As it has in previous guidances, FDA attempts to provide “a flexible, patient-centric, benefit-risk approach” that is “tailored to the type and intended use of the device and the type of decision” required.

The Food and Drug Administration recently issued draft guidance entitled “Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions.” Comments to this draft guidance should be provided by December 5, 2018.

FDA provides authorization for marketing a device when its benefits outweigh its risks. Uncertainty surrounding these benefits and risks is a factor that FDA considers when making its determination with respect to premarket approval application (PMA) approvals, de novo classifications, 510(k) clearances, humanitarian device exemption (HDE) approvals and investigational device exemption approvals. As it has in previous guidances, FDA attempts to provide “a flexible, patient-centric, benefit-risk approach” that is “tailored to the type and intended use of the device and the type of decision” required. For example, PMA and de novo requests require a demonstration of reasonable assurance of safety and effectiveness. However, HDE applications inherently have a greater uncertainty surrounding the benefit-risk profile as Congress provided that these applications need not show a reasonable assurance of effectiveness as the patient population is generally very small.

As always, FDA considers the totality of evidence regarding benefits and risks for the device, as well as the type of decision and its context, the extent of uncertainty and the applicable patient population’s willingness to accept that uncertainty. Uncertainty can include the type, magnitude, duration, frequency and other aspects of a device’s benefits and risks. For example, for de novo requests, the risks associated with the device will play a larger role in analyzing uncertainty; however, greater uncertainty with respect to benefits may be acceptable for a device due to its nature or with imposition of special controls. 

FDA provides a list of several factors it will use in determining appropriate uncertainty depending on the circumstances:

• The extent of probable benefits of the device;
• The extent of probable risks of the device;
• The extent of uncertainty as to the benefit-risk profile of alternative treatments or diagnostics;
• If available, patient perspective on appropriate uncertainty;
• The extent of public health need;
• The feasibility of generating premarket clinical evidence;
• The ability to reduce or resolve uncertainty postmarket;
• The effectiveness of postmarket mitigation;
• The type of decision being made; and
• The probable benefits of earlier patient access to the device.

FDA will also consider the appropriateness of risk mitigation and use of postmarket data to address these uncertainties, depending on the context. In some cases, resolving or reducing uncertainty postmarket may not be warranted (e.g., HDE pathways, extent of uncertainty is small, minimal risk to patients, postmarket data collection is not feasible or other postmarket controls may address uncertainty). 

For breakthrough devices subject to PMA, FDA may accept greater uncertainty when there are greater public health benefits to early patient access or where the likelihood of timely postmarket data may be collected (provided the statutory standards for premarket approval are met—known as “premarket-postmarket data shift”). In these cases, FDA may use one or more postmarket controls, such as postmarket studies (as listed on FDA’s website), labeling requirements, inclusion of certain information in the summary of safety and effectiveness data, (SSED) and advisory committee meetings. 

When postmarket studies are required as a condition to approval, FDA plans to make the timely collection and submission of data a condition of approval. This can be done through a registry or other use of “real-world data” sources. Further, FDA may require that the device’s labeling describe the postmarket data collection and its purpose. FDA may also include this information in the SSED and flag the postmarket studies on its website. 

Once sufficient postmarket data is provided, FDA will make appropriate changes to the SSED and inform sponsors they may change the device’s labeling to reflect the new information. However, if FDA has questions on whether the data still supports the reasonable assurance of safety and effectiveness of the device, it will hold an advisory committee meeting. After the advisory committee meeting, FDA may issue a withdrawal order, place restrictions on the sale and distribution of the device, or narrow the device’s indications of use. Conversely, if postmarket data is not generated or submitted within the specified timeframe, FDA intends to take appropriate administrative or enforcement action.

For devices for small patient populations subject to PMA, FDA understands that it is generally infeasible or highly resource- and time-intensive to generate extensive clinical evidence premarket. In these situations, the disease or condition is generally rare and patients are often unlikely to have alternative therapeutics or diagnostics available to them. Some options for dealing with the uncertainty in these situations may include “smaller premarket data collection with larger postmarket data collection and other postmarket controls, greater premarket data collection with smaller postmarket data collection and no or fewer other postmarket controls, or even greater premarket data collection with no or little postmarket data collection and other postmarket controls.”

Some examples are included in the guidance for demonstrative purposes only.

Overall, FDA recognizes that there are many different ways for sponsors to demonstrate reasonable assurance of safety and effectiveness and strongly encourages sponsors to discuss potential programs with FDA early in the process. FDA also suggests meetings to establish appropriate and reasonable time frames for submission of postmarket data and to determine how to “appropriately characterize postmarket data collection and its purpose and other circumstances associated with their applications.” Therefore, where there is a concern that uncertainty will be an issue for getting approval of a device, sponsors should take advantage of presubmission meetings and other opportunities to meet and discuss any potential concerns and issues with FDA.

For Further Information

If you have any questions about this Alert, please contact Frederick R. Ball, Carolyn A. Alenci, any of the attorneys in our Life Sciences Group or the attorney in the firm with whom you are regularly in contact. 

Disclaimer: This Alert has been prepared and published for informational purposes only and is not offered, nor should be construed, as legal advice. For more information, please see the firm's full disclaimer.