**Guidance for Industry**

**Developing Products for Weight Management**

***DRAFT GUIDANCE***

**This guidance document is being distributed for comment purposes
only.**

Comments and suggestions regarding this draft document should be
submitted within 60 days of publication in the *Federal Register* of the
notice announcing the availability of the draft guidance. Submit
comments to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All
comments should be identified with the docket number listed in the
notice of availability that publishes in the *Federal Register*.

For questions regarding this draft document contact Eric Colman at
301-796-1190.

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**February 2007**

**Clinical/Medical**

**Revision 1**

**Guidance for Industry**

**Developing Products for Weight Management**

*Additional copies are available from:*

*Office of Training and Communications*

*Division of Drug Information, HFD-240*

*Center for Drug Evaluation and Research*

*Food and Drug Administration*

*5600 Fishers Lane*

*Rockville, MD 20857*

*(Tel) 301-827-4573*

*http://www.fda.gov/cder/guidance/index.htm*

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**February 2007**

**Clinical/Medical**

**Revision 1**

##  {#section .TOC-2}

**TABLE OF CONTENTS**

#  {#section-1 .TOC-1 .unnumbered}

# I. INTRODUCTION [1](#i.-introduction)II. background [2](#ii.-background) {#i.-introduction-1ii.-background-2 .TOC-1}

# III. overweight and obesity CLINICAL BACKGROUND [2](#iii.-overweight-and-obesity-clinical-background) {#iii.-overweight-and-obesity-clinical-background-2 .TOC-1}

## A. The Adult Population [2](#a.-the-adult-population) {#a.-the-adult-population-2 .TOC-2}

## B. The Pediatric Population [4](#b.-the-pediatric-population) {#b.-the-pediatric-population-4 .TOC-2}

# IV. CLINICAL Assessment of Weight-Management Products in Adult PATIENTS [5](#iv.-clinical-assessment-of-weight-management-products-in-adult-patients) {#iv.-clinical-assessment-of-weight-management-products-in-adult-patients-5 .TOC-1}

## A. Phase 1 and Phase 2 Trials [5](#a.-phase-1-and-phase-2-trials) {#a.-phase-1-and-phase-2-trials-5 .TOC-2}

## B. Phase 3 Clinical Trials [5](#b.-phase-3-clinical-trials) {#b.-phase-3-clinical-trials-5 .TOC-2}

### 1. Trial Design and Patient Populations [5](#trial-design-and-patient-populations) {#trial-design-and-patient-populations-5 .TOC-3}

### 2. Trial Size and Duration [6](#trial-size-and-duration) {#trial-size-and-duration-6 .TOC-3}

### 3. Efficacy Endpoints [6](#efficacy-endpoints) {#efficacy-endpoints-6 .TOC-3}

#### a. Primary efficacy endpoint [6](#a.-primary-efficacy-endpoint) {#a.-primary-efficacy-endpoint-6 .TOC-4}

#### b. Secondary efficacy endpoints [6](#b.-secondary-efficacy-endpoints) {#b.-secondary-efficacy-endpoints-6 .TOC-4}

#### c. Efficacy benchmarks [7](#c.-efficacy-benchmarks) {#c.-efficacy-benchmarks-7 .TOC-4}

### 4. Standard of Care and Concomitant Medication [7](#standard-of-care-and-concomitant-medication) {#standard-of-care-and-concomitant-medication-7 .TOC-3}

### 5. Patients with Type 2 Diabetes [7](#patients-with-type-2-diabetes) {#patients-with-type-2-diabetes-7 .TOC-3}

## C. General Safety Assessment of Weight-Management Products [8](#c.-general-safety-assessment-of-weight-management-products) {#c.-general-safety-assessment-of-weight-management-products-8 .TOC-2}

## D. Weight-Management Products Used in Combination [9](#d.-weight-management-products-used-in-combination) {#d.-weight-management-products-used-in-combination-9 .TOC-2}

## E. Weight-Management Products for Patients with Medication-Induced Weight Gain [9](#e.-weight-management-products-for-patients-with-medication-induced-weight-gain) {#e.-weight-management-products-for-patients-with-medication-induced-weight-gain-9 .TOC-2}

# V. Clinical Assessment of long-term Weight-management Products in Pediatric Patients [11](#v.-clinical-assessment-of-long-term-weight-management-products-in-pediatric-patients) {#v.-clinical-assessment-of-long-term-weight-management-products-in-pediatric-patients-11 .TOC-1}

