On August 14, 2014, the U.S. Food and Drug Administration (FDA or the Agency) released an updated draft guidance document regarding de novo premarket review applications, De Novo Classification Process (Evaluation of Automatic Class III Designation). The guidance proposes to formally implement changes to the de novo process required by the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012. The guidance document was issued by the FDA in draft form and the Agency will be accepting comments on the proposed guidance until October 14, 2014. These comments will be reviewed and considered by the Agency prior to issuing a final guidance document.

As background, a device that is not otherwise classified by regulation technically defaults to the highest risk (class III) classification. The de novo process allows the FDA to “automatically downclassify” such a device if it is low to moderate risk, and if general controls in combination with special controls (where appropriate) are sufficient to provide a reasonable assurance of safety and effectiveness.

Historically, the FDA allowed for submission of a de novo petition only after a 510(k) premarket notification was found “not substantially equivalent" (NSE) by the Agency and the device was deemed to be a candidate for de novo review. The process was lengthy and cumbersome as it required two in-depth reviews of information related to the device, first in the 510(k) notice and second in the de novopetition. In 2011, the Agency issued a draft guidance proposing to allow companies with products appropriate for the de novo process to submit a parallel 510(k) notice and de novo petition, thus eliminating the sequential review process. Then, Section 607 of FDASIA amended thede novo application process to allow the submission of de novoapplications for low to moderate risk devices without first submitting a 510(k) notice. Since 2012, the FDA has been accepting these so-called “direct de novo” applications, but without formal written procedures for doing so. The FDA has now updated its draft de novo guidance to describe what largely amounts to the process that is currently in place for the submission of such applications. 

In light of the new provisions, the draft guidance outlines two pathways to obtaining de novo reclassification of a device: (1) submission of a 510(k) notice resulting in an NSE determination, provided the device is not addressed in a class III classification regulation, followed by submission of a de novo petition; or (2) the new direct de novoapplication pathway. Note that while the option of first submitting a 510(k) notice followed by a de novo petition remains acceptable, a complete, comprehensive de novo application likely must be submitted regardless of whether it is preceded by a 510(k) notice.

The FDA encourages use of the pre-submission program

Although the Agency is no longer requiring a 510(k) notice in advance of a direct de novo petition, the FDA is now strongly recommending that companies file a pre-submission in advance of a de novo application, particularly for a device that was not previously the subject of a 510(k) notice. This recommendation is consistent with the earlier 2011 guidance in which the FDA required a pre-submission meeting prior to parallel submission of a 510(k) notice and de novo. While the Agency is no longer requiring such a meeting, it is strongly recommended. The FDA notes that the pre-submission process will facilitate the review of a subsequent de novoapplication by allowing the Agency to review whether the de novo process is appropriate for the device, provide the Agency’s preliminary perspective on the likely regulatory controls necessary to provide a reasonable assurance of safety and effectiveness, and provide feedback on the appropriate level of data that will be needed to support the de novo.

The FDA recommends that a pre-submission for a de novo application include the recommended pre-submission content (device description, proposed intended use/indications for use, previous submissions, etc.), as well as the following information:

  • Proposed classification - statement of whether the device should be class I or class II and subject to 510(k) requirements
  • Adequacy of controls - description of why general and/or special controls are adequate to provide a reasonable assurance of safety and effectiveness
  • Classification summary - description of searches of FDA databases and other resources to establish there are no legally marketed predicates and a justification for why the device does not fit into the available product codes and regulations
  • Questions for FDA feedback - specific questions regarding the review issues relevant to the planned de novo; the guidance document provides examples of specific questions that may be relevant for a de novopre-submission
  • It may also be helpful to include the following, as needed:
    • risk information including the testing that will be completed to establish the device risk profile and the proposed mitigations and controls
    • information regarding the safety and effectiveness of the device including already conducted testing and protocols for any planned testing

Content and review of de novo application

For the de novo application itself, the FDA states that all information and evidence regarding the safety and effectiveness of the device should be submitted. The application should provide the following:

  • Classification summary
  • Risk Information - a summary of known and potential risks to health, as well as a description of how the identified risks will be mitigated; the FDA also recommends that the risk mitigation information be provided in a table that links each identified risk, the recommended mitigations measurements, and the data contained in the de novo application which address the implementation of the mitigations
  • Benefits of device use - this information should be supported by data and published literature that supports device effectiveness
  • Proposed general and/or special controls - note that a proposal for special controls is required for any device proposed for classification as class II
  • Benefit-risk considerations - a discussion demonstrating that, when subject to the identified general and/or special controls, the probable benefits to health outweigh the probable risks
  • Supporting data - the application should provide data demonstrating that the controls provide a reasonable assurance of safety and effectiveness of the device 
  • Device labeling

Upon receipt of a de novo application, the FDA will initially review the appropriateness of the device for the de novo pathway and ensure that the application includes all required elements. This initial review includes confirming that the same device is not currently under review in a pending marketing submission, as well as a classification review establishing that there is no legally marketed predicate upon which to base substantial equivalence and that the device does not fall under a class III classification regulation. Following successful completion of this initial completeness and classification review, the FDA will begin a substantive review of the submission. The FDA has a total of 120 days to complete its review of the submission, though the Agency may stop its review clock by requesting additional information from the submitter at any time. Typically such a request occurs at approximately 60 days. Multiple, iterative requests for additional information have been common in the past with these submissions. Thus, while the nominal total review timeline is 120 days, this timeline has frequently been exceeded in recent direct de novo applications. 

Upon granting a de novo application, an order will be published in the Federal Register codifying the device identification, classification, and applicable requirements. A summary of the Agency’s review of the de novoapplication will be provided on its website.

Conclusion

In general the revised draft guidance formally describes the general process the Agency has already been using for direct de novo applications since 2012. However, the guidance remains helpful in outlining when a de novoapplication is appropriate and the content of such submissions. While this guidance document is still in draft form, it represents the Agency’s current thinking on such applications and will assist the industry in ensuring that submissions meet the FDA’s expectations.