FDA Regulation of Obesity Drugs: 1938 1999

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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 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)

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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

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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

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

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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)

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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

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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.

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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

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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, 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

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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

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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.

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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

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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 the amphetamines

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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

from IMS America
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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

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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

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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.

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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

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Conclusion