# VI. Statistical Considerations [12](#vi.-statistical-considerations) {#vi.-statistical-considerations-12 .TOC-1}

## A. Sample Size [12](#a.-sample-size) {#a.-sample-size-12 .TOC-2}

## B. Preventing Missing Data from Premature Subject Withdrawal [12](#b.-preventing-missing-data-from-premature-subject-withdrawal) {#b.-preventing-missing-data-from-premature-subject-withdrawal-12 .TOC-2}

## C. Analysis Methods [12](#c.-analysis-methods) {#c.-analysis-methods-12 .TOC-2}

## D. Graphical Methods [13](#d.-graphical-methods) {#d.-graphical-methods-13 .TOC-2}

# VII. Labeling Considerations [13](#vii.-labeling-considerations) {#vii.-labeling-considerations-13 .TOC-1}

# VIII. Stand-Alone Indications for the Prevention or Treatment of Weight-Related Comorbidities [13](#viii.-stand-alone-indications-for-the-prevention-or-treatment-of-weight-related-comorbidities) {#viii.-stand-alone-indications-for-the-prevention-or-treatment-of-weight-related-comorbidities-13 .TOC-1}

# IX. Metabolic Syndrome [14](#ix.-metabolic-syndrome) {#ix.-metabolic-syndrome-14 .TOC-1}

# REFERENCES [15](#references) {#references-15 .TOC-1}

#####  {#section-2 .TOC-5 .unnumbered}

**Guidance for Industry**[^1]

**Developing Products for Weight Management**

This draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic. It does not
create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach, contact the
FDA staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number listed
on the title page of this guidance.

# I. INTRODUCTION 

This guidance provides recommendations to industry regarding the
development of drugs and therapeutic biologics (hereafter *products*)
regulated within the Center for Drug Evaluation and Research (CDER) in
the Food and Drug Administration (FDA) for the indication of weight
management. This guidance applies to products intended to be used for
medical weight loss, which can be defined as a long-term reduction in
fat mass with a goal of reduced morbidity and mortality through
quantifiable improvements in biomarkers such as blood pressure, lipids,
and HbA1c. This guidance revises the draft *Guidance for the Clinical
Evaluation of Weight-Control Drugs* that issued in September 1996. When
finalized, this guidance will replace the September 1996 draft guidance.

The September 1996 draft guidance is being revised to provide advice on
conducting studies to evaluate the efficacy and safety of products for
weight management in patients with medication-induced weight gain and
weight management in obese pediatric patients. Recommendations on the
design of studies evaluating the efficacy and safety of combinations of
weight-management products are also provided.

This guidance does not explicitly discuss indications for weight loss or
maintenance of lost weight (which also can be described as prevention of
weight regain); however, weight loss and weight maintenance should be
demonstrated over the course of at least 1 year before a product can be
considered effective for weight management. Thus, the weight management
indication incorporates and signifies weight loss and weight
maintenance.

This guidance also does not discuss the general issues of clinical trial
design or statistical analysis. Those topics are addressed in the ICH
guidances for industry *E8* *General Considerations for Clinical Trials*
and *E9* *Statistical Principles for Clinical Trials*.[^2]

FDA's guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency's current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# II. background

In January 2004, the FDA issued a notice in the *Federal Register*
requesting public comment on the September 1996 draft guidance for the
purpose of incorporating the latest scientific and clinical advances in
weight management drug development. In September 2004, the FDA convened
an advisory committee meeting to discuss the public comments received
and to identify specific scientific, clinical, and regulatory issues
that should be included in an updated guidance.

As a result, this revised guidance discusses several key areas of
interest that are not covered in the September 1996 draft guidance.
These areas include recommendations on the development of products for
weight management in pediatric patients and in patients with
medication-induced weight gain, and recommendations on the development
of combinations of weight-management products.

# III. overweight and obesity CLINICAL BACKGROUND

## A. The Adult Population

Obesity is a chronic, relapsing health risk defined by excess body fat.
The pathogenesis of obesity involves the interaction of genetic,
environmental, and behavioral factors. Total body fat can be accurately
measured using hydrodensitometry and dual-energy x-ray absorptiometry
(DEXA). Because body mass index (BMI), expressed as kilograms of weight
divided by height in meters squared (kg/m^2^), is simple and inexpensive
to calculate, and correlates strongly with total body fat in non-elderly
adults, it is commonly used as a surrogate for total body fat.

Excess body fat increases the risk of death and major comorbidities such
as type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease,
osteoarthritis of the knee, sleep apnea, and some cancers (Caterson and
Hubbard et al. 2004; Calle and Thun et al. 1999). The relationships
between BMI and risks for death and major comorbidities vary by age,
sex, race, and smoking status, but, in general, are lowest in
individuals with BMIs of 18.5 kg/m^2^ to 24.9 kg/m^2^ and increase in a
curvilinear or linear manner with BMIs of 25 kg/m^2^ to approximately 40
kg/m^2^.

