrequirement to products that are the subject of new drug appli-cations. FDA explained that the approval process was a set ofadditional requirements on the new products in order to makea showing of safety and efficacy.

Thousands of drugs in U.S. commerce are not the subjectof a new drug application. These drugs are legally marketedbecause they are not ‘‘new drugs’’ under the law, and so theyare not required to have an approved application coveringthem. This includes many prescription drugs as well as thevast majority of over-the-counter products. While the appli-cation regulatory pillar for assurance of manufacturing qualityis not available to the FDA oversight program, the CGMPrequirement does apply. CGMP inspections are made toassess methods, facilities, and controls used to make these pro-ducts to ensure that the consuming public gets the productattributes mandated for all drugs by the law. The CGMPrequirement also provides protection against adverse condi-tions and practices in the distribution of drugs not requiredto be submitted for approval in new drug applications.

In the FDA Modernization Act of 1997 (FDAMA), Con-gress again linked CGMP with new drug applications in estab-lishing certain procedures for the regulation of the quality ofa special category of drugs and in establishing an exemptionfrom the federal regulation of quality. Section 121 recognizedthe special characteristics of positron emission tomography(PET) drugs. That section directed FDA to establish specialprocedures for the approval of applications on PET drugs anddirected the preparation of a special CGMP requirement forthese drugs. The agency has prepared draft rules for meetingthese directions and is now conducting a public debate of the

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proposed approaches. The resulting procedures and require-ments will be closely coordinated as a result of their concurrentdevelopment.

A discussion of the regulation of the quality of pharma-ceuticals in U.S. commerce would not be complete withouta discussion of the approach and role of the official compendia.A compendium is a collection of products recognized, by theinclusion in the collection, as having medical value.Standards for each product are specified in monographs. Thethree compendia now recognized are the USP, the NF, and theHomeopathic Pharmacopoeia. Section 501(b) of FDCA providesthat a compendium drug is adulterated if any sample is testedby the method specified and the result falls outside theacceptance limits.

Standards for a new drug established in the FDA appli-cation review process enter the compendium monographupon the product’s acceptance into the compendium. In theapplication review process at FDA, standards for new genericdrugs are closely coordinated with the existing standards ina compendium monograph. Compendia standards for non-application drugs, along with technical information on testing,are accepted as primary guidance in meeting many CGMPrequirements, especially in testing procedures.

DISCLAIMER

This chapter was written by Mr. Buhay in his private capacity.No official support or endorsement by the Food and DrugAdministration is intended or should be inferred.



15

CMC Post-approval RegulatoryAffairs: Constantly Managing

Change

LEO J. LUCISANO and KEVIN A. MILLER

GlaxoSmithKline, Research Triangle Park

North Carolina, U.S.A.

1. INTRODUCTION

You arrive at work this morning feeling refreshed and unbur-dened. Last night was the first time in the last 6 months thatyou had a full and restful sleep. Late yesterday afternoonyou finally received the approval letter for the New DrugApplication (NDA) for your company’s projected blockbusterproduct, and you are savoring the moment. You casually saun-ter to the break room for your morning cup of coffee, take a fewminutes to celebrate with your coworkers, and return to your

469


office, expecting a light day by recent standards. As you waitfor your computer to boot up so you can catch up on the see-mingly infinite backlog of e-mail, the phone rings. You note onthe caller ID display that it’s the marketing director for thenew product. ‘‘She’s probably calling to congratulate me on theapproval letter,’’ you speculate as you reach for the receiver.The tone of her greeting immediately tells you otherwise. Newmarket research data just arrived on her desk that morningindicating that patients preferred a blister package comparedto a plastic bottle. She wants to know if a submission isrequired for a blister package and, if so, how long it will takefor preparation and approval. She indicates that time is ofthe essence to maximize market penetration, as a competitor’sproduct is anticipated to be approved imminently. While speak-ing with the marketing director, you receive an urgent messagefrom your administrative assistant to call the vice-president ofmanufacturing as soon as possible. You tell the marketingdirector that you will research the regulatory implications ofthe proposed packaging change and will call her back with ananswer as soon as possible.

You phone the vice-president, and he tells you that contentuniformity failures have been encountered during processvalidation of the commercial batch size for the new product.To correct the problem, it appears the blending speed and timefor the bulk powder need to be modified. He wants to know ifthe changes have any regulatory implications and commentsthat any production downtime will almost certainly delay thelaunch. You advise that you will research the regulatory impli-cations of the proposed manufacturing change and will call himback with an answer as soon as possible. ‘‘Well, so much forthe light day,’’ you think to yourself as you hang up the phone.What will you do?

While the above scenario is fictitious, it is an accuratedepiction of the dynamic world of Chemistry, Manufacturing,and Controls (CMC) (referred to by the authors as ‘‘constantlymanaging change’’) Post-approval Regulatory Affairs. Thischapter provides an overview of the scope of CMC post-approvalregulatory affairs, the recent U.S. history of CMC post-approvalregulations and their current status, the different types of

470 Lucisano and Miller


regulatory submissions to file CMC changes, and the rela-tionship of Current Good Manufacturing Practice (cGMPs)regulations to CMC post-approval activities. Measurements ofperformance are suggested to gauge the effectiveness of the CMCpost-approval regulatory function, and commentary is providedregarding the development of professionals in this field. Thechapter concludes with a discussion of the forces affecting thefuture of this expanding arena of regulatory oversight.

2. CMC POST-APPROVAL REGULATORYAFFAIRS OVERVIEW

CMC regulatory affairs is concerned with the technical char-acteristics of a drug molecule and the dosage form used for itsadministration. The regulatory affairs professional is responsi-ble for assuring that sufficient CMC knowledge is accumulatedabout the molecule to permit evaluation by the U.S. Food andDrug Administration (FDA) through the product life cycle.Table 1 depicts a typical list of CMC information required forevaluation.

In the pre-approval phase of the product life cycle, CMCinformation is initially provided to FDA through the applica-tion of an Investigational New Drug (IND). Depending on theoutcome of clinical trials conducted under the IND, an NDAmay be filed with an additional level of CMC information that

Table 1 CMC Database for a New Drug Application

Drug substance Drug product

Physicochemical properties Components and compositionSynthetic process ManufacturersControls for starting materials,

reagents, etc.Method of manufacturing and

packagingProcess controls for intermediates Specifications and analyticalSpecifications and analytical methods methodsList of impurities Stability informationStability and life to retest

CMC Post-approval Regulatory Affairs 471


may result in approval of the drug product and its commercial-ization. The CMC section of the NDA establishes the approvedconditions for manufacturing and testing the drug substanceand its dosage form(s). In the post-approval phase the regula-tory affairs professional is responsible for managing changes tothese conditions.

Table 2 compares the different environments encoun-tered during the two phases of the product life cycle. Prior toapproval of the NDA, the CMC regulatory professional inter-acts primarily with a research and development (R&D) teamthat is dedicated to developing the body of information requiredto gain FDA approval of the drug product. The sequence ofsteps from the application of the IND to NDA approval takesseveral years, and the process is well defined. Various initia-tives supported by FDA, such as the International Conferenceon Harmonization, provide a clear roadmap regarding the CMCinformation and data that need to be accumulated to adequa-tely characterize a new drug product and its active ingredient.

Following approval of the NDA, the CMC regulatoryprofessional interacts primarily with marketing and manufac-turing, whose priority is to maximize the commercial poten-tial and return on the investment of the drug product.These drivers may result in a stream of requested changes tothe originally approved CMC conditions in the NDA. Unlike

Table 2 Comparison of CMC Regulatory Environments

Pre-approval Post-approval

Type of submissions INDs and NDAs Supplemental NDAsAnnual ReportsCMC Commitments

Internal customer R&D ManufacturingCustomer priority Supporting INDs

and NDAsManufacturing product

Timelines Months and years Weeks and monthsFormat of submission Well-defined Less definedReference base of

informationBeing developed as

part of the NDAApproved conditions in

NDA


(Refer to www.ich.org for additional information.)


http://www.ich.org

R&D, the productivity of the manufacturing environment ismeasured in weeks and months, and multiple changes to thedrug substance and/or drug product often need to be evalua-ted and implemented in a parallel timeframe. Additionally, theapproval of an NDA often results in a number of CMC post-approval commitments that must be fulfilled, including thestatutory requirement to file Annual Reports. The regulatoryprofessional supporting these CMC post-approval activitiesmust be diligent in providing regulatory oversight and strate-gies that ensure that CMC changes are implemented in a rea-sonable time frame while adhering to appropriate regulations.

3. CMC POST-APPROVAL REGULATIONSAND GUIDANCE

In order to make CMC changes to the conditions of approvalin the NDA, the drug manufacturer must file the changes withFDA through one of the various types of post-approval submis-sions described below. An appropriate level of information anddata must be included in the submission to demonstrate thatthe changes do not adversely affect the quality attributes of thedrug substance and/or drug product.

Prior to 1997 the regulation governing CMC changesto an approved New Drug Application was 21 CFR 314.70(Supplements and Other Changes to an Approved Application)(1). This statute was established in February 1985 as partof a comprehensive effort to improve the NDA and post-approval application process. It defined three reporting catego-ries for post-approval changes: (a) prior approval supplement,(b) changes being effected supplement, and (c) Annual Report.

In practice, the provisions in the original version of 21CFR 314.70 were vague, and the interpretation and reviewof CMC changes by different review divisions within FDAwere inconsistent. The situation led to increasing criticism bythe pharmaceutical industry that the post-approval regulationsstifled changes in the manufacturing environment.

On November 21, 1997, the Food and Drug ModernizationAct was signed into law by the President. Section 116 of the



Act required that 21 CFR 314.70 be revised to streamline theregulatory process for CMC post-approval changes. Two yearslater 21 CFR 314.70 expired without an updated version inplace. As a result FDA issued an interim guidance document,Guidance for Industry: Changes to an Approved NDA or ANDA(CANA), that has been the current reference for determiningthe appropriate regulatory submission for CMC post-approvalchanges (2). In April 2004 the revised 21 CFR 314.70 rule waspublished, and the CANA Guidance was updated accordingly.The final rule became effective on June 22, 2004.

The revised rule and CANA Guidance retained the samereporting categories identified in the original rule but expandedthe Changes Being Effected (CBE) Supplement into two types,CBE-30 and CBE-0. They also linked the submission reportingcategory to the potential for a change to have an adverseeffect on the identity, strength, quality, purity, or potency ofa product as it relates to the safety or effectiveness of theproduct. By establishing this link, the revised rule and CANAGuidance integrated the quality and regulatory perspectivesin evaluating CMC changes.

The revised rule and CANA Guidance providerecommended filing categories for changes to the following:(a) components and composition, (b) manufacturing sites,(c) manufacturing process, (d) specifications, (e) packaging,(f ) labeling, (g) miscellaneous changes, and (h) multiple relatedchanges. However, neither defines the information and datarequired in the application. Recommendations regarding theappropriate information and data package required to assessthe impact of CMC changes are contained within the battery ofguidance documents issued by FDA in recent years. The con-tent of information and data packages may also be dependentupon historical precedence with a particular drug substance

a spectrum of guidance documents that the CMC post-approvalregulatory professional can consult in determining the appro-priate submission category and supporting data and informa-tion package to appropriately assess and file changes.

FDA issued the first guidance document in 1995 thatspecifically addressed CMC post-approval changes, namely the


and/or drug product and FDA review division. Figure 1 depicts


Guidance for Industry: Immediate Release Solid Oral DosageForms: Scale-Up And Post-Approval Changes: Chemistry,Manufacturing and Controls; In Vitro Dissolution Testing;In Vivo Bioequivalence Documentation (3) (commonly knownas the SUPAC-IR Guidance). Since that time the FDA Centerfor Drug Evaluation and Research has issuedmore than 20 addi-tional guidance documents in draft and final form (4–25). Theyrange from covering changes to specific dosage forms to addres-sing relevant scientific and technical topics in assessing change(e.g., equipment design and dissolution testing). Many conceptsand the vocabulary introduced in these post-approval docu-ments have now been embedded into the New Drug Applicationprocess. Examples include the terminology associated with thedesign and operating principles of manufacturing equipment, aswell as the various approaches to demonstrating dissolutionsimilarity when changes are made to the drug product.

4. CMC POST-APPROVAL REGULATORYSUBMISSIONS

lists the types of CMC post-approval submissionsaddressed in the revised rule and CANA Guidance.

4.1. Prior Approval Supplement

A Prior Approval Supplement is required for a CMC changethat has a substantial (major) potential to have an adverse

Figure 1 Regulations and guidance affecting CMC post-approvalchanges.


3Table


effect on the identity, strength, quality, purity or potency of theproduct as they may relate to its safety or effectiveness. Its titleis self-defined, meaning that FDA must approve the changebefore drug product incorporating the change can be distrib-uted for patient consumption. Occasionally, a Prior ApprovalSupplement may need to be approved as soon as possible inthe interest of the public health (e.g., drug shortage) or if adelay in implementation will cause extraordinary hardship onthe drug manufacturer (26,27). When these situations arise,the applicant can request an Expedited Review of the supple-ment. The supplement should be clearly labeled Prior ApprovalSupplement—Expedited Review Requested, and a justificationfor the request should be provided in the accompanying coverletter (26).

4.2. Changes Being Effected Supplement

A Changes Being Effected Supplement is required for a CMCchange that has a moderate potential to adversely affect thedrug product as it relates to its safety or effectiveness. The1999 CANA guidance provided for two types of ChangesBeing Effected supplements: (1) Supplement–Changes BeingEffected in 30 Days (CBE-30) and (2) Supplement–ChangesBeing Effected (CBE-0). The revised 21 CFR 314.70 rule andCANA Guidance have retained these filing categories.

Table 3 Types of CMC Post-approval Submissions

Submission typePotential impacton product quality Implementation

Prior ApprovalSupplement

Major (substantial) 4–6 months followingsubmission

Changes Being EffectedSupplement—30 Day

Moderate 1 month after FDAreceipt of submission

Changes Being EffectedSupplement—0 Day

Moderate Immediately upon FDAreceipt of submission

Annual Report Minor (low) Immediate—filedyearly on anniversarydate of NDA approval



A CBE-30 Supplement requires that an applicant wait atleast 30 days following receipt of the submission by FDA beforedistributing product incorporating the change. This waitingperiod permits FDA to conduct a cursory review of the supple-ment to assess if the proposed change has been filed in theproper reporting category and is supported by a sufficientdata package to justify its implementation (1,2). Unlike aCBE-30 Supplement, a CBE-0 Supplement does not require awaiting period. Drug substance/product incorporating thiscategory of change can be distributed immediately followingreceipt of the submission by FDA.

4.3. Annual Report

The Annual Report is a periodic, postmarketing submissionrequired by 21 CFR 314.81(2) (other postmarketing reports)(28). From a CMC perspective its purpose is twofold: it pro-vides a reporting mechanism for changes that are considered tohave minimal potential to adversely affect the drug product,and it serves as a conduit for providing updates to nonsupple-mental post-approval commitments (e.g., stability updates).Unlike changes requiring supplemental applications, annualreportable changes are filed after implementation has alreadytaken place and do not undergo a formal review and approvalprocess. However, FDA has the authority to disagree with achange filed in the Annual Report and require the submissionof a supplemental application if the Annual Report filing cate-gory is deemed inappropriate for the change or additional infor-mation is requested to support the change.

4.4. Impact of Revised 21 CFR 314.70 Rule andCANA Guidance

The Food and Drug Modernization Act in 1997 was intended tostreamline the regulatory process, and the revised 21 CFR314.70 rule and CANA Guidance that emerged has accom-plished this objective in several areas of CMC changes. Forexample, a move to a different manufacturing site for a drugsubstance intermediate can now be reported in an Annual



Report, where previously it required the submission of a PriorApproval Supplement.

However, the revised rule and guidance also increased theregulatory burden for other types of changes. For example, achange in a packaging component that controls the dose deliv-ered to the patient (e.g., the valve of a metered dose inhaler)now requires a Prior Approval Supplement, whereas underthe original 21 CFR 314.70 rule it was possible to file thischange in an Annual Report.

The revised rule and CANA Guidance (Section IV, Assess-ment of the Effects of the Change) also require that the effectsof any CMC changes be assessed by the holder of the applica-tion regardless of the submission category required to reportthe change. Assessment includes evaluation of the postchangeproduct to assure that the changes do not negatively affectthe quality attributes of the drug product. This may requireadditional testing beyond that required by the specificationsapproved in the NDA. If an assessment concludes that thechange has an adverse impact and the applicant still desiresto implement the change, then the applicant must file a PriorApproval Supplement for the change, regardless of the recom-mended filing category for the change being considered.

5. CURRENT GOOD MANUFACTURINGPRACTICES AND CMC POST-APPROVALREGULATORY AFFAIRS

The previous sections described the various submission mecha-nisms and information requirements for supporting CMCpost-approval changes. However, the submission process is notconducted in isolation. Many complementary activities occurbefore, during, and after the submission to comply with cGMPs,and these activities are described below.

5.1. Change Control

Change control is required by 21 CFR 211.180(e) (GeneralRequirements) and entails proper review, assessment,



implementation, and adherence to written procedures formaking CMC changes (29). A drug manufacturer’s changecontrol process is frequently scrutinized by FDA duringinspections and is often the subject of objectionable citationsin inspection reports. An effective change control system is thefoundation for successful management of CMC post-approvalchanges.

In providing the appropriate regulatory perspective toa change control request from manufacturing, four stepsare conducted by the CMC post-approval regulatory affairsprofessional:

1. Define the change: This may require several itera-tions of discussion with the manufacturing site inorder to understand the change(s) being propo-sed. For example, a change request may specify thatthe site is considering a batch size change. This typeof change may require related changes to equipmentand process. The full extent of the changes mustbe understood in order to provide comprehensiveregulatory advice.

2. Establish the regulatory basis for the change:Once the true extent of the changes is elucidated, thechange scenario needs to be evaluated againstthe context of the approved conditions in the NDAfile and current FDA guidance. A small change inbatch size for an immediate-release solid dosageform, with no additional changes, is categorized asan annual report change in Section VII.D.1 of theCANA Guidance. If multiple changes are requiredto attain the increase in scale, Section XII (MultipleRelated Changes) of the Guidance requires that thefiling category be defined for each individual changeand the most restrictive filing category applied. Ifthe increase in scale requires adopting equipmentof different design and operating principles, a PriorApproval Supplement would be required to imple-ment the sum of the changes.



3. Determine the data and information requiredto assess and implement the change: This infor-mation can be obtained from the various guidancedocuments issued by FDA that address specific dosageforms and regulatory topics, as well as prior experi-ence with FDA in implementing related changes.In the above example, the SUPAC IR Guidance wouldprovide the information and data package requiredto support the changes in scale and equipment (3).The guidance document on dissolution testing addres-ses the considerations in developing and evaluatingcomparative dissolution profiles to assess the impactof the changes on the release profile of the drugproduct (7).

4. Provide the appropriate regulatory advice: Oncethe above steps have been completed, a recommenda-tion should be prepared that integrates the regula-tory, quality, and commercial aspects surroundingthe proposed change(s) to the drug product. It maybe as straightforward as communicating the requiredregulatory submission and the associated datapackage, or it may require that the change not beprogressed at this time due to mitigating circum-stances. In the example of the batch size increase,the regulatory affairs professional might be awarethat an alternate supplier of the drug substance isbeing considered. Consequently, it may be prudentto advise the manufacturing site to delay the evalua-tion of the batch size increase and equipment changefor the drug product until a supply of the alternatesource of the drug substance is available for con-comitant evaluation.Occasionally, the filing category cannot be defined

until the information and data package requiredfor the submission has been provided for assess-ment. In this case a two-stage response may berequired from the regulatory affairs professional. Theinitial response describes the submission require-ments, regardless of filing category, and includes



a statement that the reporting category will be deter-mined when the data and information package hasbeen assembled and assessed. Upon completion ofthe assessment, a second (final) response is providedconfirming the appropriate filing category for the pro-posed change. A flow diagram of a two-stage regula-tory response is provided in Figure 2.

5.2. Validation

Post-approval CMC changes that pertain to the manufacturingprocess or analytical method of a drug substance or drug pro-duct may have validation implications. cGMPs (21 CFR211.100 and 211.160) require that manufacturing processesand analytical methods be appropriately validated (30,31).The implementation requirements of a CMC change mayinclude revalidation of the manufacturing process or analyticalmethod, even if the change does not require a submission.Regardless of whether a submission is required, validationdocumentation should be available for FDA inspection pur-poses to support the implemented change.

Figure 2 CMC regulatory change control—two-stage process.



5.3. FDA Inspections

FDA periodically inspects manufacturing and testing facilitiesfor adherence to cGMPs, and inspections may require involve-ment by the CMC post-approval regulatory professional depen-ding on their purpose. In a general inspection questions aboutthe regulatory advice provided in a change control proposalmay arise, and the regulatory professional must be preparedto respond accordingly. Other inspections may be the directresult of a CMC post-approval submission, in which case theregulatory representative is likely to be a member of the coreinspection team or possibly even the inspection team leader.In either case the regulatory affairs professional must bethoroughly knowledgeable of relevant regulations and sub-mission information, as well as the systems and processesused by the manufacturing site for managing CMC changes.This overview is required to interact effectively with FDAinspectors and facilitate a successful outcome of the inspection.

6. PERFORMANCE MEASURES FOR CMCPOST-APPROVAL REGULATORY AFFAIRS

The manufacturing environment that is the primary internalcustomer of the CMC post-approval regulatory affairs pro-

number of recalls, batch rejects, cost of goods, and utilizationof manufacturing capacity. Similarly, a number of performancemeasures can be used to gauge the activities within CMC post-approval regulatory affairs.

6.1. PDUFA Goals and First-Time Approvalsof sNDAs

The Prescription Drug User Fee Act of 1992 (PDUFA) defined

provides the action dates for supplements reviewed in the fiscalyear 2004. These goals are intended for FDA’s Office ofPharmaceutical Sciences and provide a level of predictabilityregarding the timing of feedback and the acceptability of


fessional is monitored by various measurements such as the

FDA review targets for manufacturing supplements. Table 4


changes filed through sNDAs. After review is completed, anaction letter is issued indicating that the supplement isapproved, approvable upon resolution of deficiencies found inthe application, or not approved (32). If an Approvable letter isissued subsequent to the implementation of a change filedthrough a CBE or CBE-30 Supplement, generally the manufac-turer can continue to distribute the post-change product whileaddressing the deficiencies unless FDA specifically objects(1,2,20).

While the PDUFA Goals establish guidelines for timelyreview, a regulatory affairs group is in the business of obtain-ing approvals, and goals should be set with respect to achievingapproval of supplemental New Drug Applications (sNDAs)within the PDUFA time frame. A low percentage of first-timeapprovals is an indication that the sNDAs being filed do notprovide a sound regulatory justification for the changes orthat an insufficient information and data package is providedto support the changes. It may also signal a poor rapportwith the particular FDA review division within the Office ofPharmaceutical Sciences that may need to be addressed.

6.2. Submission of Annual Reports

Section 21 CFR 314.81(2) requires that Annual Reports be sub-mitted within 60 days of the anniversary date of the approvalof the New Drug Application (28). A CMC post-approval groupshould strive to collaborate with the manufacturing sites to

Table 4 FDA Review Goals for Manufacturing Supplements

Supplement categoryPDUFA goal FY2004a

(Oct. 1, 2003–Sept. 30, 2004)

Prior ApprovalSupplement

90% reviewed and acted upon within 4 months

Changes Being EffectedSupplement-30 Day


Changes Being EffectedSupplement-0 Day


aPDUFA—Prescription Drug User Fee Act of 1992 provided FDA additional resources

for accelerated drug evaluation without compromising review quality.



compile and submit the CMC section of the Annual Reports ontime. A consistent trend of providing late Annual Reports or onesthat are lacking in sufficient detail may affect the Agency’sreview of related supplemental applications.

6.3. CMC Commitments

Both NDAs and supplemental applications are often approvedwith commitments to provide additional data once themanufacturer has gained a greater level of experience withthe drug product and related changes. The post-approval CMCfunction needs to monitor these commitments and assure thatthe firm appropriately fulfills its obligations according tothe deadline specified by the FDA or proposed by the drugmanufacturer.

6.4. Continuity of Supply

Situations sometimes arise that may prevent the manufactureof the drug product according to the approved conditions ofan NDA. For example, an accident at a packaging site mayprevent it from continuing operations, or a supplier of a keycomponent (e.g., drug substance or packaging material) may nolonger be able to maintain inventory.

In these situations the CMC post-approval regulatoryaffairs professional may be able to negotiate a strategy withthe appropriate branch of FDA to quickly restore supply. Forexample, the review division may grant Expedited Review ofa Prior Approval Supplement for an alternate supplier of thedrug substance if the currently approved supplier can no longermanufacture the drug substance. Successful negotiations underthese circumstances reflect active engagement by the CMCpost-approval regulatory affairs professional.

6.5. NDA Conformance

Site inspections conducted by FDA may result in observationsof nonconformance to the approved conditions in the NDA. Thefirm’s quality organization may also conduct internal audits toverify site practice and correct conditions of nonconformance



to the NDA. These instances typically point to a lapse in com-munication between the manufacturing site and the CMC reg-ulatory affairs function. A useful measurement of the adequacyof the change control process is to track the number of NDAnonconformance observations resulting from these externaland internal audits.

6.6. Due Diligence (Divestments)

Pharmaceutical companies seeking to purchase an establishedproduct conduct a due diligence exercise prior to purchaseto assess the status of the CMC aspects of the NDA file.The buyer seeks to verify that all commitments to the FDAhave been met and that there are no regulatory deficien-cies that may result in nonconformance or jeopardize supplyfollowing the sale. For example, the analytical testing of an olderproduct may not meet current standards such that it maybe viewed as a regulatory risk. A product that is well managedby the CMC post-approval regulatory function should facili-tate the current application holder’s efforts to divest the drugproduct.

6.7. Regulatory Strategies and Cost Savings

In a complex supply chain in which multiple sites supply eitherthe drug substance and/or drug product, CMC regulatoryaffairs may be the only department that has a comprehensive

illustrates the number of changes that may be simultaneouslyaffecting a drug product and its active pharmaceutical ingre-dient in a global supply chain. From this vantage point theregulatory affairs professional has the opportunity and bearsthe responsibility to recommend that various changes beassessed concurrently or staged in a reasonable manner.The data required to support CMC post-approval changesoften cost tens, sometimes hundreds of thousands of dollars,and it may be possible to evaluate several changes in an inte-grated set of experiments (e.g., reducing the number of stabi-lity studies to evaluate multiple changes through a matrixapproach) (11).


overview of the various changes affecting the NDA. Figure 3


7. DEVELOPMENT OF THE CMC POST-APPROVAL REGULATORY AFFAIRSPROFESSIONAL

The competencies required for effectively supporting the CMCpost-approval regulatory arena differ somewhat from the CMCpre-approval arena due to differences in customer base and thetypes of submissions that are filed to the FDA. Figure 4 depictsthe steps associated with the development of a post-approvalregulatory affairs professional. These steps are described ingreater detail below.

Figure 3 Change control in a global supply chain.

Figure 4 Career development in CMC post-approval regulatoryaffairs.



7.1. Change Control

Change control is fundamental to CMC post-approval regula-tory affairs and is the area in which new personnel shouldstart in order to develop a sound foundation in the field.Addressing change control inquiries from the manufacturingsites requires the regulatory professional to evaluate thechange, research the drug product history in the NDA file,and read the pertinent regulations and guidance. This informa-tion must then be interpreted and articulated in a succinct,clearly written response to the customer at the manufacturingsite.

7.2. CMC Conformance Guides

CMC Conformance Guides are a distillation of the conditionsapproved in the NDA for the drug product and its active ingre-

Conformance Guide for a tablet formulation. Compiling a CMCConformance Guide for a product that has been marketed forseveral years requires researching the entire NDA file to estab-lish the currently approved CMC conditions. Developing andmaintaining CMC Conformance Guides is a worthwhile activityfor the regulatory affairs professional. The guides provide areference tool for both regulatory affairs and the manufac-turing sites in the regulatory ramifications ofproposed changes.

7.3. Annual Reports

The compilation of Annual Reports is the next appropriate stepfor the CMC post-approval regulatory affairs professional.It requires a review of the data and information provided bythe manufacturing sites to support the filed changes with across check to the change control advice provided earlier forthose changes.

Annual Reports also contain an updated stability profile ofthe drug substance/product that requires a critical review bythe CMC post-approval regulatory affairs professional. Thedata reported need to be consistent with approved stability


determining

dient(s). Table 5 is a representative table of contents of a CMC


Table 5 Contents for CMC Conformance Guide for TabletFormulation

I. Product description

A. Name, dose formB. NDA numbersC. List of approved pack configurations with NDC codesD. Outstanding commitmentsE. Approval date

II. Drug product

A. Components

B. Composition

C. Specifications and analytical methods for inactive-components1. Inactive components included in the USP/NF2. Inactive components not included in the USP/NF3. Quality control of inactive components

D. Manufacturers1. Name and address of manufacturer(s), packager(s), tester(s),

and what part is done by each2. List of DMF references (if any)

E. Method of manufacture and packaging1. Description of the manufacturing process2. In-process controls3. Reprocessing/Rework operations4. Container–Closure system

a. Bulk product containerb. Bottlesc. Child-resistant closuresd. Blister pack

F. Specifications and analytical methods1. Sampling plan (if any)2. Specifications3. Description of analytical methods and any alternates

G. Stability information1. Stability protocols2. Storage conditions and expiration dating3. Other

a. Commitment for on-going studiesb. List of batches for continued monitoring (if applicable)c. Analytical methods used during stability studies

III. Index of approved changes

IV. History of changes



protocols and support the approved retest date/shelf life for thedrug substance/product while being reported in a format con-sistent with current FDA guidance (33). Fulfilling this respon-sibility may require the CMC post-approval regulatory affairsprofessional to have several iterations of discussion with themanufacturing sites involved with the Annual Report.

7.4. Simple sNDAs

Understanding the process and obligations associated withfiling the CMC Section of the Annual Report leads to the abilityof the post-approval CMC regulatory affairs professionalto compile and submit sNDAs. Working on submissions thataddress a single change (e.g., change in analytical testing site)and progressing to submissions that combine multiple changes(e.g., change in manufacturing site coupled with changes inpackaging and testing) is a logical progression. Starting withthe less complex type of CMC submission allows the matur-ing professional to gain an understanding of the review andapproval process for sNDAs. Filing a supplemental NDArequires the post-approval regulatory affairs professional tounderstand the responsibilities associated with being a‘‘responsible agent’’ for the NDA holder and to begin inter-acting with FDA personnel, such as project managers andmembers of the CMC review team.

7.5. Complex sNDAs

With time and experience the regulatory affairs professionalcan support very complex supplemental NDAs, such as thoserequiring a biostudy or biowaiver to gain approval of CMCchanges. Examples include reformulation of a drug productor a manufacturing site change associated with a modified-release solid oral dosage form. These complex sNDAs oftenrequire meetings with FDA in which the regulatory affairsprofessional needs to submit a formal meeting request with anaccompanying Information Package. The Information Packageoutlines the issues that need to be resolved and the supportingdata that are the basis for discussion at the meeting (34). Theregulatory affairs professional is expected to chair the meeting



with FDA and to appropriately prepare the project team anddirect the dialogue during the meeting to achieve the desiredoutcome.

7.6. FDA/Industry Interactions

After gaining proficiency with complex sNDAs and chairingmeetings with FDA, the CMC post-approval regulatory affairsprofessional likely has achieved the experience, confidencelevel, and stature to participate in FDA/industry interactions.Activities include giving presentations at professional meetingsor assisting in workshops that address CMC regulatory issues.It typically takes several years to progress to this level ofdevelopment.

8. THE CMC POST-APPROVALREGULATORY PROFESSIONALAS THE ‘‘RESPONSIBLE AGENT’’

All regulatory submissions are accompanied by FDA Form 356hsigned by the regulatory affairs professional acting as a ‘‘respon-sible agent’’ for the drug manufacturer (35). The form includesa number of certification statements that define the scope ofresponsibility associated with this role. They require that theregulatory professional attest to the veracity of the informationprovided in the supplement and assure that the application com-plies with all applicable laws and regulations, including adher-ence to cGMPs. It also includes a reminder that it is a criminaloffense to willfully provide fraudulent information.

The role of acting as a responsible agent is what differ-entiates the CMC regulatory affairs professional from otherfunctional groups involved with compiling and submitting apost-approval application. Although the regulatory affairs pro-fessional does not generate the data and information includedin a CMC submission, specific measures need to be taken toassure the authenticity of its contents.

Such steps may include reviewing source documentationhoused at the manufacturing site, which may not be included



in the application. Examples include internal technical reports,supplier specifications, and batch records. The regulatory affairsprofessional may also conduct a submission audit at the site asa double check prior to submission. These measures providethe necessary checks and balances to assure that the regula-tory affairs professional fulfills the associated requisite obliga-tions of the responsible agent while at the same time becomingfamiliar with the systems utilized by the site to evaluate andsupport manufacturing changes.

9. FUTURE OF CMC POST-APPROVALREGULATORY AFFAIRS

The SUPAC-IR guidance issued in November 1995 was thefirst guidance document that specifically addressed CMC post-approval changes, and it marked the beginning of a transfor-mation in the level of sophistication in this regulatory arena(3). It provided a scientific basis for the evaluation of changesto an approved product and introduced a new vocabulary withwhich to discuss these changes.

The publication of the SUPAC-IR Guidance coincided witha trend toward consolidation of the pharmaceutical industrythat spurred a number of mergers and acquisitions. Thisoften resulted in an overabundance of desired manufacturingcapacity for an acquiring or postmerger firm requiring theclosure of a number of manufacturing sites. Drug substance/product transfers require active management by the CMC post-approval regulatory affairs function and increase the impor-tance of this role in supporting the manufacturing environment.

A number of business and regulatory drivers will likelycontinue to increase the complexity and demand for specializedCMC post-approval regulatory affairs support. Developinga new medicine takes 10–15 years and costs approximately$800 million (36–38). Consequently, timelines are constantlybeing shortened in the NDA pre-approval phase to reduce thetime to market. These pressures may result in non-optimizedmanufacturing processes or analytical specifications that



require post-approval modification. Advances in manufactur-ing experience and technology provide opportunities toreduce production costs and increase profitability, while con-sumer preference is ever-dynamic and satisfying this need willrequire continual changes in product presentation to maintainmarket share.

The regulatory environment also continues to evolve, andseveral ongoing initiatives will present new challenges for CMCpost-approval regulatory affairs:

9.1. FDA Initiative for Process AnalyticalTechnologies

In February 2002 FDA launched a new initiative called ProcessAnalytical Technologies (PAT), a ‘‘system for designing,analyzing, and controlling manufacturing through timelymeasurements (i.e., during processing) of critical quality andperformance attributes of raw and in-process materials andprocesses with the goal of ensuring final product quality’’

information.)On September 23, 2003, FDA approved the first PAT sub-

mission. It provided for the adoption of rapid microbiologicalmethods for product release using a Comparability Protocolfiled as a Prior Approval Supplement (40,41). The regulatoryreview and approval process for the implementation of PAT isstill evolving but holds the promise of having a major impacton the CMC post-approval environment. The initial thrust forPAT will be its application to approved products throughthe filing of sNDAs with the subsequent application to newproducts through NDAs occurring after the utility of PAThas been established.

9.2. Globalization of the RegulatoryEnvironment

The efforts invested in the International Conference on Harmo-nization and the Common Technical Dossier continue to makeprogress in defining global standards for the content and formatof regulatory submissions (42–44). Although these advances will


(39). (Refer to www.fda.gov/cder/OPS/PAT.htm for additional


http://www.fda.gov

initially have their greatest impact on new applications (INDsand NDAs), they will establish a new reference upon which toevaluate and file the changes made after product approval.

9.3. Electronic Publishing

The future may see the electronic filing of all regulatory sub-missions throughout the product life cycle (45). Although mostcompanies are focusing on applying this technology to the NDAprocess and clinical sNDAs, it will eventually find its way intoCMC post-approval submissions. This will pose a challenge tothe CMC post-approval regulatory affairs professional to inte-grate the requirements for electronic publishing into themanufacturing environment.

10. CONCLUSION

Recall that at the beginning of this chapter, the fictional CMCpost-approval regulatory affairs professional faced a day ofunexpected changes that required urgent attention. Continuingthis story, the regulatory affairs professional had to reviewthe CMC section of the NDA files, consult FDA guidancedocuments, interact with various functional groups withinthe company, and potentially contact the FDA to address thechange scenarios posed by marketing and manufacturing. Asthe day concluded, the regulatory affairs professional was ableto offer a variety of regulatory strategies and timelines to assuretimely supply of the drug product and address marketing pre-ferences within the boundaries of the approved conditions of theNDA and current FDA regulations and guidance. Such is a typi-cal day in the career of the CMC post-approval regulatory affairsprofessional—constantly managing change.

ACKNOWLEDGMENTS

The authors are gratefully indebted to Lorien Armour for hermeticulous research and Christie Ahlheit for her word proces-sing expertise in completing the manuscript.



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2. FDA, Center for Drug Evaluation and Research, Changes to anApproved NDA or ANDA, Guidance Document (April 2004).

3. FDA, Center for Drug Evaluation and Research, ImmediateRelease Solid Oral Dosage Forms: Scale-Up And Post-approvalChanges: Chemistry, Manufacturing and Controls; In VitroDissolution Testing; In Vivo Bioequivalence Documentation,Guidance Document (November 1995).

4. FDA, Center for Drug Evaluation and Research, SterilizationProcess Validation in Applications for Human and VeterinaryDrug Products, Guidance Document (November 1994).

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8. FDA, Center for Drug Evaluation and Research, ExtendedRelease Oral Dosage Forms: Development, Evaluation, andApplication of In Vitro/In Vivo Correlations, GuidanceDocument (September 1997).

9. FDA, Center for Drug Evaluation and Research, SUPAC-MR:Modified Release Solid Oral Dosage Forms: Scale-Up and Post-approval Changes: Chemistry, Manufacturing, and Controls, InVitro Dissolution Testing, and In Vivo Bioequivalence Docu-mentation, Guidance Document (October 1997).

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11. FDA, Center for Drug Evaluation and Research, Stability Test-ing of Drug Substances and Drug Products, Draft GuidanceDocument (June 1998).

12. FDA, Center for Drug Evaluation and Research, Metered DoseInhalers (MDI) and Dry Powder Inhalers (DPI) Drug Products:Chemistry, Manufacturing, and Controls Documentation, DraftGuidance Document (November 1998).

13. FDA, Center for Drug Evaluation and Research, SUPAC-SS:Nonsterile Semisolid Dosage Forms Manufacturing EquipmentAddendum, Draft Guidance Document (January 1999).

14. FDA, Center for Drug Evaluation and Research, SUPAC IR/MR: Immediate Release and Modified Release Solid OralDosage Forms, Manufacturing Equipment Addendum, Guid-ance Document (February 1999).

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20. FDA, Center for Drug Evaluation and Research, Changes to anApproved NDA or ANDA: Questions and Answers, GuidanceDocument (January 2001).

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Post-approval Changes: Chemistry, Manufacturing, and Con-trols Documentation, Guidance Document (February 2001).

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33. FDA, Center for Drug Evaluation and Research, Format andContent for the CMC Section of an Annual Report, GuidanceDocument (September 1994).

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16

The Influence of the USP on theDrug Approval Process

EDWARD M. COHEN

Consultant in Pharmaceutical Sciences

Newtown, Connecticut, U.S.A.

