NEW YORK – The US Food and Drug Administration's final rule on laboratory-developed tests (LDTs) was a major topic of discussion at the Association for Diagnostics & Laboratory Medicine's (ADLM) annual meeting in Chicago last week as stakeholders considered a number of outstanding questions and concerns.
ADLM staunchly opposed the FDA's efforts to regulate LDTs as did many of the organization's individual members. With regulation having now come to pass, however, laboratories are beginning to tackle implementation of the new agency requirements, even as the industry continues to lobby against the rule and battle it in court.
The rule's requirements around medical device reporting, corrections and removals, and complaint recording go into effect in less than a year, on May 6, 2025. A year later, on May 6, 2026, the rule's requirements around device registration, listing, labeling, and investigational use go into effect, with the rule's quality systems requirements taking effect a year after that on May 6, 2027. On May 6, 2028, premarket review requirements for high-risk LDTs will go into effect, while premarket review for moderate- and low-risk LDTs will be required starting May 6, 2029.
The FDA rule provides a number of carve-outs. Among the most prominent are for LDTs that were on the market when the rule went into effect in May and LDTs offered by a lab within an integrated healthcare system to patients of that system in order to serve an unmet testing need. Such LDTs must comply with only the 2025 and 2026 requirements, meaning they won't be subject to quality systems requirements or premarket review.
These carve-outs aren't entirely straightforward, however. For instance, while existing LDTs are exempt from quality systems requirements and premarket review, they are no longer exempt if modified in certain ways. And an LDT offered under the unmet need exemption may lose that exemption if an equivalent FDA-cleared test becomes available. Uncertainty around how the FDA will interpret its rule with regard to these carve-outs was a major concern for meeting attendees.
"Modifying existing FDA-approved assays is the second most common reason for running an LDT," Patricia Jones, clinical director of the chemistry and metabolic disease labs at Children's Medical Center of Dallas, said during an ADLM session on the FDA rule, noting that such modifications are commonly made for a variety of reasons, including to extend an assay's reportable range, to change its intended use population, or to use it in a different sample type.
Whether such changes will trigger premarket review requirements is unclear, Jones said.
"Nobody knows what is a significant change," she said. "It has not been in any way, shape, or form defined yet."
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."
Nonetheless, as Jones indicated, many labs feel they lack clarity around whether and how to proceed with potential modifications of existing tests.
These questions 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.
Stephen Master, division chief and director of metabolic and advanced diagnostics at Children's Hospital of Philadelphia, noted that his lab "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 "existing LDT" exemption.
He cited the example of the prealbumin assay offered on his lab's new platform. The assay is approved to run in serum, but, Master noted, 80 percent of his hospital's specimens are plasma. 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 was highly unlikely the lab would put in the work required to take a modified version of the test through the FDA, however. Sending out such a basic test and buying a separate platform specifically for prealbumin testing are likewise "absurd" options, he said.
One solution, Master said, might be to begin collecting serum samples from patients along with the more typical plasma samples. Another solution, he suggested, might be to "lean on the vendor" to get approvals for the various sample types a lab might need to test in.
At a separate ADLM session on the LDT rule, Dennis Dietzen, professor of pathology and immunology and section head of the pediatrics lab at Washington University School of Medicine in St. Louis, also raised the role IVD vendors might play in helping labs deal with the new regulations by, for instance, validating their tests in a broader range of sample types. He noted, however, that it is unclear whether vendors will be willing to do this or how labs can start such conversations with vendors.
The LDT rule's unmet need carve-out could also present complications, Master noted during the ADLM discussion. While healthcare systems can offer their patients LDTs for which there are no FDA-authorized IVDs, if an FDA-authorized IVD becomes available, systems must either take their LDT through the FDA or begin using the FDA-authorized IVD.
Master highlighted CHOP's ferritin assay as an example of how this could impact laboratories. He and his colleagues have modified a vendor assay to extend the manufacturer's reference range in order to better monitor patients experiencing a cytokine storm post CAR T-cell injection. For now, they are able to offer the assay under the unmet need exemption, but they would no longer be able to do so if an FDA-authorized version came to market. If that authorized version ran on their existing lab analyzers, moving to it would be relatively simple. If, however, the authorized assay is brought to market by a vendor the lab doesn't work with, the situation becomes more challenging.
"Are we going to get a new instrument just to support ferritin?" Master said. "I have no idea, and I don't think that anyone I've talked to really understands how FDA is going to handle that."
More generally, labs developing tests to offer under the unmet need carve-out "have to be very, very well informed" about IVD vendors' test development pipelines, Master said. "If you're not … figuring out what upcoming major vendor releases are, you're going to get burned."
To effectively deal with the final rule, labs need to identify which tests they offer may fall under heightened scrutiny and then assess how essential those tests are to their lab and institution, he said.
"If my institution wants to have a specialty center in disease X, and these LDTs are critical for disease X, then I better know that, because I'm not going to undermine the priority of my institution," he said. The institution "just needs to know that it is going to cost more because it has gotten more expensive to develop LDTs."
On the other hand, a lab might make a different decision with regard to LDTs for diagnosing or managing conditions for which patients typically go to a different institution, Master said.
"We need to be able to more systematically assess the medical need of every test we run, how quickly it is required, how much it costs, and to put all of that [information] in one place so we can prioritize," he said, "because no institution is going to be able to do everything."
Amid the gloom there was some hope that the American Clinical Laboratory Association will succeed in its efforts to overturn the final rule via its ongoing lawsuit challenging the FDA. Dietzen noted, in particular, the recent Supreme Court ruling overturning the legal principle known as "Chevron deference," under which the courts have generally deferred to regulatory agencies' interpretations of ambiguously written laws. He suggested that the court's decision to upend Chevron deference made ACLA's case against the FDA "a lot stronger." Some legal observers have similarly suggested the decision likely strengthened ACLA's case.
An ADLM session on the European Union's In Vitro Diagnostic Regulation, meanwhile, suggested another route that the FDA's final rule might take: delay.
During the session, Patrick Bossuyt, a professor of methodology and personalized medicine at Amsterdam UMC, provided an update on the implementation of the IVDR's rules on "in-house" tests, the EU equivalent of LDTs. Under IVDR, labs can only offer in-house tests when an equivalent CE-IVD-certified device is not available and cannot transfer the device to outside facilities. Additionally, the test must be produced and used under a quality management system, and labs must document the test manufacturing, design, and performance data.
Bossuyt noted that IVDR does not require premarket review of in-house tests, making the regulation less onerous than the FDA rule. Nonetheless, implementation of the in-house test regulation, along with the IVDR more broadly, has been delayed. Originally slated for enforcement starting in 2024, the new in-house rules are now scheduled to go into effect in 2030.