From The Editor | February 7, 2017

50 Shades Of FDA: Some 2017 Guidance Documents Will Require Clarity

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By Bob Marshall, Chief Editor

An Analysis Of FDA FY2016 Drug GMP Warning Letters

In December, the FDA’s Center for Devices and Radiological Health (CDRH) announced its “A-list” of medical device guidance topics for 2017. I was not overly impressed.

Now, don’t get me wrong — I have no desire nor intent to bash the FDA. First of all, the medical device industry has been seeking transparency on the part of the FDA, and efforts like these, where the agency telegraphs its proposed guidance development for the year, provide insight into what the FDA is concerned about, as well as offer some direction as to where regulation is heading. In addition to providing transparency, the FDA has also shown good progress in developing the planned guidance documents. Of the 12 final guidance topics selected for the A-list, the FDA has released final guidance for three of them to date. That’s good progress. There is, however, one thing that caught my eye as I reviewed the A-list topics. Below the seemingly smooth surface of usual-suspect topics lay a trio of guidance initiatives with some real teeth, directives that medical device companies may find difficult, if not impossible, to follow.

Risky Benefits?

Two of the three topics that may present some ambiguity for the medical device industry involve the use of benefit-risk determinations. One is related to Investigational Device Exemptions (IDE), and the other concerns 510(k) clearances when the device under review has different technological characteristics than the predicate device. At first, the concept of using benefit-risk assessment in matters such as these seems like a practical approach to making difficult decisions with an analytical mindset.

It also should be noted the FDA has done well in including numerous example situations in both the now-released final guidance for benefit-risk determination in IDE approvals, and in the draft guidance for benefit-risk factors affecting 510(k) clearance. In spite of these examples, there still will be a considerable amount of confusion.

In Factors to Consider When Making Benefit-Risk Determinations for Medical Device Investigational Device Exemptions, issued as final guidance on Jan. 13, 2017, the FDA wrote, “FDA’s benefit-risk assessment of IDE applications focuses on completeness of risk control measures and whether residual risk outweighs anticipated benefits to the subject.” That is a traditional and conservative statement – very black and white. But, the same guidance document also states, “…absence of definitive evidence of benefit or the presence of purely hypothetical risks are not sufficient justification, in and of themselves, to disapprove an IDE application.” This second statement seems to be at odds with the first, opening the door to interpretation and many shades of gray. It is hard to imagine an IDE being approved for which there is no definitive evidence of benefit to the patient or society.

In a similar manner, Benefit-Risk Factors to Consider When Determining Substantial Equivalence in PreMarket Notifications [510(k)] with Different Technological Characteristics — issued as a draft guidance in July 2014 and slated for finalization this year — provides the potential for relativity where the FDA wrote, “When a new device has technological improvements that are important for public health, we may accept greater uncertainty in an assessment of benefits and risks as compared to the predicate device…to facilitate patient access to these innovative technologies…innovative changes are evaluated on a case-by-case basis….” How will the FDA decide what is truly innovative, and when to accept greater uncertainty? I would expect that most entrepreneurs, investors, and device company executives believe their new devices to provide innovative improvements that are important for public health.

FDA Gets Real

The third A-List topic that may lead to turmoil covers the use of real-world evidence (RWE) in regulatory decision-making. The FDA is looking to provide guidance on how things like case reports, electronic health records, and data contained within medical devices (among other things) may be used to help inform or augment their understanding of a device’s benefit-risk profile at various points in its life cycle.

In Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices, FDA confirms, “…evidentiary standards for regulatory decision-making are not changing.” At the same time this draft guidance document posits, “Analyses of RWD (real-world data), using appropriate methods, may in some cases provide similar information with comparable or even superior characteristics to information collected through a traditional clinical trial.” If RWD provided superior information to a clinical trial, why wouldn’t the agency accept that data in lieu of a clinical trial? And if it did, wouldn’t that be a change in evidentiary standards for regulatory decision-making? These are questions to which medical device companies deserve answers.

If we consider that, in addition to ensuring devices are safe and effective, the FDA is also chartered to foster innovation, then the progressive ideas at work here are very understandable. Inventors, entrepreneurs, investors, and medical device company executives would all appreciate a more practically thinking regulatory approach. However, the question is:  How do we keep the playing field level?

As the FDA makes decisions on a case-by-case basis, it will be difficult for the agency to remain consistent. This will be especially true in the eyes of those submitting IDEs and 510(k) submissions in a highly-competitive environment. Perhaps, when medical device companies pay their establishment registration fee each year, they could be issued three “challenge” flags that could be used for instant replay when IDE or 510(k) decisions do not go their way?