Outreach 2001: A Tour of the Pharmaceutical Sciences

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Outreach 2001A Tour of thePharmaceutical
Sciences

• University of Colorado
• School of Pharmacy

Annual Meeting - Denver CO October 21 25, 2001
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The Long Journey From Drug Discovery to
Marketplace

• Lane J. Brunner, Ph.D.
• College of Pharmacy
• The University of Texas at Austin

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The long, difficult, expensive, frustrating,
bureaucratic, risky, nerve-racking, did I mention
really expensive, path this little molecule has
to take before it finally reaches the people who
desperately need it. Or what we affectionately
call . . .
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DrugDevelopment
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Outline

• Introduction
• History of drug regulations
• Innovator drug development process
• Generic drug development process
• Generic equivalence
• Current regulatory issues

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History of Drug Regulations

• No specific drug regulations until 1848
• Import Drug Act of 1848
• American troops given substandard drugs
• Biologics Act of 1902
• Contaminated diphtheria antitoxin kills 12
• Pure Food and Drugs Act of 1906
• Designates USP and NF as standards

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Drug Regulations (cont.)

• Federal FDA established in 1931
• Federal Food, Drug, and Cosmetic Act of 1938
• Sulfanilamide formulated with antifreeze
• New Drug Application (NDA)
• Drugs must be safe

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Drug Regulations (cont.)

• Durham-Humphrey Amendment to Act of 1938 (Amended
  in 1951)
• Prescription Amendment
• OTC and prescription classes
• Legend
• Caution Federal law prohibits dispensing
  without a prescription

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Drug Regulations (cont.)

• Kefauver-Harris Amendment to the Act of 1938
  (Amended in 1962)
• Thalidomide teratogenicity
• Drugs must be effective
• Drug Price Competition and Patent Term
  Restoration Act of 1984
• Generic Law
• Created abbreviated NDAs (ANDAs)

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Drug Development Process

• Discovery and formulation
• Preclinical evaluation
• Clinical evaluation
• Phases I-IV
• Post-marketing surveillance

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Discovery Process

• Serendipity
• Folk medicine
• High throughput screening
• Rational drug design
• Targeted screening
• Molecular modeling
• Physiological models
• Biotechnology

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Preclinical Testing

• Assess primary safety, biological activity, and
  therapeutic ratio
• In vivo animal models
• In vitro physiological models
• 1 in 10,000 compounds pass
• 3.5 years to develop compound

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Phase I Clinical Trials

• Determine primary safety and dosing range in
  humans
• Normal, healthy volunteers (20-100)
• 2 of 3 drugs pass
• 1 year in Phase I trials

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Phase II Clinical Trials

• Evaluate effectiveness, examine adverse effects,
  and select optimal dose
• Volunteer patients (100-500)
• 1 in 3 drugs pass
• 2-3 years in Phase II trials

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Phase III Clinical Trials

• Verify effectiveness, monitor long-term safety,
  establish optimal dose
• Volunteer patients (1000-3000)
• 4 of 5 drugs pass
• 3 years in Phase III trials
• Apply for a New Drug Application (NDA)

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Phase IV Clinical Trials

• Post-marketing surveillance
• Long-term safety and efficacy
• New indications for use
• Special disease-state and populations
• Drug interaction studies
• Pharmacoeconomic studies

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Drug to Market Timeline

• Preclinical testing 4 years
• Phase I clinical trials 1 year
• Phase II clinical trials 2 years
• Phase III clinical trials 3 years
• FDA review 2 years
• Total time 12 years

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Drug Attrition Rate

• New chemicals 8,000-10,000
• Drugs enter development 12-18
• Drugs enter clinical trials 6-9
• Drugs marketed 1

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Innovator Development Costs
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Abbreviated NDA (ANDA)

• Application for generic versions of off-patent
  drugs to receive FDA approval with less costly
  preclinical and clinical testing
• Intent is to minimize duplication of available
  information
• No safety or efficacy trials

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ANDA (cont.)

• Complete chemistry, manufacturing, and controls
  information
• Information regarding the bioavailability of
  solid dosage forms

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Generic Candidate Costs
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Generically Equivalent

• Pharmaceutically equivalent
• Therapeutically equivalent
• The same drug with the same effect, but the
  product is from a different manufacturer
• AB rating in Orange Book

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Excipients
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Current Regulatory Issues

• Patent life extension
• Inactive ingredients
• Specific drug classes

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Why develop drugs?