Nonprescription Orlistat GlaxoSmithKline NDA 21-887

Joint Nonprescription Drugs and Endocrinologic and Metabolic Joint Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committee Meeting Drugs Advisory Committee Meeting January 23, 2006

Nonprescription OrlistatNonprescription Orlistat GlaxoSmithKline GlaxoSmithKline NDA 21-887 NDA 21-887

Nonprescription OrlistatNonprescription Orlistat GlaxoSmithKline GlaxoSmithKline NDA 21-887 NDA 21-887

Nonprescription and Metabolic and Endocrinologic Drugs Advisory Committees

January 23, 2006

Eric Colman, MDDivision of Metabolism and Endocrinology Products

Nonprescription and Metabolic and Endocrinologic Drugs Advisory Committees

January 23, 2006

Eric Colman, MDDivision of Metabolism and Endocrinology Products


The Regulation of Prescription The Regulation of Prescription Weight-Loss Drugs Weight-Loss Drugs

The Regulation of Prescription The Regulation of Prescription Weight-Loss Drugs Weight-Loss Drugs

• Part I 1947 to 1973Approval of the amphetamines and the

amphetamine congeners• Part II 1974 to 1995

Short-term treatment• Part III 1996 to present

Long-term treatment

• Part I 1947 to 1973Approval of the amphetamines and the

amphetamine congeners• Part II 1974 to 1995

Short-term treatment• Part III 1996 to present

Long-term treatment


Part IPart IAmphetamines Amphetamines

Amphetamine CongenersAmphetamine Congeners1947 - 19731947 - 1973

Part IPart IAmphetamines Amphetamines

Amphetamine CongenersAmphetamine Congeners1947 - 19731947 - 1973


Approval of Amphetamines and Approval of Amphetamines and Amphetamine Congeners Amphetamine Congeners

Approval of Amphetamines and Approval of Amphetamines and Amphetamine Congeners Amphetamine Congeners

• 1947 – desoxyephedrine • Indication: As an adjunct to therapy of obesity

• 1960 – phenmetrazine, diethylpropion, phentermine, phendimetrazine, benzphetamine • Indication: Treatment of obesity in any patient

including the adolescent, geriatric, and gravid as well as special-risk situations of the cardiac, hypertensive, and diabetic

• 1947 – desoxyephedrine • Indication: As an adjunct to therapy of obesity

• 1960 – phenmetrazine, diethylpropion, phentermine, phendimetrazine, benzphetamine • Indication: Treatment of obesity in any patient

including the adolescent, geriatric, and gravid as well as special-risk situations of the cardiac, hypertensive, and diabetic


Drug Efficacy Study Implementation Drug Efficacy Study Implementation (DESI)(DESI)

Drug Efficacy Study Implementation Drug Efficacy Study Implementation (DESI)(DESI)

• 1962 Kefauver-Harris Drug Amendments

• 1966 - National Academy of Sciences reviews the efficacy of all drugs approved between 1938 and 1962

• Psychiatric Drug Panel reviews efficacy of the weight-loss drugs

• 1962 Kefauver-Harris Drug Amendments

• 1966 - National Academy of Sciences reviews the efficacy of all drugs approved between 1938 and 1962

• Psychiatric Drug Panel reviews efficacy of the weight-loss drugs


Psychiatric Drug Panel’s ConclusionsPsychiatric Drug Panel’s ConclusionsPsychiatric Drug Panel’s ConclusionsPsychiatric Drug Panel’s Conclusions

• Amphetamines and the amphetamine congeners are less-than-effective√ Trials are of short duration√ Effect often plateaus or diminishes after 4-

6 weeks√ No available evidence that the drugs alter

the natural history of obesity

• Need longer-term data

• Amphetamines and the amphetamine congeners are less-than-effective√ Trials are of short duration√ Effect often plateaus or diminishes after 4-

6 weeks√ No available evidence that the drugs alter

the natural history of obesity

• Need longer-term data


FDA’s Response To Psychiatric FDA’s Response To Psychiatric Drug Panel’s ConclusionsDrug Panel’s Conclusions

