CDRH Issues Final Guidance on De Novo Submission Acceptance Review

On September 9, 2019, FDA issued a final guidance, Acceptance Review for De Novo Classification Requests.  The guidance is meant to provide clarity on the Agency’s expectations for information to be submitted in a De Novo request and to ensure predictability and consistency for sponsors.  The final version supersedes the draft guidance issued on October 30, 2017, both of which FDA agreed to issue as part of its performance goals under MDUFA IV.  See Title II of the FDA Reauthorization Act of 2017 (Public Law 115-52).  A discussion of the draft guidance on our blog can be found here.

As was the case with the draft, there is nothing remarkable about this guidance, nor are there many changes between the draft and the final version.  There were four comments submitted to the docket for the draft guidance, none of which FDA incorporated into the final version.  Unlike the draft, the final guidance provides additional clarity around De Novo requests involving combination products as well as statements of compliance for clinical investigations and declarations of conformity.  All of the changes discussed below are included not only in the narrative of the guidance but are also reflected in changes to the checklists FDA provides as Appendices A (Acceptance Checklist for De Novo Classification Requests) and B (Recommended Content Checklist for De Novo Classification Requests).  FDA acknowledged that both the Agency and industry would need time to “operationalize the policies and procedures within the guidance.”  As a result, FDA expressed its intent to exercise leniency in reviewing De Novo requests for the 60 days following the publication of the final guidance.

A quick overview of De Novo requests:  New devices (i.e. devices not substantially equivalent to a previously cleared or pre-amendment device) are automatically classified as class III without any action by FDA, regardless of the level of risk posed by the device.  This is the case unless and until FDA takes an action to classify or reclassify the device, as per section 513(f)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA) (21 U.S.C. 360c(f)(1)).  One mechanism to classify a device is through the De Novo classification process, a pathway authorized under section 513(f)(2) of the FDCA.  Upon receipt of a De Novo request, FDA is required to classify the device by written order according to the criteria under section 513(a)(1) of the FDCA.  Before this substantive review FDA staff conducts an acceptance review of all De Novo requests based on objective criteria using the Acceptance Checklist to ensure that it is administratively complete.

The Checklist – Preliminary Questions

FDA identifies a series of preliminary questions intended to serve as an initial screening of the De Novo request.  Depending upon the answers to these preliminary questions, the remainder of the acceptance review may or may not be necessary.  As part of FDA’s preliminary analysis, the final guidance instructs the reviewer to determine whether a De Novo request for a combination product contains as a constituent a drug that has the same active moiety as an approved drug with exclusivity, as described in section 503(g)(5)(C)(ii)-(v).  In such a case, the lead reviewer should contact the CDRH Product Jurisdiction Officer or CBER Product Jurisdiction Officer to determine the appropriate action and inform management.

FDA clarifies that, should De Novo requests for the same device type from different requesters be under review concurrently, this would not result in an automatic Refuse to Accept decision.  FDA directs readers to its guidance document, “De Novo Classification Process (Evaluation of Automatic Class III Designation),” for additional information regarding this situation.

The Checklist – Acceptance Review

The main elements of the acceptance review are largely unchanged from the draft guidance.  However, the final guidance includes additional information regarding combination products.  The 21st Century Cures Act, which amended section 503(g) of the FDCA, requires requesters seeking action on a combination product to identify it as such.  Requests for combination products with a device primary mode of action that contain an approved drug as a constituent product must include patent information and one of four patent certifications such as,

• That the patent information has not been filed (Paragraph I),
• That the patent has expired (Paragraph II),
• The date on which the patent will expire (Paragraph III),
• That the patent is invalid or will not be infringed by the manufacture, use, or sale of the drug for which this submission was made (Paragraph IV).

If it is asserted that the patent is invalid or will not otherwise be infringed, the sponsor must also provide notice to the owner of the patent and the holder of the approved application that lists the patents that are being challenged, as set forth in section 505(b)(3) of the FDCA.

The sponsor must also submit to FDA the documentation of the date of receipt of notice by the holder of the approved application and the owner of the patents (see our previous post here).

Checklists

As part of the classification information for the De Novo request, FDA added that, to the extent the request recommends classification as class II, it also identifies proposed special controls and describes how those special controls provide a reasonable assurance of safety and effectiveness.

FDA also added a section on Statements of Compliance for Clinical Investigations to the checklist.  For each clinical investigation conducted in the U.S. that is used to support the request, it must include either a statement of compliance with 21 C.F.R. Parts 50, 56, and 812 or a brief statement explaining the reason for the noncompliance.  For each clinical investigation conducted outside the U.S. that is used to support the request, the request must include either

• a statement that the clinical investigations were conducted in accordance with good clinical practice;
• evidence that the clinical investigations were subject to a waiver of GCPs pursuant to 21 C.F.R. § 812.28(c);
• or an explanation as to why the studies did not comply with GCPs and the steps taken to ensure the data and results from the study were credible and accurate.

Lastly, the final guidance checklist includes a section on the use of voluntary consensus standards.  If using such standards, the request should include a declaration of conformity or an explanation of how the data support the use of the standard.  To the extent a request references a non-FDA-recognized voluntary consensus standard, the request must include the basis of use of that standard with the underlying information or data that support how it was used.

Impacts of Government Shutdowns

Likely a result of the government shutdown from 2018 to 2019 that closed FDA’s doors for 35 days, FDA provides clarification on how a future shutdown would impact the timing for an acceptance review.  In such an instance, the 15-day review period would be expanded by a comparable number of business days that the FDA buildings are closed.  FDA notes that, in the event of a shutdown, the requester may receive an automated notice that the acceptance review was not completed because the screening period exceeded 15 days, but that this notice would be corrected upon FDA becoming operational.

As noted above, the issuance of this final guidance does nothing to change the landscape of the De Novo review process.  It is, however, an important step in increasing transparency of Agency expectations, resulting in a more efficient review process for De Novo requests.