US FDA Clarifies 510(k) Submission and Substantial Equivalence Requirements
New guidance from the US Food and Drug Administration updates the agency’s recommendations for what to include in 510(k) premarket notification submissions, with particular emphasis on Substantial Equivalence (SE) applications and proper predicate device identification.
Six key steps in the 510(k) SE decision process are laid out in the new guidance:
- Is the applicant’s predicate device legally marketed in the US?
- Do the applicant’s device and its predicate device have the same intended use?
- Do the applicant and predicate devices share the same technological characteristics?
- Do different technological characteristics between the applicant and predicate devices raise questions about safety and effectiveness?
- Are scientific methods used to evaluate new technological characteristics acceptable?
- Do performance data demonstrate substantial equivalence?
Split versus multiple predicates
First, the new guidance lays out examples of when manufacturers may use multiple predicate devices to establish their products’ Substantial Equivalence. Most significantly, the guidance states that 510(k) registrant may no longer use “split predicates” in their SE applications—in other words, an applicant may not claim that its device has the same intended use as one marketed device and the same technological profile as another marketed device to show substantial equivalence. Rather, the FDA asserts that its reviewers must be able to verify SE to just one predicate device; use of split predicates could result in Not Substantially Equivalent (NSE) decisions.
However, the FDA will continue allowing manufacturers to use multiple predicate devices in some instances, but those predicate devices must have the same intended uses. Furthermore, agency reviewers will consider the validity of firms’ multiple-predicate SE applications on a case-by-case basis.
The guidance also emphasizes a sharp distinction between predicate devices and reference devices. Reference devices can be identified by applicants to support acceptable scientific methods. Manufacturers should be aware that FDA reviewers do not consider reference devices acceptable substitutes for predicate devices; applicants must also provide scientific rationale to support their use of reference devices in their SE applications.
Intended use and indications for use
The guidance also identifies criteria used by FDA reviewers to determine when a device’s new indications for use require a new intended use, and when they do not. In general, if new indications for use are found to “significantly affect” a device’s safety and effectiveness, that device will likely need to be ascribed a new intended use.
Examples provided by the guidance of when new indications for use could require new intended use include:
- Changing a functional indication to a treatment indication
- Changing a diagnostic indication to a screening indication
- Changing an indication’s anatomical structure of use
- Changes in patient populations
- Changed clinical contexts or settings
Technological characteristics and descriptions
Manufacturers should be prepared to provide thorough technological details about both their device and their predicate device to FDA reviewers, according to the guidance. These details should include complete descriptions of device designs; materials used, including chemical formulations used in construction materials if necessary; energy sources both for powering a device and for functional aspects; and descriptions of any other relevant features such as software and hardware that should be included in the device description section of a 510(k) submission.
Performance data requests
In some instances, most often for Traditional 510(k) submissions, FDA reviewers require performance data from applicants to show SE to predicate devices. Nonclinical bench performance testing, non-clinical animal and biocompatibility information and non-clinical laboratory studies may be requested from applicants to support their SE claims.
In some cases, FDA reviewers may require clinical performance data for SE determination. According to the guidance, the agency requests clinical data for less than 10% of 510(k) submissions that go through the Office of Device Evaluation. FDA reviewers typically request clinical data for applicants whose devices have the same intended uses as their predicates but different indications for use; devices with significant technological differences from their predicates; and in situations where non-clinical testing methods cannot adequately address questions of safety and effectiveness.
Finally, the guidance explains the FDA’s intention to carefully evaluate 510(k) summary content submitted for SE determinations. Information in 510(k) summaries is displayed on the FDA’s website; the agency is attempting to establish more consistency in the content included in these summaries.
Premarket notification applicants should ensure that their summaries meet all requirements laid out in 21 CFR Part 807.92, and that any requests for additional information or testing be reflected in 510(k) summary revisions.
Bottom line: nothing necessarily new
“This guidance document does not actually provide any new information from our experience submitting 510(k) premarket notifications to the FDA over the last few years,” says Richard Vincins, Vice President of Quality Assurance Consulting at Emergo Group.
“We’re pleased, though, that the new guidance more clearly explains the FDA’s current thinking and expectations. Clearly delineating guidance for use of predicate devices, intended use and performance testing should help registrants provide more consistent 510(k) applications.”