The FDA’s Center for Devices and Radiological Health (CDRH) has concluded its rewrite of the guidance for Section 522 postmarket studies, retaining the deadlines that populated the draft guidance of May 2021. These deadlines are much less forgiving than those in the previous final guidance, a fact of which manufacturers should be aware if they are to avoid a controversy with the agency.
We previously explained the characteristics of the 2021 draft guidance, which the FDA introduced with an emphasis on transparency regarding the conduct of these studies. The FDA press release posted with the draft guidance also places a heavy emphasis on compliance, a stance that seems to resonate in the final guidance, given that none of the primary deadlines seen in the draft have been relaxed despite pleas from manufacturers to ease some of those requirements.
One of the guidance’s more open-ended justifications for the issuance of a Section 522 study is to obtain additional information on device performance in real-world clinical usage. Otherwise, the guidance states that the FDA is authorized to require a Section 522 in at least four scenarios, including when a class II or class III device:
- Carries a risk of serious health consequences in the event of device failure;
- Is expected to see significant use in pediatric patients;
- Is an implant with an expected term of implant of longer than a year; and
- Is intended as a life-sustaining or life-supporting device used outside of a device user facility (a non-physician office health care facility).
The final guidance repeats the draft’s recommendation that these studies commence within 15 months of the date of the Section 522 order, and that 20% of subjects be enrolled within 18 months. At least half the enrollment target must be met within 21 months and the entire planned enrollment volume must be met at 24 months, but more than one trade group had argued that the 24-month enrollment target may be impracticable in some circumstances. Among the concerns cited by manufacturers is that pediatric studies and studies of rare diseases are often difficult to fully enroll in that amount of time.
In both the draft and the final guidance, a Section 522 study plan is deemed overdue if more than 60 days have passed since the FDA issued the study order, and the final retains the draft’s requirement that a final study report be filed within three months after the last study subject completes the last follow-up visit. Other timelines that are unchanged from the draft include that the manufacturer must submit the study plan within 30 days of the date of the order, and that the FDA will review and respond to the study plan within 60 days of receipt.
One of the more interesting aspects of this guidance is that the FDA has issued a diminishing number of Section 522 studies over the past few years. A list of all active and inactive studies discloses only one such order in calendar year 2022, and only two in 2021. There were eight orders in 2020, but the FDA had ordered more than 40 of these studies in 2013. In no year since then has the FDA ordered more than the eight studies for 2020.
Real-world Data Cited in PAS Final Guidance
The FDA also released the final guidance for post-approval studies (PAS) for class III, PMA devices, a policy that carries many of the same deadlines seen in the Section 522 guidance. One important difference between the draft and final versions of the PAS guidance is that the final explicitly acknowledges the potential use of real-world data (RWD) in fulfillment of these requirements, a policy that itself is the subject of a guidance issued in August 2017. That 2017 guidance states that RWD can be used for both Section 522 and PAS studies, giving sponsors alternatives to the randomized, controlled trial (RCT) for fulfilling these responsibilities. We had previously blogged about the draft version of this guidance last year.
Under the terms of both the draft and final guidance, the sponsor can argue that a PAS is unnecessary, but in most instances, the FDA will expect to see a completed protocol by the date of the approval of the device application. If the protocol is not completed by the date of the approval, the sponsor should expect to present at least an outline of the proposed study along with the final PMA submission. As with the draft guidance, the final states that any PAS proposals that are filed with the agency after the date of device approval should be filed as a PMA supplement, and should be filed no later than 30 days after the date of approval.
The final guidance provides somewhat greater detail on a sponsor’s modification of the PAS compared to the draft, such as that any modifications may be justified by enrollment difficulties. The FDA will consider any related changes to a study’s milestones on a case-by-case basis, and any agreed-upon changes will be reflected in adjustments to the official status of the study’s progress. The draft offered little information about such considerations other than to recommend that any such changes be filed as a PMA supplement. However, both versions of the guidance state that a PAS protocol will be officially deemed overdue if the agency cannot complete its review of a protocol within 60 days because of a failure of the sponsor to address any deficiencies identified by the FDA.
The PAS final guidance, like the draft, replicates the study enrollment timelines seen in the Section 522 final guidance, such as full enrollment at 24 months. Both the PAS and Section 522 final guidances call upon the sponsor to file progress reports every six months until full enrollment is reached, at which point this becomes an annual requirement. Both the draft and the final PAS guidance raise the prospect of the convening of an advisory panel to review the progress of the study, although this is not routinely practiced by the FDA.