On March 28, 2012, the Food and Drug Administration (FDA) published written guidance (the Guidance) on the benefit-risk analysis undertaken by FDA staff in determining medical device premarket approval (PMA) and de novo classifications. The purpose of the Guidance is to improve “the predictability, consistency, and transparency of the premarket review process.” The Guidance represents the first time that the FDA has explained in writing the principal factors that the FDA considers when making benefit-risk determinations in the premarket review of medical devices. Beginning on May 1, the FDA’s Center for Devices and Radiological Health will begin applying the Guidance to “incoming PMA and de novo submissions and to submissions already under review with decisions.” Currently, there are three pathways for a medical device to be approved for use in treating or diagnosing conditions in humans: (1) the PMA application; (2) de novo classification petitions; and (3) the 510(k) program. The Guidance only addresses the first two methods.  

Current Law Requires a Benefit-Risk Analysis of Scientific Evidence to Determine Safety and Effectiveness of Medical Devices

Under Section 513(a) of the Federal Food, Drug & Cosmetic Act (the Act), in considering PMA applications, the FDA must determine whether such applications provide a “reasonable assurance of safety and effectiveness” by “weighing any probable benefit to health from the use of the device against any probable risk of injury or illness from such use.” In support of this analysis, the FDA will only consider “valid scientific evidence” (as defined in the Act) to determine whether the device “will have the effect it purports or is represented to have under the conditions of use prescribed, recommended or suggested in the labeling of the device.” While the FDA relies heavily on clinical data in making this evaluation, it will also weigh non-clinical testing including animal and cell-based studies and computer simulation.  

Similarly, under Section 513(f)(2) of the Act, for devices that are determined to not be substantially equivalent under the 510(k) program, sponsors may submit a de novo petition requesting that the FDA make a risk-based classification determination in order to grant marketing authority. De novo petitions assert that all risks associated with the device are well understood and therefore can be mitigated appropriately (as opposed to PMA applications, which typically involve higher risk-reward trade-offs). Accordingly, these devices need not confer as substantial a benefit to patients, and therefore the threshold for approval is lessened. Nonetheless, the Guidance applies equally to the PMA and de novo processes.

Factors the FDA Considers in Making Benefit-Risk Determinations  

The FDA examines several factors related to the benefits and risks of medical devices as well as a host of related issues that may color the analysis and sway the balance in one direction or the other. There is no precise formula that a sponsor can concoct in order to guarantee approval. Rather, the analysis is as much art as science. The FDA will examine each device on its own merits, taking into consideration the particular indication, patient population, alternative treatments, and other matters that might make the device approvable. In the end, the question is whether, on balance, the device is likely to do more good than harm, acknowledging no device is perfect and that risk never can be completely eliminated.

With regard to the benefits the FDA considers, it examines the type of benefits, the magnitude of the benefits, the probability of a patient experiencing one or more of the benefits, and the duration of the beneficial effects. For devices that treat disease, the analysis does not end at reducing probability of death or severity of symptoms. The quality of life of the patient, including loss of function, are important criteria to be weighed, especially when viewed over the patient’s expected lifetime. With regard to diagnostics, identification remains key, but devices that aid in predicting future onset of disease or that provide earlier diagnosis are also viewed as providing appreciable benefits.  

In assessing risks of devices, the FDA examines the severity, type, number and rates of harmful events associated with the use of the device, as well as the probability and duration of such harmful events. Procedure-related complications are included in this analysis. In addition, the aggregate effect of multiple minor harmful events is weighed when considering the likely use of the device in combination with other treatments. False-positive and false-negative results are also considered with diagnostic devices.

Finally, the FDA will consider other factors that are not necessarily device-specific, including: (1) degree of uncertainty, (2) characterization of the disease, (3) patient tolerance for risk and perspective on benefit, (4) availability of alternative treatments/diagnostics, (5) risk mitigation, (6) postmarket data, and (7) whether the device represents a novel technology addressing an unmet need.  

While the Guidance goes into significant detail regarding each of these factors, a few highlights are worth mentioning. Particular attention is paid in the Guidance to the patient tolerance for risk and perspective on benefit, and the FDA encourages sponsors who are considering developing data concerning patient risk tolerance and other patient-centered metrics “to have early interaction with the appropriate FDA review division” due to the many factors that impact this data. The Guidance notes that these assessments should take into account the patient’s willingness or unwillingness to use a device or tolerate risk. Because some patients are willing to take on much higher degrees of risk than others, even for relatively small benefits, the FDA will consider “evidence relating to patients’ perspective of what constitutes a meaningful benefit … as some patients may value a benefit more than others.”

Certainty of risks and less impactful benefits are viewed less narrowly when there are no better alternatives or where the device is particularly novel. In these situations, the FDA recognizes that as long as the overall probable benefit outweighs the probable risks, there is value in trying novel approaches in order to encourage innovation and provide expanded patient access to new devices.  

Worksheet for Benefit-Risk Assessments

To aid FDA staff in reviewing and analyzing the benefit-risk factors, the FDA has created a worksheet and provided it as an appendix to the Guidance. In addition, the Guidance works through several hypothetical examples to reach a conclusion on whether to recommend approval for a fictitious device. The worksheet is particularly helpful in providing a systematic mechanism to highlight the determining factors for device review. The worksheet can be found at: www.fda.gov.