Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

For-Profit Developers, Nonprofit Academic Labs Challenge FDA Over LDTs

A year after the FDA proposed regulating “high-risk” laboratory-developed tests (LDTs) along the lines of Class III medical devices, through draft guidances friendlier to for-profit diagnostic developers than nonprofit academic medical centers, both sides have advanced detailed regulatory counterproposals in hopes of swaying the agency.

The Association for Molecular Pathology (AMP), whose membership includes academic and community medical centers, has released its own recommended rules for LDTs. AMP contends that the FDA is overreaching in its proposed regulation of LDTs—which it calls “laboratory-developed testing procedures”—because the tests are not medical devices subject to the Food, Drug, and Cosmetic Act (FDCA).

Instead, the AMP is advocating the most extensive updates to the Clinical Laboratory Improvement Amendments of 1998 (CLIA) since they took effect in phases through 1994, with the goal of accommodating current laboratory practices and technology. Labs may develop and use their own diagnostic tests internally, without FDA oversight, if certified under the waiver program of CLIA, overseen by the Centers for Medicare and Medicaid Services (CMS).

The AMP’s “Proposal for Modernization of CLIA Regulations for Laboratory Developed Testing Procedures” creates a three-tier, risk-based regulatory system for LDTs. Labs can validate “low risk” tests and put them into service, subject to inspection in the normal course of the inspection process. For “moderate risk” tests, labs would have to submit information to CMS or a CMS-approved nongovernmental “third party” reviewer at least 30 days before being offered to the public, with a 30-day review time limit. That limit extends to 90 days for “high-risk” tests, which also require submissions to CMS or a third party at least 90 days before offering to the public.

The FDA made its proposals in two draft guidance documents: 1) Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs), and 2) FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs). The FDA has received more than 300 substantive comments on the draft guidance, spokeswoman Jennifer Dooren told Clinical OMICs.

“We expect to amend the proposed oversight framework for LDTs to incorporate some of the suggestions provided by commenters, and in cases where suggestions were not incorporated, we intend to explain why,” Dooren said. “We cannot comment on the timing of any final guidance on the LDT oversight framework.”

The FDA would assign LDTs risk classifications of low, moderate, and high, based on existing classes of medical devices. The FDA generally envisions reviewing premarket approval applications for high-risk Class III LDTs, while third parties would review Class II tests. The agency would continue exercising enforcement discretion on premarket reviews for Class I tests.

Under the AMP’s proposal, the FDA would be limited to reviewing one type of high-risk LDT, multi-analyte assays with algorithmic analysis (MAAAs) with proprietary algorithms—unless the lab behind the MAAA subject its algorithm to third-party review and inspection.

“Not a Radical Break”

“In looking at the regulations themselves, we recognize that they were designed and written at a different time, that technologies and practice standards have changed. What we’re talking about is an attempt to accommodate those changes. It’s not a radical break from CLIA,” Roger D. Klein, M.D., J.D., AMP professional relations chair, told Clinical OMICs. “We would reiterate that neither the FDA nor anybody else has come forward with evidence, with data that suggest a systematic problem with laboratory testing in general or with LDTs in particular.”

The FDA asserts that as LDTs have become more complex over the past generation, many consist of components that are not legally marketed for clinical use while others are used beyond local populations and manufactured in high volume. The FDA also is concerned that many are used widely to screen for common diseases and for directing critical treatment decisions such as prediction of drug response.

Dr. Klein, who is also medical director, molecular oncology at the Cleveland Clinic, added that in practice, most laboratories that perform significant molecular pathology testing exceed CLIA requirements—either because of more stringent standards developed by professional groups such as the College of American Pathologists (CAP) or because these labs serve New York state patients. The Empire State became the first state in the nation to establish licensing for laboratories performing clinical testing in 1965: “In a sense, we’re raising the floor of the CLIA regulations.”

While acknowledging that CLIA modernization would add to the costs of labs, he said the costs of complying with CLIA are much less than with FDA. Costs would be assessed on a sliding scale, as at present, for laboratories based on their volumes of tests.

“The AMP has a number of industry members, and they have told us that their costs run into the hundreds of thousands, and even millions, of dollars for 510(k)s and PMAs. We’re talking about orders of magnitude lower costs to comply with enhanced CLIA regulations,” Dr. Klein said.

