The National Center for Health Research (NCHR) appreciates the opportunity to comment on the FDA’s draft guidance titled “Obesity and Overweight: Developing Drugs and Biological Products for Weight Reduction.” We support the guidance’s outline of key considerations for sample size (3,000 patients); the importance of randomized, double blind clinical trials with a control group; the inclusion of standard of care support for diet and physical activity; the inclusion of patients who are overweight with substantial health concerns or who are obese; and the ways to evaluate weight loss. We strongly support the section on the need to have specific guidance for the development of drugs intended for weight reduction in patients with obesity or overweight caused by or exacerbated by medication-induced weight gain. We agree with the Guidance that prior to initiating long-term clinical studies in patients with medication-induced weight gain, “a sponsor should evaluate potential clinically significant drug-drug interactions and perform appropriate nonclinical toxicological studies” and that the design of the clinical program should consider unique efficacy of safety issues for these drugs.
However, several important factors related to long-term safety and efficacy need to be stregthened to ensure that weight-loss medications provide meaningful and sustained benefits. The following recommendations are supported by evidence from recent studies and clinical trials:
- Effect of Treatment Discontinuation and Long-Term Outcomes
A major shortcoming is that the guidance suggests that a one-year study is adequate to study “weight reduction and long-term maintenance of body weight” and “sustained weight reduction.” We strongly disagree, because one year should not be considered “long-term maintenance” and there is clear evidence that most patients gain back the weight they lose from any weight loss strategy after a year or more. This has important implications for any benefits of the weight loss for health, well-being, or physical functioning. There are three important reasons why these studies should follow patients for at least 3 years:
1) Patients and health professionals need to make informed decisions based on the safety and efficacy of the drugs for patients who stay on the weight loss drug for more than 1 year and for those that do not;
2) Patients and health professionals can only make informed decisions if there is evidence regarding how many patients will discontinue the drug in the first, second, and third year, and for what reasons; and
3) Making informed decisions requires information about the weight and health of patients after they discontinue the drug after taking it for different periods of time. This is important for children and adults.
We agree with the guidance that studies should delineate why the patient has stopped treatment, such as specifying “nausea” rather than “patient decision.” However, the draft guidance should provide more detailed recommendations on evaluating the effects of different durations of treatment and the reasons for discontinuation, particularly in relation to weight regain and long-term metabolic health. In the SCOUT trial, subjects receiving sibutramine initially achieved greater weight loss over the first 12 months of treatment compared to those in the placebo group, with a mean additional weight loss of 1.7 kg in the sibutramine group.[1] Patients were in the study for an average of 3.4 years, and weight gradually increased in both groups after that first year. In the sibutramine group, although some weight regain occurred, a modest net loss was maintained during the treatment period. This trend highlights the importance of evaluating how patients’ weight changes over time even if they stay on the drug.
Findings from the STEP 1 trial extension further support this concern. In the STEP 1 trial, participants receiving semaglutide experienced an average weight loss of 17.3% over 68 weeks.[2] However, one year after stopping semaglutide treatment and lifestyle intervention, participants regained approximately two-thirds of the lost weight, resulting in a net loss of only 5.6% from baseline at week 120. Additionally, cardiometabolic improvements seen during treatment—including reductions in HbA1c, systolic blood pressure, and triglyceride levels—were largely reversed after treatment discontinuation, returning close to baseline values. Importantly, participants who lost greater amounts of weight during treatment tended to experience more pronounced weight regain after discontinuation. It is important to note that all participants stopped at the same time because the study design required it, rather than due to individual choice. In a real-world setting, people stop weight loss drugs for various reasons (cost, side effects, access), and the pattern of weight loss and weight regain may vary depending on those contexts.
- Effect on Health and Well-Being After Treatment Ends
The guidance specifies that it is intended to focus on studying efficacy in terms of weight loss, not health parameters, unless the latter are specifically evaluated to be included in the indication. However, unsuccessful experiences with a weight loss drug could potentially cause harm to patients health and well-being, and those negative side effects or complications should be evaluated. Those measures should therefore be added to any evaluation of a weight loss drug, especially since research indicates that most patients will stop using weight loss drugs after a few months or years.
There is also evidence that long-term use of some of these drugs can be harmful to patients with pre-existing conditions. For example, the SCOUT trial demonstrated that long-term sibutramine use by patients with preexisting cardiovascular disease were more likely to experience nonfatal myocardial infarction (4.1% vs. 3.2%; HR, 1.28; p = 0.02) and nonfatal stroke (2.6% vs. 1.9%; HR, 1.36; p = 0.03) compared to placebo patients, despite achieving modest weight loss.1 In addition, the overall rate of cardiovascular death did not differ between the sibutramine and placebo groups, raising concerns about whether the short-term cardiovascular improvements that have been widely reported translate to meaningful long-term cardiovascular benefits.[3]
These findings underscore the need for the draft guidance to require long-term follow-up on cardiovascular outcomes, for those staying on the drugs as well as those who discontinue treatment for any reason, to fully evaluate the safety and efficacy of weight loss drugs. Tracking cardiometabolic parameters such as blood pressure, glucose, and lipid levels over an extended period would provide a more comprehensive understanding of the broader clinical impact of weight loss therapies.
