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New Drug Application Content andReview Process for ClinicalPharmacology and Biopharmaceutics

Chandrahas Sahajwalla, Veneeta Tandon,

and Vanitha J.Sekar*

Food and Drug AdministrationRockville, Maryland, U.S.A.

INTRODUCTION

The regulation and control of new drugs in the United States has been basedon the new drug application (NDA) that is evaluated by the U.S. Food andDrug Administration (FDA). The data gathered in preclinical studies andhuman clinical trials as an investigational new drug (IND) during the drugdevelopment process become part of the NDA. The goal of the drug

development process is to provide sufficient information to the FDA in theNDA to evaluate the efficacy and safety of the new drug as well asrecommendations to adjust the dose in special circumstances. The drugdevelopment process for new drugs has evolved over the years especially in thefield of Clinical Pharmacology and Biopharmaceutics. In response to the

* Current affiliation: Aventis Pharmaceuticals, Bridgewater, New Jersey, U.S.A.

Copyright 2004 by Marcel Dekker, Inc.

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evolving technology, advancement of knowledge in the field, and to ascertainconsistency and quality of the data available during the development process,the US FDA, including, office of clinical pharmacology and biopharmaceutics(OCPB) has issued several regulatory guidance documents. Office of clinicalpharmacology and biopharmaceutics has several guidances in the publicdomain that are available to drug companies (often referred to as sponsors)which provide recommendations in the areas of clinical pharmacology/biopharmaceutics such as exposure-response assessments, design and conductof population pharmacokinetic studies, in vitro and in vivo drug metabolismand drug interactions, dissolution testing requirements for immediate andextended release dosage forms, design and conduct of bioavailability,bioequivalence and food-effect studies, and studies in patients with renal andhepatic impairment. This chapter integrates the information from availableOCPB and other FDA-issued guidances that aid in the drug developmentprocess, and also provides insight into some of the issues that should beconsidered from a regulatory perspective regarding the ClinicalPharmacology and Biopharmaceutics aspects of drug development. It shouldbe noted that some of the guidances are published as a draft and reflectcurrent scientific understanding and thinking of the FDA scientist.

The sponsors now have option submitting new drug application in NDA

format or Common Technical Document (CTD) format. Common technicaldocument format is a format in which clinical, pharmacology/ toxicologyand manufacturing data can be submitted to obtain marketingauthorization for new drugs in the United States, European Union, andJapan. It should however be noted that CTD and NDA do not differ in thecontent of the information but mainly the format in which data should beprovided.

This chapter provides an insight into the review process by the Clinical

Pharmacology and Biopharmaceutics staff.

STAGES IN DRUG DEVELOPMENT AND REGULATORY

PROCESS

Once the sponsor has identified a lead compound, traditionally, the drugdevelopment process follows a plan. Most pharmaceutical companies have

a drug development plan that is unique to their company based on their ownexperiences. In general all pharmaceutical companies proceed withdevelopment to answer several questions about the drug, i.e., is the drugsafe, up to what dose or exposure it is safe, how should the dose be adjustedin certain specific populations or when co-administered with other drugs tohave optimized formulation for delivery of the drug.


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Clinical Pharmacology and Biopharmaceutics 73

When a compound has been identified, a Pre-IND (IND-investigationalnew drug) meeting is occasionally requested with the FDA by sponsors.Sponsor may be a pharmaceutical company or individual investigators.Prior to the meeting, the sponsor usually submits a Pre-IND package. ThePre-IND package may include summary of preclinical data and a conceptsheet of a study protocol in order to obtain scientific input from the FDAreviewers regarding the initial IND. The FDA review team consists of aMedical Officer, Clinical Pharmacologist and Pharmacokineticist, Chemist,Pharmacologist/Toxicologist Statistician, and a Microbiologist (dependingon the proposed indication). Input requested by the sponsor before the filingof the initial IND usually involves questions regarding appropriate doseand/or dosing regimen selection, safety parameters to be assessed, samplingtimes (pharmacokinetics and safety), etc., for the first time in humansstudy. Generally, the first study conducted in human volunteers is a clinicalpharmacology study to evaluate the safety and pharmacokinetics/pharmacodynamics of the drug in healthy volunteers or, in some cases,patients. Prior to conducting this first-time-in-humans study, the FDArequires the sponsor to have conducted adequate preclinical studies tosupport such a study. The sponsor may also request FDA input regardingthe development plan for their compound, generally if human data on the

drug is available from studies conducted outside the USA. In this case, theOCPB reviewer would review the sponsors plan and provide additionalsuggestions, whenever necessary. Examples of OCPB input at the Pre-INDstage regarding overall drug development include formulation developmentplans, dissolution method development, exploring mechanisms of action,design and conduct of in vitro metabolism studies, clinical pharmacologystudy designs, identifying potentially useful biomarkers, proof of conceptand doseranging studies, exposure-response and/or population

pharmacokineticpharmacodynamic assessments, as well as design and doseselection plans for Phase 3 studies. Depending on the complexity of the Pre-IND, the Agency would respond either via a letter or a meeting may be setup with the sponsor.

