NEW YORK – With the recent release of a draft guidance on the use of Predetermined Change Control Plans (PCCPs), the US Food and Drug Administration has provided details on how medical device manufacturers, including laboratories offering lab-developed tests (LDTs), might use such plans to more easily update their products.
But while the draft guidance lays out some of the agency's thinking on PCCPs, industry observers and stakeholders said that more clarity is needed. They also indicated that based on the guidance, the FDA's policy on PCCPs may be more restrictive than hoped.
Codified in the Food and Drug Omnibus Reform Act of 2022 (FDORA), PCCPs allow manufacturers to make certain changes and updates to FDA-cleared or -approved devices without having to take them back through the regulatory process.
A PCCP is documentation submitted as part of a device's larger regulatory package that details future changes or updates a manufacturer may want to make to the device as well as how those changes will be implemented and validated. If approved, the PCCP allows the manufacturer to make those changes without having to take the device back through premarket review.
PCCPs have most commonly been discussed as tools for updating software and AI-based devices, but they are applicable to medical devices more broadly. In the wake of the FDA's final rule on LDTs, some in the lab and diagnostics industries have suggested PCCPs could help test developers more quickly and easily update their tests to stay current with rapidly changing clinical needs, which many see as a major challenge presented by the agency's regulation of LDTs.
Scott Danzis, a partner at law firm Covington & Burling, said he believes "there is no question that PCCPs can be a useful tool" for diagnostics developers and laboratories. He noted that while the FDA's final rule on LDTs still faces legal challenges, assuming it is implemented in its current form, "laboratories would be really well suited to consider PCCPs as they develop diagnostic products."
The scope of changes that the FDA will allow as part of a PCCP is still somewhat unclear, however.
In the draft guidance, the agency provides a series of general principles detailing changes that are and are not appropriate for a PCCP. For instance, "certain changes in the labeling and/or the indications for use to specify use of the device with an additional device, component, or human genetic variant" may be appropriate for inclusion in a PCCP. Meanwhile, "changes in the labeling and/or the indications for use to include a new patient population" are "generally not appropriate" for inclusion, the guidance states. Broadly speaking, the guidance indicates that modifications are not appropriate for inclusion in a PCCP if they introduce a "major change" to a device's intended use, "significantly affect" its safety or effectiveness, or introduce a new risk.
The guidance also offers a number of examples of specific medical devices, including several clinical tests, along with modifications that would and would not be appropriate for inclusion in a PCCP.
Nathan Brown, a partner at law firm Akin Gump, said that in his opinion, it is somewhat difficult to "connect a straight line" from the general principles laid out at the beginning of the document to the specific examples presented toward the end.
He suggested that this is in part due to the challenge of formulating a set of principles that cover the broad range of device types regulated by the FDA.
PCCP decisions "will probably be decided heavily on a case-by-case basis, and we're going to see differences among the review divisions," he said.
The specific examples detailed in the guidance also indicate a narrower scope for PCCPs than some had hoped.
For instance, in its discussion of an over-the-counter test for BRCA1 and BRCA2 mutations, the agency said that while a PCCP would be an appropriate route for adding new single nucleotide variants or insertion and deletion variants of up to 20 base pairs, it would not be appropriate for adding new genes or copy number variants.
And in the case of an antimicrobial susceptibility test for determining the susceptibility of Candida to the antifungal drug caspofungin, the guidance said a PCCP could not be used to add a new drug or a new species.
Danzis said he believed that for most stakeholders, the draft guidance is largely in line with expectations for how the FDA would approach the use of PCCPs, but he added that stakeholders were hoping the agency would signal greater flexibility in the scope of PCCPs. In particular, the FDA's position that most modifications to indications for use would not be appropriate for including in a PCCP "is disappointing," he said.
Jonathan Genzen, chief medical officer and medical director of automation at ARUP Laboratories, highlighted changes in sample type as an area where the guidance was less expansive than labs had hoped. For instance, in one example provided in the guidance, a serum test for prostate specific antigen could be modified to use lithium heparin plasma as a sample type using a PCCP. Modifying the assay to use capillary whole blood, on the other hand, could not be done via PCCP, the agency said. Similarly, an IVD for measuring potassium levels in serum could be modified via PCCP to use lithium heparin plasma but not to use urine or capillary whole blood.
Genzen said that based on the guidance he doesn't fully understand the FDA's thinking on what sample changes were and were not appropriate for PCCPs. He added that he had hoped PCCPs could help labs more easily modify tests for use in different sample types, noting that this is a common modification in clinical labs and one that will be made more difficult by the new LDT rule.
"You never quite know what [sample type] is going to be sent to you, and you validate more and more over time depending on what body fluids you start receiving," he said. "I was hoping body fluids would be one place where PCCPs could be helpful, but I think their comments on sample types suggests that perhaps they don't believe that would be an appropriate use of a PCCP."
Genzen said he had hoped PCCPs could be useful in areas including toxicology and flow cytometry where they might let labs add new drugs or antibodies to test panels. However, he said that based on the guidance he is concerned such uses will not be deemed appropriate.
Another point of concern for Genzen is the FDA's stance on the automation of manual tests. In several of the specific examples provided in the guidance, the agency said that changing from a manual to automated process would not be an appropriate modification to include in a PCCP, a position that he said fit with its broader view on the issue.
"I have grave concerns about how the FDA has approached the concept of automation," he said. "I've seen countless examples of how automation improves efficiency and improves quality. Within the final rule and [FDA's] description of automation, there is always a tone of it increasing risk, and I just disagree with that, at least as a blanket statement about automation in general."
More generally, Genzen said the industry "still needs significant additional guidance" on PCCPs. "There is still a lot of ambiguity."
Brown similarly said he expects members of industry in public comments to request "additional specificity and clarity" on some of the principles laid out by the FDA.
The draft guidance is open for public comment through Nov. 20.