The latest efforts by the U.S. Food and Drug Administration (FDA) to modernize regulation of the 510(k) program come in the form of a trio of new draft guidance documents regarding its Premarket Notification program for medical devices, otherwise known as the 510(k) program. The three guidances are titled:
- Best Practices for Selecting a Predicate Device to Support a Premarket Notification [510(k)] Submission;
- Recommendations for the Use of Clinical Data in Premarket Notification [510(k)] Submissions; and
- Evidentiary Expectations for 510(k) Implant Devices.
These guidance documents come in the midst of increasing device complexity and continued questions about the rigor of 510(k) standards. They also represent a continuation and revisitation of FDA's 2018 proposal to modernize the 510(k) program.
Importantly, these guidances are in draft form, meaning that FDA is requesting comment on the guidances and has not formally determined its policy, but they do inform the public about FDA's general expectations for implementation of the 510(k) program internally and by other stakeholders and the industry in general. The deadline for public comments is December 6, 2023.
Predicate Selection Guidance
"Best Practices for Selecting a Predicate Device to Support a Premarket Notification [510(k)] Submission" ("Predicate Selection Guidance") revisits the question of how medical developers can select an appropriate predicate. FDA noted a large volume of comments received in response to its 2018 proposal that focused on the age of predicate devices and acknowledged there can be benefits to an established track record. Instead, the new guidance takes a more nuanced approach and suggests a further narrowing of a list of "valid predicate" devices by considering the list of legally marketed devices that (1) have the same intended use as the subject device and (2) do not raise different questions about safety and effectiveness with respect to any technological differences. Once a list of valid predicates has been made according to the two criteria above, additional best practices should be used to narrow predicate selection. These practices include:
- Selecting a valid predicate device that was cleared using "well-established methods," meaning that, for example, submitters should prioritize predicate devices cleared using voluntary consensus standards, subject to public comment or peer review, etc. FDA also "recommends conducting a search of the nonclinical tests submitted, referenced, or relied on in the 510(k) submission to support a determination of substantial equivalence."
- Selecting a valid predicate device that continues to perform safely and as intended. FDA suggests searching several FDA databases for reports of unexpected injury, deaths, or malfunctions.
- Selecting a valid predicate that does not have "unmitigated use-related or design-related safety issues, including consideration of emerging signals or safety communications." For example, this includes new information about a causal or known association between a device and an adverse event that FDA has initially evaluated, to determine whether it affects the benefit-risk profile of the device. An additional search of certain FDA databases is further recommended.
- Selecting predicate devices that have not been subject to design-related recalls.
Finally, FDA recommends that 510(k) submissions include a discussion of how the predicate device was chosen and the extent to which the submission followed the draft guidance.
Practice Tip: If the proposed predicate device cannot satisfy some (or all) of the new "best practices" criteria, the 510(k) submission should explain how the subject device mitigates any known concerns about the predicate device (e.g., change in design features, performance testing).
Clinical Data Guidance
"Recommendations for the Use of Clinical Data in Premarket Notification [510(k)] Submissions" ("Clinical Data Guidance") suggests general scenarios in which clinical data may be necessary to determine substantial equivalence. At present, FDA considers scientific evidence when determining whether a device is substantially equivalent to a predicate device in a 510(k) submission when it is necessary to evaluate "data comparing the technological characteristics of the new device to the predicate device, data assessing whether a change in the indications for use results in a different intended use, or data supporting the assessment of the benefit-risk profile of a new device to demonstrate that the new device is as safe and effective as a predicate device." In this guidance, FDA specifies four scenarios in which clinical data may be necessary:
- Differences in indications for use, including differences in the intended patient population; differences in the disease, anatomical site, structure, or pathology; expansion of the currently cleared indications for use; and an unknown or different benefit-risk profile for the proposed indications for use.
- Differences in technological characteristics, including a significant change in materials, design, energy source, or other device features.
- Where substantial equivalence cannot be determined by nonclinical testing, such as where there is no animal model available, or the limitations of the existing nonclinical model do not allow for an adequate SE assessment, or where it may not be predictive of clinical outcomes, and anatomical questions remain outstanding that necessitate clinical evidence.
- Newly identified or increased risk for the predicate device, such as where a predicate device is the subject to the unexpected adverse events; predicates should in fact not be used where they exhibit new or increased risks, but FDA outlines specific example scenarios where FDA may consider additional data to support substantial equivalence where no alternative predicate devices are available.
Practice Tip: While some of the scenarios in this guidance are relatively straightforward, others are more subjective. Sponsors may ask FDA questions about the need for clinical testing for specific devices in a pre-submission request.
Implant Device Guidance
"Evidentiary Expectations for 510(k) Implant Devices" ("Implant Device Guidance") contains general principles that can help guide submissions for implantable devices, which warrant special consideration, given the scientific and clinical considerations that implants often raise. FDA outlines in detail the considerations submitters should bear in mind regarding the data used to support 510(k) submissions for implanted devices, highlighting the intended duration of implantation and types of risks that are inherent with any implant (e.g., risks associated with everyday activities, risks of revision or reoperation).
The guidance also identifies nonclinical issues that are generally relevant to 510(k) implants, including (1) biocompatibility; (2) sterility and shelf life; (3) reprocessing and cleaning; (4) software and cybersecurity; (5) electrical safety and electromagnetic compatibility; (6) magnetic resonance compatibility; (7) other nonclinical performance testing; (8) animal testing; and (9) design considerations. Finally, the guidance considers how human factors testing, clinical performance testing, patient experience information, and labeling should be addressed in 510(k) submissions for implants.
Practice Tip: While the regulation defines an "implant" as a device that is "intended to remain implanted continuously for a period of 30 days or more" (21 CFR §860.3(d)), FDA intends to apply the principles in this draft guidance more broadly. The guidance recommends that submitters of devices implanted for fewer than 30 days also consider the recommendations, and notes that the amount of data needed to support a substantially equivalent determination may vary, based on intended duration of implantation. Here, too, developers should consider judicious use of a pre-submission request to clarify the expectations for their device.