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

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fda regulation of obesity drugs 1938 1999

FDA Regulation of Obesity Drugs: 1938 - 1999

Eric Colman, MD

Division of Metabolic and Endocrine Drugs

September 8, 2004

food and drug laws
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 drug’s safety prior to marketing (sulfanilamide)
    • New Drug Applications (NDA)
the amphetamines
The Amphetamines
  • Lesses, M.F. and Myerson A. Benzedrine sulfate as an aid in the treatment of obesity. 1938 New Engl J Med; 218:119-124
  • 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
the amphetamine like drugs 1956 1960
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”
an epidemic
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
1962 kefauver harris amendments
1962 Kefauver-Harris Amendments
  • Legislation mandated that new drug applications contain substantial evidence of a drug’s 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)
the drug efficacy study 1966 1969
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
the drug efficacy study results
The Drug Efficacy Study Results
  • Amphetamines “Possibly effective”
  • Amphetamine-like drugs “Effective but……….”
  • Reasons for Psychiatric Drug Panel’s 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.
regulatory consequences of desi
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
formation of fda s obesity drug policy in the early 1970s
Formation of FDA’s Obesity Drug Policy in the Early 1970s
  • The Prout Consultant Group
  • Neuropharmacology Drugs Advisory Committee
  • The Amphetamine-Anorectic Drug Project
the prout consultant group
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
the neuropharmacology drugs advisory committee
The Neuropharmacology Drugs Advisory Committee
  • September 1971
  • What criteria should be used to define clinically significant weight loss?
  • Reference made to Prout’s recommendation that efficacy be defined as statistical superiority of drug to placebo
  • Still no answer on what defines clinically significant weight loss
the amphetamine anorectic drug project
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.
consequences of the amphetamine anorectic drug project
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
fda s continued action against the amphetamines
FDA’s 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
phentermine fenfluramine
Phentermine + Fenfluramine
  • Phentermine – stimulant
  • Fenfluramine – sedative
  • Long-term studies in the 1980s by Weintraub et al.
  • The rise of Phen-Fen

#from IMS America

regulatory shift
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
obesity guidance 1996
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
long term treatment of obesity
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.
  • 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