Center for Professional Advancement Generic Drug Approvals Course

1. Center for Professional AdvancementGeneric Drug Approvals Course Introduction to the Legal Basis for Generic Drug Approvals Michael A. Swit, Esq. Vice President

2. FDA’s Legal Authority • Statute • Via US Congress, signed by President • 21 US Code sections 301-399 • Regulations • Via public notice in Federal Register • 21 Code of Federal Regulations Parts 1-1299 • Guidance Documents • Via FDA alone • Good to follow, but not binding on industry • On FDA’s website, www.fda.gov

3. Early Statutory Provisions • The Pure Food and Drugs Act of 1906 • Drug provisions (patented medicines): no misbranding or adulteration • The Federal Food, Drug, and Cosmetic Act of 1938 • Defined “drug” and “new drug” • Created “New Drug Application” • Required proof of safety and mfg. process info. • No affirmative FDA approval • “Me-Too”/Generic drugs had no FDA oversight

4. Regulations of Drugs, 1962-1984 • The Drug Amendments of 1962 (Kefauver-Harris Drug Amendments) • Review NDA requirements • To add proof of effectiveness (efficacy) • To add affirmative FDA approval • Created Drug Efficacy Study Implementation (“DESI”) Review • To review safety-only NDAs for efficacy • Applied to NDA and Me-Too drugs • Drugs not reviewed yet are known as “DESI II”

5. Regulations of Drugs, 1962-1984 • Created Abbreviated New Drug Application (“ANDA”) • Safety and efficacy was assumed • Required submission of mfg. process info. & labeling • Outgrowth of DESI process – thus limited in scope • OTC Drug Review • Safety and efficacy determined by FDA on a therapeutic class basis • Marketing permitted if compliance with OTC monograph (active ingredients, indications, directions, warnings) • The Paper NDA Policy • Me-Too drugs established safety and efficacy via published literature, public data

6. DRUG DRUG(OTC) DRUG MARKETING/FDA APPROVAL PROCESS 1906 1938 1962 1972 1984 20?? [ DESI II List ] DRUG (MARKET) SAFE / GRAS [ DESI II List ] DRUG (MARKET) NAS/NRCPANELREVIEW ANDAW/O BIOSTUDY SAFETY NOT ESTABLISHED (NDA) (DESI) SAFE & EFFECTIVEGRAS & E (MARKET) [ DESI II List ] ANDA IFEQUIVALENTBIOSTUDY SAFETY AND/OREFFECTIVENESSNOTESTABLISHED (NDA) OTC REVIEWESTABLISHESGRAS & E (MARKET) SAFETY AND/OREFFECTIVENESSNOTESTABLISHED ANDA IFEQUIVALENTBIOSTUDY (NDA) ANDA IF BIOEQUIV AND PATENT OR EXCLUSIVITY RIGHT EXPIRED DRUG-NDA Courtesy of K&L Gates 495138

7. Statutory Provisions (cont’d) • The Orphan Drug Act of 1983 • Drugs for rare diseases and disorders in US • Tax incentives and federal grants • Awards market monopoly for 7 years • The Drug Price Competition and Patent Term Restoration Act of 1984 (Waxman-Hatch Act) • Revised ANDA to modern day requirements, adds bioequivalence studies • Patent extensions and market exclusivity for NDA drugs

8. 505(b)(1) New Drug Application (NDA) • FDA must pre-approve • New ingredient (chemical) • New labeling indication • New formulation (i.e., transdermal patch) • Animal and clinical data • Market protection: patent extension and exclusivity by orphan drug, new chemical entity, clinical or pediatric studies

9. 505(b)(2) New Drug Application (NDA) • FDA must pre-approve • Reference the literature or marketed drug (NDA) • Data required will be based on unanswered questions (animal tox – clinical) • Must file patent certification • Market protection: patent extension and exclusivity by clinical or pediatric studies

10. Abbreviated New Drug Application (ANDA) • FDA must preapprove • Must be based on Reference Listed Drug (NDA) • Can change strength/dosage/formulation by petition request • Bioequivalence data • Labeling must be identical • Must file patent certification

11. OTC Monograph Drug • No FDA preapproval • Active ingredients • Labeling claims • Dosage limitations • No market protection • Must submit labeling to drug listing

12. DESI II Drugs • No FDA preapproval • Must be identical to pre-1984 marketed drug in: • Ingredient • Labeling indications • Formulation • Dosage form • No market protection • Must submit labeling to drug listing • Regulatory risk

13. Statutory Provisions (cont’d) • Generic Drug Enforcement Act of 1992 • Mandatory or permissive debarment for bribery, fraud, conspiracy, unlawful act • Temporary denial of ANDA • Withdrawal of approval of ANDA • Civil money penalties • Prescription Drug User Fee Act of 1992 • Applies to NDAs only • FDA Export Reform and Enhancement Act, 1996 • Import for export without substantial FDA involvement • APIs, components, unapproved drugs

14. Statutory Provisions (cont’d) • FDA Modernization Act of 1997 • Permits “Rx Only” and “FDA Approved” labeling • Sets up qualifications for FDA application reviewers • Created pediatric market exclusivity for NDAs with pediatric studies • Codified permissible post-approval manufacturing changes • Best Pharmaceuticals for Children Act, 2002 • Reauthorized pediatric exclusivity • National Preparedness for Bioterrorism, 2002 • Reauthorized user fees • Pediatric Research Equity Act of 2003 • Gave FDA authority to require pediatric studies

15. Medicare Prescription Drug Improvement and Modernization Act of 2003 • Title XI – access to affordable pharmaceuticals • Implemented changes to sections 505(j) and 505(b)(2) of FDC Act, and Title 35 of Patent Law • Changed rules for ANDAs containing Paragraph IV certifications to a patented drug • Codified bioequivalence definitions from FDA regulations • Codified FDA rule permitting bundling of several strengths under one ANDA