[authors: James S. Cohen, Glenn Engelmann, and Michael W. Ryan]
In an attempt to improve the predictability, consistency and transparency of the medical device review process, the U.S. Food and Drug Administration (FDA) recently released final guidance describing the principal factors the agency will consider when making benefit-risk determinations during the premarket approval and de novo classification processes, respectively. In this newsletter, we provide a brief summary of the final guidance document and describe some of its implications.
Scope of the Final Guidance
The final guidance applies to both diagnostic and therapeutic devices that are subject to premarket approval (PMA) or de novo classification petitions. This represents a shift from the scope of the draft guidance, which addressed the factors for PMA devices and, “in limited cases, [for] devices subject to premarket notification (510(k)) requirements,” but did not address the factors for devices that are the subject of a de novo classification petition.
FDA states the contents of the final guidance should be considered during the design, non-clinical testing, pre-Investigational Device Exemption (IDE) and IDE phases, as well as in assembling and assessing PMAs or de novo petitions. Under the Federal Food, Drug, and Cosmetic Act, sponsors of low- to moderate-risk devices that have been determined by FDA to be not substantially equivalent to a predicate device may submit a petition to the FDA requesting de novo classification and marketing authorization for the device.
Types of Scientific Evidence that Will Be Considered During Risk-Benefit Analysis
Unsurprisingly, FDA states it puts a “great deal of emphasis” on results obtained using clinical testing methods (e.g., randomized controlled trials, well-controlled investigations, testing on clinically-derived human specimens). However, FDA acknowledges that, in certain situations, non-clinical data (e.g., data generated by performance testing for product safety, reliability and/or characterization, computer simulations) may play an important role in demonstrating the safety and effectiveness of a medical device, as medical devices often have attributes that cannot be tested using clinical methods alone. As such, both clinical and non-clinical data may be useful in demonstrating the safety and/or effectiveness of a device.
Factors FDA Considers in Making Benefit-Risk Determinations
In the final guidance, FDA groups into three categories the factors the agency will use when making benefit-risk determinations: the factors to be used in assessing the benefits of devices, the factors to be used in assessing the risks of devices, and additional factors to be used in the assessment of the probable benefits and risks of devices.
In assessing the benefits associated with the use of a device, FDA will consider:
With respect to the assessment of risks, FDA will take the following factors into account:
Appendix B of the final guidance includes a worksheet that clearly summarizes the above-listed factors that reviewers will use in making benefit-risk determinations as part of the PMA or de novo classification process. Appendix C provides useful examples of how reviewers might utilize the worksheet in the review of products. As such, these appendices provide a clear roadmap for device manufacturers to follow and may facilitate smoother approval of innovative devices.
In issuing this helpful final guidance, FDA indicates a commendable willingness to undertake a more flexible and transparent approach to benefit-risk determinations, at least as to devices subject to PMA and de novo review. The multi-factor approach to benefit-risk assessment described in the final guidance, if appropriately implemented, will enable FDA to conduct an individualized assessment of each medical device subject to PMA or de novo classification. Moreover, by explicitly stating the criteria FDA will use to assess the above-referenced submissions, device manufacturers should be better able to anticipate the types of data they will need to submit to support a PMA or de novo petition.
In particular, the final guidance is notable in that it indicates FDA is willing to consider a patient’s informed request to utilize a device as evidence that such device should be made publicly available—even in situations where the agency might otherwise consider such device to be too risky. In recent years, FDA has been the subject of some criticism for declining to approve products intended to treat serious or chronic conditions when it deems them to raise issues relative to their risk. Although it remains to be seen whether FDA will consider patient risk tolerance data to be persuasive, the final guidance represents, at minimum, a nominal step toward embracing broader benefit-risk factors and potentially increasing patient access to innovative medical devices.