Originally published March 29, 2012
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 update 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.