The Food and Drug Administration: then and now Satish R Raj MD MSCI (with slides from Nancy Brown) October 2008Slide 2
1906 Food and Drugs Act 1 (a) Response to useless and additionally perilous prescriptions asserted as cure alls (b) Adulterated nourishments 2 No FDA part in premarketing assessment (unchanged until 1937)Slide 3
Gerard Domagk (1932) Prontosil rubrum (red color stuff) shielded mice from deadly measurements of Staph and hemolytic Strep subsidiary of sulfanilamide (1908) Daughter with extreme Strep infn Prontosil - > finish recuperation He didn\'t report this for a long time Nobel Prize in Physiology or Medicine (1939)Slide 4
January 1932 Animal and human studies exhibited sulfanilamide\'s adequacy in streptococcal diseases Because initially combined in 1908, sulfanilamide not patentableSlide 5
Within months Squibb Merck Eli Lilly Parke Davis Each had gotten AMA support (deliberate commentator)Slide 6
Samuel E. Massengill SE Massengill Company (Bristol TN) Pharmaceutical organization Produced sulfanilamide tablets Salesman requirement for fluid planning for youngsters Problem sulfanilamide insoluble in EtOHSlide 7
Harold Watkins Chief Chemist, SE Massengill Co Tried heaps of vehicles Eventually – raspberry-tasting pink arrangement 10% sulfanilamide 72% diethylene glycol 16% water Flavor, raspberry remove, saccharine, amaranth and caramel "Remedy sulfanilamide"Slide 8
Massengill\'s research facility tried readiness for: Appearance Flavor Fragrance Ok - Therefore prepared for conveyance No Toxicity Testing No Clinical TrialsSlide 9
"Tossing drugs together and on the off chance that they didn\'t detonate, they were put discounted." FDA Agent\'s depiction of Massengill Company\'s medication advancement systemSlide 10
September 1937 240 gallons of mixture sulfanilamide made 1304 shipments all through the US Major circulation to Tulsa, OKSlide 11
2 nd October 1937 Editorial in JAMA "Cautioning against enthusiastic grasp of sulfanilamide" Adverse responses Dermatitis Photosensitivity Granulocytopenia Hemolytic Anemia Sulfanilamide—a notice (Editorial). JAMA. 1937; 109:1128Slide 12
Telegraph to AMA Dr. Stephenson President of the Tulsa County Medical Society "6 patients dead from renal disappointment out of the blue after ingestion Elixir Sulfanilamide stop ask for structure of the mixture."Slide 13
AMA never knew about this planning Telegraphed Mr. Massengill asking for piece Massengill "exclusive data" … yet discharged it proposed the passings because of corresponding meds Admitted to no danger testingSlide 14
Have you attempted it? Watkins self managed little add up to show trust in his item Told AMA - > No antagonistic impactsSlide 15
20 th October 1937 Telegraph Massengill to AMA "Please wire gather by Western Union proposal for cure and treatment taking after utilization of Elixir Sulfanilamide" AMA to Massengill " Antidote for Elixir Sulfanilamide – Massengill not known. Treatment probably symptomatic"Slide 16
Diethylene Glycol (DEG) Similar to ethylene glycol (radiator fluid) 1931 Von Oettinger deadly measurements 5 ml/kg in mice DEG causes kidney disappointment in miceSlide 17
Mid October 1937 News of Tulsa passings achieved Washington All FDA\'s overseers and physicists on to the case All 239!!Slide 18
FDA Acts FDA seized 228/240 ladies 240 ladies would have brought on >4000 passings FDA mediated because of mislabeling not because of passings Marketed as a remedy but rather did NOT contain ethanol. Anything called a remedy must contain ethanolSlide 19
353 patients got Elixir Sulfanilamide over a 4 week term 105 passings (case casualty rate of 30%) 34 youngsters & 71 grown-ups kicked the bucket GI side effects kept the majority of the survivors from ingesting enoughSlide 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 show item security – idea of creature/human testing before interstate transportation (2) equation must be unveiled (3) Directions for utilize and safety measures on solutionSlide 21
1938 Food Drug and Cosmetic Act Changed medication use to medicine Up to this time just 25% of medications were remedySlide 22
Epilog Senator Copeland kicked the bucket of "depletion" 4 days after bill was marked Dr. Massengill Pleaded blameworthy to 112 tallies of misbranding – fined $26,100 Harold Watkins Shot himself while cleaning his handgun Gerhard Domagk 1939 Nobel PrizeSlide 23
1938 Food, Drug and Cosmetic Act "Sufficient tests by all techniques sensibly material to demonstrate regardless of whether the medication is sheltered" Important stride was that the FDA must be fulfilled that the medication was protected – NOT only the maker – before circulation "Default" position was that the FDA would endorseSlide 24