1. INTRODUCTION

The objective of this chapter is to provide the reader with anoverview of the United States Pharmacopoeia/National Formu-lary (USP/NF) and its formal and legal role in the U.S. Foodand Drug Administration’s (FDA) drug regulatory process inthe United States (1). When considering the history of the USPand NF, once separate drug standards compendia originatingfrom two different sectors of the health-care–delivery system,it is interesting to note in parallel the key milestones of U.S.Food and Drug Law History (2,3). The role of the USP

499


(inception 1820) and NF (inception 1888) has always been toestablish public standards for purity, quality, and strength formedicinal articles and compounding information. The role ofFDA, formally established in 1930, and all of its predecessororganizations, starting with the Bureau of Chemistry of theDepartment of Agriculture in 1862, has always been involvedwith the enforcement of purity and potency standards fordrug materials, in addition to other stipulated regulatoryresponsibilities (2,3). The earliest recorded interface betweenthe USP, as a private, nongovernmental drug standards–setting organization, and the federal government regardingenforcement of public standards for strength and purity ofdrugs occurred in 1848. Congress passed the Drug ImportationAct in 1848 to prevent the importation of adulterated andspurious drugs and medicines into the United States. The U.S.Customs Service was empowered to test or have tested drugsand determine if they were inferior in strength and purity tothe ‘‘standard established in the United States Pharmacopoeia,and therefore improper, unsafe, or dangerous to be usedfor medicinal purposes, the articles shall not pass the customhouse’’ (4). Currently the USP/NF is recognized in federalstatutes as a drug standards–setting body, which in turn man-dates that all marketed medicinal articles in the United Statesthat are the subject of USP/NF monographs must be fullycompliant with all standards established in the monographfor the medicinal article. Noncompliance of the medicinal arti-cle with the USP/NF monograph standards makes the articleadulterated. Marketing of adulterated articles is illegal andsubjects the marketer to FDA compliance actions. In additionto the formal monographs in USP/NF there are sections termedGeneral Notices and Requirements and General Chapters,which contain information applicable to all drug substances,inactive ingredients (excipients), drug products, and all otherofficial articles (5).

Finally, it should be noted that the USP operated asa private, not-for-profit organization without any legal statusuntil 1900, when the United States Pharmacopeial Convention(USPC) incorporated in the District of Columbia, with a formalconstitution and by-laws. The USPC has a formal elected

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Board of Trustees, which oversees the overall operations. Cur-rently there is a staff of about 320 and a volunteer force of over1200 to support USP/NF activities. The volunteers representpractitioners from virtually all sectors of global health-care–delivery systems. Volunteers participating in USP activities(including participation at the 5-year cycle conventions of theUSPC) include individuals representing accredited schools ofmedicine and pharmacy, state medical and pharmacy associa-tions, national and international scientific and industry tradeassociations, consumer organizations, public interest groups,U.S. and international governmental and pharmacopeial agen-cies, and other sectors of health-care–delivery activities. A verydescriptive overview of the current USP can be found in thepublication ‘‘USP, People, Programs, Policies, Procedures’’(USP PPPP) (6). Included in USP PPPP is a complete break-out of the USP Council of Experts, Expert Committees, Infor-mation and Standards Development organization, and a listingof all USP products and services and relationships, as well asexplanations of how the reference standards system works andthe evolution of compendial changes (1,6).

2. BRIEF HISTORY OF THE USP AND NF

The United States Pharmacopoeia traces its origins to 1820.American physicians in the post–Revolutionary War periodwere forced to depend on imported texts for information andcounsel on the use, composition, and preparation of medicines.The need for a national pharmacopoeia became apparent to keypracticing physicians at the time. A number of independentlydeveloped formularies and pharmacopoeias emerged, eachservicing regional needs. Dr. Lyman Spalding took the leadand was instrumental in getting the medical establishment torecognize the need for a true national formulary. The processinvolved bringing together the major medical establishments ata national ‘‘convention’’ in Washington, DC, in January 1820to work out the basis for a ‘‘national formulary.’’ His vision,diligence, and leadership finally resulted in the compilation,preparation, and publication of the first U.S. Pharmacopoeia on

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December 15, 1820, under the auspices of the ‘‘convention’’ (7).The first edition of USP bears on the title page the state-ment that the text was issued under the authority of theMedical Societies and Colleges. The pharmacopoeia includeda primary list of 221 drugs and a secondary list of 71 drugs.The so-called listing of drugs was referred to as the ‘‘materiamedica’’ and represented what the medical experts of the timedetermined to be the critical medicines needed to treat thepopulation. Primary objectives of the first USP were to providethe correct Latin and English names for a medicine and a des-cription of the material. This point of nomenclature remains asa critical ongoing activity of USP, through the United StatesAdopted Names (USAN) Council and the USP Dictionary ofUSAN and International Drug Names (1). At the beginningof the USP process there were no formal standards or qualityspecifications included in the compendia for the official articles.Preparations sections gave the reader recipes to prepare spe-cific products. The scope of formulation types included solid,semi-solid, and liquid dosage forms recognized at that time.The end result of the USP would be to help physicians acrossthe country provide defined and standardized medicines to thepublic without having to depend on importation of the articlesfrom overseas. The listing of a medicinal article in the USP wasakin to that named material being an official medicinal agent.As the USP continued to grow in stature and public recogni-tion, a revision process was put in place to assure that thecompendia included the most current recognized medicines andthat articles no longer in common use would be removed fromcompendial status. Augmentation of USP monographs withtests for identification and drug quality began in 1840 (4,7).As the USP continued on its path of growth and update,practicing pharmacists founded a national organization, theAmerican Pharmaceutical Association (APhA), in 1852. Theirprimary concerns centered on dealing with the continuingproblem of inferior-quality medicinal articles coming into theUnited States from Europe. The approach to this problemwas to establish quality standards to incorporate into officialmonographs to augment the USP. There was concern aboutgiving physicians the option to forego ready-made medications

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and write out prescriptions for such articles that could becompounded by practicing pharmacists. Many of the ready-made medicines were not included in the USP—thus theimpetus to establish a formal compendia of unofficial prepara-tions. This activity came under the leadership of Charles Riceand Joseph Remington. The first National Formulary appearedin July 1888. The formal title of the compendium was the‘‘National Formulary of Unofficial Preparations,’’ publishedunder the authority of the American Pharmaceutical Associa-tion. NF I contained 435 recipes for preparations, covering allof the oral dosage forms recognized at that time. The theme ofNF I was that it was not going to be only a repository for USPdiscards or a proving ground for novelties, but a source ofreliable preparation information for established medicines (8).

As the USP and NF evolved independently as compendiaof medicinal agents, their formats and general content becamequite similar. The APhA established a laboratory in 1936 forconducting tests to establish adequate drug standards (9).Prior to that point in time, laboratory testing incidental tothe development of NF standards was done voluntarily or sup-ported by an APhA subsidy at outside laboratories. The USPdid not have its own testing laboratory in place, but relied onoutside laboratories. In 1962 an integrated laboratory servicingthe USP, NF, and AMA was put in place—the Drug StandardsLaboratory. Key responsibilities of the laboratory were pre-paration and testing of reference standards (10). The work ofthe laboratory advanced to investigations of analytical tech-niques. In 1975 the acquisition of the NF by the USP resultedin the combination of the USP and NF into one compendium,with two separate sections of entry for monographs. The DrugStandards Laboratory became the Drug Research and TestingLaboratory in 1978. The focal point for the laboratory wasto qualify reference standards and establish standards for dis-solution testing. Currently USP maintains and operates twolaboratories. The Reference Standards Laboratory (RSL) isresponsible for the validation of testing procedures developedto support the qualification and release of material to serveas USP reference standards. Currently a batch of materialtargeted to be a lot of a reference standard article is tested in



two outside laboratories plus the USP RSL. The Research andDevelopment Laboratory (RDL) provides scientific support tothe Expert Committees for the evaluation of analytical testsand methods proposed for inclusion in the USP (11).

Until 1906 there were no federal or state laws requiringadherence of medicinal articles being produced or sold in theUnited States that were the subjects of USP and NF mono-graphs, to meet the standards of the USP and NF. In 1906 theFederal Food and Drugs Act clearly and specifically acknowl-edged that drugs sold in interstate commerce under namesmen-tioned in the USP or NF monographs must comply with thelisted standards of strength, quality, or purity for these drugs(4). Noncompliant articles would be considered as misbrandedand subject to the legal actions of the Bureau of Chemistry (partof the Department of Agriculture). Products sold under the com-pendial monograph name that had quality attributes differingfrom those specified in the USP or NF monographs had then todeclare on the product labeling the strength, purity, and qualityof the article (4). In 1927 the Bureau of Chemistry was reorga-nized into two separate entities, one of which was the Food,Drug, and Insecticide Administration. In 1930 the unit wasrenamed the Food and Drug Administration. The administra-tive control of FDA was changed from the Department ofAgriculture to the Federal Security Agency in 1940. In 1953the Federal Security Agency became the Department of Health,Education, and Welfare. An excellent summary of the history ofFDA and all key milestones in the history of U.S. food and druglaws is provided in Ref. 2.

Continuing concerns about the shortfalls of the 1906federal legislation regarding false therapeutic claims for patentmedicines and food adulteration led to efforts to revise the1906 Food and Drugs Act. The revision efforts were acceleratedby the deaths of more than 100 people in 1937 attributed tothe ingestion of Massengill’s Elixir Sulfanilamide, which wasformulated with highly toxic diethylene glycol. In June 1938Congress passed The Federal Food, Drug, and Cosmetic Act,which required manufacturers of drugs to submit a New DrugApplication to FDA that included full reports of investigationsmade to show that the such a drug is safe for use. The section of

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the law dealing with the New Drug Application is Section 505.There was no stipulation to require manufacturers to providedata to support the efficacy of new drugs or new formulationsof already marketed drugs. A key element in the legislationwas the retention of the recognition of the USP and NF asofficial public standards for medicines, including packagingand labeling requirements (12). Additionally, the new legisla-tion extended control of the FDA to cosmetics and therapeuticdevices.

In 1962 the Kefauver-Harris amendments to the 1938Food, Drug, and Cosmetic Act (Drug Amendments) becameU.S. legislation to further strengthen the role of the FDA incontrolling prescription drugs, new drugs, and investigationaldrugs. The public standards role of the USP and NF was notmaterially affected by the legislation, except for the establish-ment of the antibiotic certification program. The compendialrole in assigning official nomenclature to new drugs was notreduced (13). It is interesting to note that in the 1965 Medicareamendments to the Social Security Act regarding payments for‘‘medical and other health services . . .which cannot be self-administered and which are provided in a physician’s office,’’such as drugs and biologics, must be included or approved forinclusion in theUSP orNF (or in hospital formularies for admin-istration in hospitals) to be eligible for Medicare coverage (14).

In 1994 the Dietary Supplement Health and Education Act,amendments to the Food, Drug, and Cosmetic Act, named theUSP, NF, and the Homeopathic Pharmacopeia as official com-pendia for dietary supplements. If a USP-NF monograph existsfor a dietary supplement and the material in the marketplacerepresents that it meets USP standards, it is considered as mis-branded if it fails to comply with all monograph requirements.The program is voluntary and a nutritional supplement thatmakes no assertion of compliance to USP cannot be heldaccountable to the monograph standards (15).

In 1997 the Food and Drug Administration ModernizationAct was passed, which included in Sections 353 (a) and (c)the allowance for pharmacy compounding of drug products,outside the jurisdiction of the Food, Drug, and Cosmetic Act.The restriction on compounding in the FDAMA legislation was



that compounding of drug products would not become an un-regulated manufacturing sector. The role of the USP/NF incompounding matters is that compounded articles that arethe subject of USP/NF monographs must comply with all stan-dards of the compendia (15). Currently, Sections 353 (a) and (c)of the act have been ruled invalid by the U.S. Supreme Courtregarding restrictions in the act to publicly advertise certaincompounding services. Pharmacy compounding falls under thejurisdiction of State Boards of Pharmacy. There is no changewith respect to requirements regarding compliance of com-pounded articles to USP monograph and general chapterstandards dealing with compounding.

3. BRIEF OVERVIEW OF THE CURRENTCONTENTS OF THE USP-NF

The USP 27 and NF 22 (USP/NF 2004), combined in onevolume, are actually two separate compendia. Each compen-dium consists of independent monographs for official articles.Supporting information to aid in the conduct of testing require-ments included in individual monographs are contained in asection of the USP/NF called ‘‘General Chapters.’’ Typically,each monograph will have specifications and test proceduresrelevant to the monograph article. Additionally, there will bereferences within each monograph to general chapter informa-tion for conducting certain tests, as needed. Finally, as a pre-lude to the individual USP and NF sections of the compendia,there is a general umbrella coverage of information that pro-vides details about USP/NF terminology and clarification ofpractices provided under the banner of ‘‘General Notices andRequirements.’’ There is a separate entry of this section justprior to the USP monographs and a second separate entry ofthis section just prior to the NF monographs (16). Finally, inaddition to the formal sections of the compendia identified asUSP and NF, there is a section entitled ‘‘Dietary Supple-ments.’’ This section contains monographs structured in simi-lar fashion to the USP and NF monographs. Unlike the USP

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and NF sections there is no entry prior to the DietarySupplement monographs of a ‘‘General Notices and Require-ments’’ section. It should be noted that the DietarySupplement section monographs can be considered as beingincluded in the USP, but are distinguished from the formalUSP monographs.

3.1. Official Monographs

An official substance or article is defined in a USP or NF mono-graph and includes an active drug entity or drug substance, arecognized nutrient ingredient, a recognized dietary supplementingredient, a pharmaceutic ingredient or excipient or inactiveingredient, or a component of a finished device. An officialpreparation is a drug product that contains a drug substanceor a dietary supplement active ingredient. It is the finished orpartially finished product or preparation containing one ormore official substances intended for patient use. There are acertain number of compounding monographs that providedetailed instructions for the preparation of the finished pro-duct. Currently the USP section has monographs that includevirtually all of the above. The NF monograph section is princi-pally devoted to pharmaceutic ingredients or excipients. TheNF also has some monographs for botanical articles, includingsome ‘‘compounding formulations.’’ There is a monograph andgeneral chapter section between the USP and NF sections dedi-cated to nutritional supplements.

3.2. Informational Sections of the USP/NF

1. General Notices and Requirements: Applies to allsections of the USP and NF.

2. General Chapter: General requirements for tests andassays for monograph articles.

Includes sections dealing with specific chemical,microbiological, biological, physical tests, and a listingof all current USP Reference Standards. Currentlyabout 1400 standards are sold by the USP. Thesestandards are listed in each revision of USP and



additions in the supplements. Just prior to the formalpresentation of all General Chapters, there is a newfeature in USP 27/NF 22 identified as ‘‘Charts/Guideto General Chapters.’’ The charts shown in USP 2004break out the contents of the USP into all of the cate-gories of articles present and identify which GeneralChapters and General Information Chapters haverelevance for any particular type of article in the com-pendium. There is also a break out of all GeneralChapters that have relevance for the entire sector ofDrug Product Distribution, broken out by the indivi-dual portion of the distribution chain, starting withthe drug product manufacturer.

3. General Information Chapters: Not currently man-dated in any Compendial monograph but reflect goodscientific practices and procedures provided as sup-plemental information. The General Informationchapter listings start at 1000 and proceed upward.There is no scientific rationale for the order of chap-ters within the section or assignment of chapternumbers. For Dietary Supplements there is a listingof General Chapter–General Information chapters,starting as Chapter 2021. Again one must regardthese chapters as supplemental, non-binding informa-tion, as is the case for General Information chapterscovering the USP and NF sections of the compendia.

4. Reagents, Indicators, and Solutions: Covers materialsrequired for all monograph tests and assays.

5. Reference Tables: Covers ancillary information thatsupplements the monograph content. Included withinthe reference tables are two very useful chapters aboutthe monograph articles: ‘‘Description and Solubility’’and ‘‘Solubility.’’

Browsing through these general information sections of USPis valuable to assess the extraordinary scope and depth ofthe information available. For example, there is one breakoutsection in the beginning of the NF that categorizes thefunctionality of all USP and NF excipients (17).

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A key initiative at USP is the process of harmonizationof monographs and general chapters with the EuropeanPharmacopoeia (EP) and Japanese Pharmacopoeia. Underan umbrella organization called the Pharmacopoeial Discus-sion Group (PDG) (formed in 1989), the USP, EP, and JPwork to identify monograph or general chapter candidatesfor harmonization. The World Health Organization is presentat PDG meetings as an observer. The PDG works in har-mony with the International Conference on Harmonizationof Technical Requirements (ICH), with a focus on compendialissues. The USP General Information Chapter, ‘‘Pharmaco-peial Harmonization’’ h1191i, which first appeared in Supple-ment 2 of USP 2003, provides a detailed explanation ofthe PDG process and the current metrics for the harmoniza-tion for excipients and general chapters. To date noactive ingredients have been considered for harmonization.Advantages of harmonization relates to global use of an arti-cle and the need to have only one compendial standard fortesting.

4. REVISION PROCESS FOR USP/NF

Both the USP and NF developed publication cycles for revi-sions, with interim revision announcements. The cycle timeswere 10 years, then 5 years. In 1975 the USP purchased theNF, and their new title became the USP/NF. In 2002 the USP/NF became an annual publication with two formal supple-ments issued in the calendar year. For the current USP, USP27/NF22, Supplement 1 was published in February 2004 withan official date of April 2004. Supplement 2 was published inJune 2004 with an official date of August 2004. Updates ofUSP/NF are carried out with a publication termed Pharma-copeial Forum (PF). It is published on a bimonthly basis andis the manner in which the USP advises the public aboutchanges being considered for both monograph and nonmono-graph content of the USP-NF. Public comment is invited aboutall content in the PF and USP. A typical PF issue provides



the reader with potential revisions (Pharmacopeial Previews),proposed revisions (In-Process Revisions), and adopted revisions(Interim Revision Announcement). Additionally, PF encour-ages public involvement in the revision process, and thereis a section devoted to public comments called ‘‘Stimuli ToThe Revision Process.’’ Instructions for public comment areprovided in the PF (18). Finally, each entry in PF that concernsa proposed change to USP/NF provides the reader with a guidefor the future about the revision proposal. There are definedperiods for public comment before a subsequent step occursin the revision process. It is very important for PF readers tounderstand the cycle time for events so that changes that maybe untoward or unclear or possibly even errata may be inter-cepted by direct communication to the specified USP staff liai-son person designated in the PF entry for the item in question.The ‘‘interim revision announcement’’ provides the readerwith the date that the revision will become official. It identifieswhich subsequent publication of the USP will contain theofficial change. This could be either a future supplement or afuture revision of USP.

5. FORMAL AND INFORMAL LINKAGE OFTHE USP AND FDA

All official articles (active or inactive ingredients or prepara-tions or drug products) dictate that the user must assurethat the articles are fully compliant with all specified USP/NF monograph requirements and ancillary compendialrequirements. The submission of a drug application to theFDA that includes any article covered by a USP/NF mono-graph directly links the USP to the submission. The drugapplication sponsor must provide FDA with data and infor-mation that demonstrate that the compendial articles or drugpreparation included in the drug application are fully com-pliant with all compendial requirements. Included in theinformation sections of the compendia are procedures forvalidation of compendial methods and the conduct of

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virtually all monograph test procedures. The concept ofcompliancy is that the article or preparation will maintaincompliancy to the monograph requirements throughoutthe labeled expiry date or use period for the article orpreparation.

Following satisfaction of the FDA drug product reviewbranch with the drug application, the second tier of demon-stration of compliance with all USP/NF requirements occursduring field inspections at the sponsor’s manufacturing site.Typically this could be a preapproval inspection or a cGMPinspection. The drug application sponsor must be prepared toshow FDA that all USP/NF requirements were met from useof the appropriate USP reference standards (or qualified housestandards), equipment qualification, and assay validation. It isvery important to have complete understanding of the contentof the general chapters in USP and be prepared to explain anyinconsistencies that may be in internal SOPs or ControlDocuments versus the USP content.

As noted above, USP monograph requirements are notjust release requirements but expected quality attributesthrough the defined expiry period for the product. This canonly be confirmed by continued stability evaluation of the pro-duct.

Some of the typical issues that a drug application spon-sor has to deal with are continued vigilance to respond to amonograph change(s) that may occur over time. Any changemust be a catalyst to upgrade all procedures and documentsaffecting the drug article due to monograph or general chap-ter change(s). It is not uncommon for a drug applicationsponsor to use alternate methods for the monograph article.Any monograph change dictates that a revalidation be imple-mented to demonstrate that the monograph change does notalter the comparability of the alternate method to the newmonograph procedure. Evaluation of proposed monograph orgeneral chapter changes must be made on a critical pathto assure that appropriate comments are conveyed to USPin a timely manner to assure that inappropriate changes donot get to the final step of approval in the USP changeprocess.



6. CURRENT ISSUES: USP INFORMATIONVERSUS FDA REQUIREMENTS

The USP includes in the general chapters and general informa-tion topics that impact on compendial testing. Frequently thesame topics are the subject of FDA guidances or ICH guid-ances. Updates occur, and it is very important to assess thecurrency of the information in the USP versus updated FDA orICH guidances. Any inconsistencies or conflicts must be imme-diately conveyed to the USP. It is critical that stakeholdersof USP products and services become cognizant of the USPchange control processes. The contact persons for specificissues at USP should be defined and continually monitored.Participation and awareness of USP conferences and work-shops can be a very important source of information aboutchanges that USP may be considering that could impact afirm’s understanding of USP-defined procedures and practices.Updating internal controls and procedures and updating drugproduct applications based on USP changes is an eternal taskthat simply cannot be overlooked.

7. FUTURE ROLE OF THE USP IN THE DRUGREGULATORY PROCESS

As the USP continues to evolve with the introduction of newanalytical technologies into general information chapters, suchas near-IR spectrophotometry, the impact may be that USPstakeholders will be encouraged to consider the use of thenew analytical technology as a replacement for the current,and possibly outmoded, USP monograph procedure. Suchupgrades in analytical technology will find their way into regu-latory filings, likely associated with compendial monographtesting changes.

The arena of process analytical technology (PAT), whichcurrently has a very strong endorsement by FDA, dictatesthe need for USP to reengineer its mindset about referencestandards to support future drug product monographs, which

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may have two tiers of testing. Tier 1 might be the traditionalmonograph portfolio of ‘‘universal tests’’ and ‘‘specific tests.’’Universal tests include description, identification, impurities,and assay. Specific tests include uniformity of dosage units,performance tests such as dissolution drug release, pH, etc.For process monitoring and control, where virtually everydosage unit can be expected to be within an acceptance bound-ary of critical quality attributes, end product testing mayneed to be totally redefined in Tier 2 testing requirements.What type of reference standards will be needed is currentlyunknown. With respect to USP monograph development—boththe preparation of a new monograph and revision of an existingmonograph—the USP has just completed the preparation of aguideline for monograph development. The guideline goesacross all types of articles, active ingredients, excipients,drug products, etc. The guideline is now on the USP websitefor public purview.

Heretofore USP involvement in process development wasvery limited. With this new horizon of process monitoring/process control, a new era is upon the USP. The changingtesting objectives will have a very important impact on regu-latory submissions and routine quality control. PAT, at itsultimate refinement, is perceived to be an on-line/in-line con-tinuous monitoring and control-based operation during routinemanufacturing of a drug product (19,20). Every advancein process analytical chemistry and analytical technologiesintroduced to the pharmaceutical industry will have animpact on compendial testing. In turn, this will impact onregulatory filings.

8. CONCLUSIONS

The USP/NF continues to serve the health-care–delivery systemby providing public standards for pharmaceuticals and dietarysupplements. It is critical for USP actions to assure thatmonographs and informational (both mandatory and optional)chapters reflect current scientific technology and that the con-tent of USP is in line with EP and JP standards and meets FDA



expectations. By such practices, the FDA will almost certainlycontinue to rely on the USP as a reliable bearer of critical qual-ity attributes for pharmaceutical raw materials and finishedproducts and be a benchmark for regulatory submissions per-taining to product description, identification, impurities, assay,and specific tests related to performance.

It is critical that the industry maintain strong vigilanceand interaction with USP to make sure that the public stan-dards satisfy the needs of stakeholders and the regulatorysector.

ACKNOWLEDGMENT

To the dedicated and interactive staff at USP, with whom I amin contact on a frequent basis, thank you for educating meabout the USP.

REFERENCES

1. Mission and Preface, United States Pharmacopoeia 27 –National Formulary 22 (USP/NF 2004), The United StatesPharmacopeial Convention, Rockville, MD, 2004, pp. v–xiii.

2. Milestones in U.S. Food and Drug Law History, FDA

3. Janssen, W.F., The Story of the Laws Behind the Labels, Part I,1906 Food and Drugs Act, Part II, 1938 The Federal Food,Drug, and Cosmetic Act., Part III, 1962 Drug Amendments,FDA Consumer, June 1981 (available on FDA website; Part

Part 3 history1b).

4. L. Anderson and G.J. Higby, The Spirit of Voluntarism,A Legacy of Commitment and Contribution, The United StatesPharmacopoeia 1820–1995, United States PharmacopeialConvention, 1995, p. 71.

5. General Notices, USP/NF 2004, 2004, pp. 1–12; GeneralChapters, USP/NF 2004, 2004, pp. 2108–2402.

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Backgrounder, http://www.cfsan.fda.gov/mileston.html.

1, http://www.cfsan.fda.gov/lrd/history1.html, Part 2 history1a,


http://www.cfsan.fda.gov

http://www.cfsan.fda.gov

6. USP, People, Programs, Policies, Procedures (USP PPPP),United States Pharmacopoeial Convention, Rockville, MD,2002.

7. L. Anderson and G.J. Higby, The Spirit of Voluntarism, 1995,pp. 25–27.

8. L. Anderson and G.J. Higby, The Spirit of Voluntarism, 1995,pp. 155–156.

9. History of the National Formulary, The National Formulary,10th ed. (N.F. X), American Pharmaceutical Association, 1955,pp. xxii–xxiii.

10. L, Anderson and G.J. Higby, The Spirit of Voluntarism, 1995,pp. 363–365.

11. USP PPPP, 2002, p. 104.

12. L. Anderson and G.J. Higby, The Spirit of Voluntarism, 1995,p. 281.

13. L. Anderson and G.J. Higby, The Spirit of Voluntarism, 1995,p. 357.

14. J. G. Valentino, USP Admissions Policy on Approving NewDrugs for Inclusion in the United States Pharmacopeia(USP) Is Presented, Pharmacopoeial Forum, Vol. 26(6),Nov.–Dec. 2000, p. 1519.

15. Mission and Preface, United States Pharmacopeia 17 –National Formulary 22 (USP/NF 2004), The United StatesPharmacopeial Convention, Rockville, MD, 2004, pp. xii.

16. General Notices and Requirements, USP 2003, 2003, pp.1–12.

17. Excipients, USP/NF 2004, 2004, pp. 2809–2812.

18. Pharmacopial Forum, USPC, Bimonthly Publication.

19. A. Hussain, FDA’s PAT & cGMP Initiative for the 21stCentury: Status Update and Challenges to be Addressed,NJPhAST 2003 Symposium, Rutgers University, Piscataway,NJ, 2003.

20. Gary Ritchie, Topic 3, Process Analytical Technology: Near-IR,Analytical Methods and General USP Topics, Philadelphia,2003.



17

Ways and Means to U.S. Registrationof Foreign Drugs

ALBERTO GRIGNOLO, JILL E. KOMPA,RICHARD J. SCHWEN,and DAVID SKARINSKY

PAREXEL International Corporation

Waltham, Massachusetts, U.S.A.

1. INTRODUCTION

The economics of pharmaceutical development have a signifi-cant impact on the strategy for global marketing approvalof new drugs. This is particularly true when sponsors developand register a drug in one country and then seek marketingapproval for the new drug product from regulatory bodies in

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a different country or region. Although the drug developmentprocess may be similar in different regions, differences due toculture, medical practice, demographics, and other factors canimpact how and how rapidly new drugs gain access to differentmarkets. For instance, such differences could complicate theregistration process when sponsors seek U.S. Food and DrugAdministration (FDA) registration of a pharmaceutical productfor the U.S. market based on data gathered outside the UnitedStates. A thorough understanding of the issues involved andcareful execution of the U.S. regulatory strategy can help makethe process manageable.

This chapter addresses the following topics:

FDA requirements for registration of foreign drugs, includ-ing criteria for acceptability of foreign data, as well asthe impact of the International Conference on Harmo-nization (ICH) guidelines.

Challenges facing foreign drugs, including chemistry,manufacturing, and control (CMC), clinical and non-clinical issues.

Factors that can facilitate FDA approval of foreign drugs,including a comparison of the requirements for the NewDrug Application [NDA] and the Common TechnicalDocument (CTD).

Practices and behaviors that increase the likelihood ofFDA approval of foreign drugs, including communi-cations with the FDA.

2. REGULATORY FRAMEWORK RELEVANT TOU.S. REGISTRATION OF FOREIGN DRUGS

Two regulatory entities have impact on the issues surroundingU.S. registration of foreign drugs. FDA plays the major role,as it sets the criteria for acceptance. Additionally, the ICH,under the auspices of the six founding members represen-ting the regulatory bodies and research-based industry in theEuropean Union, Japan, and the United States, has addressedthe issue with specific guidances and the CTD.

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2.1. U.S. Food and Drug Administration

FDA regulations governing the approval to market a newdrug are covered in the Code of Federal Regulations (CFR),Title 21, Part 314. The regulations do allow the approval ofan NDA based solely on foreign clinical data, provided that theapplication meets three criteria outlined in 21 CFR 314.106.

The regulation states that an application based solely onforeign clinical data meeting U.S. criteria for marketingapproval may be approved if:

1. the foreign data are applicable to the U.S. popula-tion and U.S. medical practice;

2. the studies have been performed by clinical inves-tigators of recognized competence; and

3. the data may be considered valid without the needfor an on-site inspection or, if FDA considers suchan inspection to be necessary, FDA is able to vali-date the data through an on-site inspection or otherappropriate means. The FDA will apply this policyin a flexible manner according to the nature of thedrug and the data being considered.

The regulation also encourages consultation betweenapplicants and the FDA. It specifically suggests a ‘‘presubmis-sion’’ meeting between applicants and Agency officials whenthe sponsor intends to seek approval based solely on foreign

If the Agency feels that the criteria listed above have beenmet, it may approve the product based on foreign studies.As illustrates, FDA has approved approximately 80drugs based solely or predominantly on clinical data generatedoutside the United States.

2.2. International Conference on Harmonization

Recognizing the need to eliminate redundancies in researchwhile supporting the sovereignty of the respective regulatorybodies, ICH has ways to help make clinical datacollected in one region acceptable to the regulatory authorityof another region. One outcome of this ongoing effort is the

Ways and Means to U.S. Registration of Foreign Drugs 519

data. (For more about presubmission meetings, see Sec. 5.)

1

examined

Table


ICH Guideline E5, ‘‘Ethnic Factors in the Acceptability ofForeign Clinical Data.’’ Developed to facilitate registration ofmedicines within ICH regions, the guideline suggests a frame-work for evaluating the impact of a wide range of ethnicfactors—genetic and physiological, as well as cultural and envi-ronmental—on the safety and efficacy of the drug for whichregistration is being sought.

For sponsors of foreign drugs, ICH Guideline E5 comple-ments the FDA regulations. The ICH guidance notes that alldata in the clinical section should meet the standards for studydesign and conduct and should satisfy the regulatory require-ments of the region in which the sponsor seeks approval.

Table 1 Drugs Approved by FDA on the Basis of Non-U.S. Data

Acutect Genotropin PlavixAlbenza Gonal-F PosicorAmbisome Granisetron PravacholAnzemet Halfan PrografArimadex Haloperidol PropafenoneBetaxolol Hycamtin ProsynapBravavir Indium IN-111 QuinaprilBuspirone Isosorbide mononitrate RefludenCalcitonin-Salmon Lamictal RilutekCarboplatin Lamivudine RivizorCellcept Levonorgestrel SalmeterolCrixivan Lutamide SeroquelCysteamine Merrem StromectolDalteparin Mesna Strontium ChlorideDenavir Metoprolol SumatriptanDesogestrel/ethinyl Mifepristone Tacrine

estradiol Myotrophin TacrolimusDiazepam emulsion Nafareline nasal solution Tamoxifen citrateDinoprostone Naropin ThalidomideDostinex Nefazodone TiclopidineDronabinol Neufolie Tranexamic acidEnoxaparin Nimodipine TrovanExelon Novantrone VenlafaxineFemara Olsalazine VinorelbineFinasteride Omeprazole ViramuneFollistim Ondansetron ZithromaxGabapentin Paclitaxel Zoladex

520 Grignolo et al.


Once that has been accomplished, the sponsor must be ableto extrapolate the study data to the population of the newregion—in this case, the United States. If the sponsor or theregulatory agency is concerned that ethnic differences couldhave a significant impact on the safety or efficacy of the drugin the new population, additional data may be necessary.

The core concept of ICH Guideline E5 is the ‘‘bridgingstudy.’’ ICH defines the bridging study as ‘‘a study performedin the new region to provide pharmacodynamic or clinicaldata on efficacy, safety, dosage and dose regimen in the newregion that will allow extrapolation of the foreign clinicaldata to the population in the new region. A bridging studyfor efficacy could provide additional pharmacokinetic informa-tion in the population of the new region. When no bridgingstudy is needed to provide clinical data for efficacy, a pharma-cokinetic study in the new region may be considered as abridging study.’’

The concept assumes that the need for any new data isbased on the drug’s level of sensitivity to ethnic differencesbetween the two regions. If the bridging study results insimilar data in the new population, the original efficacy andsafety data should be sufficient to support approval in the newregion. In such cases, the sponsor should not need to replicatethe original studies in the new population. On the other hand,if the bridging study fails, the sponsor would generally need toconduct new efficacy and safety study in the population of thetarget region.

In writing Guideline E5, ICH suggested that increasingexperience with cross-regional acceptance would diminish theneed for bridging studies. To date, that has not been the case.Bridging studies have become much larger than ICH intended,and many fall outside the spirit of Guideline E5. ICH is inthe process of reevaluating Guideline E5 in order to make theguidance more practical and useful to sponsors.

The impact of Guideline E5 on FDA approval of foreigndrugs can be favorable to sponsors if FDA agrees that a bridg-ing study can help satisfy the requirements for approval ofa specific new drug, consistent with 21 CFR 314.106. Sponsorsshould discuss this possibility well in advance with FDA and



determine if in fact the Agency might require additional, largerPhase 3 confirmatory trials conducted in the United States.

3. POTENTIAL OBSTACLES TO THEREGISTRATION OF FOREIGN DRUGS

Sponsors of foreign drugs face a number of challenges whenattempting to persuade the FDA that a new drug is approvable.Most of these obstacles are inherent in the drug developmentprocess. They are not unique to foreign drugs; however, dif-ferences in culture, testing procedures, standard medicalpractices, demographics and other factors can magnify thechallenges. Sponsors must recognize the potential pitfalls andplan ahead in order to minimize the impact of ethnic factors onthe approval of an NDA.

The issues that sponsors of foreign drugs must addressfall into three broad categories: CMC, nonclinical and clinical.

3.1. Chemistry, Manufacturing andControls Issues

FDA requires the same CMC information for foreign drugsas it does for unapproved new domestic drugs. The amountof CMC information required varies, depending on the type ofsubmission. Specific requirements are stipulated in the variousFDA guidances relevant to Investigational New Drug (IND)applications, NDAs, Abbreviated New Drug Applications(ANDAs), etc.

All drug manufacturers must comply with current GoodManufacturing Practices (cGMPs) for finished pharmaceu-ticals, as specified in 21 CFR 211. Manufacturers must meetUnited States Pharmacopoeia (USP) standards for the drugsubstance, its excipients, or the drug product, if available.If the substance is not listed in the USP, the sponsor mayreference other pharmacopoeial standards, such as the BritishPharmacopoeia (BP) or European Pharmacopoeia (EP). If nopharmacopoeial standards exist, the sponsor must providea full characterization of the new ingredient in the NDA.

522 Grignolo et al.


As is true with all drugs, sponsors of foreign drugs shouldfollow ICH quality guidelines regarding stability, validation ofanalytical procedures, acceptable levels of impurities, residualsolvents, etc.

Sponsors may submit information regarding the chem-istry and manufacturing of drug substances, products, excipi-ents or packaging in a Drug Master File (DMF), which can bereferenced in ongoing submissions to FDA. A U.S.-based agentacting on behalf of the sponsor must submit foreign DMFs.

Foreign sponsors must comply with the same require-ments for establishment registration and product listing thatapply to U.S.-based manufacturers. Foreign manufacturersmust register with FDA’s Drug Listing Branch and have a drugestablishment number assigned to them. Individual drug prod-ucts to be imported must also be registered with this FDAbranch. In order to import a foreign drug product throughU.S. Customs, the importer should provide relevant documen-tation. This might include an IND number, an approval letterif the drug is a marketed product, and proof that the producthas been appropriately listed with the Drug Listing Branch.The import process is often best handled through an experi-enced import broker who can facilitate a positive outcome andavoid potential delays. Retrospectively, foreign drug establish-ments often cite delays in the import process as a commonoccurrence that they might have avoided had they used anexperienced broker.

Foreign manufacturers must also have a U.S. agent whoresides in or maintains a physical place of business in theUnited States. The agent facilitates communication betweenFDA and the foreign manufacturer. FDA will contact the U.S.agent in regard to both facility and drug listing issues for theforeign-based manufacturer.

FDA may inspect a foreign manufacturing site if, at anytime, the Agency determines that an inspection is warranted.Sometimes the initial act of registering an establishment withthe Drug Listing Branch may prompt an inspection, particu-larly if the sponsor intends to import the listed drug in thevery near future. FDA is likely to consider an inspection ifthe facility has not been inspected previously.



If FDA conducts an inspection and finds problems,the inspector will report his or her observations of the condi-tions and practices observed at the site on FDA Form 483.The firm is then required to respond to FDA’s findings andto indicate the corrective actions that they will take to resolvethe issues. Depending on their nature and volume, the overallfindings can be the basis of the FDA’s determination as towhether the establishment is compliant with cGMPs. If FDAdoes not consider a facility to be in compliance with cGMPs, itwill not approve pending drug applications until the establish-ment resolves GMP facility–related issues. If the findings aresignificant, the FDA will likely reinspect the facility to ensureadequate resolution of previous concerns.

Reinspection often takes time, and the additional leadtime required for inspectors to travel to foreign sites can leadto approval delays. It is important to be aware that lack ofinspection readiness on the part of the manufacturing site isa common reason why the FDA considers submissions to benonapprovable.

3.2. Nonclinical Issues

FDA’s nonclinical testing requirements for foreign drugs areidentical to the requirements for unapproved new U.S. drugs.In all cases the data must demonstrate safety for humansubjects during clinical trials and for patients when the drugis marketed.

The efforts of the ICH have resulted in the harmonizationof basic requirements for nonclinical study design; however,specific requirements for nonclinical studies can be very spe-cific to each drug and indication. ICH Guideline M3, ‘‘Timingof Pre-clinical Studies in Relation to Clinical Trials,’’ addressesgeneral considerations in regard to when nonclinical studiesare conducted in a ‘‘prototypical’’ drug development program.The guideline provides a point of reference, but it is not a sub-stitute for communication with FDA. Consultation with FDAis appropriate at pre-IND, end of phase 2, and pre-NDA confer-ences in order to clarify specific requirements on a case-by-casebasis. However, the sponsor should not necessarily expect FDA

524 Grignolo et al.


to provide guidance and direction spontaneously. Rather, itis the responsibility of the sponsor to design and propose thenonclinical testing program for FDA’s concurrence and pos-sible modification.

