The US Food and Drug Administration is seeing traction among medical device sponsors for predetermined change control plans (PCCPs) following omnibus reform legislation that granted the agency related authorities in December 2022.
According to analysis posted in August by consultant Brendan O’Leary, who served for more than a decade at the FDA, including as founding deputy director of the Digital Health Center of Excellence and its acting director through 2022, there are roughly three-dozen authorizations in FDA’s public databases of devices that include PCCPs.
O’Leary shows the PCCPs count spiked markedly in 2024, concentrated in areas where the FDA is authorizing higher numbers of AI- and machine learning-enabled solutions, namely cardiovascular and radiology devices.
That should come as no great surprise, as the FDA’s first reference to PCCPs was in a 2019 discussion paper describing a potential approach to premarket review of projected AI/ML-based software modifications. (Also see "A Brave New World: Regulatory Flexibility Key To AI Development, Stakeholders Say" - Medtech Insight, 29 July, 2019.)
The agency has since issued draft guidance providing “Marketing Submission Recommendations for a Predetermined Change Control Plan for Artificial Intelligence/Machine Learning (AI/ML)-Enabled Device Software Functions,” followed by August 2024 draft guidance on PCCPs for medical devices. (Also see "FDA Drops Draft Guidance on Predetermined Change Control Plans for Medical Devices" - Medtech Insight, 21 August, 2024.)
Per the FDA, “By including a PCCP in a marketing submission for a device, manufacturers can prospectively specify and seek premarket authorization for intended modifications to a device without needing to submit additional marketing submissions or obtain further FDA authorization before implementing such modifications – provided the changes are implemented consistent with the PCCP that has been reviewed and established through a device marketing authorization.”
Streamlining device modifications over a foreseeable timeline via an approved PCCP is an intriguing prospect, and industry leaders including Medtronic, Abbott, BD, and Apple – all sponsors of technologies cleared along with PCCPs – would seem to agree.
At the same time, “I think there are also a lot of companies that are approaching PCCPs with some caution,” said Joshua Oyster, a partner in Ropes & Gray’s Washington, D.C. office, in an 8 October interview.
He continued, “As with any new initiative, there are the early adopters and there are the followers trying to see whether this is going to be useful or not. It’s one of those things that sounds like it could be very useful on paper. But I think it remains to be seen if industry is able to figure out: What are the right modifications where a PCCP is actually going to speed up our process and be useful for us to go down this road, and is FDA going to review them in a way that that doesn’t add more burdens to our process than just coming back and getting a new 510(k) clearance or PMA supplement later?”
In its guidance, the FDA encourages manufacturers to leverage its Q-Submission Program to obtain agency feedback on a proposed PCCP before filing a marketing submission.
“Alright,” Oyster said, “but we’re trying to do this more efficiently. So if you have to do a pre-sub to talk about what would go in the PCCP, is that actually going to be saving us time?”
Additional FDA guidance, which Oyster expects will roll out in due time, could help to build industry confidence. The attorney looks forward to FDA “illustrating and sharing information about ‘wins’ through the program and examples where PCCPs have been used. To date, the information about exactly what devices have been cleared with PCCPs is a little bit limited. Ideally, it would be a little easier to find those things and understand exactly what the PCCP was,” he said.
The 510(k) summary for Apple’s Irregular Rhythm Notification Feature (IRNF) 2.0, an OTC digital application used with the Apple Watch to analyze pulse rate data and identify episodes of irregular heart rhythms suggestive of atrial fibrillation, offers a glimpse into a PCCP green-lighted as part of the company’s submission.
According to the FDA, Apple’s PCCP comprised a list of software modifications defining “the region of potential changes” that could be made to algorithms powering its device, as well as an algorithm modification protocol describing verification and validation activities to support proposed changes, and specific test methods to establish substantial equivalence relative to IRNF 2.0 (see table).
Beacon Biosignals included a PCCP in its 510(k) submission forSleepStageML, an ML-enabled software that stages sleep from electroencephalogram signals of clinical polysomnography recordings to aid in the diagnosis of sleep and sleep-related disorders, cleared by the FDA in December 2023.
According to the 510(k) summary, Beacon’s PCCP allows for the modification of algorithmic components of SleepStageML “including the signal preprocessing, machine learning model, postprocessing, or signal quality check to achieve increased sleep staging performance.”