Based on data relating BMI to mortality risk, the World Health
Organization in 1995 and the National Institutes of Health in 1998
adopted the weight classifications by BMI that are shown in Table 1
(Clinical Guidelines on the Identification and Treatment of Overweight
and Obesity in Adults 1998).

Table 1. Weight Classification Guidelines

  ------------------------------------ ----------------------------------
  **Classification**                   **BMI**

  Underweight                          \< 18.5 kg/m^2^

  Normal weight                        18.5 kg/m^2^ -- 24.9 kg/m^2^

  Overweight                           25 kg/m^2^ -- 29.9 kg/m^2^

  Obesity (class 1)                    30 kg/m^2^ -- 34.9 kg/m^2^

  Obesity (class 2)                    35 kg/m^2^ -- 39.9 kg/m^2^

  Extreme obesity (class 3)            [\>]{.underline} 40 kg/m^2^
  ------------------------------------ ----------------------------------

An increased level of visceral or intra-abdominal adiposity, independent
of BMI, increases the risk for metabolic derangements and perhaps
cardiovascular disease (Janssen and Katzmarzyk et al. 2004; Rexrode and
Carey et al. 1998; Zhu and Wang et al. 2002). Visceral fat content can
be accurately measured with computed tomography (CT) or magnetic
resonance imaging (MRI). Waist circumference, like BMI, is inexpensive
and easy to measure and correlates with CT- and MRI-derived measurements
of visceral fat content (Pi-Sunyer 2004). In general, a waist
circumference greater than 40 inches (greater than 102 cm) in men and
greater than 35 inches (greater than 88 cm) in women is accepted as
indicating increased visceral adiposity (The Practical Guide.
Identification, Evaluation, and Treatment of Overweight and Obesity in
Adults 2000).

In overweight and obese individuals, particularly individuals with
comorbidities such as hypertension, dyslipidemia, and type 2 diabetes,
long-term weight loss greater than or equal to 5 percent following diet,
exercise, and in some cases, drug treatment, is associated with
improvement in various metabolic and cardiovascular risk factors
(Douketis and Macie et al. 2005).

Although some, but not all, observational studies suggest that modest
degrees of intentional weight loss in overweight and obese individuals
can reduce the incidence of some cancers, cardiovascular disease, and
all-cause mortality, at the time of this writing, there are no data from
randomized, controlled trials on the effects of drug-induced weight loss
on these clinical outcomes (Parker and Folsom 2003; Eilat-Adar and Eldar
et al. 2004; Gregg and Gerzoff et al. 2003).

Lifestyle modification, consisting of changes in patterns of dietary
intake, exercise, and other behaviors, is considered the cornerstone of
overweight and obesity management. Because all drug and biological
therapies impose some risk for adverse events, the use of a
weight-management product should be contemplated only after a sufficient
trial of lifestyle modification has *failed* and the risks of excess
adiposity and the anticipated benefits of weight loss are expected to
outweigh the known and unknown risks of treatment with a particular
weight-management product.

Patients with BMIs greater than or equal to 30 kg/m^2^ or greater than
or equal to 27 kg/m^2^ if accompanied by weight-related comorbidities
historically have been considered appropriate populations for treatment
with weight-management medications (Clinical Guidelines on the
Identification and Treatment of Overweight and Obesity in Adults 1998).
Although these patient-selection criteria are to a degree arbitrary, and
an argument may be made for criteria that are more or less restrictive,
we believe that individuals with BMIs greater than or equal to 30
kg/m^2^ or greater than or equal to 27 kg/m^2^ if accompanied by
weight-related comorbidities represent patient groups with sufficient
baseline risk to justify inclusion in studies of investigational
weight-management products.

## B. The Pediatric Population

As in adults, BMI correlates with more direct measures of adiposity in
children and adolescents (American Academy of Pediatrics 2003; Barlow
and Dietz 1998; Dietz and Robinson 2005; Speiser and Rudolf et al.
2005). Also similar to adults, BMI correlates with obesity-related
comorbidities such as hypertension, dyslipidemia, and type 2 diabetes
mellitus in pediatric patients.

In contrast to adults, the terms overweight and obese are used
synonymously in pediatric patients (American Academy of Pediatrics
2003). The American Academy of Pediatrics (AAP) defines a pediatric-aged
patient with an age- and sex-matched BMI of greater than or equal to
95th percentile as overweight or obese.

