1

APPROVED DRUG PRODUCTS WITH THERAPEUTIC

EQUIVALENCE EVALUATIONS( T H E O R A N G E B O O K )

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Health Care Costs Continue to Increase upto 44% by 2006

Clinicians are increasingly encouraged to prescribe GENERIC drugs for effective treatment

So health cost of patient increases since branded drugs are costly

Before substituting a generic product, physicians and other decisions makers should consider the potential clinical and pharmacoeconomic consequences like Over and Undertreatment, Adverse effects, Additional expenses and Cost savings

To help avoid complications arising from product substitution, the FDA established a list of generic drugs that can be safely and appropriately substituted for brand products

The FDA has prepared a list of drugs that are bioequivalent they can be substituted for each other

These drugs are listed in a federal publication called Approved Drug Products With Therapeutic Equivalence Evaluations

known as the Orange Book

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CONTENTCONTENT . . .

A. WHAT IS THE NEED OF “ THE ORANGE BOOK ” ?

B. INTRODUCTION TO “ THE ORANGE BOOK ” ?1. Definition2. History 3. Objectives

C. CONTENTS OF “ THE ORANGE BOOK ”

D. CUMMULATIVE SUPPLEMENT

E. WHAT IS “ THE GREEN BOOK ” AND “ THE BLUE BOOK ” ?

F. QUESTIONS

G. REFERENCES

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B. INTRODUCTION TO “ THE ORANGE BOOK ” ?

1. Definition

2. History

3. Objectives

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1. Definition1. Definition

It is the publication of “Approved Drug Products With Therapeutic Equivalence Evaluations” by the Food and Drug Administration.

It is prepared by The Orange Book Staff, Center for Drug Evaluation and Research.

It identified drug products on the basis of safety and effectiveness by the Food and Drug Administration under the Federal Food, Drug, and Cosmetics Act.

Drugs marketed only on the basis of safety or pre-1938 drugs.

The list is independent of any current regulatory action against a drug product.

The main criterion for the inclusion of any product is that the product is the subject of an application with an effective approval that has not been withdrawn for safety or efficacy reasons.

The FDA does not recommend substituting drugs that have not been determined to be bioequivalent.

Drugs that are not listed as bioequivalent should not be substituted for each other.

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2. History 2. History

YEAR ACTION

May 31, 1978

The Commissioner of the Food and Drug Administration sent a letter to officials of each state stating FDA's intent to provide a list of all prescription drug products that are approved by FDA for safety and effectiveness, along with therapeutic equivalence determinations for multisource prescription products.

January, 1979The list was distributed (included only currently marketed prescription drug products approved by FDA through NDAs and ANDAs under the provisions of section 505 of the Act)

October 31, 1980The final rule (includes FDA’s response to the public comments on the proposal) was published in the Federal Register (45 FR 72582). The list incorporated appropriate corrections and additions.

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3. Objectives3. Objectives 3. Objectives3. Objectives

To allow review of patterns of

access and usage

To allow review of patterns of

access and usage

To allow discovery of

use of unusual

privileges

To allow discovery of

use of unusual

privileges

To allow discovery of

repeated attempts to bypass

protections

To allow discovery of

repeated attempts to bypass

protections

To serve as a

deterrent by its

existence

To serve as a

deterrent by its

existence

To supply an

additional form of user

assurance

To supply an

additional form of user

assurance

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C. CONTENTS OF “ THE

ORANGE BOOK

(PREFACE TO 27 EDITION)

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1.1. INTRODUCTIONINTRODUCTION

1.1 Content and Exclusion

1.2 Therapeutic Equivalence-Related Terms

1.3 Statistical Criteria for Bioequivalence

1.4 Reference Listed Drug

1.5 General Policies and Legal Status

1.6 Practitioner/User Responsibilities

1.7 Therapeutic Equivalence Evaluations Codes

1.8 Description of Special Situations

1.9 Therapeutic Equivalence Code Change for a Drug Entity

1.10 Change of the Therapeutic Equivalence Evaluation for a Single Product

1.11 Discontinued Section

1.12 Changes to the Orange Book

1.13 Availability of the Edition

2.2. HOW TO USE THE DRUG PRODUCTS LISTSHOW TO USE THE DRUG PRODUCTS LISTS

2.1 Key Sections for Using the Drug Product Lists

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2.2 Drug Product Illustration

