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

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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

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Topics

• Overview
• Science Technical Issues
• Harmonization
• Summary

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The First Pharmacopeia
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How Does a Pharmacopeia Help?
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USPs 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
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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)
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
Information
Complex Actives
5 Expert Committees
31 Expert Committees
14 Expert Committees
12 Expert Committees
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Groups of Economic IntegrationRegion of the
Americas
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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
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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

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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

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Topics

• Overview
• Science Technical Issues
• Trade Opportunities
• Summary

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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
  Equivalence2. Bioequivalence3. Chemistry,
  Manufacturing, Controls (Impurities,
  Stability/expiry date, Packaging, Other
  Requirements)

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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

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Not All Dosage Forms Need Clinical Bioequivalence
Studies
Reference
Generic/Similar
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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

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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)
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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

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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

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Summary

• GENERIC DRUG (ANDA) Requirements

• PIONEER DRUG (NDA) Requirements

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

• Chemistry
• Manufacturing
• Controls
• Labeling
• Testing
• Bioequivalence
• GMPs/USP-NF

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USP-NF Ibuprofen Monograph
Ibuprofen
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USP-NF Ibuprofen Tablet Monograph
Ibuprofen Tablets
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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

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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!

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What trade agreements require of medicines
regulators.

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

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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

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FTAA could include details or obligations...

• Harmonization?
• Equivalence?
• Mutual recognition?

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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

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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
Nonclinical Study Reports 4.0
Clinical Study Reports 5.0
Source ICH Implementation Coordination
Group
Quality 3.0
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Pan American Network forDrug Regulatory
Harmonization
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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 WHATS
THIS?
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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

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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.