Confidentiality, Exclusivity, and Bioavailability and Bioequivalence in the Context of Pharmaceutical Data Protection

1. Confidentiality, Exclusivity, and Bioavailability and Bioequivalence in the Context of Pharmaceutical Data Protection and Registration of Medicines Roger L. Williams, M.D. Chief Executive Officer United States Pharmacopeia International Seminar Intellectual Property and Access to Medicines July 5, 2004 Lima

2. Topics • Overview • Science Technical Issues • Harmonization • Summary

3. The First Pharmacopeia

4. How Does a Pharmacopeia Help?

5. USP’s Leadership Bodies Scientific Body Fiduciary Body Council of Experts Board of Trustees Staff Strategic, Business, and Fiduciary Oversight Science Policy and Direction Chief Executive Officer Chief Executive Officer (Chair) Policy Body Convention Membership General Direction through Resolutions Convention President

6. USP Council of Experts Chairperson (USP's Executive Vice President and Chief Executive Officer) Council of Experts Executive Committee (12 individual member—Division Executive Committee chairpersons and at-large members selected by COE chairperson) Council of Experts (62 members elected by USP Convention) Elect Executive Committee chairpersons for their divisions Elect members to the Expert Committees Division Executive Committees General Policies and Requirements Non-Complex Actives and Excipients Complex Actives Information 5 Expert Committees* 31 Expert Committees* 14 Expert Committees* 12 Expert Committees*

7. NAFTA MERCOSUR SICA ANDEAN COMMUNITY CARICOM Groups of Economic IntegrationRegion of the Americas

8. Pioneer and Generic Drugs Patent/ Exclusivity Expiration Approval Single Manufacturer IND/NDA Post-approval Change Additional Manufacturers Shelf-life Efficacy Safety Time Specifications Equivalence Equivalence Equivalence Formulation, Quality, and Performance Time

9. Important WHO (OMS) Documents • Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability WHO Expert Committeee on Specifications for Pharmaceutical Preparations, Thirty-Fourth Report, 1999 • Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) productsWHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-Sixth Report, 1999

10. Glossary • Bioavailability (rate and extent as measured by system exposure) • Bioequivalence (relative bioavailability) • Dosage form • Therapeutic equivalence • Generic product (confusing—use instead ‘interchangeable product’) • Innovator pharmaceutical product • Interchangable pharmaceutical product • Multisource pharmaceutical product • Pharmaceutical equivalence (same amount of active ingredient, same dosage form, same route) • Reference product

11. Topics • Overview • Science Technical Issues • Trade Opportunities • Summary

12. What Does a Generic Manufacturer Do? • No Need to Access Private Data of Pioneer • Reverse Engineers from Pioneer Product in the Market Place • This is the Comparator Pharmaceutical Product (WHO Term—in the US: Reference Listed Drug) • What is Needed?1. Pharmaceutical Equivalence2. Bioequivalence3. Chemistry, Manufacturing, Controls (Impurities, Stability/expiry date, Packaging, Other Requirements)

13. Generic Versus Pioneer ProductEquivalence Concepts (CFR 320) • Pharmaceutical Equivalence • Same active ingredient • Same strength • Same dosage form and route of administration • Comparable labeling • Meet compendial or other standards of identity, strength, quality, purity and potency • Bioequivalence • In vivo measurement of active moiety (moieties) in biologic fluid (blood/urine) • In vivo pharmacodynamic comparison • In vivo clinical comparison • In vitro comparison • Other THEN: THERAPEUTIC EQUIVALENCE

14. Study No Study (BE Self Evident) In Vivo In Vitro Not All Dosage Forms Need Clinical Bioequivalence Studies Reference Generic/Similar

15. What About the Active Ingredient • 70-90% of Active Ingredients (Drug Substance) in US Come from India and China • Control of Quality Important • Change in Route of Synthesis Can Change Impurity Profile • Impurities Can Also Arise from Excipients and from Degradation of the Active Ingredient • Some Impurities May Be Dangerous

16. Enantiomer Racemate Non-Glycosylated Glycosylated Complex Protein Protein Mixture Moiety(ies) Impurities Product Related Substances 1. Product-related 1. Post-translational 2. Process-related 2. Manufacturing ICH: Draft guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. (FR June 9, 1998)

17. What Does a Generic Manufacturer Do? • Looks at All Impurities in Innovator’s Marketed Dosage Form • Compares with Planned Product • Follows ICH Q3A R for isolation, characterization, qualification • Generics Come in Market about Ten Years after Pioneer • Newer Products (Pioneers and Generics) May Have Better Quality than Older Products