For patients aged 2 to 7 years, the AAP recommends weight loss through
lifestyle modification if the BMI is greater than or equal to the 95th
percentile for age and sex with the presence of one or more
comorbidities. For patients who are 7 years of age or older, weight loss
through lifestyle modification is recommended if the BMI is between the
85th and 95th percentile for age and sex with the presence of one or
more comorbidities or if the BMI is greater than or equal to the 95th
percentile for age and sex regardless of the presence of comorbidities.

Before therapeutic intervention, pediatric patients should receive a
medical assessment to identify genetic (e.g., Prader-Willi syndrome) or
endocrinologic (e.g., Cushing's syndrome) causes of their obesity.
Patients also should be screened for the presence of comorbidities such
as hypertension, glucose intolerance, and dyslipidemia.

The use of weight-management products in pediatric patients, as in
adults, should be contemplated only after a sufficient trial of
lifestyle modification has *failed* and the risks of excess adiposity
and the expected benefits of weight loss are believed to outweigh the
known and unknown risks of treatment with a particular weight-management
product. Such a population might include obese pediatric patients with
weight-related comorbidites.

# IV. CLINICAL Assessment of Weight-Management Products in Adult PATIENTS

## A. Phase 1 and Phase 2 Trials

Before initiating phase 3 clinical trials, the pharmacokinetics and
dose-response profiles of a new weight-management product should be
well-characterized. Because excess adiposity may influence a product's
metabolism and disposition, the pharmacokinetics profile of a
weight-management product should be examined in patients with a broad
range of BMIs (e.g., 27 kg/m^2^ to 35 kg/m^2^) (Cheymol 2000). To
increase the likelihood of identifying the most appropriate dose for the
pivotal clinical trials, early phase clinical studies should include a
range of doses and be designed to identify no-effect and maximally
tolerated doses. Studies should be designed to differentiate the
efficacy of all the active doses versus placebo. The duration of the
phase 2 trials should be sufficient to capture the maximal or
near-maximal weight loss effects of the active doses. Forethought should
be given to whether the product will be ultimately used in a fixed-dose
or dose-titration scheme, as this dosing decision will also influence
the size and duration of the studies.

Patients included in the early phase efficacy and safety studies
generally should have BMIs greater than or equal to 30 kg/m^2^ or
greater than or equal to 27 kg/m^2^ if accompanied by comorbidities. The
primary efficacy endpoints should be a comparison of the mean absolute
or percent change in body weight between the active-product and
placebo-treated groups and the proportion of patients in each treatment
group who lose greater than or equal to 5 percent of baseline weight.
The effects by dose of the weight-management product on common
weight-related comorbidities also should be examined and taken into
account when choosing the most appropriate dose for the phase 3 studies.

## B. Phase 3 Clinical Trials

### 1. Trial Design and Patient Populations

In general, phase 3 clinical trials examining the efficacy and safety of
weight-management products should be randomized, double-blind, and
placebo-controlled. The lifestyle modification programs used in the
preapproval trials should be applicable to individual patients
prescribed the product post-approval (i.e., programs should strike an
appropriate balance between effectiveness and simplicity).

In general, patients should have or be at significant risk for
weight-related morbidity and mortality. Such patients include those with
BMIs greater than or equal to 30 kg/m^2^ or greater than or equal to 27
kg/m^2^ in the presence of comorbidities (e.g., type 2 diabetes,
hypertension, dyslipidemia, sleep apnea, cardiovascular disease).

Effort should be made to include in the studies a representative sample
of patients from the various demographic, ethnic, and racial groups in
which the prevalence of obesity is highest. Development programs also
should include a representative sample of patients with extreme obesity
(BMI greater than 40 kg/m^2^).

### 2. Trial Size and Duration

The number of subjects necessary to demonstrate the efficacy of a
weight-management product will be smaller than the number needed to
adequately assess safety. A reasonable estimation of the safety of a
weight-management product upon which to base approval generally can be
made when a total of approximately 3,000 subjects are randomized to
active doses of the product and no fewer than 1,500 subjects are
randomized to placebo for 1 year of treatment.

For example, the above sample size will provide 80 percent power to rule
out with 95 percent confidence an approximately 50 percent increase in
the incidence of an adverse event that occurs at a rate of 3 percent in
the placebo group (i.e., 4.5 percent versus 3 percent). This sample size
also should allow for efficacy and safety analyses to be conducted
within important subgroups such as sex, ethnicity, and baseline BMI.

### 3. Efficacy Endpoints

#### a. Primary efficacy endpoint

The efficacy of a weight-management product should be assessed by
analyses of both mean and categorical changes in body weight.

-   Mean: The difference in mean percent loss of baseline body weight in
    the active-product versus placebo-treated group.

-   Categorical: The proportion of subjects who lose at least 5 percent
    of baseline body weight in the active-product versus placebo-treated
    group.

