FDA Aims to Start Regulating Custom Diagnostic Tests

Since 1976, the U.S. Food and Drug Administration (FDA) has maintained that it has the authority to regulate laboratory-developed tests (LDTs), including those that screen for genetic mutations that increase an individual’s risk of certain cancers. But the agency has taken a largely hands-off approach—until now.

Advances in genomic technologies have made possible the development of many new, more complex tests with higher-risk uses, prompting the FDA to voice concern over health care decisions based on potentially incorrect results.

In late July, the agency announced it had started a process that could allow it to initiate more vigorous monitoring of LDTs because it “is concerned that people [based on the results of these tests] could initiate unnecessary treatment or delay or forgo treatment altogether for a health condition, which could result in illness or death.” While proponents of stricter supervision contend it is long overdue, others fear it will inflate costs and curb innovation.

“LDTs have been tremendously important in advancing medicine,” says Jan A. Nowak, medical director of the molecular diagnostics laboratory at NorthShore University HealthSystem in suburban Chicago. “If there are very burdensome oversight regulations—costly kinds of things—then it will certainly take away the availability of tests, not only in the future, but tests that we’ve relied on for years.”

LDTs have played a significant role in cancer diagnostics. Newer LDTs, known as companion diagnostics because their use is linked to a specific drug or class of drug, fall into the evolving category of personalized medicine, which tailors therapies to individual patients. Once a test pinpoints a genetic mutation, a medicine at a specific dosage may be prescribed to target that mutation. A companion diagnostic test could help determine which patients would benefit from a particular treatment. Sometimes a companion test also can predict which patients could be harmed by a treatment.

To date, 19 companion diagnostic tests, some of which are for the same indication, have been cleared for the selection of drugs to target various diseases and conditions. Most therapies with a companion diagnostic test are cancer treatments aimed at specific mutations.

The premarket review process for tests regulated by the FDA is capped at 180 days, but often takes longer. If modifications are made to diagnostic tests after FDA approval, the agency can mandate new premarket submissions, says Roger D. Klein, medical director of molecular oncology at the Cleveland Clinic in Cleveland.

“It can be a very long and costly process,” Klein adds. The shift would be an intrusive measure, he says, that would decrease innovation in the production of relatively inexpensive laboratory tests that perform well. This “would lock people into FDA-approved tests,” he says, which “are typically static—unable to adjust to rapid change in technological development and medical knowledge.”

In the past, the FDA did not typically enforce premarket review of LDTs, because of their relative simplicity and limited availability. The agency recently stated on its website that it had found inconsistencies in several high-risk LDTs, such as claims lacking adequate evidence, insufficient controls leading to faulty results, and falsification of data.

Clinical laboratories analyzing LDTs have been under the regulation of the Centers for Medicare & Medicaid Services (CMS), as stipulated in the Clinical Laboratory Improvement Amendments (CLIA), enacted in 1988. CLIA requires laboratories to obtain certification to report results to health care providers. The FDA and CMS, through CLIA, have different regulatory goals, according to a report from the Congressional Research Service. The FDA is primarily concerned with “the safety and effectiveness of the diagnostic tests themselves and the quality of the design and manufacture of the diagnostic tests,” whereas CLIA aims to regulate “the quality of the clinical testing process itself, mostly by assessing the quality of the clinical laboratory,” although there is some overlap.

Alan Mertz, president of the American Clinical Laboratory Association, says his group supports strengthening CLIA rather than adding more FDA oversight, which would be duplicative and financially burdensome. CLIA-proposed enhancements would include a registry of available tests and a database for tracking adverse events.

“Most of these LDTs will never even have that much revenue in the lifetime of that test,” Mertz says. “It is a concern with those requirements that labs will not even develop the test, because there’s no way that they could ever recoup the costs of approval.”