In issuing these new draft guidance documents, the FDA has followed through on its plan to further update the 510(k) clearance pathway.

The FDA recently released three draft guidance documents that aim to “modernize” the 510(k) premarket notification process. This process permits medical device manufacturers to market a new device in the United States provided that they can show it is “substantially equivalent” to a device that has already been cleared by the FDA (i.e., a “predicate device”). The 510(k) clearance pathway is used for the vast majority of devices that the FDA reviews as it recognizes a balance between promoting innovation and patient safety. Starting in 2018, the agency began to express an intent to modernize the pathway while still ensuring a proper balance of the dual aims of innovation and patient safety.

In issuing these new draft guidance documents, the FDA has followed through on its plan to further update the 510(k) clearance pathway. A summary of these documents and an assessment of their practical implications for the 510(k) process is provided below.

Best Practices for Selecting a Predicate Device

The first document, “Best Practices for Selecting a Predicate Device to Support a Premarket Notification [510(k)] Submission,” outlines four best practices that 510(k) submitters should follow when choosing a predicate device:

“Well-Established Methods”

The FDA recommends that submitters select a predicate device that was cleared using “well-established methods.” The guidance provides a nonexhaustive list of the kinds of methods the FDA has in mind, such as those from an “FDA-recognized voluntary consensus standard, an FDA guidance document, a qualified medical device development tool (MDDT), or a widely available and accepted method published in the public domain or scientific literature… or found acceptable through the submitter’s own previous premarket submission.” In noting these methods, the guidance stresses that 510(k) submitters should stay abreast of changes to the methods used to evaluate the predicate device—methods are often subject to revision, and those that had previously been used to clear a predicate device may no longer be appropriate in light of new advances in testing.

“Meet or Exceed Expected Safety and Performance"

The guidance further states that it is a best practice for a predicate device to “meet or exceed expected safety and performance” in its intended use environment. Specifically, the “FDA recommends selecting a valid predicate device after considering how any reported medical device-related adverse events, malfunctions, or deaths may [impact] the safety and effectiveness of the device.” This expectation effectively requires submitters to continually be on the lookout for new information about the predicate device’s use and whether any safety concerns have arisen since its commercial distribution. To this end, the FDA recommends that submitters search its databases (e.g., the Manufacturer and User Facility Device Experience Database or MedSun Reports) for information about potential adverse events.

No “Unmitigated Use-Related or Design-Related Safety Issues”

The guidance also recommends selecting predicate devices that do not have any “unmitigated use-related or design-related safety issues.” This best practice calls upon manufacturers to look for new information about a device’s safety and effectiveness. In particular, 510(k) submitters should be on the lookout for any emerging safety signals announced on FDA webpages. An “emerging signal” is new information about a device that supports (but does not conclusively establish) a causal connection between that device and a set of adverse events. To the extent that a device is mentioned in an emerging signal notification, the guidance suggests that manufacturers should not choose it as a predicate.

Not Associated with a “Design-Related Recall”

Finally, the guidance provides that a predicate device should not be associated with a “design-related recall.” This recommendation encourages 510(k) submitters to search the FDA’s databases for any information on associated recalls. For example, if one of the materials used in the design of the device is subject to recall, this would be an associated recall that would bring into question selecting that device as a predicate.

While these best practices are not intended to introduce any changes to relevant regulatory standards, they do propose a new process for predicate device selection and evaluation that may well alter the 510(k) process in practice. For instance, while submitters are not currently required to do anything onerous to justify their choice of predicate device, the best practices indicate that submitters will need to spend much more time justifying their predicate device choices. Specifically, the guidance suggests that submitters could demonstrate compliance with the best practices by including a table in their submission detailing how each valid predicate device under consideration meets (or does not meet) each of the four best practices. Notably, the guidance contemplates a scenario where no valid predicate device accords with the best practices, and in such cases the FDA recommends that the submitter describe “how any known concerns with the valid predicate device have been mitigated with the subject device.” In other words, the submitter would have to articulate how its own device improves upon (and is not just substantially equivalent to) the predicate device in question.

In addition, while these best practices are intended to be voluntary recommendations rather than rigid requirements, it is unclear whether the FDA will effectively require conformity with them in practice. For instance, if 510(k) submitters fail to provide evidence that they searched relevant databases for updated product safety information or fail to demonstrate how they used the best practices to select a particular predicate device as opposed to a different device, it is an open question whether the FDA will require more information before completing its review.

Recommendations for Use of Clinical Data

The second document, “Recommendations for the Use of Clinical Data in Premarket Notification [510(k)] Submissions,” outlines four main scenarios where clinical data may be necessary to support a 510(k) submission. This development is significant because the FDA has typically only requested clinical data in a minority of 510(k) submissions. The four scenarios are as follows:

Differences in Indications for Use

When there are differences between the indications for use of the new device and the intended use of the predicate device, clinical data may be necessary to determine substantial equivalence. Under these circumstances, the FDA will consider the following factors to determine whether clinical data is needed: differences in patient population (e.g., if a new device is intended for a higher risk population, clinical data may be required); differences in the target disease; differences in anatomical site, structure or pathology; and expansion of the new device’s currently cleared indications for use.

Differences in Technological Characteristics

Differences in technological characteristics between a new device and a predicate device may also warrant clinical data to establish substantial equivalence. Such differences may include significant changes in materials, device design, energy source and other device features.

Substantial Equivalence Cannot Be Determined by Nonclinical Testing

Where nonclinical testing is inappropriate for a particular device, 510(k) submitters should submit data from clinical testing. The guidance lists the following considerations to determine whether nonclinical testing is insufficient: where there is no model (e.g., analytical, bench or animal) available; where a model is available but has certain limitations that do not allow for adequate assessment; where the model may not be predictive of clinical outcomes; and where there are anatomical or pathophysiological species-specific questions that rely upon clinical evidence.

Newly Identified or Increased Risk for the Predicate Device

Finally, where new information arises regarding the risks associated with a predicate device, the FDA may request clinical data in support of a 510(k) submission.

Evidentiary Expectations for Implant Devices

The third document, “Evidentiary Expectations for 510(k) Implant Devices,” provides generally applicable recommendations for implants where a 510(k) is required. This draft guidance outlines various questions that submitters should consider when determining the evidence they may need to demonstrate substantial equivalence, such as the intended duration of the implant, the indications for use of the device, clinical performance testing, nonclinical testing, and patient and physician experience information. For example, performance testing should be tailored to the intended duration of the implant in question—testing requirements for implants that are meant to be replaced repeatedly may be different than testing for implants that are expected to degrade over longer periods of time. Likewise, submitters should consider using patient and physician experiences to bolster their risk assessments and performance testing. They should consider, for example, whether certain features of their devices increase risks associated with everyday activities (as reported by patient experience) relative to the predicate device.

Implications

At this point, these documents are just draft guidance—they have been issued only for the purpose of public comment. However, if implemented, the documents have the potential to impact the 510(k) process in a number of ways. For one, the best practices for selecting a predicate device would call on submitters to provide more information than is currently required to establish substantial equivalence; indeed, in cases where no valid predicate satisfies these best practices, submitters may well have to demonstrate how their device is superior to the predicate device in terms of product safety. For another, the guidance documents demonstrate a clear emphasis on prioritizing clinical data in some cases. Finally, it remains to be seen whether these purportedly voluntary recommendations will ultimately evolve into de facto requirements for 510(k) submitters going forward.

For More Information

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