The long-awaited update to the 1997 guidance, Deciding When to Submit a 510(k) for a Change to an Existing Device, was released in draft on August 8. In contrast to its 39-page predecessor, this 73-page document is impressive in the level of detail provided, the much improved flow charts and more extensive examples, and discussion of documentation that should be retained if a manufacturer elects not to file a new 510(k). Whether the ultimate outcome of this draft will be a reduction or increase in the circumstances in which a 510(k) must be submitted for a modification to a cleared device is not entirely clear, but at least this draft guidance provides additional detail that should be useful to manufacturers making that determination.
The draft focuses on conducting risk assessments of the modified device to determine whether a new 510(k) is required, stating, “the assessment of risk in deciding whether to submit a new 510(k) should identify all possible risks, and then focus on risks whose existence and characteristics are supported by objective scientific evidence. It is not necessary to focus on hypothetical risks that are not supported by scientific evidence or those that are determined to be negligible due to both the low probability of occurrence and low severity of harm.” Though it may seem obvious that it is not necessary to consider “hypothetical” risks, this language indicates that manufacturers need not analyze all potential risks that may occur from use of the modified device, but only those “supported by objective scientific evidence.” This sounds like a fairly high bar, and should give manufacturers some level of comfort when contemplating potential risks. How this would be applied in practice is, of course, another question. For example, there may not be agreement what constitutes “low probability” or “low severity.”
This emphasis on risk assessment will cause many companies to rethink how they analyze changes. Under 21 C.F.R. § 807.81(a)(3), the issue is whether a change could significantly affect safety or effectiveness. While there is a linkage between that question and risk assessments, the two approaches are not identical.
The draft guidance also includes a discussion of how to properly document a modification to a 510(k)-cleared device, as well as a sample “Regulatory Change Assessment,” more commonly known in industry as a “Letter to File.” The inclusion of this information should prove useful to manufacturers in preparing these assessments. The draft guidance does make clear that simple “yes” or “no” answers will not suffice. Nor will it be enough just to complete a flowchart, a process many companies follow today.
As for how to determine whether a modification requires a new 510(k), the draft guidance states that “the first question is always whether the change is being made with the intent to significantly improve the safety or effectiveness of the device, for example, in response to a known risk, adverse event, etc. If so, then the change likely ‘could significantly affect the safety or effectiveness’ and a new 510(k) likely must be submitted.” The language about the “first question” implies that this has always been the standard for determining whether a change requires a new 510(k). This is notable, because of course this standard is being introduced for the first time here. This language is not in the regulation, or the 1997 guidance.
The reference to “intent” is new. To the extent that the draft guidance interjects a subjective element – focusing on the manufacturer’s state of mind rather than purely objective factors – it introduces a new factor.
If FDA wishes to take the approach expressed above, further explanation will be needed for how this should work in practice. According to the draft guidance, a manufacturer who learns of a safety issue associated with a product and makes modifications to reduce that risk must submit a 510(k) for that modification. Of course, clearance for that improved, safer version will take at least 90 days, and probably more. So in the interim, is the manufacturer to continue distributing the less safe product, when it knows, through testing, that it has a safer product ready to be marketed?
This quandary would seem particularly troublesome if the marketed product is not per se unsafe, and is performing according to its specifications and operating in conformance with the 510(k) clearance. Manufacturers may be dissuaded from proactively seeking to improve the device since, under the plain language of the guidance, such improvement requires a 510(k), regardless of the results of the validation and verification testing.
The revised guidance is emphatic that a 510(k) is required if the change improves safety or effectiveness. That approach is consistent with the regulation, which refers to a “change” in safety or effectiveness, without regard to direction. Yet it is easy to imagine scenarios where companies will forego making modifications under the guidance because a new 510(k) would be needed. It may well be that the guidance will deter modest incremental innovations by device manufacturers if, for example, a risk assessment shows a modest but identifiable reduction in risk.
Second, unlike the 1997 guidance, this draft explicitly addresses the ever-complex area of a change from a general to more specific use—although not necessarily in a way that provides more certain direction to manufacturers. The draft states that “[m]anufacturers should carefully consider the potential effects on their device’s risk profile in making [a change from a general to specific indication], as they are among the most difficult to assess. If a change of this type has the potential to expand device use to different users, different use environments, use in or on a different type of joint, organ, bone, vasculature, or tissue, use in different patient populations, or new therapeutic or diagnostic uses, it should be evaluated using the guidance provided above.”
It is interesting that the above is framed in terms of “expanding” device use, when the issue often relates to “narrowing” the use—going from a general (more expansive) use to a specific (narrower) use. If FDA considers “narrowing” an indication to be an “expansion,” then there is likely to remain a fundamental disagreement between industry and FDA. FDA is clearly right about one aspect: the general-to-specific changes will remain “among the most difficult to assess.”
FDA’s choice of the word “different” is also worth noting. In common understanding, something that is “different” is something that is not similar to the original object. Promotion of a device for a more specific use would not generally be considered promotion for a “different” use, since the use is incorporated in the general clearance. For example, as we discussed in a prior blog post, in the Vascular Solutions case, the government alleged that the company’s “Vari-Lase” product line could only be promoted for the treatment of superficial veins, and that the company’s promotion for the ablation of “perforator” veins, which connect the superficial vein system to the deep vein system, was outside the scope of the cleared indication. The government lost, at least in part due to the fact that the jury found the specific use was within the scope of the general clearance, i.e., it was not a use for a “different” type of vasculature. It is unlikely that the discussion provided in the draft guidance will prove useful in assessing when a new 510(k) will be needed for a more specific use.
As noted, there are still areas that will require additional consideration before the guidance should be finalized. Nevertheless, this draft guidance appears to be an improvement with respect to the number of examples, flow charts, and more detailed explanations by FDA. At the same time, other elements deserve careful scrutiny, such as the use of subjective intent, the role of risk assessment, and the recurring general vs. specific issue, as well as FDA’s revamped expectations for documentation.