By Yarmela Pavlovic and Gerry Prud'homme
The U.S. Food and Drug Administration (FDA) recently released a revised guidance document addressing the de novo premarket review pathway for medical devices. The draft guidance, titled “De Novo Classification Process (Evaluation of Automatic Class III Designation),” updates an earlier draft released in 2011 and seeks to implement changes to the de novo process required by the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012.
Historical BackgroundAll medical devices, absent a specific exemption, require premarket clearance or approval by the FDA. Nearly all Class I (lowest risk) devices and some Class II (moderate risk) devices are exempt. The remainder typically are cleared via the 510(k) premarket notification pathway, requiring companies to demonstrate that their product is “substantially equivalent” to a legally marketed Class I or II device already on the market. Class III devices undergo the more burdensome premarket approval (PMA) pathway, requiring the sponsor to demonstrate the safety and effectiveness of the device. Technically, a novel, previously unclassified device defaults to a Class III classification. Previously, the FDA had the ability to reclassify a device and would typically do so after gaining extensive experience regulating a particular category of devices.
However, in 1997, Congress enacted the Food and Drug Administration Modernization Act, which, among other things, provided the agency with the ability to review novel low- to moderate-risk unclassified devices and automatically “downclassify” them from Class III to Class I or II before FDA ever approves a PMA for the type of device in question. Historically, this required that medical device firms first submit a 510(k) premarket notification, arguing that the device is substantially equivalent to a predicate device, and receive a negative (a not substantially equivalent or NSE finding) finding from the agency. The company then was permitted, following agreement with FDA, to file a de novo submission seeking reclassification and clearance of the device. This process was cumbersome and often very lengthy.
In 2011, the FDA released a draft guidance document proposing to allow sponsors to simultaneously submit 510(k) and de novo submissions, thus eliminating the sequential portion of the process. The revised process required a pre-submission meeting with the agency and agreement between the sponsor/company and agency that the de novo pathway was appropriate for the device. In practice the 510(k) and de novo submissions often were duplicative in terms of content. Then, in 2012, Congress passed FDASIA, which provided for submission of a “direct de novo,” eliminating the need for the accompanying 510(k) submission. Since that time, FDA unofficially has been permitting direct de novo submissions. FDA’s newly revised guidance document seeks to formally implement the processes that the agency has been using since 2012.
Using the Current Pathway
In accordance with the current statutory provisions, the draft guidance notes that a de novo petition may be submitted to FDA either: (1) following a negative decision on a 510(k) submission based on a lack of predicate device, or (2) a direct de novo submission. If after reviewing a submitted 510(k), the FDA believes that there are no appropriate predicates but that the device may be a candidate for the de novo process, before issuing an NSE letter FDA may advise the applicant that the device may be suitable for de novo classification.
As a general matter, it appears that a complete de novo submission must be provided to the agency regardless of whether it was preceded by a 510(k) submission. A complete submission requires that all information and evidence regarding the safety and effectiveness of the device be provided. The general format of a de novo petition, per the draft guidance, requires the following items:
• Administrative Information including sponsor name, address and other contact information;
• Regulatory History including any prior submissions related to the device;
• Device Description including a discussion of the intended use and technological characteristics;
• Classification Summary including a discussion of any similar devices or other factors supporting classification of the subject device in Class I or II;
• Proposed Special Controls. Discussion of any proposed special controls and a justification explaining why special controls, in combination with the FDA’s general controls (e.g., quality system compliance, adverse event reporting, etc.) are sufficient to provide reasonable assurance of the safety and effectiveness of devices of this type;
• Supporting Protocol and Data. Discussion of the data supporting the safety and effectiveness of the device and supporting the conclusion that special and general controls are sufficient to provide reasonable assurance of the safety and effectiveness of future devices of the same type;
• Summary of Benefits;
• Summary of Known and Potential Risks to Health, including a table summarizing proposed risk mitigations;
• Risk-Benefit Balance Discussion; and
• Device Labeling.
Upon receipt of the de novo application, the FDA initially reviews the appropriateness of the device for the de novo pathway and ensures the application includes all required elements. This initial review includes confirming the same device is not currently under review in a pending marketing submission, 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 review, the agency conducts a substantive review of the submission. 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 novo application then will be provided on its website. For examples, visit www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/denovo.cfm.
It also is important to understand that while all subsequent devices of the same type may seek 510(k) clearance, it is not uncommon for an initial de novo submission to be somewhat more burdensome than the typical 510(k). This is likely not surprising as the de novo represents the first instance in which the FDA is encountering a new device type. However, in practice, companies often are surprised to learn that far more de novo submissions involve clinical data than is the case for 510(k)s. As a result, when pursuing the de novo pathway, it is important to consider the possibility that the data requirements for the first-of-a-kind device may be higher than for subsequent 510(k)s. Nonetheless, as noted above, one aspect of a de novo submission is a special controls guidance document. Typically, the FDA requests the sponsor company prepare the first draft. This provides an opportunity to lay out the types of data that would be appropriate for all future devices in the category be required to provide, including clinical data if that appears warranted. Thus, there is some opportunity for the sponsor to assist in setting the reasonable threshold for data requirements for future submissions.
The Pre-Submission Meeting
Although a pre-submission meeting no longer appears to be required prior to submission of a de novo petition, it strongly is recommended. For such a meeting to be scheduled, the sponsor must first submit a pre-submission meeting request, including the standard pre-submission elements (device description, proposed intended use/indications for use, previous submissions, etc.), as well as the following specific items:
• Discussion of Proposed Classification: a statement explaining whether the device should ultimately be classified in Class I or II, whether the device should be exempt for 510(k) requirements.
• Discussion of Controls: an explanation of why general and any proposed special controls are adequate to provide a reasonable assurance of safety and effectiveness for the device type.
• Predicate Search: a discussion of searches conducted to identify any possible predicate devices and a justification as to why the subject device does not fit into an existing classification regulation.
• Questions for FDA: a list of specific questions for the agency regarding the planned submission. The guidance document provides examples of specific questions that may be relevant for a de novo pre-submission.
Timeline for Review
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 this occurs at approximately 60 days and multiple, iterative requests for additional information have been common in the past with these submissions. Further, while the nominal total review timeline is 120 days, this timeline has not uncommonly been exceeded in recent direct de novo applications.
* * *
While the revised guidance document essentially formalizes the approach FDA has been taking since 2012, having the process documented in writing may assist many companies new to the FDA process in better understanding this more unusual regulatory pathway. It remains to be seen whether, as the agency becomes increasingly comfortable with the pathway, review times may decrease.
Yarmela Pavlovic is a partner in the Philadelphia, Pa., office of law firm Hogan Lovells. Her practice focuses primarily on U.S. Food and Drug Administration (FDA) regulation of medical devices. Yarmela works with medical device manufacturers to develop regulatory strategies for obtaining FDA marketing approval for their devices and has extensive experience in assisting companies in matters pertaining to product development and product submissions—510(k)s, investigational device exemptions and premarket approval applications. Gerard Prud’homme is a partner in Hogan Lovells’ Washington D.C., and Baltimore, Md., offices. He advises clients on a wide variety of FDA regulatory issues and focuses his practice on the regulation of medical devices. He has extensive experience in assisting companies in matters pertaining to regulatory strategy, product development, product submissions and pre-submissions. He advises clients on regulatory and scientific requirements, and on designing and analyzing clinical and other studies, in support of product submissions.