Protocols for all studies conducted in human volunteers in the UnitedStates or that would become part of the NDA have to be submitted to theFDA. Once an IND has been filed FDA assigns a number to the IND.Subsequent study protocols, study reports or sponsors correspondences

have to refer to the IND number.Once the sponsor has submitted an IND to the FDA, FDA has 30 days to

review the submitted protocol for human study. During this review, if thereare any concerns about the safety of the subjects to be enrolled in the study,FDA would call the sponsor and place the protocol on clinical hold until theconcerns identified by the FDA reviewers are satisfactorily addressed. TheIND review process is shown schematically in Fig. 1.


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FIGURE 1The IND review process, http://www.fda.gov/cder.

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There is keen interest on the part of the pharmaceutical companies to beinvolved in screening INDs (at the time of the initial IND submission) inwhich several drugs are screened at the same time and one of thecompounds is identified for further development. Further details of thisapproach can be found in manual of policy and procedures (MAPP) on theFDA website [1].

The drug development stages are not rigid, that is, several phases of earlydrug development (traditionally called Phase 1 and 2 studies) are generallyon going simultaneously. Typically, Phase 1 studies are in healthyvolunteers, Phase 2 are studies in small numbers of patients, and Phase 3 arelarger clinical trials with adequate number of subjects to determine safetyand efficacy of the drug. Phase 1 studies typically include studies related toformulation development, assessment of metabolic pathways, assessment ofeffects of extrinsic and intrinsic factors such as age, gender, disease, otherdrugs and food, and assessment of PKPD. Phase 2 studies are typicallydose-ranging and proof of concept studies in a small number of patientswho comprise the target population (traditionally called Phase 2A).Assessment of PK-PD is also performed in these studies to help provide anunderstanding of the doses and dose regimens to be further studied. Thesestudies provide the sponsor as well as the regulatory agencies with the type

of knowledge about the drug that is needed to design appropriateconfirmatory or definitive large clinical trials in the target patientpopulation (traditionally known as Phase 3 trials). Generally, the FDA needstwo positive adequately well controlled Phase 3 trials that support the safetyand efficacy of the drug in the target population prior to approval formarketing in the U.S. The overall drug development stages are shownschematically in Fig. 2.

Prior to the start of definitive efficacy or Phase 3 trials, the sponsor

usually requests to meet with the FDA at an End-of-Phase 2 meeting. At thismeeting, the sponsor discusses with the Agency the information that hasbeen learned about the clinical pharmacology and the limited informationobtained in patients about the safety and efficacy of the drug. End-of-Phase2 meeting discussions with the FDA usually revolve around the decision asto whether the sponsor should proceed to conduct the larger Phase 3 trialsand, if so, the appropriate study design for these larger Phase 3 studies.Clinical trial simulations using the in vitro and in vivo data collected from

the early phases of development may also aid in optimal design of the Phase3 trials. The sponsor can request a special protocol assessment [1] forevaluating issues related to the adequacy (e.g., design, conduct, analysis) ofcertain proposed studies associated with the development of their drugproducts. Three types of protocols are eligible for this special protocolassessment: (1) animal carcinogenicity protocols, (2) final product stabilityprotocols, and (3) clinical protocols of Phase 3 trails whose data will form


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the primary basis for an efficacy claim (if the trials had been discussed at anEnd-of-Phase 2/pre-Phase 3 meeting or if the review division is aware of thedevelopmental context in which the protocol is being reviewed). The FDAhas 45 days to review the protocol and provide scientific/regulatorycomments to the sponsor as needed [2]. The guidance recommends that a

sponsor submit a protocol intended for special protocol assessment to theAgency at least 90 days prior to anticipated commencement of the study.The protocol should be complete and sufficient time should be allowed todiscuss and resolve any issues before the study begins. Special protocolassessments are not to be provided after a study has begun.