A proper toxicology program is designed with considera-tion for the following:

Known safety data on the drug (in vitro animals andhumans)

Results of an early risk assessment identifying datagaps that need to be addressed

Relevant FDA and ICH guidelinesProposed exposure and use/indication of the drug in

humans, whether in clinical trials or on the marketDirect input from FDA andSound toxicology advice

In order for the foreign nonclinical data to be acceptableto FDA, the testing must be conducted according to GoodLaboratory Practices (GLPs, found in 21 CFR 58). FDA mayinspect the nonclinical testing facility, the nonclinical data, orboth. FDA is most likely to select for closer scrutiny thosestudies that suggest potential and significant safety issuesin humans. In these cases, FDA tries to determine whetherthe study was designed and conducted properly, that is tosay, in accordance with GLPs. (References and guidancefor monitoring GLPs are available on the FDA website

Agency will also address the significance of the animal data inrelation to humans. Although nonclinical investigational stu-dies, such as dose-ranging or pilot studies, are technicallyexempt from the GLP requirement, safety (toxicology) studies,which are critical for safety assessment, certainly are not.

Serious concerns regarding the quality of the data cantrigger a ‘‘for-cause’’ inspection of the animal facility.

The drug substance and drug product, or formulation,tested in nonclinical studies should be relevant to the productthat the sponsor intends to market in the United States. Thisrequirement is based on the need for the data from safety stud-ies to be relevant to the risk assessment process, particularly


at www.fda.gov/ora/compliance_ref/bimo/glp/default.htm.) The


http://www.fda.gov

if the product formulation or quality are different from that tobe marketed in humans. Studies of such variants do not neces-sarily predict response in humans. This relevance is a criticalfactor in FDA’s acceptance of foreign data.

As is usually the case in drug development, sequential‘‘improvements’’ in the drug substance and/or drug productare made as the development program progresses frompreclinical to clinical stages. The sponsor may need to repeatpreclinical studies if the earlier studies were conducted witha product that the FDA considers significantly different fromthe clinical product.

While the final safety database should reflect knownsafety concerns that have been observed in either animalsor humans throughout drug development, the actual timingof nonclinical studies should be linked to the drug’s stage ofdevelopment. The nonclinical testing should generate sufficientquantity and quality of data to allow for a reliable risk/benefitanalysis prior to each clinical trial in a drug developmentprogram

The sponsor should address the safety observationsmade in clinical trials and should work with nonclinicalmodels addressing relevance to humans when appropriate.Dose relationship and reversibility of observed effects are nor-mally required in order to allow for a proper risk assessmentin humans. It is important that the sponsor conduct thenonclinical testing in a species whose absorption, distribution,metabolism, and excretion (ADME) are relevant to humans.

As human data become available, the sponsor shouldreevaluate the selected nonclinical testing models in order toassure the programs relevance to humans. In reality, safetymodels and programs must be revised if the data collectedindicate that different, more appropriate, studies are requiredto make an accurate risk assessment.

3.3. Clinical Issues

Regulatory bodies such as FDA are cautious about basing regis-tration solely on foreign data, due to the potential impact ofethnic differences on the product labeling and selection of dose

526 Grignolo et al.


and dose regimen. By planning to address intrinsic (i.e., geneticand physiological) and extrinsic (i.e., cultural and environ-mental) ethnic differences throughout the drug developmentprocess, the sponsor of a foreign drug may save time, reducethe need to replicate studies, and build a stronger case forFDA acceptance, including nearly every aspect of clinical devel-opment from study design, to patient issues, to investigatorselection, to study conduct.

3.3.1. Investigator/Site Selection

In order to evaluate the quality of foreign data, FDA mustfeel comfortable with the selection of investigators and sites.Selecting academic or high-visibility centers of excellence andproviding standardized investigator training can help addressconcerns about quality of data. However, the reputation ofa center is not, in and of itself, an assurance that clinical trialsconducted there are GCP compliant or relevant to the U.S.population.

Selected investigators must be familiar with conductingcontrolled clinical trials according to Good Clinical Practice(GCP) guidelines; they must also understand the criticalnature of timely safety reporting to support labeling. Selectedsites should have sufficient research training and experiencein conducting trials that may eventually be audited by FDA.In case of an audit, documentation of adherence to GCPsand timely safety reporting may be a critical determinant ofwhether the data will be acceptable to FDA for purposes ofNDA approval.

Qualified investigators and savvy sponsors need to be awareof the differences between local and cross-border standardsof diagnosis and patient care. Standardization of diagnosticcriteria and treatment measures prior to initiating a foreignstudy intended for U.S. registration helps minimize variabilityacross sites and provides for validation of the criteria early inthe development process. Linking those criteria and measuresto analogous ones known to be acceptable in the United Statesmay prove essential to ensuring acceptance of the trial datato the U.S. medical community and to FDA.



Control of investigational drug product and control overthe conduct of the investigation are essential for U.S. registra-tion. If the study is conducted under an IND, FDA requiresthe investigator to sign FDA Form 1572, the Statement ofInvestigator. By signing this form, the investigator makes alegally binding commitment—under the U.S. federal law andwith federal penalties—to conduct the study according to theprotocol, to personally conduct and supervise the investigation,and to maintain study records and submit all materials tothe Institutional Review Board (IRB) or local ethics committee(EC). No such commitment or enforcement mechanism existsfor a non-IND study.

Therefore, the sponsor must provide training and care-fully document that the investigator has full control over theinvestigation and understands his or her ultimate responsi-bility for the quality of the outcome. It is important to realizethat it is not necessary to conduct a foreign clinical trial underan IND for it to be acceptable to FDA, nor will its conductunder an IND make it ‘‘more acceptable’’ to FDA. The keysuccess factors for clinical data acceptance are GCP compli-ance and relevance of the data to the appropriate U.S. patientpopulation.

3.3.2. Ethics Committee/Institutional ReviewBoard Selection

An FDA concern regarding some foreign studies is the lack oflocal control or inspection of studies by local ethics committees.It is important to be aware of how local ethical standardsand review processes differ from the standards followed inthe United States and how those differences may affect thecredibility of the foreign data. For a successful submissionof foreign data, it is critical to select sites governed by ethicscommittees with membership and rules of conduct that will beacceptable for U.S. registration. One obstacle that is common,particularly in developing countries, is inadequate or biasedrepresentation on the ECs. The EC should include sufficientrepresentatives with the appropriate technical expertise andshould provide objective evaluation by both the scientist and

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the patient advocate. It is also important to avoid the appear-ance of bias or conflict by excluding individuals from the votingprocess who might have a direct interest in the study—forexample, the investigator or the discoverer of the drug.

Selection of sites with an ethics committee that will beacceptable in case of an FDA audit may be a potential sourceof conflict for the sponsor. The sponsor must be careful tobalance the needs and customs of the host country and theinvestigator who will conduct the study against the require-ments of GCP.

3.3.3. Consent Process

Inadequate study subject consent, as well as both overt andindirect coercion of patients to participate in the study, canundermine the acceptability of foreign data for U.S. registra-tion. Providing choice of treatment and a comprehensibleunderstanding of risk in the patient consent document is acritical test of adequate consent, governed by the Declarationof Helsinki and GCP guidelines. Lack of adequate consent canbe problematic, particularly if FDA finds that the study doesnot provide medically indicated treatment or conducts coercivetrials in locations where sufficient medical care is not available.Additionally, local medical acceptability and cultural differ-ences in patient beliefs may limit therapeutic choices andexcessively expand what is acceptable, resulting in a biasedinformed consent process that may preclude the use of foreigndata to support a U.S. application.

3.3.4. Choice of Comparator and Dose

The relevance of foreign clinical data may also be judged bythe choice of comparator, as well as relevant dose or dose rangefor both test and comparator drugs. Active comparators needto be chosen based on whether the drug, dose and dosage areapproved by FDA. Demonstrating superiority or non-inferiorityversus an active comparator is only meaningful if the com-parator, dose, and dosage are labeled in a previously approvedU.S. marketing application based on established safety andefficacy trials.



The choice of dose and dosage of a drug in a pivotal trialused to support a U.S. application should also be carefullyconsidered. Differences in local medical standards of practice,as well as cultural differences, often lead to different risk/benefit ratio considerations when selecting dose and dosage formarketing. For example, some foreign countries may favor agreater safety margin over additional effectiveness.

3.3.5. Concomitant Medications andDrug–Drug Interactions

Drug–drug interaction data from foreign studies may have lim-ited utility in the United States. A wide range of factors maycomplicate the extrapolation of foreign data to support label-ing for the U.S. population. These include cultural, economic,genetic, and ethnic differences. Genetic and ethnic differencemay lead to differences in absorption, distribution, metabolism,and excretion. Limited availability of pharmaceutical products,cultural bias toward the use of homeopathic remedies, andthe wide use of certain co-medications, nutritional supple-ments, and/or herbal remedies in some locations may playa limiting role in FDA’s ability to consider drug-drug interac-tion data from foreign sources. In such circumstances, thesponsor and ultimately FDA may determine that additionaldrug–drug interaction trials may be necessary to supportU.S. labeling.

3.3.6. Contraception and Reproductive Toxicity

Local practice, economic conditions, levels of education, andcultural differences often drive decisions regarding contracep-tive methods. FDA is particularly concerned with the safety ofa test product for trial participants, as well as with definingan appropriate level of reproductive safety for labeling. FDArequires any study to assure the safety of female and malepatients and their offspring. In the United States, animalreproductive toxicity data—including gestation and effects onthe various stages of fetal development—drive inclusion crite-ria for pivotal trials and labeling. Nonclinical reproductive tox-icity data, and the potential effect that such data may have on

530 Grignolo et al.


patient selection, the product safety profile and labeling, shouldbe considered prior to initiating pivotal clinical trials.

3.3.7. Patient Issues

Study treatment compliance, or lack thereof, can also be abarrier to acceptance of foreign data. In populations with lowlevels of education, it can be difficult to assure patient compli-ance and diary retention. Underreporting of adverse eventsmay also be common due to cultural differences. In some cul-tures, for example, tolerance for higher degrees of pain or simplereverence for the physician may preclude complete and accu-rate patient reporting of adverse events. Incomplete reportingof adverse events leads to inadequate reporting of incidence ofexpected adverse events needed for U.S. labeling.

3.4. Study Design and Controls

When designing a study destined for eventual U.S. registration,it is helpful to begin with the intended labeling in mind. Pivotaltrials should be designed prospectively. When studies are notconducted under an IND, little opportunity exists to obtainFDA input. In such cases, it is advisable to obtain external,expert consultations regarding regulatory strategy that incor-porates consideration of FDA’s ability to label safety andactivity claims. In the United States, labeling claims principallydepend on data derived from two adequate and well-controlledpivotal trials. U.S. labeling claims often are (a) limited to thespecific patient population studied, (b) limited to the route ofadministration, dose, and dosage used in the pivotal trial, and(c) limited to the prospectively stated objectives in the pivotaltrials that proved to be statistically significant.

A number of common pitfalls in foreign trials may compli-cate U.S. approval. Outside the United States, medical experts,rather than statisticians, often define sample size based onclinical exposure comfort levels rather than on statisticalmodels that are the basis of appropriate sample-size calcula-tions used to test a hypothesis. Whenever possible, the spon-sor should allow an expert U.S. statistical consultant toreview the statistical analysis plans in advance of the study.



Targeted review can help anticipate issues that may be raisedby FDA statisticians.

When selecting active comparators or permissible con-comitant treatment, sponsors should consider using drugs,doses, and dosages that are approved for marketing in theUnited States. It will be difficult for FDA to interpret safetydata or to compare drug activity if the agency is not familiarwith the active comparator, dose, route of administration, ordose regimen.

Whenever ethically possible, the sponsor should considerplacebo control, rather than active control, for pivotal trials.In the United States and the European Union, it is common forregulators and researchers to hold different opinions regard-ing the ethics of placebo control in clinical trials. Outside theUnited States, the use of retrospective historical controls andactive comparators has been considered to be the more ethi-cal approach. However, FDA still considers placebo-controlledtrials to be the gold standard for demonstrating and labelingsafety and efficacy. The exception is in the case of specific life-threatening indications, such as those in the fields of oncologyand infectious diseases.

In addition to the careful consideration of a control arm,complete blinding of treatment arms is critical to limit bias andgain acceptability of foreign data. One way to achieve completeblinding is through the use of a ‘‘jury of resemblance,’’ whichis a blinded group of individuals who help confirm the integrityof the blinding process. Such a jury will examine packaging andblinded product samples in order to identify matching homo-geneous versus heterogeneous treatment samples. Completeblinding is achieved if the jury cannot differentiate betweenthe two blinded treatments.

Finally, in order to maximize chances for success andto support labeling efficacy for a particular subset population,it is preferable to stratify patients prospectively based on rele-vant endpoints. Such endpoints may be diagnostic criteria aswell as severity of the disease and/or treatment. Prospectivestratification assures appropriate balance of patients in thesubset treatment arms and provides results that are easier tointerpret. Compared to retrospective analyses conducted after

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the trial has been completed, prospective stratification is morelikely to lead to successful identification of activity in a subsetpopulation. With retrospective analyses, low numbers in anyone treatment arm may prevent achievement of the statisticalpower to detect a difference. Prospective stratification can beaccomplished by using a telephone randomization system or avariety of site-specific randomization schemes that an expertstatistician can design.

3.5. Endpoints

In addition to study design considerations, an appropriatechoice of clinically relevant endpoints is key to help drivelabeling and gain FDA acceptability of foreign data.Surrogate markers of activity, expert medical opinion and non-validated, nonstandardized endpoints are often unacceptableto support labeling. A life-threatening condition or an orphandrug indication might be an exception, but even in thesecases the sponsor has negotiated the strategy in advancewith FDA. Clinically relevant endpoints, such as diseaseactivity, patient mobility, symptom control, or survival, areall preferable to endpoints, such as an obscure lab test resultwithout a historical correlation in the clinic, that lack a clearclinical interpretation.

The sponsor should avoid choosing endpoints that lackcross-cultural applicability and validation. For example, foodintake questionnaires or quality-of-life scales may contain ques-tions that limit their use to support labeling when consideredin a different cultural setting.

Even for studies with subjective endpoints that requireratings by the investigator or patient, the sponsor shouldprovide adequate training and, whenever possible, define thelimits of interrater variability. Interrater variability amonga group of investigators can be assessed proactively by pre-senting patient case scenarios and having each investigatorrate the symptoms or diagnose based on a uniform patientcase. Variability should be assessed. Raters whose results lieoutside of the predefined acceptable range should be providedwith additional training or excluded from trial participation.



3.6. Local Medical Practice, TherapeuticDifferences, and Unmet Medical Needs

Considering variability in local medical practice is criticalto understanding the relevance of the development programand the acceptability of foreign data in the United States.Variability may be based on differences in disease prevalence,diagnostics, test-ordering practices, prescribing practices, treat-ment options, treatment and medical care reimbursement,and standard treatment guidelines. If differences are identified,the sponsor should address these differences prospectively byplanning for culturally relevant locations for conducting trialsor retrospectively via a bridging study.

Equally important are subtle cultural differences that mayprevent a sponsor from identifying the maximal effective dosefor U.S. registration. A physician’s approach to adequate dosingmay be culturally driven. For example, the standard of practicein Japan is often to identify a dose that is associated with feweradverse drug reactions. In comparison, U.S. researchers mightchoose a dose based on maximal activity combined with anacceptable safety profile.

Additionally, unmetmedical needs that are often the targetof pharmaceutical development plans may differ from oneregion of the globe to another. Health needs are often definedby socioeconomic policy, levels of education, and cultural biases.Development plans and trial designs often incorporate localstandards of practice, available therapy, and accessible rescuedrugs. These local realities may not apply and may precludethe foreign drug sponsor’s ability to collect data that will beapplicable for labeling in the U.S. environment.

For example, in Africa and certain parts of Southeast Asia,standard diagnoses and treatment guidelines may be limitedby a variety of factors that include the patient’s (a) level of sup-plemental insurance and access to testing, (b) education, and(c) ability to read. In some areas of the world, the availabilityof alternative medicine and/or the reliance on traditionalhealers may play a role in defining medical need. Finally, insome regions providing early access to study-associated medicalcare and investigational treatment may be more acceptable,

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and even expected. Prospective planning, a focus on cross-cultural acceptability, and use of multinational advisory boardsmay be the best way to design a single development programthat has cross-cultural acceptability.

3.7. Collecting Foreign Clinical Data

One issue for sponsors of foreign drugs to consider iswhether to collect foreign clinical data under an IND prospec-tively. Clinical studies conducted outside the United Statescan be sponsored under an IND, but this is not an FDArequirement.

Two common and related misconceptions exist regardingforeign studies and INDs. Many sponsors believe that FDA willgive greater weight to studies that are conducted under an INDthan to studies that are not. This is not true. Nor is it true thatstudies conducted under an IND are more compliant with GoodClinical Practices than are non-IND studies. Another commonmisconception is that by conducting the study under an IND,the sponsor does not need to obtain local country approval toconduct the study.

Conducting a foreign study under an IND offers bothbenefits and drawbacks. Among the benefits is the fact thatmultinational studies and investigators are documented tothe IND, which then becomes a ‘‘common archive’’ of studyinformation. This approach allows the sponsor to conduct asingle, global protocol for a multinational study, rather thanconducting separate, though identical, protocols. Althoughstudies conducted under an IND are not automatically moreGCP compliant, such compliance is likely to be higher wheninvestigators are aware that FDA may inspect them. In point offact, FDA will audit investigator sites in pivotal studies regard-less of country and regardless of whether the studies wereconducted under an IND.

Conducting a foreign study under an IND can also havedrawbacks. For one, some non-U.S. investigators may object tosigning the FDA Form 1572. The concept of an FDA-mandatedInvestigator Statement may be unpalatable to them.



Another potential drawback to conducting a foreign studyunder an IND can occur if FDA places the IND on hold. In thatcase, all IND studies underway in all countries must stop.

After weighing the pros and cons, the sponsor may decidenot to conduct the foreign clinical studies under an IND. Ifthat is the case, the studies must nevertheless conform to theregulations in 21 CFR 312.120, which describe the criteria forforeign studies not conducted under an IND:

1. In general, FDA accepts such studies provided theyare well designed, well conducted, performed byqualified investigators, and conducted in accordancewith ethical principles acceptable to the worldcommunity. Studies meeting these criteria may beutilized to support clinical investigations in theUnited States and/or marketing approval. Marketingapproval of a new drug based solely on foreignclinical data is governed by Sec. 314.106.

2. Data submissions: A sponsor who wishes to rely on aforeign clinical study to support an IND or to sup-port an application for marketing approval shallsubmit to FDA the following information:

(a) A description of the investigator’s qualifications(b) A description of the research facilities(c) A detailed summary of the protocol and results

of the study and, should FDA request, caserecords maintained by the investigator oradditional background data such as hospital orother institutional records

(d) A description of the drug substance and drugproduct used in the clinical study, if available

(e) If the study is intended to support the effective-ness of a drug product, information showingthat the study is adequate and well controlledunder Section 314.126

3. Conformance with ethical principles:

(a) Foreign clinical research is required to havebeen conducted in accordance with the ethical

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principles stated in the ‘‘Declaration ofHelsinki’’ or the laws and regulations of thecountry in which the research was conducted,whichever represents the greater protection ofthe individual.

(b) For each foreign clinical study submitted underthis section, the sponsor shall explain how theresearch conformed to the ethical principlescontained in the ‘‘Declaration of Helsinki’’ orthe foreign country’s standards, whichever wereused. If the foreign country’s standards wereused, the sponsor shall explain in detail howthose standards differ from the ‘‘Declaration ofHelsinki’’ and how they offer greater protection.

(c) When the research has been approved by anindependent review committee, the sponsor shallsubmit to FDA documentation of such reviewand approval, including the names and qualifi-cations of the members of the committee. In thisregard, a ‘‘review committee’’ means a commit-tee composed of scientists and, where practi-cable, individuals who are otherwise qualified(e.g., other health professionals or laymen).The investigator may not vote on any aspect ofthe review of his or her protocol by a reviewcommittee.

3.8. FDA Inspections of Foreign ClinicalInvestigators

As noted above, FDA inspects selected foreign clinical investi-gator sites for studies considered pivotal for approval. SuchFDA inspections of foreign clinical investigators have increased

in the number of sponsors submitting NDAs that containpivotal foreign clinical data. In addition, some pivotal trialsare so large—10,000–20,000 patients or more—that suffi-cient patients are not available for enrollment from the UnitedStates alone, requiring the inclusion of foreign data.


dramatically in recent years (see Fig. 1) due to an increase


The violations that lead FDA to reject foreign studiesinclude nonavailability of source documentation, inadequaterecord-keeping, failure to follow the protocol, unreported con-comitant therapy, and unavailability of patient diaries.

It is interesting to note that FDA inspections of clinicalinvestigators uncover similar types and incidence of GCP viola-tions at both U.S. and foreign sites (Fig. 2).

4. THE NEW DRUG APPLICATION AND THECOMMON TECHNICAL DOCUMENT

ICH has promulgated a common format for marketing appro-val applications in the United States, Europe, and Japan.

Figure 1 FDA inspections of foreign clinical investigators,1991–2000. (From A. El-Hage, FDA.)

Figure 2 FDA inspection of European clinical sites reveals mostcommon GCP deficiencies.

538 Grignolo et al.


This format is called the Common Technical Document (CTD).The CTD follows a logical and highly structured format (seeFig. 3) designed to facilitate the preparation of marketingapplications to multiple countries. Its common elements areintended to save time and labor by minimizing the need toreformat documentation or alter the sequence in which dataare presented.

The CTD format is now compulsory in the EuropeanUnion and Japan; Australia will make it compulsory in 2004.Currently in the United States and Canada, the CTD is notrequired, but its use is highly recommended.

In the United States, marketing applications submitted inthe CTD format are still referred to as NDAs. As FDA receivesmore applications in CTD format, reviewers are becoming

Figure 3 Diagrammatic representation of ICH Common TechnicalDocuments. Module 1 contains documents specific to each region,such as application forms and proposed labeling. The other modulesare relatively common to all submissions.



familiar with using the format. Neither FDA nor other agen-cies such as the European Medicines Evaluation Agency(EMEA) report significant difficulties in working with thenew format. On the other hand, some sponsors have experi-enced difficulty in determining where certain information, suchas the Integrated Summary of Safety (ISS) and IntegratedSummary of Efficacy (ISE), should be placed within the CTDmodules. Communications with FDA at presubmission meet-ings (see below) can help resolve such issues.

The CTD benefits foreign drug development by stream-lining the documentation process. Sponsors can submitdocumentation to FDA and other authorities with minormodifications to tailor the submission to local Agency needs.This allows the sponsor to apply more focus on the docu-ment’s scientific and medical content and less on its format.Ultimately, the need to submit a document that demon-strates quality, safety, and efficacy remains unchanged. Thoserequirements are driven by both FDA regulations and ICHguidelines.

FDA has the same expectations for an NDA regardlessof whether the data was collected in the United States orabroad. The submission must present a convincing, data-driven demonstration of quality, safety, and efficacy, andthe data must be relevant to the U.S. patient population. Inreality, however, FDA may be more skeptical of data from‘‘particular unnamed countries.’’ When presented with exten-sive data from these regions, FDA sends its inspectors to verifycompliance with GCP, GLP, and GMP.

Whether the NDA is submitted to FDA in the tradi-tional format or in CTD format, the FDA will look for thesame standards:

ClarityNavigabilityReviewer-friendlinessCompletenessLogical presentationData that enable FDA to make sound scientific and

medical decisions.

540 Grignolo et al.


5. COMMUNICATIONS WITH FDA

Communication with FDA is of paramount importance inthe drug development and approval process. For both foreignand U.S. sponsors, FDA can be an ‘‘arm’s-length partner’’in drug development. The sponsor should keep FDA informedof drug development plans and progress so that the Agencycan provide the best advice throughout the process and helpthe sponsor prevent costly errors. Foreign-based companiesmust be especially diligent about communicating with FDAthroughout the drug development process. Misunderstandingsregarding the Agency’s expectations for the NDA can destroya drug development program. The most significant concernis the potential that the foreign clinical data will have lim-ited applicability to the U.S. patient population. If FDA hasconcerns regarding limited applicability, the sponsor mustbe aware of these concerns early enough in the process to beable to take appropriate action, such as conducting studies inthe United States rather than abroad.

Communicating with FDA may differ from communicat-ing with other Agencies. Some methods of communicationare more effective than others, and FDA has issued preciseguidances regarding communications and meetings withindustry. As noted above, foreign companies that wish to com-municate with FDA must do so through a U.S.-based agent.

Meetings with the FDA take place at several predeter-mined milestones in the drug development process.

5.1. Pre-IND Meetings

The purpose of the pre-IND meeting is to introduce the sponsorand the drug to the FDA. (The introduction may not be neces-sary if the sponsor is a well-known global pharmaceuticalcompany.) Many FDA divisions will grant pre-IND meetingsto sponsors, but some may be reluctant to do so, pre-ferring to review a submitted IND and then provide commentsto the sponsor. When granted, a pre-IND meeting can help asponsor design additional nonclinical data or refine the clinicalprotocol prior to submitting the IND; in turn, this level of



communication and preparation can prevent the imposition ofan IND clinical hold based on FDA concerns about safety. It isimportant to note, however, that holding a pre-IND meeting isno guarantee that the FDA will not issue an IND hold on thestudy.

In presenting the drug at the pre-IND meeting, thesponsor generally discusses the characterization of the drugand presents manufacturing and nonclinical data. The pre-sentation should also address the proposed clinical inves-tigational plan in relation to the desired final labeling(prescribing information). At this time the company shouldidentify any foreign clinical studies that it will sponsor andindicate whether they will be conducted under an IND. Thesponsor should also present and discuss the initial clinicalprotocol.

In discussions during the pre-IND meeting, it may bepossible to agree to the details of the initial clinical protocol.Critical issues will be identified; some may be resolved at themeeting. Examples of such issues include the inclusion andexclusion criteria, the use of concomitant medications orcomparators that may not be approved drugs in the UnitedStates, or the use of patient populations that are underrepre-sented in the United State.

5.2. The End-of-Phase 2 meeting

Phase 3 of the drug development process represents the finalpath to the NDA. Phase 3 trials also require significant invest-ment on the part of the sponsor. The end-of-phase 2 meet-ing gives the sponsor an opportunity to obtain the FDA’scommitment on pivotal study designs and key endpoints.It allows the sponsor to make any necessary adjustments tothe development plan regarding CMC, toxicology, clinical orlabeling claims. End-of-phase 2 meetings are probably themost important meetings that sponsors will have with FDA.End-of-phase 2 meetings are especially critical for foreign spon-sors, because the meetings help identify ‘‘show-stopper issues’’such as poor applicability of proposed phase 3 studies to the

542 Grignolo et al.


U.S. patient population. This will help avoid large invest-ments in misguided trials.

Several factors determine when it is most advantageousto hold end-of-phase 2 meetings. By the time the meetingis held, labeling claims should be reasonably well articulated,and the apparent effective dose should have been establishedin phase 2 studies. The sponsor should be certain that thedose-finding is sound and the pharmacokinetics/pharmaco-dynamics (PK/PD) work is well advanced. The meeting shouldtake place when the sponsor has designed the phase 3 program,and is ready to present it to FDA and before the companymakes the significant investments required for the phase 3program, since Agency recommendations may drive changesto the trial plans.

5.3. Pre-NDA/BLA Meetings

Meetings with FDA prior to submitting the NDA or the Bio-logics License Application (BLA) can be helpful. These confer-ences should be held when phase 3 studies near completion—usually about 6 months before the planned NDA submissiondate. One goal of these meetings is to uncover unresolvedissues that might stand in the way of approval. Another goalis to identify those studies that are critical for approval and toensure that they are adequate and well controlled to establishthe drug’s effectiveness and safety. In the case of a foreigndrug, it is necessary to identify which of the critical studiesfor approval are foreign studies.

The meeting is held with the FDA Division responsiblefor the drug’s review. During the meeting, the sponsor shouldorient the reviewers to the technical content to be submittedin the NDA as well as the best formatting of the data. Proposedanalyses and subanalyses of study data to be included in theapplication should also be discussed.

It is critical to understand the FDA’s expectations for theNDA. As already noted, misinterpretations can derail a drugdevelopment program. Foreign sponsors may find it particu-larly helpful to discuss in advance the FDA’s intentions to



inspect the foreign studies so as to be able to alert investigatorsand prepare the clinical sites for FDA inspection.

5.4. Advisory Committee Meetings

AdvisoryCommitteemeetingsmaybeadvantageous to bothFDAand the sponsor. FDA initiates these meetings, usually whenthe Agency needs advice from the medical and patient commu-nities before deciding on the approval of an NDA. These meet-ings provide an opportunity for FDA to obtain the adviceof medical experts regarding the approvability of the NDA.At the same time, Advisory Committee meetings enable thesponsor to present key findings of efficacy and safety to medicalexperts. The Advisory Committee includes outside expertsin the appropriate medical specialty as well as consumer andpatient representatives. The meetings are open to the public.

Advisory Committee members are primarily interestedin the quality and persuasiveness of the data presented and inthe relevance of the data to the U.S. patient population. Atthe end of the meeting, the Advisory Committee votes onrecommending approval or disapproval of the NDA. Althoughthe vote is nonbinding, FDA usually follows AdvisoryCommittee’s advice.

Although Advisory Committee meetings offer the sponsoran opportunity to make its case, several unique characteristicscan make them especially challenging for sponsors. Theseformal, structured meetings are governed by the Federal Advi-sory Committee Act of 1972, which governs all governmentAdvisory Committees, and by regulations outlined in Section120 of the Food and Drug Administration ModernizationAct. Proceedings of these face-to-face meetings are recordedon audio- and video-tape, and the meetings themselves arewebcast; written transcripts of each meeting are prepared andpublished on FDA’s web site. The meetings include sponsorand FDA presentations and committee discussions, all of whichare open to the public, including financial analysts and com-petitors of the sponsor. The sponsor may present informationthat it considers to be trade secrets in a closed portion of the

544 Grignolo et al.


meeting. Personal information about clinical subjects may alsobe presented in the closed portion of the meeting.

As noted above, the committee’s vote is not binding;however, FDA rarely contradicts an Advisory Committeerecommendation. As a result, committee recommendationscarry great weight, not only with FDA, but also with thefinancial community and the pharmaceutical industry at large.A negative committee vote can effectively devastate years ofdevelopment work.

Considering the potential impact of the committee’s recom-mendation for or against NDA approval, the sponsor mustbe prepared to make a persuasive presentation to the AdvisoryCommittee members. A successful Advisory Committee meetingdemands extensive preparation and infrastructure. Meetingsmay be scheduled as long as a year in advance, and committeemembers must be provided with materials for review severalweeks prior to the meeting. The sponsor’s presenters, and anyexternal parties presenting on the sponsor’s behalf, shouldbe excellent speakers who can clearly present the sponsor’scase for approval. Presentations should be well rehearsedand supported with audio-visual aids to make the strongestpositive impression possible.

5.5. Labeling Meetings

Labeling meetings are held with FDA after the sponsor hassubmitted the NDA. The purpose of labeling meetings is toreach agreement on the exact wording of the package insertfor the pending application. The sponsor and FDA may alsodiscuss the need for any revisions to the label that might berequired based on new safety information.

Reaching agreement on the exact wording for the labelmay require several rounds of negotiation. In contrast withmost other FDA meetings, labeling meetings usually areteleconferences, rather than face-to-face sessions. Teleconfer-encing allows participants on both sides to take advantageof ‘‘muted caucusing’’ during the negotiation process. Theforeign sponsor may wish to have its U.S. distributor partici-pate in the negotiations regarding labeling language.



Much is at stake, because the final package insert wordingwill either facilitate or restrict the promotion and sale ofthe drug. Ideally, the labeling meeting results in packageinsert wording that satisfies both the sponsor and FDA.Such an agreement is a critical milestone toward the launchof a safe and effective product.

6. SUMMARY AND CONCLUSIONS

In many ways, development of a foreign drug for approval inthe U.S. market is similar to the development of U.S. drugs.Regardless of where the drug originates or where data werecollected, sponsors must meet the same requirements: adhereto recognized standards, protect patient rights, design studiesthat support labeling safety and efficacy claims, ensure thequality and integrity of the data, and submit a complete andclearmarketing application. The differences that do exist amongcountries are due to geography, culture, medical practice, localpreferences and practices, and level of comfort of regulatoryagencies such as FDA with data collected in other countriesand patient populations. To minimize the impact of these dif-ferences and to reduce the need to conduct duplicate trials inmultiple regions, companies that develop foreign drugs mustplan carefully and communicate with FDA ‘‘early and often.’’

Foreign drug sponsors can facilitate the process ofobtaining U.S. approval by communicating with the FDAappropriately and frequently. They should look after the detailsof development work conducted outside the United States toensure that it is in line with FDA expectations and require-ments. Finally, when sufficient data have been collected, thesponsor should make a solid case for approval.

Drug development is challenging for pharmaceutical com-panies everywhere. The ‘‘foreign’’ element may complicate theprocess somewhat, but it is not an insurmountable obstacle.Savvy planning and sound execution make obtaining U.S.approval rather manageable.

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18

Common Technical Document—Quality (M4-Q): One Regulatory

Participant’s Perspective

UBRANI V. VENKATARAM


Rockville, Maryland, USA

1. INTRODUCTION

The International Conference on Harmonization (ICH) hasset itself the laudable goal to harmonize the technical require-ments for the approval of medicinal products in the threemost prosperous regions of the world: the United States,Japan, and the European Union (EU). Towards this goal, ithas published many guidelines, covering such topics as carci-nogenicity testing, good clinical practices, stability testing,impurity testing, etc. This author had the unique and excitingopportunity to be involved in the development of the Common

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Technical Document—Quality (CTD-Q) that is part of one suchguideline, the Common Technical Document (CTD). As amember of the CTD-Q Expert Working Group (EWG), thisauthor had the opportunity to learn from fellow EWG membersthe regulatory processes in Japan, Canada, and the EU. TheICH employs a unique process to manage the development andpublication of these guidelines that affords intense discussions/negotiations between the various parties, but is efficient inproducing the guidelines in a timely fashion. In this article theauthor has attempted to provide his perspective of the CTD-Qbased on his experiences as a CTD-Q EWG member andChemistry Reviewer in the Office of Generic Drugs. This articlewas written by the author in his private capacity. No officialsupport or endorsement by the Food and Drug Administration(FDA) is intended or should be inferred. The information pro-vided here is also based on many guidances that are publishedor unpublished draft guidances. The reader should exercisecaution in using draft guidances when preparing submissionsto FDA as the content of these draft guidances may changebefore final publication.

Additionally, the reader should note that the guidancesrepresent the Agency’s current thinking on the topic. It doesnot create or confer any rights for or on any person and doesnot operate to bind FDA or the public. An alternative approachmay be used if such approach satisfies the requirement of theapplicable statute, regulations, or both.

2. INTERNATIONAL CONFERENCE ONHARMONIZATION

Globalization of the pharmaceutical business provided theimpetus for the harmonization of the technical requirementsfor the approval of medicinal products in three regions of theworld—the United States, Japan, and EU where most ofthe drug discovery and development occurs. Harmonization oftechnical requirements has led to uniform standards for drugproduct quality and resulted in considerable cost reduction to

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the regulated industry. It is expected that harmonization wouldlead to a reduction in research and development (R&D) costand time in developing safe and efficacious products.

2.1. Purpose

The following statement was issued by the ICH SteeringCommittee in Tokyo, Japan, at the end of the October 1990meeting:

The Parties cosponsoring this Conference, represented atthe 2nd Steering Committee Meeting in Tokyo, October23–24, 1990, reaffirmed their commitment to increasedinternational harmonization, aimed at ensuring thatgood quality, safe, and effective medicines are developedand registered in the most efficient and cost-effectivemanner. These activities are pursued in the interest ofthe consumer and public health, to prevent unnecessaryduplication of clinical trials in humans, and to minimizethe use of animal testing without compromising theregulatory obligations of safety and effectiveness.

This Conference will provide a unique opportunityfor regulators and industry to reach consensus on thesteps needed to achieve this objective through greaterharmonization of technical requirements and to set outpractical and realistic targets for harmonizing require-ments where significant obstacles to drug developmentand the regulatory process have been identified.

Recognizing the substantial progress which has alreadybeen made in achieving harmonization within Europeand through bilateral contacts between Europe, Japan,the United States, and other regions, the Conferencewill seek to make further progress through a trilateralapproach, with clearly defined priorities, methodsof work, and recommendations to both industry andregulatory authorities.

While the Conference will be an important step forward,it is not seen as an end in itself, but as a stage in adeveloping process, at a high level, between regulatorsand industry.

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The Conference, its preparations and follow-up activities,will be conducted in an open and transparent manner,and the presence of observers from other regulatoryauthorities and WHO is welcomed as a means of ensur-ing that the benefits of progress towards harmonizationcan be utilized worldwide.

The Conference will not only look at existing issuesbut will, based on past experience, seek to minimizefuture divergence of new registration requirements, asa consequence of technical progress.

2.2. Structure and Process

ICH is a joint initiative involving both the regulators andindustry as equal partners. The six founding members ofICH who also constitute the steering committee are the EU,the European Federation of Pharmaceutical Industriesand Associations (EFPIA), the Ministry of Health, Labor andWelfare, Japan (MHLW), the Japan Pharmaceutical Manu-facturers Association (JPMA), U.S. FDA, and the Pharma-ceutical Research and Manufacturers of America (PhRMA).The steering committee is responsible for the administrationof ICH.

In addition, there are three observers: the World HealthOrganization (WHO), the European Free Trade Area (EFTA)represented at ICH by Switzerland, and Canada representedat ICH by Therapeutic Products Directorate, Health Canada.The observers attend the steering committee meeting as non-voting members.

The ICH Secretariat is managed by the InternationalFederation of Pharmaceutical Manufacturers Association(IFPMA).

Harmonization proposals for action may come from anyinterested parties but must be submitted to ICH through oneof the six parties to ICH or one of the observers on the steeringcommittee. Such proposals may include new types of medicinalproducts resulting from advances in technology and techni-ques for producing medicines, lack of harmonization in current

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technical requirements, further harmonization of existingrequirements, transition to technically improved testing proce-dures, review of an existing ICH guideline, and maintenanceof an existing guideline. The sponsoring ICH steering commit-tee member presents the proposal as a ‘‘concept paper’’ thatdetails the (a) type of proposed harmonization action, (b) state-ment of problem, (c) issues to be resolved, (d) background to theproposal, and (e) type of EWG. The steering committee evalu-ates the proposal for sufficient interest by the ICH parties andalso whether it can be accommodated within the ICHframework. Proposals that are deemed worthwhile are thenpresented to the interested parties. Upon selection, thesteering committee formalizes the proposal by confirming the‘‘objectives and expected outcome,’’ constitute the EWG, andset a timetable (normally not to exceed 2 years) and actionplan. The EWG is composed of two technical experts fromeach of the six member parties and one technical expert fromany of the other observer parties, as designated by the steeringcommittee. One of the two technical experts is designated thetopic leader for that member party. The role of a rapporteur,nominated by one of the member parties to lead the EWGat the behest of the steering committee, is unique. The rappor-teur is not only the technical expert on the topic, but is alsoresponsible for the smooth functioning and success of theEWG. The rapporteur serves to resolve disputes betweenmember parties and acts as the counselor, timekeeper, scribe,and reporter. The EWGs meet during the same time and atthe same location as the steering committee. The meetingsare held once every 6 months, and the locations are rotatedamong the member states. The meeting expenses (travel andhotel) are the responsibility of each member party, and eachmember party also shares expenses for hosting the meetingwith the host member. The EWG may request for additionalmeetings to meet the timetables and goals that were set bythe steering committee. All the member parties are requiredto be present for the EWG to convene, but the EWG maymeet in the absence of ‘‘observer parties.’’ At the end of eachmeeting, the rapporteur presents a progress report to thesteering committee.



