On July 28, 2014, the U.S. Food and Drug Administration (FDA) finalized its guidance, The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] (Final Guidance), the draft version of which was released two and a half years ago, on December 27, 2011 (2011 Draft Guidance) and discussed in ourJanuary 12, 2012 Medical Device Alert. This document supersedes the FDA’s 1986 guidance, CDRH Premarket Notification Review Program, 510(k) Memorandum K86-3, and provides insight into the FDA’s current review practices for premarket notification (510(k)) submissions.

The principles outlined in the Final Guidance are largely carried over from the 2011 Draft Guidance, with additional clarifying information and examples provided. The major differences between Final Guidance and the 2011 Draft Guidance boil down to the following:

  • While the 2011 Draft Guidance addressed the Special and Abbreviated 510(k) Programs, these programs are not discussed in the Final Guidance. The FDA intends to finalize guidance on these programs separately.
  • The Final Guidance includes a more fulsome discussion of the Least Burdensome Principle, which was articulated in the FDA Modernization Act of 1997 and updated after the 2011 Draft Guidance was issued by the FDA Safety and Innovation Act of 2012.
  • The Final Guidance includes an updated discussion of the 510(k) review process, which affirms that in most cases, the FDA will issue a request for additional information to allow manufacturers to address the agency’s concerns regarding the equivalency of a new device’s intended use or technology. Furthermore, once a complete response is received, the FDA will work with the manufacturer to try to resolve remaining deficiencies interactively.  
  • The Final Guidance clearly states that the use of a “split predicate” is inconsistent with the 510(k) regulatory standard and provides additional guidance on the appropriate use of multiple predicate devices and “reference devices,” which is a concept first articulated in the 2011 Draft Guidance.
  • The Final Guidance includes four appendices: (A) 510(k) Decision-Making Flowchart, which is slightly modified from that in the 2011 Draft Guidance; (B) The 510(k) Summary Document Requirements; (C) Sample of 510(k) Summary Complying with 21 C.F.R. 807.92; and (D) Glossary of Significant Terms.

Just weeks before releasing the Final Guidance, on July 15, 2014, the FDA released a completely new draft guidance impacting the 510(k) Program and substantial equivalence determinations, entitled, Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notification [510(k)] with Different Technological Characteristics (Draft Benefit/Risk Guidance). The stated purpose of the Draft Benefit/Risk Guidance is to assist the FDA reviewers in making substantial equivalence determinations during the 510(k) premarket review process at the point in the 510(k) review process when it has been determined that a new device has different technological characteristics from the predicate device, but that those differences do not raise new questions of safety or effectiveness.

Taken together, these guidance documents provide industry with further insights into the FDA’s decision-making process in connection with determining whether a new device is substantially equivalent to a legally marketed predicate device.

Background

To be cleared via the 510(k) pathway, pursuant to Section 513(i) of the Federal Food, Drug, and Cosmetic Act (FDC Act), a new device must be found substantially equivalent (SE) to a predicate device. To be found SE, the new device must have the same intended use as the predicate and either the same technological characteristics as the predicate, or, if different technological characteristics exist, those differences cannot raise different questions of safety and effectiveness than those of the predicate device. Additionally, information submitted in the 510(k) notice must demonstrate that the device is as safe and effective as the legally marketed device.

When different technological characteristics are presented by a new device, performance data may be necessary to assess the safety and effectiveness of the new device as compared to the predicate device. To demonstrate that a new device is as safe and effective as a predicate, data from performance testing using accepted scientific methods (i.e., bench tests, animal studies or clinical investigations) is submitted in the 510(k) notice. The FDA reviews the data to determine whether the data demonstrate equivalence as compared to the predicate for the proposed indications for use.

FDA’s Determination of Substantial Equivalence

The Final Guidance affirms the FDA’s process for determining the intended use of a new device and assessing whether that intended use is the same as, or different from, that of the predicate device, as articulated in the 2011 Draft Guidance. Similarly, the agency’s process for identifying the technological characteristics of the new device and its predicates, as well as determining their differences and assessing whether those technological differences raise different questions of safety or effectiveness, have been affirmed by the Final Guidance. The Final Guidance also clarifies the appropriate selection and use of predicate devices to support a determination of substantial equivalence.

The Final Guidance stresses the FDA’s preference for manufacturers to identify a single predicate device with indications for use and technological characteristics similar to that of the new device. The Final Guidance also clearly states that “split predicate” arguments, or the use of one predicate with the same intended use and different technological characteristics and a second predicate with the same technological characteristics and different intended use as compared to the new device, is inconsistent with the 510(k) regulatory review standard and will not be accepted. This position is consistent with recent FDA review practices but is at odds with the agency’s approach from 1986 to at least 2009.

While “split predicate” arguments will not be accepted, the FDA has articulated the appropriate use of multiple predicates to support substantial equivalence. The Final Guidance indicates that multiple predicates can appropriately be used to support the substantial equivalence of a new device when combining the technological features of two or more predicates that have the same intended use, or when seeking more than one indication for use under the same broad intended use. The FDA has articulated several examples in the Final Guidance to illustrate this principle.

