Authors: Gerald L. Klein, MD; Roger E. Morgan, MD; Johannes Wolff, MD; Freddy Byrth; Marion Stamp-Cole; Melissa Palmer, MD

Developing Drugs for Obesity and Weight loss

The general recommendation for a sample size to assess the safety of a weight-reduction drug is 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. Sponsors developing multiple dosing regimens should consider a randomization scheme that assigns more subjects to higher doses and are encouraged to discuss the overall size of the safety database with the Agency at or before the end of Phase 2.[1] In addition to these safety considerations, sponsors should align with FDA guidance recommending at least one unsuccessful attempt at lifestyle modification (e.g., diet and exercise) prior to enrollment and should consider removing the ≥5% long-term weight loss requirement as a singular efficacy benchmark. Inclusion of electronic Clinical Outcome Assessments (eCOA) and validated Quality of life (QOL) measures as secondary endpoints is also advised to support potential labeling claims. Furthermore, sponsors are encouraged to propose a pediatric sub-study to address the pressing issue of childhood obesity and explore opportunities for pediatric exclusivity through regulatory pathways that may support patent extension.[2]
The recommended sample size will provide 80% power to detect, with 95% confidence, an approximately 50% increase in the incidence of an adverse event that occurs at a rate of 3% in the placebo group (i.e. 4.5% vs. 3%).
This sample size would also allow for efficacy and safety analyses to be conducted within important subgroups such as age, sex, race, ethnicity, and baseline BMI, provided that a sufficient number are enrolled in each of these groups.

For all products

We recommend strategic refinement to the traditional FDA requirement of two well-controlled Phase 3 clinical trials. Specifically, we propose a hybrid development and approval model designed to maintain scientific rigor while enhancing speed to market and real-world relevance demonstrating robust and statistically significant results. Notably, the FDA has previously granted approval based on a single pivotal study in certain high-need indications, such as Elzonris, approved for blastic plasmacytoid dendritic cell neoplasm (BPDCN) based on a single Phase 2 trial of 94 patients, and Lumoxiti, approved for relapsed/refractory hairy cell leukemia based on a single-arm, open label Phase 3 trial of 80 patients.[3] These examples demonstrate that regulatory flexibility exists when the benefit-risk profile is compelling. We suggest the following approach:
- Primary Pivotal Trial: Conduct one well-controlled Phase 3 trial demonstrating statistically robust efficacy, safety and tolerability under traditional randomized, controlled conditions. This trial would serve as the primary basis for conditional approval.
- Conditional Approval Linked to real-World Validation: Upon successful completion of the pivotal trial, conditional approval would be granted with a clear commitment to complete a second Phase 3 trial within a defined timeframe. This second trial would be designed to:
  - Incorporate real-world evidence (RWE) methodologies (e.g., pragmatic design, broader inclusion criteria, decentralized elements).
  - Provide confirmatory data on effectiveness, safety, and tolerability in routine clinical practice.
  - Serve as a tool for refining labeling, guiding post-marketing surveillance, and supporting payer decisions.

This two-step model offers several advantages:

Accelerates access to promising therapies for patients in need.
Incentivizes real-world accountability through mandatory confirmatory RWE trials.
Mitigates risk by anchoring initial approval to high-quality evidence while ensuring continued scrutiny.
Aligns with FDAs evolving openness to RWE and flexible development frameworks (e.g., as reflected in 21st Century Cures Act and FDAs guidance). This approach has the potential to accelerate approvals, prevent the approval of ineffectual medications and provide greater safety and tolerability of actual real-world events.[4]

planned protocol deviations

Planned protocol deviations should be avoided in clinical trials to maintain scientific integrity and regulatory compliance. However, in certain complex settings, such as oncology or cell and gene therapy trials, predefined deviations may be necessary due to the individualized nature of treatment or logistical constraints. In such cases, advanced Institutional Review Board (IRB) approval must be obtained, and the rational clearly documented on the protocol or amendment to ensure ethical oversight and participant safety.[5]

References:

https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pediatric-drug-development-regulatoryconsiderations-complying-pediatric-research-equity-act-and?utm
U.S. Food and Drug Administration. Drug Trial Snapshot: ELZONRIS. FDA website. Published December 21, 2018. Accessed July 2, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-elzonris
Burns L, Roux NL, Kalesnik-Orszulak R, Christian J, Hukkelhoven M, Rockhold F, Khozin S, O’Donnell J. Real-world evidence for regulatory decision-making guidance from around the world. Clinical Therapeutics. 2022;44(3):420-437. doi:10.1016/j.clinthera.2021.12.013.
U.S. Food and Drug Administration. Protocol Deviations – A Regulatory Perspective: Draft Guidance for Industry. Silver Spring, MD: FDA; April 2024. Available at: https://www.fda.gov/media/184745/download.