New FDA Guidance: Developing drugs and biological products for weight reduction in Obesity and Overweight (January 2025).

My attempt to identify ten differences between the FDA’s 2007 and 2025 guidance documents on developing products for weight reduction failed because there are far more than ten. However, the key principles remain consistent:

1. Subtle but Important Changes in Terminology:

The 2007 guidance used the following terminology to describe the primary indication: “weight loss or maintenance of lost weight (which also can be described as prevention of weight regain).”

The 2025 guidance, on the other hand, refers to “sustained weight reduction.” It defines weight reduction as a long-term reduction in excess adiposity (body fat) with the goal of reducing morbidity and mortality. The term “long-term” refers to maintaining weight loss for at least one year on the maintenance (!) dose of the drug, therefore the total duration of the studies, consisting of dose escalation and maintenance phases, should be greater than one year.

2. Lifestyle Interventions:

The 2007 guidance straightforwardly stated: “The use of a weight-management product should be contemplated only after a sufficient trial of lifestyle modification has failed.”

While the 2025 guidance also includes recommendations on lifestyle modification, it does so in the context of comprehensive weight management, where non-pharmacological and pharmacological treatment approaches may be combined rather than sequential. For example: “The lifestyle-modification programs used in the preapproval trials should be applicable to patients who would be prescribed the drug after approval. At least one phase 3 trial should incorporate a standard-of-care diet and physical activity program.” In my opinion, this reflects a shift in overall treatment approach: “Weight management is not about endless exercising of willpower.”

In terms of clinical trial design, this means that we will continue using standard eligibility criteria, requiring participants to have at least one unsuccessful attempt at diet or exercise in the past and a willingness to comply with the study-required lifestyle intervention. The 2025 guidance remains vague about what a lifestyle-modification program should entail, emphasizing the balance between effectiveness and simplicity, which is probably for better, considering poor adherence to very complicated or restrictive lifestyle interventions in clinical trials.

3. Acknowledgment of BMI limitations:

The 2025 guidance acknowledges the limitations of BMI but continues to use it as the most practical method for evaluating adiposity. "BMI is inexpensive, universally available, easy to calculate, reproducible, and correlates strongly with total body fat in nonelderly adults".

4. Adjusted Efficacy Assessments:

The 2025 guidance accounts for the results of recent clinical trials showing >10%, 15%, and 20% weight loss. While long-term weight loss greater than or equal to 5% remains a clinically meaningful outcome, the recommendation to use it as a categorical primary efficacy endpoint (i.e., the proportion of patients losing ≥5% of baseline weight) has been removed. Instead, the guidance recommends responder analyses using continuous variables (e.g., the proportion of patients achieving prespecified thresholds such as ≥5%, 10%, or 15% weight reduction compared to the control arm). However, it cautions that this approach may exaggerate treatment effects, and is generally not recommended.

Changes in weight-related comorbidities continue to be part of the efficacy assessment, but the requirement to measure meaningful dose reduction or complete withdrawal of concomitant medications has been softened. The 2025 guidance now recommends collecting data on medication initiation, discontinuation, or dose reduction to support evidence of the drug’s effect on blood pressure or glycemic control.

A new concept introduced in the 2025 guidance is the use of clinical outcome assessments (COA) as secondary endpoints to support labeling claims. These may include improvements in physical functioning or sleep apnea.

5. Additional Indications in Labeling Claims

New remarks have been made regarding the delay and prevention of type 2 diabetes as a stand-alone indication. Whereas in 2007 it was required to demonstrate that a product effectively prevents or treats comorbidities through mechanisms independent of weight loss, the new guidance stipulates that an additional indication for delaying the onset of type 2 diabetes must be supported by evidence of clinical benefits resulting from the delay. Trials showing a delayed biochemical (!) diagnosis of type 2 diabetes alone are likely insufficient. Additionally, it is noted that since some weight-reduction drugs may have glycaemic effects, a trial would need to demonstrate that diabetes diagnosis is delayed or prevented, rather than concealed by early antihyperglycemic treatment initiation. ‘How’ is a question to be clarified.

The metabolic syndrome is no longer questioned as a distinct disease entity. However, the requirements for inclusion of metabolic syndrome as an additional indication in a label remain unchanged. Approval would require evidence of a reduction in cardiovascular morbidity or mortality risks or another clinically meaningful benefits achieved through improvements in most or all components of the syndrome.

6. Key Study Design Elements

A requirement to implement a diversity plan is reiterated across the document. Representation of studied population should extend beyond BMI categories to include comorbidities such as cardiovascular disease, heart failure, liver disease, and chronic kidney disease.