Both the Final Guidance and the Draft Benefit/Risk Guidance clarify the FDA’s decision-making at the point in the 510(k) review process when it has determined that a new device has different technological characteristics from the predicate device, but that those differences do not raise new questions of safety or effectiveness. At this point, the agency must determine the acceptability of the proposed scientific methods for evaluating the effects of the new or different technological characteristics on the overall safety and effectiveness of the new device as compared to the predicate. To aid in this determination, the Final Guidance indicates that a manufacturer may wish to use a “reference device” to direct the agency’s attention to similar situations that it has previously addressed via the 510(k) pathway. The Final Guidance clarifies that reference devices are not considered predicate devices; reference devices appropriately may be used to support the acceptability of the scientific methodology or standard reference values proposed by the company to demonstrate the substantial equivalence of new technological characteristics of the device that do not raise different questions of safety or effectiveness when compared to the predicate device. Several examples to illustrate the appropriate use of reference devices are provided in the Final Guidance. The reference device concept is a new approach proposed by the FDA with no direct foundation in the statute or regulations.

At this point in the substantial equivalence analysis, the Draft Benefit/Risk Guidance steps in and provides that the FDA will consider a number of risk and benefit factors to assess whether the new device is as safe and effective as the predicate device. The Draft Benefit/Risk Guidance clarifies that a new device may be found substantially equivalent to a predicate device even if there are differences in the risks and benefits presented by the new device as compared to the predicate. For example, a device with a decreased benefit as compared to the predicate device may be found substantially equivalent if it is still reasonably beneficial and also presents fewer risks than the predicate device. Similarly, a device having somewhat increased risks as compared to the predicate may be found substantially equivalent if it also presents increased benefits; however, if the risks are sufficiently increased, the device may still be found not substantially equivalent (NSE), despite the increased benefits of the device.

Per the Draft Benefit/Risk Guidance, the agency will consider the following factors in assessing the probable benefits of a new device described in a 510(k) notice:

  • types of benefits
  • magnitude of benefits 
  • probability of the patient experiencing one or more benefits 
  • duration of effects

With respect to risk, the FDA will consider the following factors in assessing the extent of the probable risks of using a new device being evaluated via the 510(k) pathway:

  • severity, types, number and rates of harmful events associated with the device
  • probability of a harmful event 
  • probability of the patient experiencing one or more harmful events 
  • duration of harmful events 
  • risk from false-positive or false-negative results for diagnostics 
  • aggregate effect of adverse events

In addition to enumerating the factors it will consider in assessing risks and benefits, the Draft Benefit/Risk Guidance provides additional factors the FDA may also consider, such as the following:

  • uncertainty 
  • characterization of disease/condition 
  • patient tolerance for risk and perspective on benefit 
  • benefit for the healthcare professional or caregiver 
  • risk mitigation 
  • postmarket Data 
  • innovative technology

Discussion

The Final Guidance affirms the concepts and standards for the substantial equivalence decision-making process originally articulated in the 2011 Draft Guidance, including a definitive statement that “split predicate” arguments are inconsistent with the 510(k) review standard. It also affirms the agency’s novel concept of a “reference device,” which was first articulated in the 2011 Draft Guidance, and clarifies that the FDA will rely on such “reference devices” only in assessing the acceptability of the scientific methods proposed in a 510(k) notice for determining whether a new device with different technological characteristics that do not raise different questions of safety or effectiveness is as safe and effective as the predicate. While the Final Guidance largely formalizes what has become agency practice since the release of the 2011 Draft Guidance, the affirmation of the concepts and standards originally set forth in the 2011 Draft Guidance can be expected to lead to continued preclusion of the 510(k) pathway for a fair number of devices that would otherwise not have raised any questions under prior guidance and practice. It is this new approach on substantial equivalence that has led to an increase in the NSE rate from a historically low rate of 2% to over 10% in the current environment.

With respect to the various factors presented in the Draft Benefit/Risk Guidance that the FDA intends to consider in assessing the risks and benefits of medical devices when making substantial equivalence determinations, such factors are consistent with the benefit-risk factors the agency considers in its review of premarket approval (PMA) applications and de novo classification requests, as set forth in the March 28, 2012, guidance entitled Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approvals and De Novo Classifications (PMA and De Novo Guidance). Indeed, the Draft Benefit/Risk Guidance notes the parallels between the factors, but also highlights that, unlike with PMAs and de novo classifications, the Draft Benefit/Risk Guidance calls for an evaluation of benefits and risks of the new device as compared to the predicate device.

Consistency of the factors aside, while the Draft Benefit/Risk Guidance specifically states that it “does not change the 510(k) premarket review standard or create extra burden on a submitter of a 510(k) to provide additional performance data from what has traditionally been submitted during the review process for 510(k) submissions,” arguably, the application of a risk/benefit assessment to substantial equivalence determinations introduces a new concept to the standard. Section 513(i) of the FDC Act, which specifically addresses the assessment of substantial equivalence, does not contain specific language calling for a weighing of probable benefits against probable risks.

There is no doubt that a number of the factors enumerated in the Draft Benefit/Risk Guidance are routinely, and in many cases, appropriately considered as part of an assessment of performance data that has been submitted in a 510(k) notice to support that the new device is as safe and effective as the predicate. However, it is not clear how the evaluation of benefits and risks of a new device as compared to the predicate device will not, in practice, extend beyond the standard that the device be as safe and effective as the predicate, and introduce some flavor of clinical utility into the mix.

Finally, as noted earlier, the new FDA approach to substantial equivalence, especially the denunciation of split predicates, has led to a significantly higher rate of NSE findings. The FDA has indicated that the higher NSE rate is not of great concern because the subject device may, in many cases, proceed through the de novo process. It remains to be seen whether the increased NSE findings will prove a major hindrance to the 510(k) process.

Interested parties may submit comments on the Draft Benefit/Risk Guidance document until October 14, 2014, referencing Docket No. FDA-2014-D-0900. Electronic comments can be submitted at http://www.regulations.gov. Written comments can be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD, 20852.