CDRH Issues Draft Guidance on Substantial Equivalence Determinations

By Jennifer D. Newberger –

To finish out a year in which the Center for Devices and Radiological Health ("CDRH") issued what appeared to be an unprecedented number of draft guidance documents, CDRH issued two more on December 27, 2011.  This blog post discusses one such draft guidance, titled “The 510(k) Program:  Evaluating Substantial Equivalence in Premarket Notifications [510(k)].”  A primary purpose of the draft guidance is to clarify certain critical points in the substantial equivalence decision-making process, and to do so, the draft guidance proposes a new decision-making flowchart.  It also updates the approaches to the Special 510(k) and the Abbreviated 510(k) programs.  If finalized, this draft guidance document could potentially have a more significant impact on the 510(k) notification process than any of the other draft guidance documents issued this year, since it addresses the heart of the 510(k) program:  how FDA determines substantial equivalence. 

Perhaps most interesting is CDRH’s attempt to do away with its longstanding acceptance of “split predicates,” with nothing more than a conclusory statement in a footnote.  A split predicate refers to a situation in which a manufacturer is attempting to “split” the 510(k) decision-making process by demonstrating that a new device has the same “intended use” as one marketed device and the same “technological characteristics” as a second marketed device.  In its 510(k) Working Group Preliminary Report and Recommendations (Preliminary Report), CDRH stated that it should “explore the possibility of explicitly disallowing the use of ‘split predicates.’”  Rather than “exploring” this possibility, the draft guidance document states in footnote 15 that the use of a split predicate “is inconsistent with the 510(k) regulatory standard.”  It does not explain how it reached this conclusion.  Perhaps by changing its longstanding approach to split predicates in a footnote, CDRH hoped the change would go unnoticed.  We hope that, by pointing it out, this policy reversal can at least be “explored” before being finalized.

While the draft guidance officially does away with split predicates, it introduces a new concept called “reference devices,” stating that, in certain circumstances, “a manufacturer may refer to legally marketed devices that have a different intended use or different technological characteristics that raise different questions of safety and effectiveness, to address specific scientific questions for a new device.”  In other words, reference devices may be used “to address certain performance characteristics of the new device.” 

The draft guidance is clear that a reference device is not a predicate device, which raises the question:  if it is not a predicate device, what is it, and why is it permitted?  The statute allows comparison to a predicate device, not to a reference device.  The draft guidance states that the reference device scenario is “very complicated,” and therefore FDA “will need to rely on its scientific and regulatory expertise to determine when this scenario may be applied.”  While the draft guidance provides one illustrative example, it is not clear when a reference device may be appropriate, or what factors FDA will consider in making this determination, giving FDA broad leeway to accept—or, perhaps more importantly to industry, reject—a reference device at its discretion.

Although the draft guidance indicates that FDA will continue to permit multiple predicates, “FDA recommends that the manufacturer identify the primary predicate device to which a substantial equivalence claim is being made” (emphasis added).  Perhaps in exchange for requiring that of the 510(k) submitter, FDA will require itself to “clearly cite the predicate device relied upon in determining substantial equivalence.”  Additionally, the submitter “should identify each device and explain why more than one predicate or a reference device” is necessary and appropriate to support substantial equivalence.  Of course, because the draft guidance does not describe the circumstances in which either multiple predicates or a reference device may be appropriate, such justification may be difficult.

The draft guidance also attempts to clarify the distinction between “intended use” and “indications for use,” and states that the intended use “encompasses the indications for use.”  It also describes how CDRH determines intended use, and seems to take an approach slightly different from that described in the statute.  Section 513(i)(1)(E)(i) of the Federal Food, Drug, and Cosmetic Act ("FDCA") states that a determination of the intended use of a device “shall be based upon the proposed labeling submitted in a report for the device under section 510(k).”  The statute does not allow for consideration of information outside the proposed labeling in determining the intended use of a device.  Nevertheless, the draft guidance states that “FDA may rely upon publicly-available scientific information or Agency knowledge about how a disease progresses to determine whether indications for use to treat a certain disease or anatomical site constitute a new intended use.”   Not only does this go beyond FDA’s statutory authority, but allowing FDA to use “Agency knowledge” to determine the intended use of a device without providing scientific support will only further hinder the transparency and predictability of FDA’s decisions.

Finally, the draft guidance addresses whether differences in technological characteristics raise different questions of safety and effectiveness, stating: “A ‘different question of safety or effectiveness’ is a question raised by the technological characteristics of the new device that was not applicable in the 510(k) for the predicate device, and poses an important safety or effectiveness concern for the new device.”  The draft guidance includes examples of differences in technological characteristics that it believes raise different questions of safety and effectiveness.  It seems, however, that whether the questions are “different” just depends on how the question is phrased.  For example, FDA states that there are different questions of safety and effectiveness for a new device made of “significantly different materials and processes” than the predicate.  In explaining why the questions of safety and effectiveness are different, the draft guidance asks questions very specific to the new material, rather than more a more general question about whether the material might negatively interact with the body.  It seems like the latter question could lead to a conclusion that there are not different questions of safety effectiveness, while the former will.  If FDA poses the questions such that they are too specific to the new technology, it seems that there will nearly always be different questions of safety and effectiveness.  By virtue of having new technological characteristics, there will be specific questions not raised by the predicate.  This should not necessarily preclude a finding of substantial equivalence.

As with all the draft guidance documents issued this year, it remains to be seen whether FDA gives any weight to the comments submitted, what the guidance will look like when finalized, and how FDA will implement it.