CEO SUMMARY: FDA Commissioner Scott Gottlieb said the FDA wants to reduce the regulatory burden on developers of next-generation sequencing (NGS) and laboratory-developed tests (LTDs). He also wants to give the FDA more flexibility in how it conducts clinical analysis and validation. To do so, the agency would work with third parties, such as the New York State Department of Health, to speed test review and approval. It also wants to use third-party databases to cut the time needed for review of clinical validity.
EARLIER THIS MONTH, Scott Gotlieb, MD, Commissioner of the Food and Drug Administration, outlined how the federal agency is reforming the premarket review process for diagnostic and laboratory-developed tests (LDTs).
Premarket review is a high-profile issue for clinical laboratories because in 2012, the FDA said it intended to change how it regulated LDTs. At the time, lab executives and pathologists directed harsh criticism at the agency’s draft LDT rules. (See TDRs, Nov. 3, 2014; Dec. 28, 2015.)
Rethinking Earlier Proposals
Since the Trump administration took office last year, the FDA has shown a willingness to rethink its earlier proposals for regulating clinical laboratory tests, including LDTs.
In a presentation at the annual meeting of the American Clinical Laboratory Association (ACLA) in Washington, D.C., on March 6, Gottlieb discussed two possible reforms intended to reduce the regulatory burden on developers of next-generation sequencing (NGS) technologies and the potential for giving the FDA more flexibility in how it conducts clinical analysis and validation of new lab tests.
First, he mentioned that it may be possible to qualify third-party reviewers, such as the New York State Department of Health, to help with reviews and approvals for clinical laboratory tests, including LDTs.
Second, Gottlieb stated that it might be feasible to exempt from premarket review many individual tests that meet pre-specified standards in cases where the FDA has confidence in the lab’s underlying standards.
“We must continue to ask ourselves, How do we adapt payment schemes, regulations, and enforcement policies that were designed for the technologies and market of the 1970s for today’s innovations?” he said.
“The FDA is clearly trying hard to be innovative,” commented Bruce Quinn, MD, PhD, Principal, at life science consultant Bruce Quinn Associates LLC. “That said, meeting any of these FDA standards would still be very costly for a hospital or regional lab. A lab’s customers are its doctors, patients, and payers. Until it’s clear that these FDA accreditations matter to them, it would be a doubtful investment for the lab.”
From his remarks, Gottlieb appears to understand the challenges labs face. As test developers innovate, the FDA needs to ensure that regulations keep pace, he commented.
Two of the most significant innovations Gottlieb discussed involve the FDA’s review and approval of LDTs. “The first is qualification of the New York State Department of Health as a third-party reviewer,” the commissioner said. “The second is the agency’s flexible, modern approach to how it reviews next-generation sequencing or NGS.
One Application; Two Okays
“The New York State accreditation means that labs whose tests have been approved by the New York Health Department—including laboratories with advanced NGS-based tumor profiling tests—do not need to submit separate applications to FDA,” he explained. “Instead, they can choose to request that their New York 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,” Gottlieb added. “Going forward, we hope that additional accredited, third-party reviewers will become eligible to conduct reviews, make recommendations to FDA, and provide even more options to test developers.”
The second innovation involves writing policies to improve the development and review of advanced NGS tests, he said.
“To take one example, we recently provided public information describing the three-tiered approach that FDA is taking to our review of NGS onco-panel tests in order to minimize the burden on developers,” he added.
Reduced Burden on Labs
“Under this approach, we’re communicating with developers about the flexibility they have in developing analytical and clinical evidence to support marketing authorization, depending on the type of claim being made,” Gottlieb explained.
Soon, the FDA will provide final guidance to developers on a broader and more flexible regulatory approach to NGS tests, he said. “We’re developing policies that will permit more clinical lab tests to be exempt from the burdens of premarket review,” he commented. “For some tests, we may be able to establish initial controls that provide a reasonable assurance of analytical and clinical validity.”
All of these changes are among the FDA’s new approaches to reviewing diagnostic tests. “These new policies recognize that we have unique opportunities to reform and innovate as we consider the right role for FDA with respect to laboratory-developed tests,” he added. The best way to do so is with legislation, he commented, but, in the meantime, the FDA recognizes the need for increased efficiency in how it reviews LDTs.
Changes to PMA Review
Therefore, the agency’s device center has proposed changes to the premarket review of diagnostics by developing what Gottlieb called a pre-cert pilot. Pre-certification is commonly used for digital health products but was first used to review direct-to-consumer (DTC) genetic health risk tests.
“In the setting of these DTC tests, we realized that if we had enough confidence in the quality of a lab’s underlying system, we could exempt from premarket review many individual tests that met pre-specified standards,” he said. “And we could better leverage post-market data to make our processes more efficient.”
Meeting Scientific Standards
Another way the FDA seeks to improve efficiency is by developing innovative approaches for labs to demonstrate analytical and clinical validity, Gottlieb said. “For example, a developer may be able to demonstrate analytical validity by showing that its test conforms to FDA-recognized standards—perhaps including standards established by the scientific community or standards-development organizations.”
To implement this approach, the FDA plans to qualify third-party databases that the FDA could use to help establish clinical validity, he added. “For next-generation sequencing, in particular, this could include our adoption of ClinGen as a reference database,” he said.
ClinGen is a database the National Institutes of Health maintains that aggregates information about genomic variations and their effects on health. “Under this approach, a new NGS test can rely on a reference database, such as ClinGen, to help demonstrate clinical validity,” commented Quinn. “We are closely following all the work in this space and want to leave the door open to other databases, in addition to ClinGen, to qualify.”
FDA Seeks to Speed Lab Test Okays Through Parallel Review With CMS
IN REMARKS to the American Clinical Laboratory Association, FDA Commissioner Scott Gottlieb, MD, touted the work the agency did last year with the Medicare program to review and approve an NGS-based in vitro diagnostic test for Foundation Medicine.
Last fall, the FDA worked with the federal Centers for Medicare and Medicaid Services under a new FDA-and-CMS initiative called the Parallel Review Program. This program helps Medicare patients gain access to innovative medical technologies and helps labs secure payment approval, he said.
In November, the FDA approved the FoundationOne CDx (F1CDx), which was the first breakthrough-designated, NGS-based IVD test that can detect genetic mutations in 324 genes and two genomic signatures in any solid tumor type, the agency said. At the same time, CMS proposed coverage of the F1CDx. The test is the second IVD to be approved and covered under the program’s overlapping procedure.
The first use of the FDA-CMS parallel approval program involving an IVD test came in August 2014, when the FDA approved Cologuard, from Exact Sciences.
By leveraging the FDA’s Breakthrough Device Program and Parallel Review with CMS, Foundation Medicine secured FDA approval and an immediate proposed Medicare coverage determination, within six months of the FDA receiving the application, Gottlieb explained.
To do so, the FDA helped Foundation Medicine use the agency’s Breakthrough Devices Program to speed review of tests that help doctors diagnose life-threatening or debilitating diseases and for which there are no approved or cleared alternatives, or for which the test offers significant advantages over alternative tests, he added.
For diagnostic tests submitted under this program, FDA and CMS concurrently review for marketing authorization and coverage and work with sponsors during test development to provide guidance on the evidence laboratories will need to support the two agencies’ decisions. These efforts reduce the decision-making time for the two agencies, Gottlieb added.
