INVESTIGATIONAL NEW DRUG ,ORANGE BOOK,

UNDERSTANDING ON 505(b) (2) APPLICATIONS

INVESTIGATIONAL NEW DRUG ,ORANGE BOOK,

UNDERSTANDING ON 505(b) (2) APPLICATIONS

Prepared By: S.Susena( M. Pharm Sem-2)I.P.R . Department

Guided by: Y.MalyadriS. S. J. Pharmacy College

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CONTENTS

INVESTIGATIONAL NEW DRUG (IND)INTRODUCTIONPRE-IND MEETING THE CONTENT AND FORMAT OF AN IND APPLICATION

ORANGE BOOKUNDERSTANDING ON 505(b) (2) APPLICATIONSCONCLUSIONREFERENCES

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New Drug Development Process.

InitialSynthesis

AnimalTesting

IND

APPLICATION

Phase I

Phase II

Phase III

Phase IV

AdverseReactionReporting

Surveys/SamplingTesting

Inspections

Range 1-3 Yrs.Avg:18 Mos.

FDA Time30 DaySafety Review

Range 2-10 Yrs.Avg : 5 Yrs.

NDASubmitted

NDAApproved

Range 2 Mon –7 Yrs. Avg:24 Mos.

Average of Approximately 100 Months From Initial Synthesis to Approval of NDA

Treatment Use

Preclinical Clinical Development NDA Review Post-Marketing

Introduction

An Investigational New Drug Application (IND) is a submission to the Food and Drug Administration requesting permission to initiate a clinical study of a new drug product.

The Federal Food, Drug, and Cosmetic Act requires that all drugs have an approved marketing application (NDA, BLA, ANDA) before they can be shipped in interstate commerce.

 

The IND application allows a company to initiate and conduct clinical studies of their new drug product.

The IND application provides the FDA with the data necessary to decide whether the new drug and the proposed clinical trial pose a reasonable risk to the human subjects participating in the study.

When Do I Need an IND?An IND is required any time you want to conduct a clinical trial of an unapproved drug The Act further defines a new drug, in part, as “any drug the composition of which is such that such drug is not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling

When You Don’t Need an IND?

An IND is not required to conduct a study if the drug: Is not intended for human subjects, but is intended for in vivo testing or laboratory research animals (non clinical studies) Is an approved drug and the study is within its approved indication for use.

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Pre-IND Meeting A meeting between the sponsor and

the FDA frequently is useful in resolving questions and issues raised during the preparation for an IND.

The FDA encourages such meetings to the extent that

1.They aid in the solution of scientific problems and

2. To the extent that the FDA has available resources. 8

The Content and Format of an IND Application

The content and format of an initial IND is laid out in 21 CFR Part 312 Cover Sheet —312.23(a)(1)FDA Form 1571 Table of Contents —313.23(a)(2) Introductory Statement and General Investigational Plan —312.23(a)(3) Investigator’s Brochure —312.23(a)(5) Clinical Protocol —312.23(a)(6) Chemistry Manufacturing and Controls Information —312.23(a)(7)

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Pharmacology and Toxicology Information —312.23(a)(8) Previous Human Experience —312.23 (a)(9) Additional Information —312.23(a)(10)Relevant Information —312.23(a)(11)Other Important Information about the Format, Content and Submission of an INDThe FDA Review of the IND

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 IND review flow chart

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Additional Information —312.23(a)(10) : 

This section is used to present information on special topics. Drug dependence and abuse potential. Radioactive drugs. Pediatric studies. Any plans the sponsor has for assessing the safety and effectiveness of the drug in the pediatric population. Other information. Any other relevant information that might aid in the evaluation of the proposed clinical investigations.

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Relevant Information —312.23(a)(11) :

Any information specifically requested by the FDA that is needed to review the IND application.

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Other Important Information about the Format, Content and Submission of an IND :

For clinical studies that will be submitted as part of an NDA or BLA, IND sponsors must collect financial disclosure information from each investigator or sub investigator who is directly involved in the treatment or evaluation of clinical trial subjects. The sponsor may also reference a drug master file (DMF) in the IND application that contains important information necessary to complete review of the IND. Reports or journal articles in a foreign language must be accompanied by a complete and accurate English translation. Each IND submission must include a four-digit serial number. 14

IND Annual Reports : The IND regulations require IND sponsors to submit an annual report that provides the FDA with a brief update on the progress of all investigations included in the IND. The annual report must contain the following information: Individual study information ,Summary Information ,The general investigational plan for the coming year. If the investigator brochure was modified during the year, a list of the changes along with a copy of the new brochureA listing of any significant foreign marketing developments with the drug, e.g., approval in another country or withdrawal or suspension of marketing approval.

