NEW YORK – While the US Food and Drug Administration's recent final rule on laboratory-developed tests (LDTs) most directly impacts the clinical lab industry, in vitro diagnostic companies will likely also feel effects from the new regulation.
In particular, new FDA requirements around modifying IVDs could lead labs to push IVD vendors to validate their tests across a wider variety of use cases, potentially creating new customer expectations and competitive dynamics.
Labs modify FDA-approved assays for a variety of reasons including to change a test's reportable range, to change its intended use populations, or to use it in a different sample type. When a lab makes such a modification, the modified test then becomes an LDT. During a presentation at the recent Association for Diagnostics & Laboratory Medicine's (ADLM) annual meeting, Patricia Jones, clinical director of the chemistry and metabolic disease labs at Children's Medical Center of Dallas, noted that "modifying existing FDA assays is the second most common reason for running an LDT."
The FDA's rule on LDTs complicates this relatively common practice, as certain modifications will now require a lab to take the modified test through premarket review. In the preamble to the final rule, the FDA listed several kinds of modifications to existing LDTs that would require premarket review: changes to the indications for use; changes to the operating principle of the test; a switch to a "significantly different technology," such as the addition of AI or moving from targeted to whole-genome sequencing, from immunoassay to mass spectrometry, or from manual to automated testing; or "adversely" changing the test's "performance or safety specifications."
Exactly what test modifications will trigger the FDA's premarket review requirements remains uncertain, but the LDT rule will likely complicate labs' decisions around when to modify a test. It could also come to impact lab decisions around IVD vendors and equipment purchases as vendor tests and platforms may differ with, for instance, one vendor offering an assay cleared in one sample type and a second vendor offering the same test but cleared in a different sample type.
At the ADLM meeting, Stephen Master, division chief and director of metabolic and advanced diagnostics at Children's Hospital of Philadelphia, offered the example of his lab, which, he noted, "just happened to be in the process of getting all new core chemistry instruments," meaning any previously modified assays would no longer qualify for the final rule's "existing LDT" exemption.
This presented an issue for the lab's prealbumin assay. The assay provided by its new IVD instrument vendor is approved to run in serum, but most of the lab's samples are plasma. Master said that he and his colleagues hadn't considered this a significant issue when they originally decided to switch from their previous instrument platform (which did offer a prealbumin assay approved for plasma) as they expected to simply modify the test for use in plasma. Under the new LDT rule, however, they might have to take such a modified test through premarket review.
Master said it is highly unlikely the lab will put in the work required to take a modified version of the test through the FDA, however. He said it is also unlikely to send out such a basic test or buy a separate platform specifically for prealbumin testing.
One solution, Master suggested, could be to "lean on the vendor" to get approvals for the various sample types his lab might need to test in.
It is uncertain if and how IVD firms might respond to such requests from their lab customers. While test offerings validated in a wide variety of sample types and across different reference ranges could provide a competitive advantage for a vendor's tests and instruments, that advantage might not justify the extra investment required.
"I think the challenge is in figuring out what sample types to validate and where it is a competitive advantage or a real customer need," said Donna Hochberg, a partner with Newton, Massachusetts-based healthcare consulting firm Health Advances. "I think the manufacturers are aware this is now something that they have to pay attention to. I think they have a hard road ahead to figure out where those opportunities are."
Large IVD vendors contacted by 360Dx had little to share regarding their thoughts on the issue. Roche, Siemens Healthineers, and Beckman Coulter declined to comment while Abbott did not respond to requests for comments.
Thermo Fisher Scientific provided a statement saying that it "is prepared and committed to supporting our customers with research and clinical solutions designed to drive discovery and diagnose disease," adding that its "team of regulatory affairs experts stand ready to assist our customers to navigate the new regulatory requirements now and in the future."
Zach Rothstein, executive director for trade organization AdvaMedDx, whose members include a number of major IVD vendors, said that "right now, just like the LDT community, we are still working to understand the impact of the final rule on the broader testing ecosystem and how we can continue to meet the needs of our lab partners."
He added that AdvaMedDx continues to support the Verifying Accurate Leading-edge IVCT Development (VALID) Act, noting that the technical certification program included in the bill "would enable IVD makers and LDT developers to more efficiently bring tests to patients, and that would include when the sample might need to be altered from the initial FDA clearance." Many clinical lab players opposed VALID as they believed it would overly restrict their development and use of LDTs and hurt patient care.
Jonathan Genzen, chief medical officer and medical director of automation at ARUP Laboratories, said that while "there are many vendors who recognize they are going to have to work with their customers in adapting to the final rule, I have not seen vendors who have said they anticipate increasing the number of sample types in their submissions to alleviate that work from their customers."
He suggested that in many cases — including the prealbumin example Master detailed at the ADLM meeting — the market advantage will not be large enough to incentivize vendor investment.
Hochberg suggested that vendors are unlikely to invest in FDA submissions for modified versions of assays already on the market as this will not meaningfully drive revenues. She said that for new assays, however, the calculus may change "in terms of how you decide what sample types to validate."
An IVD industry stakeholder who requested anonymity to speak about regulatory matters indicated, though, that validating in different sample types is a taxing process, noting that "obtaining FDA clearance for a diagnostic test across multiple specimen types is exceedingly challenging for IVD manufacturers."
Genzen offered another example of how the LDT rule could complicate vendor-lab relationships, positing a situation in which a number of labs have modified an IVD vendor's FDA-cleared test and taken those modified tests through premarket review.
"What are the implications if that vendor then reformulates their [underlying] assay?" he asked. "I think [vendors] get more intertwined with the FDA submissions of their customers than they currently are, and that could create unexpected pressures or unexpected liabilities."
One important question is which test modifications the FDA will consider minor changes not requiring premarket review and which it will consider major changes that do require such review. In the preamble to its final rule, the agency said that it will require premarket review for modifications that "could significantly affect the safety or effectiveness of the test or … constitute a major change or modification in intended use."
In its recent draft guidance on Predetermined Change Control Plans (PCCPs) — documentation manufacturers can include in initial test submissions detailing future changes they may make to the test and which allows them to make such changes without premarket review — the FDA provided some insight into how it views certain specific test modifications.
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 and would require premarket review. 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. An extension of the potassium IVD's sample stability claims, meanwhile, could be done via PCCP.