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FDA Outlines to Congress its Long-Awaited Approach toward LDT Regulation

This article has been updated from an earlier version with additional comments from FDA officials and industry stakeholders.

NEW YORK (GenomeWeb) – Over the next decade, the US Food and Drug Administration will phase in its risk-based approach toward regulating laboratory developed tests, the agency announced today.

The agency provided the US Congress notice of its plans to release the long-awaited draft guidance for LDT regulation, as required by a provision in the Food and Drug Administration Safety and Innovation Act. The FDA will formally publish its draft guidelines for public comment after 60 days. Simultaneously, the agency also finalized a draft guidance, issued in 2011, on the development, review and premarket regulatory requirements for companion diagnostics – tests that predict whether patients will respond to certain drugs.

"With today's notification of the agency's intent to issue the lab-developed test draft guidance, the FDA is seeking a better balanced approach for all diagnostics," said Jeffrey Shuren, director of the FDA's Center for Devices and Radiological Health. "The agency's oversight would be based on a test's level of risk to patients, not on whether it is made by a conventional manufacturer or in a single laboratory, while still providing flexibility to encourage innovation that addresses unmet medical needs."

The draft framework follows the agency's previously articulated intent to advance a risk-based approach for overseeing LDTs – tests designed, manufactured, and used within a single lab. According to the guidance, the FDA's requirements for reporting, registration, 510(k) clearance, and premarket review of LDTs increase depending on the risk classification of a particular LDT – Class I (lowest risk); Class II (moderate risk), Class III (highest risk).

The FDA plans to continue to exercise its practice of "enforcement discretion" – leaving oversight responsibilities largely with the Centers for Medicare & Medicaid Services under CLIA – for Class I devices, as well as for LDTs for rare diseases and for unmet medical needs, especially when no other testing option exists. For these types of tests, the agency will not require premarket or quality systems review, but labs will have to register and list these tests. Additionally, the agency said it will exercise enforcement discretion for LDTs used in forensics and tests for transplantation performed in CLIA-certified, high complexity histocompatibility labs.

Developers of moderate-to-high risk lab tests will be subject to premarket review (510(k) or PMA), as well as registration, listing, and adverse event reporting requirements. Labs marketing the highest-risk devices will have to begin meeting premarket review requirements 12 months after the LDT guidance is finalized, and then the remaining high-risk tests will be phased in over the next four years. While the FDA is conducting its review, the agency said tests can remain on the market.

The agency will first prioritize those high-risk devices with the same intended use as cleared or approved companion diagnostics. Then the FDA will bring into compliance LDTs with the same intended use as FDA-approved Class III devices, and finally tests that determine safety and efficacy of blood products.

For moderate risk LDTs, the agency expects labs to begin registration, listing, and adverse events reporting six months after the guidance is finalized. After the agency has completed its regulatory activities for high-risk devices, or five years after the guidance is finalized, the premarket review requirements will take effect for labs marketing Class II LDTs. The FDA expects to "complete phase-in enforcement of premarket regulatory requirements for Class II devices within nine years of finalization of the guidance," the agency said in the draft document.

"The FDA recognizes that some laboratories may currently be offering devices as LDTs, even though they do not meet FDA's definition of an LDT," the agency informs in the draft guidance. "In the interest of ensuring continuity in the testing market and avoiding disruption of access to these tests, FDA intends to apply the same risk-based framework … to any in vitro diagnostic that is offered as an LDT by a CLIA-certified laboratory."

The agency also clarified that the LDT guidance does not apply to LDTs marketed directly to consumers. Genomic testing firm, 23andMe, used to market lab-developed genetic tests directly to consumers, until the FDA last year asked the company to stop doing so until its tests received the agency's approval or clearance.

The FDA plans to issue draft guidance describing in more detail the criteria for classifying LDTs as Class I, II, and III, 18 months after finalization of the LDT guidance. The agency also intends to publish a draft guidance laying out how labs can notify the FDA that they're manufacturing and using LDTs and how they can comply with device reporting requirements.

FDA Commissioner Margaret Hamburg said during a call today that the agency is concerned that faulty or unproven LDTs are causing people to be under treated or receive erroneous care. Just as drugs must be reviewed by the agency to ensure they are safe and effective, Hamburg asserted that diagnostics must also be established by the FDA as accurate and reliable.

This draft guidance has been many years in the making. According to Shuren, FDA oversight of LDTs has been under discussion since the 1990s and has the backing of other government agencies.

During this time, the FDA's decision to regulate LDTs has also been hotly contested and consistently resisted by sectors of the laboratory industry that claim that the agency's regulation would hinder innovation and insist that CLIA regulation is sufficient.

"Laboratories have been regulated for decades by CMS under CLIA and by state law," Alan Mertz, president of the American Clinical Laboratory Association, said in a statement. "Under the CLIA framework, a thorough and detailed regulatory process, we’ve seen an explosion of innovation in laboratory diagnostics that has allowed labs to diagnose and measure disease with an accuracy and precision never before possible. This has changed how the medical world views and treats everything from rare diseases to infectious disease to cancer."

ACLA last year issued a citizen petition to this effect, charging that the FDA doesn't have the legal authority to regulate LDTs because such tests don't meet the definition of devices under federal laws.

FDA's Shuren maintained that the agency does have legal authority to regulate LDTs, which in the agency's view are devices. Furthermore, he pointed out that the two-pronged regulatory pathway for LDTs and diagnostic devices creates an uneven playing field particularly when the tests address the same indication. Drug and test makers often decry this disincentive in the context of companion diagnostics development, where kits that they have had to garner FDA approval for must compete with LDTs offered with CLIA certification, which analyze the same marker (ie. KRAS or BRAF mutations).

AdvaMedDx, a group representing diagnostics manufacturers, supported the release of the LDT guidance. "[LDTs] are increasingly being used to diagnose and guide the treatment of potentially life-threatening conditions, and FDA oversight of higher risk diagnostic tests including companion diagnostics, regardless of the manufacturer, is essential to patient safety," the group said in a statement. "A number of patient groups and professional societies have expressed concern regarding the current lack of FDA oversight in this area."

The FDA said it will hold a public meeting to allow stakeholders to express their concerns about the guidance.