There is also a keen interest on the part of the sponsors and the FDA tohave a pre-Phase 2 meeting (Phase 2A meeting; i.e., prior to starting thepivotal Phase 2 study in a small set of patients). During this meeting,

information available on preclinical studies and Phase 1 studies conductedup to that time can be integrated to assess and discuss Phase 2 protocols.These meetings could provide great opportunity to discuss dosing rationalefor the Phase 2 trials, evaluation of appropriate biomarkers, and assessmentof exposure-response relationships. There is great interest in these earlyinteractions between the sponsor and the FDA because resources can beused more efficiently and effectively by early communications. There is great

FIGURE 2 Stages in drug development and regulatory process. http://www.fda.gov/cder.

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opportunity for the sponsor and FDA to identify any limitations in the drugdevelopment plan early on, so that all relevant information is available atthe time NDA/CTD is submitted to the FDA. These meetings have potentialto reduce number of review cycles that some times result, and to produce abetter drug product label.

Data and information from all studies conducted during the IND phaseare summarized and submitted in one package, i.e., NDA. Prior tosubmission of the NDA, generally the sponsor requests the FDA for a face-to-face Pre-NDA meeting (usually a few months prior to the submission ofthe NDA). Issues discussed during this meeting include the content andformat of the different sections of the NDA that would be consideredfileable, including issues related to electronic submission of the NDA. Atthis meeting, assessment is also made if any critical piece essential forregulatory decision-making is missing. The FDA has issued a guidance to theindustry on the format and content of electronic submissions that are madeto the Agency and are available on the FDA Website.

Once an NDA is submitted to the FDA, the agency assigns an NDAnumber to the drug. Since not all drugs being investigated as IND become asuccessful candidate for marketing, it should be noted that NDA number isa different number than an IND number. Once an NDA has been submitted,

all correspondence for that NDA should reference that NDA number. FDAhas 60 days to file that submitted NDA, or FDA could refuse to file an NDAdue to format and content issues or absence of critical piece(s) ofinformation/data needed for the FDA to make a decision on theapprovability of the NDA.

Under the Prescription Drug User Fee Act of 1992 (PDUFA), the FDAhas defined timeframes applicable to drug application reviews. The FDAusually takes 6 to 10 months from the date of submission of the NDA to

make a decision of the acceptability of the application, often referred to asNDA action. This time frame depends on the type of NDA submitted. TheFDA gives a priority designation for a product that if approved would be asignificant improvement compared to marketed products in the treatment,diagnosis, or prevention of a disease. Evidence of increased effectiveness,elimination, or reduction of treatment related drug reactions, safety, andeffectiveness in a new subpopulation, or enhanced patient compliance candemonstrate improvement. All applications not qualifying as priority are

classified as standard applications. Priority applications are reviewedwithin six months, where as standard applications have a 10-monthreview clock. A decision regarding the assignment of a standard or apriority rating to the application is made before the 60 day filing ofthe NDA.

There are certain types of drug approval processes that facilitate thedevelopment and expedite the review of the new drugs that are intended to


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treat serious life threatening conditions and to demonstrate the potentialas treatment for an unmet medical need. Some of these programs are theaccelerated drug approval/fast track programs or rolling submissions. Theaccelerated drug approval program (Subpart H) is a highly specializedmechanism for speeding the development/review of drugs that promisesignificant benefit over existing therapy for serious or life-threateningillnesses like AIDS, cancer, Parkinsons disease etc., and for a condition forwhich no therapy exists. This program involves the modification of thecriteria on which the approval is based on. It allows for approval to bebased on a surrogate endpoint or an effect on a clinical end point otherthan survival or irreversible morbidity. Under such circumstances, theprogram may require appropriate post approval studies to validate thesurrogate endpoint or otherwise confirm the effect on a valid clinicalendpoint.

When certain sections of an application are accepted by the Agency priorto the receipt of the complete application, the submissions are referred to asrolling NDA submissions (i.e., pre-submission of pharm-tox reports, clinicalstudy reports, and even data summaries and listings from the first of two ormore pivotal trials). Sponsors of designated fast track products can requestthis type of submission by submitting certain completed portions of an NDA

prior to submitting the other sections of the application. In such cases thesponsor is required to provide a schedule for submitting the informationnecessary to make the NDA submission complete. Further details of theseprograms can be found under Regulatory Guidance and Mapp (Manual ofPolicy and Procedure) on the FDA website [1, 3].

