Orlistat OTC 60 mg capsules Glaxo Smith Kline

Orlistat OTC, 60 mg capsules Glaxo. Smith. Kline (GSK) Consumer Healthcare New Drug Application 21 -887 Actual Use Study NM 17285 Joint Meeting of the Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Advisory Committee Bethesda, Maryland January 23, 2006 Karen B. Feibus, M. D. Medical Officer Division of Nonprescription Clinical Evaluation Center for Drug Evaluation and Research

Important elements of an actual use study (AUS) § Attempts to simulate OTC use of the product § Few exclusion criteria § Self selection: – Do people correctly choose to use or not use the product based on the label (ideally tested previously in LC studies)? § Compliance: – Do people dose and use the product based on the label directions? § Efficacy information often limited by open-label, uncontrolled design. § Objectives are product dependent Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 2

Actual Use Issues and Objectives for Orlistat OTC § Who will use orlistat OTC? § Do subjects correctly choose to use or not use orlistat OTC based on label warnings and indications? § Do subjects dose orlistat correctly? § Do subjects lose weight? § Are there safety concerns? – Do subjects take a multivitamin correctly while using orlistat? – Do non overweight subjects choose to use orlistat? – Are there unexpected adverse events with orlistat use in the OTC environment? Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 3

Study Design § 90 days § 18 U. S. pharmacies, six geographical areas § Certified weight scale in each pharmacy § Recruitment: in-store advertising; newspaper ads where recruitment slow. § Advertising notified consumers of compensation § Enrolled individuals ages 18 years and older § Subjects able and available to complete telephone interviews § Subjects with a “Do Not Use” condition could participate in self-selection but could not purchase orlistat. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 4

Self-selection process § Consumer presented with orlistat package and told: Imagine you are in a store and this is a new over-the -counter medicine. You can take as much time as you need to look at the packaging. Let me know when you are finished. § Self-selection question asked when consumer finished examining the package: Do you think this medication is appropriate for you to use? Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 5

Purchase Decision § The cost of this medicine is $45 for a bottle of 90 capsules. Would you like to purchase the medicine today? § Information collected: – Reason why did or did not want to purchase orlistat – Height, weight Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 6

Treatment § All purchasers initially received an OTC orlistat package containing: – Up to 3 bottles (#90) orlistat, 60 mg – Supplementary educational materials (behavioral and nutritional support) • Orlistat User Guide: “How to Lose Weight with Orlistat. ” • Personal food diary • Pocket fat gram counter • Fat gram wheel • Portion size information card • Orlistat Diet Success Planner: Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 7

Data collection § Scripted telephone interviews – At about 14, 30, 60, 90, and 104 days after enrollment – Conducted by trained clinical interviewers – Interview content: • • Started orlistat? Contact with healthcare provider? Use patterns: dose, frequency, timing with food Multivitamin (MVI) use Diet and exercise Discomforts? Changes in health or other medicines? Weight loss? Use of label, educational materials, website – Interviews with at least one question answered were included in analysis. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 8

Data collection § Pharmacy visits – Subjects could return to pharmacy as needed to purchase more orlistat (up to 3 bottles at a time) – One pharmacy visit required after enrollment, time unspecified – Information collected: • Drug log form: dates, amount of drug purchased • Weight measured • Adverse events recorded Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 9

AUS Design: Comments § The Drug Facts label and supplementary educational materials used are similar to those submitted to the NDA; however, – some elements of Drug Facts are different in content or location – the actual educational materials submitted to the NDA were not tested. § Objective weight measurements were not required at the end of the study. § Subject diaries were not analyzed or collected. § Some telephone interactions may have influenced subject orlistat use behaviors. § No assessment of discontinuation of use. Joint Meeting of the Nonprescription Drugs Advisory Committee § 90 day AUS. Proposed duration orlistat use: 6 months. And Endocrinologic and Metabolic Drugs Advisoryof Committee January 23, 2006 10

Actual Use Study Results Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 11

Disposition of Subjects 703 Screened subjects Eligible for analysis? At one pharmacy site, subjects were given information at enrollment that potentially biased the self-selection process. “Do you think this medicine is appropriate for you to use? ” Yes No 22 subjects protocol violation 681 Eligible subjects Yes No 52 No 86 Don’t know 543 answer “YES” Regardless of self-selection decision, all eligible subjects: • Take REALM test • Provide demographic and health history information Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 12

Disposition of Subjects (cont. ) 681 Eligible subjects Would you like to purchase the medicine today? Yes No 261 No 66 Don’t know 15 missing 339 Want to purchase Subject met inclusion/ exclusion criteria? 28 did not Yes No 49 did not meet criteria purchase 262* Subject used orlistat and completed an interview? All 22 subjects excluded for protocol violations purchased orlistat, 21 used it. Purchasers Yes No 7 did not use 18 no interview 237 Evaluable users Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 13

