Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Agency envisions a tiered approach—baseline regulations for all LDTs plus special requirements for riskier LDTs.

Balancing the need to bring innovative laboratory-developed tests (LDTs) to market with the need to ensure those tests are safe and effective is pitting nonprofit academic medical centers against for-profit diagnostic developers—with the FDA intent on subjecting the academic labs to the same rules governing diagnostics companies.

The FDA has signaled to Congress its intent to regulate LDTs that it deems “high-risk” as Class III medical devices. The agency said July 31 it will issue within “at least” 60 days a formal draft guidance laying out a detailed, risk-based framework for approving such LDTs.

While FDA has long reviewed diagnostic tests, the agency has historically exercised only enforcement discretion over LDTs designed and used within a single laboratory, and had not sought to regulate their entry to market as is now required for Class III devices.

That would change under the guidance. FDA plans to begin premarketing approval (PMA) review requirements within 12 months after a final guidance for the highest-risk devices, and phase it in over four years for the remaining high-risk devices. The devices would stay on the market during FDA review.

FDA said it will begin with LDTs having the same intended use as a cleared or approved companion diagnostic, followed by LDTs with the same intended use as an FDA-approved Class III medical device; and some LDTs designed to determine the safety or efficacy of blood or blood products. FDA said it “intends to” publish priority lists for its review of high-risk LDTs within 24 months of a final guidance, and “moderate-risk” LDTs within four years.

Labs would have to begin registration, listing and adverse-event reporting for “moderate risk” LDTs, which would be deemed Class II medical devices, six months after a final guidance is set. PMA for these LDTs would begin five years after final guidance, and be phased in over four years.

The FDA has justified its interest in regulating LDTs in part on what Commissioner Margaret A. Hamburg, M.D., has called “faulty or unproven” tests leading to over- or undertreatment for disorders that included heart disease, cancer, and autism. In April, the CDC expressed “serious concerns” about the potential for misdiagnosis due to false positive results from a Lyme disease LDT that used a culture method to identify Borrelia burgdorferi. CDC recommended that the diagnosis of Lyme should be left to FDA-approved tests.

Venerable “Western”

Academic labs, however, cite the story of the Western blot, a confirmatory clinical diagnostic for HIV-AIDS and Lyme disease that is among the most widely used tests in molecular biology. Developed in 1981 by W. Neal Burnette, then working in the lab of Robert Nowinski, Ph.D., at the Fred Hutchinson Cancer Research Center in Seattle, the test’s name pays homage to the Hutch’s West Coast location and the test’s similarity to Edwin Southern’s namesake “Southern” blot technique, where gel, nitrocellulose, and blotting paper are used for identifying DNA sequences in complex organisms.

The academic labs note that while clinical labs developed Western blot tests to establish definitive diagnoses of HIV-1 in 1985, soon after the virus was identified, an FDA-approved Western blot test didn’t become available until 1987 (from DuPont), and hasn’t changed much since then.

“Because obtaining additional FDA approvals for test kit modifications would be so burdensome, the manufacturer has not modified the test to keep up to date with the medical science. As a result, FDA regulation has stifled that test’s improvement and product innovation,” lab directors from 23 academic medical centers wrote in a July 16 letter to Brian Deese, acting director of the U.S. Office of Management and Budget.

AdvaMedDx, the diagnostics manufacturers’ division of the Advanced Medical Technology Association (AdvaMed), contends the guidance will protect academic labs by leaving with them enforcement discretion for LDTs for rare diseases and for unmet medical needs, when no other testing options exist. However, the labs will be required to register and list these tests with FDA. And the agency will exercise enforcement discretion for forensic-exclusive LDTs and transplantation LDTs when used in high-complexity histocompatibility labs certified under Clinical Laboratory Improvement Amendments (CLIA) standards.

“FDA has worked to support health care professional labs through proposing to except rare disease and unmet needs testing, and thereby continue to promote public health and innovation,” Khatereh Calleja, AdvaMed’s vp, technology and regulatory affairs, told Clinical OMICs. “Even in other testing areas, FDA is allowing significant transition time for higher and moderate risk products to permit laboratories time to complete requirements and to support continuity in availability of testing.”

While AdvaMedDx represents corporate diagnostics developers, it denies trying to squelch competition from academic labs: “AdvaMed has supported risk-based regulation for all diagnostics, regardless of where they are made. Risk to patients is irrespective of where tests are made,” Calleja said.

Defining LDTs

FDA and the Centers for Medicare and Medicaid Services, which oversees CLIA, view LDTs as medical devices since the tests have entailed chemical reads, instruments, and systems used to diagnose, cure, mitigate, treat, or prevent disease.

The academic labs view the tests as “laboratory testing services” subject to the Food, Drug, and Cosmetic Act. At present, labs certified under the CLIA waiver program may develop and use their own diagnostic tests internally, without FDA oversight. The Association for Molecular Pathology (AMP), whose membership includes academic and community medical centers, agrees.

A former senior reviewer and policy advisor at FDA’s Center for Devices and Radiological Health told Clinical OMICs that larger diagnostic manufacturers experienced in FDA regulations won’t see much of an effect. Smaller academic medical labs will face a greater challenge than larger ones, which are likely able to meet FDA’s Guidance within a reasonable period.

“The labs’ business model will slightly change,” Lakshman Ramamurthy, Ph.D., director of FDA strategy and regulatory policy for Avalere Health, an advisory company focused on healthcare business strategy and public policy, and based in Washington, DC. “Many of the larger labs attached to universities are at the very source of discovery and innovation. So they have an existing pipeline of new things to innovate and work on. Therefore, they will probably focus less on creating say a me-too for an existing FDA-approved product, and instead innovate by developing their own products to meet more unmet needs.”

“The labs will have to figure out how to work around and maintain financial liquidity while also contributing clinical quality,” he added.

The labs will also have to figure out which tests the FDA will deem “high-risk.” “I would imagine companion diagnostics would always range high. Cancer screening devices will range high, because when you screen an average risk person for cancer, you are making a life-altering decision for them, rightly or wrongly. So, therefore, the risk associated with that is very high,” Dr. Ramamurthy said.

Helping drive LDTs toward FDA regulation are several payers. In 2011, Palmetto GBA, a Medicare administrative contractor, disallowed labs from submitting claims for all nonstandardized organ or disease-oriented LDTs that, among other criteria, were not FDA-cleared. A similar policy was introduced by TRICARE, the healthcare program for active and retired uniformed military members and their families—though on July 15 it said it will allow reimbursement for some non-FDA-approved LDTs under a pilot program.

“This has to sort itself out,” he said. “It will take some time. But I am optimistic that in the long term, it will sort itself out.”

This article was originally published in the September 10 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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