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Lab Industry Looks to Recently Added Regulatory Tool for Flexibility as FDA LDT Rule Looms


NEW YORK  With the US Food and Drug Administration's final rule on laboratory-developed tests looming, some in the industry are looking to the agency's emerging policy on Predetermined Change Control Plans (PCCPs) as a possible source of flexibility.

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 commonly been discussed as a tool for updating software and AI-based devices, but they are applicable to diagnostics more broadly.

The PCCP idea "is not entirely new," said Nathan Brown, a partner at law firm Akin Gump, noting that the FDA has previously incorporated the concept on one-off bases in certain clearances and approvals.

Inclusion of the provision in FDORA, however, "codified and clarified it as a tool FDA can use and that submitters can propose and ask about," said Brown, who was involved in developing the legislation.

Depending on how broadly the FDA chooses to implement these plans, they could help mitigate the challenges involved in updating tests to stay current with rapidly changing clinical needs — a frequently voiced concern regarding the agency's plan to regulate LDTs.

"People are absolutely talking about" PCCPs, said Jonathan Genzen, chief medical officer and medical director of automation at ARUP Laboratories. He added that in the event of FDA regulation of LDTs, labs and test developers will be looking for opportunities for flexibility "to move forward with diagnostic testing that meets clinical needs."

Scott Danzis, a partner at law firm Covington & Burling, said that he believes that "without a doubt" labs and diagnostics companies will look to PCCPs for flexibility in updating tests if the FDA takes over the regulation of LDTs.

"Some of those conversations are already happening broadly across the diagnostics landscape," he said, adding that he believes there will be many opportunities where predetermined change control plans could prove useful.

He noted that it remains an open question whether the FDA has legal authority to regulate LDTs, but putting that aside, "there's no question that developers … are looking for whatever tools they can use to reduce the burden of iterative FDA review with respect to changes."

"LDTs in particular are subject to numerous modifications, improvements, tweaking … in order to perfect those tests," Danzis said.

"The statutory provision is fairly expansive and gives pretty wide latitude with the main limitation being that the PCCP is limited in the case of an approved device or cleared device to staying within the same intended use," Brown said. "If you're not changing the intended use, you can make any number of other changes, including to what are referred to as 'indications for use.'"

How the FDA will interpret and implement the provision remains to be seen, though.

"FDA has put out a draft guidance on PCCPs in the context of software and AI and seemed to cast a little bit of doubt on [applying PCCPs to] indications for use, but the statute allows it," Brown said. "The real limiting factor should be more the technical perspective of can the [device] developer anticipate and describe a type of change that they anticipate needing or wanting to make and describe in enough detail how they would go about validating that change so there can be a kind of meeting of the minds with FDA."

Examples of where PCCPs might be used include a manufacturer adding a new strain to a previously cleared flu test or adding new strains to an antimicrobial resistance test, according to Brown.

More questionable might be whether a PCCP could be used to, for instance, add an entirely new virus to a respiratory panel or new drugs of abuse to a toxicology panel.

"There's definitely some play in the joints in terms of how for a particular device FDA would define the intended use versus the indications for use," Brown said.

Danzis likewise said that both industry and the FDA itself are still working through what exactly the scope of PCCPs will be.

"It all boils down to what the guidance and rulemaking around [PCCPs] is, and how strict versus how flexible" the FDA will be, Genzen said. "I applaud any concept that potentially could make oversight more feasible for clinical laboratories, but … there's a lot of uncertainty."

Brown said he hopes and expects that the FDA will see PCCPs as a potential tool for managing the influx of test submissions that many anticipate will follow if the agency's rule on LDT regulation goes into effect.

"I certainly think that it should be front and center," he said.

"I think FDA, like industry, will look at [PCCPs] as a tool that would be helpful to reduce the burden of future submissions, and undoubtedly that is something that I think would be a net positive for FDA," Danzis said.

The agency has indicated interest in the PCCP idea. At the American Clinical Laboratory Association annual meeting in March, Brittany Schuck, deputy office director in the Office of Health Technology 7, Office of In Vitro Diagnostics at the FDA's Center for Devices and Radiological Health, said that it is "really excited about PCCPs, receiving them, reviewing them, authorizing them."

She suggested that PCCPs could be used for purposes like adding new specimen types or genetic variants to a test.

Last year, the FDA approved a PCCP as part of its 510(k) clearance for an expansion of 23andMe's BRCA1/BRCA2 (Selected Variants) Genetic Health Risk Report. Under the PCCP, the company can add new validated BRCA1 and BRCA2 variants without having to go through premarket review.

Brown noted, though, that at least in the beginning, applications with PCCPs might take longer for the FDA to review as the agency will still be establishing its process for evaluating them.

"I think as more of these come out, you will start to see clearances and approvals that include PCCPs, and you'll see, OK, that's the way it was handled, and it will become more routine," he said.

Danzis likewise noted that reviewing and approving PCCPs will be time-consuming and suggested that the agency's policy toward PCCPs will be something of a balancing act.

"Is FDA going to expend the resources to encourage and develop these PCCPs on the front end, or is that going to be so much work for the agency while they are going through what could be an initial crush of [LDT] applications that they will be a little more restrictive on what they will do with PCCPs?" he said.

Genzen emphasized that while PCCPs could prove useful for labs taking tests through the FDA, they do little to assuage his broader concerns about the agency's proposed rule.

"I worry that it is [part of] a series of band-aids to try to fix a flawed proposal that may not be fixable," he said.

That said, Genzen noted that he "can see people very clearly focusing on this area and making change protocols wide enough to minimize the damage of the" proposed rule.