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Proposed FDA Regulation of LDTs Could Impact Labs' Ability to Alter Test Assays

NEW YORK – At the beginning of March, lawmakers from the House and Senate introduced legislation to establish a framework for US Food and Drug Administration oversight of diagnostic testing.

Called the Verifying Accurate, Leading-edge IVCT Development (VALID) Act, the bill would resolve longstanding questions over FDA's authority to regulate laboratory-developed tests (LDTs), explicitly giving the agency the authority to review and approve these tests.

That has some labs and test developers concerned about increased regulation as they try to move assays into practice, but according to Jenna Rychert, medical director, microbial immunology at ARUP Laboratories and an adjunct assistant professor at the University of Utah School of Medicine, the proposed legislation could also make it more difficult for labs to make changes to existing assays.

In a recent commentary in Clinical Chemistry, Rychert and her co-authors noted that under current guidelines, even minor changes to existing tests could require labs to treat them as LDTs, a fact that could take on new significance if the VALID Act or similar legislation becomes law.

At root, Rychert said, the issue stems from a lack of specificity in the US Centers for Medicare and Medicaid Services' CLIA guidelines, which provide the quality standards for clinical lab testing.

While FDA has specific guidances spelling out how in vitro diagnostic manufacturers can determine whether a modification to an approved test is significant enough to warrant notification to the agency, CMS has no equivalent system, Rychert said. "They basically just say that any modification needs to be evaluated."

Broadly speaking, this requirement, "is totally reasonable," she noted. "I think any laboratory is going to evaluate a change and make sure the performance characteristics haven't changed."

However, she said, the lack of clear distinctions in the CMS guidelines between major and minor modifications imply that any change requires the altered assay to be validated as if it were an LDT, "which requires much more extensive validation studies."

The water is further muddied by the fact that different auditors may interpret the CMS requirements differently, Rychert added.

"Different inspectors and different auditors read the regulations and understand the requirements differently," she said.

Additionally, different regulatory bodies — the College of American Pathologists versus COLA, for instance — may have slightly different interpretations, she said.

"You might have different interpretations of what is a modification and how it should be treated from a documentation standpoint and what verification studies are necessary," she said.

"It's a little too loose, is the problem," and more specific guidance from CMS around test modifications could help resolve the issue.

"I think that would really make a big difference," she said. "It means that we would have to agree on what is a modification, which means we would have to agree on what is major and significant versus minor and non-significant. If we had that categorization, it would be very helpful."

In the Clinical Chemistry commentary, Rychert and her co-authors cited as an example the case of wanting to use a microscope with an LED bulb for a test that instructs labs to use a microscope with a mercury bulb.

"That doesn't make any sense if I have an LED bulb microscope that works just as well or better," she said. "I think we could all agree that an LED bulb is going to be better, or at least as good as a mercury bulb and that that really shouldn't be a stumbling block," Rychert said. "Those kinds of [changes] happen in practice probably more often than we fully appreciate, especially in a high-complexity lab. We just handle them normally."

There are implications for moderate-complexity labs, as well, the authors noted, as "any modification of an FDA test recategorizes it as high complexity, which requires the laboratory to meet the personnel, proficiency testing, quality requirements of high-complexity testing."

Labs that aren't high complexity may not even be aware they need to be careful of making changes to such a test or that doing so would make them technically out of compliance, she noted.

There are probably many labs that run things in the way that manufacturers recommend without putting much thought into it, she said. Then there are the large reference labs with large R&D teams that are more prone to making changes to a test.

"A big part of our culture is looking to see if there is something we can do to use a test in a way that is better for patients," she said.

Rychert said that while labs are occasionally "dinged" by auditors over such changes, the recent proposals and legislation around FDA regulation of LDTs potentially raise the stakes. If even minor changes to tests require that labs treat those tests like LDTS, and FDA takes a more active role in regulating LDTs, it could make for a more onerous test modification process.

The FDA has long held that it had the power to regulate LDTs, even as the lab industry has said that that power rested with CMS. The VALID Act would clear up any doubts about FDA's purview on the matter, and in the matter of making changes to existing tests, it would codify that alterations to such tests could require another regulatory review, this time by FDA.

This possibility has sparked increased interest among labs in the existing rules around test modifications, Rychert said.

"I think that because FDA has brought up this idea of regulating LDTs, we're all kind of in that state of, 'uh-oh, am I in compliance?'" she said. "I think it is just coming into people's thoughts now because of the FDA LDT issue and the VALID Act and all of those kinds of things. There is heightened awareness now, and we're concerned that labs won't be ready if they haven't thought through this."

"It's all dependent on how FDA finally decides to handle these things," she said. "But it certainly is worrisome."