FDA and Health Orgs Renew Focus on LDT Oversight

Late last year, the U.S. Food and Drug Administration (FDA) announced that it would not finalize the guidance on agency oversight of laboratory developed tests (LDTs) that it proposed back in 2014—at least not yet. Instead, the FDA said it would work with the new administration and Congress "to get our approach right." See "FDA Oversight of LDTs Delayed for Consultation with New Administration, Stakeholders," DTET, Nov. 2016, p. 1.

With that in mind, on Jan. 13, 2017, the FDA issued a discussion paper summarizing the public feedback it has received on the 2014 draft guidance and outlining the key features of a possible alternative approach to FDA regulation of LDTs. Later that same month, health care organizations emphasized the urgency of addressing LDT safety with a letter urging Congress to act sooner rather than later in addressing oversight.

Here is an overview of these latest developments concerning LDTs.

FDA Discussion Paper Analyzes Stakeholder Feedback
As part of the feedback process, the FDA asked stakeholders to suggest how they think the agency should regulate LDTs. The agency summarized the feedback it received in its January discussion paper, noting that the various proposals shared some similar features, including:

• Risk-based approach;

• Premarket review for some tests, with exemptions for certain categories;

• Test approval based on analytical and clinical validity;

• Adverse event reporting;

• Quality systems;

• "Grandfathering" for certain existing tests; and

• Transparency regarding test performance information.

"Based on the feedback received, a prospective oversight framework that focuses on new and significantly modified high and moderate risk LDTs would best serve the public health and advance laboratory medicine," the new discussion paper concludes.

FDA Describes Alternative Oversight Model
The FDA discussion paper also sets out the agency's own thinking on LDT regulation and how it has changed since 2014. Over the two years of "engagement," "positions of many groups, including the FDA, have evolved," the FDA acknowledged. The paper then sets out key features that may be incorporated in an alternative to the framework it proposed back in 2014, including:

• Phased-in oversight program over four years rather than the originally proposed nine years;

• Grandfathering for many LDTs already on the market;

• Broader definition of LDTS for unmet needs;

• Collaboration between FDA and third parties to use existing review standards and certification programs—such as the National Glycohemoglobin Standardization Program or the Cholesterol Reference Method Laboratory Network—for evidence standards;

• Potential use of existing review programs for third-party review, such as New York State's Clinical Laboratory Evaluation Program and independent CLIA accreditation programs;

• Clinical collaboration with stakeholders and health care professional organizations on standards for analytical and clinical validity;

• Public availability of evidence regarding analytical and clinical validity;

• Reliance on CLIA certification requirements plus three FDA quality systems requirements regarding test development processes—design controls, acceptance activities, and procedures for corrective and preventive action (CAPA); and

• Postmarket surveillance requiring labs report serious adverse events for tests except for traditional LDTs, LDTs for public health surveillance, specific transplantation related LDTs, and forensic-use LDTs.

The FDA expressly states that its discussion paper and the proposal it outlines is not a final version of the 2014 guidance and "does not represent the formal position of the FDA, nor is it enforceable. We hope to simply advance the public discussion by providing a possible approach to spur further dialogue."

"There is no systemic way to be sure of the accuracy and reliability of these tests. The current oversight framework creates inconsistencies in oversight and can leave FDA with limited options to catch and address problematic LDTs."

—American Cancer Society
Cancer Action Network

Health Care Orgs Ask Senate to Address LDTs
Meanwhile, shortly after the FDA released its discussion paper, some health care organizations sought to make sure the FDA's deference to working with the new administration did not mean significant delays in addressing oversight issues. Calling the current regulatory system for LDTs "inadequate and in urgent need of updating," the American Cancer Society Cancer Action Network and 32 other organizations sent a letter to U.S. Senate leaders urging them to update the oversight framework for all molecular diagnostic tests, with an emphasis on LDTs.

"It is imperative that patients and physicians are assured of the accuracy and reliability of these test results when making vital health decisions," write the letter's signees. "Currently, diagnostic tests undergo widely different levels of oversight depending on whether they are submitted to the U.S. Food and Drug Administration for review or are offered as LDTs."

Citing the increased complexity of current LDTs and the fact these tests are increasingly performed in reference laboratories with national reach, the organizations, representing patients, scientists, advocates, caregivers, and health care professionals, say that CLIA regulation does not adequately address the "safety and effectiveness" of LDTs.

Under CLIA, laboratories are required to demonstrate the analytical validity of the tests they offer (the test's reproducibility), but CLIA does not ensure consistent performance for measuring the same analyte across laboratories, the Cancer Action Network says. Additionally, the organizations stress that CLIA does not evaluate the clinical validity of a test—the test's ability to accurately diagnose a condition.

"There is no systemic way to be sure of the accuracy and reliability of these tests," say the signees. "The current oversight framework creates inconsistencies in oversight and can leave FDA with limited options to catch and address problematic LDTs."

As further evidence of the need for updates to the oversight framework, the organizations cite a Dec. 15, 2016 study in JAMA Oncology that reported "markedly" different test results from two different commercially available, next-generation sequencing-based tumor profiling tests (See the March issue of DTET for more details).

Takeaway: LDTs remain very much a work in progress, one that has evolved since 2014, and you need to stay tuned for further developments.