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After the Food and Drug Administration (FDA) announced in 2010 its intention to regulate laboratory-developed tests (LDTs), lab advocacy groups, biotech companies, and even Congress pushed back so hard that by 2013, FDA leaders described their efforts as mired in politics and, at best, uncertain. Now, with a surprise announcement in July that FDA will proceed with plans to regulate LDTs followed by a draft guidance published October 3, a newly confident and determined FDA has hit the ground running.

According to FDA, its plan will give labs plenty of time to accommodate stepped-up oversight. During a September 10 AACC webinar, FDA Director of In Vitro Diagnostics Alberto Gutierrez, PhD, laid out a 9-year timeframe to implement LDT regulation. But the clock doesn’t even start on that timeline until after FDA issues a final guidance, a process that could take years. Based on FDA’s history with LDTs, the one thing certain is that the initial plan will not look exactly like the final plan—and it will probably take even longer to implement than the agency would like.

Don’t Panic

A 120-day comment period on the draft guidance began on its publication date, which means FDA will be gathering feedback through January 2015. Officials told CLN a public meeting is in the works for early 2015 that is expected to draw a large number of participants.

Even when FDA issues a final draft, the framework calls for a lengthy incubation period, the first 5 years of which FDA would almost exclusively focus on bringing high-risk tests under premarket review. “We could be looking at two years before a final guidance emerges,” said Mya Thomae, vice president of regulatory affairs at Illumina. “If it takes FDA two years to get a final guidance, and then five years to get to anything but high-risk tests, that means a lot of the tests on the market today wouldn’t even come into focus for FDA for possibly seven to nine years. For the majority of laboratories out there, there is a long time to plan.”

FDA has signaled a measured pace of change, according to Thomae. “My message for laboratorians today is, don’t panic.”

The Name Game

Even with the long history of public meetings, draft guidance documents, and controversy over LDTs, FDA is only now officially defining what this term means. “Our concept all along, which was never put in writing, was that an LDT is a test that is developed, validated, and offered in a single laboratory under a single CLIA certificate,” FDA’s Director of Personalized Medicine, Elizabeth Mansfield, PhD, told CLN.

Any test not completely developed and offered within a single hospital lab is not really an LDT, according to FDA. A test distributed among several labs, licensed from another organization, or which uses components not cleared for clinical use is not an LDT. According to FDA, such tests are devices out of compliance with the law and are marketed illegally. However, in the interest of “ensuring continuity in the testing market and avoiding disruption of access,” FDA still will call these tests LDTs and regulate them within the same framework as true LDTs.

For hospital labs, the ultimate effect of FDA’s plan may hinge on whether FDA considers particular assays “traditional.” For these tests, the draft guidance carves out an exemption from significant FDA oversight. Those labs whose testing falls into this category will have to notify FDA of the LDTs they’re running within 6 months of the final guidance, as well as promise to monitor and report on adverse events—a relatively minor burden compared to submitting data for premarket review.

As such, the burden on hospital labs may not be as great as some expected, according to William Clarke, PhD, DABCC, an associate professor of pathology at the Johns Hopkins University School of Medicine and director of clinical toxicology at the Johns Hopkins Hospital in Baltimore, Maryland. “I believe we’re still performing what FDA terms traditional LDTs. We only serve patients inside our hospital, and we are not performing genetic testing or multi-marker tests with an algorithm for interpretation,” he said. “It looks like FDA would expect us to register and begin adverse event reporting, but I—along with ­others—have advocated for laboratories to do better with monitoring performance of their lab-developed tests after implementation anyway.”

At the same time, just because a test is validated and performed only within a single laboratory does not automatically make it a traditional LDT. “The traditional LDT is intended to encompass those types of tests over which we would have originally exercised enforcement discretion in 1976,” Mansfield emphasized. “So they are things like hematoxylin and eosin staining—tests using slides and microscopes—as well as other types of testing that we would have considered LDTs in 1976.” One purpose of the notification period for LDTs is to help FDA know who is offering what so that the agency can refine its determination of what is truly traditional, Mansfield added.

What is not a traditional LDT? First, any test in which the patient, laboratory, and physician are not confined to a single healthcare system. The test must also not produce a result through an automated system—for example, molecular testing. “One distinction we make with molecular diagnostic testing is that there is essentially a machine that gives you results—you’re not looking at something and deciding what you see, the instrument itself is giving you results. We think that’s very different than the type of tests for which we originally exercised enforcement discretion in 1976,” Mansfield said.

In testimony before a September 9 U.S. House of Representatives Energy and Commerce Committee hearing, FDA’s Director of the Center for Devices and Radiological Health Jeffrey Shuren, MD, JD, emphasized that the agency would use a transparent approach. He promised that FDA would use advisory panels with experts from the lab community to guide FDA in which tests need premarket review first, as well as how the agency will assure clinical validity.

Already FDA has suggested it would work with accrediting agencies and possibly combine inspections for CLIA standards with those for FDA standards.

Mansfield emphasized that reviewing LDTs is not actually new. The agency has cleared several tests under the rubric of in vitro diagnostic multivariate index assays, including the Mammaprint test for breast cancer recurrence in February 2007, the Pathwork Tissue of Origin test in July 2008, and the Allomap test for transplant management in August 2008.

Reference Labs Face Biggest Hurdles

Those organizations that will likely bear the brunt of FDA’s new regulatory scheme will be reference labs, hospital outreach businesses, and commercial biotechnology companies that sell proprietary testing services. These business arrangements all break away from what FDA considers the low-risk, traditional LDT model. Their services will be regulated according to the risk-based system FDA plans to develop over the next several years along with its new advisory committees.

Even though Clarke expects the LDTs run in his Johns Hopkins lab would fall under the traditional LDT category, he worries that reference labs will eventually be limited in which tests they will be able to offer. “Reference labs are a vital resource for our ability to support good patient care. Currently I offer five lab-developed­ tests, and I’m maxed out in my resources,” Clarke said. “I think there is a real risk that if reference labs have to cope with more regulation and additional costs, some current tests will go away or new tests may not become available that I’d never be able to develop in-house.”

Now that FDA has reasserted its right to regulate LDTs, laboratorians will have to take FDA at its word and submit comments on the draft guidance, attend public meetings, and work closely with FDA on the new advisory committees. There will be several ways to contribute input. AACC has drafted a position statement on oversight of LDTs on which it is seeking comments, and laboratorians can speak at CDC’s public meeting and through the official docket for the regulation.

FDA’s Proposed Laboratory-Developed Test Regulation Timeline

The clock on the timeline starts when the Food and Drug Administration (FDA) issues final guidance on laboratory-developed­ test (LDT) regulation, which could take up to several years. FDA will require premarket clearance or approval for all moderate and high-risk LDTs beginning 3 years after publication of the final guidance. The exception to this is certain high-risk LDTs that FDA wants to review within 1 year of the final guidance. These include LDTs that have the same intended use as companion diagnostic tests and other currently approved Class III devices, as well as certain LDTs for blood and blood products.

Timeline After FDA Issues Final Guidance:

Premarket review for all new, high-risk LDTs — Immediate

Notification and adverse event reporting for currently marketed and new LDTs — 6 Months

Premarket review for certain current high-risk LDTs, including companion diagnostics — 1 Year

FDA publishes priority list for remaining high-risk LDTs — 2 Years

Premarket review for first group of high-risk LDTs — 3 Years

Premarket review for remaining high-risk LDTs — 3-5 Years

FDA publishes list for moderate-risk LDTs — 4 Years

Premarket review for all moderate-risk LDTs announced at year 4. FDA anticipates use of third-party reviewers. — 5-9 Years