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FDA Regulation of Obesity Drugs: 1938 1999

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Endocrinologic and Metabolic Drugs Advisory Committee. September 8, 2004 ... There was no available evidence that the drugs altered the natural history of obesity; ... – PowerPoint PPT presentation

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Title: FDA Regulation of Obesity Drugs: 1938 1999


1
FDA Regulation of Obesity Drugs 1938 - 1999
  • Eric Colman, MD
  • Division of Metabolic and Endocrine Drugs
  • September 8, 2004

2
Food and Drug Laws
  • 1906 President T. Roosevelt signs the original
    Food and Drugs Act
  • 1938 - President F. Roosevelt signs Food, Drug,
    and Cosmetic Act
  • Labeling provisions
  • Advertising provisions
  • Drug manufacturers must submit evidence of a
    drugs safety prior to marketing (sulfanilamide)
  • New Drug Applications (NDA)

3
The Amphetamines
  • Lesses, M.F. and Myerson A. Benzedrine sulfate as
    an aid in the treatment of obesity. 1938 New Engl
    J Med 218119-124
  • Benzedrine (amphetamine sulfate) approved by the
    FDA in 1939
  • Desoxyephedrine approved in 1943
  • Obesity indication for desoxyephedrine approved
    in 1947
  • The sympathomimetic amines have been found of
    value, when administered under the supervision of
    a physician, as an adjunct to the dietary
    management of obesity
  • warned against its use in persons with
    cardiovascular disease, hypertension, or insomnia
    and in those who were neurotic or
    hyperexcitable.
  • Amphetamines amphetamine sulfate,
    desoxyephedrine (methamphetamine),
    dextroamphetamine, amphetamine barbiturate

4
The Amphetamine-Like Drugs1956-1960
  • Phenmetrazine
  • Phendimetrazine
  • Phentermine
  • Benzphetamine
  • Diethylpropion
  • any obese patient, including the adolescent,
    geriatric, and gravid, as well as the
    special-high risk situations of the cardiac,
    hypertensive, and diabetic patient.
  • tolerance, habituation, or addiction did not
    develop, ideal for long-term use

5
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 of
    manufacture, distribution, prescription, and sale
  • Controlled Substances Act of 1970
  • Schedules 1-5

6
1962 Kefauver-Harris Amendments
  • Legislation mandated that new drug applications
    contain substantial 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)

7
The Drug Efficacy Study 1966-1969
  • Psychiatric Drug Panel reviewed the available
    data on the efficacy of the amphetamines and the
    amphetamine-like drugs
  • Categories of efficacy
  • Effective
  • Effective, but
  • Probably effective
  • Possibly effective
  • Ineffective

8
The Drug Efficacy Study Results
  • 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
    altered the natural history of obesity
  • There was some evidence that the anorectic
    effects may have been strongly influenced by the
    suggestibility of the patient
  • There were concerns about the adequacy of the
    controls in some of the clinical studies.

9
Regulatory Consequences of DESI
  • 1970 - FDA concluded that the amphetamines were
    Possibly effective. as a short term (a few
    weeks) adjunct in a regimen of weight reduction
    based on caloric restriction
  • Industry directed to submit evidence of
    weight-loss efficacy from adequate and
    well-controlled trials of more than a few weeks
    duration
  • No formal FDA position regarding the efficacy of
    the amphetamine-like drugs

10
Formation of FDAs Obesity Drug Policy in the
Early 1970s
  • The Prout Consultant Group
  • Neuropharmacology Drugs Advisory Committee
  • The Amphetamine-Anorectic Drug Project

11
The Prout Consultant Group
  • Eight external consultants headed by Thaddeus
    Prout, an endocrinologist 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

12
The Neuropharmacology Drugs Advisory Committee
  • September 1971
  • What criteria should be used to define clinically
    significant weight 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

13
The Amphetamine-Anorectic Drug 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
    to another nor that the amphetamines as a class
    were more effective than the amphetamine-like
    drugs.

14
Consequences of the Amphetamine Anorectic Drug
Project
  • 1973 Agency declared the amphetamine and
    amphetamine-like drugs effective for the
    treatment of obesity
  • Class labeling - concern about abuse led FDA to
    impose a short-term (a few weeks) indication for
    obesity on all amphetamine and amphetamine-like
    drugs

15
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 the amphetamines

16
Phentermine Fenfluramine
  • Phentermine stimulant
  • Fenfluramine sedative
  • Long-term studies in the 1980s by Weintraub et
    al.
  • The rise of Phen-Fen

from IMS America
17
Regulatory Shift
  • 1992 regulatory responsibility for obesity drugs
    transferred from the Division of
    Neuropharmacology Drugs to the Division 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
    Obesity Guidance document

18
Obesity Guidance - 1996
  • Efficacy criteria
  • Mean weight loss in drug group is at least 5
    greater than mean weight loss in placebo group
  • Proportion of patients who lose at least 5 of
    baseline weight is greater in drug vs. placebo
    group
  • Size and duration of phase 3 trials
  • 1500 patients studied for one-year under
    placebo-controlled conditions
  • 200-500 patients for an additional year of
    open-label study

19
Long-Term Treatment of Obesity
  • 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 reduced calorie diet.
  • Orlistat approved in 1999
  • XENICAL is indicated for obesity management
    including weight loss and weight maintenance when
    used in conjunction with a reduced-calorie diet.
    XENICAL is also indicated to reduce the risk for
    weight regain after prior weight loss.

20
Summary
  • Benefits defining or quantitating the efficacy
    of weight-loss drugs 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 of the weight-loss drugs
  • Illicit use and abuse
  • Primary pulmonary hypertension
  • Cardiac valvulopathy
  • Blood pressure and pulse

21
Conclusion
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