In January 2025, the FDA released a draft guidance titled Obesity and Overweight: Developing Drugs and Biological Products for Weight Reduction. The document outlines recommendations for the development of drugs and biological products aimed at weight reduction and long-term weight management in adults and children. The guidance underscores the importance of sustainable weight loss to improve overall health rather than focusing solely on numerical weight reduction.

Understanding the Clinical Landscape

The guidance defines obesity as a chronic disease characterized by excess adiposity, which is linked to an increased risk of mortality and major comorbidities, including type 2 diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, nonalcoholic steatohepatitis, osteoarthritis, sleep apnea, and certain cancers. Given these serious health risks, accurately assessing obesity and its impact is essential for evaluating treatment effectiveness.

The guidance acknowledges body mass index (BMI) has a multitude of limitations, but states that BMI is more clearly associated with clinical outcomes than changes in fat mass measured by imaging or other methods. This reinforces the role of BMI as a practical, albeit imperfect, tool for measuring obesity-related health risks and treatment benefits in clinical trials.

Designing Robust Clinical Trials

For new weight-management drugs, the FDA outlines expectations for clinical trials: 

• Phase 1 and 2 Trials: Early studies should establish the drug’s pharmacokinetics (PK), pharmacodynamics (PD), and tolerability across a broad range of BMIs. Phase 2 should be used to identify the appropriate dosage(s) for phase 3. 
• Phase 3 Trials: The guidance suggests enrolling 3,000 participants in the treatment group and 1,500 in the placebo group. The FDA wants the trials to be big enough to represent accurate statistical differences between the drug and the placebo. Phase 3 trials “should be randomized, double-blind, and placebo-controlled, with the investigational drug used as an add-on to standardized recommendations for diet and physical activity in all randomized subjects.” 

To understand the impacts of weight loss drugs, diverse representation is essential. The trials should reflect the U.S. population in terms of age, race, sex, ethnicity. Sponsors are encouraged to implement a diversity action plan that reflects obesity and its comorbidities in the United States. 

Efficacy and Safety Benchmarks

The guidance emphasizes mean percentage weight reduction as a primary efficacy measure. To demonstrate effectiveness, a drug should achieve a statistically significant difference compared to placebo, with at least a 5% average weight loss after one year of treatment. While 5% may seem modest, it can lead to significant health improvements, particularly for individuals with high blood pressure or type 2 diabetes. The focus is on improving health outcomes rather than just lowering body weight.

Special Considerations for Pediatric Populations 

Given the rising prevalence of childhood obesity, the guidance offers advice on pediatric trials. Separate trials should be held for children aged six to eleven, and adolescents aged twelve and older. All pediatric subjects “should have age-matched and sex-matched BMIs greater than or equal to the 95^th percentile.”

Statistical and Analytical Best Practices

Missing data is an unavoidable challenge in clinical trials, and how it is handled can significantly impact the reliability of study results. The FDA recommends that sponsors predefine their approach to missing data in a statistical analysis plan and use multiple imputation methods to account for missing values while preserving statistical integrity.

If a participant stops taking the drug but continues attending follow-up visits, their later data should still be included in the analysis. The FDA recommends using available data from participants who left the treatment group to estimate missing values, ensuring that the results remain as accurate as possible.

With these best practices in mind, it’s important to consider how they align with the FDA's broader vision for developing impactful and sustainable therapies.

Bringing Effective Treatments to Market

The FDA’s draft guidance establishes a clear framework for developing safe and effective weight-management therapies. By setting rigorous clinical trial expectations, defining efficacy benchmarks, and emphasizing diverse representation, the guidance ensures that new treatments prioritize long-term health improvements over short-term weight loss. The FDA is currently accepting comments on this draft guidance until April 8, 2025, providing an opportunity for stakeholders to contribute to shaping the final framework.

For companies developing weight-reduction therapies, aligning with these evolving regulatory standards is essential. Medpoint’s team of regulatory and clinical experts can help navigate these requirements, from trial design to compliance strategies, ensuring that your drug development process meets FDA expectations. Reach out to learn how we can support your efforts in bringing effective, evidence-based weight-management solutions to market. Just click here. 

Author: Ashlee Bailey, Project Coordinator and Social Media Manager

References

1. U.S. Food and Drug Administration. "Obesity and Overweight: Developing Drugs and Biological Products for Weight Reduction: Draft Guidance for Industry." FDA, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/obesity-and-overweight-developing-drugs-and-biological-products-weight-reduction.
2. National Library of Medicine. "Childhood obesity has increased significantly in recent decades and has quickly become a public health crisis in the United States and all over the world." PubMed Central, https://pmc.ncbi.nlm.nih.gov/articles/PMC6887808/.