ICH follows a five-step process for developing and issuingtechnical guidelines.

Step 1. Consensus is built among the member partieson the contents of the guideline. The rapporteurprepares an initial draft of a guideline or recom-mendation, based on the objectives set out inthe Concept Paper, and in consultation withexperts designated to the EWG. The initialdraft and successive revisions are circulatedfor comment, giving fixed deadlines for receiptof those comments. Interim reports are made toeach member of the ICH steering committee.If consensus is reached within the agreed time-table the consensus text with EWG signatures(see below) is submitted to the steering commit-tee for adoption as Step 2 of the ICH process.Where complete consensus has not been

achieved within the timetable, a report will bemade to the steering committee indicating theextent of agreement reached and highlighting thepoints on which there are differences betweenthe parties. Experts from all parties representedon the EWG will have the opportunity toexplain their position to the steering committee.The Steering Committee may then:

Allow an extension of the timetable, on thebasis that the EWG can give assurancesthat consensus could be reached within ashort, specified period

Decide to suspend or abandon the harmoniza-tion project

Decide to proceed to Step 2 on the basis ofthe current draft, notwithstanding absence ofcomplete consensus in the EWG

When consensus is reached on the technicalissues, all parties represented on an EWGwould be invited to sign the document to indi-cate their agreement to the consensus text,

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which is submitted to the steering committee.Circumstances could be envisaged, however,when not all parties are present or able tosign the consensus text. It would then be forthe steering committee to decide whether toproceed to Step 2.

Step 2. The Step 1 document is signed-off by each of thesix ICH steering committee members whenthe steering committee agrees, on the basis ofthe report from the expert working group, thatthere is sufficient scientific consensus on thetechnical issues for the draft guideline or recom-mendation to proceed to the next stage.

Step 3. The Step 2 document is now released for regu-latory consultation in the three regions. Inthe United States, this means the document ispublished in the Federal Register as draft guid-ance for comments. At the end of the commentperiod the EWG members representing theregulatory bodies collate the comments fromeach region and, after consultation, arrive at asingle harmonized document. At this stage, therapporteur is a regulator who is responsible forfinalizing the harmonized guideline and obtain-ing the consent, in the form of signature, fromall the EWG member parties.

Step 4. The regulatory rapporteur presents the Step 3harmonized document to the steering commit-tee. It is generally expected that there are nosubstantial differences between the Step 2 andStep 3 documents. If it is satisfactory to bothregulatory and industry parties, then the steer-ing committee adopts the document as a Step 4document The guideline is now recommendedfor adoption by the regulatory bodies in thethree regions.In the event that one or more parties repre-

senting industry have strong objections to the



adoption of the guideline on the grounds thatthe revised draft departs substantially from theoriginal consensus or introduces new issues,the regulatory parties may agree that therevised text should be submitted to furtherconsultation.

Step 5. The final step of the process is the regula-tory implementation of the guideline. Imple-mentation is specific to the region and is thesame as other guidelines put forth in eachregion.

The maintenance process is intended to provide a rapidand flexible way of making minor changes and revisionsto published ICH guidelines. The process provides for updatingthe guidelines with new, current, and relevant information. Aconcept paper is prepared once a maintenance issue has beenidentified and sent to the ICH Secretariat and the Coordinatorsfor agreement. With their concurrence, the concept paper iscirculated among the ICH parties ‘‘maintenance network.’’The consultation among the maintenance network parties isquite informal and is accomplished by emails and telephoneconferences. If there is an agreement among the parties, thenthe ICH Secretariat presents the revisions to the steeringcommittee, and with their concurrence the subject guidelineis revised and published. If there is no agreement, the steeringcommittee may initiate the Step 2 process for further consulta-tion among the ICH parties. A successful example of mainte-nance is Guideline Q3C, Impurities: Residual Solvents. Themaintenance of this guideline includes identifying new residualsolvents and revising existing permitted daily exposure (PDE)levels,* as information on them become available.

An interesting example that illustrates the ICH process ofconsultation and concurrence is the adoption of Guideline Q3A:Impurities in Drug Substances. Q3A provides guidance onlimits and qualification of impurities in new drug substances,

*PDE is defined in Q3C as pharmaceutically acceptable intake of residualsolvents.

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produced by chemical synthesis. The intent of the guideline isto ensure that a single drug substance specification is devel-oped that is acceptable in all three regions. The guideline wasfirst recommended for adoption at Step 4 of the ICH processon March 30, 1995. However, several inconsistencies relatingto language usage and the scientific principle of roundingwere discovered in the Step 4 document. Consensus couldnot be found on several proposals for revision. The guidelinereverted to Step 2 of the ICH process on October 7, 1999.A revised guideline was recommended for adoption underStep 4 for the second time on February 7, 2002, by the ICHsteering committee. It then reached the implementation stage(Step 5). The revised guidance document, designated Q3A(Revision 1), was published on the FDA website on February10, 2003.

2.3. Guidelines

ICH has been prolific in producing guidelines for harmonizingtechnical requirements in pharmaceutical applications. Accord-ing to the ICH web site, the current tally is 45 at the end

of quality topics and associated guidelines. A complete list of allpublished guidelines (including the safety and efficacy topics)may be accessed at the ICH web site.*

In addition to the safety (S), efficacy (E), and quality (Q)topics described above, ICH is working on four multidisciplin-ary (M) topics: medical terminology (M1), electronic standardsfor transmission of regulatory information (ESTRI, M2),timing of preclinical studies in relation to clinical trials (seeSafety Topics, M3), and the Common Technical Document(M4). The advantages of harmonized electronic Standardsand the Common Technical Document in a global economyare obvious. A harmonized medical terminology document isa necessity in the preparation of CTD. With advances in tech-nology and globalization of pharmaceutical business, the desire

*The number of guidelines (at various stages of development) was 57 as of1/2003.


of ICH 4 (9 active and 36 at Step 4/5). Table 1 provides a list


Table 1 ICH Quality Guidelines and Their Status

Topics Status

ICH designation Brief description ICH FDA (date of FR notice)

Q1 Stability testing of New Drug Substancesand Products

Step 5: Hassince beenrevised—see Q1A(R)

See Q1A(R)

Q1A(R) Stability testing of New Drugs and Products(Revised)

Step 5 FR, Vol. 66, No. 215,11/07/2001, pp. 56332–3

Q1B Photostability Testing Step 5 FR, Vol. 62, No. 95,05/16/1997, pp. 27115–22

Q1C Stability Testing for New Dosage Forms Step 5 FR, Vol. 62, No. 90,05/09/1997, pp. 25634–35

Q1D Matrixing and Bracketing Designs for StabilityTesting of Drug Substances and Products

Step 5 To be notified

Q1E Evaluation of Stability Data Step 3 FR, Vol. 67, No. 115,06/14/2002, pp. 40949–50

Q1F Stability Data Package for Registration inClimatic Zones III and IV

Step 3 FR, Vol. 67, No. 115,06/14/2002, pp. 40951–52

Q1H Labeling Step 1 N/AQ2A Text on Validation of Analytical Procedures Step 5 FR, Vol. 60, No. 94,

03/01/1995, pp. 11260Q2B Methodology Step 5 FR, Vol. 62, No. 96,

05/19/1997, pp. 27463–7

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Q3A(R) Impurities in New Drug Substances—Revised Step 5 To be notifiedNote: Q3A (Step 4, 03/30/1995) was revised under

Step 2 of ICH process and recommended atStep 4 for adoption on 07/02/2002

Q3B(R) Q3B (Step 5) is an extension of Q3A, Impuritiesin Drug Substances (The revised guideline hasreached Step 3.)

Step 3 FR, Vol. 65, No. 139,07/19/2000, pp. 44791–97

Q3C Impurities: Residual Solvents Step 5 FR, Vol. 62, No. 247,12/24/1997, p. 67377

Q3C(M)-2Guidelines

PDE for N-Methylpyrrolidone (NMP)and Tetrahydrofuran (THF)

Step 5 To be notified

Q4 Pharmacopoeia Harmonization N/A N/AQ5A Quality of Biotechnological Products: Viral Safety

Evaluation of Biotechnology Products Derivedfrom Cell Lines of Human or Animal Origin

Step 5 FR, Vol. 63, No. 185,09/24/1998, p. 51074

Q5B Analysis of the Expression Construct in Cells Usedfor Production of r-DNA Derived Protein Products

Step 5 FR, Vol. 61, 02/23/1996,p. 7006

Q5C Stability of Products (proteins and/or polypetidecontaining drug products)

Step 5 FR, Vol. 61, 07/10/1996,p. 36466

Q5D Derivation and Characterization of Cell SubstratesUsed for Production of Biotechnological/BiologicalProducts

Step 5 FR, Vol. 63, No. 182,09/21/1998, pp. 50244–49

Q6A Specifications for New Drug Substances andProducts—Chemical Substances; includes aDecision Tree

Step 5 FR, Vol. 65, No. 251,12/29/2000, pp. 83041–63

Q6B Specifications for New Drug Substances andProducts—Biotechnological Substances

Step 5 FR, Vol. 64, 08/18/1999,p. 44928

Q7A Good Manufacturing Practices for ActivePharmaceutical Ingredients

Step 5 FR, Vol. 66, No. 186,09/25/2001, pp. 49028–29

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to be able to produce and submit a common regulatory dossierhas become urgent. As discussed in the next sections, the goalis reachable within a reasonable time.

2.4. Common Technical Document—ICHGuideline

The ICH Guideline, Common Technical Document, is a sub-topic in the multidisciplinary topic M and is designated M4.The proposal for development of this guideline came from theregulated industry and was accepted in principle by the steer-ing committee in the summer of 1996. However, the steeringcommittee requested a feasibility study because of the complexand comprehensive characteristics of the proposal. The feasi-bility study was to evaluate the readiness of the regulatorsto accept reform in the technical requirements and documentpresentation of a New Drug Application. A major concern wasresources. It was recognized that the traditional EWG struc-ture would be inadequate for accomplishing the task, and ahigh-level team would be necessary to bring out the harmo-nized guideline. The work on M4 began in the winter of 1998at the ICH Meeting in Tysons Corner, Virginia.

The CTD itself consists of several subtopics.provides the status of these guidelines at the time of publica-

FDA (eCTD). The CTD—Quality EWG was one of the larg-est ever involved in such an endeavor. Separate groups wereformed from within this EWG to work on new molecular enti-ties (NMEs) of chemical origin and NME of biotech origin.

respective guidances. There was even discussion regardingissuance of separate guidelines. However, with time itbecame apparent that the scientific and regulatory issues forthe two types of products are similar and that a common docu-ment that addressed all the issues pertaining to NMEs of bothchemical and biotech origin could be developed.

The overall structure of CTD is best represented graphi-

558 Venkataram

Table

are: EFPIA (quality), JPMA (safety), PhRMA (efficacy), and

The two subgroups generally met separately to develop their

2

tion. Rapporteurs who led the EWGs for each of the subtopics

cally (Fig. 1). The CTD is composed of five modules designated


Table 2 ICH CTD Guidelines and Their Status

Topics Status

ICH designation Brief description ICH FDA (date of FR notice)

M4 Organize withAnnex: Granularity

Organization of the Common Technical Documentfor the Registration of Pharmaceuticals for HumanUse Including the Granularity document thatprovides guidance on document location andpagination

Step 5 Earlier version published inFR, Vol. 66, 10/15/2001,pp. 46464–65(reeditedversion to be published)

M4 Quality Format of the Quality sections including the OverallSummary section

Step 5 As above

M4 Safety Format of the Safety sections includingNon-Clinical Overview and Non-clinicalWritten and Tabulated Summaries

Step 5 As above

M4 Efficacy Format of the Efficacy sections includingClinical Overview and Clinical Writtenand Tabulated Summaries

Step 5 As above

e-CTD The Electronic Common Technical Document Step 5 To be published

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1 through 5. It is beyond the scope of this article to describeeach of these modules in detail. The reader is referred to thedraft guidance ‘‘Guidance for Industry—Submitting MarketingApplications According to the ICH-CTD Format—GeneralConsiderations’’ and the topic-specific CTDs (i.e., CTD-Q,

able in the Acrobat PDF and HTML formats) for completedetails. The reader should note that, as of the date of prepa-ration of this article, the guidance is still in draft status andits contents may change with time. The following informationis presented to provide an overview of the contents of thisguidance.

Module 1—Administrative and Prescribing Information

1. FDA Form 356h2. Comprehensive table of contents3. Administrative documents

Figure 1 Common Technical Document Organization.

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CTD-S, and CTD-E) at http://www.fda.gov/cder/guidance (avail-


http://www.fda.gov

Module 2—Common Technical Document Summaries

1. Overall CTD table of contents2. Introduction to the summary of documents3. Overviews and summaries

Module 3—Quality

1. Module 3 table of contents2. Body of data3. Literature references

Module 4—Nonclinical Study Reports

1. Module 4 table of contents2. Study reports and related information3. Literature references

Module 5—Clinical Study Reports

1. Module 5 table of contents2. Study reports and related information3. Literature references

nical documentation required in a New Drug Application. It isreserved for regional administration information such as appli-cation forms, labeling, and others. The regional authoritiesspecify the format and content of this module. The harmonizedformat of the CTD is described in Modules 2 through 5 andforms the basis for submission of the technical documentation.The CTD-Q (Module 2—overall summary—and Module 3) isdiscussed in more detail in the next section. Discussion of thesafety and efficacy documents is not in the purview of theauthor’s expertise and is deferred to experts in those topics.

2.5. Future

The work on the Common Technical Document was completedat Step 4 and the document was released to the public at ICH 5in San Diego, California, in November 2002. An implementationgroup consisting of topic experts and eCTD-EWG and steeringcommittee members (approximately 70 members) has been


As illustrated in Fig. 1, Module 1 is not part of the tech-


formed. The implementation group has since met three times.The quality implementation group has produced a question-and-answer document that addresses various implementationquestions. These implementation questions concern locationissues, polymorphism, multiple drug substance sources, combi-nation products, multiple dosage forms, etc. A Federal Registernotice announcing the availability in the United States of thisguidance document for comment was published on December30, 2002 (67 FR 79639). The guideline for eCTD has reachedStep 5, although FDA has yet to publish this in a FederalRegister Notice seeking public comments. The question-and-answer guideline related to eCTD has reached Step 4.

Preparing and submitting a single dossier to the regu-latory authorities in the three ICH regions for approval tomarket drug products may be years away. For the CTD—Quality subtopic, some of the issues pertain to harmonizationof the pharmacopoeia, lack of guidelines pertaining to manu-facturing of the drug substance and drug product, packaging,use of drug master file for submission of proprietary informa-tion, and differences in GMP and filing requirements. Harmo-nization in these topics is essential before the goal of a singledossier may be realized.

In addition to the ongoing work on implementation ofthe CTD, ICH has identified many new areas where harmoni-zation of technical requirements would provide great benefit tothe public and the regulated industry. One such topic is ‘‘genetherapy.’’ ICH has held workshops to develop this topic.Information on all future ICH activities is available at the

3. COMMON TECHNICAL DOCUMENT—QUALITY

3.1. Scope

One of the first tasks the CTD-Q EWG set upon working wasto define the scope of this guideline. Two aspects of definingthe scope of the document were (a) the type of drug productsthat will be covered by this guideline and (b) whether the

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official website at http://www.ich.org/.


http://www.ich.org

guideline would address both the format and content require-ments of the quality section of a dossier. Agreement on the firstaspect was easy to achieve. It was agreed that the drug pro-ducts that will be covered by this guideline would be the sameas those covered by Q6A and Q6B. However, much discussionensued regarding the second aspect. It was realized that muchwork was needed to harmonize the content of the quality sec-tion of a dossier, and it may not be achievable within the timeframe proposed for this guideline. The task of harmonizingthe content was made onerous by the lack of ICH guidelineson such key quality topics as manufacturing of drug substancesand drug products and container closure systems (packaging).Additionally, progress in harmonization of the pharmacopoeiawas slow. The differences in regional requirements, such as therequirement for executed batch records, method validationpackages, etc., in the United States, and the Process ValidationScheme for the Drug Product in the EU, Drug Master Files(DMF), complicated the issue. Although the initial draft pro-posed used the term ‘‘illustrative examples,’’ it was argued thatthe language may be construed as defining the content. Hence,clarification such as ‘‘not all-inclusive’’ was sought to be inclu-ded in the scope. The finalized ‘‘scope’’ statement is as follows:

This section of the document is intended to provide guidanceon the format of a registration application for drug substancesand their corresponding drug products as defined in the scopeof ICH Guidelines Q6A New Chemical Entities (NCE) andQ6B Biological/Biotechnological (Biotech). This format mayalso be appropriate for certain other categories of products.To determine the applicability of this format for a particulartype of product, applicants should consult with the appropriateregulatory authorities.

The text following the section titles is intended to be explana-tory and illustrative only. The content of these sections shouldinclude relevant information described in existing ICH guide-lines, but harmonized content is not available for all sections.The Body of Data section in this guidance merely indicateswhere the information should be located. Neither the type norextent of specific supporting data has been addressed in thisguidance, and both may depend on regional guidance.



The section titles listed in the Regional Information section(3.2.R) represent examples of typical topics of information thatare not common to all ICH regions. Hence, the information tobe provided in these sections should be based on the relevantregional guideline.

In the United States, it is intended that the respectiveguidances on Drug Substance, Drug Product, Stability, Con-tainer Closure Systems, Validation of Analytical Procedures,Impurities, DMF, etc., will describe the content of the registra-tion application. The reader is directed to the following website for a complete list of the available guidances:

Many of these guid-ances are being revised to be instructive about the use of theCTD-Q format. The draft guidances are also available at thesame web site.

3.2. Process

The concept of one internationally acceptable registrationapplication had been discussed at various avenues. The BasicInternational Registration Dossier (BIRD) was developed bya group of farsighted industrialists and regulators with theaim of providing a common format and structure to the qualitysections of a registration application. During the diagnosticphase of evaluating the feasibility of a Common TechnicalDocument, the industry sponsors color-coded the BIRD docu-ment to identify areas of commonality among the three ICHregions. Table 3 provides a summary of that analysis. Greenindicated that the requirements in the three regions werealready harmonized. Yellow-coded areas indicated differingrequirements but that harmonization was thought possible.The red-coded areas were of the most concern, and harmoniza-tion was thought not to be possible.

The CTD-Q EWG consisted of members well versed inthe submission of dossiers for NMEs of both chemical originand biological origin. This large group was split into twosubgroups: one to develop the guideline for NMEs of chemicalorigin and a second group for NMEs of biological origin. There

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www.fda.gov/cder/guidance/index.htm.http://


http://www.fda.gov

http://www.fda.gov

Table 3 Summary of Analysis of BIRD Document

Review item Color code Comments

Drugsubstance

Nomenclature Green Requirements same in all 3 regionsManufacture Green for EU and Japan; red for

United StatesMore detail required in United States

Controls Green for most controls; red for testmethods and reference standard

Compendial harmonization required fortest methods; United States hasdefinitive requirement for referencestandard

Container closure Green for United States andJapan; red for United States

United States has higher requirement

Stability Green for stability conclusion andpostapproval protocol; stabilitydata—Red for United States

United States has the requirementfor site-specific stability data

Drugproduct

Composition/MasterProduction formula

Yellow for the 3 regions Minor differences between the3 regions

Manufacture Green or yellow for EU and Japan;generally Red for United States

United States requires greater detail andexecuted batch records; EU requiressite-specific validation data

Excipients Red for all 3 regions Compendial harmonization requiredControls for

finished productRed for all 3 regions; green for

justification of specification andvalidation

Compendial harmonization required

Container closure Red for all 3 regionsStability Green for all 3 regions except stability

data, which is Red for all 3 regionsUnited States requires site-specific data

CommonTech

nical

Docu

men

t—Quality

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was some thought during this guideline development phasethat separate guidelines should be issued. However, a singleguideline was formulated when it became apparent that thereview process was similar for the two different types ofNMEs. Technical staff from the respective Centers served astopic leaders for discussions regarding NMEs of chemical originand NMEs of biological origin, supported by review staff fromseveral review divisions. The FDA team also regularly con-sulted with the Technical Committees and the Chemistry,Manufacturing and Controls Coordination Committee of theCenter for Drug Evaluation and Research (CDER) andCenter for Biologics Evaluation and Research (CBER) commit-tees for evaluation of the draft guideline. Unlike other ICHguidelines, the CTD-Q guideline was issued twice at Step 2.This became necessary when it became apparent that theEWG would be unable to complete work on the ‘‘illustrativeexamples’’ that explained to the applicant the purpose of eachsection and subsection heading in a timely fashion. It wasdesired that public comments be elicited on the Format, i.e.,the section and subsection headings, and hence the first of theStep 2 document was released in September 1999. The com-pleted guideline with ‘‘illustrative examples’’ was released atStep 2 again in the spring of 2000. The Step 4 document wassigned-off by the ICH Steering Committee in November 2000and is currently at Step 5.

3.3. FDA Guidance

The Agency has published three draft guidances with regard tothe CTD. The FDA Draft Guidance ‘‘M2 - Electronic CommonTechnical Document Specifications’’ provides details for thepreparation of CTD in electronic format. It provides informa-tion on the media (preparing the media, media transport, andsecurity), file formats (XML, PDF, SVG files), instructions foramendments, supplements or variations, etc.

The FDA Draft Guidance ‘‘Submitting MarketingApplications According to the ICH/CTD Format: General Con-siderations’’ is a procedural guidance . It is the Agency versionof the ICH document M4: Organization of the CTD, and is

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intended to describe how to organize New Drug Applications(NDAs), Abbreviated New Drug Applications (ANDAs), andBiological License Applications (BLAs) for submissionin the United States. It is intended to be used with otherCTD Guidances CTD-Q, CTD-E, and CTD-S, and when fina-lized it will supersede the previous Agency guidelines ‘‘Guide-lines on Formatting, Assembling, and Submitting of New Drugand Antibiotic Applications (February 1987)’’ and ‘‘Guidancefor Industry: Organization of an ANDA (February 1998).’’ Thedraft ‘‘General Considerations’’ guidance discusses require-ments for both paper (size, margins, fonts, binding volumes,volume numbering and identification, pagination, cross refer-encing documents, packing carton, and sending in the sub-mission) and electronic submission. Information is providedon the nontechnical, region-specific Module 1, including form356h, comprehensive table of contents, and other administra-tive documents. It also describes Agency recommendation forsubmission of amendments and supplements, number of copiesto be submitted, etc.

The FDA Draft Guidance ‘‘M4 Common TechnicalDocument—Quality: Questions and Answers/Location Issues(Posted December 30, 2002)’’ provides clarification on theissues of location of content in the CTD-Q.

To date the Agency has received few NDAs in the CTDformat but many inquiries from interested A/NDA and BLAapplicants. The Agency is gearing itself to review the A/NDAsand BLAs when submitted in the CTD format by revising thereview template to conform to the CTD format. Many of thequality guidances are being revised to provide information onthe use of the CTD-Q format. While a true CTD submissionthat is acceptable to regulatory authorities around the worldmay take many more years, the first steps being taken areencouraging and foretell a bright future for CTD.

3.4. Format of an A/NDA

The basic structure of a Common Technical Document was

tions will be on CTD-Q. The guidance ‘‘M4: The CTD-Quality’’


described in Sec. 2.4. and Fig. 1. The focus in the following sec-


It should be when perusingthis document.

The quality technical information required to gainapproval to market a drug product in the United States isdescribed in 21 CFR 314.50 (d) and 314.94. The Chemistry,Manufacturing, and Controls (CMC) section should describecomposition, manufacture, and specification of the drug sub-stance and the drug product including environmental impactassessment (per 21 CFR 25.30, or 25.31, or 25.40). The CTD-Q,in general, follows this regulatory requirement by separatingthe drug substance and drug product information into twoseparate sections. The environmental impact information isincluded as part of Module 1.

The CMC information, when submitted in the CTD format,will appear in Modules 2 and 3. In Module 2, the QualityOverall Summary, the applicant is expected to present a com-prehensive summary of the CMC information that is includedin Module 3. Module 2 ‘‘Quality Overall Summary’’ followsthe same format as ‘‘Body of Data’’ in Module 3. The samesection headings and subheadings as in Module 3 are to beused. In Module 2 the applicant is not expected to provideany new CMC information, data analysis, and/or conclusionsnot already described in Module 3. The inclusion of QualityOverall Summary in Module 2 was much debated in the EWG.21 CFR 314.50 (c) requires that an application ‘‘contain a sum-mary of the application in enough detail that the reader maygain a good general understanding of the data and informationin the application, including an understanding of the quantita-tive aspects of the data.’’ A stated purpose of such summary isthat it could be furnished to FDA advisory committee membersand agency officials whose duties require an understandingof the application. Yet the February 1987 ‘‘Guideline for theFormat and Content of the Chemistry, Manufacturing, andControls Section of an Application’’ did not provide for sub-mission of a well-prepared summary. The safety and efficacyreviewers extensively use the summary documents pertain-ing to their review disciplines. The chemistry review process,however, is such that the CMC reviewers conduct their own

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is available at the following website: http://www.fda.gov/cder/guidance/4539Q.htm. consulted


http://www.fda.gov

http://www.fda.gov

data analysis without depending on the summary provided bythe applicant. It should be noted that summary documents arealso used in EU (Expert Reports) as part of their review process.After many debates, the EWG agreed to provide for a summarydocument as part of Module 2. It was agreed that the ‘‘QualityOverall Summary’’ (QOS) should be concise and not includeany information that is not already present in the ‘‘Body ofData.’’ The QOS may include justification for deviations; forexample, it may include justification for not following particu-lar guidances. It is most useful when QOS synthesizes informa-tion from other modules that is pertinent to CMC review.

The Module 3 format clearly distinguishes between thedrug substance and drug product information. The drugsubstance and/or product information is supplemented withinformation in the Appendices, Regional Information, andLiterature Reference sections. In writing this format documenta conscious decision was made by the EWG to leave out theGood Manufacturing Practices (GMP) issues and focus insteadonly on those issues that are reviewed by the regulatoryscientific personnel.

3.5. Content of an A/NDA

In this author’s perspective, the CMC content requirement foran A/NDA will not change with the forthcoming adoption of theCTD-Q format document. The exception is the introductionof the ‘‘Pharmaceutical Development’’ (CTD-Q designation3.2.P.2) section as part of the drug product section. Currentand draft guidance documents describe the content for sub-mission to FDA. Many of the guidances are being revised toprovide information on the use of the CTD-Q format. The guid-ances have been revised to clearly delineate the placement ofcontent in each section and/or subsection identified in the CTD-Q format document. The discussion below provides illustrativeexamples of the use of the guidance documents in developing thecontent for an A/NDA to be submitted in the CTD-Q format.

The revised guidances will be published as draft docu-ments for public comment in the near future. The author isgrateful to the CDERmanagement for permission to refer to the



unpublished guidances in this article. The reader is cautionedthat the content of these unpublished draft guidances maychange before final publication. The reader should also notethat the guidances represent FDA’s current thinking on thattopic. They do not create or confer any rights for or on anyperson and do not operate to bind FDA or the public. An alter-native approach may be used if such approach satisfies therequirements of the applicable statutes and regulations.

In the United States, the regulations (21 CFR 314.50(a) (1),314.50(g)(1), and 314.420) also provide for referencing perti-nent information in other applications and/or Drug MasterFiles (DMFs). This is especially true of ANDAs, where theapplicants rely on outside sources for the drug substance.These outside sources furnish the drug substance informationto FDA in a Type II DMF. By reviewing the DMF indepen-dent of the application, FDA is able to maintain the confi-dentiality pertaining to manufacture and controls of the drugsubstance. The reader is referred to the above-cited regulationsfor additional information. It may be useful for the format ofType II DMFs to be the same as the Drug Substance sectionof CTD-Q (i.e., 3.2.S) and the content that is recommended inthe forthcoming Drug Substance Guidance.

The content of QOS in Module 2 should follow closely thatin Module 3 and will not be discussed separately. The discussionon Module 3 here will focus on the format and content of thosetopics that differ from past practice and do not have an ICHguideline. What follows is one regulatory participant’s perspec-tive on CMC technical content of an A/NDA. Although thefollowing discussion addresses some technical content topicsrelated to CDER guidances, the discussion is not intended torepresent CDER recommendation on submission content forthese topics. Instead, when preparing an A/NDA, applicantsshould refer to current Agency guidances for recommendations.

3.5.1. Drug Substance Manufacture (CTDDesignation—3.2.S.2)

This CTD section includes six subsections: Manufacturers(3.2.S.2.1), Description of the Manufacturing Process and

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Process Controls (3.2.S.2.2), Control of Materials (3.2.S.2.3),Controls of Critical Steps and Intermediates (3.2.S.2.4),Process Validation and/or Evaluation (3.2.S.2.5), and Manufac-turing Process Development (3.2.S.2.6). In Section 3.2.S.2.1, itis recommended that the applicant provide the name, address,and manufacturing and/or testing responsibility for each firmand each site involved in the manufacture and/or testing of thedrug substance.

The description of the drug substance manufacturingprocess and process controls in Section 3.2.S.2.2 representsthe applicant’s commitment for the manufacture of the drugsubstance. Inclusion of a flow diagram would provide lucidityto the description of the manufacturing process. This detailedflow diagram would include each manufacturing step, showingwhere materials (starting materials, intermediates, reagents,solvents, and auxiliary materials) enter the process, operatingparameters (reaction conditions such as temperature, pH,pressure), and identification of critical steps and controls.Inclusion of chemical structures reflecting stereochemistry,where applicable, of starting materials, intermediates, reagents,and the drug substance will assist the reviewing chemistin understanding and evaluating the reaction sequence. A well-constructed flow diagram will facilitate discussion of possiblesynthetic impurities and controls thereof.

The description of the manufacturing process and processcontrols should also include a narrative description of themanufacturing process. This narrative description is expectedto be more detailed than the flow diagram and should identifythe scale of production. All process controls should be identi-fied, and the associated ranges, limits, or acceptance criteriashould be specified. Critical process controls should be identi-fied. Additional information such as storage and transportationconditions for biological starting materials, preparation proce-dures, isolation process, holding times and storage conditionsduring manufacture, and procedures used to maintain trace-ability of all intermediates and drug substance batches tothe starting material is recommended for drug substance thatis derived from natural source or for a semisynthetic drugsubstance. For ANDAs, a copy of the executed production



record may be provided in the Regional Information section(3.2.R) of the application or the Type II DMF.

1. An important consideration in describing the manu-facturing process is the selection of the starting mater-ial. It should be noted that more than one startingmaterial may be used in a synthetic sequence (con-vergent synthesis). In the United States, the startingmaterial marks the beginning of the manufacturingprocess as described in an application. For NDAs, thestarting material may be identified during phase 2consultations. However, this consultation may not beavailable to Type II DMF holders who may have torely on the review process. Our EWG wrestled withthe definition of the starting material and also con-sulted with the Q7 EWG repeatedly. However, anacceptable definition was difficult to fashion. Thedraft drug substance guidance intends to address thestarting material issues comprehensively and provideto applicants guidance on justifying their proposedstarting materials.

2. Another important consideration in preparing the‘‘Description of the Manufacturing Process andProcess Controls’’ section is the selection of criticalprocess controls. This author has heard a wide spec-trum of opinions on what constitute process controls.Even the regulations have different language when itcomes to describing the requirements for drug sub-stance and drug product manufacture (21 CFR 314.50(d)). The Description of the Manufacturing Process isa document that contains cGMP information as wellas scientific information and is evaluated by both thefield inspectors and the reviewing chemists at theCenter for Drug Evaluation and Research. The inten-tion in the CTD-Q was to create placeholders thatallow the applicants to separate the Center reviewedprocess controls from those subject to field over-sight. It is recommended that the applicant includecomplete manufacturing information in Section

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3.2.S.2.2. However, the applicant should identifyand justify those process controls that are criticalto the manufacturing process (reviewed by Centerchemists) in Section 3.2.S.2.4. This section shouldalso include information on the intermediates iso-lated during the process. Figure 2 illustrates theinformation distribution.

3. The regulations at 21 CFR 211.115 provide for repro-cessing of materials (intermediates and finisheddrug substance). The Guideline Q7 describes repro-cessing as follows: introducing an intermediate or API,including one that does not conform to standards orspecifications, back into the process and repeating acrystallization step or other appropriate chemical orphysical manipulation steps (e.g., distillation, filtra-tion, chromatography, milling) that are part of theestablished manufacturing process. Continuation of aprocess step after an in-process control test has shownthat the step is incomplete is considered to be partof the normal process and is not reprocessing. TheCTD-Q recommends that applicants identify and

Figure 2 Manufacturing process information distribution.



justify reprocessing steps in Section 3.2.S.2.2 and thejustification data in Section 3.2.S.2.5. It is recognizedthat different approaches (types of processes) may beutilized to bring failed material into compliance. Theapplicant may subject the failed material to one ormore of the already described process steps. However,in some instances process steps that have not beendescribed in Section 3.2.S.2.2 may be necessary tobring the failed material into compliance. The differ-ent operations may be described as follows:

Reprocessing—Repetition of one or more of theprocess steps is generally performed prior to com-pletion of the manufacturing process and qualitycontrol release of the material. Examples of repro-cessing steps are crystallization, distillation,filtration, chromatography, milling, etc.

Reworking—Subjecting the failed material to one ormore manufacturing process steps that are differ-ent from that described in the application. Rework-ing is a nonroutine event and may occur mostlyduring post-approval phase.

Recovery—Recovering solvents during drug sub-stance manufacturing for reuse in the manufactur-ing process is both economical and environmentallysound. Filtrates (mother liquors) are recoveredwith the purpose of recovering a second crop ofthe intermediate or drug substance. The impuritylevels in the recovered material (solvents, inter-mediates, drug substance, etc.) should be closelymonitored. The physical form of the drug substancethat is recovered from the more concentrated filtra-tes may differ from the desired form. The applicantshould provide data to demonstrate that the qualityof the drug substance is unaltered by the use ofrecovered material.

Regeneration—Column resins and catalysts may beregenerated and used in the manufacturing proc-ess. The regeneration steps should be described in

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Section 3.2.S.2.2 but controls should be included inSection 3.2.S.2.3.

Salvaging—The drug substance may be recoveredfrom aged material (past expiration dating) or fromdrug product. Salvaging is also expected to be non-routine and may occur mostly during the post-approval phase.

In all these instances it is recommended that theapplicants describe the process and provide justifica-tion in Section 3.2.S.2.2 and specifications in Section3.2.S.2.3.

3.5.2. Drug Substance CTD-Q Sections 3.2.S.2.3to 3.2.S.2.7

There are few differences in the content requirements ofthese sections from past practice. ICH guidelines and Agencyguidances are available on such topics as analytical methodsvalidation, impurities in drug substances, container closuresystems, and stability. One issue that generated some discus-sion is the location of the data from stress studies required fordemonstrating that the analytical method is stability indicat-ing. The author recommends that stress studies data should beincluded in Section 3.2.S.7.

3.5.3. Drug Product (CTD-Q Designation 3.2.P)

The Center for Drug Evaluation and Research is in the processof revising the 1987 Drug Product Guideline ‘‘SubmittingDocumentation for the Manufacture of and Controls for DrugProducts.’’ The new draft guidance ‘‘Guidance for Industry,Drug Products: Format and Content for Submission of NewDrug Applications (NDAs) and Abbreviated New Drug Appli-cations (ANDAs)’’ is also based on the CTD-Q format. Asa result of this, the draft guidance features some significantdifferences from the 1987 Guideline. One such difference isthe addition of the section on Pharmaceutical Development(3.2.P.2 section in CTD-Q). Section 3.2.P.2 is modeled afterthe Development Pharmaceutics section of the EU dossier.



Introduction of this section as part of an A/NDA submissionin the United States was discussed in the EWG at length.European regulators made special presentations to convincethe U.S. industry and regulators of the need for inclusion ofthis section in the CTD-Q. The draft guidance also providesdetailed instructions on the content of Section 3.2.P.3.3: Des-cription of the Manufacturing Process and Process Controls.An attempt has been made to separate the cGMP issues fromthe CDER-reviewed content.

3.5.4. Pharmaceutical Development(CTD-Q Designation 3.2.P.2)

The content in this section provides an overview of develop-ment studies that rationalizes the choice of dosage form,formulation, manufacturing process, container closure system,microbiological attributes, and labeling. It may be pertinentto describe and discuss in this section drug substance charac-teristics that may or may not have influence on the choiceof drug product formulation, manufacturing process, stability,bioavailability, and other quality issues. An example of onesuch drug substance characteristic may be its ability to formvarious polymorphic forms. Results of studies that demon-strate that the choice of a particular drug substance poly-morphic form was dictated by its effect on the drug productdissolution profile and possibly on the drug product bio-availability should be included in this section. Section 3.2.P.2comprises six subsections that provide for a chronology of thedrug product development process. In this author’s opinion,the content of Section 3.2.P.2, except for the content of sub-sections 3.2.P.2.2.1 (Formulation Development), 3.2.P.2.2.3(Physicochemical and Biological Properties), and 3.2.P.2.3(Manufacturing Process Development), is similar to thatexpected in a current A/NDA submission. For example, at thepresent time the information on the suitability of the contai-ner closure system is submitted under the container closuresection. In the CTD-Q format, this information will be submit-ted in Section 3.2.P.2.4. Another example is the compatibilityof an injectable drug product with reconstitution diluents or

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dosage devices. This information will be presented in Section3.2.P.2.6 in an A/NDA submitted in the CTD-Q format,whereas at the present time it may be submitted with thestability data.

3.5.5. Description of Manufacturing Process andProcess Controls (CTD-Q Designation 3.2.P.3.3)

The description of the drug product manufacturing process andprocess controls in Section 3.2.P.3.3 represents the applicant’scommitment for the manufacture of the drug product. To pro-vide an overview of the manufacturing process, a flow diagramthat includes themanufacturing steps and showing wheremate-rials enter the process, equipment used, and sampling points isrecommended. A brief description of the sampling process iden-tifying number of samples taken should also be included. ForNDAs, a detailed description of the manufacturing process maybe included in place of an actual Master Production and ControlRecord (MPCR) (see 21 CFR 314.50(d) (1)(ii)(c) and Section3.2.R of CTD-Q). However, for ANDAs it is recommended thatthe applicant always submit a MPCR. The description of themanufacturing process and process controls should also includea narrative description of the manufacturing process. This nar-rative description is expected to be more detailed than the flowdiagram and should identify scale of production and equipmentto be used, including those for packaging operations. All processcontrols should be identified, and the associated ranges, limits,or acceptance criteria should be specified. Critical process con-trols should be identified in this section, but details should beprovided in Section 3.2.P.3.4.

The discussion pertaining to reprocessing, reworking, andsalvaging in the drug substance section is also pertinent here.However, a drug product that includes many components inits formulation is more complex than a drug substance itself.In a proposal to perform any of these operations, the applicantis urged to consider the impact of the operation on drug pro-duct quality and submit appropriate data to the Center.

