On March 27, 2012, FDA announced the release of a final guidance document, “Factors to Consider When Making Benefit-Risk Determination in Medical Device Premarket Approval and De Novo Classifications.” (A copy of FDA's March 28, 2012 Federal Register notice announcing the guidance is available here.) Considering that FDA only released the draft guidance in August 2011, the issuance of the final guidance is remarkably fast. Despite the speed with which FDA finalized this guidance, it seems to do a good job of addressing industry concerns with the draft guidance, and setting forth reasonable standards for benefit-risk determinations.
The one area in which the guidance falls short is its scope. Unlike the draft guidance, which stated that, at least in “limited cases,” the benefit-risk determinations would be applicable to 510(k) notifications as well as premarket approval applications (“PMAs”), the final guidance applies only to PMAs and de novo petitions. While the application of this guidance to de novo petitions will benefit sponsors who know upon submitting a 510(k) notification that the product will ultimately have to be brought to market via a de novo petition, and could therefore include benefit-risk information in the 510(k) submission, this is not always the case. If a sponsor does not have this knowledge, it likely will not have put forth the risk-benefit discussion in its 510(k) submission. This further supports current congressional proposals that would allow for an early determination of the appropriateness of a de novo review.
Notably absent from this scope are 510(k) notifications. Because the vast majority of devices are brought to market through the 510(k) process, and because FDA regularly engages in benefit-risk determinations in its 510(k) decision-making process, it is not clear why the scope of the final guidance is more limited than that of the draft. If FDA will be applying a different framework for considering the benefits and risks of devices cleared via the 510(k) process, it will be important for FDA to provide insight into that process as well.
The limited scope appears to be the one major area in which the final guidance takes away from the draft. Otherwise, it addresses several of the concerns expressed by industry about benefit-risk determinations in response to the draft guidance. Of note, the guidance states that “a ‘probable risk’ and ‘probable benefit’ do not include theoretical risks and benefits, and instead are ones whose existence and characteristics are supported by valid scientific evidence.” This statement is significant, and seems designed to respond to assertions by sponsors that reviewers sometimes cite hypothetical risks unsupported by data as the basis for not approving or clearing a device. Whether this practice will change as a result of this position in the guidance remains to be seen.
Additionally, while the draft guidance only briefly addressed patient tolerance for risk, the final guidance contains substantial discussion of patient tolerance for risk as well as perspective on benefit. Including the perspective on benefit demonstrates FDA’s awareness that patients will not only consider risk in making their decisions about product use, but will also consider the benefits that may be achieved, despite the associated risk. In this discussion, FDA acknowledges that “risk tolerance will vary among patients, and this will affect individual patient decisions as to whether the risks are acceptable in exchange for a probable benefit.” The guidance further notes that “FDA would consider evidence relating to patients’ perspective of what constitutes a meaningful benefit when determining if the device is effective, as some set of patients may value a benefit more than others.” Perhaps most importantly in this regard, the guidance states that “it may be appropriate to approve a device where only a minority of the intended patient population would accept the risks as weighed against the benefits if the information necessary for patients and health care practitioners to make well-informed decisions is available and can be presented in a manner that can be understood by the practitioners and patients.” By incorporating this discussion of patient tolerance for risk and perspective on benefit, FDA is recognizing that patients and practitioners should ultimately be responsible for determining whether a certain risk is acceptable for that particular patient in light of the potential benefits.
The guidance also would allow use of validated surrogate endpoints, rather than direct endpoints, for measuring clinical benefit, and notes that “FDA may consider the collection of postmarket data as a way to clarify the magnitude and effect of mitigations or as a way to develop additional information regarding benefits or risks for certain device types or in specific patient populations when making a benefit-risk determination.” This use of postmarket data may alleviate some of the premarket data burdens of sponsors. Of course, FDA has long had the ability to reduce premarket data requirements through postmarket data collection, but has made sparing use of that authority.
In general, this guidance has the potential to be very useful to sponsors of PMAs and de novo petitions, though unfortunately the same cannot be said for sponsors of 510(k) notifications. FDA’s implementation of the guidance will, of course, determine its ultimate value.