2.3 Therapeutic Equivalence Evaluations Illustration

DRUG PRODUCT LISTS

Prescription Drug Product List

OTC Drug Product List

Drug Products with Approval under Section 505 of the Act Administered by the Center for Biologics Evaluation and Research List

Discontinued Drug Product List

Orphan Products Designations and Approvals List

Drug Products Which Must Demonstrate in vivo Bioavailability Only if Product Fails to Achieve Adequate Dissolution

APPENDICES

A. Product Name Index A-1

B. Product Name Index Listed by

C. Uniform Terms

PATENT AND EXCLUSIVITY INFORMATION ADDENDUM

A. Patent and Exclusivity Lists

B. Patent and Exclusivity Terms

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CONTENTS OF “ THE ORANGE BOOK

1. INTRODUCTION

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1.1 Content and Exclusion1.1 Content and Exclusion

Approved OTC drug products for those which are not marketed

Approved prescription drug withtherapeutic equivalence evaluations

Drug products with Biologics Evaluation and Research

List of approved products that have been discontinued from marketing

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Cont…

The List also includes: Indices of prescription and OTC drug by trade or

established name (if no trade name exists) and by applicant name (holder of the approved application).

The list includes applicants’ names in abbreviated form.

An Addendum contains drug patent and exclusivity information for the Prescription.

It includes only full approval products and not tentative approval products.

The List excludes: Distributors or re-packagers of products

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1.2 Therapeutic Equivalence-Related Terms

Pharmaceutical equivalents

Pharmaceutical alternatives

Therapeutic equivalents

Bioequivalence Bioavailability

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Pharmaceutical Equivalents

1. Contain the same active ingredient(s),

2. Have the same dosage form and route of administration, and

3. Identical in strength or concentration

4. May differ in shape, release mechanisms, and packaging

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Pharmaceutical Alternatives

Contain the same therapeutic moiety but might differ in ,

1. Salts, esters, or complexes form of the same moiety,

2. Different dosage forms,

3. Different strengths

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Therapeutic Equivalents

Therapeutic equivalents are expected to have the same clinical effect and safety profile.

Drug products are considered therapeutic equivalents if they are all of the following

1. Pharmaceutical equivalents

2. Bioequivalent

3. Approved as safe and effective

4. Adequately labeled

5. Manufactured in compliance with current Good Manufacturing Practice regulations

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Bioequivalence

Drug products are considered bioequivalent if they are pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to subjects at the same molar dose under similar experimental conditions

Bioequivalence use to determine Therapeutic Equivalents

comparative clinical trials

pharmacodynamic studies

in vivotest methods

in vitrotest methods

Demonstrated by

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1.3 Statistical Criteria for Bioequivalence

In short Bioequivalence refers to equivalent release of the same drug substance from two or more drug products.

The standard bioequivalence (PK) study is conducted in 24-36 adults using a two-treatment crossover study design.

Alternately, a four-period, replicate design crossover study can also be used.

The statistical methodology for analyzing these bioequivalence studies is called the two one-sided test procedure.

Two situations are tested with this statistical methodology.

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Cont…

Pharmacokinetic parameters determine are AUC and Cmax.

Two criteria includes, 1. Whether a generic product (test), when substituted for a brand-name

product (reference) is significantly less bioavailable. (A limit of test-product average/reference-product average of 80%)

2. Whether a brand-name product when substituted for a generic product is significantly less bioavailable. (A limit of reference-product average/test-product average 125%)

A difference of greater than 20% for each of the above tests was determined to be significant

The confidence interval for both pharmacokinetic parameters, AUC and Cmax, must be entirely within the 80% to 125% boundaries cited above

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Example,

Product A is bioequivalent to the reference drug; its confidence interval of the AUC falls within 80% to 125% of the reference drug

Product B is not bioequivalent to the reference drug; its confidence interval of the AUC falls outside of 80% to 125% of the reference drug

125%

100%

80%

Product ABioequivalent

Reference Drug

Product BNot Bioequivalent

Pha

rmac

okin

etic

Ref

eren

ce R

ange

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1.4 Reference Listed Drug

A reference listed drug means the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA.

The aim of FDA is to avoid possible significant variations among generic drugs and their brand name counterpart.

The reference listed drug is identified by the symbol "+" in the Prescription and Over-the-Counter (OTC) Drug Product Lists.