18. What About Other Factors? • Generic Manufacturer Does Stability Studies in Package to Get an Expiry Date • Manufacturing Must Be Controlled and Follow GMPs (WHO, FDA, ICH, other) • Excipients Can Be Different • Labeling General the Same But Can Differ • IN SUMMARYScience/Technical Issues to Obtain an Interchangeable Generic Interchangeable with an Innovator Product are NOT a Problem

19. PIONEER DRUG (NDA) Requirements GENERIC DRUG (ANDA) Requirements Summary • Chemistry • Manufacturing • Controls • Labeling • Testing • Preclinical/Clinical Studies • Bioavailability • GMPs/USP-NF • Chemistry • Manufacturing • Controls • Labeling • Testing • Bioequivalence • GMPs/USP-NF

20. USP-NF Ibuprofen Monograph Ibuprofen

21. USP-NF Ibuprofen Tablet Monograph Ibuprofen Tablets

22. Statutory authority for FDA approval of pre-and post-1962 generic drugs Reduce the cost of health care with generic drugs Eliminate Duplication of Clinical Trials Assure continued development of new drugs through patent extension and exclusivity granted to certain NDAs Hatch Waxman Successful—Over 50% of All Prescriptions in US Are Generic Innovators Make Generics 1984 US GENERIC LAW: PATENT AND EXCLUSIVITY

23. Types of Exclusivity • Orphan Drug Exclusivity (ODE) - 7 years • New Chemical Entity (NCE) - 5 years • “Other” (non-NCE) exclusivity - 3 years for a “significant change” if criteria are met • Pediatric exclusivity (PED) - 6 months added to existing patents or exclusivity EXCLUSIVITY HAS NOTHING TO DO WITH PATENTS!

24. What trade agreements require of medicines regulators. World Trade Organization (WTO) Technical Barriers to Trade (TBT) Agreement

25. “Core discipline” of TBT The Parties shall ensure that their technical regulations are not prepared, adopted or applied with a view to or with the effect of creating unnecessary barriers to international trade. For this purpose, technical regulations shall not be more trade- restrictive than necessary to fulfil a legitimate objective, taking account of the risks non-fulfilment would create. TBT Article 2.2

26. FTAA could include details or obligations... • Harmonization? • Equivalence? • Mutual recognition?

27. INTERNATIONAL CONFERENCE ON HARMONIZATION • Japan’s MHW, FDA, EU/EC • JPMA, PhRMA, EFPIA • Observers: WHO, Canada, EFTA • First Conference: Brussels 1991 • Second Conference: Orlando 1993 • Third Conference: Yokohama 1995 • Fourth Conference: Brussels 1997 • Fifth Conference: San Diego 2000 • Sixth Conference: Osaka 2003

28. 1.0 Regional Administrative Information 1.1 ToC of Module 1 or overall ToC, including Module 1 2.1 ToC of CTD (Mod 2,3,4,5) 2.2 Introduction 2.3Quality Overall Summary 2.4 Nonclinical Overview 2.5 Clinical Overview 2.6 Nonclinical Summary 2.7 Clinical Summary Common Technical Document Module 1 1.0 2.1 Module 2 2.2 2.5 2.4 2.3 2.6 2.7 Module 3 Module 4 Module 5 Clinical Study Reports 5.0 Nonclinical Study Reports 4.0 Source: ICH Implementation Coordination Group Quality 3.0

29. Pan American Network forDrug Regulatory Harmonization

30. PAN AMERICAN NETWORK FOR DRUG REGULATORY HARMONIZATION Working Groups 1. Bioequivalence and Bioavailability 2. Good Manufacturing Practices 3. Good Clinical Practices 4. Classification of Products 5. Counterfeit Drugs 6. Good Pharmacy Practices 7. Pharmacopoeia 8. Drug Regulatory Agencies (Study) 9. Regional Entity: WHAT’S THIS?

31. Rapidly Changing Environment • ICH: efforts have helped generic manufacturers • PAHO and PANDRH: more work but a start • US Congress considering parallel imports (equivalence approach) • Recent US law limits ways to impede generics • USP working on science/technical approaches to generic biologics

32. What Might Help? • New ApproachesA Single Comparator Pharmaceutical Product in the Americas?A Pharmacopeias of the Americas? • USP is working with pharmacopeias of the Americas and is planning a Spanish translation of USP-NF.