The distribution of information between Sections3.2.P.3.3 and 3.2.P.3.4 for the drug product is similar to that



for a drug substance. In-process tests are generally used toestablish the completion of a manufacturing process step orthe suitability of an intermediate for the next process step.Examples of in-process tests performed during critical manu-facturing steps include, but are not limited to, pH, blenduniformity, viscosity, particle size analysis, bioburden, etc.Information on these tests, including analytical procedures andacceptance criteria should be included in Section 3.2.P.3.4.When a certain in-process specification is not met, it is con-ceivable that the applicant may repeat the process step to bringit into compliance. However, for other in-process tests suchas individual tablet weight, hardness, and thickness onlymachine adjustment may be needed. Such process controlsshould not be reported in Section 3.2.P.3.4.

3.5.6. Control of Excipients(CTD-Q Designation 3.2.P.4)

A variety of excipients are used in the formulation of drugproducts. A careful consideration of the excipient propertiesmay prevent future manufacturing and drug product qualityproblems. Development data describing the choice of the excipi-ents is presented in Section 3.2.P.2. The extent of documen-tation for controls of the excipients is dependent upon thefollowing:

For excipients that have monographs in USP/NF com-pendium, only additional specifications should be des-cribed in detail. The USP/NF specifications may bereferenced.

Noncompendial excipients may be proprietary mixturesof compendial components or noncompendial compo-nents that have been used in CDER-approved drugproducts. It is recommended that the applicant includeall the specifications that would form the basis for lotacceptance, including, at minimum, an identificationtest to be performed by the applicant.

Novel excipients are those that are used in a drug prod-uct formulation for the first time or by a new route of

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administration. Documentation is similar to that of adrug substance and should include details of manufac-ture, characterization, and controls. Cross-references tosafety data should be provided.

In recent years there has been much concern thatthe marketplace is inundated with counterfeit drug prod-ucts. Tracers or markers have been used to identify authen-tic products. The draft drug product and other guidancesunder revision have made provisions for reporting inclusionof these tracers or markers in the drug product formu-lation. The chief concern is one of safety and the applicantshould submit appropriate information for Agency’s safetyassessment.

3.5.7. Control of Drug Product(CTD-Q Designation 3.2.P.5)

The ICH Guideline Q6A defines specification as a list oftests, analytical procedures, and acceptance criteria, which arenumerical limits, ranges, or other criteria for the tests descri-bed. Specifications are critical quality standards that confirmthe quality of the drug product and should be selected based ontheir relevance to safety and efficacy of the drug product. Thepurpose of the following discussion is to highlight some newconcepts that have been introduced in the draft drug productguidance in response to CTD-Q and Q6A documents. Thesenew concepts will help to ease the regulatory burden on thepharmaceutical industry.

Periodic or Skip Testing: The performance of specifiedtests at release on pre-selected batches and/or at pre-determined intervals, rather than on a batch-to-batchbasis, may be acceptable. The batches that were nottested should still conform to all the specifications. Theapplicant should justify such testing schedule andimplement it with Agency approval.

Setting of Specifications: An applicant may justify itschoice of specifications based on available develop-ment data.



Reevaluation of the Acceptance Criteria: Limited dataare available at the time of approval to set meaningfuldrug product acceptance criteria. An example is thedissolution specifications for extended-release products.In the Office of Generic Drugs, the dissolution accep-tance criteria for an extended-release drug productmay be approved with data from one batch of 100,000dosage units. Manufacturing efficiencies realizedduring scale-up to commercial production batches maynecessitate adjustments to the dissolution acceptancecriteria. The Office of Generic Drugs, as a condition ofapproval, requires ANDA applicants to submit datafrom the first three validation batches and finalizethe dissolution acceptance criteria. However, reevalu-ation of the acceptance criteria for impurities and/ordegradants should be treated with caution. An appli-cant should consider safety implications when revisingacceptance criteria for impurities and/or degradants.

Parametric Release: An example of parametric release issterility testing of terminally sterilized drug products.The terminal sterilization process parameters, such astemperature, pressure, and time, are accurately con-trolled and are more reliable in predicting sterilityassurance than the end product sterility testing. It isrecommended that an applicant obtain Agency approvalbefore using parametric release testing as an alter-native to routine testing.

Alternative Procedures: It is expected that drug prod-ucts that have monographs in the compendium shouldmeet compendial specifications. However, applicantsare encouraged to assess and adapt alternate methodsthat are superior to compendial methods.

Drug Substance Specifications: It is not necessary toinclude in the drug product specifications those speci-fications that are unique to the drug substance.An example is the acceptance criteria for syntheticimpurities present in drug substances. It is not nec-essary to include this specification in those for a drugproduct also.

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3.5.8. Drug Product CTD-Q Sections 3.2.P.6,3.2.P.7, and 3.2.P.8

Section 3.2.P.6 includes information about reference standardsor reference materials used for testing of the drug product. Ifthese reference standards and reference materials are the sameas those used in the testing of drug substance, then Section3.2.S.5 should be cross-referenced.

Section 3.2.P.7 is the placeholder for the routine controlsinformation that is submitted in support of the container clo-sure system used in packaging the drug product. Data thatdemonstrate the suitability of the proposed container closuresystem is included in the 3.2.P.2 section.

ICH has published many guidelines that cover variousaspects of drug product stability. A draft Stability Guidanceis in preparation at CDER. It is recommended that an appli-cant consult the CDER guidance document when it becomesofficial to develop content for Section 3.2.P.8.

3.5.9. Appendices (CTD-Q Section 3.2.A),Regional Information (Section 3.2.R), andLiterature References (Section 3.3)

Information on facilities and equipment, adventitious agentssafety evaluation, as they relate to biotech products, areincluded in Sections 3.2.A.1 and 3.2.A.2. As noted earlier,novel excipients require extensive documentation, similar to adrug substance. This information is included in Section 3.2.A.3.

The content to be included in the Regional Informationsection 3.2.R is diverse. For the United States they includeexecuted batch records, methods validation package, andcomparability protocol. Process validation scheme for the drugproduct is required for EU only.

Key literature referenced in the application should beprovided.

3.6. What Is New and Different?

An A /NDA submitted in the format of the CTD-Q will lookdifferent from that based on the 1987 guideline. An application



based on the CTD-Q format and the revised Drug SubstanceGuidance and Drug Product Guidance will provide a logicalstory of the drug product development. Information pertinentto cGMP will be clearly delineated. Inclusion of the Pharma-ceutical Development section (Section 3.2.P.2) will help thereviewing chemist to understand the implications of the drugsubstance and drug product characteristics on the choice ofdrug product formulation, manufacturing process and packag-ing. It will help the regulators in the three regions to cometo common rational conclusions regarding the drug product.

4. FUTURE

The future of CTD lies with eCTD. With its vast capabilitiessuch as multimedia presentation, hyperlinking various sectionsand/or documents, and others, an eCTD will offer the applicantmany creative avenues to communicate with the reviewers.The reviewer will have the ability to search and compare infor-mation, copy and paste information, and in general producebetter documentation more efficiently. Adopting single submis-sion standards will allow the applicant to communicate betterwith the various regulatory bodies. It will help the regulators inthe three regions to come to common rational conclusionsregarding the drug product. ICH has already begun the processof developing a common dictionary for medical terms. Suchan effort is needed for CMC sections. With time, both theregulated industry and the regulators will gain experience tofine-tune an already useful guideline.

ACKNOWLEDGMENTS

I wish to acknowledge the help and encouragement of thefollowing individuals during my tenure in the EWG and inthe preparation of this manuscript: Frank Holcombe, FlorenceFang, Chuck Hoiberg, Don Klein, and the Packaging TechnicalCommittee members.

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19

21 CFR Part 11 Complianceand Beyond

RICHARD L. BURCHAM

BPI Technologies

Arlington, Texas, U.S.A.

1. INTRODUCTION TO FDA 21 CFR PART 11

1.1. What Is 21 CFR Part 11 and What Is It Not?

21 CFR Part 11 is FDA’s ruling on the requirements for theacceptability of records recorded and signed electronically.It covers nearly everything that is created and stored in anelectronic form, and it applies to all businesses regulated bythe FDA—not just pharmaceuticals.

Part 11 was first introduced in 1997 and is part ofFDA’s attempt to modernize the regulation and compliance

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of industries under their auspices. It is widely viewed by FDAas an opportunity for industry to improve business processesas opposed to just another regulatory burden. In February2003 FDA issued its current thinking on the topic andwithdrew the draft guidance for industry, 21 CFR Part 11,because it wanted to avoid loss of time spent by industry inan effort to review and comment on the draft guidance whenthat guidance may no longer be representative of FDA’sapproach under the new current good manufacturing practice(CGMP) initiative.

These regulations, which apply to all FDA program areas,are intended to permit the widest possible use of electronictechnology, compatible with FDA’s responsibility to promoteand protect public health. The use of electronic records aswell as their submission to FDA is voluntary.

The agency intends to exercise enforcement discretionwith regard to legacy systems that otherwise met predicaterule requirements prior to August 20, 1997, the effective dateof Part 11. This means that the agency will not normallytake regulatory action to enforce compliance with any Part11 requirements. However, all systems must comply with allapplicable predicate rule requirements and should be fit fortheir intended use (1).

In short, 21 CFR Part 11 is not a mandate to replace paperor manual record-keeping systems. If a record is not generatedor stored electronically, the ruling does not cover it. What’smore, Part 11 is not just another IT exercise and is not solvablewith vendor-supplied software alone. Compliance also requiresplanning, resource, and process change.

Compliance with Part 11 will require investment in timeand capital. It is estimated that the worldwide cost of compli-ance will range from $1 to $5 billion. The wide range is furtherevidence that FDA must strive for clearer definition of theprinciples and practices of Part 11.

Do not make the mistake of assuming that this is anotherunenforceable government regulation. FDA is very seriousabout implementation and compliance. Expect more warningletters as 2004 continues.

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1.2. Background

In 1991, members of the pharmaceutical industry met with theagency to determine how they could accommodate paperlessrecord systems under the CGMP regulations in parts 210and 211 (21 CFR parts 210 and 211). FDA created a TaskForce on Electronic Identification/Signatures to develop auniform approach by which the agency could accept electronicsignatures and records in all program areas. In a February 24,1992, report, a task force subgroup, the Electronic Identifica-tion/Signature Working Group, recommended publication ofan advance notice of proposed rule making (ANPRM) to obtainpublic comment on the issues involved.

FDA received 49 comments on the proposed rule. Thosecommenting represented a broad spectrum of interestedparties: human and veterinary pharmaceutical companies aswell as biological products, medical device, and food interestgroups, including 11 trade associations, 25 manufacturers,and one federal agency (2).

1.3. Highlights of the Final Rule

The final rule provides criteria under which FDA will con-sider electronic records to be equivalent to paper records andelectronic signatures equivalent to traditional handwrittensignatures. Part 11 (21 CFR part 11) applies to any paperrecords required by statute or agency regulations and super-sedes any existing paper record requirements by providingthat electronic records may be used in lieu of paper records.Electronic signatures that meet the requirements of the rulewill be considered to be equivalent to full handwritten signa-tures, initials, and other general signings required by agencyregulations (2).

Section 11.2 provides that records may be maintained inelectronic form and electronic signatures may be used in lieuof traditional signatures. Records and signatures submittedto the agency may be presented in an electronic form providedthe requirements of Part 11 are met and the records havebeen identified in a public docket as the type of submission

21 CFR Part 11 Compliance and Beyond 585


the agency accepts in an electronic form. Unless recordsare identified in this docket as appropriate for electronicsubmission, only paper records will be regarded as officialsubmissions.

Section 11.3 defines terms used in Part 11, includingthe terms biometrics, closed system, open system, digital signa-ture, electronic record, electronic signature, and handwrittensignature.

Section 11.10 describes controls for closed systems—systems to which access is controlled by persons responsiblefor the content of electronic records on that system. Thesecontrols include measures designed to ensure the integrity ofsystem operations and information stored in the system. Suchmeasures include validation, the ability to generate accurateand complete copies of records, archival protection of records,use of computer-generated, time-stamped audit trails, use ofappropriate controls over systems documentation, and a deter-mination that persons who develop, maintain, or use electronicrecords and signature systems have the education, training,and experience to perform their assigned tasks.

Section 11.10 also addresses the security of closedsystems and requires that (a) system access be limited toauthorized individuals, (b) operational system checks beused to enforce permitted sequencing of steps and events asappropriate, (c) authority checks be used to ensure thatonly authorized individuals can use the system, electronicallysign a record, access the operation or computer systeminput or output device, alter a record, or perform operations,(d) device (e.g., terminal) checks be used to determine thevalidity of the source of data input or operation instruction,and (e) written policies be established and adhered to, holdingindividuals accountable and responsible for actions initiatedunder their electronic signatures, so as to deter record andsignature falsification.

Section 11.30 sets forth controls for open systems, includ-ing the controls required for closed systems in x 11.10 andadditional measures such as document encryption and useof appropriate digital signature standards to ensure recordauthenticity, integrity, and confidentiality.

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Section 11.50 requires signature manifestations to con-tain information associated with the signing of electronicrecords. This information must include the printed nameof the signer, the date and time when the signature wasexecuted, and the meaning (such as review, approval, respon-sibility, and authorship) associated with the signature. Inaddition, this information is subject to the same controlsas for electronic records and must be included in any humanreadable forms of the electronic record (such as electronicdisplay or printout).

Under x 11.70, electronic signatures and handwritten sig-natures executed to electronic records must be linked to theirrespective records so that signatures cannot be excised, copied,or otherwise transferred to falsify an electronic record byordinary means. Under the general requirements for electronicsignatures, at x 11.100, each electronic signaturemust be uniqueto one individual and must not be reused by, or reassigned to,anyone else. Before an organization establishes, assigns, cer-tifies, or otherwise sanctions an individual’s electronic signa-ture, the organization shall verify the identity of the individual.

Section 11.200 provides that electronic signatures notbased on biometrics must employ at least two distinct identifi-cation components such as an identification code and pass-word. In addition, when an individual executes a series ofsignings during a single period of controlled system access,the first signing must be executed using all electronic signaturecomponents and the subsequent signings must be executedusing at least one component designed to be used only bythat individual. When an individual executes one or moresignings not performed during a single period of controlledsystem access, each signing must be executed using all of theelectronic signature components.

Electronic signatures not based on biometrics are alsorequired to be used only by their genuine owners and adminis-tered and executed to ensure that attempted use of an indi-vidual’s electronic signature by anyone else requires thecollaboration of two or more individuals. This would makeit more difficult for anyone to forge an electronic signature.Electronic signatures based upon biometrics must be designed



to ensure that such signatures cannot be used by anyone otherthan the genuine owners.

Under x 11.300, electronic signatures based upon use ofidentification codes in combinationwith passwordsmust employcontrols to ensure security and integrity. The controls mustinclude the following provisions:

1. The uniqueness of each combined identification codeand password must be maintained in such a waythat no two individuals have the same combinationof identification code and password.

2. Persons using identification codes and/or passwordsmust ensure that they are periodically recalled orrevised.

3. Loss management procedures must be followed todeauthorize lost, stolen, missing, or otherwise poten-tially compromised tokens, cards, and other devicesthat bear or generate identification codes or passwordinformation.

4. Transaction safeguards must be used to preventunauthorized use of passwords and/or identificationcodes and to detect and report any attempt tomisuse such codes.

5. Devices that bear or generate identification codesor password information, such as tokens or cards,must be tested initially and periodically to ensurethat they function properly and have not beenaltered in an unauthorized manner.

1.4. Goals and Expectations

FDA has released a Part 11 draft guidance on electroniccopies that outlines seven key principles and practices thatthe agency advises industry to follow—and its inspectors toscrutinize:

1. Electronic copies of e-records provided to FDAshould be accurate and complete, but they do notnecessarily have to be in the same file format and inthe same media as the original e-records.

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2. The process of making an electronic copy of ane-record in a file format that differs from the origi-nal should be validated.

3. Copies of hyperlinked records incorporated by refer-ence should be included with the electronic copy ofthe electronic record.

4. Electronic copies of database queries should beincluded with electronic copies of electronic recordswhen appropriate.

5. Electronic copies of electronic records should include,or be appended with, an authentication value.

6. Electronic copies of electronic records should be in afile format and on media that enable FDA to readand process record data.

7. If the original electronic records were signed electron-ically, electronic copies of the original electronicrecords should have electronic signatures that arecapable of being authenticated.

FDA has done this to prevent and detect data falsification inorder to ensure that electronic records are reliable. The pur-pose is to enable data reconstruction that can be checked andverified. Confidence in the data integrity is foremost. As aresult, records must be under control of the company, notthe individuals.

While FDA’s reexamination of Part 11 is underway, itplans to narrowly interpret the scope of Part 11. What’smore, FDA intends to exercise enforcement discretion withrespect to certain Part 11 requirements. FDA will not normallytake regulatory action to enforce compliance with the valida-tion, audit trail, record retention, and record copying require-ments of Part 11 while it is under review. However, recordsmust still be maintained or submitted in accordance with theunderlying predicate rules (1).

1.5. Implications for Regulated Businesses

FDA recognizes that it will take time for existing systems toattain compliance. This is a major undertaking for regulated



industries because all systems generating GxP records arecovered in the ruling. For noncompliance situations FDA willconsider the following factors when deciding appropriatecorrective action:

Extent of deviationsImpact on product quality and data integrityTimeliness of planned corrective measuresCompliance history of establishment

The extent of remediation will be determined by FDA on acase-by-case basis and may include:

Acceptance of corrective action planDelay of product approvalHalt product shipments

FDA warning letters (a.k.a Form 483) relative to electro-nic records are actively being issued today. Many cite computersystems validation and security, and a growing number citePart 11 specifically. These warning letters, of course, are andwill continue to be public record. They can be accessed at

or a phased approach over 5–10 years. It also requests prior-itized remediation based on risk and availability of compliantsoftware. Unfortunately, FDA disagrees strongly and will con-tinue to aggressively issue warnings.

The risk grows at each stage of the process where compu-ter systems are used to manage the production process forregulated industries. An illustration of this for process manu-

Given the potential for escalating risk, most companiesare scrambling to hire expertise to get systems running inthe short run. In the long run they are developing in-houseexpertise. Companies must change their processes and learnto ‘‘think’’ like a regulator while keeping in mind that com-pliance is a continuous process. What’s more, companiesmust demonstrate to the FDA that they have control over allchanges.

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facturing is shown in Fig. 1.

www.fda.gov/foi/warning.htm.PhRMA’s response to Part 11 guidance asks for more time


http://www.fda.gov

2. UNDERSTANDING THE PART 11 RULING

2.1. Archiving Data and Part 11 Compliance

As previously discussed, Subpart B of Part 11 is broken downinto three major sections:

1. 11.10 Controls for Closed Systems2. 11.50 Signature Manifestations3. 11.70 Signature/Record Linking

Each of these sections will be discussed in detail, but first afew common definitions are needed.

2.2. Definitions

There are several terms used in the Part 11 ruling that need tobe defined and understood in order to interpret compliancerequirements. Interpretation of Part 11 centers on the followingterms:

Definition—Electronic Record (ER): ‘‘Any combination oftext, graphics, data, audio, pictorial or other informa-tion representation in digital form that is created,modified, maintained, archived, retrieved, or distribu-ted by a computer system’’ (2).

Definition—Electronic Signature (ES): ‘‘A computer datacompilation of any symbol or series of symbols,

Figure 1 Risk escalation. (From Ref. 4.)



executed, adopted, or authorized by an individual tobe the legally binding equivalent of the individual’shandwritten signature’’ (2).

Definition—Biometrics and digital signatures:

Biometrics: ‘‘A method of verifying an individual’sidentity based on the individual’s physical feature(s) orrepeatable action(s) where those features and/or actionsare both unique to that individual and measurable’’;

Digital Signature: ‘‘An electronic method of signingelectronic records based on cryptographic techniquesof authentication that enables the verification of theidentity of the signer and the integrity of the electronicrecord’’ (2).

Definition—Closed system: ‘‘An environment in whichsystem access is controlled by persons who areresponsible for the content of the electronic records onthe system.’’

Definition—Open System: ‘‘An environment in whichsystem access is not controlled by persons who areresponsible for the content of the electronic records onthe system’’ (2).

2.3. Understanding Section 11.10 Controls forClosed Systems

According to the ruling, ‘‘Persons who use closed systems tocreate, modify, maintain, or transmit electronic records shallemploy procedures and controls designed to ensure the authen-ticity, integrity, and, when appropriate, the confidentiality ofelectronic records, and to ensure that the signer cannot readilyrepudiate the signed record as not genuine.’’

Section 11.10 goes on to define what types of controls needto be in place for closed loop systems:

1. Systems must be validated.2. Copies of records must be provided to the FDA.3. Protection of records must be done throughout the

retention period.

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4. Limited access to the electronic records must exist.5. All audit trails must be recorded.6. There must be operational system checks.7. Controls must be in place for user authority.8. Device source controls must be in use.9. Users must be trained on requirements.

10. Policies must exist for electronic signatures.11. There must be controlled access to documentation.

The closed loop system must have the ability to generateand complete copies of records in both human readable andelectronic form. What’s more, it must be suitable for inspec-tion, review, and copying by the agency. Records must be pro-tected to enable their accurate and ready retrieval throughoutthe records retention period.

The agency agrees that providing exact copies of elec-tronic records in the strictest meaning of the word ‘‘true’’ maynot always be feasible. FDA nonetheless believes it is vital thatcopies of electronic records provided to the agency be accurateand complete. Accordingly, in 11.10(b) the original language‘‘true’’ has been replaced with ‘‘accurate and complete.’’ Theagency expects that this revision should obviate the potentialproblems noted in the draft comments. The revision should alsoreduce the costs of providing copies by making clear that firmsneed not maintain obsolete equipment in order to make copiesthat are ‘‘true’’ with respect to format and computer system.

How we store data is just as important as the informationit contains. As an example, consider the 1986 BBC DoomsdayProject. Text, pictures, documents, video, audio, etc. were allrecorded on state of the art laser disks. One would expectthat this would pass FDA Part 11 compliance. Unfortunately,15 years later these electronic records are now ‘‘unreadable.’’What’s more, who has a laser disk reader? The lesson learnedis that organizations must look forward as much as possiblewhen deciding on how they are going to manage electronicrecords. Obviously, the ability to perform migration as technol-ogy changes is a fundamental requirement (3).

The question arises as to just how long a lifetime does theFDA expect an electronic record to have? Relative to regulatory



compliance, is the time frame equal to the lifetime of theproductþ x years? Or is it the statue of limitations on intellec-tual property: 17 years, legal statute of limitations? These areissues that still need to be clearly defined.

Also clouding the lifetime issue is the fact that thereare many different types of electronic data. So, should thelifetime be different for each data type? Again, no clearanswer. Table 1 shows some of the many different types ofelectronic data.

In particular, rich data types present an archivingproblem because storage formats are often proprietary. Con-sequently, data are only accessible via specialized softwareapplications and may be platform specific, including proprie-tary operating systems, databases, and software versions.There are also concerns with application integration. Thatis, is it practical and/or possible to broadly distribute spe-cialized applications software for accessing the data? Lastly,rich data types have more finite lifetimes than commondata types—e.g., will the specialized applications still be avail-able, supported, and operational throughout the lifetime ofthe data?

Fortunately FDA realizes that it must provide guidance onthese issues. In a September 5, 2002 statement, FDA provided

Table 1 Data Types

Common data types Rich data types

Images: Chemical structures/reactionsJPEG MOLGIF SDFEtc. PDB

Etc.ASCII text: Instrument applications

CSV Vendor equipment specificEtc.

Web pages: Oce applicationsHTML Documents

SpreadsheetsEtc.

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additional guidance for maintenance of electronic records.FDA defined two acceptable practices:

1. ‘‘Time Capsule’’ Approach:

a. Preserve exact computing environment hard-ware and software.

b. FDA admits that this is only viable as a short-term solution.

2. ‘‘Data Migration’’ Approach:

a. Translate and migrate data forward as computertechnology changes.

b. Viable long-term strategy.c. In the migration approach, the new computer

system should enable organizations to search,sort, and process information in the migratedelectronic record at least at the same level aswhat could be attained in the old system, eventhough the new system may employ differenthardware and software.

Another major requirement of Section 11.10 relates to Securityand Authentication. Section 11.10 requires limited systemaccess to authorized individuals only. Authority checks mustbe used to ensure that only authorized individuals can usethe system, electronically sign a record, access the operationor computer system input or output device, alter a record, orperform the operation at hand. All individuals must havea unique identifier for access to, creation of, and modificationof electronic records (2).

Many individual data systems already have security capa-bilities. However, organizations must keep in mind that dataarchive systems are generally independent of other systemsand there likely will be a need to integrate multiple authenti-cation mechanisms. An example would be the need to integrateOracle/database, MS, Networking, MS Active Directory PKI,and LDAP.

A commonmisconception about archives and audit trails isthat a compliant system can make noncompliant instruments



and applications compliant by adding security and audittrail capabilities to the process. The reality is that archivingsystems can only audit trail changes made to their own data.What’s more, archiving systems cannot track/approve specificchanges made to rich data types with native applications.Reprocessing, method alteration, and data manipulations arekey considerations.

FDA’s guidance on archives and audit trails is to usesecure, computer-generated, time-stamped audit trails to inde-pendently record the date and time of operator entries andactions that create, modify, or delete electronic records. Inshort, record changes shall not obscure previously recordedinformation. Moreover, audit trail documentation shall beretained for a period of at least as long as that required forthe subject electronic records and shall be available for agencyreview and copying.

2.4. Understanding Sections 11.50,Signature Manifestations, and 11.70,Signature/Record Linking

Section 11.50 provides guidance on signed electronic recordsin that such records must clearly indicate:

1. The printed name of the signer2. The date and time when the signature was executed3. The meaning (such as review, approval, responsibil-

ity, or authorship)

The above items are subject to the same controls as forelectronic records. Furthermore, Part 11.70 requires thatelectronic signatures and handwritten signatures executed toelectronic records shall be linked to their respective electronicrecords to ensure that the signatures cannot be excised, copied,or otherwise transferred to falsify an electronic record byordinary means.

According to FDA, compliance can be ensuredwith ‘‘closed-loop’’ systems where signatures and data can be linked viaspecific implementations. Unfortunately, current implemen-tations are generally proprietary and there is a lack of industry

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standards in this area. Also, migration will be difficult withlarge volume of data. However, this is where we are today.

3. ACHIEVING COMPLIANCE—COMPLIANCEENABLING TECHNOLOGIES

3.1. Compliance and Flexibility

Electronic records and/or signatures must meet several con-ditions in order to be acceptable as an alternative to a paperrecord or handwritten signature. These conditions are neces-sary to permit the agency to protect and promote the publichealth. For example, FDA must retain the ability to auditrecords to detect unauthorized modifications, simple errors,and to deter falsification.

Whereas there are many scientific techniques to showchanges in paper records (e.g., analysis of the paper, signsof erasures, and handwriting analysis), these methods do notapply to electronic records. For electronic records and submis-sions to have the same integrity as paper records, they mustbe developed, maintained, and used under circumstances thatmake it difficult for them to be inappropriately modified.Without these assurances, FDA’s objective of enabling elec-tronic records and signatures to have standing equal to paperrecords and handwritten signatures, and to satisfy the require-ments of existing statutes and regulations, cannot be met.

Within these constraints, FDA has attempted to selectalternatives that provide as much flexibility as practicablewithout endangering the integrity of the electronic records.The agency decided not to make the required extent and strin-gency of controls dependent on the type of record or transac-tions, so that firms can decide for themselves what level ofcontrols is worthwhile in each case.

For example, FDA chose to give firms maximum flexi-bility in determining (a) the circumstances under whichmanagement would have to be notified of security problems,(b) the means by which firms achieve the required linkbetween an electronic signature and an electronic record,



(c) the circumstances under which extra security and authen-tication measures are warranted in open systems, (d) when touse operational system checks to ensure proper event sequen-cing, and (e) when to use terminal checks to ensure that dataand instructions originate from a valid source.

As a rule of thumb, for records required to be maintainedbut not submitted to the agency, persons may use electronicrecords in lieu of paper records or electronic signatures in lieuof traditional signatures, in whole or in part, provided that therequirements of Part 11 are met.

For records submitted to the agency, persons may useelectronic records in lieu of paper records or electronic signa-tures in lieu of traditional signatures, in whole or in part, pro-vided that (a) the requirements of Part 11 are met, and(b) the document or parts of a document to be submittedhave been identified in public docket no. 92S-0251 as beingthe type of submission the agency accepts in electronic form.This docket will identify specifically what types of documentsor parts of documents are acceptable for submission in elec-tronic form without paper records and the agency receivingunit(s) (e.g., specific center, office, division, branch) to whichsuch submissions may be made. Documents to agency receivingunit(s) not specified in the public docket will not be consideredas official if they are submitted in electronic form; paperforms of such documents will be considered as official andmust accompany any electronic records. Persons are expectedto consult with the intended agency receiving unit for detailson how (e.g., method of transmission, media, file formats, andtechnical protocols) and whether to proceed with the electronicsubmission (2).

4. STRATEGIES FOR IMPLEMENTATION

We have discussed the rules and guidelines of the Part 11ruling, but the question remains: How do organizationscomply? Most technologies, as previously mentioned, areproprietary, nonglobal, and lack universal standards to be aneffective means for Part 11 compliance. However, XML, or

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Extensible Markup Language, is one exception in that indus-try, and governments worldwide have embraced it as a meansof compliance.

4.1. What Is XML and What Is Its Role?

XML is a standardized representation for data content. It isused for text, instrumentation data, and application integra-tion. What’s more, it is not proprietary and was developed andis supported by the W3C, a nonprofit consortium. There areseveral standards developed by the W3C that relate to XML,including schema definition, style sheet and transformation,and search capabilities—all of which make it easier to complywith Part 11.

XML is global in scope and according to a December 2000survey; over 75% of life sciences executives responding saidthat they are currently planning to deploy XML as part oftheir R&D strategy. As depicted in Fig. 2, nearly all expectedto be employing XML by 2003 (4). What’s more, XML has thesupport of FDA and, according to SQA CVIC meeting 6/10/97with Paul Motise (FDA): ‘‘The problem of system obsolescencecan be solved by careful migration from one electronic fileformat and platform to another. E-commerce and e-govern-ment are moving toward, not away from, common e-record

Figure 2 XML in life sciences. (From Ref. 5.)



formats that are interoperable on many different platforms.Consider the rise of XML, for example.’’

XML can be used to represent any type of data, and it isspecifically designed for strong typing of rich data—therebysolving some of the rich data problems discussed earlier in thischapter. Furthermore, XML is platform independent, whichsimplifies distribution and forward migration to avoid obsoles-cence. XML is extensible, a requirement to support futuredata types, and it is a public domain standard. Perhapsmost importantly, it allows data models to be made availableto anyone, but be ‘‘closed’’ to interpretation—a key Part 11requirement.

XML can satisfy electronic data collection requirementsof Part 11 as well. XML schemas exist for all instrument datatypes, and different archiving systems may be implemented fordifferent data types such as:

1. Analytical and lab instruments2. Chemical structures/reactions3. Clinical trials/studies4. Documents

Application integration, internal or external to your organiza-tion, can be accomplished through the exchange of data andtransaction instructions as XML. This has wide industrysupport in the life sciences as well as with application vendors.Practically everyone and everything is involved with web ser-vices making application integration, for the purposes of Part11 compliance, both feasible and achievable (3).

All of the major application and database vendorsare committed to XML and web support, including IBM,Hewlett-Packard, Sun Microsystems, Oracle, Microsoft, SAP,etc. The languages supported include Java, C, Cþþ, Python,Perl, and Microsoft languages (VB, C#, etc.) Supportingplatforms include .NET, J2EE, Apache, Zope, etc., and oper-ating systems include Unix (Solaris, Linux, etc.), Windows,MacOS X, etc.

In short, companies have a wide selection of technolo-gies utilizing XML with which to achieve ongoing Part 11compliance.

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4.2 Example of Part 11 Compliance

Discussed below is an example of how Part 11 compliance canbe achieved even when two separate companies are workingtogether on a common project but with different systems andtechnologies. In this example, a CRO is collaborating with apharmaceutical company to research a new product (4).

Assumptions:

1. A CRO based in the United Kingdom is working ona research project with a pharmaceutical companyin the United States.

2. The CRO uses Lotus Notes ELN authoringapplication.

3. The pharmaceutical company uses Thermo LabSys-tems Nautilus LIMS and eRecordManager.

4. The companies worked separately over the web todevelop system interfaces.

Transaction process:

Step 1: ELN user at CRO in the UK logs in and creates asample request in the LIMS of the PharmaceuticalCompany. This is done directly from the ELN and theuser has no awareness that the request was sent tothe LIMS.

Step 2: LIMS user logs in, sees the request and pro-cesses the sample request. Analysis results are entereddirectly into LIMS, and eRM automatically capturesthe chromatogram. The LIMS user has no idea that thesample request came from the CRO’s ELN.

Step 3: The ELN user at the CRO refreshes his screen/page and the analysis results and chromatogram auto-matically appears. The chromatogram can be zoomedusing an XML enabled plug-in and data are pulled fromLIMS and eRM systems using XML.

The only thing that needs to be added to this set of trans-actions for Part 11 compliance is electronic signatures—i.e.,the electronic record criteria of Part 11 has been satisfied.


The set of transactions is illustrated in Fig. 3.


Two criteria must be added to the electronic record of thistransaction in order to be compliant with electronic signatures:(a) identifying information for the individual and date/timeand (b) connective links to the information that was signed.

Implementation of the first criterion requires authentica-tion of the individual. This can be satisfied in a variety of ways,including passwords and digital codes of identification plus theprinted name of the signer, the date and time that the signa-ture was executed, and the meaning such as review, approval,responsibility, or authorship.

Implementation of the second criterion requires encrypt-ing hash calculation of data and signature, strong encryptionalgorithm (i.e., SHA), and, at a minimum, a private digital key.Public/private key mechanisms can also be used.

The technologies available for electronic signatures arelargely application specific in that many Part 11 applicationshave internal signature-data linking. However, the proprie-tary nature of these applications makes forward migrationof data and signature difficult, if not impossible. Thereare also commercial packages available including Verisign,Entrust, ValiCert, Microsoft (Passport), and Liberty Alliance.However, perhaps the best solution for all of the reasons pre-viously discussed is to use the public domain, that is, XMLSignature Encryption.

Figure 3 Example of Part 11 compliance. (From Ref. 4.)

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The final step to make the above example Part 11 compli-ant is to archive the transaction. Archiving systems must beimplemented as ‘‘closed’’ systems. To this end, FDA guidancerequires the following:

Record validity must not be challenged.Inseparability of data, audit trail, e-signatures, etc.Must be maintained when moving from application-

specific implementations to more open technologies(e.g., XML Signature).

With respect to infrastructure, the FDA focus is on‘‘system’’ security, not ‘‘application’’ security. Specifically,they are interested in whether or not the records are storedso that only the ‘‘system’’ has access—no back doors—and thattampering can be detected.

5. BENEFITS OF 21 CFR PART 11 TOORGANIZATIONS

Because the Part 11 affects such a broad range of industries,no data currently exist to estimate precisely the total numberof entities that will potentially benefit from the rule, butthe number is substantial. For example, within the medicaldevices industry alone, the Small Business Administration(SBA) estimates that over 3221 firms are small businesses(i.e., have fewer than 500 employees). SBA also estimatesthat 504 pharmaceutical firms are small businesses withfewer than 500 employees. Of the approximately 2204 regis-tered blood and plasma establishments that are neither govern-ment-owned nor part of the American Red Cross, most arenonprofit establishments that are not nationally dominantand thus may be small entities as defined by the RegulatoryFlexibility Act (2).

Not all submissions to FDA will immediately be acceptableelectronically, even if the submission and the electronic recordconform to the criteria set forth in this rule. A particularrequired submission will be acceptable in electronic formonly after it has been identified to this effect in public docket



92S-0251. (The agency unit that can receive that electronicsubmission will also be identified in the docket.)

Thus, although all entities subject to FDA regulationsare potentially affected by this rule, the rule will actuallyonly benefit those that (a) are required to submit recordsor other documents that have been identified in the publicdocket as acceptable if submitted electronically and (b) choosethis method of submission, instead of traditional paper recordsubmissions. The potential range of submissions includessuch records as new drug applications, medical device pre-market notifications, food additive petitions, and medi-cated feed applications. FDA will consider these, and all otherrequired submissions, as candidates for optional electronicformat.

Although the benefits of making electronic submissionsto FDA will be phased in over time, as the agency acceptsmore submissions in electronic form, firms can, upon therule’s effective date, immediately benefit from using electronicrecords/signatures for records they are required to keep,but not submit to FDA. Such records include, but are notlimited to pharmaceutical and medical device batch productionrecords, complaint records, and food-processing records.

What’s more, as stated earlier in this chapter, the activ-ities regulated by this rule are voluntary—no entity is requiredby this rule to maintain or submit records electronically if itdoes not wish to do so. Presumably, no firm (or other regulatedentity) will implement electronic record keeping unless thebenefits to that firm are expected to exceed any costs (includingcapital and maintenance costs). Thus, the industry will incurno net costs as a result of this rule.

Ultimately, the rule will permit regulated industry andFDA to operate with greater flexibility, in ways that willimprove both the efficiency and the speed of industry’s opera-tions and the regulatory process. At the same time, it ensuresthat individuals will assign the same level of importance toaffixing an electronic signature, and the records to whichthat signature attests, as they currently do to a handwrittensignature.

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For any firm choosing to convert to electronic record keep-ing, the direct benefits are expected to include (2,4):

1. Improved ability for the firm to analyze trends,problems, etc., enhancing internal evaluation andquality control

2. Reduced data entry errors, due to automated checks3. Reduced costs of storage space4. Reduced shipping costs for data transmission to

FDA5. More efficient FDA reviews and approvals of FDA-

regulated products6. More efficient data mining and analysis

There may be some small organizations that currentlysubmit records on paper, but that archives records electro-nically. These entities will need to ensure that their existingelectronic systems conform to the requirements for electronicrecord keeping described in this rule. Once they have done so,however, they may also take advantage of all the other benefitsof electronic record keeping. Therefore, no individual smallentity is expected to experience direct costs that exceed bene-fits as a result of this rule. Furthermore, because almost all ofthe rule’s provisions reflect contemporary security measuresand controls that respondents to the ANPRM identified, mostfirms should have to make few, if any, modifications to theirsystems.

For entities that do choose electronic record keeping, themagnitude of the costs associated with doing so will depend onseveral factors, such as the level of appropriate computer hard-ware and software already in place in a given firm, the types ofconforming technologies selected, and the size and dispersionof the firm. For example, biometric signature technologies maybe more expensive than nonbiometric technologies; firms thatchoose the former technology may encounter relatively highercosts. Large, geographically dispersed firms may need someinstitutional security procedures that smaller firms, withfewer persons in more geographically concentrated areas,may not need.



Firms that require wholesale technology replacements inorder to adopt electronic record/signature technology may facemuch higher costs than those that require only minor modifi-cations (e.g., because they already have similar technologyfor internal security and quality control purposes). Amongthe firms that must undertake major changes to implementelectronic record keeping, costs will be lower for those able toundertake these changes simultaneously with other plannedcomputer and security upgrades. New firms entering themarket may have a slight advantage in implementing technol-ogies that conform to this rule, because the technologies andassociated procedures can be put in place as part of the generalstartup.

There is an additional cost often overlooked that will beincurred as part of compliance—professional skills. If a firmelects electronic record keeping and submissions, it musttake steps to ensure that all persons involved in developing,maintaining, and using electronic records and electronic signa-ture systems have the education, training, and experience toperform the tasks involved.