List is available for oral dosage forms, injectables, ophthalmics, otics, and topical products.

Applicant's productBioequivalence study carried out

Compared with reference standardIn vivo & Invitro

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1.5 General Policies and Legal Status

The List contains public information and advice.

It is not compulsory the drug products which may be purchased, prescribed, dispensed, or substituted for one another, nor does it, should be avoided.

Exclusion of a drug product from the List does not necessarily mean that the drug product is not safe or effective, or that such a product is not therapeutically equivalent to other drug products.

Rather, FDA has not evaluated the safety, effectiveness, and quality of the drug product.

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1.6 Practitioner/User Responsibilities

Professional care and judgment should be exercised in using the list.

Practitioner should be aware of the multi-source and single-source drug products.

1. Multisource Drug Product means those pharmaceutical equivalents available from more than one manufacturer. For such products, a therapeutic equivalence (TE) code is included and, in addition, product information is highlighted in bold face and underlined.

2. Single-Source Drug Product means only one approved product is available for particular active ingredient, dosage form, route of administration, and strength. For such product no therapeutic equivalence code is included.

Products on the List are identified by the names of the holders of approved applications (applicants) who may not necessarily be the manufacturer of the product:

Applicants like Manufacture, Contract Manufacturer, Repackager, Distributor or Marketer.

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1.7 Therapeutic Equivalence Evaluations Codes

A CODES

1. TE rating is assigned to PE products as they are manufactured in accordance with cGMP regulations and meet the other requirements of their approved applications or

2. For those DESI (Drug Efficacy Study Implementation) drug products and for post-1962 drug products in a dosage form presenting a potential bioequivalence problem, an evaluation of TE is assigned to PE, if approved application contains scientific evidence establishing through in vivo and in vitro studies.

B CODES

1. Documented bioequivalence problems and no adequate bioequivalence have been submitted to FDA

2. The quality standards are inadequate to determine therapeutic equivalence

3. The drug products are under regulatory review

The coding system for therapeutic equivalence evaluations

First letter : therapeutically equivalent to other pharmaceutically equivalent products

Second letter : provide additional information on the basis of FDA's evaluations

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Code ‘A’: Drug product that FDA considers to be therapeutically equivalent

Sr. Codes Description

1. AA Products in conventional dosage forms not presenting bio-equivalence problems (All oral dosage forms)

2. AB (AB1, AB2, AB3 …)

Products meeting necessary bio-equivalence requirements (Multisource drug product )

(In certain instances, a number is added to end of the AB code to make a three character code, which is assigned only in situations when more than one reference listed drug of the same strength has been designated under the same heading.

Two or more reference listed drugs are generally selected only when there are at-least two potential reference drug products which are not bio-equivalent to each other)

3. AN Solutions and powder for aerosolization (Marketed for use in any of several delivery systems)

4. AO Injectable oil solutions

5. AP Injectable aqueous solutions and in certain cases, intra-venous non-aqueous solutions (Different routes of administration, Different preservatives or no preservatives, Dry powders for reconstitution, Concentrated sterile solutions for dilutions, Sterile solutions ready for injection Should produce same concentration prior to injection)

6. AT Topical products

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Code ‘B’: Drug product that are not to be therapeutically equivalent

Sr Codes Description

1. B* Drug products requiring further FDA investigation and review to determine therapeutic equivalence.

2. BC Extended release dosage forms (capsules, injectable and tablets bioequivalence data have not been submitted).

3. BD Active ingredients and dosage forms with documented bio-equivalence problems (Adequate studies have not been submitted to FDA since due to bio-equivalence problems).

4. BE Delayed release oral dosage forms (Significant differences in absorption).

5. BN Products in aerosol-nebulizer drug delivery systems (differences in the dose of drug and particle size delivered by different products)

6. BP Active ingredients and dosage forms with potential bio-equivalence problems

7. BR Suppositories or enemas that delivers drug for systemic absorption

8. BS Products having drug standard deficiencies (variation in pharmacologically active components)

9. BT Topical product for which the data are in-sufficient to determine therapeutic equivalence

10 BX Drug products for which the data are insufficient to determine therapeutic equivalence

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1.8 Description of Special Situations

Drugs Description of Special Situations

Amino-acid and Protein Hydrolysate injections

These products differ in the amount and kinds of amino-acids they contain, and therefore, are not considered pharmaceutical equivalents. For this reasons, these products are not considered therapeutically equivalent.

