Laboratory developed tests (LDTs) can be game changers: They allow laboratories to create tests tailored to their patient populations, and they can save labs time and money by eliminating the need to send tests out to another laboratory. But they also come with risks, especially in a changing regulatory world.
CLN spoke to Danyel Tacker, PhD, clinical professor of pathology and medical director of special chemistry and mass spectrometry laboratories at West Virginia Hospital and J.W. Ruby Memorial Hospital, about how to use LDTs to innovate and adapt while staying within regulatory lines.
This is part one of a two-part series on implementing LDTs. You can read part two here.
From a business and quality perspective, what differentiates labs that are successful in launching LDTs from those that struggle?
In a nutshell, it comes down to careful planning. To launch an LDT effectively, you need to engage with the clinicians who will be using the test and develop a quality assurance system that detects real errors. You can’t just check a box; you must know the intricacies of the method and be able to detect drift. If you plan well, you will have systems in place that will give you confidence in the performance of the test.
What typically triggers your lab to consider developing an LDT instead of adopting a commercially available in vitro diagnostic (IVD) assay?
With commercial IVDs, sometimes there are aspects of the performance criteria that don’t quite meet the needs of the population we’re trying to serve. I’ll use an example from my colleague Amy Pyle-Eilola, PhD, DABCC, FADLM, director of clinical chemistry at Nationwide Children’s Hospital. She had to use Food and Drug Administration (FDA)-approved urine drug toxicology screens in a pediatric population, whose urine is more dilute than older patients’ urine. This can lead to false-negative results in a group for whom any incidence of drugs is potentially clinically relevant.
If an FDA-approved test isn’t engineered to suit your purpose, it’s up to you to build one or modify an existing test. In Dr. Pyle-Eilola’s case, she modified the cutoff threshold to improve the test’s sensitivity among pediatric patients. Any presence of a drug was her first signal to do more digging. Then she’d send for a more extensive analysis in a mass spectrometer.
My lab’s development of a test to confirm toxicology results onsite instead of sending them to a reference laboratory was driven by cost concerns — but we knew we needed to have the onsite capabilities and knowledge to do mass spectrometry testing to pull it off. We did a “toe dip” first, starting with alcohol biomarkers on a limited panel. When we saw that, yes, we were doing a good job with building this method around it, we then built opioid and tetrahydrocannabinol (THC) tests.
It can also be helpful to take input from the clinical team. When we engaged with behavioral medicine, they said they would like us to add tramadol to the opioid panel and asked if the THC test could distinguish between delta-8 THC and delta-9 THC.
What does your feasibility assessment look like before you commit resources to an LDT?
We go so far as to build the program we intend to use. If it’s in mass spectrometry, we will tune standards, ask how we’re going to calibrate the test, and then build a calibration method. We will simulate a clinical scenario and assess what kind of quality assurance is needed and what operational conversations we’ll need to have.
For example, with our opioid test, our first results were a mess. In the development phase, we realized we were going to have to add an enzymatic digestion step to cut glucose moieties off the drugs. It took us 6 months just to present a validation plan to the clinical director.
You may need to pour thousands of dollars and hundreds of hours into that development phase. Or, if it’s a modification or something smaller like adding a filtration step, you might only have to devote tens of hours and a few hundred dollars of materials to get off the ground.
With some tests, we’ve gotten to the point where we realized right away that feasibility was a big no with what we have onsite right now. The hospital administration was disappointed, and we told them that this is why our lab needs space, staff, and equipment. When the “no” comes and your institution is surprised by it, it’s a good time to emphasize: “Well, you've supported us really well so far, and now that support must continue so we can expand.”
What are the biggest implementation challenges you’ve faced? Are there any that caused the lab to move on from the contemplated LDT?
We’ve had to extensively educate our administration about the different methods for tests and feasibility. For example, if they request that we do a test for lead, we must explain that, although we have mass spectrometry in our lab, we’d need a different kind of mass spectrometer to perform that analysis.
For every possible LDT, we must consider: Do we have the space? Do we have the cash? Do we have the means to sustain it? Do we need new equipment?
There are also concerns about regulatory pressures. For example, we were building the delta-8 check for our THC test during the last round of policy discussions about LDT oversight. We did it as a qualitative yes/no test for whether delta-8 was present. The hospital really wanted that to be a quantitative test, but we were facing an uncertain regulatory structure. We didn’t even know if our baseline method modification would be approved.
While we’re generally good at taking our cues from a regulatory standpoint, labs are heading into a dangerous environment right now.
If we find out a user is trying to inappropriately alter a method in terms of clinical interpretation, we might put a halt on a launch and say, “Hold on, that’s not what we talked about. What are you telling people this thing can do? How are you putting that out in the world?”
Some teams are afraid to go into that territory. They’re worried they don’t have the onsite expertise or that they could do clinical harm, so they would rather leave the situation as it is.
How would you advise a health system on integrating LDTs alongside commercially available IVD assays?
Consider alternative collection techniques. This is something we faced in COVID. The FDA kits had those “tickle your brain” type swabs. Labs were looking into swabbing the mouth and developing self-collection techniques so they didn’t have to put nurses in tents outside. They thought through how they might modify the FDA-approved kit.
Also think about instances where labs can complement broader efforts. For example, with the recent measles outbreak, many labs did not have collection techniques because the disease had been eliminated. But now that unvaccinated people are getting measles and spreading it in their communities, local testing options would be a great idea.
Sending all those tests to the state lab or the Centers for Disease Control and Prevention would flood them. So creating that “hub and spoke” model, where local labs can develop and offer tests would help a lot, like it did with COVID.
Once an LDT is live, how do you monitor its performance and decide when revalidation is needed?
Any time you’re going to change a test, you may have to go back to the drawing board on validation. I have an example that isn’t even an LDT. It’s an FDA test with a new generation of reagents for our primary chemistry analyzers. Right after go-live, providers signaled to us that they were getting a bunch of elevated results.
We discovered that gold-top tubes (for serum) did not show an elevation in the outreach population, but the green-top tubes (for plasma) did. So we switched the outpatient population over to serum.
How does your lab balance innovation with concern over potential future FDA oversight?
Through careful consideration. We mapped every LDT we had and did a brief risk matrix. What are the pros and cons? What is the turnaround time if we can’t do this test? Would turning off an LDT delay decision-making in the hospital units?
Maybe you can rank and prioritize tests that are critical for care, and balance your fears by streamlining the number of tests or developing contingency plans — things along those lines.
What advice would you give to a lab preparing to launch its first modern molecular LDT?
Get familiar with the guidelines from your accrediting agency. Look into the questions you will be required to answer before an inspector is in front of you. Ask yourself: How am I going to respond? What are we ensuring? Are staff competent? Do we have good inventory and a supply of everything that we need?
Jen A. Miller is a freelance journalist who lives in Audubon, N.J. +Bluesky: @byjenamiller.bsky.social
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