Center for Professional Advancement

Generic Drug Approvals Course

Introduction to the Legal Basis for

Generic Drug Approvals

Michael A. Swit, Esq.Vice President

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

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

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”

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

495138

DRUG MARKETING/FDA APPROVAL PROCESS1906 1938 1962 1972 1984 20??

DRUG (MARKET)

DRUG (MARKET) [ DESI II List ]SAFE / GRAS

SAFETY NOT ESTABLISHED (NDA)NAS/NRC

PANELREVIEW

(DESI) ANDAW/O BIOSTUDY

SAFE & EFFECTIVEGRAS & E (MARKET)

SAFETY AND/OREFFECTIVENESS

NOTESTABLISHED

(NDA)ANDA IF

EQUIVALENTBIOSTUDY

DRUG

OTC REVIEWESTABLISHES

GRAS & E(MARKET)

SAFETY AND/OREFFECTIVENESS

NOTESTABLISHED

ANDA IFEQUIVALENT

BIOSTUDY

(NDA)

DRUG(OTC)

DRUG-NDA

[ DESI II List ]

[ DESI II List ]

ANDA IF BIOEQUIV AND PATENT OR EXCLUSIVITY RIGHT EXPIRED

Courtesy of K&L Gates

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

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

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

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

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

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

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

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

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