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

Topics

Overview Science Technical Issues Harmonization Summary

The First Pharmacopeia

How Does a Pharmacopeia Help?

USPs Leadership Bodies

Scientific Body Fiduciary Body

Council of Experts Board of Trustees

Science Policy and Direction

Staff Strategic, Business,

and Fiduciary Oversight

Chief Executive Officer (Chair)

Chief Executive Officer

Policy Body
Convention Membership

General Direction through Resolutions

Convention President

USP Council of Experts

Chairperson (USP's Executive Vice President and Chief Executive Officer) Council of Experts Executive Committee
(12 individual memberDivision Executive Committee chairpersons and at-large members selected by COE chairperson)

Elect Executive Committee chairpersons for their divisions

Council of Experts
(62 members elected by USP Convention)

Elect members to the Expert Committees

Division Executive Committees

General Policies Non-Complex Actives Complex Actives and Requirements and Excipients Information

5 31 14 12 Expert Committees* Expert Committees* Expert Committees* Expert Committees*

Groups of Economic Integration Region of the Americas

NAFTA MERCOSUR SICA ANDEAN COMMUNITY CARICOM

Pioneer and Generic Drugs

Approval Patent/ Exclusivity Expiration

IND/NDA

Single Manufacturer
Post-approval Change

Efficacy

Safety

Additional Manufacturers
Shelf-life

Specifications Equivalence Time

Ti m e

Equivalence

Equivalence

Formulation, Quality, and Performance

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) products
WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-Sixth Report, 1999

Glossary

Bioavailability (rate and extent as measured by system exposure) Bioequivalence (relative bioavailability) Dosage form Therapeutic equivalence Generic product (confusinguse 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

Topics

Overview Science Technical Issues Trade Opportunities Summary

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 Termin the US: Reference Listed Drug) What is Needed? 1. Pharmaceutical Equivalence 2. Bioequivalence 3. Chemistry, Manufacturing, Controls (Impurities, Stability/expiry date, Packaging, Other Requirements)

Generic Versus Pioneer Product

Equivalence 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

Not All Dosage Forms Need Clinical Bioequivalence Studies

Reference

Generic/Similar

Study In Vivo In Vitro

(BE Self Evident)

No Study

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

Enantiomer

Racemate

Non-Glycosylated Protein

Glycosylated Protein

Complex Mixture

Moiety(ies)

Impurities 1. Product-related 2. Process-related

Product Related Substances 1. Post-translational 2. Manufacturing

ICH: Draft guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. (FR June 9, 1998)

What Does a Generic Manufacturer Do?

Looks at All Impurities in Innovators 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

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 SUMMARY Science/Technical Issues to Obtain an Interchangeable Generic Interchangeable with an Innovator Product are NOT a Problem

Summary
PIONEER DRUG (NDA) Requirements

GENERIC DRUG (ANDA) Requirements

Chemistry Manufacturing Controls Labeling Testing Preclinical/Clinical Studies Bioavailability GMPs/USP-NF

Chemistry Manufacturing Controls Labeling Testing Bioequivalence GMPs/USP-NF

USP-NF Ibuprofen Monograph

Ibuprofen

USP-NF Ibuprofen Tablet Monograph

Ibuprofen Tablets

1984 US GENERIC LAW: PATENT AND EXCLUSIVITY

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 SuccessfulOver 50% of All Prescriptions in US Are Generic Innovators Make Generics

Types of Exclusivity

Orphan Drug Exclusivity (ODE) - 7 years New Chemical Entity (NCE) - 5 years for a

Other (non-NCE) exclusivity - 3 years significant change if criteria are met

Pediatric exclusivity (PED) - 6 months added to existing patents or exclusivity EXCLUSIVITY HAS NOTHING TO DO WITH PATENTS!

What trade agreements require of medicines regulators.

World Trade Organization (WTO) Technical Barriers to Trade (TBT) Agreement

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

FTAA could include details or obligations...

Harmonization? Equivalence? Mutual recognition?

INTERNATIONAL CONFERENCE ON HARMONIZATION

Japans 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

Common Technical Document

1.0 Regional Administrative Information

Module 1

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 2.3 Quality Overall Summary 2.4 Nonclinical Overview 2.5 2.7
Module 5

1.0 2.1
Module 2

2.2 2.4 2.3 2.6

2.5 Clinical Overview 2.6 Nonclinical Summary 2.7 Clinical Summary

Source: ICH Implementation Coordination Group

Module 3 Quality 3.0

Module 4 Nonclinical Study Reports 4.0

Clinical Study Reports 5.0

Pan American Network for Drug Regulatory Harmonization

Participants
Regulators

Andean CARICOM MERCOSUR NAFTA SICA Industry

Consumer

Pan American Conference on Drug Regulatory Harmonization

Executive Secretariat PAHO

Steering Committee

Group
WG WG WG

Academia Professional As

PAN AMERICAN NETWORK FOR DRUG REGULATORY HARMONIZATION

Working Groups
1. 2. 3. 4. 5. 6. 7. 8. 9. Bioequivalence and Bioavailability Good Manufacturing Practices Good Clinical Practices Classification of Products Counterfeit Drugs Good Pharmacy Practices Pharmacopoeia Drug Regulatory Agencies (Study) Regional Entity: WHATS THIS?

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

What Might Help?

New Approaches A 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.