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Endocrinologic and Metabolic Drugs Advisory Committee

September 8, 2004

FDA Regulation of Obesity Drugs:1938 - 1999

Eric Colman, MD

Division of Metabolic and Endocrine Drugs

September 8, 2004

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Food and Drug Laws

1906 President T. Roosevelt signs the original Food andDrugs Act

1938 - President F. Roosevelt signs Food, Drug, andCosmetic Act Labeling provisions Advertising provisions Drug manufacturers must submit evidence of a drugs

safety prior to marketing (sulfanilamide) New Drug Applications (NDA)

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The Amphetamines

Lesses, M.F. and Myerson A. Benzedrine sulfate as an aidin the treatment of obesity. 1938 New Engl J Med;218:119-124

Benzedrine (amphetamine sulfate) approved by the FDA in1939

Desoxyephedrine approved in 1943 Obesity indication for desoxyephedrine approved in 1947

The sympathomimetic amines have been found ofvalue, when administered under the supervision of aphysician, as an adjunct to the dietary management ofobesity

warned against its use in persons with cardiovasculardisease, hypertension, or insomnia and in those who

were neurotic or hyperexcitable. Amphetamines: amphetamine sulfate, desoxyephedrine

(methamphetamine), dextroamphetamine, amphetamine +barbiturate

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The Amphetamine-Like Drugs1956-1960

Phenmetrazine Phendimetrazine Phentermine Benzphetamine Diethylpropion

any [obese] patient, including the adolescent, geriatric, andgravid, as well as the special-high risk situations of thecardiac, hypertensive, and diabetic [patient].

tolerance, habituation, or addiction [did] not develop, ideal for long-term use

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An Epidemic

Widespread illicit use and abuse of amphetamines 1958 3.5 billion tablets 1967 8 billion tablets 1967 23 million prescriptions (80% female)

Most commonly prescribed for obesity Drug Abuse Control Amendments of 1965

Increased record keeping throughout the system ofmanufacture, distribution, prescription, and sale

Controlled Substances Act of 1970 Schedules 1-5

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1962 Kefauver-HarrisAmendments

Legislation mandated that new drug applications containsubstantial evidence of a drugs effectiveness

adequate and well-controlled investigations

What should be done regarding efficacy assessments for

drugs approved between 1938 and 1962? National Research Council of the National Academy of

Sciences

Drug Efficacy Study (DESI)

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The Drug Efficacy Study1966-1969

Psychiatric Drug Panel reviewed the available data on theefficacy of the amphetamines and the amphetamine-likedrugs

Categories of efficacy: Effective Effective, but Probably effective Possibly effective Ineffective

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The Drug Efficacy StudyResults

Amphetamines Possibly effective

Amphetamine-like drugs Effective but.

Reasons for Psychiatric Drug Panels conclusions:

Studies were of short duration;

There was no available evidence that the drugs alteredthe natural history of obesity;

There was some evidence that the anorectic effects mayhave been strongly influenced by the suggestibility ofthe patient;

There were concerns about the adequacy of the controlsin some of the clinical studies.

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Regulatory Consequences of DESI

1970 - FDA concluded that the amphetamines werePossibly effective. as a short term (a few weeks) adjunctin a regimen of weight reduction based on caloricrestriction

Industry directed to submit evidence of weight-loss efficacy

from adequate and well-controlled trials of more than a fewweeks duration

No formal FDA position regarding the efficacy of theamphetamine-like drugs

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Formation of FDAs Obesity Drug

Policy in the Early 1970s

The Prout Consultant Group

Neuropharmacology Drugs Advisory Committee

The Amphetamine-Anorectic Drug Project

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The Prout Consultant Group

Eight external consultants headed by Thaddeus Prout, anendocrinologist from Johns Hopkins

April 1971 meeting: Weight-loss drugs are potentially of value Efficacy trials should be at least 12 weeks in duration Long-term follow up of patients was not the

responsibility of drug companies Efficacy of the weight-loss drugs should be defined as

statistical superiority of drug to placebo

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The Neuropharmacology DrugsAdvisory Committee

September 1971

What criteria should be used to define clinically significantweight loss?

Reference made to Prouts recommendation that efficacy

be defined as statistical superiority of drug to placebo Still no answer on what defines clinically significant weight

loss

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The Amphetamine-AnorecticDrug Project

A meta-analysis of clinical data submitted to FDA

All amphetamine and amphetamine-like compounds(including fenfluramine and sanorex)

200 clinical studies

10,000 patients Patients treated with active medication lost some

fraction of a pound a week more than those on placebo

Data did not suggest that one drug was superior toanother nor that the amphetamines as a class were

more effective than the amphetamine-like drugs.

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Consequences of theAmphetamineAnorectic Drug

Project 1973 Agency declared the amphetamine and amphetamine-like

drugs effectivefor the treatment of obesity

Class labeling - concern about abuse led FDA to impose ashort-term (a few weeks) indication for obesity on allamphetamine and amphetamine-like drugs

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FDAs Continued Action Against

The Amphetamines 1979 Federal Register notice calling for removal of the obesity

indication for the amphetamines Continued evidence of abuse from DAWN No evidence that the amphetamine were more effective for

obesity than the amphetamine-like drugs Industry response

Analyses of data from DAWN were incorrect Problems with illicit production and use were the purview of

state medical boards and the DOJ, not FDA Abuse required use beyond a few weeks, so this was off-

label use of the drug; again not an issue for FDA More favorable risk-to-benefit profiles for the amphetamine-

like drugs not a legitimate reason to take action against theamphetamines

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Phentermine + Fenfluramine

Phentermine stimulant

Fenfluramine sedative

Long-term studies in the 1980s by Weintraub et al.

The rise of Phen-Fen

Prescriptions for Phentermine and Fenfluramine#

1992 1996

Phentermine 2,000,000 11,000,000

Fenfluramine 69,000 7,000,000

#from IMS America

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Regulatory Shift

1992 regulatory responsibility for obesity drugs transferred

from the Division of Neuropharmacology Drugs to theDivision of Metabolic and Endocrine Drugs

Effective drug treatment requires long-term or indefinite

use Pre-approval studies should therefore be long-term

Jan. 1995 Advisory Committee discusses the ObesityGuidance document

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Long-Term Treatment ofObesity

Dexfenfluramine approved in 1996 Removed from market in 1997

Sibutramine approved in 1997 MERIDIA is indicated for the management of obesity,

including weight loss and maintenance of weight loss,and should be used in conjunction with a reducedcalorie diet.

Orlistat approved in 1999 XENICAL is indicated for obesity management including

weight loss and weight maintenance when used inconjunction with a reduced-calorie diet. XENICAL is alsoindicated to reduce the risk for weight regain after prior

weight loss.

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Summary

Benefits: defining or quantitating the efficacy of weight-lossdrugs has been problematic 1940s-1960s: ???? 1960s: statistically significantly more weight loss 1990s: clinically significant weight loss is 5%

Risks: safety issues have dominated the regulatory history ofthe weight-loss drugs Illicit use and abuse Primary pulmonary hypertension Cardiac valvulopathy Blood pressure and pulse

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Conclusion