NEW YORK – As the Verifying Accurate Leading-edge IVCT Development (VALID) Act makes its way through Congress, confusion remains about what will happen to existing laboratory-developed tests.
The bill is intended to officially give the US Food and Drug Administration jurisdiction over the regulation of LDTs, which has been debated among the laboratory and diagnostic manufacturing communities for decades.
Proponents of the bill have cited the need for a universal regulatory framework encompassing all in vitro diagnostic tests that would create a level playing field for everyone developing an IVD and would protect patient safety and provide transparency. Detractors, including many in the clinical laboratory space, have concerns, however, about the potentially lengthy and burdensome bureaucratic process that diagnostic tests would have to go through to reach the market under VALID.
Another looming concern is the status of existing LDTs if and when VALID is made law. The bill as it stands now has a grandfathering clause that would allow tests that were on the market before VALID is enacted to stay in use, as long as no major modifications are made to the test. A modification must not "constitute a significant change to the indications for use" or "significantly and adversely change performance claims or … performance," according to the bill. A modification must also not "constitute an adverse change in the safety" of the test.
However, many stakeholders have expressed confusion about what qualifies as a significant modification. Karen Kaul, the chair of the department of pathology and laboratory medicine at NorthShore University HealthSystem, noted that there are "a lot of unanswered questions" about how grandfathering would work in practice.
As she understands it, using different materials or a different format or adding another gene to a panel would move the test out of its grandfathered state and would require a laboratory to submit it to the FDA for review. "We do make changes to tests," she said. "The field is evolving." But VALID, in her view, would "cause assays to be frozen in time."
Although the grandfathering clause currently in VALID allows for minor modifications of existing LDTs without FDA review, Kaul said the bill would "make labs less nimble," since labs would "not have the latitude to just add other analytes." Some changes "can have a major impact" on the test, and while a laboratory would internally validate that added target before using the test, needing to submit the test to FDA without knowing how long that review could take would discourage labs from innovating.
Dennis Dietzen, the medical director of laboratory services at St. Louis Children's Hospital, echoed Kaul's comments, saying that LDTs are "meant to be malleable, they're not meant to be static." As the bill stands now, it's hard to know "what changes will bolt us into the FDA's gun sight." The question of what counts as a significant change is up in the air — does a change in sample volume qualify as a modification that would require an FDA submission, Dietzen asked.
Jonathan Genzen, the chief medical officer at ARUP Laboratories, said that the grandfathering clause in VALID "needs some additional review" to ensure LDTs stay on the market. The FDA "should have authority to protect public safety," he noted, but there "should be mechanisms and boundaries to do that in an appropriate way that does not disrupt the ability of an individual clinician to order and seek appropriate diagnostic testing for their patients."
Like both Dietzen and Kaul, he said he has concerns about the definition of grandfathering and whether it would prohibit small changes to tests. "It is often necessary … to make minor test modifications to keep a test robust and healthy," and if laboratories are "locked out" of making those changes, it "could make grandfathering hard to sustain" as labs would simply drop existing LDTs, particularly if they're low-volume.
Eric Konnick, the associate director of University of Washington Medicine's Genetics and Solid Tumor Lab, said that the devil is in the details when it comes to the grandfathering clause. There's a question of "who gets to decide" what a significant change is and what would need to go to the FDA. While it's a good thing that — under the current clause — tests would still be available and there wouldn't be an immediate cessation, there could be "a lot of arbitrariness" if individual FDA reviewers disagree on the limits of a modification and "uncertainty" in how those regulations are applied, he said.
That uncertainty could cause individual labs to step back from modifying LDTs because the uncertainty of a review may be a bigger risk to them, and the cost and development efforts to send a test to the FDA may not be supportable. "The decision will be just to let things languish," he said.
