The Food and Drug Administration: then and now

1. The Food and Drug Administration: then and now Satish R Raj MD MSCI (with slides from Nancy Brown) October 2008

2. 1906 Food and Drugs Act 1 (a) Response to worthless and/or dangerous medicines claimed as cure alls (b) Adulterated foods 2 No FDA role in premarketing evaluation (unchanged until 1937)

3. Gerard Domagk (1932) • Prontosil rubrum (red dye stuff) • protected mice from lethal doses of Staph and hemolytic Strep • derivative of sulfanilamide (1908) • Daughter with severe Strep infn • Prontosil -> complete recovery • He did not report this for many years Nobel Prize in Physiology or Medicine (1939)

4. January 1932 Animal and human studies demonstrated sulfanilamide’s efficacy in streptococcal infections Because first synthesized in 1908, sulfanilamide not patentable

5. Within months • Squibb • Merck • Eli Lilly • Parke Davis Each had received AMA endorsement (voluntary reviewer)

6. Samuel E. Massengill • SE Massengill Company (Bristol TN) • Pharmaceutical company • Produced sulfanilamide tablets • Salesman • need for liquid preparation for children • Problem • sulfanilamide insoluble in EtOH

7. Harold WatkinsChief Chemist, SE Massengill Co • Tried lots of vehicles • Eventually – raspberry-tasting pink preparation • 10% sulfanilamide • 72% diethylene glycol • 16% water • Flavor, raspberry extract, saccharine, amaranth and caramel • “Elixir sulfanilamide”

8. Massengill’s laboratory tested preparation for: • Appearance • Flavor • Fragrance Ok - Therefore ready for distribution No Toxicity Testing No Clinical Trials

9. “Throwing drugs together and if they did not explode, they were placed on sale.” FDA Agent’s description of Massengill Company’s drug development strategy

10. September 1937 240 gallons of elixir sulfanilamide manufactured 1304 shipments throughout the US Major distribution to Tulsa, OK

11. 2nd October 1937 • Editorial in JAMA • “Warning against overzealous embrace of sulfanilamide” • Adverse reactions • Dermatitis • Photosensitivity • Granulocytopenia • Hemolytic Anemia Sulfanilamide—a warning (Editorial). JAMA. 1937; 109:1128

12. Telegraph to AMA • Dr. Stephenson • President of the Tulsa County Medical Society • “6 patients dead from renal failure unexpectedly after ingestion Elixir Sulfanilamide stop request composition of the elixir.”

13. AMA never heard of this preparation • Telegraphed Mr. Massengill requesting composition • Massengill • “proprietary information” • …but released it • suggested the deaths due to concomitant meds • Admitted to no toxicity testing

14. Have you tried it? • Watkins • self administered small amount to show confidence in his product • Told AMA -> No adverse effects

15. 20th October 1937 Telegraph Massengill to AMA “Please wire collect by Western Union suggestion for antidote and treatment following use of Elixir Sulfanilamide” AMA to Massengill “Antidote for Elixir Sulfanilamide – Massengill not known. Treatment presumably symptomatic”

16. Diethylene Glycol (DEG) • Similar to ethylene glycol (anti-freeze) • 1931 Von Oettinger lethal doses 5 ml/kg in mice • DEG causes kidney failure in mice

17. Mid October 1937 • News of Tulsa deaths reached Washington • All FDA’s inspectors and chemists on to the case • All 239!!

18. FDA Acts • FDA seized 228/240 gals • 240 gals would have caused >4000 deaths • FDA intervened due to mislabeling not due to deaths • Marketed as an elixir but did NOT contain ethanol. • Anything called an elixir must contain ethanol

19. 353 patients received Elixir Sulfanilamide over a 4 week period • 105 deaths (case fatality rate of 30%) • 34 children & 71 adults died • GI symptoms prevented most of the survivors from ingesting enough

20. November 1937 – Congress to the Rescue • Senator Royal Copeland (R-MI, D NY) • 1938 Food Drug and Cosmetic Act • (1) New Drug Application to demonstrate product safety – concept of animal/human testing before interstate shipping • (2) formula must be disclosed • (3) Directions for use and precautions on prescription

21. 1938 Food Drug and Cosmetic Act • Changed drug use to prescription • Up to this time only 25% of drugs were prescription

22. Epilogue • Senator Copeland • died of “exhaustion” 4 days after bill was signed • Dr. Massengill • Pleaded guilty to 112 counts of misbranding – fined $26,100 • Harold Watkins • Shot himself while cleaning his handgun • Gerhard Domagk • 1939 Nobel Prize

23. 1938 Food, Drug and Cosmetic Act • “Adequate tests by all methods reasonably applicable to show whether or not the drug is safe” • Important step was that the FDA had to be satisfied that the drug was safe – NOT just the manufacturer – prior to distribution • “Default” position was that the FDA would approve

24. C. Estes Kefauver (D-TN) • Anti-Trust and Monopoly Subcommittee • hearings on the pharmaceutical industry (1959-1963)

25. "The drug companies themselves were shown to be engaged in frenzied advertising campaigns designed to sell trade name versions of drugs that could otherwise be prescribed under generic names at a fraction of the cost; this competition, in turn, had led to the marketing of new drugs that were no improvements on drugs already on the market but, nevertheless, heralded as dramatic breakthroughs without proper concern for either effectiveness or safety."

