FDA finalizes guidance on weight-loss devices: Five things manufacturers need to know

In a December 2012 article in Surgical Endoscopy, FDA reviewers proposed a benefit-risk paradigm for clinical trial design of weight-loss devices. The paradigm had four risk levels, each linked to progressively higher effectiveness targets measured by percentage of total body loss (TBL). That proposal grew out of a 2011 FDA co-sponsored workshop and a 2012 advisory panel meeting, and is the conceptual precursor to the final guidance, now titled Medical Devices with Indications Associated with Weight Loss – Premarket Considerations.

Manufacturers planning pivotal studies and premarket submissions should take note of these five elements from the final guidance:

1.  The effectiveness thresholds are unchanged from the draft guidance—but represent a significant shift from the 2012 paradigm.

The final guidance retains the co-primary effectiveness endpoint framework from the September 2023 draft without material change. FDA recommends that manufacturers design pivotal studies around the following requirements:

• Superiority margin. For a “weight loss” indication, FDA recommends at least a 5% superiority margin for mean percentage of total body weight loss (TBWL) over control. For “limited weight loss,” at least 2%. For “weight management,” less than 2% may suffice if the responder rate endpoint is also met.
• Responder rate. FDA recommends that at least 50% of treated participants achieve at least 5% TBWL, applicable across all weight-loss indication categories.

The 2012 paradigm set escalating effectiveness targets directly linked to four device risk levels—ranging from 5% mean TBL at six months for the lowest-risk devices to 13% mean TBL over sham at three years for the highest-risk devices. The final guidance replaces that risk-tiered effectiveness approach with indication-specific thresholds that are uniform across risk levels: the same 5% superiority margin applies to any “weight loss” device regardless of whether it is a low-risk oral appliance or a higher-risk intragastric balloon. Instead, FDA addresses risk tolerability through the evaluation matrices discussed below.

2.  Four indication categories drive study design and duration.

Table 5 of the final guidance carries forward the draft’s four distinct indication categories, each defined by the combination of demonstrated weight loss and duration of device use:

These categories are identical to those in the draft. Manufacturers should also note that a separate “obesity treatment” indication requires endpoints showing clinical benefits beyond weight loss alone (e.g., improvement in comorbidities), and a “weight management” indication may apply to devices used for less than six months or with benefit below the thresholds above.

The final guidance also specifies how “duration of device use” is measured for different device types—for implantable devices, it is the total time in the body; for devices that transiently alter anatomy, it is the terminal time point at which weight loss is measured; and for devices used on a recurring basis, it is the course of time the device is used before measuring results.

3.  The evaluation matrices are the central benefit-risk decision aid.

Figure 1 of the final guidance retains the draft’s four evaluation matrices, which pair each of the four weight-loss indications against a modified Clavien-Dindo adverse event classification system. Once again, this reflects a shift from the 2012 proposal, which used a 12-category adverse event taxonomy with risk levels defined by the percentage of patients experiencing each event type during the first year after device placement.

The matrices use a shading system—from light, indicating favorable, to dark, indicating unfavorable—to signal FDA’s likely view of the “weight loss to adverse event profile.” Importantly, the device’s overall risk is characterized by the cell of greatest risk; the guidance states that the “cell with the darkest shading suggests the outcome of the decision aid.”

The guidance describes these matrices as “only one part of FDA’s assessment.” FDA states it will also consider the additional factors set forth in Table 4 of the final guidance, including uncertainty, patient preferences, alternative therapies, additional clinical data, and post-market data.

4.  The final guidance consolidates clinical and non-clinical recommendations into one document.

One of the most notable structural changes between draft and final is the merger of clinical and non-clinical content. The September 2023 draft addressed only clinical study design and benefit-risk considerations, with a separate companion draft covering non-clinical testing. The final guidance brings both together and articulates in detail FDA’s expectations for bench and pre-clinical testing for weight-loss devices. FDA recommends early engagement through the Q-Submission Program to confirm that testing plans align accordingly.

5.  Several refinements from draft to final are worth noting.

Although the core clinical and benefit-risk provisions are largely consistent between the draft and final, several changes merit attention:

• Expanded exclusion criteria. The final guidance adds “syndromes associated with recurrent vomiting” to the recommended exclusion for history of dysmotility and delayed gastric emptying. It also adds a new recommended exclusion for “[p]ersons without access to adequate follow up to monitor device safety and/or function.”
• New language on modified intent-to-treat (mITT) analysis. The final guidance adds a paragraph stating that, “in general,” FDA considers mITT analysis to be “a supportive analysis” and that estimates based on an mITT population “may not be generalizable to the overall intended use population.” FDA recommends that submitters using mITT analysis include a study-specific definition for the mITT group and use the Q-Submission Program if they intend to propose mITT as their primary analysis.
• Removal of “gender” from demographic and subgroup analysis recommendations. The draft recommended enrollment of participants from “sex, gender, age, ethnic, and racial” groups, and recommended “gender and sex-based subgroup analyses.” In accordance with administration executive orders, the final guidance removes “gender” from both provisions.
• Sham control clarification. FDA continues to recommend a sham-controlled study but now only “[w]here scientifically feasible”—a modest softening from the draft’s approach, though FDA now particularly recommends a sham control for “first-in-kind devices.”

One notable omission is a lack of discussion of GLP-1 medications in clinical study design and analysis. The introduction and popularity of these medications has complicated ongoing clinical studies of multiple medical devices intended for weight loss indications in recent years. In addition, a reluctance to report use of these medications by some subjects can complicate analyses. FDA has focused closely on GLP-1 use in device studies, thus the silence in the guidance is unexpected.

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For device manufacturers, the final guidance provides a clear and consolidated regulatory roadmap for both non-clinical and clinical testing for weigh loss devices after more than a decade of evolving expectations. The benefit-risk framework—from the indication-specific effectiveness thresholds to the evaluation matrices—is now the reference for pivotal study design.

If you have questions about how the final guidance may affect development of your weight-loss device, please contact the authors or your usual Hogan Lovells medical device and technology attorney.

Authored by Kristin Zielinski Duggan and Megana Sankaran