FDA’s Response To Psychiatric FDA’s Response To Psychiatric Drug Panel’s ConclusionsDrug Panel’s Conclusions

• FDA agreed that the available evidence did not support a conclusion that the amphetamines or the amphetamine congeners were effective for weight loss

• Companies told to conduct adequate and well-controlled trials to demonstrate that their weight-loss drugs are effective

• FDA agreed that the available evidence did not support a conclusion that the amphetamines or the amphetamine congeners were effective for weight loss

• Companies told to conduct adequate and well-controlled trials to demonstrate that their weight-loss drugs are effective


What is Efficacy? What is Efficacy? What is Efficacy? What is Efficacy?

• FDA asks: How should efficacy of weight-loss drugs be defined?

• FDA’s consultants stated that efficacy should depend on the demonstration of statistical superiority of drug to placebo

• The consultants explicitly declined to require biological superiority, e.g., some minimum loss in terms of percentage of excess weight

• FDA’s Advisory Committee endorsed the use of statistical superiority of drug to placebo

• FDA asks: How should efficacy of weight-loss drugs be defined?

• FDA’s consultants stated that efficacy should depend on the demonstration of statistical superiority of drug to placebo

• The consultants explicitly declined to require biological superiority, e.g., some minimum loss in terms of percentage of excess weight

• FDA’s Advisory Committee endorsed the use of statistical superiority of drug to placebo


FDA’s Amphetamine FDA’s Amphetamine Anorectic Drug ProjectAnorectic Drug ProjectFDA’s Amphetamine FDA’s Amphetamine

Anorectic Drug ProjectAnorectic Drug Project• Meta-analysis of data from the trials FDA required

manufacturers to conduct to demonstrate efficacy of the amphetamines and the amphetamine congeners

• All amphetamines and amphetamine congeners including fenfluramine

• 206 double-blind studies of more than 10,000 patients

• Duration of studies 3 to 24 weeks; most 12 weeks or less

• Patients treated with active drug “lost a fraction of a pound more a week” than those treated with placebo – differences statistically significant

• Meta-analysis of data from the trials FDA required manufacturers to conduct to demonstrate efficacy of the amphetamines and the amphetamine congeners

• All amphetamines and amphetamine congeners including fenfluramine

• 206 double-blind studies of more than 10,000 patients

• Duration of studies 3 to 24 weeks; most 12 weeks or less

• Patients treated with active drug “lost a fraction of a pound more a week” than those treated with placebo – differences statistically significant


FDA’s Official Position on FDA’s Official Position on Weight-Loss Drugs in 1973Weight-Loss Drugs in 1973FDA’s Official Position on FDA’s Official Position on Weight-Loss Drugs in 1973Weight-Loss Drugs in 1973

• Although effective, the weight-loss drugs have limited usefulness in the treatment of obesity√ Fraction of a pound more a week lost on drug

vs placebo√ Weight loss plateaus early√ Weight is regained after the drug is stopped√ No data on the effects of the drugs on

morbidity or mortality Overriding concern about the growing

abuse of the amphetamines and to a lesser extent the amphetamine congeners

• Although effective, the weight-loss drugs have limited usefulness in the treatment of obesity√ Fraction of a pound more a week lost on drug

vs placebo√ Weight loss plateaus early√ Weight is regained after the drug is stopped√ No data on the effects of the drugs on

morbidity or mortality Overriding concern about the growing

abuse of the amphetamines and to a lesser extent the amphetamine congeners


Part IIPart IIShort-Term Treatment Short-Term Treatment

1974 - 19951974 - 1995

Part IIPart IIShort-Term Treatment Short-Term Treatment

1974 - 19951974 - 1995


Short-Term Indication InstitutedShort-Term Indication Instituted Short-Term Indication InstitutedShort-Term Indication Instituted

“indicated in the management of exogenous obesity as a short-term adjunct (a few weeks) in a regimen of weight reduction based on caloric restriction”


