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?