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 drug’s 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; 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

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 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)

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 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.

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 FDA’s 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 Prout’s 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. 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

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