In a letter to the US Senate Committee on Health, Education, Labor and Pensions from May, the American Clinical Laboratory Association provided recommendations intended to strengthen the grandfathering provision in the bill. The organization recommended that the FDA only be able to request additional information about a test by "detailing scientific concerns" indicating the test lacks sufficient valid scientific evidence of analytical or clinical validity, is being offered with false or misleading claims, or is likely to cause serious adverse health consequences, it wrote in the letter.
ACLA also recommended that the agency provide opportunities to meet with the developer and clarify information and said that premarket review for a grandfathered test should be required only if the issues can't be resolved another way.
A driving factor behind the introduction of VALID is the need for transparency surrounding LDTs and to stop bad actors from marketing faulty tests. But Kaul noted that clinical hospital labs, such as the one she runs, aren't marketing their LDTs broadly and that there is no data that shows that FDA-approved tests perform better. Kaul said that she has seen no data suggesting major problems at hospital labs. These labs already have oversight to ensure quality control of LDTs, she added.
Hospital laboratories are subject to evaluations through the Clinical Laboratory Improvement Amendments under the Centers for Medicare and Medicaid Services, as well as accreditation processes under the College of American Pathologists and other organizations, such as the New York State Department of Health. These organizations already review validation and proficiency testing data, and adding an FDA review with different requirements would create an additional layer of reporting that would add significant burden to already strained labs, Kaul said. Also, CLIA oversight "covers the entire testing process, from sample collection through analysis to reporting, whereas the FDA only addresses the test reagent kit."
Her lab would need to hire personnel to oversee regulatory submissions to the FDA, which would be "a lot of work" and require handling a lot of information. Because hospital labs don't have the resources that a for-profit company with an entire regulatory compliance division has, they may choose not to offer such tests. "It's an expensive undertaking," she said.
Kaul also emphasized that hospital labs often use FDA-approved tests if they're available, but "often there are assays needed for which there is not an option for an FDA kit."
Like Kaul, UW's Konnick said that his lab often purchases FDA-approved tests when they're available and meet the need of the lab: The "problem comes when those commercial tests don't fit the need" or need to be modified for clinical use, he said. Some of those modifications could be adapting the test to work on a platform the laboratory already has in use, he said.
According to Konnick, some groups have been against grandfathering existing LDTs because the performance of the tests is unknown, but most LDTs in common use have undergone proficiency testing and are overseen by medical directors, he said, adding that most of the tests have no problems.
Konnick also mentioned ways to make LDTs and their performance more transparent, such as allowing proficiency testing data to be de-identified and published. If there are problems that multiple labs have in common with certain tests, those can be determined and fixed without involving the FDA.
ARUP's Genzen said that there is a "narrative … that the public deserves more visibility" into LDTs, which he called a fair concern, but he believes that implementing such transparency doesn't require legislation, particularly legislation that increases the regulatory burden. "Clinical laboratory settings will not have the resources to comply and keep up with … notification and reporting processes," he said.
Even beyond the need for additional staff to take care of submissions, Genzen noted the potential cost of submissions fees and notification fees. If it's similar to medical device user fees, "we're talking tens of thousands of dollars per test, if not more" for labs that already are strapped financially, he said.
The current notification and submission structure under VALID is "not well aligned" with high complexity CLIA labs, but rather with existing diagnostic manufacturers, he said. For IVD manufacturers, there is a need for an "incredibly rigid regulatory structure" because the operators of those tests likely didn't develop them. That's a different model than a laboratory modifying an FDA-approved test to work with a different sample type, for example. "A one-size-fits-all approach just doesn't make a lot of sense from a regulatory cost and burden perspective," he said.
Burdens across the board
Another consideration Kaul and other stakeholders have raised is the burden evaluating LDTs will put on the FDA, especially if existing LDTs also need to be reviewed. The FDA "is not equipped to handle this review," Kaul said.
Many labs "didn't necessarily have the optimal experience" during the COVID-19 pandemic when dealing with the FDA, leading to hesitancy about whether the agency will be able to cope with the influx of LDTs. "The number of LDTs is tenfold beyond what the FDA is expecting," she said.
