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In furtherance of the Transparency Initiative launched in 2009, the FDA published its first ever guidance document on benefit-risk analysis for medical devices. This groundbreaking document is the first to attempt an explanation of the sometimes nebulous benefit-risk analysis that forms the cornerstone of FDA approval. The self-proclaimed purpose of the guidelines, which will take effect on May 1, is to “improve the predictability, consistency, and transparency of the premarket review process.”

Unfortunately, the guidance does not address the most commonly used (and debated) regulatory pathway—510k notification. Under the 510k process, medical device manufacturers need only demonstrate that their device is substantially equivalent to a legally marketed device. If a manufacturer of a class III medical device cannot demonstrate substantial equivalence, the device must undergo the cumbersome Premarket Approval (PMA) process. For class I or II devices with no substantial equivalent on the market, they are automatically deemed a class III device and must be approved through the de novo process.

Although the published draft of the guidelines encompassed all three pathways, the final guidelines are limited to the latter two—PMA and de novo submissions. Given the controversy over the legitimacy of the 510k process, it is somewhat surprising that the FDA did not attempt to enhance transparency of this process as well. The exclusion of the 510k process from the final version of the document may be an implied concession that the FDA does not believe that a risk-benefit analysis is relevant to 510k submissions, in spite of language in the governing regulations requiring evidence of safety and effectiveness for some 510k devices.

For PMA and de novo devices, the guidance lists a number of vague but intuitive factors to consider in the benefit-risk analysis. In assessing benefits, the FDA will look to the type of benefits imparted by the device, the magnitude of those benefits, the probability that the patient will experience those benefits, and the duration of the effects. Similarly, the assessment of risks encompasses the harmful events associated with the device, the probability of a harmful event, the duration of the harmful event, and, in the case of diagnostic devices, the risk arising from false positive or false negative results.

The guidance emphasizes that the FDA will consider only scientific data in assessing risks and benefits, not “theoretical risks and benefits.” It defines scientific data as encompassing clinical and non-clinical data, and suggests that non-clinical data may even be more relevant than clinical data for demonstrating long-term effects. Although it has long been the case, the guidance confirms that the manufacturer’s agreement to provide postmarket data through post-marketing studies and surveillance can also constitute part of the approval process under appropriate circumstances.

In addition to the standard benefit-risk analysis, the FDA will consider a list of “additional factors,” many of which open the approval process to patients. Notably, the guidance allows for patient input on their risk tolerance, and indicates that the FDA may even be willing to approve a device that many patients would perceive as too risky so long as all patients are provided with sufficient information about the risks to make a well-informed decision. The FDA will also consider the severity of the disease the device is intended to diagnose or treat. Patients with more severe conditions and fewer treatment options are presumed to have a higher risk tolerance than patients with less severe conditions.

Given the breadth of the factors to be considered and the absence of insight into the FDA’s previous benefit-risk calculation, the impact of this first ever guidance is difficult to predict. Perhaps the most helpful information is the extensive list of examples applying the suggested risk-benefit analysis to a variety of factual scenarios, attached at the end of the document. Although, like all FDA guidance, the document merely “contains nonbinding regulations,” the examples may prove to be very instructive for companies with similar profiles.

This advisory was prepared by the Life Sciences practice group at Nutter McClennen & Fish LLP. For more information, please contact your Nutter attorney at 617-439-2000.

This advisory is for information purposes only and should not be construed as legal advice on any specific facts or circumstances. Under the rules of the Supreme Judicial Court of Massachusetts, this material may be considered as advertising.