# Presentation: 343148

##     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**

## 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**

## Part IAmphetamines Amphetamine Congeners1947 - 1973

## 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**

## 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**

## Psychiatric 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 **

## FDA’s Response To Psychiatric Drug 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**

## 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’s 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**

## FDA’s 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**

## Part IIShort-Term Treatment 1974 - 1995

## 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”**

## The 1980s 

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

## 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/m****2**

## 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**** **

## 1992

**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 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**

## 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" **

## Development of FDA’s 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**

## 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**

## 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  **

## Part IIILong-Term Treatment 1996 - present

## Weight-Loss Drugs Approvedfor 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)**

## 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**

## 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**

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

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

## Revising FDA’s 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**

## Revising FDA’s Obesity Drug Guidance - 3

**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****                          **

## Revising FDA’s Obesity Drug Guidance - 4

**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 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)**

## 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 patient’s excessive adiposity **

## 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 **

## 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**

## 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**