26. 1962 Kefauver-Harris Amendment • Following Thalidomide tragedy • Effectiveness requirement introduced • Exposure to Thalidomide in US • never approved in the US • Research • no record-keeping requirement for INDs • New record keeping requirement • Responsibility of investigator not to give out drug • Informed consent required

27. 1962 – New Data Quality Requirement • “Adequate well-controlled studies” • Generics • Initially -> same requirements • Too great a hurdle • 1984 Generics became available under abbreviated NDAs (ANDA) • Demonstrate bioequivalence • Product quality

28. Kefauver-Harris Amendments • Required “statistical evidence” of effectiveness from “adequate and well controlled studies” • Substantial evidence • Preponderance of the evidence • Evidence beyond a reasonable doubt • No requirement that drugs be better than standards or even as good

29. Requirements for Approval • Usually at least 2 studies • P<0.05 • 0.05 x 0.05 = 0.0025

30. FDA Advisory Committee • Unique aspect of US drug regulation • Hearings are public • open • recorded • notification in advance • Public accountability • Risk sharing

31. Freedom of Information Act Allows access to the basis for approval

32. FDA – 1990s Onward

33. 1992 Prescription Drug User Fee Act (PDUFA) • 5-year life • Authorized collection of fees • Application fees • Establishment fees • Product fees • Revenue to hire reviewers, support staff, upgrade IT • $135 million users fees in FY 2000 • $438 million projected FY2008

35. FDA Modernization Act of 1997 (FDAMA) • Reauthorized PDUFA for 5 years • Codified several FDA initiatives under the “Reinventing Government” program • Modernized regulation of biological products • Eliminated batch certification for insulin and antibiotics • Streamlined approval for manufacturing changes • Reduced need for environmental assessment

36. FDAMA 1997 (cont) • Abolished prohibition against dissemination by manufacturers of information about unapproved (“off label”) uses • If sponsors commit to submission of supplemental data • Allows drug companies to provide economic information to formulary committees, managed care organizations, large-scale buyers • Gave exemption for compounded drugs (versus manufacturing) • Directed FDA to focus post-marketing surveillance on high risk medical devices

37. FDAMA - Pediatric exclusivity • 6 months of marketing exclusivity to manufacturers who conduct and file pediatric studies in response to written requests • 218 proposed study requests • 188 written requests • 58 studies conducted and submitted – exclusivity granted to 28 drugs • http://www.fda.gov/cder/pediatric/index.htm

39. FDA – Drug Recalls

40. Fenfluramine (1973/1997) Ticrinafen (1979/1980) Zomepirac (1980/1983) Benoxaprofen (1982/1982) Nomifensine (1984/1986) Suprofen (1985/1987) Terfenadine (1985/1998) Encainide (1986/1991) Astemizole (1988/1991) Flosequinan (1992/1998) Temafloxacin (1992/1992) Cisapride (1993/2000) Dexfenfluramine (1996/1997) Bromfenac repafloxin (1997/1999) Mibefradil (1997/1998) Troglitazone (1999/2000) Rapacuronium (1992/2001) Alosteron (2000/2000) Phenylpropanolamine (-/2000) Baycol (2000/2001) Safety-based withdrawals (approval/withdrawal)

42. Top 10 reasons for drug recalls in fiscal 2000 • Lack of assurance of sterility in production or testing of sterile drug products • Deviations from current good manufacturing practices • Subpotency • Microbial contamination of nonsterile products • Chemical contamination

43. Top 10 reasons for drug recalls in fiscal 2000 • Penicillin cross-contamination of other products • Failure of or inability to validate manufacturing processes • Drug product marketed without an approved new or generic application • Failure or drug to dissolve properly • Product found to exceed limits set for impurities or degradation

45. Recent Concerns at FDA

46. Concerns at FDA - Drugs & Science • Adverse events/ drug-drug interactions • QT prolongation • Hepatic toxicity • Use of surrogate markers • To predict outcome • To predict AEs • Definition of the “correct dose” • Maximally effective • Toxic

47. Concerns at FDA – Drugs & Science (cont) • Active versus placebo controlled trials • Role of pharmacogenomics • In predicting response • In predicting AEs • Approval of drugs for over-the-counter

48. Concerns at FDA – Appearance of Ethics • Registration of Clinical Trials • The approval process – conflicts of interest

49. Concerns at FDA - Drugs Safety IOM “The Future of Drug Safety” (2006) • Increase funding for FDA • especially post-approval • Better coordination between Office of New Drugs and Office of Surveillance and Epidemiology • Improve postmarketing surveillance • increase use of population data bases • Mark new drugs

50. Concerns at FDA - PDUFA PDUFA IV • Do user fees compromise oversight? • Only 5% of user fees applied to postmarketing safety monitoring • Authorized by the Senate May 2007 • Includes a 5-year plan for enhancing and monitoring drug-safety system • Includes limits on patent life for “blockbusters”