**M E M O R A N D U M** DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Food and Drug Administration

Center for Drug Evaluation and Research

**DATE:** 7 August 2004

**FROM:** David Orloff, MD

Eric G. Colman, MD

Division of Metabolic and Endocrine Drug Products (DMEDP)

Office of Drug Evaluation 2 (ODE 2)

Center for Drug Evaluation & Research (CDER)

Food & Drug Administration (FDA)

**TO:** Members and Consultants,

Endocrinologic & Metabolic Drugs Advisory Committee

**SUBJECT:** 8 September 2004, Advisory Committee meeting on the draft
guidance: *Clinical Evaluation of Weight-Control Drugs*

On 8 September 2004, key personnel from the Division of Metabolic and
Endocrine Drug Products will meet with its Advisory Committee members
and consultants to discuss the FDA draft guidance document entitled,
*Clinical Evaluation of Weigh-Control Drugs* (hereafter, Obesity Drug
Guidance) (**enclosed**). The meeting agenda includes five oral
presentations during the morning session, with open discussion in the
afternoon (**enclosed**).

Broadly speaking, drugs that are FDA approved for the treatment of
obesity fall into two categories: those approved for short-term use
(i.e., a few weeks) and those approved for long-term use (Table
enclosed). All of the drugs indicated for short-term use were approved
prior to 1974. In general, the pre-approval trials for these drugs
included fewer than 100 patients and were no more than 12 weeks in
duration.

In the spring of 1996 the Agency approved dexfenfluramine for the
long-term treatment of obesity. Pre-approval trials for this drug
included hundreds of subjects exposed to drug for as long as 52 weeks.
As you know, dexfenfluramine (and fenfluramine) were withdrawn from the
market due to reports linking their use to left-sided cardiac
valvulopathy.

In the fall of 1996, following input from its advisory committee, the
Division of Metabolic and Endocrine Drug Products issued the Obesity
Drug Guidance. Among other things, the guidance recommended the
following:

-   The study population include those with a body mass index (BMI) of
    27 kg/m^2^ to \< 30 kg/m^2^ when accompanied by comorbid conditions
    (i.e., hypertension, type 2 diabetes mellitus) and those with a BMI
    of [\>]{.underline} 30 kg/m^2^, with or without comorbidities;

-   Efficacy be based on weight loss following at least one year of
    double-blind, placebo-controlled treatment;

-   Safety be based on one year of double-blind treatment and a second
    year of open-label therapy;

-   That approximately 1500 subjects complete 12 months of therapy, with
    200-500 of those completing a second year of study.

The FDA approved sibutramine in 1997 and orlistat in 1999, both for the
long-term treatment of obesity. Like dexfenfluramine, the pre-approval
trials for these two compounds involved hundreds of patients exposed to
drug for a minimum of one year.

Recent estimates indicate that phentermine, approved in 1959 for the
short-term treatment of obesity, is still the most widely-used
weight-loss drug, followed by orlistat and sibutramine (paper by
Stafford and Radley, **enclosed**).

While it has been more than five years since the Agency approved an
obesity drug, a large number of weight-loss agents, with a variety of
mechanisms of action, are currently being studied under Investigational
New Drug applications. Given the increasing magnitude of the obesity
problem, the Division anticipates that development of drugs in this
therapeutic class will greatly expand in the coming years. The Obesity
Drug Guidance will therefore continue to be an important source of
direction for pharmaceutical sponsors of weight-loss drugs.

To ensure that the Obesity Drug Guidance reflects up-to-date scientific
information and advice, the FDA requested public comment on the document
in the 26 January 2004, issue of the Federal Register. Seventeen
responses, mostly from the pharmaceutical industry, were received by the
closing date of 26 April 2004 **(enclosed)**. Comments and suggested
revisions related to all aspects of the guidance were submitted, but
several areas received considerable attention. These included:

-   Broadening the inclusion criteria for trial participation to include
    subjects who are overweight (extending the lower bounds of the entry
    criterion to a BMI [\>]{.underline} 25 kg/m^2^);

-   Eliminating the need for a second year of open-label study;

-   Reducing the number of subjects required to evaluate a drug's safety
    profile from 1500 studied for one year to approximately 300-600
    patients exposed for 6 months and 100 patients for one year. These
    latter numbers reflect the International Committee on
    Harmonization's general recommendations for assessing clinical
    safety of a new drug (**enclosed**).

We anticipate that these topics, among others, will be discussed in
great detail at the September 8^th^ meeting and ask that you keep them
in mind as you read the enclosed briefing material.

We sincerely appreciate your willingness to participate in the advisory
committee process and look forward to a productive meeting in September.