the food and drug administration: then and now
Post on 14-Jan-2016
44 Views
Preview:
DESCRIPTION
TRANSCRIPT
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 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”
Massengill’s laboratory tested preparation for:
Appearance Flavor Fragrance
Ok - Therefore ready for distribution
No Toxicity Testing
No Clinical Trials
“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
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
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
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”
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 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
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 ApprovalsMedian times, approvals
13.8
16.0
15.8
15.9
23.1
24.7
23.0
12.5
12.3
15.7
15.4
14.4
15.9
14.0
14.6
13.4
19.0
19.9
15.0
16.3
15.1
17.8
35
30
51512
10
17181614
19
0
15
30
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004* 2005*
Calendar year*Includes BLAs for therapeutic biologics
Mo
nth
s
0
20
40
Nu
mb
er
Median FDA review time Median total approval time Number approved
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
412 17 23 20 23 17 153
1112 19 15 25 25
31
98
45
69
21 24 1910
20
60
120
1998 1999 2000 2001 2002 2003 2004 2005
Calendar year
Nu
mb
er
Pediatric exclusivity determinations Pediatric exclusivity labeling changes
Written requests issued
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
191226 248
352 354
254215
40160
53 34
88
72 156 83
88
71
101
248316
176
72
0
300
600
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Fiscal year
Nu
mb
er
Prescription Over-the-counter
Top 10 reasons for drug recalls in fiscal 20001) Lack of assurance of sterility in
production or testing of sterile drug products
2) Deviations from current good manufacturing practices
3) Subpotency4) Microbial contamination of nonsterile
products 5) Chemical contamination
Top 10 reasons for drug recalls in fiscal 20006) Penicillin cross-contamination of other
products
7) Failure of or inability to validate manufacturing processes
8) Drug product marketed without an approved new or generic application
9) Failure or drug to dissolve properly
10) Product found to exceed limits set for impurities or degradation
Safety-Based WithdrawalsNMEs approved Jan. 1, 1971, to May 31, 2006BLAs approved Oct. 1, 2003, to May 31, 2006
3.1%3.5%
0%
2%
4%
Pre-PDUFA (488/15) PDUFA (345/12)
Receipt periods (approvals/withdrawals)
Per
cen
tag
e
Recent Concerns at FDA
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
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 SafetyIOM “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
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”
Concerns at FDA - PDUFA
FDA funding
Higher Percentage of Budget from Industry
Questions?
top related