Doctors’ groups share concerns about FDA draft guidances for developing weight-loss devices

Two US Food and Drug Administration (FDA) draft guidances for sponsors developing weight-loss devices have received scrutiny from medical associations concerned about the agency’s treatment categorization and approach to benefit-risk recommendations.

FDA’s draft guidances include recommendations for clinical and non-clinical studies, and benefit-risk analyses for devices with weight loss indications. The draft guidances contain recommendations for devices with product codes for intragastric implants, aspiration therapy systems, neuromodulators, and specific ingested space-occupying devices, with an eye towards potentially including additional product codes and classification regulations later (RELATED: FDA weight-loss device guidances address clinical and non-clinical studies, Regulatory Focus 18 September 2023).

More specifically, FDA recommended sponsors conduct randomized controlled trials, keeping indirect staff supporting those studies blinded when possible. For clinical trials involving foreign data, the agency recommended sponsors should use no more than half of data in pivotal studies from outside of the US, and to limit enrollment at study sites to no more than 20% of the total study population. In studies with a potential placebo effect, FDA recommended using sham-controlled studies, or a concurrent control arm in situations where sham controls are not feasible.

Groups of medical societies made their concerns to the agency known in a set of joint public comments. In one joint comment, the Obesity Action Coalition (OAC) and the American Society for Metabolic and Bariatric Surgery (ASMBS) said they were appreciative that the agency was considering benefit-risk analyses for weight-loss devices, but emphasized that a continuum of care is needed for treating obesity.

“Use of language quantifying ‘weight loss’ treatment as short-term or long-term when applied to devices might not reflect real world care,” according to their submitted comments. “A device might remain only inside the patient for a few months and be short-term, but how it fits into an overall comprehensive (and therefore long-term) plan should also be considered.”

OAC and ASMBS also suggested FDA use a staging system for care that includes patients who are well and for whom obesity has a small impact, and those who are sick for whom obesity might have a high impact.

A joint comment from the Association for Bariatric Endoscopy, American College of Gastroenterology, American Gastroenterological Association and the American Society for Gastrointestinal Endoscopy (ASGE) criticized FDA’s approach for benefit-risk analyses, arguing that the questions posed by the agency related to benefit “are confounded by a glaring problem with benefit categorization.”

“Overall, these recommendations might profoundly and negatively impact the perception of ‘benefit’ from these trials to patients and their care teams in practice,” they said.

The medical associations took issue with FDA’s recommendations for sham controls in clinical studies, noting that the agency’s statement could be interpreted to mean FDA would require sponsors to conduct randomized controlled trials with sham controls in situations where it is feasible. They also argued that concept of using a categorization scheme to compare open-label studies and sham-controlled studies is flawed, using the example of weight-loss device studies with a sham-control design to highlight the potential for misclassifying devices and leading to inaccurate benefit categorization.

For instance, some devices like the ReShape Intragastric Balloon used in the REDUCE study and Obalon balloon system used in the SMART trial had similar rates of weight loss in treatment arms, and both devices would be placed in the FDA’s Short-Term Weight Loss category, and “held to higher safety standards” than the Orbera intragastic balloon in the unblinded Orbera Balloon Study “solely based on trial design, not true clinical benefit,” the groups noted in their comments.

“Sham-controlled studies expose both the treatment arm and the control arm with risk but provide decreased benefit in the treatment arm compared with clinical practice and very little benefit in the control arm,” the medical associations argued. “Moreover, initial weight loss may have long-term effects on weight loss maintenance extending well beyond the immediate benefit-risk paradigm, resulting in far-reaching effects on industry sponsors—those who are able to perform open-label studies (compared with sham studies) will likely be able to report higher weight loss in their labeling despite similarity among devices in actual practice.”

FDA should instead use an open-label control arm study design if the agency wants to move forward with the benefit categorization system as outlined in the draft guidances, they said.

Members of industry also weighed in on the draft guidances. Medical technology company Apollo Endosurgery noted in their comment that the agency should use the defined threshold of efficacy developed by the ASGE and ASMBS to evaluate an endoscopic bariatric therapy in their assessment of weight-loss device benefit-risk framework.

Apollo Endosurgery also noted that obesity treatment will vary depending on factors such as disease stage, comorbidities, and current manifestations. “Physicians will need and should have a menu of options to choose from. We have learned from longstanding positive experiences with both short-term and long-term weight loss devices inside and outside the US that these are important menu choices for the managing physician,” they wrote.

Medical technology company Neurovalens asked the agency to consider the ratio of fat to lean muscle mass, rather than weight loss, as a metric for considering the criteria for a device. A patient does not benefit from losing weight from muscle mass, they said, and “the focus on weight loss prejudices against neuromodulators that target the set-point and generate a shift towards a leaner physique with less fat, more muscle and potentially denser bones.”

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Doctors’ groups share concerns about FDA draft guidances for developing weight-loss devices

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