Health Care Organizations Urge Congress to Update LDT Oversight

Late last year, the U.S. Food and Drug Administration (FDA) announced that it would not finalize its 2014 proposed guidance on agency oversight of laboratory developed tests (LDTs) but would work with the new administration and Congress "to get our approach right." (See "No Final LDT Framework in 2016: FDA Seeks Further Input from Stakeholders, New Administration," NIR, Nov. 26,
2016.) But that doesn't mean the FDA is passively waiting for the new administration to act—it issued a discussion paper in January outlining a possible alternative approach to FDA regulation of LDTs.

Shortly thereafter, health care organizations emphasized the urgency of addressing LDT safety with a letter urging Congress to act sooner rather than later in addressing oversight. 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."

The letter cites Theranos' invalidation of thousands of test results as "an example of why proactive oversight by FDA based on a risk-based approach paradigm is necessary." 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. The letter explained that in the study, "[r]esearchers sent samples from the same cancer patients to different LDT providers for cancer testing, and found only 25 percent of the drug recommendations based on test results overlapped."

That study compared results from the tissue-based FoundationOne test (F1; Foundation Medicine) with the blood-based Guardant360 (G360; Guardant Health) test in nine patients seen at a community oncology practice. Previous published studies have shown that both the F1 and G360 tests have high specificities (above 99 percent), but lower sensitivities. The level of concordance between the platforms was compared among two men and seven women (mean age, 61 years). In addition to comparing identified genomic alterations, test results were compared regarding recommended drugs.

For eight patients with identified alterations, 36 drugs were recommended, in

"Since both the F1 and the G360 tests are performed in thousands of patients with cancer each year, these findings are clinically relevant."

— Nicole M. Kuderer, M.D.

total. However, only one-quarter of the drugs were recommended for the same patients by both platforms. In five patients there was no overlap between the drugs recommended by the two tests. Concordance among recommended drugs improved to 62 percent (8 of 13 drugs), when reported mutations were also concordant.

In seeking an explanation for the discordant test results, the authors cite differences in timing between the two tests as a possible source, but note that seven of the eight patients with reported alterations underwent both tests within a 2.5-month period. Other potential sources of the discordance are tumor heterogeneity and differences in the variant-interpretation process.

"Since both the F1 and the G360 tests are performed in thousands of patients with cancer each year, these findings are clinically relevant," write the authors led by Nicole M. Kuderer, M.D., from University of Washington, Seattle. "In-depth comparisons of next-generation sequencing tests across larger numbers of patients with cancer are needed to improve concordance and clinical utility."

The authors note that theirs was not the first to identify "significant discordance." Two studies comparing tissue-based next-generation sequencing tests and another report also comparing the F1 and G360 tests, all found discordant test results.

Takeaway: As a recent study compares results of different sequencing platforms, health care organizations argue there's an urgent need for oversight of LDTs.