1. Orlistat 60 mg Joint Meeting Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committees January 23, 2006 Andrea Leonard-Segal, M.D. Acting Director Division of Nonprescription Clinical Evaluation Joint Meeting Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committees January 23, 2006 Andrea Leonard-Segal, M.D. Acting Director Division of Nonprescription Clinical Evaluation Center for Drug Evaluation and Research

2. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 2 Introduction Historical approach to approving weight loss drugs: Rx and OTC –Few words about Obesity and Overweight Regulatory history of Orlistat Regulatory requirements for non-prescription marketing Outline agenda Historical approach to approving weight loss drugs: Rx and OTC –Few words about Obesity and Overweight Regulatory history of Orlistat Regulatory requirements for non-prescription marketing Outline agenda

3. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 3 Historical Approach to Prescription Weight Loss Drugs FDA’s approach to approving Rx weight loss drugs –Mirrored treatment recommendations in National Institute of Health guidelines –Target populations for drug therapy Obese: Body Mass Index (BMI) ≥ 30 kg/m 2 Overweight: BMI ≥ 27 kg/m 2 + other risk factors for cardiovascular disease and mortality (e.g., hypertension, diabetes mellitus, dyslipidemia) FDA’s approach to approving Rx weight loss drugs –Mirrored treatment recommendations in National Institute of Health guidelines –Target populations for drug therapy Obese: Body Mass Index (BMI) ≥ 30 kg/m 2 Overweight: BMI ≥ 27 kg/m 2 + other risk factors for cardiovascular disease and mortality (e.g., hypertension, diabetes mellitus, dyslipidemia)

4. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 4 Historical Approach to Nonprescription Weight Loss Drugs Approach to OTC weight loss drug availability guided by OTC Monograph –1982 Advance Notice of Proposed Rulemaking –Published in Federal Register –Recognizes weight control as an OTC indication Treatment indication not based upon BMI Approach to OTC weight loss drug availability guided by OTC Monograph –1982 Advance Notice of Proposed Rulemaking –Published in Federal Register –Recognizes weight control as an OTC indication Treatment indication not based upon BMI

5. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 5 Obesity Associated Diseases In addition to cardiovascular risk factors, NIH’s 2000 guidelines list non- cardiovascular conditions for which obese patients are at risk –Osteoarthritis –Gynecological abnormalities –Gallstones –Stress Incontinence In addition to cardiovascular risk factors, NIH’s 2000 guidelines list non- cardiovascular conditions for which obese patients are at risk –Osteoarthritis –Gynecological abnormalities –Gallstones –Stress Incontinence

6. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 6 Overweight as Risk Factor (BMI 25 – 29.9) Medical literature is replete with articles demonstrating non-cardiovascular risks of being overweight and obese Examples –End Stage Renal Disease Hsu C et al: Body Mass Index and Risk for End Stage Renal Disease. Ann Intern Med 2006;144:21-28 Medical literature is replete with articles demonstrating non-cardiovascular risks of being overweight and obese Examples –End Stage Renal Disease Hsu C et al: Body Mass Index and Risk for End Stage Renal Disease. Ann Intern Med 2006;144:21-28

7. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 7 Overweight as Risk Factor (BMI 25 – 29.9) Osteoarthritis –Felson DT, et al: Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study. Ann Intern Med. 1992;116:535-9. –Manninen P, et al: Weight changes and the risk of knee osteoarthritis requiring arthroplasty. Ann Rheum Dis. 2004 Nov;63(11):1434-7 –Holmberg S, et al: Knee osteoarthritis and body mass index: a population-based case-control study. Scand J Rheumatol. 2005;34(1):59-64. Arthritis → physical inactivity → increased risk for Cardiovascular Disease and Diabetes –For OA, a little weight loss helps Osteoarthritis –Felson DT, et al: Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study. Ann Intern Med. 1992;116:535-9. –Manninen P, et al: Weight changes and the risk of knee osteoarthritis requiring arthroplasty. Ann Rheum Dis. 2004 Nov;63(11):1434-7 –Holmberg S, et al: Knee osteoarthritis and body mass index: a population-based case-control study. Scand J Rheumatol. 2005;34(1):59-64. Arthritis → physical inactivity → increased risk for Cardiovascular Disease and Diabetes –For OA, a little weight loss helps

8. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 Regulatory History of Orlistat

9. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 9 Xenical® (Orlistat 120 mg) Approved in 1999 as prescription product –Pancreatic lipase inhibitor for obesity management –Roche Laboratories Dose –120 mg TID – Take with fat-containing meal Approved in 1999 as prescription product –Pancreatic lipase inhibitor for obesity management –Roche Laboratories Dose –120 mg TID – Take with fat-containing meal

10. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 10 Xenical® (Orlistat 120 mg) Indications –Obesity management including weight loss and maintenance when used with reduced calorie diet –Reduce risk for weight gain after prior weight loss Indications –Obesity management including weight loss and maintenance when used with reduced calorie diet –Reduce risk for weight gain after prior weight loss

11. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 11 Xenical® (Orlistat 120 mg) Target population –BMI ≥ 30 kg/m 2 –BMI ≥ 27 kg/m 2 + other risk factors (e.g., hypertension, diabetes mellitus, dyslipidemia) Duration of therapy –Not limited by labeling Target population –BMI ≥ 30 kg/m 2 –BMI ≥ 27 kg/m 2 + other risk factors (e.g., hypertension, diabetes mellitus, dyslipidemia) Duration of therapy –Not limited by labeling

12. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 12 Xenical® (Orlistat 120 mg) Pediatric Population –December, 2003 Labeling updated to include efficacy and safety data for obese adolescents ages 12 – 16 years No pediatric indication, per se Pediatric Population –December, 2003 Labeling updated to include efficacy and safety data for obese adolescents ages 12 – 16 years No pediatric indication, per se

13. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 13 Alli (Orlistat 60 mg) NDA under consideration today for Rx to OTC switch –GlaxoSmithKline –1 to 2 capsules with each fat-containing meal Not to exceed 6 capsules daily Indication –Promote weight loss in overweight adults when used along with a reduced calorie and low fat diet Target population –Overweight adults ≥18 years Duration of therapy –6 months NDA under consideration today for Rx to OTC switch –GlaxoSmithKline –1 to 2 capsules with each fat-containing meal Not to exceed 6 capsules daily Indication –Promote weight loss in overweight adults when used along with a reduced calorie and low fat diet Target population –Overweight adults ≥18 years Duration of therapy –6 months

14. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 Regulatory Requirements for Nonprescription Marketing

15. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 15 1951 Durham Humphrey Amendment to the Food, Drug and Cosmetic Act Formally differentiates Rx from Non Rx Drugs 2 Criteria carve niche for Prescription Drugs: –Drug can be used safely only under supervision because of: drug's toxicity or other potentiality for harmful effect, or method of its use, or collateral measures necessary to its use –If drug approved as result of a NDA for use under professional supervision Otherwise, the drug should be available without a prescription. Formally differentiates Rx from Non Rx Drugs 2 Criteria carve niche for Prescription Drugs: –Drug can be used safely only under supervision because of: drug's toxicity or other potentiality for harmful effect, or method of its use, or collateral measures necessary to its use –If drug approved as result of a NDA for use under professional supervision Otherwise, the drug should be available without a prescription.

16. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 16 Prescription to Nonprescription Switch Considerations Does the product have: –Acceptable safety profile? –Low potential for misuse and abuse? –Reasonable therapeutic index of safety? Can the condition to be treated be self- recognized? When used under non-Rx conditions is the product safe and effective? Do the benefits outweigh risks in OTC setting? Does the product have: –Acceptable safety profile? –Low potential for misuse and abuse? –Reasonable therapeutic index of safety? Can the condition to be treated be self- recognized? When used under non-Rx conditions is the product safe and effective? Do the benefits outweigh risks in OTC setting?

17. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 Issue for Today Does Orlistat meet regulatory requirements for nonprescription marketing?

18. Advisory Committee Meeting NDAC/EMDAC January 23, 2006 18 AgendaAgenda 8:40FDA: Hx Weight Loss Drugs / Monograph 9:20GlaxoSmithKline 10:45Break 11:15FDA Safety and Efficacy Label Comprehension Study Actual Use Study 12:15Lunch 1:15Committee Discussion 1:30Open Public Hearing 2:30Committee Deliberations 8:40FDA: Hx Weight Loss Drugs / Monograph 9:20GlaxoSmithKline 10:45Break 11:15FDA Safety and Efficacy Label Comprehension Study Actual Use Study 12:15Lunch 1:15Committee Discussion 1:30Open Public Hearing 2:30Committee Deliberations