The Role of Orange Book in Bioequivalence. Aaron W. Sigler, Pharm.D., BCPS Office of Generic Drugs Division of Bioequivalence II

Transcription

1 The Role of Orange Book in Bioequivalence Aaron W. Sigler, Pharm.D., BCPS Office of Generic Drugs Division of Bioequivalence II 1

2 The following presentation reflects the opinions of the author and does not necessarily represent the official position of the US-FDA 2

3 Topics for Discussion Brief drug approval history Define a Listed Drug Describe the history of the Orange Book Describe the role of FDA s Orange Book as related to the drug approval process Discuss Therapeutic Equivalence and Bioequivalence, how they are determined, and the basis of Therapeutic Equivalence as it is coded in the Orange Book Describe the process of product selection with respect to choosing a Reference Listed Drug in the Orange Book 3

4 How is a drug approved? FD&C SEC [21 USC 355] New Drugs (a) Necessity of effective approval of application. No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug. 4

5 What is the definition of a prescription drug product? Prescription drug product means a specific strength or potency of a drug in final dosage form for which a human drug application has been approved and which may be dispensed only by prescription under section 503(b) of the FD&C Act, and, after October 1, 2002, is also on the list of products described in section 505(j)(7)(A) or is on a list created and maintained by the Secretary of products approved under human drug applications under section 351 of the Public Health Service Act. (Section 351 of the PHS Act provides the authority for regulating biological products. Biological products are regulated by the Center for Biologics Evaluation and Research.) 5

6 CFR Title Definitions. Listed drug means a new drug product that has an effective approval under section 505(c) of the act for safety and effectiveness or under section 505(j) of the act, which has not been withdrawn or suspended under section 505(e)(1) through (e)(5) or (j)(5) of the act, and which has not been withdrawn from sale for what FDA has determined are reasons of safety or effectiveness. Listed drug status is evidenced by the drug product's identification as a drug with an effective approval in the current edition of FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations" (the list) or any current supplement thereto, as a drug with an effective approval. A drug product is deemed to be a listed drug on the date of effective approval of the application or abbreviated application for that drug product. 6

7 CFR Title Definition Reference listed drug means the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its abbreviated application. 7

8 Reference Standard (RS) and Reference Listed Drug (RLD) RLD is defined in CFR RS is defined in the preamble of the proposed Waxman-Hatch regulations, " Currently, the agency uses one product as a reference standard for bioequivalence (in vivo) determinations. Usually that reference standard is the pioneer drug product. Applicants will be required to refer and show bioequivalence ( in vivo) to the listed drug selected by the agency as the standard for bioequivalence determinations". 8

9 RLD vs. RS A RS is a RLD and a listed drug A RLD is a listed drug and may not be a RS. 9

10 History and Purpose of the Orange Book Proposed by the FDA Commissioner in January 1979 and finalized in October 1980 Contains a list of drug products that are approved as safe and effective Approved multiple source drug products on this list are evaluated for therapeutic equivalence and assigned a Therapeutic Equivalence (TE) code - the basis for generic drug substitution 10

11 History and Purpose of the Orange Book Public information and advice to State and Federal Health Agencies, physicians, pharmacists Promote public education in the area of DRUG PRODUCT SELECTION Foster containment of health care costs 11

12 505 (j)(7)(a) This is the act that refined the Orange Book (7) (A) (i) Within sixty days of the date of the enactment of this subsection [enacted Sept. 24, 1984], the Secretary shall publish and make available to the public (I) a list in alphabetical order of the official and proprietary name of each drug which has been approved for safety and effectiveness under subsection (c) before the date of the enactment of this subsection [enacted Sept. 24, 1984] ; (II) the date of approval if the drug is approved after 1981 and the number of the application which was approved; and (III) whether in vitro or in vivo bioequivalence studies, or both such studies, are required for applications filed under this subsection which will refer to the drug published. 12

13 Purpose of the Orange Book (continued) 1989 CFR Notice to codify the 1984 Act Contains a list of patent and marketing exclusivities that play a key role in when the Agency may approve generic drugs Designates the RLD Not included: BLAs, OTC monograph products, applications with tentative approval Official Title Approved Drug Products with Therapeutic Equivalence Evaluations 13