C. Estes Kefauver (D-TN) Anti-Trust and Monopoly Subcommittee hearings on the pharmaceutical business (1959-1963)Slide 25
"The medicate organizations themselves were appeared to be occupied with excited publicizing effort intended to offer exchange name adaptations of medications that could somehow or another be recommended under bland names at a small amount of the cost; this opposition, thusly, had prompted the promoting of new medications that were no enhancements on medications as of now available yet, all things considered, proclaimed as sensational leaps forward without legitimate sympathy toward either viability or safety."Slide 26
1962 Kefauver-Harris Amendment Following Thalidomide disaster Effectiveness prerequisite acquainted Exposure with Thalidomide in US never affirmed in the US Research no record-keeping necessity for INDs New record keeping prerequisite Responsibility of specialist not to give out medication Informed assent requiredSlide 27
1962 – New Data Quality Requirement "Sufficient all around controlled studies" Generics Initially - > same prerequisites Too incredible an obstacle 1984 Generics got to be accessible under condensed NDAs (ANDA) Demonstrate bioequivalence Product qualitySlide 28
Kefauver-Harris Amendments Required "measurable proof" of adequacy from "satisfactory and all around controlled studies" Substantial confirmation Preponderance of the proof Evidence past a sensible uncertainty No prerequisite that medications be superior to models or even as greatSlide 29
Requirements for Approval Usually no less than 2 studies P<0.05 0.05 x 0.05 = 0.0025Slide 30
FDA Advisory Committee Unique part of US medication direction Hearings are open recorded notice ahead of time Public responsibility Risk sharingSlide 31
Freedom of Information Act Allows access to the reason for endorsementSlide 32
FDA – 1990s OnwardSlide 33
1992 Prescription Drug User Fee Act (PDUFA) 5-year life Authorized gathering of expenses Application charges Establishment expenses Product charges Revenue to contract analysts, bolster staff, overhaul IT $135 million clients charges in FY 2000 $438 million anticipated FY2008Slide 35
FDA Modernization Act of 1997 (FDAMA) Reauthorized PDUFA for a long time Codified a few FDA activities under the "Rethinking Government" program Modernized control of natural items Eliminated group affirmation for insulin and anti-microbials Streamlined endorsement for assembling changes Reduced requirement for ecological evaluationSlide 36
FDAMA 1997 (cont) Abolished denial against spread by makers of data about unapproved ("off name") utilizes If supports focus on accommodation of supplemental information Allows sedate organizations to give financial data to model boards of trustees, oversaw mind associations, huge scale purchasers Gave exception for exacerbated drugs (as opposed to assembling) Directed FDA to center post-showcasing observation on high hazard restorative gadgetsSlide 37
FDAMA - Pediatric eliteness 6 months of advertising restrictiveness to makers who lead and document pediatric studies in light of composed solicitations 218 proposed study demands 188 composed solicitations 58 ponders led and submitted – selectiveness conceded to 28 drugs http://www.fda.gov/cder/pediatric/index.htmSlide 39
FDA – Drug RecallsSlide 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 (endorsement/withdrawal)Slide 42
Top 10 explanations behind medication reviews in monetary 2000 Lack of certification of sterility underway or testing of clean medication items Deviations from ebb and flow great assembling hones Subpotency Microbial tainting of nonsterile items Chemical sullyingSlide 43
Top 10 purposes behind medication reviews in financial 2000 Penicillin cross-pollution of different items Failure of or powerlessness to approve fabricating forms Drug item promoted without an affirmed new or non specific application Failure or medication to break up appropriately Product found as far as possible set for debasements or corruptionSlide 45
Recent Concerns at FDASlide 46
Concerns at FDA - Drugs & Science Adverse occasions/tranquilize medicate communications QT prolongation Hepatic danger Use of surrogate markers To foresee result To anticipate AEs Definition of the "right measurement" Maximally compelling ToxicSlide 47
Concerns at FDA – Drugs & Science ( cont ) Active versus fake treatment controlled trials Role of pharmacogenomics In foreseeing reaction In foreseeing AEs Approval of medications for over-the-counterSlide 48
Concerns at FDA – Appea
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