The level of training and experience that will berequired depends on the tasks that the person performs. Forexample, an individual whose sole involvement with electronicrecords is infrequent might only need sufficient training tounderstand and use the required procedures. On the otherhand, an individual involved in developing an electronicrecord system for a firm wishing to convert from a paperrecord-keeping system would probably need more educationor training in computer systems and software designand implementation. In addition, FDA expects that sucha person would also have specific on-the-job training andexperience related to the particular type of records kept bythat firm.

The relevant education, training, and experience of eachindividual involved in developing, maintaining, or using elec-tronic records/submissions must be documented. However, nospecific examinations or credentials for these individuals arerequired by the rule.

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REFERENCES

1. Guidance for Industry, Part 11, Electronic Records; ElectronicSignatures—Scope and Application. Food and Drug Administra-tion, February 2003.

2. Fed. Reg., Department of Health and Human Services, 21 CFRPart 11.

3. Institute of Validation Technology, conference proceedings,Process Analytical Technology, October 2002.

4. BPI Research Centre, Validation, compliance and beyond,November 2002.

5. XML in the life sciences, Sillico Research Limited, 2001.



20

Marketing and Advertising/Promotion: The Impact ofGovernment Regulations

DANIEL GLASSMAN, PHILIP W. McGINN, Jr.,and GENE GOLDBERG

Bradley Pharmaceuticals Inc.

Fairfield, New Jersy, U.S.A.

1. INTRODUCTION

Prior to 1900, the pharmaceutical industry was initiallyrelatively small and fragmented. Expenses for marketing andadvertising/promotion were rather modest. Products weregenerally produced, promoted, and sold with a minimum ofregulation or scrutiny.

Today, the pharmaceutical industry spends billions ofdollars in marketing and advertising/promotion activities and

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does so under rather rigid regulations by the U.S. Food andDrug Administration (FDA). The industry is heavily regulatedby FDA concerning proof of the effectiveness and safety of itsproducts and the manner in which it promotes its therapeutics.

To understand how this dramatic change in regulationhas affected the industry’s overall promotional activities, it isimportant to review the evolution of the government’s involve-ment in this important area of the pharmaceutical business.

2. EVOLUTION OF GOVERNMENT DRUGADVERTISING/PROMOTIONREGULATIONS

Several minor efforts were directed towards the classificationof medicines in the 1800s. However, the regulation of drugpromotion started in 1905 when the American Medical Asso-ciation (AMA), through the Council on Pharmacy and Chem-istry, initiated a voluntary drug approval program that forcedpharmaceutical companies to submit evidence on their respec-tive drugs for review by the AMA Council and outside expertsin order to earn the right to advertise in AMA and relatedjournals (1). This AMA program lasted until 1955.

In addition, in 1906 Congress passed the original PureFood and Drug Act, which was designed to provide safe drugsto patients. Though well intentioned, this Act did not preventfalse promotional claims for drugs. It was not until 1912 thatCongress enacted the Shirley Amendment, which prohibitedthe labeling of medicines with false therapeutic claims.

Throughout the following years, it was repeatedly demon-strated that the original 1906 Pure Food and Drug Actwas obsolete and ineffective for the regulation of promotionalclaims. However, it was not until 1938 that Congress passedand President Franklin Roosevelt signed the new broad-basedFederal Food, Drug and Cosmetic Act into law. This Actrequired that new drugs be tested for safety prior to marketingand that new drugs have adequate labeling for safe use. At thattime, all drug advertising regulation was assigned to theFederal Trade Commission (FTC) (2,3).

610 Glassman et al.


But, much more was to happen in the efforts to providesafe and effective drugs for the nation’s public and to regu-late promotion to accurately reflect and restrict claims to theboundaries of the approved prescription information/labeling.During the next 20 years, the strength and scope of the FDAwas substantially increased, due to safety problems related to avariety of drugs tested, produced, and prescribed in the UnitedStates. Drug safety and related promotion had become a majorissue for FDA.

The year 1960 marked dramatic steps designed tofurther strengthen and expand FDA’s powers. Senate hear-ings on strengthening the drug provisions of the 1938 Actwere chaired in June 1960 by Senator Estes Kefauver, whohad an established reputation as a crime investigator. Duringthe course of the Senate pharmaceutical hearings, FDAreceived a request from a pharmaceutical company for theapproval, via a New Drug Application (NDA), of the sedativedrug thalidomide, which was found to have caused birthdefects in thousands of babies in Western Europe. Thoughpressure had been exerted by the U.S. manufacturer hopingto introduce the product, FDA medical officer Dr. FrancesKelsey refused to allow the NDA to be approved, thus avoid-ing what would have been a substantial tragedy in theUnited States. This striking event gave impetus to SenatorKefauver to submit a bill tightening the regulation ofall drugs in the U.S., which was approved and signed intolaw (4).

Basically, the 1962 Kefauver amendments to the original1938 Federal Food, Drug and Cosmetic Act required drugmanufacturers to prove that their products were both effectiveand safe prior to marketing and that all antibiotics had to becertified, and, most important from the perspective of promo-tional regulation, FDA was given control over all prescriptiondrug advertising.

Though the various divisions of FDA were becoming morecomprehensive and sophisticated in nature, concern about thesafety of America’s drug supply continued. This concern wouldlead to greater FDA oversight of drug marketing and advertis-ing/promotion.

Government Regulations of Marketing and Advertisement 611


Pressure from FDA on drug marketing and advertising/promotion escalated in the 1970s. In the early 1970s FDAstarted two new forums in order to increase drug communica-tion with the public. One result was the production of the FDABulletin (1971) by the Bureau of Drugs, which alerted physi-cians and pharmacists to changes in drug use and labelingrequirements (5). The other result was the National DrugExperience Reporting System (1971), which allowed FDA tocollect expanded data on drug adverse reactions, drug abuse,and drug interactions and provided a mechanism for FDA totake the lead in creating and maintaining the system for healthprofessionals.

In the 1980s, in order to render its operations moreefficient, the FDA made a number of changes, one of whichwas the change of the Division of Drug Advertising to thatof the Division of Drug Advertising and Labeling in order toincrease the public’s assurance of pharmaceutical promotionaladherence to approved drug safety and efficacy.

By this time, drug advertising in professional journalsand direct mail and promotion through pharmaceutical salesrepresentatives, were well-accepted practices. However, thefirst direct-to-consumer television advertising of prescriptiondrugs occurred in 1983, via Boots Pharmaceuticals, andencountered resistance from FDA. Action was taken by FDAbecause of concern that the consumer could not possibly readthe long list of side effects flashing across the screen. This waspromptly addressed (6) via an accurate but simpler listing ofpotential side effects.

3. REORGANIZATION OF THE FOOD ANDDRUG ADMINISTRATION

The various divisions of FDA were reorganized in the 1980sto improve its overall efficiency relative to the regulation ofdrug approval, distribution, and advertising/promotion. Thereporting requirements for drug adverse reactions were alsostrengthened.

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Although the primary agency that had jurisdiction overthe advertising of drugs was the FTC, the Federal Food, Drugand Cosmetic Act (FD&C Act), as amended in 1962, gave FDAprimary jurisdiction over the regulation of prescription drugadvertising (7), which continues to this date.

To understand how FDA regulates pharmaceuticalmarketing and advertising/promotion, it is important to firstunderstand how FDA is organized.

4. FDA ORGANIZATION

It is within the Office of the FDA Commissioner that theFDA-wide policies are established, and the various Centerswithin the FDA set the policies applicable to the products

regulate a specific area of health-related products.Each Center monitors marketing and advertising/promo-

tion in several ways, namely:

1. Review product materials submitted by companies2. Review medical journals, trade publications, medical

exhibits, and publicly available documents that areissued by various firms

3. Review complaints received from competitors, orothers, about marketing and advertising/promo-tional materials used by companies

4. Review materials supplied by the product reviewdivisions

The Center for Drug Evaluation and Research (CDER) isthe focus of this review of FDA’s regulation of pharmaceuticaldrugs.

5. CENTER FOR DRUG EVALUATION ANDRESEARCH

The CDER represents the largest staff Center within the FDAthat regulates marketing and advertising/promotion. When the


they regulate. Figure 1 illustrates the five FDA Centers that


CDER was established in 1987, it consisted of few offices andstaff. By 1994, it consisted of six office buildings, which formedthe largest headquarters component of FDA and encompassednearly 1500 people. Drug reviews had become very complex

Figure 1 FDA centers.

614 Glassman et al.


and challenging as the sophistication of drug design and manu-facturing increased (8).

The CDER Division responsible for the regulation ofpharmaceutical marketing and advertising/promotion is theDivision of Drug Marketing, Advertising and Communication(DDMAC). Figure 2 illustrates the manner in which DDMACis organized.

The staff of DDMAC monitors drug marketing andadvertising/promotion from a variety of sources. They havethe power to identify volatile and incorrect practices andimplement corrective action directly with the pharmaceuticalcompanies concerned (9). Members of the DDMAC staffregularly consult with CDER medical reviewers relative tospecific product labeling issues and claims and also coordinatewith the review divisions when companies request preclear-ance of product launch materials for newly approved drugs.Other DDMAC responsibilities include conducting researchon marketing, advertising, and labeling activities.

Figure 2 DDMAC organization as of September 1999.



6. MARKETING AND ADVERTISING/PROMOTION REGULATIONS

FDA regulates the marketing and advertising/promotion ofprescription medicines, biological products, restricted devicesand prescription animal products. On the other hand, theFTC regulates, with scientific input from FDA, the marketingand advertising/promotion of foods, over-the-counter (OTC)drugs, nonrestricted devices, and cosmetics and nutritionalproducts, i.e., vitamins.

The focus of FDA’s enforcement of advertising and label-ing laws has centered on prescription drugs, primarily becauseit has been actively regulating in this area the longest—since1962. However, FDA has broadened its regulatory scope toencompass virtually any information issued by a medical prod-ucts manufacturer of drugs, biologics, veterinary medicines,or medical devices.

What is considered to be the FDA’s true ‘‘crackdown’’on the enforcement of marketing and advertising/promotionactivities began in the late 1980s. This was not a result ofcongressional legislation but, rather, FDA’s expansion of itsauthority was based on their interpreted powers, resultingfrom concerns of a number of sources that the Agency’senforcement was not vigorous enough. Public sentiment wasthat FDA was not establishing rules (regulations) to keep pacewith the new methods of advertising/promotion of medicalproducts in the industry.

This so-called ‘‘crackdown’’ originally focused on the mar-keting and advertising/promotion of prescription drugs (espe-cially nontraditional forms of promotion) and has now beenshown to have far-reaching implications for all medical productmarketing and advertising/promotion. This crackdown reallybegan in the 1960s and accelerated in the 1980s, a result ofa string of ground-breaking, aggressive commissioners. Thisaggressive approach resulted in antagonism between FDA,pharmaceutical companies, and representatives of the pharma-ceutical industry, including the Pharmaceutical ManufacturersAssociation (PMA), led for many years by the powerful asso-ciation leader C. Joseph Stetler (Pharma, Executive Vice

616 Glassman et al.


President and General Council from 1963 to 1965 andPresident from 1965 to 1979 and 1984 to 1985).

7. FDA’S AUTHORITY OVER MARKETINGAND ADVERTISING/PROMOTION

The authority for FDA’s regulations emanates from theFederal Food, Drug and Cosmetic Act of 1962, which estab-lished FDA’s control over the marketing and advertising/promotion of prescription drugs, restricted medical devices,prescription veterinary medicine, and biological products.Through the authority granted, FDA has issued extensiveregulations on marketing and advertising/promotion ofprescription drugs.

From the overall standpoint of prescription drug market-ing and advertising/promotion, 1962 was a key legislative yearbecause, until that year, Congress had exempted drug adver-tising from FDA control. However, as a result of the 1962Kefauver hearings (previously discussed), it was required thatall drugs be demonstrated not only to be safe, as was the priorrequirement, but also to be effective. As a result, marketingand advertising/promotion became one of the more importantaspects of FDA control.

It should be noted, again, that FDA’s regulations on drugpromotion were written at the time in which journal advertis-ing, direct mail, and ‘‘detailing’’ were the most common waysin which prescription drugs were promoted to the medical pro-fession. As the years progressed, the following communicationmedia were added to the traditional forms of product promo-tion: manufacturers’ press releases, medical symposia and othermedical education programs, electronic advertising, direct-to-consumer (DTC) advertising, therapeutic monographs,dinner meetings, and verbal communications between physi-cians and company staff or consultant representatives (10).

Much has changed regarding the FDA’s regulation ofprescription medicine marketing and advertising/promotion.After years of initial combat between the industry and the



FDA expansion of regulatory power, companies and industryrepresentatives, through experience with the FDA, have becomereluctant to challenge FDA jurisdiction. The expanded roleof informal rules that FDA applies to various product commu-nications mechanisms has made it difficult to predict what theFDA will deem as acceptable. It should be noted that althoughmembers of the FDA are not law officers, their Warning andRegulatory Letters to companies have nearly the same effectas issued laws.

8. EXTERNAL PRESSURES ON FDAREGULATION OF MARKETINGAND ADVERTISING/PROMOTION

This new intensity of regulatory enforcement, in the late1980s, was due to the fact that the FDA staff recognized thatnew methods of communicating product information werebecoming prevalent and were being extensively and intenselyutilized by pharmaceutical companies. Also, concern had beenexpressed by external observers concerning the FDA’s level ofenforcement of misleading advertisements by the drug indus-try. This new FDA initiative coincided with increased externalpressures on FDA to increase its activities in regulating themarketing and advertising/promotion not only of prescriptiondrugs but also of other medicinal products.

In 1990, FDA’s activities were further intensified bythe arrival of Dr. David A. Kessler as the new Commissioner.He increased the staff in the CDER, as well as other Centers,and ‘‘began the process of setting forth written guide-lines for certain marketing and advertising/promotionalactivities’’ (11).

9. COMPLAINTS BY COMPETITORS

Two methods are used by FDA to identify potential companyviolations in marketing and advertising/promotion practices.

618 Glassman et al.


The first is through FDA’s monitoring activities, which, withsignificant additions in staff, have increased substantially. Thesecond method of FDA scrutiny involves complaints receivedfrom competitive firms who monitor the activities of theircompetition, including marketing and advertising/promotion.In fact, in the late 1980s, competitive complaints formed thebasis of half of the regulatory actions taken by DDMAC withinCDER. In addition, pressures on FDA can emanate fromCongress, the Office of the Inspector General, public press,and others.

10. IMPACT OF THE U.S. CONGRESS

A significant and continuing influence over FDA policies andenforcement activities is exerted by the U.S. Congress (i.e., viaSenators and members of the House of Representatives) who,periodically, send letters to FDA (receiving priority attention),hold congressional hearings with FDA officials invited totestify, and conduct staff investigations and issue subsequentreports.

A major focus of these congressional issues is the amountof money that the pharmaceutical industry spends on market-ing, including marketing and advertising/promotion (12). Thisis a continual area of contention between Congress and thepharmaceutical industry.

11. INSPECTOR GENERAL OF THEDEPARTMENT OF HEALTH ANDHUMAN SERVICES (HHS)

The Office of Inspector General (OIG) operates as a politicallyindependent office that conducts investigations, frequentlyas the result of a complaint or external request concerningwhat are deemed to be illegal activities. Reports by the OIGare considered significant because of their presumed objectivityand are regarded as credible. As a result, OIG reports usually



result in publicity with resultant pressure on FDA to take someform of regulatory action.

During the period from 1981 through 1992, OIG focusedstrongly on FDA regulatory matters, such as the ‘‘generic drugscandal,’’ prescription drug advertising, and gifts or paymentsby firms to physicians. The OIG report noted that many of thegifts to physicians are regarded under the AMA Guidelines onGifts to Physicians as inappropriate.

This led to the recommendation that FDA shouldfinalize guidelines that defined what was considered to bepromotional activity, including gifts, and what was consi-dered scientific exchange. The recommendation was issuedin the November 27, 1992 publication concerning propo-sed policy on scientific exchange and continuing medicaleducation.

12. IMPACT OF CONSUMER ADVOCACYGROUPS

Consumer advocacy groups provide an important source ofexternal pressure on the FDA in a number of areas. The mostprominent consumer advocacy group is the Health ResearchGroup (HRG), founded by Ralph Nader in 1971 and headedby Dr. Sidney Wolfe. HRG has a special interest in pharmaceu-tical marketing and advertising/promotion and is known for itsopposition to certain marketing and advertising/promotionpractices.

Though the HRG has no policy paper or quantifying dataon the subject, it claims, as an empirical observation, that themedical products industries spend too much on marketing andadvertising/promotion and that much of this marketing andadvertising/promotion is misleading. Therefore, HRG, relyingheavily on the media, attempts to pressure FDA to monitor themarketplace more closely and to take more aggressive enforce-ment actions (13).

HRG and other advocacy groups have enjoyed significantsuccess in their endeavors to pressure the FDA to action.

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13. AUTHORITY OF THE FTC OVERMARKETING AND ADVERTISING/PROMOTION OF FDA-REGULATEDPRODUCTS

A relationship pertaining to the regulation of product advertis-ing/promotion that is often not understood is the interaction ofFDA and the FTC: ‘‘Under the Federal Food, Drug, andCosmetic Act (FD&C), the FDA regulates the safety, efficacy,functionality (when appropriate) and labeling of foods (exceptmeat and poultry), prescription and over-the-counter drugs,biologics, veterinary medicine, cosmetics, and prescriptionand non-restricted medical devices’’ (14).

In 1938, the FTC received the authority from Congress toregulate the advertising of foods, drugs, and cosmetics. In 1962this authority was altered by Congress to give FDA jurisdictionover most aspects of the advertising/promotion of prescriptiondrugs but not OTC drugs. With the passage of the MedicalDevice Amendments in 1976, FDA also received jurisdictionover the regulation of advertising/promotion for ‘‘restricted’’devices, while the FTC retained primary responsibility for theadvertising/promotion of nonrestricted devices.

Moreover, over the years, FDA has adopted a verybroad interpretation of marketing and advertising/promotion.While ‘‘advertising’’ is commonly considered to be paid adver-tising, FDA considers ‘‘promotion’’ to apply to any materialsissued by or on behalf of a company or any event that issponsored by or on behalf of a company that mentions one ormore products.

Because of their complex working relationship overthe regulation of labeling and advertising/promotion of identi-cal products, FDA and FTC entered into what is known as theMemorandum of Understanding (MOU) in 1971, which estab-lished the working relationship and division of responsibilitybetween FDA and FTC. As a result of this understanding, FDAand the FTC work closely on many issues that involve adver-tising/promotion. FDA retains full responsibility for all aspectsof prescription drug labeling and promotion plus the labeling ofOTC products, whose advertising the FTC regulates.



14. FDA REGULATION OF MARKETING ANDADVERTISING/PROMOTION OFPRESCRIPTION DRUGS BASICREGULATIONS AND POLICIES

The CDER is responsible for most of the regulations and broadpolicies that apply to the marketing and advertising/promo-tion of FDA-regulated products, with the marketing and adver-tising/promotion of prescription medicinal products, being themost carefully monitored product communications. WithinCDER, the DDMAC division is responsible for these regulatoryactivities.

FDA subjects to regulation any advertising or promotionalpiece issued by a drug company for a specific product. Thefollowing general requirements apply to prescription market-ing and advertising/promotion:

1. There should be no claims made for a product otherthan those that are FDA approved and are includedin the product’s labeling.

2. There must be ‘‘fair balance’’* in the product’sadvertising and promotion so that the physician,other health professionals, or consumers will havea clear understanding of the product.

3. When an advertisement contains both the name ofthe drug and its indications, it must also include anabbreviated summary of the package insert.y Thisrequirement applies to any advertisement that isdirect-to-consumer, as well as directed to physicians.Concerning electronic advertising, there must be a

*This is an evolved interpretation by FDA and refers to FDA’s requirementthat risks associated with the product’s use should be clearly identified,relative to the product’s benefits for the patient.yThe product package insert contains all of the essential information aboutthe product, including: pharmacology, clinical studies, indications and usage,contraindications, precautions, dosage, and administration. This informationis often also included in the Physicians’ Desk Reference. Abbreviated PatientInserts were briefly prepared for some products but were not successful.

622 Glassman et al.


provision for physician easy access to the productpackage insert.

4. It is illegal to make safety or efficacy claims for aproduct prior to its approval.

5. ‘‘The fact that an advertisement or promotional itemmay be completely accurate in terms of informationis not an adequate defense if any of the specificrules are violated’’ (15).

6. The product must be accurately represented in theadvertisement, even in its graphics.

7. When FDA finds an advertisement or promo-tional piece in violation, the corrective measures itwill utilize will vary as to the potential impact onpublic health.

8. Relative to company-sponsored meetings thatmention specific products, FDA then regards everyaspect of the meeting as within its jurisdiction, suchas the location of the meeting, those attending it,who is speaking and what is said, and the relation-ship that exists between the company and the orga-nization that conducts the meeting.

15. FDA DEFINITIONS OF LABEL, LABELING,MISBRANDING, AND ADVERTISEMENTS/PROMOTION

Though the Federal Food, Drug and Cosmetic Act does notdefine ‘‘advertising’’ and ‘‘promotion,’’ FDA has chosen todefine those terms in the broadest sense possible. This isespecially true of ‘‘promotion,’’ which FDA considers to beany materials that are issued on behalf of a company or anyevent that is sponsored by or on behalf of a company thatmentions one or more products. The key to these regulationsbegins with labeling and extends through policies on theadvertisement and promotion of drugs.

According to the FD&C Act, a label is defined as a displayof written, printed, or graphic material upon the immediatecontainer of any article. Any word, statement, or other



information that also appears on the label shall not be consid-ered as in compliance unless such word, statement, or otherinformation also appears on the outside wrapper (if there isany) of the retail package of such article, or is easily legiblethrough the outside wrapper or container (16).

As far as labeling is concerned, the same law refers to alllabels and written, printed, or graphic matter that appearsin any article, container or wrapper, or accompanies such arti-cle. FDA has interpreted the matter of labeling to include:brochures, booklets, mailing pieces, detailing pieces, file cards,bulletins, calendars, price lists, catalogs, house organs, letters,motion picture films, videos, CDs, sound recordings, exhibits,literature, reprints and similar pieces of printed, audio or visualmatter description of a drug and references published for useby medical practitioners, pharmacists or nurses, containingdrug information supplied by the manufacturer, packer, or dis-tributor which are disseminated by or on behalf of its manu-facturer packer, or distributor (17).

Misbranding of a product is considered when the labelingor advertising/promotion is alleged to be misleading. To deter-mine this status, FDA takes into account the representationsmade (or suggested) by the statement, word, design, device, orany combination of the aforementioned. The FDA also consid-ers the extent to which the labeling or the advertising/promo-tion fails to reveal facts that are material in light of suchrepresentations or material with respect to the consequencesthat could result from the use of the article to which the label-ing or advertising/promotion relates under the conditions ofuse prescribed in the labeling and advertising/promotion orunder such conditions of use as are customary or usual.

16. GENERAL FDA POLICIES FORADVERTISING AND PROMOTING DRUGS

FDA has made it clear to pharmaceutical firms that all adver-tising and some promotional materials to be used for prescrip-tion drugs must be submitted routinely at the time of first

624 Glassman et al.


use. The materials concerned include advertisements, detailingpieces, product brochures, price lists, audio-visual materials,and all other materials that fall into the category of advertisingor promotional labeling. These requirements apply to the stan-dard forms of marketing and advertising/promotion as well asnewer methods, such as electronic advertising.

When these submissions occur, the company concer-ned must use FDA Form 2253, entitled ‘‘Transmittal of Adver-tisements and Promotional Labeling for Drugs and Biologics forHuman Use,’’ and the name, title, and signature of the submit-ting official must be included. All such materials must be sub-mitted to CDER’s Division of Drug Marketing, Advertising andCommunications. In order to expedite the review process, com-panies are required to submit referenced materials with all pro-motional materials in which the references are cited. DDMAChas issued notice of violation letters when firms ‘‘batch’’ severalpromotions for collectivesubmission after some or all of thematerials have been disseminated.

17. PRECLEARANCE OF ADVERTISING ANDLAUNCH MATERIALS

Normally the routine submission of advertising/promotion ofthe drug is not required in advance of its being used. Thisapplies as well to all direct-to-consumer advertising. However,FDA does specify that if information on the product is notwidely known, if the medicine may cause fatalities or seriousdanger to patients, or if the company has been notified byCDER of a need to publicize such information and has notyet satisfactorily complied, then FDA requires prior approvalof the advertising/promotion. In addition, there are two othersituations in which preclearance of marketing and advertising/promotion materials is required or strongly advisable, namely:

1. When it is believed that there has been a serious orrepeated violation of FDA regulations

2. When a major new product is being introduced, inwhich case FDA generally requests that the initial



marketing and advertising/promotion materials besubmitted voluntarily

18. ITEMS FOR PRECLEARANCE

FDA requests that, as preclearance items, the company con-cerned submit only those ‘‘core’’ materials that are represen-tative of the launch campaign, i.e., the primary detail aid, theprimary journal advertisement, introductory letters, and pressreleases. These should be submitted in their most final andcomplete form. It is recommended that the launch submissionbe forwarded to FDA when the labeling for the product is in thefinal or near-final state.

FDA also requests that the submissions be accompaniedby hard copies of all references cited and annotated and thatthe company concerned highlight the specific text supportingvarious elements of the promotional materials submitted forreview. The review of launch materials is considered a highpriority by FDA, and DDMAC’s review of the launch materialsis considered a high priority. They are reviewed on a first-in, first-out basis, within 2–3 weeks of submission. It shouldbe noted that DDMAC will accommodate requests for arapid approval of certain time-sensitive advertising/promotionmaterials.

19. FAIR BALANCE

‘‘Every advertisement must meet FDA’s ‘Fair Balance’requirements’’ (18), which means that FDA has mandated,through administrative authority, that interpretative risksassociated with a product must be clearly identified to offsetthe benefits. This applies to all promotional materials, includ-ing advertisements (printed and electronic), detailing units,and public relations materials.

In April 1994 CDER indicated that fair balance appliesequally to the content and the format of promotional materials.It will consider both the representations that are made for the

626 Glassman et al.


product as well as the extent to which the labeling or advertis-ing/promotion fails to reveal ‘‘material’’ facts about potentialconsequences resulting from the product’s use. In other words,the plus (positive) aspects of the product must be in balancewith the negative (adverse) aspects of its use.

A company’s compliance with this FDA fair balance pro-vision varies depending on the nature (type) of promotionalmaterial. It also seems to ebb and flow in the extent of nega-tive balance needed, dependent on FDA pressure. For exam-ple, the inclusion of the product package insert or the briefproduct summary meets some of the requirements offair balance and is often used as fair balance, especially ifthe data or all of the product’s side effects and contraindica-tions have a prominence and readability that is comparable tothe effectiveness-related information that is presented.However, DDMAC has indicated that risk information thatis placed in the footnotes and not in the body of the text ofa promotional unit does not meet the requirements for fairbalance if the benefit information is included in the main bodyof a promotional piece.

The following are examples of situations in which fairbalance is not followed:

1. Claims made comparing the product with anotherproduct without specific proof

2. Making claims that the product is safer or moreeffective than the labeling indicates

3. Misrepresenting a study or other information per-taining to the clinical data as it pertains to theproduct

4. Using product graphics in a misleading manner

Examples of situations in which the promotional materialsmay be violative are:

1. Using a study that is badly (poorly) designed2. Misrepresenting the statistical data3. Misusing the graphics for the product material4. Misrepresenting what is accepted as the product’s

mechanism of action



5. Failing to provide a balanced emphasis of productside effects and contraindications

6. When appearing on multiple pages, failing to clarifywhere the product’s side effects and contraindica-tions information appears

7. In the case of a multiple page advertisement, fail-ing to refer readers to the product’s side effects andcontraindications information if located on a differ-ent page

20. BRIEF SUMMARY OF PRODUCTINFORMATION

When FDA required product information (PI) for all promo-tional material, the practical matter of cost to include the fullPI in journal advertising became an issue. Journal advertisingspace is sold by the page. The need to add a one-, two-, orthree-page PI to a one-page promotional message obviouslywould double, triple, or quadruple the cost of promoting a pro-duct by advertising in medical journals. Therefore, a practicalsolution was agreed upon. FDA found that the labeling con-tained in a journal ad would be in compliance if it contained anabbreviated product information summary. This usually couldbe contained in a column or a page encompassing a true (cor-rect) statement of information that relates to the product’s sideeffects, warnings, precautions, contraindications and adversereactions from the approved product package insert (19).

20.1. Wrap-Around Advertisements

DDMAC further clarified in April 1994 that ‘‘wrap-around’’advertisements, those presenting advertising copy in the frontof a publication with the brief summary in the back, were notin compliance with brief summary requirements. It stated thatthe brief summary must appear adjacent to the advertisement(20) and that an ad appearing in the front and a brief summaryin the back that is separated by the entire contents of thepublication is not in compliance.

628 Glassman et al.


20.2. Electronic Advertisements

The above requirement also applies to electronic advertise-ments. Such ads or commercials must include major side effectsand contraindications in either the audio or the audio andvideo portions of the presentation.

A number of company violations have occurred in theestablishment of rules for electronic advertisements. Thecompanies concerned were issued a violation warning witha complete explanation of the extent to which FDA consideredthat the matter of fair balance was violated. The companiesconcerned then complied with the FDA’s request to changeor modify the advertisement/commercial.

20.3. Reference to the Product Generic Name

In the 1960s FDA regulated that the generic name of each prod-uct must be referenced in advertising/promotion for brand namedrugs. The generic name must be cited, for example, the firsttime, or with the most prominent placement, on each page eachtime the brand name is featured. Also, the type size of the gen-eric name, except where there are combinations of ingredients,must be at least half the type size of the brand name and musthave prominence compared with that of the brand name. Manyin the industry consider this matter to be more political thanregulatory, especially in light of the efforts that have, and arecontinuing to bemade to drive physician prescriptions and phar-macy dispensing to the usage of generic versus trademark drugs.

20.4. Reminder and Other AdvertisementsExempt from the Brief Summary Requirement

FDA has indicated that some advertisements—generally, pre-launch and reminder ads—are exempt from the brief summaryrequirement. The ads are designed to call attention to the drugbut do not include the product indications, dosage recommen-dations, or beneficial claims. But it should be noted that theseads are not permitted for products that carry any Black BoxWarnings, which are imposed by FDA to highlight a particularmajor health issue involved in prescribing or using the product.



Reminder advertisements in the past were commonly usedfor a product with a well-established brand name. These ads,like the prelaunch ads, are designed to call attention to theproduct name but cannot include product indications, if theproduct name is used, dosage recommendations, or beneficialclaims. These FDA restrictions today make the use of reminderpromotion virtually impossible. However, reminder ads forgeneric drugs that include representations of the bioequi-valence of the products as compared to the brand name prod-ucts are not considered reminder ads and must contain fulldisclosure information.

Advertisements that focus exclusively on price are tech-nically reminders and thus exempt from the brief summaryrequirements.

Help-seeking advertisements are designed to inform theconsumer of the symptoms of a particular condition, encourag-ing the consumer to see a health-care professional in orderto discuss an appropriate treatment. This type of promotion isexempt from the brief summary requirement. However, suchads must not refer to a particular prescription product, implythat the product is the preferred treatment for the conditionfeatured, or discuss any unique properties of the drug thatallow for its identification.

Bulk-sale drugs are exempt from carrying the briefsummary if they are intended to be processed, manufactured,labeled, or repackaged in substantial quantities. Also, theymust not contain any claims of safety or efficacy.

Drugs sold to pharmacists for compounding are exemptfrom the brief summary requirement as long as they makeno safety or efficacy claims.7

21. ADVERTISING/PROMOTION OFPRESCRIPTION DRUGS FOUND LESSTHAN EFFECTIVE IN THE ‘‘DRUGEFFICACY STUDY’’

A major effort to require that all drugs be proven not onlysafe (as required under the 1938 law) but also effective was

630 Glassman et al.


put into action when Congress in 1962 amended the FD&C Actto this effect. Based on this amendment, FDA decided that alldrugs approved between 1938 and 1962 on the basis of safetyalone should be evaluated on the basis of efficacy claims.

This massive study was initially performed by panels ofexperts under the aegis of the National Academy of Sciences/National Research Council (NAS/NRC). It became known asthe ‘‘Drug Efficacy Study,’’ which placed indications for allreviewed drugs into one of the following six categories:

1. Effective2. Probably effective3. Possibly effective4. Ineffective5. Ineffective as a fixed combination6. Effective but

As a result of this extensive review, hundreds of older medi-cine formulations were removed from the marketplace.Also, claims that were unproven were eliminated from druglabeling.

The FDA regulations provide for disclosure in both label-ing and advertising of the status of those drugs and indicationsthat were found to be less than fully effective. The labeling forthose drugs with indications found to be less than fully effec-tive should carry a box statement as to this fact. Because thereare relatively few medicines remaining with ‘‘probably effectiveor possibly effective’’ indications, this section of the regulationsis seldom applied.

22. FDA ISSUES CONCERNING COMPANYEFFORTS TO PROMOTE PRESCRIPTIONDRUGS

There are a substantial number of issues concerning the FDAregulations for company advertising/promotion of prescriptionproducts, including company efforts regarding comparativeadvertising, price advertising, promotion of unapproved



product indications, advertising for investigational and orphanproducts, and promoting to formularies. In order to under-stand these issues, each will be reviewed separately.

22.1. Comparative Advertising/Promotion andClaims of Superiority

In general, FDA tends to discourage company marketing andadvertising/promotion that compares specific products or makesclaim of superiority of one product over another. However, inApril 1994 CDER released a statement that set standards forclaims that ‘‘represent, suggest or imply that their product’ssafety or effectiveness is comparable or superior to that of acompeting product or products’’ (21). But, with this provisoappeared the statement that such claims were then consideredto be subject to the same standards of review as for efficacy andsafety claims in a product’s approved labeling.

A company that makes such claims must support themwith substantial evidence or substantial clinical experiencethat supports the claims presented. CDER further stipulatedthat such a comparison must be derived from a well-controlledstudy that compares the products, head to head. The CDERstatement indicated that effectiveness claims should be basedon at least two adequate, well-controlled studies. Safety claimsnormally require direct comparisons between the productsbeing compared. Also, there should be statistical clinical ther-apeutic significance between the products in the comparison.

Another significant guideline in the CDER’s statementis that both drugs being compared must have been approvedfor at least the same indications being compared and that thedosage regimens being compared must be consistent withthe dosage recommendations in the approved labeling and inthe same part of the dose range.

Before the claim can be used in company advertising/promotion, CDER prefers that the studies be reviewed by itsmedical reviewers. But CDER indicated that the data also canbe submitted after the advertising/promotion claim appears.The matter of comparative advertising/promotion has thusbeen made quite clear from the FDA’s regulatory perspective.

632 Glassman et al.


22.2. Price Advertising/Promotion

This is an area of product advertising/promotion that is notalways well understood. Thus, the FDA has certain rules thatset the conditions for a company using this marketingapproach, namely:

1. That the only purpose of the promotion is to adver-tise price

2. That the promotion states nothing about theproduct’s safety or efficacy

3. That both the brand and generic names of the drugbe contained in the promotion as well as its dosagestrength for each ingredient

4. That the promotion explains the charge for a spe-cific product, strength, dosage form, and quantity

5. That all product charges are included in the pro-moted price

This type of promotion also may include other informa-tion, such as the identification of professional services providedby the pharmacy or pharmaceutical company, as long as it isnot false or misleading.

If some pharmaceutical manufacturers advertise nation-ally that their drugs are less expensive than competing or simi-lar products, but no specific price is indicated, the promotion isnot considered to be traditional price advertising.

22.3. Promotion of UnapprovedProduct Indications

The main concern of the FDA regarding marketing and adver-tising/promotion is the promotion of unapproved uses for mar-keted drugs. It is the agency’s contention that such promotionhas the greatest potential to damage public health because itencourages patients to seek, and doctors to prescribe, productsfor indications that have not been approved by FDA. Anothermajor concern to FDA is the promotion of products duringthe preapproval stage. This is a period during which opinionsare being formed by clinicians as to the potential range of



usefulness (i.e., the extent of indications for the product) forthe product being evaluated.

Once this product is approved, it becomes difficult forphysicians to limit their prescribing of the product only forapproved indications if, in fact, they are under the impres-sion that the drug is useful for other purposes due to thepreapproval promotion for the product.

The FDA has indicated that an unapproved product oruse can be promoted at independent scientific symposia andscientific exhibits. But the materials developed from the sym-posia may not be used in preapproval promotion campaigns.

22.4. Advertising for Investigational Products

FDA ‘‘specifically prohibits any claims of safety or efficacy forthe product being researched, or any claims that the productis equivalent or superior to another—such claims would violateFDA regulations concerning promotion of investigationaldrugs’’ (22). An FDA policy on the subject explains thatInstitutional Review Boards (IRBs) are responsible for review-ing how research subjects are selected. It also indicates that theclinical investigators may use advertising to attract researchsubjects, but an IRB should approve such advertising. FDAconsiders the IRB review to be necessary in order to ensurethat the request for participants is not misleading to subjects,especially in those circumstances in which a study will involvepersons with acute or severe physical or mental illness orpersons who are economically or educationally disadvantaged.

22.5. Promoting to Formularies

Due to the industry’s increasing promotion to managed caregroups, hospitals, and formularies, FDA presented a guidanceconcerning the promotion of products to drug formularies.FDA indicated that it considers all formulary informationalmaterial or kits to be promotional labeling. As such, the formu-lary informational kits are considered by FDA to be anymaterials prepared for review by pharmaceutic and therapeuticcommittees, etc., that review a regulated product and are pre-pared for and disseminated to hospitals, managed health-care

634 Glassman et al.


organizations, buying groups, and other institutions. However,formulary informational material kits are exempt from theFDA submission requirement if they are prepared in responseto unsolicited requests for information. In addition, ‘‘Under theFDA Modernization Act of 1997, pharmacoeconomic informa-tion provided to a formulary committee will not be consideredfalse or misleading if the information ‘directly relates to’ anapproved indication for the drug and is based on competentand reliable scientific evidence’’ (23).

23. DIRECT-TO-CONSUMER ADVERTISING

Direct-to-consumer (DTC) advertising has had an immenseimpact on the increased prescription of drugs. Many considerDTC advertising to be a prime mover in increasing the volumeof drugs used in the United States. In a study conducted bythe National Institute for Health Care Management, it wasreported that the increases in sales for the 50 drugs that weremost heavily advertised to consumers accounted for almost halfof the multibillion dollar increase in drug spending (24). DTCadvertising seems almost like the genie that regulatory groupsfind a need to contain.

FDA has been opposed to DTC advertising of prescriptiondrugs since its inception but DTC advertising remains legalas long as it fully complies with all of the FDA regulationsapplicable to prescription drug advertising and any relevantlaws or regulations enforced by other federal authorities, suchas the FTC. According to FDA, DTC advertising consists ofany materials that are intended by the manufacturer to beseen or used by a consumer, such as traditional product printand electronic advertisements, computer e-mails or websites,videotapes, cassettes, pamphlets, brochures, and other printedmaterials.

Because of FDA’s earlier negative attitude to DTC adver-tising, it was not expected that this promotional medium wouldthrive. However, the future of DTC advertising was changed in1982 when FDA Commissioner Albert Hull Hayes, Jr. predic-ted that this country ‘‘may be on the brink of the exponential



growth . . . of direct-to-consumer promotion of prescriptionproducts’’ (25).

