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In NEJM, Lander Lauds Steps at FDA to Build New Regulatory Framework for Genomic Tests

NEW YORK (GenomeWeb) – What makes next-generation sequencing-based diagnostic tests alluring also makes them complicated to regulate, but changes to the regulatory framework could ease the adoption of such tests, the Broad Institute's Eric Lander wrote in a Perspective article in the New England Journal of Medicine this week.

Lander said that it would take time to build the necessary regulatory framework at the US Food and Drug Administration to deal with NGS-based tests, but he noted that the agency had "already taken small, but significant steps" when it approved Illumina's MiSeqDx sequencing platform, two associated assays, and a library prep kit in 2013.

Lander, who is also the co-chair of the President's Council of Advisors on Science and Technology, called the issue the FDA faces in regulating NGS-based diagnostics a "knotty" one.

NGS-based tests can uncover variants throughout the genome, even ones in genes clinicians don't necessarily know to watch for. But gene tests and other in vitro diagnostics are currently evaluated by how accurately and reliably they identify the gene, protein, or other substance of interest, and whether the results from the test correctly identify the related disease or condition.

As Lander pointed out, a narrow interpretation of the FDA regulatory framework would mean that for each NGS-based test, each of the three billion nucleotides of the genome would need separate analytic studies, and each company presenting a test covering the same gene or variant would have to provide their own data supporting the link between that variant and disease.

Others, like Francis Collins, the director of the US National Institutes of Health, and Harold Varmus, the director of the National Cancer Institute, in their own recent NEJM article have also highlighted the need for changes to the regulatory framework to enable the use of new tests and the adoption of personalized medicine.

The FDA, Lander noted, has begun to investigate new regulatory approaches.

"As I've engaged in planning for the [Precision Medicine Initiative] over the past year ... I've been thrilled to see that the FDA — sometimes viewed as hidebound — has been exploring radical new approaches for cutting the Gordian helix in which genomic testing has been bound," he said.

In its recent approval of Illumina's MiSeqDx sequencing platform and related assays, the agency took a slightly different regulatory tack — one it noted in a discussion paper posted at its website — that could be implemented for other NGS-based tests.

"FDA is considering new regulatory approaches only for NGS tests because this technology allows broad and indication-blind testing and is capable of generating vast amounts of data, both of which present issues that traditional regulatory approaches are not well-suited to address," the agency said.

The MiSeqDx system, for instance, was able to demonstrate its analytic performance using a representative subset of variant types that appear in different sequence contexts. For the associated cystic fibrosis assays, Illumina was able to provide evidence for the clinical relevance of certain variants by drawing on a community-created and -curated database of cystic fibrosis mutations.

Going forward, Lander argued that software programs could be developed to validate new sequencing platforms and that community-curated databases like the NIH-funded Clinical Genome Resource project could, if scaled-up, provide the needed data about the links tying genes, variants, and diseases together.

He further envisioned a situation in which FDA could provide a "safe harbor" so that developers whose genomic tests have interpretations consistent with such databases wouldn't have to provide additional validation, though they could seek approval for tests based on other interpretations.

But, Lander noted, "Fleshing out these ideas will require a lot of work."

In its preliminary discussion paper, FDA asked the community for feedback, and the agency is to hold a public workshop this week to discuss these potential new regulatory approaches for next-generation sequencing-based tests.