Goals & Objectives Drug Development & the FDA „ Be able to describe Pharmacy 309 „ the major regulatory events in the drug development process „ the concepts of “safety” and “effectiveness” Tom Hazlet, Pharm.D., Dr.P.H. „ the importance of scientific methods in drug 616-2732 development thazlet@u...

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Outline An History of Disasters

„ History of FDA Regulations -- really fast; see „ Vaccine Act 1813 FDA web site „ fraudulent smallpox vaccines „ Drug Approval Process „ Food & Drugs Act 1906 „ Upton Sinclair, The Jungle „ Safety & Effectiveness „ truthful label (strength & purity) „ International Conference on Harmonisation „ Food, Drug & Cosmetic Act 1938 „ Questions any time „ “elixir” of sulfanilamide „ safety, IND, NDA, 60-day review

3 4 History (2) History (3)

„Durham-Humphrey Amendment 1951 „ Orphan Drug Act 1983 „collateral measures necessary for “safe” use „ rare diseases „“Caution: Federal law prohibits …” „ tax break; patent protection „Rx to OTC switch „ ANDA 1984 „Kefauver-Harris Amendment 1962 „ bioequivalence for generic drugs „thalidomide; Bay of Pigs „ Expedited Approval, Serious & Life-Threatening „effectiveness; 180 day NDA review Diseases (AIDS) 1994 [“Subpart E”] „ Phase 4

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History (4) History Summary

„ 1992 Prescription Drug User Fee Act „ 1994 Dietary Supplement Health And Education Act „ truthful label (strength & purity) „ 1997 Food And Drug Administration Modernization Act „ safety under conditions of intended use reauthorizes PDUFA, advertising of unapproved uses of approved drugs and devices, and regulate health claims for „ effectiveness under conditions of intended foods, compounding use „ 2000 Washington Legal Foundation [65 Federal Register 14286] „ adequate directions for use „ 2002 Supreme Court ruling on First Amendment violations in FDAMA „ 2003 PDUFA 3 authorizes Phase 4 studies for certain drugs

7 8 Other “Interesting” Web Sites for more information see http://www.fda.gov/fdac/special/newdrug/ndd_toc.html „ FDA -- www.fda.gov „ PhRMA -- www.phrma.org „ Public Citizen -- www.citizen.org FDA Consumer From Test Tube To Patient: New Drug Development in the United States Second Edition January 1995

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Idea Drug Development Phases „ objective: synthesis, isolation of active „ idea compound „ “preclinical” „ modes of discovery „ “combinatorial” chemistry, „ Investigational New Drug Application (IND) Affymax „ “traditional sources” -- „ Phase 1 Shaman Pharmaceuticals „ Phase 2 „ human genome project and “antisence” drugs „ Phase 3 „ targeted discovery „ New Drug Application (NDA) „ dumb luck „ Phase 4

11 12 Idea (2) Pre-Clinical Development

„ types of studies „ objective: pharmacology & toxicology in animals „ purification „ types of studies „ identification of impurities „ acute toxicity „ computer simulations „ sub-acute toxicity ( <3 months) „ validation, validation, validation „ chronic toxicity (6-18 „ time: years months) „ reproductive, teratology, „ survival: 500,000 →5,000 mutagenicity

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Pre-Clinical (2) Phase 1

„ LD50 Tissue culture methods „ objective: safety, dose ranging, pk/pd in „ ADME “normals” „Absorption, Distribution, Metabolism, Excretion „ types of studies „ study size: hundreds of animals „ first exposure in humans „ time: 6.5 years „ single dose tolerability „ survival: of 5000 pre-clinical → 5 INDs „ multiple dose tolerability „ dose-ranging based on animal doses

15 16 Phase 1 (2) Phase 1 Failures

„ study size: 20-80 „ pre-clinical animal models ≠ behavior in humans „ time: 2-3 years „ inadequate preclincal data „ change in drug formulation between time of pre- „ survival clinical and clinical testing „ 80% proceed to Phase 2 „ pk/pd relationships „ 5 → 4 „ poorly designed clinical studies „ drug too toxic in humans

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Phase 2 Clinical Studies Phase 3 Clinical Studies

„ objective: testing an hypothesis of no difference; „ objectives: testing an hypothesis of no safety difference; safety „ targeted patients „ types of studies: small controlled trials in „ “well controlled” studies patients „ placebo-controlled „ dose ranging „ double blinded „ multi-centered (bias) „ study size: 100-300 „ size: 100’s - 1000’s „ time: months - 2 years „ time: 1-4 years „ survival: 2 go on to Phase 3 „ survival: 1 19 20 Phase 2 & 3 Failures

„ infrequent adverse reactions observed; but „ New Drug Application (CDER, CBER) ... „ manufacturing facility approval included in „ drug-drug interactions application review „ drug-disease interactions in ill patients „ Product License Application (CBER) „ facility approval separate from PLA „ genetic – pharmacogenomics „ Biologics License Application – “well characterized „ effectiveness insufficient (20%) biologicals” „ economic (24%)

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Phase 4 NDA | PLA

„ FDA has 180 days for review „ post marketing surveillance „ FDA judges both benefit (efficacy) and risks „ negotiation (safety) „ accelerated approval for therapies for serious and „ one specific indication is approved life-threatening diseases (Subpart E) „ Average drug approval story „ targeted studies for cause „ 1:350,000 approved „ other stages of diseases, other sub-populations, „ cost ~ $500 million drug-drug interactions, “off-label” uses „ time ~ 15 years „ new mandates under PDUFA3

23 24 International Conference on Safety & Efficacy Harmonisation

„ Under conditions of intended use „ US, European Union & Japan „ limitations of “well controlled” studies „ efficacy (human clinical trials) „ relevance of clinical trial information to alternate „ safety (animal pharmacology / toxicology) (“off label”) uses „ quality (manufacturing) „ “promotion” of off label uses „ regulatory communication „ domestic (dis)incentives to conduct studies of alternate uses

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Is Something Missing? Summing Up

„ Drug price „ where was the science? „ phases of drug development „ major regulatory events „ questions

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