1. 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 Eric Colman, MD Division of Metabolic and Endocrine Drugs September 8, 2004

2. Endocrinologic and Metabolic Drugs Advisory Committee 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) 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 4 The Amphetamine-Like Drugs 1956-1960 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” 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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) 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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. 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 The Prout Consultant Group Neuropharmacology Drugs Advisory Committee The Amphetamine-Anorectic Drug Project

11. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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. 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 16 Phentermine + Fenfluramine Phentermine – stimulant Fenfluramine – sedative Long-term studies in the 1980s by Weintraub et al. The rise of Phen-Fen Phentermine – stimulant Fenfluramine – sedative Long-term studies in the 1980s by Weintraub et al. The rise of Phen-Fen Prescriptions for Phentermine and Fenfluramine# 19921996 Phentermine2,000,00011,000,000 Fenfluramine69,0007,000,000 #from IMS America

17. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 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. 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 20 SummarySummary 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 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. Endocrinologic and Metabolic Drugs Advisory Committee September 8, 2004 21 ConclusionConclusion