FDA Commissioner Scott Gottlieb on Tuesday (March 6) spotlighted the agency’s efforts to reform the premarket review process for diagnostic tests, and he previewed next steps, which include qualifying third-party reviewers and third-party databases to help with reviews and approvals, reducing regulatory burden on next generation sequencing (NGS) developers, and providing flexibility in clinical analysis and validation.
Gottlieb, speaking to an audience at the American Clinical Laboratory Association’s Annual Meeting on Tuesday, said that while he still believes comprehensive legislation is needed to fully address FDA’s role in overseeing laboratory-developed tests (LDTs), the agency has already taken steps to ease the regulatory burden on LDT developers.
The agency chief has, on numerous occasions, discussed the roles he sees Congress and agencies playing in LDT oversight.
In his Sept. 13 remarks at the Friends of Cancer Research’s “A Blueprint for Breakthrough” event he said Congress needs to legislate on the issue. Two weeks later, he touted FDA’s pre-certification pilot program as a “modern approach to regulation” that could be applied to LDTs.
In November, CMS agreed to cover a companion diagnostic, FoundationOne CDx, on the same day that FDA approved it. While testifying in front of Congress in December, Gottlieb told lawmakers FDA and CMS will increasingly work together on simultaneous diagnostic reviews — a move he said could serve as “a powerful incentive” for more sponsors of diagnostic tests to voluntarily go through the FDA approval process.
In his Tuesday speech, Gottlieb said the agency is developing policies — and will provide final guidance to developers — to improve the development and review of advanced NGS technologies, which he said “have the potential to detect a high number of genetic mutations with a single run of the test” and “have enormous potential to help patients learn more about their diseases and better inform their health care decisions.”
Under FDA’s three-tiered approach to reviews of NGS oncopanel tests, the agency is communicating with developers regarding flexibility they have in developing analytical and clinical evidence to support marketing authorization.
“The evidence to support a companion diagnostic can be different from the evidence to support tests that identify cancer mutations with evidence of clinical significance. And this can be different than the evidence needed to support tests that identify cancer mutations with only potential clinical significance,” Gottlieb said. “By communicating clearly, we hope to enable less burdensome review and better-informed development programs.”
FDA is examining how it can exempt more tests from “the burdens of premarket review,” including through establishing initial controls to assure analytical and clinical validity. Gottlieb noted that in demonstrating analytical and clinical validity, a developer may, for example, show that its test conforms to FDA-recognized standards, including those developed by the scientific community and standards development organizations.
To move forward in its efforts, the agency aims to qualify third-party databases that can establish clinical validity. FDA also will work with stakeholders who can assess and make recommendations about clinical validity that could support FDA premarket review or allow developers to “avoid premarket review altogether,” Gottlieb explained.
Gottlieb highlighted the agency’s qualification of the New York State Department of Health as a third-party reviewer for LDTs. The qualification means that labs — including those with advanced NGS-based tumor profiling tests — whose tests are approved by New York State’s DOH do not need to submit separate applications to FDA. Rather, they can have their NY State application and the state’s review memorandum and recommendation be shared with FDA for possible 510(k) clearance.
“The third-party accreditation program is designed to reduce the burden on test developers and streamline the regulatory assessment of eligible innovative products. Going forward, we hope that additional accredited, third-party reviewers will become eligible to conduct reviews; and make recommendations to FDA, and provide even more options to test developers,” Gottlieb said.
Marketing authorization from FDA can assure providers and payers that tests are valid, which can help with coverage decisions, Gottlieb explained. However, he added, FDA must make sure its work to oversee LDTs “is complementary to, and not duplicative of,” CMS’ role in facility accreditation, inspection and certification under the Clinical Laboratory Improvement Amendments.
“FDA and CMS have separate and well-defined roles. Whereas CMS is focused on setting laboratory standards and overseeing laboratory accreditation, inspection, and certification; FDA regulates and reviews the tests themselves,” the agency chief said. “It’s key we understand and continue to act upon that distinction; to avoid recreating the wheel and imposing unnecessary burdens, and to best leverage existing work and oversight.”