Who enrolled? Who used orlistat? The AUS study population Demographic Eligible (N = 681) Users (N = 237) 79. 4% 86% Mean age (years) 45. 4 44. 9 Age range (years) 18 – 85 18 – 75 Mean BMI (kg/m 2) 33. 1 ± 6. 7 32. 0 ± 5. 8 BMI range (kg/m 2) 20. 9 – 62. 6 21 - 53 79. 3% 8. 1% 6. 2% 82% 6% 3% Education beyond high school 76. 5% 84. 4% REALM test score Low literate (score ≤ 60) Literate, > 8 th grade (score > 60) 8. 1% 91. 5% 4. 2% 95. 8% Gender Ethnicity Female Caucasian Hispanic African American Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 14

Correct self-selection responses § Subject meets a condition listed in Drug Facts Warnings under “Do Not Use”: – No, this medicine is not appropriate for me to use. § Subject meets a condition listed in Drug Facts Warnings under “Ask a doctor before use” or “Ask a doctor or pharmacist before use”: – No, this medicine is not appropriate for me to use. – Yes (or Don’t Know), but I need to check with my doctor first. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 15

Drug Facts Label Comparison Actual Use Study Label Orlistat OTC Label Do Not Use § § Allergy to ingredients Taking cyclosporine Taking warfarin Taking prescription diabetes medicine § § § Ask Doctor Before Use § § § § Problems absorbing food § Gallbladder problems § Kidney stones More than 30 lbs to lose Given diet by doctor Diabetes High blood pressure High cholesterol/triglycerides Ask Doctor/ Pharm. Before Use § Taking medicine for high § Taking diabetes medicine blood pressure or high § Taking warfarin cholesterol/triglycerides § Taking other weight loss drugs Joint medicine Meeting of the Nonprescription Drugs Advisory Committee or supplement And Endocrinologic and Metabolic Drugs Advisory Committee Allergy to ingredients Taking cyclosporine Diagnosed with problems absorbing food § Not overweight And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 16

Self-selection 681 Eligible subjects 216 465 No labeled exclusions Labeled exclusion 107 Self-selected correctly 358 Self-selected incorrectly 209 7 Self-selected correctly Self-selected incorrectly § Correct self-selection: 107 + 209 = 316 § 46. 4% of all eligible subjects made a correct self-selection decision Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 17

AUS self-selection decisions: “Do Not Use” AUS label exclusion Subjects w/ exclusion Correct self-selection decisions Number Percentage Allergic to ingredients 0 - - Taking cyclosporine 2 1 50 Taking warfarin 14 7 50 Taking diabetes medicine 46 16 35 Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 18

AUS self-selection decisions: “Ask before use” warnings Subjects w/ exclusion % correct self selection Problems absorbing food 12 17 Gallbladder problems 25 40 High blood pressure 166 44 High cholesterol/triglycerides 147 46 More than 30 lbs to lose 346 21 Taking a weight loss medicine 33 12 On doctor-recommended diet 48 54 AUS label exclusion NDA label warnings not tested in actual use study: – “Do not use” if you are not overweight – “Ask before use” if you have kidney stones Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 19

Purchase decision § Of 631 eligible subjects, 284 purchased orlistat. § Cost was the primary reason that most subjects (60%) did not want to purchase. § 17% of those uncertain about purchasing cited a need to speak with a healthcare provider first. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 20

Baseline BMI and perceptions of body weight Baseline BMI for orlistat users BMI (kg/m 2) Users (N = 237) 21 – 24. 9 18 (8%) 25 – 29. 9 76 (32%) ≥ 30 143 (60%) Subject self perceptions of body weight Subject responses Slightly/moderately underweight Users (N = 237) 2% Average for height and weight 0 Mildly/moderately overweight 81% Severely overweight 17% Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 21

Correct use decisions: § % subjects making correct use decisions – based on self-report at telephone interviews – Contact with healthcare provider was not confirmed. # subjects w/ condition # purchasers w/ exclusion Appropriate use Decision (%) Problems absorbing food 12 1 0 Gallbladder problems 25 7 29 High blood pressure 166 54 39 High cholesterol/triglycerides 147 49 43 More than 30 lbs to lose 346 114 24 Taking a weight loss medicine 33 10 50 On diet recommended by doctor 48 12 25 AUS label exclusion Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 22

Typical subject use behaviors (N = 237) % of subjects interviewed Parameter Day 14 (N = 217) Day 30 (N = 219) Day 60 (N = 197) Day 90 (N = 148) Average capsules per dose 0– 2 more 99. 1 0 97. 3 0. 5 98. 5 0 96. 7 0. 7 Average doses per day 0– 3 more 97. 8 1. 8 96. 9 1. 8 98. 0 0. 5 97. 3 0 Average capsules per day 0– 6 more 99. 2 0 98. 1 0 98. 0 0 96. 6 0. 7 Taking orlistat with meals 97 96 98 95 Still using orlistat 87 86 63 46 Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 23

