The U.S. Food & Drug Administration (FDA) has released a final guidance document entitled, “Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions.” This document provides information on how the FDA evaluates uncertainty and the appropriate extent of uncertainty in the benefit-risk determination for medical devices that are subject to premarket approval (PMA).

“Uncertainty” in Benefit-Risk Determinations

Medical devices that are subject to premarket approval are required “to have a ‘reasonable’ assurance, rather than an absolute assurance, of safety and effectiveness.” An absolute assurance of safety and effectiveness is not required because there is an unavoidable level of uncertainty when considering the benefits and risks of medical devices. The FDA acknowledges that, “there can be uncertainty around the type, magnitude, duration, frequency, and other aspects of a device’s benefits and risks to patients.” Since uncertainty regarding the risks and benefits of medical devices exists, the final guidance document explains the scope and extent to which uncertainty impacts the benefit-risk determination.

The following is a non-comprehensive list of factors the FDA considers when evaluating uncertainty in benefit-risk determinations:

  • The extent of the probable benefits of the device
  • The extent of the probable risks of the device
  • The extent of uncertainty regarding the benefit-risk profile of approved or cleared alternative treatments or diagnostics or the standard of care
  • Patients’ perspective on appropriate uncertainty about the probable benefits and risks of the device
  • The extent of the public health need
  • The feasibility of generating extensive clinical evidence premarket based on appropriate considerations
  • The ability to reduce or resolve remaining uncertainty of a device’s benefit-risk profile postmarket
  • The likely effectiveness of mitigations
  • The type of decision being made
  • The probable benefits of earlier patient access to the device.

These factors are considered “pragmatic” and “context-dependent.” Therefore, greater uncertainty might be acceptable for one device but not for another. The FDA is willing to consider greater uncertainty with regard to two types of devices: (1) Breakthrough Devices and (2) devices for small patient populations.

Breakthrough Devices Subject to PMA

A Breakthrough Device, which is described in the FDA’s previously released final guidance “Breakthrough Devices Program,” is a medical device that “provide[s] for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions.” In the recent final guidance pertaining to uncertainty, the FDA explains how the nature of Breakthrough Devices and uncertainty affect the FDA’s benefit-risk determinations.

The FDA states that the agency might be willing to accept greater uncertainty in the context of Breakthrough Devices because (1) “of the greater probable public health benefits of earlier patient access,” (2) “patients generally may be more willing to accept greater uncertainty,” and (3) “it may be appropriate to collect additional data in the postmarket setting.” The final guidance explains that the FDA might initially accept greater uncertainty with the mandate that postmarket controls be used to reduce uncertainty in the future.

Timely Postmarket Data Collection

If the FDA initially accepts greater uncertainty with the directive that postmarket controls are to be used to reduce uncertainty in the future, then it is imperative that the “data collected in the postmarket setting [be] reliable, high quality, and collected in a timely manner.” Although the FDA might require a “specific timeframe on the collection of postmarket data,” the FDA also “intends to work with sponsors to determine a reasonable timeframe” for certain devices. Sponsors should consider using registries, which may help to curtail some of the challenges associated with timely obtaining postmarket data.


“Where postmarket data collection is required as a condition of approval to address greater uncertainty in the device’s probable benefits and risks,” the FDA may consider whether “to include as a condition of approval that the device labeling describe the postmarket data collection and its purpose.” This would require sponsors and the FDA to work together “to accurately characterize the postmarket data collection and its purpose” and convey such information to patients.


When the postmarket data that was gathered as a condition of approval to address greater uncertainty calls into question the “reasonable assurance of the device’s safety and effectiveness,” the FDA can “hold an advisory committee meeting.” After the advisory committee reviews the postmarket data and makes its recommendation, the FDA determines the appropriate action. A sponsor may be required to withdraw the device or accept certain restrictions placed “on the sale and distribution of the device” as well as “the device’s indications for use.”

Devices for Small Patient Populations Subject to PMA

In addition, the final guidance explains that the FDA also might be willing to accept greater uncertainty in the context of small patient populations subject to PMA. “While there is not a specific number of patients that would be considered a ‘small patient population,’” the FDA suggests it could apply to “patients with a rare disease or condition or for patients within a clinically meaningful subset of a broader population.” In these cases, the FDA might be willing to accept greater uncertainty with the condition that postmarket controls − such as the timely collection of postmarket data, the disclosure of postmarket data collection and its purpose, and compliance with the FDA’s actions taken at the recommendation of advisory committees − are satisfied. The postmarket controls accounting for uncertainty would be particularly helpful where “it is generally infeasible or highly resource or time intensive to generate extensive clinical evidence premarket” based on “the rarity of the disease or condition,” or where “there is an unmet medical need that is addressed by the device” and “there are no available therapeutics or diagnostics.”


The final guidance provides clarity on an elusive topic: the role uncertainty plays in the FDA’s benefit-risk determinations for the approval of medical devices. Considering the permissible scope and extent of uncertainty will help to “promote the public health by fostering medical device innovation and facilitating timely patient access to high quality, safe and effective medical devices” while allowing “greater transparency, predictability, consistency, and efficiency, using least burdensome principles.”