#### b. Secondary efficacy endpoints

Secondary efficacy endpoints should include, but are not limited to,
changes in the following metabolic parameters:

-   Blood pressure and pulse

-   Lipoprotein lipids

-   Fasting glucose and insulin

-   HbA1c (in type 2 diabetics)

-   Waist circumference

In clinical practice, waist circumference is used as an indirect measure
of visceral fat content, which when increased is associated with an
elevated risk for metabolic abnormalities such as dyslipidemia and
diabetes. Because the evaluation of investigational weight-management
products routinely includes assessment of changes in patients' metabolic
profiles, and in some cases may involve measurement of visceral fat
content by CT or MRI, waist circumference should not serve as a
surrogate for visceral fat content when measured in a clinical trial
investigating the efficacy of a product for weight loss. Rather, it can
be a means to confirm that reductions in waist circumference following
treatment with a weight-management product are associated with the
expected improvements in metabolic parameters.

It is likely that a large portion of study subjects will be taking
concomitant medications to treat weight-related comorbidities such as
hypertension, type 2 diabetes, and dyslipidemia. Since weight loss is
expected to improve these comorbidities, an important secondary efficacy
endpoint should be the proportion of subjects treated with the
weight-management product compared with placebo who have a meaningful
dose-reduction or complete withdrawal of their concomitant medication.
Algorithms that direct dose reduction or withdrawal of concomitant
medications based on changes in levels of blood pressure, lipids, or
glycemia should be included in the study protocols.

Measures of quality of life from validated instruments also can be
appropriate secondary efficacy endpoints.

#### c. Efficacy benchmarks

In general, a product can be considered effective for weight management
if after 1 year of treatment either of the following occurs:

-   The difference in mean weight loss between the active-product and
    placebo-treated groups is at least 5 percent and the difference is
    statistically significant

-   The proportion of subjects who lose greater than or equal to 5
    percent of baseline body weight in the active-product group is at
    least 35 percent, is approximately double the proportion in the
    placebo-treated group, and the difference between groups is
    statistically significant

Improvements in blood pressure, lipids, glycemia, or other areas
commensurate with the degree of weight lost are expected in patients
treated with an effective weight-management product. Therefore, changes
in common weight-related comorbidites should be factored into the
efficacy assessment of investigational weight-management products.

### 4. Standard of Care and Concomitant Medication

Overweight and obese patients enrolled in clinical studies of
investigational weight-management products should receive standard of
care, including medication, for comorbidities such as hypertension,
dyslipidemia, and glycemic control.

### 5. Patients with Type 2 Diabetes

Compared with nondiabetic patients, overweight and obese patients with
type 2 diabetes often respond less favorably to weight-management
products and may face unique safety issues such as risk for
sulfonylurea-induced hypoglycemia following weight loss (if the dose of
sulfonylurea is not appropriately lowered or the drug discontinued).
Therefore, sponsors should consider examining the efficacy and safety of
weight-management products in trials dedicated to patients with type 2
diabetes. The following recommendations should be considered when
designing such trials:

-   In general, patients should have baseline HbA1c levels between 8
    percent and 10 percent.

-   Patients should be excluded if they have fasting glucose levels
    greater than 270 mg/dl.

-   Protocols should include escape criteria for poor glycemic control.

-   Protocols should include an algorithm for the lowering or
    elimination of oral hypoglycemia or insulin dose based on fasting
    glucose levels and/or HbA1c (for patients who lose clinically
    significant amounts of weight).

-   Patient randomization should be stratified by baseline antidiabetic
    medication (e.g., metformin versus sulfonylurea versus a
    thiazolidinedione versus insulin) and baseline HbA1c level (e.g.,
    less than or equal to 9 percent versus greater than 9 percent).

-   Hypoglycemia safety should be monitored.[^3]

## C. General Safety Assessment of Weight-Management Products 

To ensure that drug or biologic-induced weight loss is caused primarily
by a reduction in fat content, not lean-body mass, a representative
sample of study subjects should have a baseline and follow-up
measurement of body composition by DEXA, or a suitable alternative.

In addition to routine safety monitoring, it may be appropriate for the
development programs of some weight-management products to have
specialized safety assessments. For example, products that directly
interact with the 5HT receptor system, specifically the 5HT~2~ receptor
subtypes, probably should include evaluation of risk for cardiac
valvulopathy using serial echocardiography. The development plans for
centrally acting weight-management products generally should include
validated assessments of neuropsychiatric function.