Sometimes there is a need for either an Advisory Committee Meeting or aface-to-face meeting with the sponsor to discuss issues that arise during theNDA review process. Once the NDA is submitted, pivotal study sites are

identified and inspected for good clinical practices (GCP) and goodlaboratory practices (GLP) compliance by the Office of Compliance. AnNDA action is taken after obtaining results from the inspection of the studysite. The action could result in the approval or non-approval of an NDA, orin an approvable NDA. An approvable NDA implies that the informationthat has been reviewed by the FDA appears to be an acceptable data;however, some additional information is needed to approve the product formarketing in the United States. This could involve collection of additional

data, data re-analysis or negotiation of labeling language. The overall NDAreview process is shown schematically in Fig. 3.

Table 1 summarizes the type of studies that are typically part of theclinical pharmacology and biopharmaceutics plan for a new drug, andTable2 gives an example of how all of the clinical pharmacology andbiopharmaceutics information can be summarized concisely. Readers are


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FIGURE 3NDA review process, http://www.fda.gov/cder.

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TABLE 1General list of Studies Submitted to Support the Clinical Pharmacologyand Biopharmaceutics Portion of the NDA


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also encouraged to refer to the FDA website and the ICH CommonTechnical Document that provides information on what information annew drug application should contain.

CLINICAL PHARMACOLOGY CONSIDERATIONS IN NEW

DRUG DEVELOPMENT

In a new drug application, the OCPB reviewer is looking for data andanalyses that provide a rational justification for the selected dose/dosingregimen as well as the sponsors attempt to individualize doses in certainpopulations and/or scenarios, e.g., in pediatrics, in elderly, in renal/hepaticimpairment, and in presence of concomitant medications. The sponsorusually generates this information in the IND stage of the regulatoryprocess. The reader is also encouraged to read the article that describes thequestion-based review approach that the Office of Clinical Pharmacologyand Biopharmaceutics follows [4]. The chapters presented in this bookprovide a general approach to drug development.

There may be some classes of drugs with certain characteristics (e.g.,chirality), formulation (e.g., liposomes) or certain indications (e.g.,

biologicals) which may need additional consideration in their evaluation.Some of these cases are discussed in various chapters of this book.

BIOPHARMACEUTICS CONSIDERATIONS IN NEW DRUG

DEVELOPMENT

Biopharmaceutics is a comprehensive term denoting the study of the

influence of pharmaceutical formulation variables on the performance ofthe drug in vivo [5]. In a new drug application, the OCPB reviewer generallylooks for the pH solubility profile, pKa of the drug substance, drugpermeability or octanol/water partition coefficient measurement which maybe useful in selecting the dissolution methodology and specifications.

Dissolution of the drug under physiological conditions is one of thefactors assessing drug absorption after oral administration. Dissolutiontesting is required for all solid oral dosage forms in which absorption of the

drug is necessary for the product to exert the desired therapeutic effect. Inaddition to predicting in vivo performance of the dosage units, dissolutiontests help in assuring drug product quality from batch to batch and may alsobe a guide in the development of new formulations. The dissolutionspecifications set forth also ensure the drug products sameness underscaleup and postapproval changes. Dissolution data also provides forassessing the waiver of a bioequivalence study. For NDAs the dissolution


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TABLE 2Summary of Clinical Pharmacology and Biopharmaceutics Characteristic of th


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specifications are based on acceptable clinical, pivotal bioavailability and/orbioequivalence batches.

Biopharmaceutics issues depend on the route of administration as well asthe kind of dosage forms (oral versus other routes of administration,immediate release dosage form, and modified release dosage forms). Someof these issues have been covered in the various chapters of this book.

The final formulation the sponsor wishes to market may not always bethe one that has been used during the drug development. These formulationchanges may be necessary due to variety of reasons ranging from aesthetic tooverall improvement in formulation performance or to accommodatemanufacturing convenience. It is essential to know that the to-be-marketedformulation will perform in the same way as the clinical trial formulationperformed in the pivotal clinical studies. For an NDA, bioequi valencestudies provide a link between the pivotal and early clinical trialformulation, a link between the formulations used in the pivotal clinicaltrial, and the to-be-marketed formulation or any other comparisons asappropriate. Bioequivalence studies provide information on the productquality and performance, when there are changes in components,composition and method of manufacture after approval of the drugproduct. The FDA has provided Guidance for the industry, such as BA/BE

guidance [6], SUPAC-IR [7], and SUP AC-MR [8], to determine when thechanges in the components and composition and/or method of manufactureof the drug product suggest a need to perform further in vitro/in vivostudies. Although, SUP AC stands for Scale-up and Post Approval Changesto the formulation, the same principals outlined in these guidances areutilized at the preapproval stage of the drug to determine the level of dataneeded for bio waivers.

