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?