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On January 7, 2025, the U.S. Food and Drug Administration (FDA) released a draft guidance for sponsors developing weight-loss drugs and biologics for obese patients.The draft guidance is intended to update a document issued in 2007 on the development of products for weight loss management. In recent years, weight-loss drugs such as Ozempic (semaglutide) and Zepbound (tirzepatide) have become breakout drugs, and the FDA said it revised the guidance to take into account the fact that the FDA has gained a greater understanding of these drugs since the original guidance was issued.
The updated draft guidance involves a focus on clinical trial design, regulatory considerations, and whether these trials can demonstrate that the drugs can maintain weight loss as determined by BMI. For reference, the following is an overview of the key elements of the draft guidance from the SDM clinical team.
1. Definition of Medical Weight Loss
The FDA defines medical weight loss as the long-term reduction of excess body fat in the body, thereby improving overall health and aiming to reduce morbidity and mortality.Indications for weight loss include not only initial weight loss, but also maintenance of weight loss (i.e., prevention of weight rebound) for at least one year.
2. The Role of Body Mass Index (BMI)
BMI remains the primary criterion for assessing obesity and overweight in clinical trials. The FDA emphasizes the use of BMI because of its broad applicability, economy, and strong correlation with overall body fat.However, the FDA also recognizes the limitations of BMI and encourages sponsors to discuss the use of other alternative measures with the FDA as necessary.BMI classification:
Overweight: BMI ≥ 25 and < 30 kg/m²
Obese: BMI ≥ 30 kg/m²
The guidance also provides BMI criteria for adult and pediatric patients.
3. Clinical Trial Design
The draft guideline outlines specific requirements for designing clinical trials of weight loss treatments, with key considerations including:
Trial phase: the guideline covers phase 1, 2, and 3 trial designs. For phase 3 clinical trials, at least one phase 3 clinical includes a control group for lifestyle interventions to include a representative population with a BMI of 40 or greater and a representative population with type 2 diabetes. The phase 3 clinical size should be no less than 3,000 people in the treatment group and no less than 1,500 people in the placebo control group, with a maintenance phase of no less than 1 year.
Study Population: The FDA emphasizes inclusion of a diverse population of obese or overweight adults and pediatric patients.
Efficacy endpoints: The primary endpoint is usually the percentage of weight loss that is sustained for a certain period of time (at least one year), and secondary endpoints may include improvement in obesity-related complications (e.g., diabetes, hypertension).
Safety assessment: monitoring of adverse events and safety risks over a longer treatment period is critical.
4. Special Considerations
Pediatric patients: The guidance provides recommendations for trials in pediatric populations, particularly trial design, participant inclusion/exclusion criteria, and safety assessment.
Diabetic patients: the FDA lists special considerations for patients with type 2 diabetes, who may have unique needs with respect to weight management therapy.
Combination therapies: If the product is planned to be used in combination with other therapies, the FDA recommends that specific guidance be provided for evaluating the safety and efficacy of combination therapies.
5. Handling of Missing Data and Intermediate Events
The guidance focuses on recommendations for handling missing data and intermediate events (e.g., early withdrawals, treatment changes) in clinical trials. FDA recommends that sponsors:
Pre-specify how missing data will be handled, including a statistical analysis plan to address missing or incomplete data.
Use treatment policy estimation methods to analyze data, ensuring that all participants should be included in the analysis unless they explicitly withdraw their consent.
Provide reasonable explanations when using other estimation methods, ensuring that they address meaningful clinical questions and rely on reasonable assumptions.
6. Statistical Considerations
The FDA emphasizes the use of robust statistical methods to assess the efficacy and safety of weight loss products. The guidance recommends clear protocols and statistical analysis plans to ensure proper evaluation of clinical data.Appropriate statistical methods for addressing missing data and analyzing long-term weight loss outcomes are also outlined.
In addition, the FDA encourages sponsors to communicate with the FDA early and frequently during the trial design process, especially on complex issues such as study endpoints, treatment of missing data, or the use of alternative measures of BMI.
This release of the draft guidance revision is open for comment until April 8, 2025, during which time anyone can make suggestions for changes to its content process. The original draft guideline is available below for reference reading.
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The updated draft guidance involves a focus on clinical trial design, regulatory considerations, and whether these trials can demonstrate that the drugs can maintain weight loss as determined by BMI.
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