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FDA Outlines Ways to Assess Analytical, Clinical Performance of NGS ahead of February Workshop

NEW YORK (GenomeWeb) – The US Food and Drug Administration is considering a standards-based approach for assessing the analytical performance of next-generation sequencing diagnostic tests and using centralized curated databases to evaluate their clinical performance, according to a recent paper published by the agency.

The preliminary discussion paper, posted on the FDA's website last month, outlines possible ways the agency might regulate NGS tests in the future and provides discussion points for a one-day public workshop entitled "Optimizing FDA's Regulatory Oversight of Next Generation Sequencing Diagnostic Tests" that the FDA will hold at the National Institutes of Health campus in Bethesda, Md., on February 20.

According to the paper, the FDA sees a need for regulating NGS tests differently from other in vitro diagnostics because the technology is unique. In particular, it detects a large number of unspecified variants, the clinical significance of which can be difficult to prove because they occur so rarely. This is in contrast to technologies like PCR and SNP arrays, which capture preselected variants and are thus more suitable for regulation under traditional approaches.

While NGS creates regulatory challenges, the FDA is also aware of its promise to advance the understanding of disease and "the unique importance of these tests to the research and clinical communities."

Starting in 2011, the agency held public workshops on aspects of NGS, discussed the technology with experts, and participated in the development of standards and tools, such as the Next Generation Sequencing: Standardization of Clinical Testing (Next-StoCT) workgroup and the Genome in a Bottle Consortium. In late 2013, it cleared the first NGS instrument, the Illumina MiSeqDx, along with two cystic fibrosis assays.

Because a "critical mass" of genomic data has accumulated, "FDA is now exploring new regulatory approaches that will enable the Agency to provide appropriate oversight, in a way that is more suitable to the complexity and data-richness of this new technology, to assure that NGS tests have adequate analytical and clinical performance," according to the paper.

The approach the agency took to approve the MiSeqDx could serve as a guideline for this. To determine the platform's analytical performance, for example, FDA found it impractical to consider every single variant in the genome, and therefore looked at "a representative subset of types of variants in various sequence contexts" instead, which "provided reasonable assurance that the test would be able to successfully identify relevant variants in the genome," according to the paper.

"FDA plans to continue to use this subset-based approach when evaluating the analytical performance of NGS platforms, but is considering novel and efficient approaches for establishing analytical performance for specific NGS tests developed using FDA cleared or approved components in clinical diagnostic laboratories," the authors wrote.

One approach would be to define quality-based standards that labs would be required to use to demonstrate analytical performance. Such standards could be developed by an expert committee, the FDA itself, or by a standards development organization such as the Clinical Laboratory and Standards Institute, and the FDA is seeking feedback on how to proceed.

Regarding clinical performance, in the case of Illumina's cystic fibrosis tests, the FDA allowed Illumina to make use of a well-curated third-party database with evidence from multiple sources, rather than to conduct a new study or dig into the literature on its own.

This approach could also work for future NGS tests, and the FDA has already "initiated a dialogue" with the NIH to see whether the ClinGen program and the ClinVar database could be used to assess the clinical significance of variants.

FDA chose those resources "because they are publically accessible, transparent, scalable, and evidence is continually curated by the scientific community using the most current data available," though other databases could meet the same need. For example, the cystic fibrosis database used to assess the Illumina assays was developed in part by a disease advocacy foundation, according to the agency.

"Ultimately the agency's goal is to allow test developers to leverage FDA-recognized evidence-based assessments of the clinical significance of genetic variants. This would minimize the need for sponsors to generate their own data in order to support a premarket submission to the FDA," the authors wrote, and would allow several developers to rely on the same evidence to establish clinical relevance.

Finally, the FDA is considering whether or not to allow test makers to communicate variants that have no clear clinical significance but are likely disease-associated and "may have some value to physicians and their patients in clinical decision-making in certain circumstances." According to the paper, the agency "would like to further explore this concept" and is seeking public comment on this.