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The Food and Drug Administration: then and now Satish R Raj MD MSCI (with slides from Nancy Brown) October 2008 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) 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) January 1932 Animal and human studies demonstrated sulfanilamide’s efficacy in streptococcal infections Because first synthesized in 1908, sulfanilamide not patentable Within months Squibb Merck Eli Lilly Parke Davis Each had received AMA endorsement (voluntary reviewer) 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 Harold Watkins Chief 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” Massengill’s laboratory tested preparation for: Appearance Flavor No Toxicity Testing Fragrance No Clinical Trials Ok - Therefore ready for distribution “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 September 1937 240 gallons of elixir sulfanilamide manufactured 1304 shipments throughout the US Major distribution to Tulsa, OK nd 2 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 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.” 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 Have you tried it? Watkins self administered small amount to show confidence in his product Told AMA -> No adverse effects th 20 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” 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 Mid October 1937 News of Tulsa deaths reached Washington All FDA’s inspectors and chemists on to the case All 239!! 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 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 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 1938 Food Drug and Cosmetic Act Changed drug use to prescription Up to this time only 25% of drugs were prescription Epilogue Senator Copeland Dr. Massengill Pleaded guilty to 112 counts of misbranding – fined $26,100 Harold Watkins died of “exhaustion” 4 days after bill was signed Shot himself while cleaning his handgun Gerhard Domagk 1939 Nobel Prize 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 C. Estes Kefauver (D-TN) Anti-Trust and Monopoly Subcommittee hearings on the pharmaceutical industry (1959-1963) "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." 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 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 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 Requirements for Approval Usually at least 2 studies P<0.05 0.05 x 0.05 = 0.0025 FDA Advisory Committee Unique aspect of US drug regulation Hearings are public open recorded notification in advance Public accountability Risk sharing Freedom of Information Act Allows access to the basis for approval FDA – 1990s Onward 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 Standard NME & New BLA Approvals Median times, approvals 30 40 35 12 14.0 16.3 15.4 19.9 15.7 19.0 12.5 15.9 13.8 23.1 16.0 24.7 20 12.3 13.4 10 14.4 15.0 16 5 14.6 15.1 0 14 15 17 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005* Calendar year *Includes BLAs for therapeutic biologics Median FDA review time Median total approval time Number approved 0 Number 15 18 15.8 23.0 19 15.9 17.8 Months 30 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 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 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 Pediatric Drug Development Number 120 69 98 60 21 24 19 12 19 15 25 25 45 11 31 0 2 4 1998 10 3 12 17 23 20 23 17 15 1999 2000 2001 2002 2003 2004 2005 Calendar year Pediatric exclusivity determinations Written requests issued Pediatric exclusivity labeling changes FDA – Drug Recalls Safety-based withdrawals (approval/withdrawal) 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) Drug Recalls 600 Number 101 72 83 156 300 53 60 71 88 352 191 88 72 34 226 401 354 316 248 254 248 176 215 0 1995 1996 1997 1998 1999 2000 2001 2002 Fiscal year Prescription Over-the-counter 2003 2004 2005 Top 10 reasons for drug recalls in fiscal 2000 1) 2) 3) 4) 5) 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 Top 10 reasons for drug recalls in fiscal 2000 6) 7) 8) 9) 10) 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 Safety-Based Withdrawals NMEs approved Jan. 1, 1971, to May 31, 2006 BLAs approved Oct. 1, 2003, to May 31, 2006 Percentage 4% 2% 3.5% 3.1% 0% Pre-PDUFA (488/15) Receipt periods PDUFA (345/12) (approvals/withdrawals) Recent Concerns at FDA Concerns at FDA - Drugs & Science Adverse events/ drug-drug interactions Use of surrogate markers QT prolongation Hepatic toxicity To predict outcome To predict AEs Definition of the “correct dose” Maximally effective Toxic 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 Concerns at FDA – Appearance of Ethics Registration of Clinical Trials The approval process – conflicts of interest Concerns at FDA - Drugs Safety IOM “The Future of Drug Safety” (2006) Increase funding for FDA Better coordination between Office of New Drugs and Office of Surveillance and Epidemiology Improve postmarketing surveillance especially post-approval increase use of population data bases Mark new drugs 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” FDA funding Higher Percentage of Budget from Industry Questions?