Details on other cleared PCCPs in FDA records, for example Merit Medical Systems’ Bearing nsPVA Express vascular embolization device, are sparser.
“There’s potential here,” Oyster said. “But I think there are similar feelings that folks had when FDA’s Third Party Review Program for 510(k)s started and it didn’t get as much uptake as maybe people thought it would. There are all these provisions in the Food, Drug, and Cosmetic Act and all this guidance about third parties and accrediting them, and I don’t know that the program is used nearly as much as the effort that was put into creating it.”
‘Hopefully More Useful’
The FDA’s 510(k) Third Party Review Program traces back nearly three decades to the 1997 FDA Modernization Act and has been the subject of continued legislative attention and revision, including as part of cyclical Medical Device User Fee and Modernization Act (MDUFA) negotiations.
The intent of the program, formally known as the Accredited Persons Program, is to provide medical device manufacturers with a voluntary alternative review process in which accredited Third Party Review Organizations are allowed to review certain low-to-moderate risk medical devices and, in theory, expedite decisions on 510(k) submissions, which account for some 99% of the FDA’s device reviews.
The FDA is relying on the program to help manage a coming flood of review applications for lab-developed tests under contentious final rulemaking promulgated by the agency in April 2024. (Also see "It’s Official: FDA Drops Final Rule On LDTs" - Medtech Insight, 29 April, 2024.)
In an August 2023 article published in the Journal of Medical Systems, Johns Hopkins University physicians contended that “[d]espite the best of intentions, the third party review program has struggled,” noting declining use from a peak of 9.3% of 510(k) submissions in 2008 to 2.4% in 2020.
The authors attribute the downturn to multiple factors, including suspected low-quality reviews by third parties too often leading to FDA re-reviews, “an issue that became increasingly common during the pandemic,” they say. (Also see "FDA Blacklists Third-Party Reviewer For Lying To Sponsors, Agency" - Medtech Insight, 19 August, 2021.)
Oyster maintains the PCCP mechanism’s utility remains to be proven. “Hopefully this is a more useful and productive program over the long term.”
‘Limited Number Of Modifications’ Only
In its August 2024 draft guidance on PCCPs for medical devices, the FDA identifies modifications to devices that may be appropriate for inclusion in a PCCP, including:
- Certain changes in device design, including dimensions, performance specifications, wireless communication, components or accessories, or the patient/user interface;
- Change in sterilization, packaging, transport, or expiration dating using well-established methods;
- Certain changes in materials/components (e.g., different raw materials, reagents, or hardware components);
- Certain changes in software related to device compatibility and/or interoperability.
It also lists modifications generally unsuited for PCCPs, including:
- Change to device control mechanism, operating principle, or energy type;
- Change in device design that could affect the intended use of the device;
- Change from a device labeled for single use only to a device labeled as reusable;
- Change to or removal of contraindications;
- Change from prescription to over-the-counter use.
“There’s a decent amount of of direction that FDA gives in the guidance,” Oyster said.
Gray areas do exist. For example, the agency advises a PCCP should encompass “only a limited number of modifications that are specific, and that can be verified and validated.”
Recalling his September alert on the topic, Oyster questioned whether the relatedness of planned modifications might affect the unspecified maximum number of modifications permitted in a PCCP.
“What’s limited? Will this be a thing where it’s going to vary from reviewer to reviewer and whether they want to deal with all this in one 510(k). Like, ‘We don’t feel like bringing in all these people to review. There’s this compatibility thing, this physical dimension change thing – we just don’t want to deal with all that.’ I think it’s going to make some companies a little bit skittish to try things,” he said.
Oyster envisions cases where a PCCP could be very sensible, facilitating device interoperability changes on the horizon, for instance, or changes in device sterilization processes.
“If we start to see some of those types of things go through, I think that has the potential to create a snowball effect of, ‘Well, our competitor did this. So we should do it.’ That could evolve to be an incentive for companies to go down this lane,” the attorney observed.
He said a prudent place for medtech companies to start when considering a PCCP is preexisting FDA guidance on expectations for postmarket device submissions, namely “Modifications to Devices Subject to Premarket Approval (PMA) – The PMA Supplement Decision-Making Process,”“Deciding When to Submit a 510(k) for a Change to an Existing Device,” and/or “Deciding When to Submit a 510(k) for a Software Change to an Existing Device.”