The AMP is seeking to translate its proposal into a federal law that would preempt FDA regulation. To that end, the association has engaged committee staffers from the U.S. Senate and House of Representatives. “The AMP had a productive discussion with bipartisan committee staff members from the House Energy and Commerce Committee and we look forward to continuing to work with them and also meeting with additional members of the Committee,” Tara Burke, PhD, policy analyst with AMP, told Clinical OMICs.

By contrast, AdvaMedDx, the diagnostics manufacturers’ division of the Advanced Medical Technology Association (AdvaMed), argues the FDA is better able than CLIA to assure clinical validity for LDTs.

“We have some labs as members who have gone through the FDA process with their LDTs, so we’re not completely unfamiliar with the issues labs face. We also know that labs can take tests through the FDA, and do so successfully,” Andrew C. Fish, executive director of AdvaMedDx, told Clinical OMICs. “There may in fact be reasons that CLIA should be updated. But there don’t seem to be good reasons for CLIA to be expanded to overlap entirely with the FDA’s expertise and functions.”

The AMP and groups representing academic labs say the proposed regulations would be burdensome enough to stifle innovation. AdvaMedDx and test manufacturers disagree. Fish noted that the FDA has promised to show greater flexibility in reviewing LDTs for “unmet needs” where no agency-approved test is available. The FDA said it “does not intend to consider” whether the tests use legally marketed components/instruments, or whether the LDT is interpreted by qualified laboratory professionals, without using automated instrumentation or software for interpretation.

Bridging the Gap

AMP’s proposal came five months after a coalition of diagnostic manufacturers and clinical labs, the Diagnostic Test Working Group (DTWG), came out with its own regulatory framework intended to bridge the gap between the AMP and the FDA. The working group agreed with AMP that lab tests should not be regulated as devices—but called instead for new FDA regulations governing LDTs, as well as kits, as “in vitro clinical tests.” This broader category would be regulated by a proposed new center within the FDA focused on in vitro diagnostics.  The group also proposed dividing oversight among two federal agencies and state governments: the FDA would oversee in vitro diagnostics development, with CMS responsible for lab operations, and states overseeing medical applications.

Like the AMP and FDA, the working group also envisions high-, medium-, and low-risk test categories: High-risk tests are not well established, and a wrong result would result in “significant impact on patient outcome or public health.” Such tests would be a “sole determinant for directing or changing clinical treatment for a serious or life-threatening disease or disorder,” the group said.

The working group would have an advisory panel recommend classification decisions that would stand unless revised by the FDA within six months.

Harry Glorikian, a life sciences and healthcare industry consultant, told Clinical OMICs the FDA needs to strike a balance between agency scrutiny to ensure that new tests measure results accurately and consistently, while retaining flexibility for labs to develop new tests in response to fast-moving disease, such as last year’s outbreak of Ebola in West Africa.

“What happens in a hospital setting when we have an outbreak? We need to develop a test very quickly in-house, and we need to test patients. You don’t want to limit the lab by not being able to do an LDT. There are so many LDTs run in the lab that if you tried to stop them, it would stop medicine. You can’t stop medicine from doing that,” Glorikian said. “That would be problematic, because a manufacturer who would need to get regulatory approval could not move fast enough. So you need to have that capability. You need to let research go on.”

The quest for balance is complicated, he said, by the greater complexity of LDTs compared with drugs or companion diagnostics. Yet new rules are especially needed for tests that drive clinical practice: “If this is narrowing the field of decisions that a physician now makes, you really want to make sure that the answer is right.”

“The technology is moving so fast that there needs to be some guardrails. I’m not saying that it needs to be draconian. But we need to understand what and how we’re going to be diagnosing patients, and then treating patients appropriately,” Glorikian added. “I don’t want to see that necessarily taken out of the hands of a physician. But there’s going to be some combination of what the working group says, what the AMP is saying, and what the FDA is saying.”  

A broader category of “in vitro clinical tests” would be regulated by a proposed new center within the FDA focused on in vitro diagnostics. [iStock/Frentusha]

This article was originally published in the October 2015 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to

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