The article describes in detail the approach to be applied with respect to clinical performance testing considerations including, inter alia, the ones associated with treatment parameters and protocols, safety and effectiveness endpoints and data, as well as adverse events
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The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a draft guidance document dedicated to medical devices with indications associated with weight loss.
In particular, the document covers the aspects related to clinical study and benefit-risk considerations. Once finalised, the guidance will provide an overview of the applicable regulatory requirements, as well as additional clarifications and recommendations to be taken into consideration by medical device manufacturers and other parties involved in order to ensure compliance thereto.
At the same time, it is important to mention that provisions of the guidance are non-binding in their legal nature, nor are they intended to introduce new rules or impose new obligations.
Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the existing regulatory framework and has been agreed with the authority in advance.
Treatment Parameters and Protocols
When planning a study-specific treatment protocol, the primary concern should be to minimize any risks to the patients involved.
This protocol should not only focus on the dangers related to the device itself and its placement but also any supplementary risks that could affect the entire group of patients participating in the study.
An example cited is the inclusion of patients with comorbidities such as Type 2 Diabetes Mellitus (T2DM).
For patients with T2DM, it’s essential to have a safety monitoring plan in place, focusing on the early detection and management of both hypoglycemia and prolonged uncontrolled hyperglycemia.
A system for adjusting or stopping the use of oral hypoglycemics or insulin, guided by fasting glucose or HbA1c levels, should be integrated for those patients who experience significant weight loss.
When a device is new or when its risk profile is not yet defined, the study might benefit from stipulated stopping rules.
Such stipulations can also include the phased enrollment of patients, starting with a limited number, to manage associated risks better.
If the device under study is a permanent implant, the design must factor in the process of its removal if such a need arises either during the study or at its conclusion.
The study should provide clear instructions on the explant process, track the reasons for any device removal, and ensure that these instructions are continually evaluated as the study progresses.
In addition, participants should continuously receive the standard of care throughout the study, including necessary medication and monitoring for associated comorbidities.
Safety and Effectiveness Endpoints
The primary safety endpoint is the documentation of all adverse events related to the device and the procedure.
All adverse events will be considered in evaluating the device’s premarket submission.
The effectiveness of weight loss is typically gauged by the percentage of total body weight loss (% TBWL).
Depending on the device’s purpose — whether for weight loss, limited weight loss, or weight management — different superiority margins over control have been suggested.
For weight loss, a minimum of 5% superiority margin over control is recommended, 2% for limited weight loss, and possibly less than 2% for weight management.
Another crucial criterion is the responder rate, which should ideally see at least 50% of the treated subjects achieving a 5% TBWL.
Secondary effectiveness indicators are also important.
These include metrics such as percent excess weight loss, weight change, BMI alterations, and changes in waist circumference.
Furthermore, capturing patient-reported outcomes (PROs) and patient preference information (PPI) is highly advised since it offers a more comprehensive understanding of how patients perceive the treatment’s risks and benefits.
Another valuable assessment criterion involves tracking changes in weight-related comorbidities.
These changes are typically viewed as secondary endpoints in weight loss-related device studies.
If these secondary endpoint analyses are intended to either support the device’s indicated use or describe its performance, it is vitally important to specify these intentions in the study protocol, complemented by a thorough description of the planned statistical methodologies.
The recommendation is to ensure that all adverse event data is diligently collected during the study.
Each event should be thoroughly evaluated to assess if it relates to the device and/or the procedure. In most cases, the authority recommends having a Data Safety Monitoring Board (DSMB) and setting up an endpoint assessment/adjudication committee.
Independent data monitoring committees play a pivotal role in ensuring participant safety by offering a comparative analysis of accumulated data on safety and effectiveness.
A recommended system for adverse event classification is modeled after the Clavien-Dindo Classification of Surgical Complications.
This classification grades adverse events based on the treatment required. The grading includes five levels:
- Grade I: Minor deviations from the normal treatment course that don’t require significant interventions.
- Grade II: Situations needing pharmacological treatment with prescription drugs.
- Grade III: Scenarios requiring surgical, endoscopic, or radiological interventions.
- Grade IV: Life-threatening complications demanding intensive care.
- Grade V: The most severe issues.
This classification focuses on deviations from a device’s standard treatment course.
As explained by the authority, it is essential to understand that each type of adverse event can fall under different grades, depending on the treatment required.
Finally, the recommendation is that all adverse events be presented in a specific format during premarket submissions.
This format includes the categorization of events, identification of unanticipated adverse device effects, time to onset, and duration of events, especially for gastrointestinal-related ones.
Device removals and their reasons should also be addressed properly.
Non-serious adverse events can be assessed using patient-reported outcome instruments, such as the gastrointestinal symptom scales provided by the National Institutes of Health (NIH) PRO Measurement Information System (PROMIS).
In summary, the present FDA guidance highlights the aspects to be considered when developing study protocols and also provides additional clarifications with respect to study endpoints, as well as on the way adverse events should be treated.
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