FDA says it will tailor its future oversight of laboratory tests and services based on risk, but experts warn that "high risk" will be hard to define for these diagnostics.

The agency held a two-day workshop in Hyattsville, Md., to discuss a future paradigm for reviewing an assay developed by a lab for the purpose of offering a testing service out of that lab.

FDA has generally not regulated such tests, versus commercial test kits made by device manufacturers and sold to labs as packaged products, but maintains that it always had the statutory authority to do so.

The July 19-20 meeting served as a kick-off for FDA's move from its traditional "enforcement discretion" policy to active regulation.

The agency says it has made no final decisions about how oversight of lab-developed tests will look. Much of the meeting consisted of FDA staff fielding comments from test kit makers, lab stakeholders, professional societies, clinicians and patient advocates.

"We are very much interested in hearing a wide variety of perspectives," FDA Principal Deputy Commissioner Joshua Sharfstein said July 19. "We will be thinking creatively."

Lab services are currently subject to oversight by CMS under the Clinical Laboratory Improvement Amendments (CLIA) and by accrediting organizations such as the College of American Pathology (CAP).

But these groups pose no requirements for clinical validation, design controls and software controls, adverse event reporting and recalls, or post-market surveillance, FDA notes.

"We worry that laboratory-developed tests could be introducing unreasonable risk to patient health through uncontrolled design and manufacture, [and] unsupported claims," Elizabeth Mansfield, director of personalized medicine within FDA's diagnostics office, said at the meeting.

Risk Categories May Be Difficult To Define

FDA says it plans to phase lab services into its oversight framework over time based on risk, regulating the highest-risk tests first and later determining appropriate oversight for moderate- or low-risk tests (¹ Also see "FDA Aims To Finalize Framework For Lab-Developed Tests In Near Term" - Medtech Insight, 21 June, 2010.).

Under FDA's current risk-based paradigm, lower-risk test kits are exempt from pre-market review but must comply with general controls for registration and listing, good manufacturing practices, labeling provisions and adverse event reporting procedures.

At the other end of the spectrum, high-risk tests are subject to a rigorous pre-market review process, sometimes requiring clinical data.

Workshop participant Richard Naples, VP of corporate regulatory affairs at Becton Dickinson, urged FDA to apply more or less the same framework to lab tests. "I think we should build on principles that already exist," he said.

But others cautioned that the line between high-, moderate- and low-risk testing services would not be so easy to define.

"The biggest challenge that FDA will face in however it progresses will actually be in the risk assessment," said Steve Gutman, former director of the agency's diagnostics office and now an associate director with Blue Cross/Blue Shield's Technology Evaluation Center. "I would like to see FDA certainly make decisions based on risk rather than on business model, but I would like them to make those carefully."

The American Association for Clinical Chemistry and CAP proposed different frameworks in which FDA reviews the highest-risk tests while CLIA or CAP handle the moderate- and low-risk tests.

Elaine Lyon of the Association for Molecular Pathology urged FDA to convene an advisory committee to better define the risk categories.

FDA's (Potential) Take On Risk

FDA's Mansfield outlined a potential risk classification strategy at the workshop.

FDA would define risk based on how an undetected false result would affect a patient, Mansfield said.

Highest risk would be tests where an undetected false result could lead to serious injury or death, where it would be difficult to detect the false result and where there was a high public health risk.

Wrong results from these tests could lead to incorrect or harmful clinical management, an unnecessary invasive procedure and failure to conduct needed follow-up, she added.

Tests that could fall into this category include companion diagnostics, cancer tests, tests that direct or very strongly influent patient management of a serious disease, and tests for serious or fatal communicable diseases, Mansfield suggested.

Moderate-risk tests might be those for which an undetected wrong result would lead to a non-serious injury, where false results are relatively easy to detect and where adjunctive tests are available.

Mansfield put in this category tests where a patient's clinical symptoms are already known, tests where multiple findings are used to direct clinical management and tests that monitor an already-detected disease.

Finally, low-risk tests might be those where false results pose little potential for injury, are easy to detect and where adjunctive testing is readily available. These tests would be unlikely to directly affect clinical management, Mansfield noted.

This category might include tests that identify one among many defining characteristics of a tissue or cell, tests that have little clinical impact, and certain instruments and equipment, she said.

FDA Options: Down-Regulation, Third-Party Review

Dividing lab tests and services into risk categories is just one of the challenges FDA faces as it prepares to regulate lab-developed tests.

To accommodate its growing workload, FDA is considering changing how it regulates commercial in vitro diagnostic test kits, perhaps down-classifying some kits.

In addition, FDA may conduct pilot projects to determine whether it could rely on accredited third parties, such as CLIA or CAP, to review pre-market submissions for lab tests or to inspect lab testing facilities, Mansfield said.

Several meeting attendees also urged FDA to grandfather in currently available lab-developed tests, at least temporarily.

Meeting participants agreed that efficient collaboration between CMS/CLIA and FDA is critical to avoiding duplication and wasted government resources.

"We've been talking to CMS about that for years," CDRH Director Jeffrey Shuren acknowledged in an interview. "We have a pretty good understanding of how CLIA works."

Speakers suggested other ways FDA could expand oversight without delaying the introduction of critical new tests - a key fear among lab stakeholders - such as using its "emergency use authorization" pathway to allow critical tests on the market while still gaining the evidence necessary for full clearance or approval.

EUAs were used during the 2009 H1N1 flu epidemic to allow earlier use of novel flu tests, for example.

Stakeholders also agreed that FDA should give special treatment and an easier path to market for tests for rare diseases.

Next Steps: Comments, Guidance And Meetings

After considering comments from the meeting and an FDA docket, closing Aug. 15, FDA plans to propose a regulatory framework for public comment "over the next few months," Shuren said.

FDA will most likely come out with a draft guidance or series of guidance documents, he indicated.

"There's lots of issues at play," the CDRH director said in an interview. "For example, how might you avoid duplication between the quality system regulation and the CLIA requirements. That itself might be a separate document."

The agency is not likely to go through rulemaking procedures, as some meeting attendees recommended, but "we can certainly explain our thinking better to folks" through guidance and perhaps additional public meetings, Shuren told "The Gray Sheet."

- Jessica Bylander ( ² j.bylander@elsevier.com )

FDA Gathers Feedback To Guide Oversight Of Lab-Developed Testing

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