Laboratory-developed Tests: An Uncertain Path

It’s a change that promises to re-shape not only laboratory processes, but also how public health laboratories both respond and innovate.

“It’s a shift in mindset and it will change approaches and which LDTs you choose to bring on,” said Kara Levinson, PhD, MPH, D(ABMM), director of the Tennessee Department of Health Division of Laboratory Services.

Her laboratory uses LDTs on the clinical side for infectious disease testing and in the newborn screening program. “We’re part of LRN-B and LRN-C,” she said. “We have an environmental testing division and while we do use lab-developed tests in that division, they’re done in accordance with ISO 17025 standards, which are different compared to where this LDT rule impacts.”

Levinson stressed the critical role of LDTs in public health. “I don’t want people to stop doing LDTs because we can’t stay stagnant in public health,” she said. “We absolutely need to continue to bring on new tests and modify tests to meet needs. We’re just going to have to go about it a different way based on this LDT rule.”

LDTs are a powerful tool to help states, counties, and municipalities meet emerging public health threats. Lange cited a multi-state chemical threat event that occurred in 2018 as an example. Multiple individuals were exposed to brodifacoum (an anticoagulant rodenticide) via smoked synthetic marijuana products.

Healthcare professionals use vitamin K to treat brodifacoum exposure. Yet at that time, no clinical quantitative testing capability for brodifacoum exposure existed, Lange said. This left doctors without critical information to determine the appropriate vitamin K dosage for treatment.

WSLH sprang into action, standing up a new LDT in about three weeks, according to Lange.

“We were the only lab in the country that had this capability at the time, and we were able to meet a multi-state need for testing to support the response,” Lange said. “The high degree of technical skill and capability to stand up what’s needed, when it’s needed, has been and will continue to be found within state public health laboratories and the response partnerships established throughout the country.”

LDTs have also helped expand testing for new disorders at a faster rate in newborn screening programs. Joseph J. Orsini, PhD, deputy director for the Newborn Screening (NBS) Program in the Wadsworth Center at the New York State Department of Health, said his laboratory has used LDTs to initiate screening for several new disorders, including Krabbe disease, Pompe disease, adrenoleukodystrophy and guanidinoacetate methyltransferase (GAMT) deficiency, among others. NBS also uses LDTs for amino acid/acylcarnitine testing, as well as for biotinidase and galactosemia. “Because we are an early adopter of new tests, we have relied on LDTs to test for conditions,” Orsini said. “We have provided these data for evidence review and served on technical expert panels for the Advisory Committee on Heritable Disorders in Newborns and Children.”

Both Lange and Orsini noted the cost-effectiveness of LDTs. “Use of LDTs lowers test cost when compared to commercially available kits,” Orsini said. LDTs also lower programmatic costs, which Orsini said “allows us to evaluate and implement tests for other disorders, including newly approved tests and those under consideration for addition to the federally recommended uniform screening panel (RUSP). Using LDTs allows newborn screening programs to add screening for new disorders in a relatively rapid manner, thus alleviating the delay of waiting for FDA clearance.”

Orsini said New York has been able to implement LDTs before some FDA-cleared kits become available. “Without the LDTs, the FDA-cleared kits may not have been developed,” he said. “I believe data generated from LDTs facilitate a manufacturer’s development of a test that ultimately becomes cleared by the FDA.”

LDTs also enable states to meet statutory requirements for testing for conditions within a predetermined timeframe, according to Orsini. “Without LDTs, at least to start, states are at risk of violating their own laws,” he said.

Lange said LDTs help ensure access to certain tests in under-served communities, such as clinical blood lead testing. Using LDTs, public health laboratories can continue to advance technology while developing cost-effective testing, she said.

Developing a new LDT begins with identifying a specific need, Lange said. Proposed tests go through an approval process that includes investigation development, proof of concept, methodology validation and testing of system compliance with all regulatory standards. At WSLH, a Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited laboratory, a final review by the CLIA/CAP laboratory director occurs before any clinical inpatient testing.

“It’s a very prescriptive process,” Lange said. “We are validating a methodology in conjunction with a test system to meet a need.”

After a method has been published, LDTs in Orsini’s laboratory undergo rigorous testing of how well the method works, he said. LDTs are formally validated using guidelines from New York State’s Clinical Laboratory Evaluation Program (CLEP).

The new FDA rule for LDTs states that a laboratory with a New York State permit, qualified director, and LDTs reviewed and approved by CLEP will not be required to have their LDTs reviewed by the FDA, according to Orsini. Yet as a whole, New York’s public health reference laboratory and other clinical laboratories regulated by the CLEP system must meet other requirements as FDA’s policy is phased in over the next four years, he said. “The Wadsworth Center is currently reviewing the new rule to identify areas that may be impacted,” Orsini said.

Lange said she expects the new FDA rule to mean the end of some LDTs used at WSLH. Adhering to the new requirements will increase the need for resources, such as additional staffing, computer systems and legal consultation.

