With the rise of “weight loss injections” led by Eli Lilly’s tirzepatide and Novo Nordisk’s semaglutide, the obesity treatment market has entered a new era. Beyond injectable formulations, oral medications and multi-target combination therapies are also gaining momentum. In response to this wave of innovation, the U.S. Food and Drug Administration (FDA) released a revised draft guidance in early 2025, outlining key principles for the development of weight management drugs.
The FDA emphasizes that the primary goal of anti-obesity medications should be the long-term reduction of excess adiposity, not just short-term weight loss. Phase 3 trials are expected to extend for at least 52 weeks, including an evaluation of how well the effect is sustained during the maintenance phase. The primary efficacy endpoint should be the mean percentage change in body weight, with the treatment group demonstrating a difference of at least 5% compared to the control group, and the result must be statistically significant. As for the commonly reported “≥10% weight loss responder rate,” the FDA cautions that this type of analysis may overstate the drug’s effectiveness and should be considered only as a supportive outcome.
In terms of safety, developers are expected to include at least 3,000 subjects who receive maintenance dosing, with no fewer than 1,500 in the control group. Safety assessments should include cardiovascular and metabolic parameters, along with additional evaluations based on the drug’s mechanism of action, such as mental health assessments, echocardiography, immunogenicity testing, or body composition analysis.
The guidance also stresses the importance of enrolling a diverse study population, including individuals across different racial and ethnic backgrounds, BMI categories, and those with obesity-related comorbidities such as type 2 diabetes, liver, or kidney disease. For certain populations, such as patients with type 2 diabetes or those with drug-induced weight gain (e.g., from antipsychotics), dedicated clinical trials may be conducted if there is sufficient supporting evidence. In addition, all trial participants should receive standardized dietary and physical activity counseling. The FDA encourages at least one Phase 3 study to use lifestyle-modification programs that reflect real-world clinical practice to enhance external validity.
Overall, this draft guidance provides not only clear benchmarks for efficacy and safety but also reminds drug developers to consider the long-term impact and real-world applicability of their interventions. In an increasingly competitive weight loss market, a thorough understanding of this guidance will help new therapies move more smoothly from the lab to the clinic.
References:
Obesity and Overweight: Developing Drugs and Biological Products for Weight Management, FDA Guidance for Industry (draft), January 2025
New England Journal of Medicine. 2022;387(3):205-16
Nature Medicine. 2022;28(10):2083-91