After seeking a voluntary moratorium on DTC adver-tising in 1983, the moratorium was lifted by FDA in 1985.Though it did not encourage DTC advertising, FDA permittedsuch advertising as long as it met all the requirements of thelabeling and advertising requirements.

Of interest is the fact that the initial results from anFDA 2002 consumer survey, released at the April 2002 DTCNational Conference in Boston, appear to justify continuedFDA support for DTC advertising. Eighty-one percent of theconsumers surveyed by FDA indicated that they had seena drug ad in the past 3 months (26). Even former FDA Com-missioner David Kessler, who spent years at the FDA rejectingstaff requests that he allow regulations to be changed to permitDTC advertising, admitted that he was wrong in adhering tothat position (27).

However, U.S. physicians continue to indicate that theydo not like DTC advertising by pharmaceutical companies.More than 46% of the physicians surveyed stated that DTCadvertising negatively affects their impression of the drug com-panies that sponsor this promotion. Contrary to these findings,the sixth biennial Scott-Levin Pharmaceutical Company Image2002 study showed that DTC-promoting companies enjoy highesteem by physicians (28).

24. FDA POLICY ON DTC ADVERTISING

The following provides general guidelines to DTC advertisingas provided by FDA:

1. Those DTC ads that meet the requirements of remin-der and/or help-seeking promotions can be sponsoredby pharmaceutical companies. But such ads should bedesigned to be educational rather than promotionaland deliver the basic message to ‘‘see your doctor.’’

2. Those ads that mention specific products are allowed,but must meet every condition that applies to

636 Glassman et al.


prescription drug advertising directed at physicians.This includes the appearance of information thatis contained in the product package insert. A fairbalance of product information is expected.

3. Those DTC ads that have been defined to includematerials, such as product brochures, that may alsobe regarded as labeling may be voluntarily submittedto FDA for clearance in advance of their use.

4. Though FDA may clear a voluntarily submitted DTCadvertisement, the agency may take regulatory actionfollowing the ad’s appearance if it considers it to bemisleading in some manner.

5. DTC ads or other promotional materials mustnot indicate that only physicians can pre-scribe prescription drugs, because there aremany instances in which nurse practitioners andphysician assistants may also prescribe such drugs.

6. The FDA, whose officers continue to object toDTC advertising in principle, expresses concern overbroadcast DTC ads. Those broadcast advertise-ments that include a major statement of the drug’scritical risk information, present all of the product’sindications and contraindications in consumer-friendly language, and are not false or misleadingmay fulfill the FDA’s adequate provision require-ments (29).

What the FDA guidance outlines is a single method ofadequate information provision, namely:

1. A toll-free telephone number. This should provide theconsumer with several options, such as: the full pack-age insert mailed to them, the full package labelingsent over Internet electronic media. Each should beprovided to the consumer in a timely manner.

2. Reference to a print ad or brochures that arepublicly available.

3. A statement that indicates that physicians and/orpharmacists may serve as another source ofinformation.



4. An address on the Internet that directs consumersto the approved package labeling.

The FDA mechanisms described will satisfy this adequateinformation provision requirement, but pharmaceutical com-panies may use an alternative approach if it satisfies theregulatory requirements.

25. ADVERTISING ON THE INTERNET

The growth of consumer interest in health-care information onthe Internet has been phenomenal. Even a few years ago, some70 million Americans searched the web for information on suchsubjects as diseases, nutrition, pharmaceuticals, and relatedtopics, and this use is growing (30). Now consumers canobtain more information from the Internet about drugs thanthey can get from their health providers. As a result, pharma-ceutical companies have substantially increased their use ofthe Internet as a vehicle for marketing to consumers and themedical profession.

The interest of physicians in health information onthe Internet seems to be moving hand-in-hand with that ofconsumers who view their respective physicians as the mostvaluable source of this information. A recent study indi-cates that physician demand for e-detailing is significant andgrowing: ‘‘Eighty-one percent of the physicians surveyedthink it’s a good idea to have access to this type of informationwhen and where it is convenient’’ (31). It must also be pointedout that many companies provide physician monetary hono-rariums for the time spent by physicians during e-detailing.

Because of the extremely rapid growth of consumer andphysician interest in health information on the Internet plusthe growing use of this vehicle for marketing promotion by thepharmaceutical industry, DDMAC has been designated to serveas an agency-wide working group to draft policy on marketingand advertising/promotion on the Internet (32). Thus, FDAwill issue a document that provides the drug companies withthis guidance in the near future.

638 Glassman et al.


26. NONTRADITIONAL PROMOTION—FDAPOLICIES

For a substantial number of years, pharmaceutical firms adver-tised and promoted their products primarily through journaladvertising, direct mail, detailing by sales representativessampling, and hospital exhibits. However, due to the adventof newer communications technologies, an increased level ofconsumers of health care, and greater competition within theindustry, many new ways to promote products have beenconsidered and adopted (33). These newer methods of productpromotion include: medical symposia, public relations tech-niques, greater use of single-sponsor publications, an increaseduse of electronic media, plus responses to unsolicited requestsfor promotional information. As a result, FDA has adapted exis-ting, traditional policies to cover these new communicationsvehicles.

Such FDA policies on nontraditional promotion arenot written in a single document but, rather, are learned andunderstood by the regulated industry through various means,such as Warning Letters, policy announcements, the issuanceof guidance documents, or by similar means. Fairness in deal-ing with these issues has been the FDA policy. These policiesare briefly explored in the following.

26.1. Educational and Scientific Events

FDA’s final guidance on industry-sponsored scientific and edu-cational activities was issued in December 1997. This applies toall FDA-regulated medical products, including prescriptionmedicines. Essentially, this FDA policy states that all suchactivities that are controlled or substantially influenced bycompanies must meet all of the traditional FDA requirementsfor marketing and advertising/promotion labeling, such as fulldisclosure and fair balance (34).

What has concerned the FDA about company-sponsoredactivities is that the companies may influence the contentof educational programs by being involved in the selectionof speakers and the direction of the content of the activities.



FDA also indicated that it would focus intense scrutiny on anydiscussion of unapproved uses of marketed products.

In an earlier guidance, DDMAC stated that materialsdeveloped from symposia could not be used in preapprovalpromotion campaigns. DDMAC also noted that, in conductingscientific exhibits, the information about unapproved drugs canbe displayed if the exhibit is clearly separated from commercialexhibit areas, are staffed by scientific personnel only, and haveno commercial materials for distribution.

Concerning the dissemination of scientific reprints,DDMAC indicated that pharmaceutical companies may dis-tribute an article about an approved product as long as itsprincipal focus is on FDA-approved uses or indications and ispublished in a reputable peer-review journal. In all of thoseinstances, the companies must use promotion informationin the reference text that is consistent with the product’sapproved labeling.

26.2. Public Relations Materials

FDA considers product-specific public relations materials aslabeling if it is included in press releases, kits, or background-ers and used with the media. It thus requires that all suchmaterials be fairly balanced, containing both the positive find-ings and uses of the product plus a fair representation ofthe warnings, side effects, and common adverse reactionsassociated with the product’s use.

FDA has no formal requirement that public relationsmaterial for drugs be submitted to the agency for review.However, if a significant drug is about to be approved byFDA, the agency often requests the materials for review.If the pharmaceutical company concerned decides to ignorethe agency’s comments on the materials, it does so at its ownrisk.

When a company plans to make a major public announce-ment about a drug, it is normally a good idea for the companyto provide the press materials to the FDA Office of PublicAffairs, plus the appropriate office within CDER (35).

640 Glassman et al.


26.3. Drug Sampling

The use of samples as an effective part of the marketing/pro-motion effort has become a point of contention in recent yearsand deserves each company’s close attention relativeto effective promotion versus violations of intended use inpromotion. The use of drug samples to physicians by companysales representatives, or through the mail, is controlled bythe Prescription Drug Marketing Act of 1987 (PDMA).

Under PDMA, physicians must request samples in writingand include the name, address, professional designation,and signature of the practitioner who makes the request. Theidentity and quantity of the sample requested must also beprovided, plus the name of the manufacturer and the date (36).This law was passed in order to correct alleged abuses suchas diverting the samples into channels where the drug couldbe sold. FDA has indicated that decades of sampling abuseshave resulted in the sale of misbranded, expired, and adulter-ated pharmaceuticals to consumers.

The matter of sample abuse in promotion has becomesuch an urgent issue to the FDA that in the October 3, 2002,issue of the Federal Register, the Office of the InspectorGeneral (OIG), Department of Health and Human Servicesstated: ‘‘The provision of drug samples is a widespread indus-try practice that can benefit patients, but can also be anarea of potential risk to the pharmaceutical manufacturer . . .PDMA. . . . The Prescription Drug Marketing Act of 1987governs the distribution of samples and forbids their sale.A drug sample . . . is intended to promote the sale of thedrug’’ (37).

A case in point was the situation in which the FDA’sOffice of Criminal Investigation and other law enforcementagencies charged a former pharmaceutical sales represen-tative with ‘‘failing to comply with federal regulations govern-ing distribution of free drug samples to physicians. Thesales representative allegedly provided samples of a steroidproduct used in the treatment of prostate cancer to urologistswho had not provided a written request for the samples asrequired by law. Apparently, the sales representative was



instructed by the district manager and other company offi-cials to use the samples as a tool to help obtain sales of thedrug’’ (38).

This issue is so critical that all drug manufacturers havebeen urged by their trade associations to closely follow PDMArequirements including all documentation that is required.The Pharmaceutical Research and Manufacturers Association(PhRMA), in the July 1, 2002, New Marketing Code indicatedthat product samples should be provided for patient use inaccordance with the Prescription Drug Marketing Act. It isquite clear to marketing executives that product samples aredesigned as an integral part of promotion to physicians, to beused as ‘‘starters’’ for patients being treated. The industry isin full agreement that abusive uses of product samples shouldnever be tolerated.

However, the current usage of samples, as mandated byFDA, has substantially increased sampling costs as part of themarketing budget for promoting each product. And yet theredo not appear to be any controls on how the physicians (whorequest samples) actually use the product samples. It is likelythat sample distribution by pharmaceutical companies andsampling dispensing to patients by doctors will be clearly main-tained and new laws/guidelines to previous abuses will bepassed.

26.4. Single-Sponsor Publications

‘‘Because the FDA regulates only materials sponsored byFDA-regulated companies, there is a question about whetheror not publications by independent publishers can be regulated,regardless of company influence’’ (41).

There has been much controversy and misunderstand-ing concerning single-sponsor publications financed by phar-maceutical firms because these publications often involveparties, such as organizations that sponsor continuing medicaleducation programs, or medical journals that publish thesedocuments as supplements.

Single-sponsor publications, including product mono-graphs, are closely monitored by the CDER because there

642 Glassman et al.


is the potential that such publications can be clearly influ-enced by companies that want to promote unapproved productindications. In general, FDA regards the publication as label-ing, and thus the publication must accurately portray the usesof the drug concerned and provide the traditional fair balance.In other words, FDA believes that simply because a medicaljournal or other commercial publication is involved in a single-sponsor publication, the sponsoring company is not relievedof regulatory responsibility.

26.5. Company Representatives—Drug-Detailing Activities

This is most companies’ strongest form of promotion andone that is always under the focus of FDA. FDA considersall of the materials utilized by drug sales representativesas subject to the advertising/promotion regulations. There-fore, during a product’s preapproval stage, sales representa-tives may not provide physicians with materials aboutproduct indications or information that is not yet approved.

Often the question arises as to whether or not drug salesrepresentatives are permitted to provide physicians withpublished clinical studies that appear in peer-approved medicaljournals. The FDA’s position is that if it concerns an approvedindication for the product, it can be provided to the medicalprofession. However, if an unapproved product indication isdiscussed in the article (i.e., for a marketed product or duringthe preapproved stage), the article may not be given to physi-cians at that time. An exception to this position would be theinstance in which the physician requests the article fromthe representative. It may then be provided, but FDA prefersthat such requests be handled by the medical department ofthe company concerned.

Verbal statements made by sales representatives tophysicians about their products are also subject to FDA regu-lation but are virtually impossible for the FDA to monitor.An enforcement action by the FDA against a drug companyin this area has not occurred.



26.6. Exhibits

Exhibits for drugs at medical meetings and conventions havebecome an increasingly popular part of the product’s/company’soverall promotion efforts. Thus, FDA considers all such materi-als used at these medical meetings to be subject to all of themarketing and advertising/promotion regulations for prescrip-tion drugs. Even the text of materials that are displayed atexhibits must meet FDA advertising/promotion regulations.

Because of FDA oversight, pharmaceutical companiesneed to pay as close attention to exhibit materials as theydo to other regulated materials, such as print advertisements.Exhibits that present drugs during the preapproval stage willbe considered violative by FDA if the materials mention aspecific product indication. The same would apply to an exhibitthat mentioned an unapproved indication for an approved drug.

The pharmaceutical industry also has been reminded byFDA that all text for program books used at professional meet-ings must meet pharmaceutical advertising regulations for fulldisclosure if the company descriptions contain informationabout the drug indications or usage.

26.7. Responding to Requests for Information

Generally, DDMAC has assured the industry that their indi-vidual, nonpromotional responses to unsolicited requests forinformation will not be considered promotional labeling ifeach firm maintains documentation concerning the natureof the requests and shows no pattern that suggests thatthese requests were solicited by the sponsor (i.e., the firm).DDMAC further notes that the use of toll-free telephonenumbers disclosed in promotional labeling or advertising,which invite or somehow prompt requests for information,are considered to be forms of solicitation and thus are subjectto all advertising and labeling requirements.

26.8. FDA Policies for Broadcast Media

The informal FDA policy regarding the use of broadcastmedia in promotion is one guidance provided to the industry.

644 Glassman et al.


If changes in broadcast advertising are required, FDA notifiesthe companies directly by letter and, subsequently, releases thechanges required to the trade press.

When it was decided that all video new releases should beroutinely submitted to FDA at the time of first use, this changein policy was communicated directly in a letter to all holdersof approved new drug applications (NDAs) and abbreviatednew drug applications (ANDAs). This information was alsoprovided to the trade press for dissemination.

26.9. FDA Criteria for Advertising Electronically

Policies were developed by FDA, over a number of years,concerning physician-oriented television advertising that isproduct specific. Such advertising, now, must refer, in theadvertisement, to the page in the Physicians’ Desk Reference(PDR) or PDR Supplement that contains full product prescrib-ing information. The network concerned must also providea toll-free telephone number that the viewers can call to heara reading of the brief summary package insert for the product.In addition, FDA requires that the product generic name mustbe used in the ad and that fair balance must be included in thebody of the advertisement, including major product warnings,side effects, adverse reactions, etc.

Further, for products required to carry special warnings(i.e., PI Back Box Warnings), information must be provided inthe audio portion of the ad. The FDA was concerned that phy-sicians not receive confusing or contradictory messages in anyvideo broadcast advertisements that might obscure or under-mine important product warning information (40).

26.10. FDA Policy on Video News Releases

Health-related stories on television are among the most com-pelling subjects for the TV viewers and, as such, are attractiveto pharmaceutical companies via video news releases (VNRs).VNRs can be used by TV stations in a manner that makes themseem to be original segments produced by the TV stations.A variant, called a ‘‘B-roll,’’ is a video that contains raw footageof the manufacturing process, interviews, animations, or other



information but not put together in a finished news segmentform.

Though specific rules for VNRs have not been set forth,FDA did issue a letter to all holders of NDAs and ANDAsthat they submit the following when the VNR is productoriented:

1. The VNR source or sponsor should be made clearto the TV station.

2. All product information or references should bewithin the approved labeling for the product.

3. When a specific product is mentioned, there shouldbe a ‘‘fair balance.’’ In other words, the major warn-ings, adverse reactions, and side effects related tothe product should be mentioned.

4. Normally, a product package insert should accom-pany the VNR. If the VNR is sent by satellite,a scroll of the package insert should be included.

5. For a product that is the subject of an NDAor ANDA, the VNR should be submitted to CDERwhen it is initially issued or disseminated. Thisincludes accompanying information issued at thesame time, i.e., letters, scripts, press releases, andpackage inserts (41).

Though there has been some controversy over the use ofVNRs, ‘‘Pharmaceutical companies . . . have become enamoredwith the VNR because it allows them to circumvent the usualrestrictions concerning the use of television advertising to pro-mote their prescription products directly to the consumer’’(42). However, FDA has treated VNRs the same as it treatswritten press releases. The VNR is treated as labeling whenspecific products are mentioned and requires fair balance,discussing not just the product benefits, but also the majorrisks of the drug.

26.11. Infomercials

Infomercials are extended advertisements used on commercialand cable television. They may appear in the format of an

646 Glassman et al.


entertainment or television show and have not been commonlyused to promote prescription medicines to consumers.

Though the FDA does not have a specific written policyon infomercials, they are regarded as advertisements that aresubject to established advertising and labeling regulations. Tothe extent that an infomercial mentions a drug or treatment,it must meet all disclosure and fair balance requirements.

26.12. Radio-Television Media Tours and theUse of Celebrities

When a pharmaceutical firm sponsors a radio-television inter-view tour, FDA considers any product-specific content ofthe interview to be subject to regulations. This applies even ifthe spokesman concerned is not employed by the pharmaceu-tical firm. It has been especially concerned when celebritiesappear on such tours. Though there are no FDA regulationsprohibiting either the use of celebrities to endorse prescriptiondrugs or the use of radio-TV tours with paid spokespeople, itsexpressed concern has served to discourage the use of celebri-ties and product-specific radio-TV tours in general.

FDA believes that firms that hire spokespersons, or usetheir employees in this role, should train them to keep theirpromotional statements in line with the product’s approvedlabeling or to provide the perspective necessary to assure fairbalance for the product.

26.13. Guidelines for Advertising toPhysicians on Radio

Concerning the advertising of prescription drugs on radio,FDA does not object as long as the product advertisementscontain clear information about the product’s side effects andcontraindications and provide a balanced presentation of thebenefits as well as the risks of the drugs promoted.

26.14. Telephone Advertising

Communications by telephone that discuss prescription medi-cines are considered by FDA to be subject to the same require-ments as for broadcast advertising. Those pharmaceutical



firms that decide to disseminate product information to health-care professionals or consumers via a toll-free telephonenumber must include a major statement that provides informa-tion about product side effects, warnings, precautions andcontraindications before the listener can branch off to othersegments of the telephone presentation. Just as with allprescription medicine advertisements, copies of the telephonerecordings and scripts must be submitted to DDMAC at thetime of initial use.

27. CHANGING IMPACT OF FDA CONTROLS

Though the FDA was charged with the responsibility to regu-late drug promotion throughout the years of its existence, itbegan to exert strong enforcement of the requlations in the late1980s. It had an especially strong concern about the level ofmisleading promotion. This level of concern has focused onwhat the FDA considers exaggerations of claims, especiallynewly approved claims.

For example, a pharmaceutical corporation was stronglywarned by DDMAC concerning its cholesterol-lowering productDTC ad that appeared in major magazines and mistakenlysuggested that this product lacked the side effects of othermembers of the same class. DDMAC stated a concern abouta ‘‘continuing pattern and practice of violative behavior.’’The company pulled the misleading ad. Several other pharma-ceutical companies have been forced to correct promotionsconsidered to be misleading by DDMAC (43).

Increased pressure continues on FDA from externalgroups, while the U.S. Congress has and continues to exertsignificant pressure on the FDA to strictly enforce marketingand advertising/promotion regulations.

Of added significance, the Office of Inspector General, ina new HHS draft guidance published in the October 3, 2002,Federal Register (44), indicated that drug companies shouldexpect prosecution or other action if they do not change someof the ways that they market prescription drugs, including the

648 Glassman et al.


giving of gifts, grants, and scholarships to physicians andhealth-care providers in exchange for help in promoting theirproducts. The OIG went to the extent of strongly recom-mending that pharmaceutical manufacturers should designatea compliance officer to serve as the point person to overseethese compliance activities.

Throughout all of its regulating activities over the years,FDA has expressed concern that there should always be a fairbalance in a company’s claims for the efficacy of its productsand its indication of the potential adverse reactions associatedwith each product’s usage. This applies to product labels,brochures, booklets, ads, mailing pieces, etc.

It has appeared that the FDA would like to increase itsregulatory authority, but potential future trends may put somelimits on its ambitions in this regard.

28. POSSIBLE FUTURE FDA REGULATORYACTIVITIES

It is doubtful that many would challenge the benefits associ-ated with FDA’s efforts, over the years, to determine that drugmanufacturers, in their efforts to market and promote theirproducts, present to the health profession and the consumera fair balance as to the efficacy and relative safety of theirrespective products. FDA controls and surveillances in thisarea have increased year by year, and the overall impact ofFDA on drug companies’ marketing and advertising/promo-tion activities will continue in the future. However, recenthappenings have begun to slow the overall regulatory effortsof the FDA relative to drug marketing and advertising/promotion activities.

In November 2001, the Bush administration’s new leader-ship in the Department of Health and Human Servicesreleased an unprecedented directive that the FDA’s ‘‘warning’’and ‘‘untitled’’ letters to the pharmaceutical industry must firstbe cleared with the new FDA chief counsel, Daniel E. Troy.This was implemented because there were so many people



and offices that could issue Warning Letters that they had losttheir overall desired impact on the industry (45).

Much concern has been brought forth that the directivewould have a chilling effect on the FDA’s ‘‘watchdog’’ activ-ities. The HHS, however, indicated that it is expecting theFDA, as a result of the directive, to set forth priorities andenforce those priorities with a much improved effectivenessfor their ‘‘Warning Letters.’’

Another development that has truly shaken the FDAis the Supreme Court Ruling in Western States v. Shalala,which endorsed the lower courts’ criticisms of the FDA culture.Basically, it said that the FDA’s DDMAC ‘‘. . . had no business,even with encouragement from the FDA Modernization Act of1997, trying to curb the free speech of compounding pharma-cists advertising their services’’ (46). Several legal decisionshave indicated that the FDA has been too accustomed togetting its own way in challenging hundreds of industry adsand other promotional pieces and has not paid enough defer-ence to the First Amendment.

Shaken by these decisions, FDA has begun to seek inputfrom the public as to how it should balance statutory respon-sibilities with First Amendment obligations. Some of the inputsought is whether certain promotional speeches about medi-cines is inherently misleading unless it complies with FDArequirements; whether its current DTC advertising policyis consistent with the effects of such ads or leads to overpre-scribing; whether product disclaimers should have the sametype size as its claims; and whether off-label promotionsundermine the approval authority of the FDA. Meanwhile,FDA’s ‘‘old guard’’ has started to argue, internally, that theSupreme Court decision threatens its control over what issaid about product effectiveness, thus allowing broadenedproduct claims.

However, a positive move by FDA has already taken place.The CDER released an article entitled ‘‘Think It Through:A Guide to Managing the Benefits and Risks of Medicines,’’which reminds consumers of the benefits and risks associatedwith different drugs and provides helpful tips designed to mini-mize the potential risk of drug use (47).

650 Glassman et al.


FDA is quite concerned that its authority will be under-mined ‘‘. . . if unapproved products can be promoted, or newuses of approved products can be promoted without FDAapproval’’ because it believes that neither consumers orphysicians can properly evaluate information about what areextremely complex products that it regulates (48). However,the courts believe that, if a drug is lawfully marketed followingits initial approval, physicians can legally prescribe productsfor off-label uses as they have access to the information onthose uses. How this matter will ultimately be resolved is notat all clear.

FDA must follow the mood of the courts, but the phar-maceutical industry has lost some of its luster due to pricingdisclosures, some related scandals, and the general publicdisenchantment with overall corporate ethics. FDA will likelyrelax its regulatory activities, but should some health acci-dents occur due to the decision of the courts, then the regu-latory pendulum will, undoubtedly, swing back in theagency’s direction. Only time will tell if and what regulatorychanges will occur and the degree to which FDA’s regulatorycontrols of drug marketing and advertising/promotion willincrease.

REFERENCES

1. Chronology of Drug Regulation in the United States: US FDA,Center for Drug Evaluation and Research’s,

2. Ibid, p. 4.

3. Patrick, W., Know Your Government—The Food and DrugAdministration, Chelsea House Publishers, 1988, p. 16.

4. Chronology of drug regulation in the United States: U.S. FDA,

5. Ibid, p. 10.

6. Ibid, p. 12.


Center for Drug Evaluation and Research, www.fda.gov/CDER/

www.fda.gov/CDER/about/history.htm. 2002, p. 1.

about/history.htm, 2000, p. 7.


http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

http://www.fda.gov

7. FDA advertising and marketing promotion manual, June 1998,p. 5.

8. Ibid, pp. 13–14.

9. FDA advertising and marketing promotion manual, October1999, p. 21.

10. FDA advertising and marketing promotion manual, October1993, p. 15.

11. FDA advertising and marketing promotion manual, March1997, p. 23.

12. Ibid, p. 25.

13. Ibid, p. 29.

14. FDA advertising and marketing promotion manual, May 1993,p. 39.

15. Ibid, p. 7.

16. Ibid, p. 7.

17. Ibid, pp. 7–8.

18. FDA advertising and marketing promotion manual, May 1997,p. 17.

19. FDA advertising and marketing promotion manual, September1997, p. 19.

20. Ibid, pp. 19–20.

21. FDA advertising and marketing promotion manual, August1994, p. 33.

22. FDA advertising and marketing promotion manual, August1997, p. 35.


24. Liebman, M., Drug industry is a winner, Medical Marketing &Media, January 2002, p. 50.

25. FDA advertising and marketing promotion manual, November1997, p. 46.

26. Dickinson, J., DTC Report—FDA Survey Data Supports DTC,June 2002, p. 32.

652 Glassman et al.


27. Ibid, p. 32.

28. Dickinson, J., DTC Report—physicians turned off by DTC ad,Medical Marketing & Media, September 2002, p. 40.


30. Mack, J., You have a brochure on the web. Now what?Pharmaceutical Executive Supplement, March 2000, pp. 16–18.

31. Dickinson, J., DTC report—E-detailing gaining acceptanceamong physicians, Medical Marketing & Media, September2002, p. 10.


33. Ibid, p. 55.

34. Ibid, pp. 55–56.

35. FDA advertising and marketing promotion manual, December1996, p. 59.

36. Ibid, pp. 62–63.

37. Federal Register, Vol. 67, No. 192, October 3, 2002, Notices,62063.

38. FDA charges TAP sales rep., Medical Marketing & Media,September 2002, p. 31.

39. FDA advertising and marketing promotion manual, December1996, p. 61.


41. Ibid, p. 73.

42. Ibid, p. 74.

43. Liebman, M., Industry update—FDA keeps up the pressure,issues repeat ad warnings, Medical Marketing & Media,October 2002, p. 18.

44. Federal Register, Vol. 67, No. 192, October 3, 2002, Notices,62063.



45. Dickinson, J., As I see it—Bush reviews FDA letters to indus-try, Medical Marketing & Media, January 2002, p. 14.

46. Dickinson, J., As I see it—Supreme Court trims DDMAC’s,Medical Marketing & Media, July 2002, p. 14.

47. FDA advises on drug benefits, risks, Medical Marketing &Media, October 2002, p. 32.

48. Castagnoli, W., Rx marketing regulations hang on firstamendment debate, Medical Marketing & Media, September2002, p. 88.

654 Glassman et al.


21

Approval and Marketing ofNonprescription or OTC

Human Drugs

WILLIAM J. MEAD

Consultant

Rowayton, Connecticut, U.S.A.

1. DEFINITION OF OVER-THE-COUNTERDRUG PRODUCTS

Prior to the advent of the 1938 Food, Drug and Cosmetic Act(FD&C Act), technically all drugs could be marketed withouta prescription. After passage of the Act, the U.S. Food andDrug Administration (FDA) decided on a case-by-case basiswhich drugs were to be considered prescription only andwhich could be sold over the counter (OTC), since the FD&CAct was silent on this matter. The usual key criterion used in

655


this decision-making process was whether or not adequatedirections for safe use existed for the products in question.

The 1951 the Durham-Humphrey amendments to theFD&C Act addressed this issue head-on for the first timein what is now Section 503(b)(1) of the Act, saying that adrug requires a prescription if (a) it is one of certain habit-forming drugs, (b) it is not safe for use except under competentprofessional supervision due to its toxicity, potential harmfuleffects, or method of use, or (c) it is specifically limited to pre-scription status by an approved New Drug Application (NDA).Thus, drug products (except as specified above) are nonpre-scription unless they require the supervision of a licensed prac-titioner for safe use. In other words, prescription status is byexception: if a drug product can be OTC, it must be OTC. It isobviously the second of the above categories that usually deter-mines whether a drug should be considered for OTC status.

FDA has a mandate from Congress to protect the publichealth (1). FDA also has the responsibility for publishing regu-lations or policy guidances to implement what the FD&CAct requires, including standards for safety, effectiveness,benefit/risk considerations, and labeling for OTC products.These standards now appear in x330.10(a)(4) of Title 21 of theCode of Federal Regulations. It is largely up to the judgment ofFDA whether a drug product meets these standards.

Safety for OTC use means a low incidence of adverse reac-tions or significant side effects under adequate directions foruse and warnings against unsafe use, as well as low potentialfor harm, which may result from abuse under conditionsof widespread availability. Effectiveness means a reasonableexpectation that when the drug is used by consumers withadequate directions and warnings, the product will provideclinically significant relief of the type claimed in the labelingfor a significant proportion of the consumers who use it. Thebenefit-to-risk ratio takes into account the benefits providedby the product versus the risks or safety problems that maybe involved with its use. FDA recognizes that while no drugcan be considered totally safe, an OTC product must havesufficient benefits to justify whatever risks are likely to beconnected with its proper use.

656 Mead


The labeling of OTC drug products must be clear andunderstandable and must be truthful in all respects withoutbeing false or misleading in any particular. The labeling mustcontain adequate directions for proper use as well as warningsagainst unsafe use, side effects, and adverse reactions. Thesemust be in terms that make them likely to be read and under-stood by ordinary individuals (including individuals withlow comprehension), under customary conditions of purchaseand use. Label comprehension studies typically constitute animportant facet of the decisions involved in allowing drugproducts to be sold without a prescription. The essential goalis to provide information to enable consumers to safely self-medicate without the intervention of a health professional.

It is assumed that the consuming public can recognizeand self-diagnose the conditions being treated and can alsosatisfactorily manage self-treatment without medical super-vision. This is usually relatively simple in that most OTCsare aimed simply at treating readily recognizable symp-toms of minor discomfort, illness, or injury, such as itching,upset stomach, headache or muscle pain, or cold symptoms.Moreover, the use of an OTC drug does not necessarily meanthat medical professionals are totally out of the picture, as itis not unusual for the initial diagnosis of the condition to bemade by a physician. An example is vaginal yeast infections,not infrequently first diagnosed by a health-care professionaland then self-medicated with an OTC product.

2. REASONS FOR INTEREST INNONPRESCRIPTION DRUGS

From the consumer’s point of view, there are definite moti-vations to use OTCs when such exist as an alternative toprescription drugs. Importantly, there is usually a significantmonetary advantage to the consumer since OTCs are con-siderably less expensive than prescription drugs. Studiesconducted for the trade association for health-care productmanufacturers have confirmed the substantial savings for

Nonprescription or OTC Human Drugs 657


consumers through the use of nonprescription medicines (2).Moreover, the convenience factor, less lost work time, andthe costs saved by not needing to visit a doctor are importantconsiderations. The expanding availability of OTC drugs is alsoa particular boon to low-income and uninsured people (3).

There is a growing sophistication and self-relianceamong consumers, with increasing interest in and knowledgeabout appropriate self-medication. Health-related issues getconsiderable media attention these days, so that consumerstoday tend to be considerably more aware of the appropriateavenues of self-treatment than in previous times. Moreover,many other countries also allow certain drug products to besold OTC that are presently marketed on a prescription-onlybasis in the United States, which necessarily puts some pres-sure on considerations of domestic prescription-to-OTC switchinitiatives (4). Older adults in particular tend to experienceincreased minor medical problems, such as arthritis, sleep-ing difficulties, muscle aches and pains, headaches and colds,so that as the population ages, the demand for nonprescriptiondrugs is escalating (5).

From the manufacturers’ point of view, the increasedsales of nonprescription medicines have tended to enhancecorporate revenue and profitability. Moreover, as older pre-scription drugs are losing patent protection, at least some ofthe lost revenue can be recouped by offering OTC versions ofthe products through life-cycle product management. In otherwords, nonprescription drug products can be good businessfor the manufacturer.

From the health professional’s point of view, particularlyin this age of managed care where medical practitionersoften have an increased patient load, individuals with minorailments and certain chronic conditions (e.g., migraines, vagi-nal yeast infections, allergies, etc.) can often handle their owncare through responsible self-medication with OTCs, giving thehealth professionals additional time and availability for attend-ing to more serious medical cases. Companies offering health-care insurance encourage OTC self-medication by patients as acost-containment strategy to reduce the more costly compensa-tion of higher priced prescription products (6).

658 Mead


Actual use studies of switched products indicate that con-sumers do use OTCs carefully and responsibly. Most do readand understand the information on OTC labels and are alertto the possible signs of tampering (7). Research has also indi-cated that OTC advertising does not exacerbate the problem ofdrug abuse as was once feared might be the case (8). Therefore,there are essentially no negative aspects to the current empha-sis on the increased use of nonprescription drugs, providedthe products meet the safety and effectiveness criteria for‘‘OTCness’’ (9). Thus, from all points of view—consumers,drug manufacturers, health-care professionals, and medicalinsurance carriers—there is indeed a growing interest in OTCdrugs.

3. ROUTES TO FDA APPROVAL OF OTCs

3.1. The OTC Review

The 1938 FD&C Act for the first time required premarketingapproval of any drug product meeting the Act’s definition of a‘‘new drug.’’ But, prior to the 1962 Kefauver-Harris amend-ments, it was only necessary to establish the safety of drug pro-ducts (prescription or OTC), not the efficacy. When the efficacyrequirement was added, all drug products (existing items as wellas new products) were required to be proved effective. This was,of course, a tremendous task facing FDA. At that point in timethere were literally hundreds of thousands of drug products onthe market that had to be retroactively evaluated.

Obviously FDA had to prioritize determining which prod-ucts were indeed effective. In 1968 they established what wascalled the Drug Efficacy Study Implementation (DESI) toestablish the effectiveness of those products originally mar-keted under approved New Drug Applications (NDAs) betweenthe time of passage of the 1938 Act and the 1962 amendments.Lacking the staff and facilities to undertake this, FDA contrac-ted the task to the National Academy of Sciences/NationalResearch Council (NAS-NRC) to study data submitted bymanu-facturers as well as published literature, and then to makerecommendations to FDA. This was accomplished by class or



therapeutic category, using panels of experts. FDA then madethe final decisions as to which products were and which werenot considered to be sufficiently effective. Those failing topass muster were ordered removed from the market. In manyinstances, manufacturers of products deemed not efficaciousstrongly disagreed, resulting in considerable litigation. Whilemost of the products in the DESI review were prescriptiondrugs, more than 400 OTC products for which there wereapproved NDAs were considered. The final DESI conclusionson those OTCs appeared in the Federal Register of April 20,1972.

Following the DESI review, FDA was faced with a similarretrospective review of literally hundreds of thousands ofexisting OTC drugs for which NDAs had never been submitted.While the 1962 amendments required such a review, they didnot specify any procedures nor timetables for doing so. Therewas consideration of reviewing each product individually, butdue to the immensity of the task it was decided to work insteadby category. The outline of the procedures was published inthe Federal Register of January 5, 1972, with the final detailsspelled out in the Federal Register of May 11, 1972. The pro-cess set forth the conditions under which OTC drugs wouldbe considered to be generally recognized as safe and effective(GRAS/E) as defined in Section 505 of the Act, and not mis-branded. This included labeling that would be neither false normisleading and bearing adequate directions for use togetherwith necessary caution and warning statements.

Again, panels of experts with broad experience in variousspecialties were employed to make recommendations to theFDA. These experts included academicians, clinicians, toxicolo-gists, pharmacists, etc., depending on the kinds of productsbeing reviewed. The panels also included persons representingthe interests of consumers. Their task was to consider andprovide recommendations on acceptable active ingredients ineach condition category, together with allowable quantities,claims, and labeling. Each panel was to prepare and submita report, as to what should be permitted for each classificationof OTC human drugs. The FDA then digested these, consider-ing the medical, scientific, and legal issues, and at intervals

660 Mead


published them in the Federal Register—first in the panel reportas an Advanced Notice of a Proposed Rulemaking (ANPR)to give the public ample opportunity to comment as requiredby the Administrative Procedure Act. Eventually, each ANPRwould progress to republication, first as a Tentative FinalRule (TFR) and then to a Final Rule (FR) or regulation thatwould be codified in the Code of Federal Regulations (CFR) andenforceable as law (10). This has been a very long, drawn-outprocess, and indeed still today has not been fully completed(11). It has been said that no other program in FDA’shistory has been more demanding in its scientific, organiza-tional, and legal requirements. It has embraced about 800active ingredients used for 2300 indications in about 300,000marketed products (counting package sizes, dose forms, dosestrengths, etc.) (12).

The active ingredients considered for each class of prod-ucts were listed as (a) Class I, GRAS/E and suitable for use, (b)Class II, unsafe and/or ineffective and should no longer beallowed in marketed products, and (c) Class III, probably safeand effective, but there are insufficient data available to permitclassification and therefore further testing is needed to estab-lish significant proof (13). FDA eventually decided that severalhundred ingredients in Classes II and III (for specific uses)would be required to be taken off the market until and unlesssufficient proof dictated otherwise (14).

3.2. OTC Monographs

The end result of the OTC Review has been the establishmentof a series of ingredient-by-category monographs that spell outin each Final Rule or regulation precisely what must be doneto legally make and sell an OTC human drug product withoutobtaining an approved NDA.

The OTC drug review system was initially established toevaluate the safety and effectiveness of all OTC drug productsmarketed in the United States before May 11, 1972, (the startof the OTC review) that were not covered by NDAs, as wellas those OTCs that were covered only by ‘‘safety’’ NDAs thatwere marketed before the enactment of the 1962 amendments.



It provided the ongoing framework to establish monographs toenable firms to make and market OTCs without the need andexpense of going through the NDA route. This system for non-prescription drug regulation is based on regulatory standardsfor each category of such drugs.

As implied above, not only are the active ingredients andtheir quantities subject to scrutiny and approval/disapprovalby FDA in establishing the OTC monographs for each prod-uct category, but product labeling is also considered. This isbecause the safety and effectiveness of OTC drug productsdepends not only on the ingredients but also on clear andtruthful labeling that can be readily understood by consumers.

However, the publication of an OTC final monographestablishes standards vis-a-vis ingredients, dosage, indicationsfor use, and certain details of labeling. If a manufacturerfaithfully follows what is spelled out in a given OTC mono-graph and the product is made in full compliance with thecGMP regulations, neither further approvals nor clearancesare required to make and market an OTC product. Obviously,the establishment where the product is made must be regis-tered with FDA, and the product or products must be properlylisted with the FDA.

The approved OTC active ingredients are each specified inthe United States Pharmacopeia (USP) describing the quality,purity, identity, and strength of the article. These monographs,coupled with the OTC monographs and FDA’s inspectionprogram, allow for adequate postmarketing control of OTCdrug product quality.

There are provisions for amending existing monographs(once a Final Regulation has been published for a given cate-gory of OTC drugs) and for the creation of new monographs.In addition, a final rule published in the Federal Register onJanuary 23, 2002, provides procedures where OTCs coveredby NDAs approved after 1972 and OTCs marketed solely ina foreign country can become eligible for inclusion in an OTCmonograph. This is accomplished by submitting a time andextent application (TEA) to show that the product has beenmarketed to a material extent for a material period of time,and then once such an application has been approved,

662 Mead


safety and effectiveness data can be submitted. Details regard-ing TEAs are covered in x330.14.