“Due to the financial constraints of being a state public health laboratory, this is stopping our implementation of new LDTs,” she said. “In fact, we also have a timeline to take down LDTs as the ruling is limiting our ability to plan for and respond to future needs. We will have to adapt and adjust with what we have since we have no funding to support additional resources to meet these FDA requirements.”

Cost is a critical part of the conversation about how the FDA rule may affect public health laboratories, according to Mandi Cosser, MPH, manager, regulatory and public policy for APHL. The cost burden is intensified in laboratories making modifications to FDA-approved tests, which then become classified as LDTs. “Public health laboratories have such limited operating budgets, and every dollar counts,” she said.

In addition to increasing costs, Lange said she also expects the new rule to affect innovation.

“How we support innovation in laboratory testing may have to shift,” she said. “We may become advisors to industry rather than the doers who can quickly stand up and meet the needs of the communities we serve.”

Lange said the rule may also have a longer-term impact on the public health laboratory workforce—one that may place public health in an uncompetitive position with industry.

“We have a lot of talented staff that want to work in emergency preparedness and response,” she said. “You get to be that novel method development chemist, QA officer or response chemist that’s actively helping to meet needs we see. That’s a unique role. There’s a potential for loss of talent, which has been a critical issue for public health laboratories across the country.”

Levinson said LDTs provide her laboratories with flexibility. “We use LDTs not only to meet emerging and other public health needs, but also to tailor our testing to the needs of our state and of the population within our state,” she said.

LDTs come in many flavors, she added. An LDT may be a modification to an existing FDA-approved test or a test that has been fully developed in the laboratory—or something in between. As an example, Levinson cited a test that may have been approved by FDA but not for a pediatric population. That’s where the flexibility of LDTs matters, she said.

“We can bring on this test and validate it for that population,” Levinson said. “It would be an LDT, but we could still meet the needs of pediatric patients. That’s the kind of flexibility I see us needing to retain. If we’re not able to do that and can’t offer that testing, we’re not meeting the needs of our clinicians and of Tennesseans.”

When asked how the FDA rule could affect the flexibility to modify existing tests, Levinson said, “A lot of it is unknown, and that’s causing concern and anxiety for myself and my team. Broadly speaking, in talking with colleagues, there’s certainly potential for this LDT rule to slow our ability and our speed to respond to urgent or novel public health needs if we now have to submit tests for approval.”

Some enforcement discretion will continue to be allowed under the FDA rule, potentially providing relief. “I consider that a huge win because that would have a drastic negative effect on laboratories if we didn’t have that flexibility built in,” Levinson said.

Historically, enforcement discretion and laboratory director approval allowed LDT development to move quickly in response to urgent needs. Levinson noted the inclusion of a carve-out in the final rule for immediate response.

“We’ve seen that come into play already with H5N1 for avian influenza,” she said. “My concern is about the unknown and trying to predict how FDA will actually employ this for future emergent needs, at what scale and how much flexibility we’re going to retain.”

Amid the uncertainty of some unanswered questions—particularly around LDTs involving toxicology—public health laboratories are preparing to meet the May 6, 2025, deadline for complying with the first stage of the new FDA rule.

Stage one requirements focus on medical device reporting, quality management systems, and correction and removal reporting requirements. “The good news is that we already have that structure in our laboratory,” Levinson said. “We’re going to lean on our quality assurance team and structures like our document control system and build them out to take us to that May 2025 deadline.”

Public health laboratories are also working together to help ensure readiness to meet the rule’s phased requirements. Lange said her laboratory is maintaining a catalog of resources, including what other states are doing.

Levinson encouraged colleagues to make use of all available tools. “FDA has provided a lot of information,” she said. “The LDT Task Force at APHL has made sure tools and resources are there to help laboratories understand what this rule is, how it will affect them, and what they need to do to comply. If you don’t have strong infrastructure in place, there are tools to help you.”

According to Levinson, Southeast ColLABborators have been talking about ways they can lean on each other, including potentially regionalizing some testing. “Maybe we don’t all have to reinvent the wheel,” she said. “Regionalized testing may help us meet those needs at a scale that’s a bit bigger than our individual jurisdictions.”

Yet Levinson noted that public health laboratories may face more significant preparatory challenges as deadlines for subsequent stages of the FDA rule approach.

“Requirements are going to get further and further from the processes we have in place and require more system and process building,” she said. “That’s going to take time and staff that we haven’t currently allocated for. My level of concern goes up as I look toward subsequent rollout of various phases. But we have time, and we’ll meet those deadlines as they come.”

The new LDT rule represents a “paradigm shift” in how public health laboratories approach regulation of their tests, according to Levinson. “It’s a big change,” she said. “At the end of the day, we all want the same thing—accurate and timely tests that meet the needs of our patients and our populations. I think that’s at the heart of the FDA’s goals and of all our federal partners. We all want the same thing. It’s a matter of coming to agreement on how we get there. This rule is in effect and the silver lining is it’s an opportunity to look at our current system for quality and make it more robust.”

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