The review process timeline was a key focus of Dietzen's distaste for the bill. "The FDA is not known for rapid responses," he said. The agency will have more than a month to respond to a submission, and any feedback that requires an additional submission of data or information will potentially have another waiting period. That length "defeats the purpose of bringing an LDT into clinical practice in rapid succession," he said. By the time some LDTs make it through the FDA process, they may not be necessary anymore, he added. It will "lengthen the time to market, it will make it more expensive."
Dietzen also emphasized the workforce burden this could put on labs, who will need to learn a whole new skill set to communicate efficiently with the FDA. Meanwhile, VALID may require labs to conduct more experiments to meet the agency's requirements than are currently needed under CLIA. The additional burden will "make practitioners think long and hard" about developing new tests and may cause labs to "rethink their existing LDTs," asking if it's worth maintaining the assays when it will require so much time and effort, he said.
And for esoteric or low-volume tests where profit margins are small or "almost nonexistent," Dietzen believes they will be driven into larger reference labs with the resources to handle them, which would increase turnaround times.
Although nimbleness is a necessity for most clinical labs, those working on assays for infectious diseases would be particularly susceptible to timeline concerns under VALID. Genzen cited the current monkeypox epidemic as an example — if clinical labs were subject to VALID, there would be no rapid mechanism to bring an LDT to market before the FDA's Emergency Use Authorization declaration, which occurred last week. There "are very real concerns that too rigid a regulatory structure … could actually further delay [a lab's] ability to bring a test online in the context of an urgent public health threat," he said.
Genzen also noted that CLIA provides necessary flexibility in emergency situations, such as a critical supply shortage requiring the validation of a test with different suppliers in order to keep a test available. VALID "doesn't reflect that day-to-day operation need and challenge … to keep testing going," he said.
Susan Van Meter, ACLA's president, said that there is "no question" that labs will need significant resources to come into compliance under VALID if it passes, noting that the notice and comment rulemaking period cited in the bill, as well as guidance on implementation, will be "very important" to labs trying to figure out how to address the new requirements.
While VALID may be the talk of the town, stakeholders have proposed alternatives that could improve transparency and address the concerns of the industry.
The CLIA model "has really worked well for decades," Konnick said. In his view, a lot of the concerns surrounding transparency are related more to the marketing of performance characteristics, which would fall under the FDA's purview. However, academic medical centers and clinical labs aren't often marketing their tests broadly — this is more of an issue with specialty labs or for-profit companies whose products are heavily marketed, particularly those marketed directly to patients, he said. Those settings "could use some additional regulatory oversight" by the FDA, he said. A lot of LDTs are for uses where "there's never going to be a big commercial market," he added.
Mary Steele Williams, the Association for Molecular Pathology's executive director, agreed that the "best option for federal regulatory authority" over LDTs is CLIA modernization, and noted that "updates to CLIA are actively being considered by the [US Centers for Disease Control and Prevention's Clinical Laboratory Improvement Advisory Committee] which provides guidance to the federal government." Williams called CLIA modernization the "most streamlined and cost-effective approach" to regulation of LDTs, and "also the least disruptive and burdensome approach to addressing clinical and analytical validity, transparency, and other concerns expressed by interested stakeholders."
Shannon Haymond, president of the American Association for Clinical Chemistry, also recommended that LDT oversight be addressed by the CLIA committee in comments via email, because the committee experts "have the knowledge and expertise to review the issue, outside of the political realm, and determine what, if any, changes are warranted."
Genzen from ARUP said that there is an opportunity to have a conversation about which components of VALID could be included in CLIA modernization efforts and how the flexibility for clinical laboratories under CLIA benefits them. However, he said that there isn't any momentum for that conversation right now.
Regardless of the alternatives, confusion seems to abound when it comes to the fate of existing LDTs, despite attempts to clarify the process. The way the grandfathering clause is written now, it "absolutely provides certainty that there will be absolute uncertainty in how this is going to be implemented," Konnick said.