PRODUCT LABEL

One of the most important products of the drug development is the drugproduct labeling. Since this is the document that will be utilized by theprescribing Physicians to appropriately dose the patients, great care is takenby the FDA and Industry Scientist to provide accurate information in a clearand concise way in the product labeling. Labeling guides the prescriber,

based on data obtained from clinical trials, in optimizing the dose anddosage regimen for all populations and outlines the adverse events whichwere experienced by patients in the clinical trials etc. Labeling generally hasthe following subheadings: Warnings, Description, Chemical Structure,Clinical Pharmacology, Indication and Usage, Contraindications,Precautions, Adverse Reactions, Overdosage, Dosage and Administration,How Supplied, and Product Photos. In general, Clinical Pharmacology


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sections describe the clinical studies conducted to obtain pharmacokineticdata in healthy subjects, patients, special populations and drug-druginteractions.

Precautions and contradictions will generally highlight data that wouldrequire a caution or adjustment of dose. The dosage administration sectiongives the approved dose and recommended dosage adjustments underspecial circumstances. Presently, there is an initiative where a working groupat FDA is working on reforming the label so that important information forthe prescriber is highlighted in the beginning of the label.

SUMMARY

Drug development is a complex process that requires collaboration ofscientists with varying expertise. For any new drug being developed, teamsof scientists are responsible within an industry to develop the drug, and ateam of scientists at the FDA are responsible to review the IND and NDAsubmitted to the FDA.

Involvement of FDA scientists generally starts with the submission of apre-IND meeting request by the sponsor. Although FDA scientists are

involved and interact with the sponsor during the entire drug developmentprocess, some of the key interaction occurs when the sponsor submits anIND, drug development plan, pre-Phase 2 meetings, End-of-Phase 2meeting, pre-NDA meeting, and when the protocols are submitted duringthe IND phase of development. For optimal drug development, FDAencourages sponsor to have open communication and reviewers areavailable to meet the industry scientists at any stage of drug development.These meetings provide a forum for interactive exchange of scientific ideas.

To encourage and facilitate meeting between the industry and sponsorscientists, a document describing process of arranging meetings has beenpublished as manual for policies and procedures for meetings and ispublished on the FDA website [1].

For ease of understanding and getting an overview of the drugdevelopment, it is important to summarize the assessment of new drugapplication in one table. One example of such a table has been provided inTable 2in this chapter.

Once the FDA scientist has completed the review, the important part is toconvey the data in a clear way, so that the physicians can make informeddecision as to what is best for the patients. Readers are encouraged to lookat completed NDA reviews available on FDAs, Freedom of Information(FOI) Website to gain insight into the regulatory issues that may arise duringreviews of NDAs.


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In this chapter we have briefly covered the IND and NDA review process.However, it is beyond the scope of this book to cover in detail severalregulatory considerations such as good clinical practices, good laboratoryprocesses, advisory committee meetings, orphan drugs, supple-mentalNDA, post approval changes, etc. Readers are referred to the FDA, ICH,and other regulatory agency Websites to get additional information orupdates on scientific and regulatory issues related to new drug development.

REFERENCES

1. http://www.fda.gov/cder/guidance/index.html

2. Guidance for Industry: Special Protocol Assessment, Food and Drug Admini-stration, May 2003.

3. Guidance for Industry: Fast Track Development Programs-Designation,Development and Application review, Food and Drug Administration, September1998.

4. Lesko, L.J.; Williams, R.L. The Question-Based Review: A ConceptualFramework for Good Review Practices. Applied Clinical Practice 1999,8,5662.

5. Rowland; Tozer. Clinical Pharmacokinetics. Concepts and Application,3rd Ed.,Williams and Wilkins, 1995.

6. Guidance for Industry: Bioavailability and Bioequivalence Studies for OrallyAdministered Drug ProductsGeneral Considerations, Food and DrugAdministration, October 2000.

7. Guidance for Industry: Immediate Release Solid Oral Dosage Forms Scale-Upand Postapproval Changes: Chemistry, Manufacturing, and Controls, In-VitroDissolution Testing, and In-Vivo Bioequivalence Documentation, Food and DrugAdministration, November 1995.

8. Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage FormsScale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls;In Vitro Dissolution Testing and In Vivo Bioequivalence Documenta-tion, Foodand Drug Administration, October 1997.
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