- Non-Medical Strategies as a Prerequisite for Enrollment (Especially in Pediatric Trials)
The draft guidance does not require that study participants make any effort to use non-pharmacological strategies (e.g., diet, exercise, behavioral therapy) before trial enrollment. This contradicts current best clinical practice as outlined in the 2016 American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Comprehensive Clinical Practice Guidelines[4], which strongly recommend that pharmacotherapy for obesity be used only as an adjunct to structured lifestyle intervention, and is inconsistent with MAHA principles which focuses on improving health habits. One justification for excluding a requirement of previous failure of non-pharmacological strategies is the assumption that everyone choosing a weightloss drug has already tried and failed diet or exercise, but that is not necessarily true, especially for children. And assuming it is true for most adults and at least some children, then it would not interfere with these studies to include that requirement.
The benefit of a non-pharmacological strategy for weight loss is to inculcate health habits that can be beneficial throughout one’s life, even if the weight loss is less dramatic in the first year. For example, a study of overweight and obese children ages 5 -18 years) demonstrated that a 20-week multidisciplinary lifestyle modification program led to significant reductions in BMI (from 29.3 to 27.8, p = 0.001) and BMI z-score (from 3.06 to 2.69, p = 0.001).[5]Improvements were most notable in the first 12 weeks, when structured interventions—intensive dietary counseling, physical activity, and behavioral therapy—were delivered more frequently. While weight reduction slowed and even slightly reversed in the final stage, BMI z-scores continued to decline, likely due to height gain, suggesting sustained benefits even with reduced supervision. Additionally, a subgroup of children with elevated triglycerides at baseline showed significant reductions after the intervention. These findings reinforce the role of structured non-pharmacological interventions as a critical first step, capable of producing measurable early improvements in weight, fitness, and metabolic markers. However, the study also underscores the need for long-term support and possibly pharmacotherapy in severe or refractory cases, given high attrition rates and challenges in maintaining progress post-intervention.
Clinical guidelines recommend offering pharmacotherapy to adolescents 12 years and older with obesity, according to medication indications, risks, and benefits, as an adjunct to lifestyle and behavioral interventions—particularly when those alone have not achieved sufficient results.[6,7] Requiring prior engagement in non-pharmacological strategies before trial enrollment would align with real-world clinical practice, improve patient selection, and enhance the validity of trial outcomes.
- Dropout Rates and Data Interpretation
The draft guidance addresses missing data and intercurrent events but does not adequately consider how dropout rates, particularly those related to side effects or lack of efficacy, may undermine the validity of trial results. High dropout rates may signal poor tolerability or limited therapeutic benefit, and can lead to biased estimates of both safety and efficacy if not adequately accounted for. As noted by Pocock and Stone in The New England Journal of Medicine, selective dropout can lead to a study population that no longer reflects the real-world patients likely to receive the intervention, thereby skewing the interpretation of long-term outcomes and potentially resulting in an overestimation of benefit or underreporting of harm.[8]
References:
[1] James et al. (2010). Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. The New England Journal of Medicine, 363(10), 905–917. https://doi.org/10.1056/NEJMoa1003114
[2] Wilding et al. (2022). Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes, Obesity & Metabolism, 24(8), 1553–1564. https://doi.org/10.1111/dom.14725
[3] Lincoff et al. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes. The New England Journal of Medicine, 389(24), 2221–2232. https://doi.org/10.1056/NEJMoa2307563
[4] Garvey et al. (2016). AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY. Endocrine Practice, 22(Suppl 3), 1–203. https://doi.org/10.4158/EP161365.GL
[5] Chen et al. (2022). The effect of a multidisciplinary lifestyle modification program for obese and overweight children.Journal of the Formosan Medical Association, 121(9), 1773–1785. https://doi.org/10.1016/j.jfma.2022.01.011
[6] Dutton et al. (2024). Clinician’s Guide for Pediatric Anti-obesity Medications. Pediatric Clinics of North America, 71(5), 957–980. https://doi.org/10.1016/j.pcl.2024.07.006
[7] Hampl et al. (2023). Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents With Obesity. Pediatrics, 151(2), e2022060640. https://doi.org/10.1542/peds.2022-060640.
[8] Pocock & Stone (2016). The Primary Outcome Fails – What Next? The New England Journal of Medicine, 375(9), 861–870. https://doi.org/10.1056/NEJMra1510064