Assessment of the immunogenic potential of therapeutic proteins should
be performed over a period of at least 6 to 12 months. If adverse events
characteristic of allergic or immunologic reactions are identified, the
FDA may ask for additional studies, with durations longer than 12
months. These additional studies may need to be conducted before
submission of an application for registration or may be conducted after
approval as a postmarketing commitment, based on the overall analysis of
the product's risks and benefits. The appropriate timing of such studies
can be discussed with the FDA at a pre-biologics license application
meeting or other similar advice meeting.

For centrally acting weight-management products, sponsors should
anticipate the need to conduct preclinical and clinical studies of abuse
liability. Sponsors are encouraged to discuss the design of these
studies with members of CDER's Controlled Substance Staff during the
early phases of product development.

The need for and details of specific safety monitoring may change as new
data emerge. Sponsors are encouraged to discuss their plans for specific
safety monitoring with the division during the early stages of product
development.

## D. Weight-Management Products Used in Combination 

Two or more products may be combined into a single fixed-dosed
combination when each component makes a contribution to the claimed
effect or effects (21 CFR 300.50).

Before initiating long-term clinical studies with fixed-dose
combinations, sponsors should conduct the appropriate preclinical and
pharmacokinetics studies. (See the guidances for industry *Nonclinical
Safety Evaluation of Drug or Biologic Combinations* and *Bioavailability
and Bioequivalence Studies for Orally Administered Drug Products ---
General Considerations*.)

We recommend that the efficacy and safety of fixed-dose combinations be
compared with the individual product components of the combination and
placebo in phase 2 trials of sufficient duration to capture the maximal
or near-maximal weight-management effects of the products. We have not
defined a minimum difference in weight loss between a fixed-dose
combination and its individual component products that should be
achieved for the combination to be considered more efficacious than
either of its components when used alone. However, a fixed-dose
combination that is associated with at least twice the weight loss
observed with that of each of the individual components will be viewed
more favorably than combinations that do not achieve this degree of
relative weight loss.

Once a fixed-dose combination has been deemed more effective than its
individual components, the combination can then be examined versus
placebo in phase 3 trials. This approach may preclude the need to
include treatment groups for the individual components of the fixed-dose
combination product in late-stage preapproval trials.

The efficacy of a product combination for weight management generally
will be assessed using the same factors as those applied to a single
product, as defined in section IV.B.3.

## E. Weight-Management Products for Patients with Medication-Induced Weight Gain 

A number of drugs, notably psychotropic and some anticonvulsant agents,
are associated with moderate-to-marked weight gain (Baptista and Zarate
et al. 2004; Pierre and Picard 2001). In addition to increasing the risk
for adverse health outcomes, medication-induced weight gain may reduce
compliance with the drug responsible for the increased body weight.

Before initiating long-term clinical studies in patients with
medication-induced weight gain, sponsors should rule out clinically
significant drug-drug interactions and perform appropriate preclinical
toxicological studies of the subject products. For details, see the
guidances for industry *Drug Metabolism/Drug Interaction Studies in the
Drug Development Process: Studies In Vitro*, *In Vivo Drug
Metabolism/Drug Interaction Studies --- Study Design, Data Analysis, and
Recommendations for Dosing and Labeling*, and *Nonclinical Safety
Evaluation of Drug or Biologic Combinations*.

Patients eligible for participation in trials examining the efficacy and
safety of products for the treatment of medication-induced weight gain
should have a documented increase in body weight of at least 5 percent
within 6 months of starting a drug known to cause weight gain. Patients
should have BMIs greater than or equal to 27 kg/m^2^ with comorbidities
or greater than or equal to 30 kg/m^2^ with or without comorbidities at
the time of screening.

Because most weight-management products act within the central nervous
system (CNS) and many of the drugs commonly associated with
moderate-to-marked weight gain are used to treat psychiatric or
neurological disorders, unique issues of efficacy and safety may arise
in studies of products used to treat medication-induced weight gain. For
example, it would be important to demonstrate that the efficacy and
safety of the medication causing the weight gain (e.g., atypical
antipsychotic) was not adversely affected by a weight-management product
with a CNS mechanism of action, and vice versa. These and similar issues
should be taken into account when designing and determining the sample
size of trials for the treatment of medication-induced weight gain.

The efficacy of a product for the treatment of medication-induced weight
gain generally will be assessed using the same factors as those for
weight management, as defined in section IV.B.3.

Serotonin syndrome, a potentially life-threatening condition
characterized by akathisia, tremor, altered mental status, clonus,
muscular hypertonicity, and hyperthermia (Boyer and Shannon 2005), has
been observed in patients exposed to a single or two or more
proserotonergic agents used in combination. Therefore, in general,
weight-management products that act as agonists at serotonin receptors,
particularly the 5-HT2~A~ subtype, should not be studied in combination
with proserotonergic medications associated with weight gain.

