1. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 FDA 2004: Revisiting the 1996 Obesity Drug Guidance David G. Orloff, M.D. Division of Metabolic and Endocrine Drug Products, CDER David G. Orloff, M.D. Division of Metabolic and Endocrine Drug Products, CDER

2. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 2 1996 Obesity Drug Guidance Patient Population –Body Mass Index (BMI) 27 – 29.9 kg/m 2 with comorbidities (i.e., HTN, DM2) > 30 kg/m 2 without comorbidities Run-in phase –Identification of placebo-responders –Avoidance of treating unnecessarily with drugs Duration of Phase 3 Studies –Historical “bad luck” with anti-obesity drugs –Absence of outcomes data First year placebo-controlled: proof of principle of efficacy Second year open-label: durable efficacy and safety in long-term use Patient Population –Body Mass Index (BMI) 27 – 29.9 kg/m 2 with comorbidities (i.e., HTN, DM2) > 30 kg/m 2 without comorbidities Run-in phase –Identification of placebo-responders –Avoidance of treating unnecessarily with drugs Duration of Phase 3 Studies –Historical “bad luck” with anti-obesity drugs –Absence of outcomes data First year placebo-controlled: proof of principle of efficacy Second year open-label: durable efficacy and safety in long-term use

3. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 3 1996 Obesity Drug Guidance - Efficacy criteria at end of year 1: presumed reduction in risk for sequelae with modest (sustained) weight loss in serious obesity - Mean placebo-subtracted weight loss > 5% - Proportion of subjects who lose > 5% of baseline body weight is greater in drug- vs. placebo-treated group - EMEA criteria at end of year 1: - Mean placebo-subtracted weight loss > 10% - Proportion of patients who lose > 10% of baseline body weight is greater in drug- vs. placebo-treated group - Efficacy criteria at end of year 1: presumed reduction in risk for sequelae with modest (sustained) weight loss in serious obesity - Mean placebo-subtracted weight loss > 5% - Proportion of subjects who lose > 5% of baseline body weight is greater in drug- vs. placebo-treated group - EMEA criteria at end of year 1: - Mean placebo-subtracted weight loss > 10% - Proportion of patients who lose > 10% of baseline body weight is greater in drug- vs. placebo-treated group

4. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 4 1996 Obesity Drug Guidance Patient Exposure –1500 patients completing one year of placebo- controlled exposure –200-500 patients completing a second year of open-label exposure ICH E1A –Drugs for long-term treatment of non-life- threatening conditions: –300 – 600 for 6 months –100 for one year Patient Exposure –1500 patients completing one year of placebo- controlled exposure –200-500 patients completing a second year of open-label exposure ICH E1A –Drugs for long-term treatment of non-life- threatening conditions: –300 – 600 for 6 months –100 for one year

5. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 5 ICH E1A : Exposure requirements dictated by demonstrated efficacy Larger/longer exposures if benefit of drug is: –Small (e.g., symptomatic improvement, less serious disease) –Experienced by only a fraction of treated patients (prevention) –Of uncertain magnitude (reliance on a surrogate) Average placebo-subtracted weight loss of drugs evaluated to date 3-5% of baseline at year 1 Not all treated patients lose weight; some gain Scant data to date from controlled trials of benefits in terms of irreversible morbidity –XENDOS (Orlistat) No data on cardiovascular morbidity or mortality –SCOUT (Sibutramine) Larger/longer exposures if benefit of drug is: –Small (e.g., symptomatic improvement, less serious disease) –Experienced by only a fraction of treated patients (prevention) –Of uncertain magnitude (reliance on a surrogate) Average placebo-subtracted weight loss of drugs evaluated to date 3-5% of baseline at year 1 Not all treated patients lose weight; some gain Scant data to date from controlled trials of benefits in terms of irreversible morbidity –XENDOS (Orlistat) No data on cardiovascular morbidity or mortality –SCOUT (Sibutramine)

6. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 6 2004: revisiting the guidance Charge from Dr. McClellan to OWG/Therapeutics (8-03) –“…[assess] real or perceived barriers to development of new or enhanced therapeutics” –“Make recommendations… on…ways to encourage development of new or enhanced therapeutics” Growing public health problem Advancing science Multiple new drugs in development; anticipated explosion in development programs in coming years Multiple novel mechanistic approaches FDA’s role in assuring that safe and effective drugs are efficiently and effectively brought forward through development to marketing for use in the treatment of human disease Charge from Dr. McClellan to OWG/Therapeutics (8-03) –“…[assess] real or perceived barriers to development of new or enhanced therapeutics” –“Make recommendations… on…ways to encourage development of new or enhanced therapeutics” Growing public health problem Advancing science Multiple new drugs in development; anticipated explosion in development programs in coming years Multiple novel mechanistic approaches FDA’s role in assuring that safe and effective drugs are efficiently and effectively brought forward through development to marketing for use in the treatment of human disease

7. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 7 2004: revisiting the guidance Goals –Guidance appropriate for development of drugs, with respect to: –Potential roles of drugs in treatment and prevention –Target populations at risk for obesity and its sequelae –Evidentiary standards for proof of meaningful efficacy –Evidentiary standards for demonstration of acceptable safety Goals –Guidance appropriate for development of drugs, with respect to: –Potential roles of drugs in treatment and prevention –Target populations at risk for obesity and its sequelae –Evidentiary standards for proof of meaningful efficacy –Evidentiary standards for demonstration of acceptable safety

8. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 8 2004: revisiting the guidance Federal Register Notice –January 26, 2004 Request for public comment on the 1996 Obesity Drug Guidance Response –Approximately 17 submissions to the docket Nearly all from industry Federal Register Notice –January 26, 2004 Request for public comment on the 1996 Obesity Drug Guidance Response –Approximately 17 submissions to the docket Nearly all from industry

9. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 9 Issues raised in comments Broadening of target population –Adolescents Burgeoning problem Long-term, population-specific risks (i.e., linear growth, bone) Most appropriate endpoint (i.e., BMI rather than weight) (Specific criteria for selection not proposed) –Lower BMI limit targeting prevention of weight gain “High-risk” treatment and prevention (without specifics) Drugs “effective” in those with lesser degrees of obesity –Diabetes, Metabolic syndrome (these are not excluded based on trials to date) Broadening of target population –Adolescents Burgeoning problem Long-term, population-specific risks (i.e., linear growth, bone) Most appropriate endpoint (i.e., BMI rather than weight) (Specific criteria for selection not proposed) –Lower BMI limit targeting prevention of weight gain “High-risk” treatment and prevention (without specifics) Drugs “effective” in those with lesser degrees of obesity –Diabetes, Metabolic syndrome (these are not excluded based on trials to date)

10. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 10 Issues-2Issues-2 Study design –Run-in Proof of efficacy only in those unable to lose weight on diet/exercise is an excessive standard More generalizable results if no run in required Measure of effect is placebo-subtracted weight change from baseline (means of assuring standard of care in context of trial not addressed) Study design –Run-in Proof of efficacy only in those unable to lose weight on diet/exercise is an excessive standard More generalizable results if no run in required Measure of effect is placebo-subtracted weight change from baseline (means of assuring standard of care in context of trial not addressed)

11. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 11 Issues-2 (con’t) Duration –One year of controlled efficacy –Safety at one year –Questionable utility of additional year if no safety concerns after 1 st year –(Approach to assessing need for additional time or patients not addressed) Controls/Combination studies –(Efficacy criteria not addressed) Duration –One year of controlled efficacy –Safety at one year –Questionable utility of additional year if no safety concerns after 1 st year –(Approach to assessing need for additional time or patients not addressed) Controls/Combination studies –(Efficacy criteria not addressed)

12. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 12 Issues-3Issues-3 Efficacy criteria –Total weight loss > 5% from baseline at 12 months –Placebo-subtracted weight loss > 5% from baseline at 12 months (current criterion) –Significantly greater proportion (drug vs. plbo) losing > 5% of weight at 12 months (current criterion) –Define categorical win more specifically (i.e., absolute or relative difference in percentage of patients achieving 5% or greater weight loss) Efficacy criteria –Total weight loss > 5% from baseline at 12 months –Placebo-subtracted weight loss > 5% from baseline at 12 months (current criterion) –Significantly greater proportion (drug vs. plbo) losing > 5% of weight at 12 months (current criterion) –Define categorical win more specifically (i.e., absolute or relative difference in percentage of patients achieving 5% or greater weight loss)

13. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 13 Issues-3 (con’t) Efficacy criteria –Define weight maintenance –Define prevention of weight regain –Define drug-induced weight gain –BMI in pediatric patients Efficacy criteria –Define weight maintenance –Define prevention of weight regain –Define drug-induced weight gain –BMI in pediatric patients

14. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 14 Issues-4Issues-4 Safety exposures –Arbitrary –Current obesity guidance 1500 patients for one year; 200-500 for second year –ICH 100 patients for one year Safety exposures –Arbitrary –Current obesity guidance 1500 patients for one year; 200-500 for second year –ICH 100 patients for one year

15. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 15 Summary/Points for discussion Populations –Lower entry criterion to a BMI > 25 kg/m 2 when accompanied by comorbidities* What evidence supports treatment or prevention in this population? What magnitude of effect would be clinically significant? What assurance of safety is required to treat lower-risk patients? –Pediatric/adolescents What factors should be weighed/addresssed in assessing risk vs. benefit? –Obesity-associated metabolic derangements/cv risk factors as primary targets of drug therapy Populations –Lower entry criterion to a BMI > 25 kg/m 2 when accompanied by comorbidities* What evidence supports treatment or prevention in this population? What magnitude of effect would be clinically significant? What assurance of safety is required to treat lower-risk patients? –Pediatric/adolescents What factors should be weighed/addresssed in assessing risk vs. benefit? –Obesity-associated metabolic derangements/cv risk factors as primary targets of drug therapy

16. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 16 Summary/Discussion-2Summary/Discussion-2 Design –Run-in prior Identification of pbo responders Avoidance of unnecessary tx Standard of care –Combination drug regimens Standards of efficacy Endpoints –Define obesity prevention, weight maintenance, prevention of weight regain* Are these distinct clinical effects? Are these distinct pharmacological effects? Are studies needed to document efficacy and safety in each? –Include requirements for approval of treatment or prevention of drug-induced obesity* Data on risks for and associated with drug-induced obesity, by drug Issues of interactions impacting safety and efficacy Criteria for efficacy –Include a section on treatment of obesity in pediatric patients* Design –Run-in prior Identification of pbo responders Avoidance of unnecessary tx Standard of care –Combination drug regimens Standards of efficacy Endpoints –Define obesity prevention, weight maintenance, prevention of weight regain* Are these distinct clinical effects? Are these distinct pharmacological effects? Are studies needed to document efficacy and safety in each? –Include requirements for approval of treatment or prevention of drug-induced obesity* Data on risks for and associated with drug-induced obesity, by drug Issues of interactions impacting safety and efficacy Criteria for efficacy –Include a section on treatment of obesity in pediatric patients*

17. Endocrinologic and metabolic Drugs Advisory Committee September 8, 2004 17 Summary/Discussion-3Summary/Discussion-3 –Reduce the number of patients in phase 3 study from 1500 examined over one year to 500 – 1000, or even fewer* Rationale based on magnitude/nature of efficacy? Rationale based on size of target population? Rationale based on expectations regarding safety? –Eliminate the second year of open-label study* Rationale based on nature of drug “toxicities”: acute vs. cumulative? –Suggested changes Require an absolute difference for the categorical weight loss criterion Include metabolic syndrome as a therapeutic endpoint Include requirements for approval of drug combinations –Cosmetic weight loss Psychological benefits Social/economic benefits QOL –Reduce the number of patients in phase 3 study from 1500 examined over one year to 500 – 1000, or even fewer* Rationale based on magnitude/nature of efficacy? Rationale based on size of target population? Rationale based on expectations regarding safety? –Eliminate the second year of open-label study* Rationale based on nature of drug “toxicities”: acute vs. cumulative? –Suggested changes Require an absolute difference for the categorical weight loss criterion Include metabolic syndrome as a therapeutic endpoint Include requirements for approval of drug combinations –Cosmetic weight loss Psychological benefits Social/economic benefits QOL