The 1980sThe 1980s The 1980sThe 1980s

• Phen-fen studies begin in early 80s

• Transition from short- to long-term treatment

• 1985 NIH Consensus Conference – Health Implications of Obesity

• Phen-fen studies begin in early 80s

• Transition from short- to long-term treatment

• 1985 NIH Consensus Conference – Health Implications of Obesity

Anti-Obesity Prescription Drugs Dispensed from 1966 - 2003

0

2000

4000

6000

8000

10000

12000

Years

TRX

(000)

PHENTERMINE

ORLISTAT

SIBUTRAMINE

PHENDIMETRAZINE

DIETHYLPROPION

BENZPHETAMINE

MAZINDOL

FENFLURAMINE

DEXFENFLURAMINE


1985 NIH Consensus Conference - 11985 NIH Consensus Conference - 11985 NIH Consensus Conference - 11985 NIH Consensus Conference - 1

• What is obesity?–An excess of body fat frequently

resulting in significant impairment of health–20 percent or more above desirable

body weight –Body mass index (BMI) ~ > 27.2 kg/m2

• What is obesity?–An excess of body fat frequently

resulting in significant impairment of health–20 percent or more above desirable

body weight –Body mass index (BMI) ~ > 27.2 kg/m2


1985 NIH Consensus Conference - 21985 NIH Consensus Conference - 21985 NIH Consensus Conference - 21985 NIH Consensus Conference - 2

• What are the indications for weight loss?– Weight reduction should be recommended to persons

with body weight of 20% or more above desirable weight (BMI ~ 27)

– Weight reduction also highly desirable, even in patients with lesser degrees of obesity, in many circumstances including NIDDM, HTN, hypercholesterolemia, COPD, and osteoarthritis

• ''We want the average American and his physician to know that obesity is a disease,'' said Dr. Jules Hirsch, the [consensus conference] committee chairman

• Physicians should measure patients’ BMIs to assess health risk

• What are the indications for weight loss?– Weight reduction should be recommended to persons

with body weight of 20% or more above desirable weight (BMI ~ 27)

– Weight reduction also highly desirable, even in patients with lesser degrees of obesity, in many circumstances including NIDDM, HTN, hypercholesterolemia, COPD, and osteoarthritis

• ''We want the average American and his physician to know that obesity is a disease,'' said Dr. Jules Hirsch, the [consensus conference] committee chairman

• Physicians should measure patients’ BMIs to assess health risk


1992199219921992• NIH sponsors a conference on the

pharmacologic treatment of obesity• Final phen-fen results published• FDA’s Division of Metabolic and

Endocrine Drug Products takes over regulatory oversight of the weight-loss drugs – Obesity Drug Guidance document

• NIH sponsors a conference on the pharmacologic treatment of obesity

• Final phen-fen results published• FDA’s Division of Metabolic and

Endocrine Drug Products takes over regulatory oversight of the weight-loss drugs – Obesity Drug Guidance document


NIH Workshop on Pharmacologic NIH Workshop on Pharmacologic Treatment of Obesity Treatment of Obesity

NIH Workshop on Pharmacologic NIH Workshop on Pharmacologic Treatment of Obesity Treatment of Obesity

• Although most other chronic diseases are treated with long-term drug therapy, drugs have played essentially no role in the treatment of obesity in America

• There is evidence that modest weight losses reduce complications and risk factors of obesity

• State and federal regulatory controls hinder or preclude drug use for longer than a few weeks

• FDA should reevaluate process by which weight-control drugs are evaluated and approved

• Although most other chronic diseases are treated with long-term drug therapy, drugs have played essentially no role in the treatment of obesity in America

• There is evidence that modest weight losses reduce complications and risk factors of obesity

• State and federal regulatory controls hinder or preclude drug use for longer than a few weeks

• FDA should reevaluate process by which weight-control drugs are evaluated and approved


Final Phen-Fen Results PublishedFinal Phen-Fen Results PublishedFinal Phen-Fen Results PublishedFinal Phen-Fen Results Published

