FDA proposes update to 18-year guidance on developing weight loss drugs

The US Food and Drug Administration (FDA) has published draft guidance for sponsors developing drugs and biologics for weight reduction for patients who are obese. The guidance focuses on using body mass index (BMI) as a key metric and is based on the agency’s current thinking on effective treatments for obesity.

The draft guidance is intended to update a 2007 document on developing products for weight management. Weight-loss drugs such as Ozempic (semaglutide) and Zepbound (tirzepatide) have become blockbuster drugs in recent years, and FDA said it revised the guidance to account for what it has learned more about such drugs in the time since the original guidance was issued.

The draft guidance focuses on FDA’s expectations for how clinical trials used to develop weight loss drugs are designed and whether they demonstrate that they can sustain weight loss in patients who are determined to be overweight or obese based on their BMI. The agency defines medical weight loss as a long-term reduction in excess body fat that aims to reduce morbidity and mortality.

“The weight reduction indication comprises the concepts of both initial weight loss and weight maintenance (i.e., prevention of weight regain) for a minimum of 1 year,” FDA explained. “Major topics in this draft guidance include discussion of appropriate adult and pediatric participants to enroll in clinical trials for chronic weight management, principles of phase 1 and phase 2 trials, and detailed discussion of phase 3 trials, including trial design, size, and duration; efficacy endpoints; safety evaluation; and statistical principles.”

“Special topics include trial considerations for patients with diabetes mellitus, assessment of weight management products in combination, and trial considerations for assessment of pediatric patients,” the agency added.

FDA noted that there are other measures to assess whether patients are overweight or obese, but in the guidance, regulators focus on study designs and endpoints that use BMI to determine whether the product is effective in sustaining weight loss because it has a long history of being used in clinical and research settings. Furthermore, they note that BMI is inexpensive, universally available, easy to calculate, reproducible, and correlates strongly with total body fat. The agency urged sponsors to talk to regulators about using other means to determine whether patients are overweight or obese.

The guidance further breaks down BMI criteria for overweight and obesity in adults and children but also notes that those classifications have limitations, just as there are limitations to evaluating excess fat by other methods.

An important part of the guidance addresses FDA's expectations for sponsors when there is missing data.

"Study protocols and statistical analysis plans should clearly prespecify how intercurrent events and missing data will be handled during the trial and how they will be accounted for in the statistical analyses," said FDA. "Sponsors should consult with FDA regarding these issues during trial design."

"Although we are open to considering alternative estimands, we generally recommend inclusion of analyses using the treatment policy estimand, in which all subjects, regardless of intercurrent events, continue to be measured at each prespecified clinical visit unless consent to collect such data is explicitly withdrawn, and in which all such measurements are included in the statistical analyses," the agency added. "For other strategies to address specific intercurrent events, sponsors should justify that the estimand addresses a meaningful clinical question of interest and can be estimated with plausible assumptions."

The guidance also includes recommendations for minimizing missing data from premature study withdrawal or loss due to patient follow-up. These include clearly differentiating between treatment discontinuation and study withdrawal in the protocol and informed consent, and properly recording the reasons for treatment discontinuation or study withdrawal.

Stakeholders can comment on the draft guidance on www.regulations.gov under docker no. FDA-2007-D-0435 until 8 April.

Draft guidance

FDA proposes update to 18-year guidance on developing weight loss drugs

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