Nonprescription Orlistat GlaxoSmithKline NDA 21887

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Nonprescription Orlistat GlaxoSmithKline
NDA 21-887

• Nonprescription and Metabolic and Endocrinologic
  Drugs Advisory Committees
  
• January 23, 2006
• Eric Colman, MD
• Division of Metabolism and Endocrinology Products

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The Regulation of Prescription Weight-Loss Drugs

• Part I 1947 to 1973
• Approval of the amphetamines and the amphetamine
  congeners
  
• Part II 1974 to 1995
• Short-term treatment
• Part III 1996 to present
• Long-term treatment

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Part IAmphetamines Amphetamine Congeners1947 -
1973
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Approval of Amphetamines and 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

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Drug Efficacy Study Implementation (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

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Psychiatric Drug Panels 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

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FDAs Response To Psychiatric Drug Panels
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

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What is Efficacy?

• FDA asks How should efficacy of weight-loss
  drugs be defined?
  
• FDAs 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
  
• FDAs Advisory Committee endorsed the use of
  statistical superiority of drug to placebo

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FDAs Amphetamine Anorectic 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

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FDAs Official Position on Weight-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

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Part IIShort-Term Treatment 1974 - 1995
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Short-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
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The 1980s

• Phen-fen studies begin in early 80s
• Transition from short- to long-term treatment
• 1985 NIH Consensus Conference Health
  Implications of Obesity
  

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1985 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

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1985 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
  

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1992

• NIH sponsors a conference on the pharmacologic
  treatment of obesity
  
• Final phen-fen results published
• FDAs Division of Metabolic and Endocrine Drug
  Products takes over regulatory oversight of the
  weight-loss drugs
  
• Obesity Drug Guidance document

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NIH Workshop on Pharmacologic 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

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Final 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"

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Development of FDAs Obesity Drug 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

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1996 FDA Draft Guidance for the Clinical
Evaluation of Weight-Control Drugs - 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

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1996 FDA Draft Guidance for the Clinical
Evaluation of Weight-Control Drugs - 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

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Part IIILong-Term Treatment 1996 - present
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Weight-Loss Drugs Approvedfor 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)

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1998/2000 NIH Clinical Guidelines on 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

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1998/2000 NIH Clinical Guidelines on Overweight
and Obesity - 2

• 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
  

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Revising FDAs 1996 Obesity Drug Guidance - 1

• September 8, 2004 Advisory Committee meeting
• Major considerations
• Size and duration of studies
• Efficacy criteria
• Patient population

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Revising FDAs Obesity Drug 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

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Revising FDAs Obesity Drug Guidance - 3

• Patient population
• Regarding individuals with BMIs 25 -
• 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

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Revising FDAs Obesity Drug Guidance - 4

• Patient population
• Should FDA change the inclusion criteria to
  include subjects with BMIs of 25 -
  comorbidity?
  
• Majority of committee members did not support
  lowering BMI to 25 -
  
• Drug treatment of subjects with BMIs 25 to 27
  would require much greater assurance of a drugs
  safety
  

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Guidelines for Prescription Drug Treatment 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)

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Guidelines for Prescription Drug Treatment of
Obesity - 2

• 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 patients excessive adiposity
  

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Major Themes in the Prescription Drug 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

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Major Themes in the Prescription Drug 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

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Major Themes in the Prescription Drug Treatment
of Obesity - 3

• 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