• “Obesity could be treated the way chronic diseases like high blood pressure or arthritis are. In those diseases, drugs can be taken indefinitely to keep symptoms in check”

• Dr. Albert Stunkard: “[this study] points to the way things are going to go"

• Dr. Michael Weintraub: “Not for the moderately overweight. If you just want to lose 10 pounds to look better at your high school reunion, it isn't worth it"

• “Obesity could be treated the way chronic diseases like high blood pressure or arthritis are. In those diseases, drugs can be taken indefinitely to keep symptoms in check”

• Dr. Albert Stunkard: “[this study] points to the way things are going to go"

• Dr. Michael Weintraub: “Not for the moderately overweight. If you just want to lose 10 pounds to look better at your high school reunion, it isn't worth it"


Development of FDA’s Obesity Development of FDA’s Obesity Drug Guidance DocumentDrug Guidance Document

Development of FDA’s Obesity Development of FDA’s Obesity Drug Guidance DocumentDrug Guidance Document

• January 19, 20, 1995 Advisory Committee meeting

• FDA official: “Biggest change we are hoping to bring about is the approval of [obesity] drugs for long-term use”

• Major considerations:– Duration and size of phase 3 studies– Criteria to define efficacy of weight-loss drugs– Appropriate patient population to study

• January 19, 20, 1995 Advisory Committee meeting

• FDA official: “Biggest change we are hoping to bring about is the approval of [obesity] drugs for long-term use”

• Major considerations:– Duration and size of phase 3 studies– Criteria to define efficacy of weight-loss drugs– Appropriate patient population to study


1996 FDA 1996 FDA Draft Guidance for the Draft Guidance for the Clinical Evaluation of Clinical Evaluation of

Weight-Control DrugsWeight-Control Drugs - 1 - 1



• Duration and size of phase 3 studies– One year of placebo-controlled exposure

in 1500 patients– Second year of open-label exposure in 200

to 500 patients• Efficacy criteria–Mean weight loss is 5% greater in drug-

vs. placebo-treated patients OR– Proportion of patients losing 5% is greater

in drug- vs. placebo-treated group

• Duration and size of phase 3 studies– One year of placebo-controlled exposure

in 1500 patients– Second year of open-label exposure in 200

to 500 patients• Efficacy criteria–Mean weight loss is 5% greater in drug-

vs. placebo-treated patients OR– Proportion of patients losing 5% is greater

in drug- vs. placebo-treated group





Weight-Control DrugsWeight-Control Drugs - 2 - 2• Patient population– BMI > 30 or > 27 with comorbidities– Criteria are to some extent arbitrary – Optimizes therapeutic risk - benefit

profile by targeting patients whose baseline risk of adverse health outcomes and expected benefits of drug treatment will outweigh the known and unknown risks of drug therapy

• Patient population– BMI > 30 or > 27 with comorbidities– Criteria are to some extent arbitrary – Optimizes therapeutic risk - benefit

profile by targeting patients whose baseline risk of adverse health outcomes and expected benefits of drug treatment will outweigh the known and unknown risks of drug therapy


Part IIIPart IIILong-Term Treatment Long-Term Treatment

1996 - present1996 - present

Part IIIPart IIILong-Term Treatment Long-Term Treatment

1996 - present1996 - present


Weight-Loss Drugs ApprovedWeight-Loss Drugs Approvedfor Long-Term Usefor Long-Term Use

Weight-Loss Drugs ApprovedWeight-Loss Drugs Approvedfor Long-Term Usefor Long-Term Use

• Dexfenfluramine approved in 1996• Sibutramine approved in 1997• Orlistat approved in 1999

– Orlistat is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet

– Orlistat is also indicated to reduce the risk for weight regain after prior weight loss

– Orlistat is indicated for obese patients with an initial BMI > 30 or > 27 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia)

• Dexfenfluramine approved in 1996• Sibutramine approved in 1997• Orlistat approved in 1999

