The new FDA goal is to reduce the De Novo review timeline to 150 days for 70% of De Novo submissions, but how long does it take now?

What is an FDA De Novo submission?

An FDA De Novo submission is an application submitted to the FDA for creating a new device product classification. There are three classifications of devices by the FDA: Class 1, Class 2, and Class 3. Class 1 devices are the lowest-risk devices, and they only require general controls. Class 2 devices are moderate-risk devices that require “Special Controls,” and Class 3 are high-risk devices that require Pre-Market Approval (i.e., PMA). De Novo applications can only be submitted for Class 1 and Class 2 devices, and most of the De Novo submissions require clinical data to demonstrate that the clinical benefits of the new device classification outweigh the risks of the device to patients and users. It’s the need for clinical data that is partly responsible for the longer De Novo review timeline.

What is the De Novo review timeline?

Initially, the FDA required that Class 2 devices must be first submitted as a 510k submission. If the device did not meet the criteria for a 510k, then the company could re-submit a De Novo Classification Request to the FDA. On July 9, 2012, the regulations were revised to allow companies to submit De Novo Classification Requests directly. This makes sense because some devices have novel indications for use, and submission of a 510k would be a complete waste of time in money. For example, the first SARS-COV-2 test had to be submitted as a De Novo by Biofire to obtain permanent approval for the test instead of emergency use authorization (EUA). This change in 2012 dramatically reduced the De Novo review timeline.

On October 4, 2021, the FDA published a final rule for De Novo Classification Requests. This new regulation identified the De Novo review timeline as 120 calendar days. Even though 120 days is 30 days longer than the FDA review clock for a 510k, the actual timeline to review De Novo submissions was much longer.

Every five years, when Congress reauthorizes user fee funding of the FDA, new MDUFA goals are established. The draft MDUFA performance goals (which impact FDA funding) were published recently. The specific performance goal to review De Novo submissions is:

FDA will issue a MDUFA decision within 150 FDA Days for 70% of De Novo requests.

There are two problems with this goal. First, the term “FDA Days” is based on calendar days minus the number of days the submission was placed on hold, and we don’t have any visibility into the number of days submissions are placed on hold. In the past, submissions could be placed on hold multiple times during the Refusal to Accept (RTA) screening process, and the “FDA Days” is reset to zero days each time the company receives an RTA hold letter. In addition, even after the submission is finally accepted, the FDA places the submission on hold when they request additional information (i.e., AI Hold). RTA and AI Hold periods can last up to 180 days, and during the Covid-19 pandemic, companies were allowed to extend this up to 360 days.

The second problem with the MDUFA goal is that we only have visibility into the outcome of De Novo submissions that were granted. More than 60 De Novo submissions are submitted each year, but the number of De Novo Classification Requests granted ranged between 21 and 30 over the past three years. Therefore, the 50%+ of De Novo applications denied could skew the % of submissions that meet the MDUFA goal for the De Novo review timeline.

What is the FDA track record in reviewing a De Novo?

Every CEO I speak with asks the same question: “How long does the FDA review take?” In preparation for a webinar I taught about De Novo Classification Requests in 2019, I researched the latest De Novo review timelines. I expected the review timelines to be close to 150 calendar days because the FDA decision goal was 150 FDA days. The 150-day goal was set in 2018 when Congress approved MDUFA IV. The 2019 data held two surprises:

only 21 De Novo requests were granted in 2019, and
the average review timeline was 307 calendar days (i.e., the range was 108 days to 619 days).

FDA days are not the same as calendar days. Only 23.8% of De Novo submissions were reviewed within 150 calendar days. The FDA doesn’t calculate the number of FDA days as calendar days, but there is no way to know how much time each De Novo spent on hold publicly. Upon seeing the announcement of a new decision goal for MDUFA V on October 5, 2022, I decided to revisit my previous analysis.

*Only 9+ months of data for 2022, because data was collected on October 17, 2022.

We can blame the Covid-19 pandemic for the slower De Novo review timeline during the past few years, but you would expect a longer average duration in 2020 if that was the root cause of the FDA’s failure to achieve the MDUFA IV target of 150 calendar days. You would also expect 2021 to have the longest review timelines. Instead, the review timelines are the slowest for 2022. The number of De Novo submissions remains small, and therefore it is hard to be conclusive regarding the root cause of the failure to reach the 150-day decision goal. In addition, the percentage of De Novo applications granted within 150 calendar days was lowest in 2021, as you would expect if the reason for delays is primarily due to the Covid-19 pandemic.

Is there any good news?

The FDA is allowing the new eSTAR templates to be used for De Novo Classification Requests. These new electronic submission templates standardize the format of all 510k and De Novo submissions for FDA reviewers. The eSTAR also forces companies to answer all questions in the FDA reviewer’s checklist to ensure the submission is complete and accurate before the new submission is submitted to the FDA.

The new eSTAR templates were first used in 2021, and our firm has observed shorter overall review timelines and fewer deficiencies identified by FDA reviewers when they submit an “Additional Information Hold” (AI Hold) to companies.

How can the FDA improve De Novo timelines?

The FDA, industry, and Congress seem to be taking the same approach pursued five years ago to improve the review timeline for De Novo submission. MDUFA V authorized additional user fees for De Novo submissions (i.e., 17.8% increase), and the FDA will be authorized to hire additional employees each year during MDUFA V if the performance goals are met. However, there are three other options that the FDA and industry should have seriously considered during the FDA-industry negotiations.

The first option that should have been considered is to allow third-party reviewers to review the elements of a De Novo that are identical to a 510k submission:

sterilization validation
shelf-life testing
biocompatibility testing
software validation
electrical safety testing
EMC testing
wireless testing
interoperability testing
benchtop performance testing
animal performance testing
human factors engineering

The above approach would require blended pricing where the FDA charges a smaller user fee than a Standard De Novo user fee, and the third-party reviewer charges a smaller fee than a 510k. The combined cost would be higher than the FDA Review of a De Novo, but this would reduce the number of hours the FDA needs to complete their review of a De Novo, and it would allow for pricing that is much lower than the De Novo standard user fee for qualified small businesses.

A second approach would be to pilot a modular review approach. A modular review would be similar to modular reviews for PMA submissions. In a modular review, the FDA can review most submission sections and provide feedback before the human clinical performance data is available. This would not help the few De Novo submissions that do not include human clinical performance data, but this would have a profound positive impact on most De Novo projects. First, the FDA would be able to complete the review of all sections in the submission except the human clinical performance data without delaying the final De Novo decision. Second, a successful review of non-clinical data by the FDA would give investors more confidence to fund pivotal clinical studies required to complete the De Novo submission.

A third approach would be for the FDA to force manufacturers to submit testing plans and protocols as pre-submissions to the FDA. This approach would give the FDA more familiarity with each device and the testing plan before reviewing the data. This approach would also reduce the hours FDA reviewers spend reviewing data that doesn’t meet the requirements and writing deficiencies. This approach would also give investors more confidence to fund De Novo projects for all V&V testing.