Follitropin alpha and beta Physico-chemical tests and bio-assay, follitropin alpha and follitropin beta are indistinguishable

Gaviscon® tablets Gaviscon® is an OTC product which has been marketed since September 1970. The active ingredients in this product, aluminum hydroxide and magnesium trisilicate, were reviewed by the Agency's OTC Antacid Panel . However, the tablet failed to pass the antacid test which is required of all antacid products. The Agency, therefore, placed the tablet in Category III for lack of effectiveness.

Patent certification (s) Reference listed drug based upon a suitability petition

ANDA that refers to a Reference Listed Drug (RLD) approved pursuant to a suitability petition must demonstrate that the proposed product is bioequivalent to the RLD

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1.9 Therapeutic Equivalence Code Change for a Drug Entity

Such change occur in response to a petition or on its own initiative.

Changes will generally occur when new scientific information affects the therapeutic equivalence of an entire category of drug products in the List.

The change may be from the code,

This procedure does not apply to a change of a particular product code (e.g., a change from BP to AB or from AB to BX).

AA BPBioequivalence problem No Bioequivalence problem

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1.11 Discontinued Section

1. When the product have been discontinued from marketing,

2. Are for military use,

3. Or have had their approvals withdrawn for other than safety or efficacy reasons

4. Drug Products for exportation

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CONTENTS OF “ THE ORANGE BOOK

2. HOW TO USE THE DRUG PRODUCT LISTS

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2.1 Key Sections for Using the Drug Product Lists.

This contains illustrations, along with Drug Product Lists, indices, and lists of abbreviations and terms which facilitate their use.

1. Illustration: Depicts the format found in the Prescription Drug Product List.

2. Drug Product Lists: The Prescription and OTC drug product lists, arranged alphabetically by active ingredient (s), contains product identification information (active ingredients, dosage forms, routes of administration, product names, application holders, strengths) for single and multiple ingredient drug products. Also shown are the application number and drug product number.

3. Product Name Index.4. Product Name Index Listed by Applicant.5. Uniform terms.

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AP

2.2 Drug Product IllustrationSINGLE INGREDIENT

ACTIVE INGREDIENT

DOSAGE FORM : ROUTE OF ADMINISTRATION

TRADE OR GENERIC NAME

REFERENCE LISTED DRUG

TE CODE FOR MULTISOURCE PRODUCT

FINAL APPROVAL DATE

SINGLE SOURCE PRODUCT (NO TE CODE)

APPLICANT

AVAILABLE STRENGTH OF PRODUCT

APPLICANT NUMBER & PRODUCT NUMBER

PRODUCT NUMBER IS FOR FDA INTERNAL COMPUTER DATA USE ONLY

N11586 001N12569 001N14458 002

Aug 11, 1987N22543 004

Aug 28, 1987

N11786 002N24765 003N03841 003

N13111 001N13111 002N13111 003

Aug 22, 1983N13111 004Jan 19, 1985

25 mg / ml50 mg / ml75 mg / ml

100 mg / ml

25 mg / ml50 mg / ml75 mg / ml

100 mg / ml

10 mg / ml25 mg / ml

150 mg / ml

AP + METRO – PHYSAP +AP +

AP +

AP DONHARE PHARMAP AP

AP

JOHONSON MEDHOLOVAC LLCOBS PHARM

MEPIRIDINE HCL

MEPIRIDINE HYDROCHLORIDE

INJECTABLE : INJECTION

HEXANON

AP

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Example

ALBUTEROL : AEROSOL, METERED; INHALATIONVENTOLIN : AB + GLAXOSMITHKLINE 0.09MG/INH N18473 001 ALBUTEROL : AB ARMSTRONG PHARMS 0.09MG/INH N72273 001 Aug 14,

1996 AB GENPHARM 0.09MG/INH N73045 001 Aug 19,

1997

Albuterol : Active IngredientAerosol, Metered; Inhalation : Dosage Form / Route of Administration Ventolin : Proprietary NameAlbuterol : Generic NameGlaxoSmithKline, : Manufacturer‘+’ sign : Indicates Ventolin is Reference Listed Drug (RLD)AB : Therapeutic Equivalence (TE) CodeAmstrong Pharm, Genpharm : Applicant0.09MG/INH : StrengthN18473 001, N72273 001, : Application Number and Product Number of respective

productsAug 14 1996, Aug 19 1997: Final Approval Date

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2.3 Therapeutic Equivalence Evaluations Illustration