– Orlistat is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet

– Orlistat is also indicated to reduce the risk for weight regain after prior weight loss

– Orlistat is indicated for obese patients with an initial BMI > 30 or > 27 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia)


1998/2000 NIH Clinical Guidelines 1998/2000 NIH Clinical Guidelines on Overweight and Obesity - 1on Overweight and Obesity - 1


• BMI classification – normal weight 18.5 – 24.9– overweight 25 – 29.9 – obese > 30

• The rationale behind these definitions is based on epidemiological data that show increases in mortality with BMIs above 25

• The increase in mortality, however, tends to be modest until a BMI of 30 is reached

• BMI classification – normal weight 18.5 – 24.9– overweight 25 – 29.9 – obese > 30

• The rationale behind these definitions is based on epidemiological data that show increases in mortality with BMIs above 25

• The increase in mortality, however, tends to be modest until a BMI of 30 is reached




• Weight loss medications should be used only by patients who are at increased medical risk because of their weight and should not be used for "cosmetic" weight loss.– BMI > 30 or > 27 with comorbidities

• Weight loss medications should never be used without concomitant lifestyle modifications

• Since obesity is a chronic disorder, the short-term use of drugs is not helpful

• Weight loss medications should be used only by patients who are at increased medical risk because of their weight and should not be used for "cosmetic" weight loss.– BMI > 30 or > 27 with comorbidities

• Weight loss medications should never be used without concomitant lifestyle modifications

• Since obesity is a chronic disorder, the short-term use of drugs is not helpful


Revising FDA’s 1996 Obesity Revising FDA’s 1996 Obesity Drug Guidance - 1Drug Guidance - 1

Revising FDA’s 1996 Obesity Revising FDA’s 1996 Obesity Drug Guidance - 1Drug Guidance - 1

• September 8, 2004 Advisory Committee meeting

• Major considerations:– Size and duration of studies– Efficacy criteria– Patient population

• September 8, 2004 Advisory Committee meeting

• Major considerations:– Size and duration of studies– Efficacy criteria– Patient population


Revising FDA’s Obesity Revising FDA’s Obesity Drug Guidance - 2Drug Guidance - 2


• Size and duration of trials– Size should be driven by safety– Rule out adverse events with incidence

rates of 1/100, 1/500, 1/1000, etc. – Continued support for one-year of

placebo-controlled exposure

• Efficacy criteria– Continued support for the 5% criterion

• Size and duration of trials– Size should be driven by safety– Rule out adverse events with incidence

rates of 1/100, 1/500, 1/1000, etc. – Continued support for one-year of

placebo-controlled exposure

• Efficacy criteria– Continued support for the 5% criterion




• Patient population–Regarding individuals with BMIs

25 - < 27• “Little information is available concerning

the health benefits of weight loss in this BMI range. Most studies of weight loss include few if any participants with BMI 25-27 and may explicitly exclude them”

Katherine Flegal, PhD, Center for Weight and Health, University of California, Berkeley, September 8, 2004

• Patient population–Regarding individuals with BMIs

25 - < 27• “Little information is available concerning

the health benefits of weight loss in this BMI range. Most studies of weight loss include few if any participants with BMI 25-27 and may explicitly exclude them”

Katherine Flegal, PhD, Center for Weight and Health, University of California, Berkeley, September 8, 2004




• Patient population– Should FDA change the inclusion criteria to

include subjects with BMIs of 25 - < 27 plus a comorbidity?

• Majority of committee members did not support lowering BMI to 25 - < 27

• Drug treatment of subjects with BMIs 25 to 27 would require much greater assurance of a drug’s safety

• Patient population– Should FDA change the inclusion criteria to

include subjects with BMIs of 25 - < 27 plus a comorbidity?