The OTC monographs are codified in Part 330 of Title 21of the Code of Federal Regulations.

Under 21 CFR x330.5, the following OTC monographshave been or will be promulgated for these categories or classesof products:

(a) Antacids(b) Laxatives(c) Antidiarrheal products(d) Emetics(e) Antiemetics(f) Antiperspirants(g) Sunburn prevention and treatment products(h) Vitamin-mineral products(i) Antimicrobial products(j) Dandruff products(k) Oral hygiene aids(l) Hemorrhoidal products(m) Hemantics(o) Analgesics(p) Sedatives and sleep aids(q) Stimulants(r) Antitussives(s) Allergy treatment products(t) Cold remedies(u) Antirheumatic products(v) Ophthalmic products(w) Contraceptive products(x) Miscellaneous dermatological products(y) Dentifrices and dental products(z) Miscellaneous (all other OTC drugs not falling

within the above categories)

The OTC monograph system provides a relatively straight-forward way to legally bring OTC products to market, andthis system has worked very well for sorting out which exis-ting products are considered safe and effective. However, froma marketing perspective, the OTC Review is essentially a



generic-based system, so that little can be created in the wayof exclusive new products using this route. It is difficult todevelop unique claims for what are essentially ‘‘me too’’ prod-ucts, although some companies have been quite successful inusing the OTC Review strategy, coupled with a positioning asthe scientific leaders in the care of a particular condition.

Technically, a company can petition the FDA to switchspecific ingredients from prescription to OTC status viathe monograph system, but in practice this is seldom done,the last being the switch of 1% hydrocortisone. This is in partbecause of the long time delays in FDA’s process of acting uponsuch petitions.

The Office of Compliance in FDA’s Center for DrugEvaluation and Research (CDER) has published a documententitled the OTC Drug Monograph Implementation ComplianceProgram to assure systematic enforcement of final OTC drugmonographs and other regulations under the OTCDrug Review.

3.3. The NDA Approach to OTCProduct Approval

By far the most common way now of obtaining approval tomarket a new entity as an OTC is by the New Drug Applicationprocess. In theory, companies could write an NDA in sucha way as to go immediately over-the-counter on approval.However, in practice, it is almost universal to first markettruly new drugs initially on a prescription-only basis and thenlater file a supplement to the NDA for permission for OTC sale.This is commonly referred to as the ‘‘Rx-to-OTC switch,’’which is enormously popular and widely used, particularlyaround the time of the expiration of applicable patents. FDAevaluates NDA requests to switch drugs from prescription-onlyto OTC on a case-by-case basis.

Abbreviated NDAs (ANDAs), covered in Section 505(j) ofthe FD&C Act, are used for obtaining FDA approval to marketgeneric versions of prescription drugs after expiration of thepatents. However, such generics must be essentially identicalto the reference listed drug (RLD) regarding active ingredient,dosage form, strength, route of administration, and labeling.

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ANDAs are ‘‘abbreviated’’ in that FDA relies on the finding ofsafety and efficacy of the pioneer RLD and therefore new clin-ical studies are not needed, although bioequivalence to theRLD is required to be established. But while ANDAs are auseful way to market for generics, the requirements do notmatch what is needed today for approval to switch a prescrip-tion drug to OTC status.

However, there is another possible route to obtain NDAapproval to market an OTC, other than the usual filing of asupplemental NDA by the originator of the product as men-tioned above. This alternate way is covered in Section 505(b)(2)of the FD&C Act, established in 1984 by the Waxman-HatchAmendments to encourage innovation without requiring costlyand time-consuming duplication of previously conducted clini-cal studies. These 505(b)(2) applications are sometimes refer-red to as ‘‘paper NDAs,’’ although this is not strictly accuratein that that term was previously applied to approvals of drugs,based on scientific literature, that were duplicates of productsapproved after 1962.

Under FDA’s interpretation of Section 505(b)(2), the firmfiling an application in this way can rely on published literatureand/or on FDA’s previous findings of safety and efficacy with-out obtaining a right to such reference from the original appli-cant. In certain circumstances, specific studies may be requiredto establish the applicability of the original clinical data to themodified formulation covered in the 505(b)(2) application. Theinnovation mentioned is a limited change from the pioneerdrug, such as a different dosage form, strength, new combina-tions of active ingredients, route of administration, a differentsalt or polymorph of the active ingredient, or new indicationsfor a previously approved ingredient. In October 1999, CDERpublished a draft guidance, entitled Guidance for Industry:Applications Covered by Section 505(b)(2).

The firm filing an NDA application using the 505(b)(2)route is required to make certain certifications regarding thepatent status. Final approval is contingent on satisfying thepatent issues.

Section 505(b)(2) can be used opportunistically to switchproducts from prescription to OTC status of products covered



by a competitor’s NDA. An example is the competitive activityusing this route in switching second-generation nonsedatingantihistamine products. Some firms in the prescription drugindustry strongly disagree with FDA’s interpretation of certainaspects of Section 505(b)(2) and have questioned the legalityof FDA’s positions. An example of this is the contention overFDA’s policy of relying on nonpublic proprietary data on safetyand effectiveness contained in approved NDA files to supportapproval of 505(b)(2) applications. These issues may eventuallybe settled through litigation in the federal courts. In additionto Rx-to-OTC switches, Section 505(b)(2) can also be usedfor an NDA for a drug product that differs from a productdescribed in an OTC monograph, such as a nonmonographindication or a new dosage form.

The Waxman-Hatch Amendments to the FD&C Actprovide for marketing exclusivity for certain products withSection 505(b)(2) NDA approvals. Exclusivity provides the NDAholder limited protection from new competition in the market-place for the innovation represented by its approved product.The limitation precludes approvals of other 505(b)(2) NDAs forcertain periods of time. Exclusivity is available for new chemi-cal entities (NCEs) and for significant changes in alreadyapproved drug products (such as a new use), which are consid-ered to be innovative. The time periods for exclusivity differ.

It is important to keep in mind that whether an OTC comesto market through the monograph system or through an NDAprocess, the standards of safety, effectiveness, and the needfor clear, complete, and understandable labeling are the same.

4. THE PROPOSED THIRD CLASS OF DRUGS

The current regulatory scheme for distributing medicines in theUnited States, as outlined above, is a two-tiered system withany given product being classified as either prescription-onlyor over-the-counter. In some other countries, however, thereis a third class, sometimes called a ‘‘pharmacy-only medicine’’(POM), where certain products are restricted and required to bekept behind the counter or in a locked glass case not accessible

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to consumers. POM places the pharmacist in a controllingposition in terms of product recommendations, often favoringthe generic (not branded) versions of OTC drug products. In theUnited States, the ‘‘third class’’ or POM class does not exist inthat FDA has concluded that, as yet, no public health need hasbeen shown for this form of distribution.

The term ‘‘transition class’’ has been used in discussingPOMs by some pharmacy interests as a way to make the con-cept seem more attractive to industry opponents. Transitionclass implies an interim period of time (e.g., 2–5 years) duringwhich the product will be so classified. At the end of thatperiod, the status would be reassessed and then classifiedeither prescription-only or OTC. The concept is that untilproved by substantial actual experience that a given productis sufficiently safe to be sold OTC, such items should only bedispensed by a pharmacist (but without requiring a prescrip-tion). Presumably the pharmacist would discuss the use of theproduct with the consumer, guiding him or her in its properuse, and over time pharmacists would become sufficientlyknowledgeable about the safety and efficacy of the productthat they could help the government decide whether it shouldbe classified as a prescription-only or as an OTC drug.

The concept of a third class of drugs has been brought upmany times, including recently, by certain trade associationsrepresenting pharmacists and retail druggists. However, it hasbeen rejected as being impractical and unnecessary by mostpharmaceutical manufacturers, by FDA, and by the GeneralAccounting Office (GAO) (15). In addition, ConsumerHealthcare Products Association (CHPA), the trade associationrepresenting manufacturers of OTC drugs, strongly opposesthe third class category (16).

5. HOMEOPATHIC DRUGS

The Food, Drug and Cosmetic Act in Section 201(g)(1)recognizes as official the Homeopathic Pharmacopeia of theUnited States (HPUS) and its supplements, mentioned againin Section 501(b). The HPUS is published by the Homeopathic



Convention of the United States, Washington, DC, and isavailable from Homeopathic Headquarters of America (FallsChurch, VA).

Some homeopathic drug products must be sold only byprescription, while others may be sold OTC. The criteria fordetermining which are which are the same for all drug prod-ucts, including homeopathic drugs, as specified in Section503(b) of the Act. In some instances HPUS specifies a distinc-tion between prescription and nonprescription homeopathicsbased on strength. In general, however, homeopathic productsintended for use in treating self-limiting conditions amenableto self-diagnosis of symptoms may be sold OTC, but otherwisethey must be marketed as prescription products. Drug prod-ucts containing homeopathic ingredients in combination withnonhomeopathic active ingredients are not considered to behomeopathic products. Moreover, homeopathic products mustbe clearly labeled as such. Homeopathic drugs must meet thestandards for strength, quality, and purity contained in theHPUS.

In general, the good manufacturing practice regulationsin Part 211 of Title 21 of the CFR apply to all homeopathicdrug products, prescription and OTC, with certain exceptions.More details about homeopathic products are contained inFDA’s Compliance Policy Guide (CPG) 7132.15 entitledConditions UnderWhich Homeopathic DrugsMay beMarketed.

6. COSMETIC DRUGS

It is not always obvious which products are legally drugs, cos-metics, or both. The difference is established by the intendeduse and the claims for the product in labeling, advertising,other promotional materials, or on the Internet. The decisioncan also be influenced by consumer perception as to what theproduct is expected to do, as well as by the inclusion of certainingredients well known for their therapeutic uses. Even somearomatherapy products may be classified as drugs because oftheir intended use (17).

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Section 201(i) of the FD&C Act defines cosmetics as ‘‘arti-cles intended to be rubbed, poured, sprinkled, or sprayed on, orintroduced into, or otherwise applied to the human body . . . forcleansing, beautifying, promoting attractiveness, or alteringthe appearance.’’ On the other hand, Section 201(g)(1) definesdrugs as ‘‘(A) articles intended for use in the diagnosis, cure,mitigation, treatment, or prevention of disease . . . and (B) arti-cles (other than food) intended to affect the structure or anyfunction of the body. . . . ’’ A few products actually fall underboth definitions. For example, toothpastes that merely cleanseare cosmetics, but those that contain fluoride are also drugs.Shampoos that simply clean the hair are cosmetics, but thosecontaining antidandruff ingredients are also drugs. Underarmproducts that just deodorize are cosmetics, but those that areantiperspirants are also drugs. Cosmetic products that makesun-protection claims (sunscreens) are also drugs. The combi-nation products must comply with the requirements for bothcosmetics and drugs.

As mentioned above, drugs are subject to FDA approval,with OTCs in general requiring either an approved NDA orcompliance with the appropriate OTC monograph. Cosmetics(with the exception of color additives) do not require premarketapproval. Firms making drug products (including OTCs) mustregister their establishments and list their drug products,whereas these steps are voluntary and not mandatory for cos-metics. There are also differences in labeling between OTCsand true cosmetics. For example, OTCs and cosmetic drugsmust include the drug facts required in x201.63 of Title 21 ofthe CFR, while true cosmetics do not. There are also differ-ences in the way the ingredients must be listed on the labelin that combination drug cosmetics must list the active ingre-dients alphabetically, followed by the inactives in order of pre-dominance. Importantly, too, there are no good manufacturingpractice (GMP) regulations for true cosmetics, but cosmeticdrug products require strict adherence to the drug GMPs con-tained in parts 210 and 211 of Title 21 of the Code of FederalRegulations.

The FDA Modernization Act of 1997 amended Section704 of the FD&C Act to allow FDA to inspect plants that



manufacture products regulated as both drugs and cosmetics tobe inspected in the same ways as are prescription drug manu-facturing facilities, including FDA’s right to ask to see mostdocumentation. However, this records inspection does not applyto facilities making only true cosmetics, albeit all cosmeticmanufacturing establishments are subject to FDA inspection.

7. DIETARY SUPPLEMENTS

Although many dietary supplement products look very muchlike OTCs and are marketed over the counter, the regulatoryschemes for these two classes of self-care products are quitedifferent. Dietary supplements are considered to be a specialclass of foods, not drugs, under the Dietary Supplement Healthand Education Act (DSHEA) of 1994. A dietary supplement is aproduct intended to supplement the diet and that contains oneor more dietary ingredients such as vitamins, minerals, herbs orother botanicals, amino acids or other specific ingredients.These products are in the form of tablets, hard-shell or soft-gelcapsules, powders, or as liquids intended for consumption insmall quantities. Only products that are intended for ingestioncan be considered to be dietary supplements, i.e., topicals, trans-dermals, and sublingual products are not dietary supplements.

Under DSHEA, dietary supplements may be legallymarketed with truthful and nonmisleading claims to affectthe structure or function of the body, but not with claimsthat state or imply that they are intended to prevent, diagnose,mitigate, treat, or cure disease (except for health claims specif-ically authorized by the FDA for use). Disease claims maycause the products to be legally classified as drugs and there-fore subject to provisions of the FD&C Act and/or regulationspertaining to drugs. The intended use of a product may beestablished through product labels and labeling, catalogs,brochures, audio and videotapes, Internet sites, or othercircumstances surrounding the distribution of the product.

Unlike OTC drugs that are regulated by CDER, dietarysupplements are regulated by the Center for Food Safety and

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Applied Nutrition (CFSAN). The regulations covering labeling,allowable claims, appropriate ingredients, and good manufac-turing practices are significantly different between OTCs anddietary supplements.

8. OTCs AND GOOD MANUFACTURINGPRACTICE

Section 501(a)(2)(B) of the FD&C Act says that a drug shall bedeemed to be adulterated if the ‘‘methods used in, or the facili-ties used for, its manufacture, processing, packing or holdingdo not conform to or are not operated or administered inconformity with current good manufacturing practice toassure that such drug meets the requirements of this chapteras to safety and has the identity and strength, and meetsthe quality and purity characteristics, which it purports or isrepresented to possess.’’ This applies to all drug productssold in the United States, whether prescription, OTC, orhomeopathic (although there are certain exceptions applicableto homeopathic drugs). The GMP regulations are in Parts 210and 211 of Title 21 of the Code of Federal Regulations. Inaddition, FDA has published many guidance documents onvarious GMP topics. FDA’s Compliance Policy Guide (CPG)7132.10, entitled ‘‘CGMP Enforcement Policy—OTC vs. RxDrugs,’’ makes it clear that the GMP regulations are thesame for OTC drug products as for prescription drugs.

Section 704 of the FD&C Act authorizes investigatorsfrom the FDA to

‘‘enter any factory, warehouse, or establishment in whichfood, drugs, devices, or cosmetics are manufactured, processed,packed, or held for introduction into interstate commerce . . .and to inspect . . . all pertinent equipment, finished and unfin-ished materials, containers therein. In the case of any factory,warehouse, establishment, or consulting laboratory in whichprescription drugs, non-prescription drugs intended for humanuse . . . are manufactured, processed, packed, or held, theinspection shall extend to all things therein (including records,files, papers, processes, controls, and facilities) bearing on



whether prescription or non-prescription drugs intended forhuman use . . . are adulterated ormisbranded within themeaningof this Act. . . .’’

Thus, establishments involved with manufacturing and/orwarehousing OTC drug products are subject to inspectionby FDA and can be cited for any GMP violations found andmay then be subject to certain regulatory actions resultingfrom such findings. This applies not only to establishmentswithin the United States but also to those in other countriesif the products are exported for sale in the United States.

Prior to the passage of the FDA Modernization Act of 1997(FDAMA), prescription and OTC drug manufacturers weresubject to the same GMP regulations, but FDAMA clarifiedthe fact that investigators are entitled to review all OTCmanufacturing records that could show whether a producthas been adulterated or misbranded. This amended Section704(a)(1) of the FD&C Act to extend the authority of FDAto inspect company records for OTCs to the same extent asfor prescription drugs. This provision of course also applies tocosmetic drug products.

Similarly, Sections 510(b) and (c) of the FD&C Act requirethe registration of the establishments of all producers ofdrugs, including OTCs. Further, the Drug Listing Act of1972 requires each registered drug manufacturer to informFDA of all of the drugs it manufacturers or processes. Themechanism for complying with these requirements are alsocontained in x207.25(a) and (b) of Title 21 of the Code ofFederal Regulations (18).

9. LABELING OF OTC DRUGS

For many years FDA has had regulations on the required label-ing of OTC drug products, both to be in conformity to theFD&C Act and the Fair Packaging and Labeling Act (FPLA).These regulations are intended to enable consumers to obtainaccurate information regarding the products, their indications,ingredients, and safe usage, as well as the quantity of contents

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to facilitate value comparisons. The labels are required to showthe dosage strength, as well as the name and address of themanufacturer, packer, or distributor. In short, OTC druglabels must contain all of the information the consumer needsfor safe and effective use without the supervision of a healthprofessional. In addition, the manufacturers, through theirtrade associations, have voluntarily diligently studied andworked over the years to improve the legibility of OTC druglabels, considering such factors as type faces and font sizes,layout, and contrast.

The FDA Modernization Act amended Section 502(e)(1)of the FD&C Act to require OTC labels to list the quantityor proportion of each active ingredient present, not merely thenames of the actives as previously. An alphabetical list ofinactive ingredients must appear on the outside container ofthe retail package and also on the immediate container,if determined to be appropriate by the FDA (19).

In 1997 FDA proposed to establish a standardized formatfor the labeling of OTCs, to make the key information clear,simple, and user-friendly. After thorough study, including inputfrom many companies, academia, trade associations, and con-sumer organizations, the new format appeared as a final regu-lation in the Federal Register for March 17, 1999. Amongother details, this requires what is known as a ‘‘drug facts’’box listing the active ingredient, purpose of the product, uses,directions, inactive ingredients, warnings, and other informa-tion (20). Regulations for the standardized format appear inx201.66 of Title 21 of the Code of Federal Regulations, whilethe definition of the principal display panel is in x201.60, thedefinition of the statement of identity is in x201.61, andthe declaration of net quantity of contents is in x201.62. FDAhas published guidance documents on labeling OTCs usingthe standardized format (21). A drug product that is not incompliance with these requirements is subject to regulatoryaction as a misbranded drug.

Most OTCs require an expiration date as specified inx211.137. There are specific exceptions for certain productsif their labeling does not bear dosage limitations and they areestablished as being stable for at least 3 years. This type of



exception applies, for example, to creams or ointments inten-ded to relieve itching. Moreover, under x211.137(e), homeo-pathic drug products are exempt from the requirement forexpiration dating.

Under x201.17, when an expiration date is required, itmust be on the immediate container and also on the outerpackage (if there is one) unless it is easily legible through theouter package. It is not acceptable to place the expiration dateon a cap, since there would be a chance of a mix-up in that capsmight inadvertently by switched from one product to anotherby the consumer. It is satisfactory to apply the expiration dateon the crimp-end of a tubed product, however.

The expiration date is established by appropriate stabil-ity studies described in x211.166, on an adequate number ofbatches, in the container/closure system in which the productis marketed. A written stability program is required and mustbe followed, using meaningful, specific, reliable, stability-indicating test methods and storage conditions.

The absence of an expiration date, except for products spe-cifically exempt, is cause for FDA to initiate regulatory actionagainst the product and/or the responsible firm. Out-of-datedrug products are considered by FDA to be adulterated, andany sale of adulterated products may result in regulatory actionsuch as seizure or injunction.

10. CHILD-RESISTANT PACKAGING

Under the Poison Prevention Packaging Act (PPPA) enactedin 1970, ‘‘hazardous substances’’ require child-resistant (CR)packaging, simply called ‘‘special packaging’’ in the PPPAand the implementing regulations. A ‘‘hazardous substance’’is defined in the Federal Hazardous Substances Act, and thisdoes include certain specific foods, drugs, cosmetics, and die-tary supplements. Thus, some (but not all) OTC drug productsrequire CR packaging. The purpose is to protect children fromserious personal injury or serious illness from handling, using,or ingesting hazardous substances.

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The Consumer Product Safety Commission (CPSC)enforces the PPPA. The implementing regulations are in Title16 of the Code of Federal Regulations, Parts 1700–1750.Since the list of products requiring child-resistant packagingchanges from time to time, it is prudent for manufacturersto keep abreast of the regulations, particularly the list entitled‘‘Substances Requiring Special Packaging,’’ in x1700.14 or tocontact CPSC in case of doubt.

The PPPA does not specify what kinds of packagingare considered to be ‘‘child resistant,’’ leaving this up to theCPSC to establish. A testing protocol is specified in Section1700.20 of the CPSC’s regulations. This involves testingwith both small children to assure they cannot easily get atthe product within a reasonable time, and also testing withadults to be sure that the features are not so restrictive asto make it overly difficult for them to open and reclose thepackage. A concern is that if packages are too difficult foradults to use, they will simply be left open in some instances,which could put children in the household at risk. Over theyears, various makers of packaging components have deviseda number of package types that comply. CPSC is convincedthat their data conclusively indicate that CR packaging hassaved over 800 children’s lives from accidental poisoning fromaspirin and other drugs (22).

Section 1700.5 of CPSC regulations and Section 4(a) ofthe PPPA authorize manufacturers and packagers of productsrequired to be in CR packages to offer one single size or SKUof the products in a non-CR version for the convenience ofelderly or handicapped persons who might otherwise be incon-venienced by having to deal with CR packaging. Such packagesmust be conspicuously labeled ‘‘This Package for HouseholdsWithout Young Children’’ within a square or rectangularborderline, in conspicuous and easily legible capital letters,on the principal display panel of the immediate container andalso on any outer container or wrapping used in the retaildisplay of the product.

ASTM International (Conshohocken, PA) has a committeeD10 on packaging, including a subcommittee D10.31 on ChildResistant Packaging and Closure Systems. This group has



issued a number of standards and test methods, including oneentitled ‘‘D3475-03 Standard Classification of Child-ResistantPackages.’’

There is no regulatory requirement for OTC manufac-turers to test their packages for CR compliance, but if theCPSC learns of a product requiring CR packaging where theCR feature is not functioning well, a recall may be neededand/or the firm involved may be penalized. Consequently, toavoid regulatory problems with the CPSC as well as to avoidpossible product liability issues, many manufacturers do testtheir packages. Since the testing protocol is difficult to conduct,many firms use specialized outside contract organizations toconduct the tests.

11. NATIONAL UNIFORMITY

The FDA Modernization Act added a new Section 751 to theFD&C Act and for the first time mandated that in general,no state or political subdivision may establish requirementsfor nonprescription drug products regulated by FDA thatdiffer from or are in addition to the requirements of the Food,Drug and Cosmetic Act, the Poison Prevention Packaging Act,or the Fair Packaging and Labeling Act. Among other things,this established that states cannot require labeling of OTCsdiffering from what FDA requires. This applies to any non-prescription drug, whether under an NDA, ANDA, or a mono-graph. This was a significant step, as prior to this changeindividual states on occasion required special labeling, whichobviously greatly complicated OTC manufacturing, warehous-ing, and physical distribution.

12. TRADE ASSOCIATION FOR OTCs

The leading trade association in the United States involved pri-marily with nonprescription drugs is the Consumer HealthcareProducts Association (CHPA), previously known first as the

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Proprietary Association (PA) and then later as the Nonpre-scription Drug Manufacturers Association (NDMA). The CHPAwas founded in 1881 and represents over 200 companiesinvolved in the research, manufacturing, and distribution ofOTC medicines. CHPA members represent over 90% of retailsales in the OTC marketplace.

CHPA organizes and sponsors meetings and seminars ona range of topics applicable to the manufacturing and market-ing of OTC drugs. It also has established voluntary codes andguidelines for the self-care industry on a variety of matters.CHPA is located in Washington, DC, and has a web site at

13. IMPRINTING SOLID ORAL DOSAGEFORM OTC DRUGS

As is the situation with prescription drugs, OTC tablets, cap-sules, or similar drug products intended for oral use (withcertain exceptions listed in x206.7) must be clearly marked,debossed, or imprinted with a code that, in conjunction withthe product’s size, shape, and color, permits the unique identi-fication of the product and the manufacturer or distributorof the product. This became a final rule in the FederalRegister of September 13, 1993, as amended on April 21, 1995,now codified in x206.3 and 206.10 of Title 21 of the Code ofFederal Regulations.

14. THE NATIONAL DRUG CODE

The National Drug Code (NDC) was originally established inconnection with the reimbursement program under Medicare,but has become a universal product identifier for human drugs.The NDC directory consists of all prescription drugs andsome (but not all) OTCs. It is strictly a voluntary matter, inthat OTCs may have NDC numbers, but are in no way requiredto do so. Inclusion of a firm of its products in the National


http://www.chpa-info.org.


http://www.chpa-info.org

Drug Code Directory does not denote approval by FDA,nor does absence of an NDC number have any negative impli-cations. Under x201.2 of Title 21 of the Code of FederalRegulations, if a firm has an NDC number, they are requestedbut not required to have it appear on the product labeling, butif used, it should be displayed as indicated in x207.35(b)(3).

15. TAMPER-EVIDENT PACKAGING

Prior to 1982 there were no regulations regarding packagingdesigned specifically to make evidence of tampering obvious tothe consumer. This changed suddenly on September 30, 1982,due to a health emergency in Chicago where seven people diedafter taking cyanide-laced Tylenol� capsules. A number ofmanufacturing executives from the OTC drug industry quicklyassembled in Washington, DC, to assess the situation and toformulate steps to minimize the likelihood of future similaroccurrences. This group was called the Expert Committee onTamper-Resistant Packaging. Their goal was to consider whatshould be done to change OTC packages to improve consumersafety and product integrity. They defined tamper-resistantpackaging (as it was then called) and evaluated features andequipment to provide tamper evidence for OTC packages.

The Expert Technical Committee met with top FDAofficials to help draft what soon became x211.132 of the GMPregulations. The final regulation on tamper-resistant packa-ging (TRP) was published in the Federal Register onNovember 5, 1982, less than 5 weeks from the advent of thefirst poisonings. On February 25, 1983, certain exemptionsto the requirements were published, followed by a clarificationpublished April 19, 1983. The regulation required that anyOTC drug product (except a dermatologic, dentifrice, insulin,or lozenge product) for retail sale be in a tamper-evidentpackage so that a breach of the package would be reasonablyexpected to produce visible evidence to consumers thattampering had occurred.

It was established that it is essentially impossible todevelop a practical package that is tamper-proof, thus the

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term tamper-resistant was adopted, which in 1998 was chan-ged to tamper-evident. FDA wisely elected to avoid settingspecific standards of performance. However, CompliancePolicy Guide (CPG) 7132a.17, entitled ‘‘Tamper-ResistantPackaging Requirements for Over-the-Counter Human DrugProducts,’’ was published. This provides background and alist of technologies that are considered acceptable.

In 1986 people died after ingesting Extra-StrengthExcedrin� capsules tainted with cyanide. Also in 1986, therewere other tragic incidents of tampering with Tylenol� cap-sules, this time in New York. FDA responded by amendingthe TRP regulation in the Federal Register, on February 2,1989, to require OTC drug products in two-piece hard gelatincapsules to use at least two separate tamper-resistant features,or at least one such feature if the capsules themselves weresealed.

Then, in February 1991 two people in Washington statedied from taking bogus Sudafed� cold capsules containingcyanide, despite adequate TRP and despite the fact that thetampering should have been obvious to the victims. There wastalk at that time of banning capsules altogether as a dosageform, but strong objections were raised by many so this conceptwas eventually dropped. It was concluded that over and abovethe TRP, what was urgently needed was consumer awarenessof the potential problems so that each individual would be alertto signs of tampering.

The TRP regulations were revised in a final rule, pub-lished in the Federal Register for November 4, 1998, changingthe term to tamper-evident packaging (TEP) instead oftamper-resistant pakaging (TRP). This version of the regula-tion requires the product labeling to refer to all packagingfeatures used to comply with the tamper-evident regulation,including those on the secondary package, the immediate con-tainer or closure, and any capsule sealing technologies used. Italso requires two-piece hard gelatin capsules to be sealed.

FDA’s Compliance Policy Guide (CPG) 7132.14,entitled ‘‘Control and Accountability of Labeling Associatedwith Tamper-Resistant Packaging of Over-the-CounterDrug Products,’’ establishes that portions of tamper-evident



packaging that contain labeling (e.g., shrink seals imprintedwith the product name) need to be carefully controlled andreconciled. Similarly, controls are required for parts of thepackaging that may be part of the container-closure system.

While the deaths resulting from tampering have receivedwide media attention, there have been many other lesserincidents of tampering with less drastic outcomes. Obviously,tampering remains a significant potential problem, particularlyin these times of concern about the possibility of bioterrorism.

In October 1983, the Federal Anti-Tampering Act wassigned into law. This defines tampering and sets forth strictpenalties for persons found guilty of tampering. A great manyconvictions have resulted from this law, further emphasizingthat tampering remains a significant issue.

16. ADVERTISING OF OTCs

The FDA and the Federal Trade Commission (FTC) by statutehave overlapping jurisdiction of advertising, labeling, andpromotion of foods, drugs, cosmetics, medical devices, anddietary supplements. In general, FDA regulates advertising ofprescription drugs, but FTC has the primary responsibilityfor enforcing the laws against false or misleading advertisingof OTC drugs. FDA and FTC have a long-standing mutualunderstanding of their respective roles, which has workedwell over the years. Both agencies are committed to preventdeception of the public and to coordinate to promote consis-tency and eliminate duplication of effort. The two agencieswork in harmony and keep each other informed on a variety ofissues.

The FTC focuses its enforcement resources on thosepractices likely to cause the most harm to consumers, whichusually involves health and safety claims. But in general, FTCstrives to eliminate deceptive and unsubstantiated advertisingclaims that could lead to consumer misinformation by mar-keters attempting to obtain an unfair competitive advantage.Section 5 of the FTC Act gives the FTC broad authority to

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prohibit unfair or deceptive acts or practices, while Sections 12through 15 prohibit the dissemination of misleading claimsfor food, drugs, devices, and cosmetics. FTC can and does issuecease-and-desist orders and can seek civil penalties in federalcourt for violations of such orders. The courts have ruled thatan advertiser is responsible for all claims, express and implied,that are reasonably conveyed in advertising and that adver-tisers are strictly liable for violations of the FTC Act.

The FTC obviously prefers voluntary self-regulation. Onestep in this is accomplished through the actions of the Councilof Better Business Bureaus. Their National AdvertisingDivision (NAD) investigates complaints about the truthfulnessand accuracy of national advertisements and encouragescorrective action be taken as appropriate. When an advertiseror challenger disagrees with the NAD’s findings, NAD’sdecisions can be appealed to the National Advertising ReviewBoard (NARB) for additional review. Many complaints broughtby a ‘‘challenger’’ (usually a competitor, but sometimes aconsumer, trade association, local Better Business Bureau,etc.) involving the accuracy and truthfulness of advertisingclaims are settled through the NAD/NARB process withoutinvolving the FTC. In most instances, advertisers volun-tarily agree to modify or discontinue potentially misleadingadvertisements.

The NAD publishes a periodical 10 times a year entitled‘‘NAD Case Reports: Voluntary Self-Regulation of NationalAdvertising,’’ and more than 3000 decisions are now availablefor review. The Council of Better Business Bureaus also pub-lishes ‘‘Do’s and Don’t in Advertising’’ in loose-leaf form andon CD-ROM, with periodic updates, including laws, guides,industry self-regulatory guidelines, and NAD case summaries.

Consumers get much of their information about OTCdrug products through advertising, and they tend to acceptthe claims on faith. This puts a burden on the advertisers tofollow high standards in the wording of and the substantiationof claims. Misplaced reliance on claims can result in consumersdelaying seeking professional help, which can result in post-poning needed medical treatment. The leading trade associa-tion of OTC drug manufacturers, the CHPA, strongly urges its



member companies to follow its voluntary code of advertisingpractices. Moreover, the media (especially television networks)typically insist on seeing claims substantiation prior to runningOTC advertising. But because there are occasionally unscrupu-lous advertisers despite the guides and voluntary programs, theFTC is vigilant in its enforcement efforts to assure that claimsare substantiated and consumers are not deceived in theirefforts to handle their own health needs.

An increasing problem is the advertising and promotion ofmedical products (including OTC drugs) on the Internet. Whilethe Internet offers tremendous benefits to consumers in bothconvenience and choice of information, it also makes fraudand deception easier. Consequently, FDA, the FTC, stategovernmental agencies, and the National Consumers Leaguehave teamed up and are closely monitoring the Internet in anattempt to minimize health fraud as well as false and unsub-stantiated claims. Strong enforcement actions are taken whennecessary against fraudulent marketing practices of OTCs onthe Internet.

CDER’s Office of Compliance has an Internet Health FraudTeam within its Division of New Drugs and Labeling Compli-ance (formerly called the Division of Labeling and Nonprescrip-tion Drug Compliance).

17. FDA’s OVERSIGHT OF OTC DRUGS

As described above, establishments manufacturing, packaging,or warehousing OTC drug products must be registered withFDA, and the products handled duly listed. Such establish-ments are subject to inspection by FDA for full compliancewith the current GMP regulations. Also, as described above,OTCs must either be in compliance with the appropriate OTCmonograph requirements or be subject to an approved NDAor ANDA. Labeling must conform with regulations, includinglot numbers and expiration dates. Where tamper-evidentand/or child-resistant packaging is required, OTCs must be incompliance.

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In addition, FDA has a Nonprescription Drugs AdvisoryCommittee (NDAC) that coordinates the activities on establish-ing or modifying the OTC monographs and on consideringswitches from prescription to nonprescription status (or viceversa). In its original charter in 1991, it was named the OTCDrugs Advisory Committee (ODAC), but since this soundedconfusingly similar to the Oncologic Drugs Advisory Commit-tee, the name was changed. This committee may also advisethe agency on other topics related to OTCs, such as scientificprograms related to FDA’s mission and regulatory responsibil-ities. The committee consists of a core of 14 voting membersinvited to serve overlapping 4-year terms. Temporary subcom-mittees are established as needed to address specific issues.The meetings of the NDAC are held in accordance with theprovisions of x14.22 of Title 21 of the Code of Federal Regula-tions. Management and support services for the NDACare provided by CDER. When the OTC subject matter overlapswith one or more expert advisory committees, as is often thecase for an Rx-to-OTC switch application, NDAC will meetin joint session with the appropriate prescription drug advisorycommittee.

There is within CDER’s Office of Drug EvaluationV (ODEV) a division of over-the-counter drug products(DOTCDP), which is responsible for all OTC review mattersand for those aspects of Rx-to-OTC switch applications relat-ing to consumer labeling and use. By mutual agreement,the clinical aspects of a switch application are the purview ofthe relevant medical review staff of another division or office,and the OTC division consults with other staff groups withinCDER (such as the Office of Drug Safety on certain adverseevent reporting matters). CDER has a specific Manual ofPolicy and Procedures (MaPP) covering the interactionbetween the OTC division and other CDER medical reviewdivisions.

There is also in the Office of Compliance (OC) an OTCdrugs team responsible for maintaining current knowledgeof the regulatory status of OTC drugs, keeping the FDA dis-trict offices informed on OTC regulatory issues, workingwith the district office in obtaining appropriate evidence to



support enforcement actions involving OTCs, monitoringproduct labeling to help assure compliance, working withagency personnel and the regulated industry to resolveissues of mutual concern and similar matters related tocompliance issues in the OTC field. In the Division ofNew Drugs and Labeling Compliance (DNDLC) in CDER’sOffice of Compliance is an OTC Drugs and Health FraudBranch, responsible for compliance and enforcement issuesrelated to labeling for OTC drugs. With this organizationalstructure, combined with FDA’s inspectional force in the field,there is a well-defined and time-tested system of oversightof OTCs. This serves well both current activities and futureOTC issues.

REFERENCES

1. FDA white paper, Protecting the public health: FDA pursues anaggressive enforcement strategy, June 23, 2003.

2. Kline & Company, Inc., Economic benefits of self-medication,a final report to the Nonprescription Drug ManufacturersAssociation, May 15, 1997.

3. Schondelmeyer, S.W., Economic aspects of switch, inProceedings Drug Information Association Workshop Rx-to-OTCSwitch, Rockville, MD, May 1989.

4. Roper Starch Worldwide, Self-care in the new millennium:American attitudes toward maintaining personal health andtreatment, a report prepared for the Consumer HealthcareProducts Association, March 2001.

5. United Seniors Health Cooperative Special Report, Aging andhealth: the role of self-medication, Washington, DC, 1998.

6. Kunz, K., Economics of self treatment . . . in a managed caresetting, J. Managed Care Pharmacy, Vol. 2, No. 3, May/June1996, p. 253–271.

7. Press release, American consumers support self-medication andpractice it responsibly, Nonprescription Drug ManufacturersAssociation, Washington, DC, January 1994.

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8. A. D. Little confirms OTC advertising doesn’t cause drug abuse,NDMA Scientific News Bulletin, Washington, DC, March 18,1991.

9. Soller, R.W., OTCness, Drug Information Journal, Vol. 32,1998, p. 555–560.

10. Mercill, A.W., The grand design, in Proceedings of the 1975Manufacturing Controls Seminar, The Proprietary Association,Cherry Hill, NJ, October 1975.

11. Oppenheimer, D.C., ‘‘It’s been a long four years—FDA’s OTCdrug product review,’’ Pharmaceutical Technology, June 1997,p. 65–66.

12. FDA’s OTC Review, NDMA Executive Newsletter, Washington,DC, May 1, 1992.

13. Progress Report: The OTC Drug Review, FDA Consumer,February 1979, p. 18–22.

14. Gilbertson on OTC review, NDMA Executive Newsletter,Washington, DC, November 16, 1990.

15. General Accounting Office, Nonprescription Drugs: Value of aPharmacist-Controlled Class Has Yet to Be Demonstrated,Report GAO/PEMD-95-12, August 1995.

16. News release from the Consumer Healthcare ProductsAssociation, CHPA statement reaffirming commitment to theU.S. two-class system of drugs, Washington, DC, May 27, 2003.CHPA also has a fact sheet on this available at

(accessed July 9, 2003).

17. FDA, Is it a cosmetic, a drug, or both? (or, is it soap?), July 8,

(accessed January 18, 2003).

18. FDA, Drug registration and listing, available at

11, 2002).

19. FDA, ‘‘Guidance for industry: national uniformity for nonpre-scription drugs—ingredient listing for OTC drugs,’’ ProceduralGuidance No. 2, April 1999.


www.chpa-info.org/pdfs/05_27_03_Third_Class_of_Drugs.pdfhttp://

http://www.fda.gov/cder/drls/registration_listibg.htm (accessed August

2002, available at http://www.cfsan.fda.org.gov/�dms/cos-218.html




http://www.fda.gov

http://www.fda.gov

20. FDA, OTC labeling: questions and answers, October 2002,available at(accessed May 25, 2003).

21. FDA, Guidance for industry: labeling OTC human drug prod-

22. Remarks by Ann Brown, Chair of CPSC, before the UsabilityProfessionals’ Association breakfast in Washington, DC, onJune 23, 1998, available at

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http://www.upassoc.org/outreach/govt.ind.brown.html (accessed June 29, 2003).

http://www.fda.gov/cder/otc/label/quesanswers.htm

www.gov/cder/guidance/3594fnl.htm (accessed May 25, 2003).ucts using a column format, March 2001, available at http://


http://www.fda.gov

http://www.upassoc.org

http://www.upassoc.org

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