FDA Proposes Sustained 5% Weight Loss to Establish Efficacy of New Antiobesity Medications
In an unusual step, the agency's draft guidance recommends the efficacy benchmark for drug approval while emphasizing clinical trial structure and cohort development.
The FDA in an uncommon move on Tuesday recommended that investigational antiobesity medications demonstrate a minimum weight loss of 5% sustained for 1 year at the maintenance dose in order to establish a new drug’s potential efficacy.
The draft guidance offered for public comment set out a slate of efficacy standards including specific thresholds that manufacturers’ clinical trial outcomes would be required to meet before the programs can be claimed effective.
The overarching objective of the guidance, titled Obesity and Overweight: Developing Drugs and Biological Products for Weight Reduction, is to provide a structured framework for the development of safe and effective weight management therapies, with a particular focus on long-term weight reduction and the associated health benefits, according to the document.
“Although FDA encourages assessment of the effect of drugs on the manifestations of obesity or overweight beyond excess adiposity (eg, obstructive sleep apnea, osteoarthritis), this guidance focuses on study designs and endpoints to assess the effectiveness of drugs on sustained weight
reduction itself in patients with obesity or overweight,” the agency states. The benchmark for efficacy will be a statistically significant difference between the investigational drug- and control- treated groups of 5% maintained after 1 year of treatment.
The major topics in the agency’s draft guidance include defining appropriate adult and pediatric populations for enrollment in clinical trials for drugs targeting chronic weight management, essential principles of phase 1 and phase 2 trials, and detailed review of the elements of phase 3 trials including study design, population size, and duration; efficacy endpoints; evaluations of safety; and appropriate statistical principles.
The draft guidance specifically addresses trial considerations in evaluation of antiobesity medications in individuals with type 2 diabetes (T2D), emphasizing the reduced efficacy of the drugs in this population as well as safety issues related to increased risk for hypoglycemia. Given the large proportion of individuals with comorbid obesity and T2D , manufacturers are expected to evaluate sufficient numbers of the population to assess safety and efficacy either in dedicated trials or in adequately powered subgroups of larger weight reduction trials that also include participants without T2D, the guidance stipulates.
Other sections highlight assessment of antiobesity medications when used in combination, when explored for reduction of medication-induced weight gain, and trial considerations for assessment of pediatric patients.
The guidance sections focused on assessing safety profiles of weight-reduction medications include evaluating comprehensive cardiovascular effects, fit-for-purpose neuropsychiatric evaluations, and investigating the immunogenic potential of therapeutic proteins. The draft guidance also addresses the growing concern of abuse liability associated with centrally acting weight-reduction drugs. Sponsors are encouraged to conduct nonclinical and clinical studies to assess this risk and to engage in discussions with the FDA during the early phases of drug development.
FDA guidance documents in general do not establish “legally enforceable responsibilities,” according to the guidance. A guidance describes agency’s “current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.” If finalized, a guidance, including this one, is not binding and manufacturers face no penalties for using alternative methods, as long as they satisfy requirements of the applicable statutes and regulations.
The document is currently open for public comment, and the FDA encourages input from various sectors to refine and enhance the guidance. Comments can be submitted electronically or in writing, with a deadline set for 90 days following its publication. The draft is available online at:
- https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
- https://www.fda.gov/regulatory-information/search-fda-guidance-documents
- https://www.regulations.gov
