Regulation of Biomarker Tests

John Jessup, chief of the Diagnostics Evaluation Branch in the Division of Cancer Treatment and Diagnosis at the NCI, pointed out that a number of reports in recent years have highlighted the risks for patients posed by new and poorly validated diagnostics. “Investigators want to use markers, but they oftentimes have not understood the rigors of clinical assay development,” he said. Jessup added that in late 2010, the FDA Office of In Vitro Devices began to enforce its oversight authority for the safety of diagnostics used for medical decision making in clinical trials.

Biomarker tests used for medical decision making, even within a clinical trial, are required by law to be performed in a CLIA-certified laboratory. These tests include companion diagnostics, which are used in conjunction with targeted therapies, as well as molecular tests that stratify risk of disease recurrence or adverse reaction to treatment or those that indicate proper dose. Biomarker tests used solely for research purposes, including prognostic, predictive, and pharmacogenomics markers, do not need to be performed in CLIA-certified laboratories.

According to the FDA, if a biomarker test has the potential to “present serious risk to the health, safety or welfare of a research subject,” clinical investigators must get an FDA Investigational Device Exemption (IDE) in order to use the test in their studies and must collect safety and effectiveness data. However, Jessup noted, “serious risk is not well defined or quantified,” despite two FDA guidances that mention it (FDA, 2006, 2012d).

To obtain an IDE, a principal investigator is expected to document the analytical performance of the assay, including its accuracy, reproducibility, and precision, and how these characteristics translate into false positives or negatives. This information is used to demonstrate to the FDA that the risk of using the device (i.e., biomarker test) is less than the potential treatment benefit. “This means that once an assay is going to be used in a trial, even at the concept stage, it is important to be submitting information about the validity and performance of that assay as soon as possible,” Jessup stressed. He added that the NCI Cancer Diagnosis Program will assist in this process by providing templates for documentation of assay performance for immunohistochemistry, fluorescence in situ hybridization, and somatic mutation detection. But Jessup also cautioned that “a lot of the tests that seem extremely exciting may not be reproducible or accurate.”

Once assay performance data have been gathered, there is a formal pre-submission program that includes meetings with FDA staff. Jessup noted

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