Because of issues related to safety and possibly efficacy that are
unique to the particular combinations of drugs studied, approval of a
product for weight management in patients with medication-induced weight
gain generally will be limited to the weight-inducing drug studied and
will not apply to the drug class in which the compound is a member. For
example, if a weight-management product is shown to be effective and
reasonably safe in the treatment of clozapine-induced weight gain, the
approved indication would be limited to clozapine-induced weight gain
and would not necessarily apply to the entire class of atypical or
second generation antipsychotics.

# V. Clinical Assessment of long-term Weight-management Products in Pediatric Patients[^4] 

Because the benefit of weight-management products should be carefully
weighed against potential toxicity, particularly in the pediatric
population, we anticipate that phase 3 data in adults generally will be
available before a new product is studied in children.

To ensure that the most appropriate dose or doses are studied in phase 3
trials, an assessment of the pharmacokinetics of a weight-management
product in pediatric patients may be appropriate before initiation of
long-term clinical studies. Pharmacokinetics and dose-ranging studies
generally should include patients with age- and sex-matched BMIs greater
than or equal to the 95th percentile.

Trials examining the efficacy and safety of a weight-management product
in pediatric patients should be randomized, double-blind,
placebo-controlled, and 1 year in duration. We suggest that initial
pediatric studies be limited to adolescents (i.e., 12 to 16 year olds).
Eligible patients should have age- and sex-matched BMIs greater than or
equal to the 95th percentile (see http://www.cdc.gov/growthcharts).
Patients should have a documented history of failing to lose sufficient
weight with lifestyle modification before enrollment into studies of a
weight-management product.

We recommend that initial clinical studies include patients with one or
more weight-related comorbidities such as type 2 diabetes, dyslipidemia,
or hypertension. Once a satisfactory risk-benefit profile has been
established in this high-risk group of patients, studies of lower risk
patients can be considered. Effort should be made to recruit equal
numbers of males and females and representative samples of patients from
ethnic groups in which the prevalence of obesity is high.

The lifestyle modification program should continue following
randomization to product or placebo and its importance emphasized at
appropriate intervals throughout the trials.

Because linear growth should be taken into account when assessing
changes in the body weight of children and adolescents, the primary
efficacy parameter in weight-management trials of pediatric patients
should be a function of the change in BMI (e.g., the mean percent change
in BMI and the proportion of patients who lose greater than or equal to
5 percent of baseline BMI). Height measurements should be obtained from
a wall-mounted stadiometer.

Since demonstration of adequate safety necessitates a larger sample size
than demonstration of efficacy, we anticipate that the sample size of
the long-term pediatric weight-management studies will be determined by
considerations of the product's mechanism of action and safety profile
in adults. Sponsors should discuss and justify their proposed sample
size with the division before initiating the study.

In addition to standard safety evaluations specific to growing children
(e.g., assessing Tanner stage at baseline and endpoint), studies of
centrally acting weight-management products in pediatric patients also
should include validated assessments of neuropsychiatric function. Other
specialized safety assessments may be appropriate depending on the
product's mechanism of action and its safety profile in adults.

The efficacy assessment of a weight-management product in pediatric
patients will take into account the product's effectiveness in
overweight and obese adults as well as the magnitude of the difference
in the mean and categorical (greater than or equal to 5 percent) changes
in BMI from baseline to Year 1 in pediatric patients treated with active
product versus placebo.

# VI. Statistical Considerations

## A. Sample Size 

The number of subjects in a placebo-controlled trial should be the
maximum of sample sizes calculated based on the co-primary endpoints of
categorical response defined as greater than or equal to 5 percent
reduction in baseline body weight after 1 year, and change from baseline
weight. Calculations should be based on two-sided tests of significance
at the 5 percent level and at least 80 percent power. Effect sizes for
the calculations should represent clinically meaningful differences.

## B. Preventing Missing Data from Premature Subject Withdrawal

Historically, there have been high rates of premature subject withdrawal
in long-term trials of weight-management products. To allow for a true
intent-to-treat (ITT) analysis, we encourage sponsors to obtain body
weight measurements in all subjects who prematurely withdraw from
late-stage preapproval trials near the calendar date at which they were
scheduled to complete the trial (Simons-Morton and Obarzanek et al.
2006). For example, a subject who withdraws from a 12-month study after
6 months of treatment should have a body weight measurement at the time
he or she would have completed 12 months of study participation.

## C. Analysis Methods

Response rates should be compared between treatment groups using
statistical methods appropriate for categorical data. A sensitivity
analysis should be conducted that considers subjects who are treated,
drop out, and do not have complete post-baseline data as treatment
failures.