Key study design elements remain largely unchanged. The core eligibility criteria include:

????????????? ???????????? BMI ≥ 30 kg/m2, with a representative sample of participants with Class 3 or severe obesity (BMI ≥ 40 kg/m2), or

????????????? ???????????? BMI ≥ 27 kg/m2 in the presence of at least one weight-related comorbidity (e.g., type 2 diabetes, hypertension, dyslipidemia, sleep apnea, or cardiovascular disease).

The general recommendation for a sample size to assess the safety of a weight-reduction drug remains at 3,000 subjects randomized to the investigational drug within the to-be-recommended dosage range and no fewer than 1,500 subjects randomized to placebo for at least one year of treatment at the maintenance dosage.

An additional comment is made for trials involving drugs with multiple dosing regimens. In such cases, the guidance recommends a randomization scheme that assigns a larger proportion of participants to the higher dose groups, ensuring sufficient data to assess the safety and efficacy of these regimens.

7. Subjects with Type 2 Diabetes

Tailored recommendations are provided for specific populations, such as those with type 2 diabetes. Considering the less favorable response of patients with concomitant type 2 diabetes and the unique safety issues, such as the risk of hypoglycaemia, the FDA continues to recommend either a dedicated trial involving subjects with type 2 diabetes (with concomitant obesity or overweight) or an adequately powered sub-study within larger weight-reduction trials that include non-diabetic subjects. The prior lower limit of 8% for HbA1c eligibility criteria has been dispensed with, replaced by the requirement for stable anti-diabetes therapy prior to enrolment. However, the exclusion of subjects with poor glycaemic control at baseline (e.g., HbA1c exceeding 10% or fasting glucose levels above 270 mg/dL) remains recommended, along with stratification by the effects of common baseline glucose-lowering medications on weight (e.g., weight-promoting, weight-neutral, or weight-reducing) and baseline HbA1c (e.g., ≤8% vs. >8%). Algorithms for adjusting or eliminating glucose-lowering medications, rescue criteria for poor glycaemic control, and hypoglycaemia monitoring are still advised as essential components of trial protocols.

8. Pediatric Population

Key changes in recommendations for the pediatric population include shifting the timelines for pediatric investigation plans to an earlier period—no later than 60 days after the end-of-phase 2 meeting, compared to the previous expectation of after phase 3 data in adults became available. Eligibility criteria for pediatric studies have also been broadened to include participants aged six years and older, compared to the previous lower limit of 12 years.

9. Expanded safety assessments:

The 2025 guidance broadens safety assessment recommendations and includes additional specialized evaluations for certain weight-reduction programs:

? Cardiovascular safety:?In addition to the standard assessments (blood pressure and heart rate) required in 2007, the 2025 guidance emphasizes comprehensive evaluations such as ambulatory blood pressure monitoring. A cardiovascular outcomes trial may be required if a signal for cardiovascular risk is identified during development.

? Neuropsychiatric function:?Fit-for-purpose assessments like the Patient Health Questionnaire-9 (PHQ-9) and Columbia Suicide Severity Rating Scale (C-SSRS) are now recommended for centrally acting weight-reduction drugs.

? Other safety considerations:?Immunogenicity assessments for biologics, abuse liability for centrally acting drugs, and evaluations for cardiac valvulopathy in 5HT2 receptor agonists remain consistent with the 2007 guidance.

The guidance also clarifies that some loss of lean mass is expected in weight reduction. It states: “Reduction of fat mass has typically accounted for 60% to 90% of weight reduction, and the accompanying reduction in lean mass has not been considered adverse.” Body composition should still be measured in a representative sample using DXA or a suitable alternative to ensure weight reduction primarily involves fat loss.

10. Statistical considerations:

The 2025 guidance addresses challenges such as high dropout rates and intercurrent events (e.g., discontinuation of treatment or use of prohibited medications). It also allows for the use of alternative estimands if justified by the sponsor to address a meaningful clinical question of interest, such as the on-treatment effect. However, the default recommendation remains the treatment policy estimand, where all participants are analyzed regardless of intercurrent events, consistent with the intent-to-treat (ITT) principle.

In summary, the updates in the FDA’s 2025 guidance integrate key lessons from major clinical development programs, such as STEP and SURMOUNT. These changes incorporate findings from recent trials, including the demonstrated efficacy of higher weight loss thresholds (≥10%, 15%, and 20%) and the importance of a sustained weight reduction accompanied by clinically meaningful improvements in obesity-related comorbidities. The new guidance reflects a significant shift in the treatment of obesity, recognizing it as a complex disease with multiple interconnected clinical manifestations rather than a simple issue of weight loss. It provides tailored recommendations for diverse patient populations and places greater emphasis on improving overall health outcomes beyond weight reduction alone.