The FDA has published two draft guidance documents aimed at streamlining its oversight of tests based on next-generation sequencing (NGS). One contains preliminary recommendations addressing the analytic validity of NGS-based tests for hereditary diseases; the other explains how test developers can obtain official recognition of their genetic variant databases, potentially speeding marketing clearance or approval.

Based on extensive work with members of the next-generation sequencing (NGS) community, the FDA has published two draft “guidances” aimed at streamlining the submission and review of data to demonstrate the analytic and clinical validity of NGS-based tests.

The agency is accepting feedback on the documents through October 6.

The guidances were issued “to encourage advances in genomic testing while assuring that NGS-based tests are safe and effective,” says FDA spokesperson Lyndsay Meyer.

The FDA noted that its current regulatory approaches are only suitable “for conventional in vitro diagnostic tests that detect a single disease or condition”—blood glucose or cholesterol levels, for instance—but that NGS techniques “contain the equivalent of millions of tests in one.” Because the field is rapidly evolving, the draft documents are viewed as a significant step toward establishing a different, more dynamic and flexible regulatory approach, while “striking the important balance between safeguarding public health and promoting innovation,” Meyer says.

The first guidance is specific to NGS-based tests for hereditary diseases: It contains preliminary recommendations for their design and development, and the use of FDA-recognized standards to demonstrate analytic validity. It does not encompass other potential applications of the technology, such as tumor genome sequencing and risk prediction, which will be addressed in the future, according to the agency.

In the second guidance, the FDA outlines how test developers can obtain official recognition of their genetic variant databases—collections of “human phenotype–genotype relationships to a disease or condition” with “documentation of evidence supporting those linkages.” Developers often cite information in such databases to support a test's clinical validity; doing so with an FDA-recognized database could speed marketing clearance or approval.

“I think the FDA is hoping to introduce some standards to maximize the utility of these databases,” says Jeff Allen, PhD, executive director of Friends of Cancer Research, a Washington, DC–based think tank and advocacy organization. “They're essentially telling the scientific community, ‘In establishing and curating your genetic variant database, if you're thinking ahead about using it as a regulatory tool to validate your NGS test, here are a few things you should consider.’”

The process envisioned by the FDA would start with a test developer submitting detailed information about the variants in their database, as well as documents that address its standard operating procedures, including data security and preservation. This information would have to be made publicly accessible after the database gains official recognition, and regularly reviewed to ensure that assertions about the genetic variants continue to be scientifically supported.

Participation in the recognition process is entirely voluntary. “There's nothing to say that a commercial entity aggregating data on genetic variants has to go this route, if there are concerns about public access conflicting with issues of intellectual property,” Allen says. “Overall, though, I think the FDA will be more comfortable making decisions about indications for a particular NGS test if they have a thorough understanding of how the pertinent database was constructed.”

The agency is “clearly thinking a lot about how to handle NGS,” Allen observes. “These guidances are just a starting framework, and I do believe there'll be oncology-specific recommendations in the future.” –Alissa Poh