Product consider therapeutically equivalent to each other

Product consider not therapeutically equivalent to any other product listed

Product consider not therapeutically equivalent to each other

SULFASALAZINE

TABLET : ORAL

FAZINE

AB

AB

PARKLAND

SULAZINE

URSA

SULFASALAZINE

BPBROWN 500 mg

500 mg

500 mg

N4 1297 001

N4 0222 001

N4 2999 001

SULFASALAZINE

BPBROWN 500 mg N4 1297 001

FAZINE

ABPARKLAND 500 mg N4 2999 001

SULFASALAZINE

TABLET : ORAL

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Cont…

Drug Product reviewed through DESI are not included

It includes only full approval products and not tentative approval products

Drug Product of Repackager/Distributor is considered to be therapeutically equivalent to the Application Holder’s product

Even if the Application holder’s drug product is single source or coded as nonequivalent, repackager’s or distributor’s product is TE to Application Holder’s product

The new approvals and required changes in data are included in each subsequent edition. Even monthly cummulative supplements are published

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DRUG PRODUCT LISTS

1. Prescription Drug Product List

2. OTC Drug Product List

3. Drug Products with Approval under Section 505 of the Act Administered by the Center for Biologics Evaluation and Research List

4. Discontinued Drug Product List

5. Orphan Products Designations and Approvals List

6. Drug Products Which Must Demonstrate in vivo Bioavailability Only if Product Fails to Achieve Adequate Dissolution

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APPENDIX

A. Appendix A: Product Name Index, is an index of Prescription and OTC Drug Products by established or trade names.

B. Appendix B: Product Name Index Listed by Applicant, is an index of Prescription and OTC Drug Products that cross references applicants to drug products.

C. Appendix C: Uniform terms, To improve readability, uniform terms are used to designate dosage forms, routes of administration and abbreviations used to express strengths.

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F. CUMMULATIVE SUPPLEMENTF. CUMMULATIVE SUPPLEMENT

It is one of a series of monthly updates to the Approved Drug Products with Therapeutic Equivalence Evaluations.

Provides information on : Newly approved drugs Revised therapeutic equivalence evaluations Updated patent and exclusivity data Applicant Name Changes

Products that have Never been marketed, Are for exportation, or for military use, Have been discontinued from marketing That have had their approvals withdrawn for other than safety or efficacy reasons will be

flagged in this. Cumulative Supplement with the "@" symbol to designate their non-marketed status. (will be included in Discontinued Section)

New additions to the Prescription Drug Product List and OTC Drug Product List are indicated by the symbol >A>.

The Patent and Exclusivity List new additions are indicated by the symbol >A>

New deletions to the Prescription Drug Product List and OTC Drug Product List are indicated by the symbol >D> (DELETE)

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G. G. THE GREEN BOOKTHE GREEN BOOK & & THE THE BLUE BOOKBLUE BOOK

THE GREEN BOOKTHE GREEN BOOK

It is a list of all animal drug products approved for safety and effectiveness.

It consist of eight sections which are as follow,

THE BLUE BOOKTHE 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 Website. For links to this information, please go to the Website’s Industry Portal<http://www.fda.gov/oc/industry/default.htm>.

Section 1 - NADA Number, Trade Names and Sponsors arranged by  Tradename, NADA Number

Section 2 - Active Ingredients

Section 3 - Patent Information

Section 4 - Exclusivity Periods

Section 5 - Products Subject to Notice of Hearing

Section 6 - Voluntary Withdrawals

Section 7 - Suitability Petition Actions

Section 8 - 2006 Monthly Updates

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H. QUESTIONSH. QUESTIONS

September 20051. Define: Pharmaceutical Equivalents, Pharmaceutical

Alternatives and Therapeutic equivalents. What are the criteria for these equivalents? (Internals July 2006)

2. What are the statistical criteria for Bio-equivalence

September 2006 What are Orange Book, Green Book and Blue Book?

Discuss the coding system for Therapeutic Equivalence Evaluation and how it can be changed giving suitable illustration? (Internals July 2006)

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I. REFERENCEI. REFERENCE

http://www.fda.gov/cder/orange/obannual.pdf http://www.fda.gov/cder/orange/obcs.pdf

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THANK THANK YOUYOU

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