The analysis of (percentage) weight change from baseline should use
ANOVA or ANCOVA with baseline weight as a covariate in the model. The
analysis should be applied to the last observation carried forward on
treatment in the modified ITT population defined as subjects who
received at least one dose of study drug and have at least one
post-baseline assessment of body weight. Sensitivity analyses employing
other imputation strategies should assess the effect of dropouts on the
results. The imputation strategy should always be prespecified and
should consider the expected dropout patterns and the time-course of
weight changes in the treatment groups. No imputation strategy will work
for all situations, particularly when the dropout rate is high, so a
primary study objective should be to keep missing values to a minimum.
Repeated measures analyses can be used to analyze longitudinal weight
measurements but should estimate the treatment effect at the final time
point. Statistical models should incorporate as factors any variables
used to stratify the randomization. As important as assessing
statistical significance is estimating the size of the treatment effect.
If statistical significance is achieved on the co-primary endpoints,
type 1 error should be controlled across all clinically relevant
secondary efficacy endpoints intended for product labeling.

## D. Graphical Methods

Graphical methods showing treatment effects over time for completers
should be presented. Cumulative distribution plots can be useful for
showing response rates for different definitions of response based on
the percentage of subjects with a change value equal to or less than the
value on the x-axis selected to define the positive response. Additional
graphical presentations of the data to illustrate the effect of the drug
are encouraged. For examples, see the guidance for industry *Clinical
Studies Section of Labeling for Human Prescription Drug and Biological
Products --- Content and Format*.

# VII. Labeling Considerations

Data on the changes in the major weight-related comorbidities are
important in assessing the overall risk-benefit profile of a new
weight-management product and can be included in the Clinical Studies
section of the product's labeling. However, it is important to recognize
that even though secondary efficacy endpoints are prespecified and the
overall type 1 error rate is controlled for, that does not necessarily
guarantee that all secondary endpoints will be included in labeling if
the differences between active-product and placebo-treated groups are of
nominal statistical significance. The clinical significance and
consistency across studies of any observed differences will be important
in determining whether the secondary efficacy data merit inclusion in
the Clinical Studies section of the labeling.

# VIII. Stand-Alone Indications for the Prevention or Treatment of Weight-Related Comorbidities

As mentioned earlier, weight loss through lifestyle modification is
associated with improvements in blood pressure, lipid levels, glucose
and insulin metabolism, and other physiometabolic endpoints.
Improvements in these comorbidites are expected following drug or
biologic-induced weight loss, and from a regulatory perspective, they
are considered part of the weight-management indication. Thus, for a
weight-management product to obtain a stand-alone indication for the
prevention or treatment of type 2 diabetes, dyslipidemia, hypertension,
or any other weight-related comorbidity, it should be shown that the
product effectively prevents or treats the comorbidity through a
mechanism that is independent of weight loss.

# IX. Metabolic Syndrome

The term *metabolic syndrome* represents a cluster of laboratory and
clinical findings that serve as markers for increased risk for
cardiovascular disease and type 2 diabetes, and, depending upon the
definition used, is prevalent in as much as 25 percent of the adult
American population. The FDA does not necessarily consider the metabolic
syndrome to represent a distinct disease entity. At present, there is no
single etiological factor or central pathogenetic abnormality identified
as mediating the constellation of excess visceral adiposity, abnormal
lipids, elevated blood pressure, and insulin resistance that comprise
the metabolic syndrome. Nonetheless, in addition to lifestyle
modification, a host of drug therapies now exist to address individual
or multiple components of the syndrome (e.g., lipid altering agents,
antihypertensives, insulin sensitizers). Ideally, a therapeutic product
intended to treat metabolic syndrome should *normalize* or improve all
components of the syndrome, independent of weight loss (see section
VIII), and ultimately be shown to prevent the development of type 2
diabetes and reduce cardiovascular morbidity and mortality.

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[^1]: This guidance has been prepared by the Division of Metabolism and
    Endocrinology Products in the Center for Drug Evaluation and
    Research (CDER) at the Food and Drug Administration.

[^2]: We update guidances periodically. To make sure you have the most
    recent version of a guidance, check the CDER guidance Web page at
    http://www.fda.gov/cder/guidance/index.htm.

[^3]: Defining and Reporting Hypoglycemia in Diabetes: A Report from the
    American Diabetes Association Workgroup on Hypoglycemia, 2005,
    *Diabetes Care*, 28(5): 1245-9.

[^4]: For details on preclinical and pharmacokinetic evaluations for
    pediatric product development, see the ICH guidances for industry
    *M3 Nonclinical Safety Studies for the Conduct of Human Clinical
    Trials for Pharmaceutics* and *E11 Clinical Investigation of
    Medicinal Products in the Pediatric Population*.