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CLASSIFICATION of INDs

INDs can be classified on four dimensions: Commercial / Noncommercial, Standard / Emergency, Paper / Electronic, Original / 505(b)(2).

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Orange book

Its official title is Approved Drug Products with Therapeutic Equivalence Evaluations .

Commonly known as the Orange Book due to the orange cover of the original print version, it is the Food and Drug Administration's list of all drugs approved in the United States as safe and effective. In addition to listing all approved drugs, the Orange Book is also the authoritative source of information on the therapeutic equivalence of drug products.

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THE GREEN BOOK: the Green Book had some additional and advantageousfeatures. For example, it listed drugs for which “authorizedgenerics” were available, information which the Orange book

does not contain

THE BLUE BOOK: The FDA publication Requirement of Laws and Regulations

Enforced by the U.S. Food and Drug Administration. It has been discontinued as of October 2002. In its place there is a Wealth Of Compliance Information on the FDA

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The Orange Book consists of five main sections: an introduction, a “how to use” section, the drug product lists, appendices, and a patent exclusivity information addendum. 

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TE CodesTE codes are divided into two categories, A and B ‘A’ Drugs are those which the FDA considers to be therapeutically equivalent and, therefore, substitutable where permitted by the prescriber. They are further divided as follows: ‘B’ Drugs are those which the FDA considers NOT to be therapeutically equivalent due to actual or potential bioequivalence problems which have not been resolved. B-rated drugs are not legally substitutable

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CODE A product that FDA considers

AA: Products in conventional dosage form. AB, AB1, AB2, AB3: Products meeting necessary bio-equivalence requirements AN: Solutions and powder for aerosolizationAO: Injectable oil solutions AP: Injectable aqueous solutions and intra-venous non-aqueous solutions AT: Topical products AB: actual or potential bioequivalence problems have been resolved through adequate in vivo and/or in vitro testing.

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BC Extended-release dosage forms (capsules, injectables and tablets) BD Active ingredients and dosage forms with documented bioequivalence problems BE Delayed-release oral dosage forms BN Products in aerosol-nebulizer drug delivery systems BP Active ingredients and dosage forms with potential bioequivalence problems BR Suppositories or enemas that deliver drugs for systemic absorption BS Products having drug standard deficiencies BT Topical products with bioequivalence issues BX Drug products for which the data are insufficient to determine therapeutic equivalence

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UNDERSTANDING ON 505(b) (2) APPLICATIONS

The 505(b)(2) New Drug Application – A Rapid Approval Route The 505(b)(2) application is one of three established types of new drug application (NDA), and it is a pathway to approval that can potentially save pharmaceutical sponsors both time and money

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Basics of the 505(b)(2)Considered a full NDA Must be the same active product (API) Reporting requirements

Previously reported safety and efficacy Information from studies not conducted by applicant Relying on FDA’s prior conclusions on safety and/or

efficacy from Non-clinical or Clinical Information where applicant lacks the right of reference

New studies to support change

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NDA 505(b)(2)Products allowed under 505(b)(2): Changes to previously approved drugsDosage regimenAPI change (salt, ester, complex, chelate,) New indicationRx/OTC switchBioinequivalent to, but not inferior bioavailabilitycompared to the Reference Listed Drug (RLD) Formulation changes outside 505(j) limits Can not be used for products eligible for ANDA

NDA 505(b)(2)

Products not allowed under 505(b)(2):• That are covered under Section 505(j) • For which the only difference is lower extent of absorption than reference drug • For which the only difference is an unintended lower rate of absorption than reference drug

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505(b)(2) NDA ExamplesRoute of Administration

IV to other parenteral routes Active Ingredient

Change in salt, racemate or enantiomerNew Molecular Entity

Prodrug of an approved drug Active metabolite of an approved drug

New combination product Combining actives previously approved individually

Formulation change Excipient not allowed under 505(j)

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The 505(b)(2) Process Major Elements

Meetings and Materials Pre-IND EOP2 Pre-NDA (pre-BLA)

Submissions IND NDA

FDA Interactions 28

CONCLUSION

The IND application allows a company to initiate and conduct clinical studies of their new drug product.

The Orange Book is also the authoritative source of information on the therapeutic equivalence of drug products.

The 505(b)(2) pathway is potentially low risk and has advantages in regards to time and money and,perhaps,exclusivity. Can get early FDA feedback

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Referenceswww.fda.gov/opacom/laws/lawtoc.htmwww.fda.gov/cder/guidance/index.htmwww.fda.gov/cber/guidelines.htmwww.fda.gov/cder/handbook/www.fda.gov/cder/mapp.htmwww.fda.gov/oc/gcp/default.htmwww.regsource.com/default.html

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