Status: Draft, revision 1

Date: February 2007

Organizations:

United States Department of Health and Human Services
United States Food and Drug Administration (FDA)
Center for Drug Evaluation and Research (CDER)

Target Audience: Persons involved in drug development, clinical research investigators, clinical trial sponsors
Guidance Laws and Regulations Referenced:

Guidance for Industry Development of Products for Weight Management, 1996: Original FDA draft guidance with recommendations for designing clinical trials for weight-management products.
Drug Interaction Studies —Study Design, Data Analysis, and Implications for Dosing and Labeling: FDA guidance addressing drug-drug interaction studies.
ICH E8 General Considerations for Clinical Trials: International Conference on Harmonisation (ICH) guideline providing general recommendation for the design of clinical trials.
ICH E9 Statistical Principles for Clinical Trials: ICH guideline (topic E9), providing general recommendations for the use of statistical analysis in clinical trials.
ICH E11 Clinical Investigation of Medicinal Products in the Pediatric Population: ICH guideline providing recommendations for designing clinical trials for children.
ICH M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceutics: ICH guidance providing recommendations for conducting nonclinical safety studies on products before testing in humans.

Definitions:
BMI: A measure of fatty tissue calculated using weight (kg) and height (m):
BMI=weight (kg)/height (m)²
Comorbidity: A pathological or disease process coexisting with, but unrelated to another.
Obese: BMI>30
Weight-management products: Products that are used to reduce body mass, primarily by reducing body fat.
Pharmacokinetics: The branch of pharmacology concerned with the way drugs are taken into, move through, and are eliminated from, the body.
Stand-alone indication: In this context, a weight-related comorbidity that could be treated with a weight-management product, but the mechanism of action is unrelated to weight loss.

Background:
Obesity is a chronic health risk caused by excessive body fat assessed by BMI. It is associated with risk of death and comorbidities, including type 2 diabetes, hypertension, and cardiovascular disease. A change in lifestyle is the recommended treatment for this condition, but when it fails, weight-management products can be used. Since these products present a potential health risk, benefits and risks should be taken into account. When conducting clinical trials, only subjects presenting a substantial amount of risk should be included in the study to avoid unnecessary harmful effects. The appropriate adult and pediatric patient population to be included in clinical trials is discussed and defined in this guidance. Other issues related to clinical trial design are: assessment of safety and efficacy, stand-alone use for prevention and treatment of weight-related comorbidities, use in patients with medication-induced weight gain, and statistical and labeling considerations.

Summary:
This guidance gives investigators and sponsors the FDA’s recommendations for developing weight-management products and designing appropriate clinical trials. This revision adds recommendations not given in the previous draft (Draft guidance September 1996), including: clinical assessment in adult and pediatric patients, safety assessment, combination products, stand-alone indications, use of weight-management products in patients with medication-induced weight gain, and statistical and labeling considerations. Lifestyle changes are always recommended as the treatment of choice, and weight-management products should only be considered after a sufficient course of personal effort. If this fails, persons to be included in clinical trials should be carefully selected by use of inclusion criteria which identify those who have sufficient risk due to their condition (BMI>30 [obese] or BMI>27 with at least one weight-related comorbidity). Clinical and safety assessment recommendations are provided for adults and pediatric patients. Products to be used in combination or in patients with medication-induced weight gain should be tested using pre-clinical pharmacokinetics and evaluated for drug-drug interactiuon. Use of these products for stand-alone indications should be proven to have a mechanism of action independent of weight loss. Advice is given for statistical considerations (sample size, methods of analysis, graphics, and missing data issues) and labeling considerations (inclusion of secondary endpoints).

Rationale:

This revision provides additional recommendations for clinical trial design not addressed in the original draft.

Resulting Recommendations:

·         Adult volunteers should not be included in a study of weight-management products unless:
o   They have a BMI>25 and have at least one other weight-related comorbidity.
·        Long-term studies on pediatric patients should only be conducted after pharmacokinetic and studies on different doses have been done (in accordance with ICH M3, ICH E11).
·         Studies on pediatric patients should first be done on obese patients with one or more weight-related comorbidities.
Weight-management products used in combination should be studied in pre-clinical and phamacokinetics studies. Efficacy and safety of combination drugs should be compared to the individual product components in phase 2 trials.
·     Stand-alone indications for the prevention or treatment of weight-related comorbidities (such as type 2 diabetes) can only be considered if there is proof that the drug works in a way unrelated to weight loss.
·        Weight-management products for patients with medication-induced weight gain and combination drugs should only be studied in a trial after doing drug-drug interaction and pre-clinical toxicology studies (FDA Drug Interaction Studies —Study Design, Data Analysis, and Implications for Dosing and Labeling).
Impact:
The development of weight-management products will be better designed, increasing the benefits compared to risks for patients involved in clinical trials.