14 FD&C 505 (j)(2)(a) An abbreviated application for a new drug shall contain (i) information to show that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the new drug have been previously approved for a drug listed under paragraph (7) (hereinafter in this subsection referred to as a "listed drug"); (ii)(i) if the listed drug referred to in clause (i) has only one active ingredient, information to show that the active ingredient of the new drug is the same as that of the listed drug; Route, dosage form, labeling, etc. 14

15 Orange Book All FDA approved drug products listed (NDA s, OTC s & ANDA s) Therapeutic equivalence codes A = Substitutable B = Inequivalent, NOT Substitutable Expiration dates: patent and exclusivity Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products 15

16 Therapeutic Equivalence Coding May substitute if A rated therapeutically equivalent A ratings AA, AN, AO, AP, AT -No known/suspected bioequivalence problem A ratings AB (most common) -Actual or potential bioequivalence problems resolved with in vivo or in vitro studies to support second letter of rating related to dosage form specifics 16

17 Therapeutic Equivalence Coding B ratings BX most common Not Therapeutically Equivalent -- May not substitute May also be BC, BD, BE, BN, BP, BR, BS, BT; depends on the dosage form 17

18 Orange Book 18

19 Orange Book 19

20 Basis of Therapeutic Equivalence Determinations The FDA considers drug products to be therapeutically equivalent if they meet the following 4 criteria: 1. They are pharmaceutically equivalent They contain the same active ingredient in the same dosage form, same strength or concentration and same route of administration; and They meet compendial standards for purity, strength, identity and quality. 20

21 Basis of Therapeutic Equivalence Determinations (continued) 2. They are bioequivalent **comparable bioavailability which is defined as the rate and extent the active moiety is absorbed from a drug product to be available at the site of action 3. They are adequately labeled 4. The are manufactured in compliance with good manufacturing regulations FDA considers a product therapeutically equivalent even though it may differ in minor aspects such as color, preservatives, labeling, etc. 21

22 Definition of Bioequivalence Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to humans at the same molar dose under similar experimental conditions. Same active ingredient, dosage form, route, and strength concentration (i.e. Diltiazem ER Capsules, Synthroid, Nifedipine ER Tablets) 22

23 Purpose of BE Therapeutic equivalence (TE) Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring. The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner. 23

24 Approaches to bioequivalence Most drugs reviewed by the Divisions of Bioequivalence are Absorbed into the systemic circulation Systemically active For such drugs, BE is best demonstrated in a study in human subjects with pharmacokinetic (PK) endpoints Certain products are eligible for a waiver of invivo testing (Q1/Q2 products, etc.) 24

25 Approaches to bioequivalence (continued) Generic products are compared to the corresponding brand product (RLD), typically in studies using the highest strength The generic product must be equivalent within certain pre-specified limits (AUC, C max ) 25

26 Orange Book Committee Meets monthly Evaluates changes, which include additions, discontinuations, applicant holder changes, etc. Assign RLD upon NDA approval and change the RLD when necessary. Typically highest strength, but may need safety evaluation and/or proportionality evaluation Assign ANDA as RLD if needed. Generic Drift MMA will not allow the RLD to be changed to a generic if the innovator is marketed - Shortage? IMS evaluation/study review Injectable products are no longer all designated as an RLD 26

27 Considerations for RLD use Must use a product approved via 505? 505 directs listing a drug approved via 505 in the Orange Book A RLD is a listed drug approved via (j) directs comparison and sameness to the listed drug but remains silent on source; assumption is US RLD definition is more vague up to FDA If the US RLD is discontinued, could we evaluate similarity by looking at the International RLD formulation? What if the same product is used in the US and internationally, and produced in the US? What if a generic has the same formulation of an internationally approved product when changing to a generic RLD? 27

28 Acknowledgements Barbara M. Davit, Ph.D., J.D. Patrick Nwakama, Pharm.D., BCPS CAPT Mary Ann Holovac, R.Ph. CAPT Harvey Greenburg, R.Ph. Dave Read, J.D. 28