• Majority of committee members did not support lowering BMI to 25 - < 27

• Drug treatment of subjects with BMIs 25 to 27 would require much greater assurance of a drug’s safety


Guidelines for Prescription Drug Guidelines for Prescription Drug Treatment of Obesity - 1Treatment of Obesity - 1


• BMI > 30 or > 27 with comorbidities• NIH Practical Guide (2000)• American Obesity Association (2005)• NAASO, The Obesity Society (ref NIH)• American Gastroenterology Association (2002)• American Association of Clinical

Endocrinologists (1998)• BMI > 30• American College of Physicians (2005)

• BMI > 30 or > 27 with comorbidities• NIH Practical Guide (2000)• American Obesity Association (2005)• NAASO, The Obesity Society (ref NIH)• American Gastroenterology Association (2002)• American Association of Clinical

Endocrinologists (1998)• BMI > 30• American College of Physicians (2005)




• American Society of Bariatric Physicians (2004)• BMI › or = 30.0 in a normal, otherwise healthy individual • BMI › or = 27.0 in an individual with associated

comorbidities • Current body weight › or = 120% of a well documented,

long-standing, healthy weight that the patient maintained after age 18

• Body Fat › or = 30% in females • Body Fat › or = 25% in males • Waist-hip ratio or waist circumference such that the

individual is known to be at increased cardiovascular and/or co-morbidity risk due to abdominal visceral fat.

• Presence of a comorbid condition or conditions aggravated by the patient’s excessive adiposity

• American Society of Bariatric Physicians (2004)• BMI › or = 30.0 in a normal, otherwise healthy individual • BMI › or = 27.0 in an individual with associated

comorbidities • Current body weight › or = 120% of a well documented,

long-standing, healthy weight that the patient maintained after age 18

• Body Fat › or = 30% in females • Body Fat › or = 25% in males • Waist-hip ratio or waist circumference such that the

individual is known to be at increased cardiovascular and/or co-morbidity risk due to abdominal visceral fat.

• Presence of a comorbid condition or conditions aggravated by the patient’s excessive adiposity


Major Themes in the Prescription Major Themes in the Prescription Drug Treatment of Obesity - 1Drug Treatment of Obesity - 1Major Themes in the Prescription Major Themes in the Prescription Drug Treatment of Obesity - 1Drug Treatment of Obesity - 1

• Short-term adjunctive therapy to enhance will-power to long-term adjunctive treatment of a complex, chronic disease

• Defining obesity– 15 to 20% above ideal body weight– BMI > 27 - 1985– BMI > 30 - 1995

• Defining overweight vs. obesity– BMI 25 to 29.9 vs. > 30

• Short-term adjunctive therapy to enhance will-power to long-term adjunctive treatment of a complex, chronic disease

• Defining obesity– 15 to 20% above ideal body weight– BMI > 27 - 1985– BMI > 30 - 1995

• Defining overweight vs. obesity– BMI 25 to 29.9 vs. > 30


Major Themes in the Prescription Major Themes in the Prescription Drug Treatment of Obesity - 2Drug Treatment of Obesity - 2


• Defining efficacy of weight-loss drugs– Achieving ideal weight– Losing 50% of excess weight– Losing 20 or 40 pounds– Statistically significant weight loss– 5-10% weight loss

• Medical vs. cosmetic weight loss

• Defining efficacy of weight-loss drugs– Achieving ideal weight– Losing 50% of excess weight– Losing 20 or 40 pounds– Statistically significant weight loss– 5-10% weight loss

• Medical vs. cosmetic weight loss




• Medical weight loss– Long-term reduction in weight and fat mass

with improvement in physical health in high-risk patients

– 5-10% weight loss• Cosmetic weight loss– Short-term reduction in weight and fat mass

with improvement in physical appearance in low- or zero-risk individuals

– ???% weight loss • Risk vs. benefit of drug treatment

• Medical weight loss– Long-term reduction in weight and fat mass

with improvement in physical health in high-risk patients

– 5-10% weight loss• Cosmetic weight loss– Short-term reduction in weight and fat mass

with improvement in physical appearance in low- or zero-risk individuals

– ???% weight loss • Risk vs. benefit of drug treatment

Nonprescription Orlistat GlaxoSmithKline NDA 21-887

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