The regulation of lab developed tests: an uncertain future

By Nicholas Smith

If the U.S. Food and Drug Administration (FDA) goes forward with its proposed guidance to regulate laboratory developed tests (LDTs) in the same way it does manufacturer-derived tests, then much is going to change for clinical laboratories, their industry partners that produce the reagents, assays, and instruments needed to perform these tests, and the clinicians and patients who have come to rely on LDTs to fill the gap in diagnostic testing.

How legislation pending in the U.S. Congress, the final form of the guidance, and what role FDA's Clinical Laboratory Improvement Amendments (CLIA), which currently regulates LDTs, will continue to play all remains to be seen. All this uncertainty and impending upheaval has created an environment defined by speculation and cautious planning for best- and worst-case scenarios. It is too early for actual solutions.

Choices, choices

What we know and think we know

Is there precedent for FDA regulation of LDTs?

Yes, there are several examples in which the FDA has reviewed and approved LDTs in the past, some in the Center for Devices and some in the Center for Biologics, according to attorney Randy Prebula, Partner, Hogan Lovells. "One of the first LDT methods the FDA looked at was a CDC method for diagnosing West Nile virus in blood donors," he says, and it was cleared in 9 days. The FDA has also listed at least one LDT in a companion diagnostic perspective associated with the treatment of HIV. "The test is described in the labeling of the drug and available as an LDT," says Mr. Prebula.

What criteria with either FDA or CLIA use to clear LDTs?

Laboratories will have to demonstrate the analytical performance of the test, including its accuracy, linear range, and limits of detection, and show that it works with clinical/patient samples, states Luann Ochs, Senior Project Manager, Clinical and Laboratory Standards, Institute. "Did you follow design controls? Can you prove that you can make the test the same way every time? Is the process controlled?" Ms. Ochs notes that laboratories can submit clinical trial and validation protocols to the FDA in advance and they will provide feedback that can facilitate the approval process.

Will any existing LDTs be grandfathered in if a new guidance is put in place?

There is no provision for grandfathering, according to James Nichols, Chair, Government Affairs Committee of the American Association of Clinical Chemistry (AACC). The FDA has indicated that it will have "enforcement discretion" over certain categories of tests," he says. Although the expectation is that routine, traditional types of LDTs will be considered as low-risk, "they have not defined what criteria will be a high-risk versus a low-risk test."

Sample questions in search of answers

• If you are using an existing test to measure an analyte in a different body fluid that originally intended, is that an off-label use of the test or an LDT?
• If you are developing a test at the request of a clinician for one specific patient, essentially for one-time use, would that be classified as an LDT?
• If you can buy an assay to measure an analyte in a body fluid, but a laboratory develops a mass spectrometry (MS)-based method to perform the test and shows that the results are comparable, does every laboratory that then uses the MS-based approach have to file for an LDT?

"We'd like to see that test developers don't have to keep showing the same information about clinical validity," says Andrew Fish, Executive Director of AdvaMedDx. While it will be important to protect innovative technology and provide incentives for innovation, "there should be a way to establish clinical validity that can be relied upon by subsequent applicants." For example, says Mr. Fish, "We're working with the FDA to make the pathway to different sample types much more streamlined."

Moving forward into an uncertain future

Legislation in development in the U.S. House of Representatives is intended to constrain the FDA's flexibility in terms of what it can ask for to show that a test is analytically and clinically valid, explains James Nichols. Based on an informal audit, he estimates that there may currently be thousands of LDTS just in the area of traditional core chemistry, not taking into consideration molecular diagnostics, infectious diseases, etc. This estimate also does not take into account the use of different sample types, alternative body fluids, MS- and chromatography-based assays, and other variations on traditional assays.

For clinical laboratories, from a preparation standpoint and for budgeting purposes, "because we don't know what is going to have to be filed and what isn't," and what resources will be needed to continue offering an LDT, this creates uncertainty, states Mr. Nichols. "If [the FDA are] going to treat us like manufacturers, but manufacturers that can't make money off those tests, then we may no longer be able to offer these tests for patients for these rare diseases."

As the LDT regulatory paradigm shifts, stakeholders need to work together to understand and prepare for its potential impact. Tecan can help. With our long history of developing automated solutions for the highly regulated IVD medical device market and our experience in partnering with both researchers and clinicians, Tecan has the knowledge, technology, highly skilled regulatory team, and a strong record of regulatory compliance to help find answers and develop solutions to meet your needs. Let's continue the discussion about LDTs and talk about how we can work together to make a difference for patients.