Multivitamin (MVI) use among orlistat users (N = 237) during the AUS Pattern of MVI use by subjects Telephone interview Day 14 (N = 217) Day 30 (N = 219) Day 60 (N = 197) Day 90 (N = 148) Currently using MVI 163 (75. 1%) 178 (81. 3%) 163 (82. 7%) 127 (85. 8%) Taking MVI daily or more than once daily 156 (71. 9%) 173 (79. 0%) 158 (80. 2%) 120 (81. 1%) Taking MVI at least 2 hours before or after orlistat 83 (38. 2%) 98 (44. 7%) 88 (44. 7%) 79 (53. 4%) Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 24

Multivitamin Use: Comments § MVI directions in Drug Facts: – AUS label: Other Information – NDA label: Directions. § LC study results: – 73% correct: How to time MVI correctly with orlistat. § Factors potentially influencing compliance: – Label comprehension – Conflicting label directions for MVI use with food Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 25

Use of educational materials Educational material % subjects using material % subjects who found material useful Fat Counter 64 86 Fat Wheel 46 79 Personal food diary 42 80 Orlistat user guide 42 85 Diet success planner 31 77 Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 26

Self-Reported Dietary Behavior Interview data Dietary behavior Day 14 (N = 217) Day 30 (N = 219) Day 60 (n = 197) Day 90 (N = 148) Following any kind of diet 80% 69% 58% 61% Reduced calorie diet 43% 41% 33% 36% Reduced fat diet 78% 76% 70% 66% Somewhat or very successful staying on diet 95% 96% 98% 97% Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 27

Weight loss efficacy § Weight loss was a secondary study endpoint § Self-reported weights collected telephone interviews. – Weight change was documented only for subjects who lost weight. § Objective weight measurements collected at enrollment and return pharmacy visits. – Only one return pharmacy visit was required at an unspecified time. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 28

% Body weight lost % body weight lost Measured weight Day 61 – 90 (N = 60) > 0 – 5% 75% > 5% 42% > 10% 5% Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 29

Measured weight loss and baseline BMI (Pharmacy visit Days 61 – 90) Baseline BMI (kg/m 2) Number of subjects Median weight loss (lbs) Range of weight change (lbs) < 25 6 1. 5 +3 to -7 25 – 29. 9 28 4. 5 +6 to -19 ≥ 30 72 6. 5 +8 to -52 Total 106 6. 0 +8 to -52 Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 30

Actual Use Study Adverse Events (AEs) Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 31

Safety Population (N = 284) § The safety population included at least 8 subjects (and as many as 26 subjects) who did not use orlistat. § 2 severe AEs possibly related to study drug: – One case of esophageal spasm – One case of abdominal pain with chronic anemia. § 43 subjects experienced 65 adverse events that led to premature study discontinuation – 12 non-gastrointestinal adverse events – 53 gastrointestinal adverse events typically associated with orlistat use. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 32

Common GI Adverse events § Abdominal pain (15. 1%) § Decreased defecation (4. 9%) § Oily spotting (13. 4%) § Soft stools (4. 2%) § Fecal urgency (12. 7%) § Nausea (3. 9%) § Flatulence (12. 7%) § Abdominal distension (3. 5%) § Liquid stools (10. 9%) § Abdominal pain, upper (3. 5%) § Flatus with discharge (10. 6%) § Dyspepsia (1. 8%) § Fecal incontinence (8. 1%) § Constipation (1. 4%) § Fatty/oily stool (7. 0%) § Hemorrhoids (1. 4%) § Oily evacuation (7. 0%) § Vomiting (1. 1%) § Increased defecation (5. 3%) Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 33

Actual Use Study Answers and Conclusions Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 34

Answers to our questions: § Who will use orlistat OTC? – 92% of orlistat users were overweight or obese. – Compared to the American population, the study population under-represented consumers of low literacy and non-Caucasian ethnicity. • This may or may not accurately reflect consumers likely to use orlistat OTC. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 35

Answers to our questions (cont. ): § Do subjects correctly choose to use or not use orlistat OTC based on label warnings and indications? – 1 of 2 subjects taking cyclosporine and 7 of 14 subjects taking warfarin incorrectly self-selected. – Overall, 46% of eligible subjects self-selected correctly. – GSK conducted 3 self-selection studies focused on cyclosporine and warfarin users and teens. Studies not submitted to FDA. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 36

Answers to our questions (cont. ): § Do subjects dose orlistat correctly? – Yes. Subjects dosed orlistat according to labeled directions throughout the study. – Most subjects followed a diet plan. As labeled, most used a low-fat and/or reduced-calorie diet. § Do subjects lose weight using orlistat OTC? – The data suggest that 75% of subjects lost some weight, and 40% lost more than 5% body weight. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 37

Answers to our questions (cont. ): § Are there safety concerns? – Do subjects take a multivitamin correctly while using orlistat? • 38 – 53% of users used a MVI according to label directions during the study. – Do non overweight subjects choose to use orlistat? • 7. 6% of users had a normal baseline BMI. No underweight individuals enrolled. – Are there unexpected adverse events with orlistat use in the OTC environment? • No. Joint Meeting of the Nonprescription Drugs Advisory Committee And Endocrinologic and Metabolic Drugs Advisory Committee January 23, 2006 38