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FDA Making Progress on NGS Panels Draft Guidance


NEW YORK (GenomeWeb) – The US Food and Drug Administration is closer to releasing a regulatory draft guidance on next-generation sequencing panel tests, according to an agency official who spoke at the Festival of Genomics in Boston this week.

David Litwack, a member of the personalized medicine staff at FDA's Office of In Vitro Diagnostics and Radiological Health, said that the agency will soon make available for public comment a draft guidance on NGS panels. "Our goal at this point is not to say this is how it is" in terms of regulation, but the draft guidance represents an initial proposal that the FDA wants additional input on, Litwack added.

As previously reported by GenomeWeb, one near-term draft guidance FDA is working on will focus on NGS oncology panels. 

The agency has hosted a number of public workshops in an effort to gather the life sciences community's advice on how to regulate NGS panels, which can interrogate large numbers of genes for a variety of disease conditions. The agency to date has mostly cleared or approved single-gene tests for specific indications.

The FDA provided a window into some of its regulatory thinking on NGS panels in 2013, when it cleared Illumina's MiSeqDx platform, two cystic fibrosis assays, and a library prep kit. The agency cleared the platform as a Class II device with special controls, so other labs with tests with the same intended use could complete the requirements the agency has laid out as "special controls" for this type of device, and market them without making a premarket submission.

The two cleared CF assays that run on MiSeqDx include a test that detects 139 variants in the CFTR gene and another test that sequences a large portion of the CFTR gene to detect differences when compared to a reference sequence. In order to clear the 139-variant test, the FDA used Johns Hopkins University's CFTR2 database, containing most of the known variants observed in patients.

At public workshops, the FDA has said that when it comes to establishing the clinical significance of the many variants that can be detected by NGS panels, it intends to make use of well-curated databases, such as CFTR2, instead of requiring test developers to submit evidence on individual variants. "This thought came from the need to not have different test developers send us the same evidence for each [variant]," Litwack said. 

Instead of reviewing clinical validity data on specific variants, the agency wants to look at the processes within specific databases, and "somehow recognize them" as being able to provide accurate evidence on the clinical significance of variants. Since evidence underlying variants change, altering their classification, Litwack noted that tracking them through databases would enable a more "seamless and dynamic" regulatory framework. "It's a more quality systems view," he said.

The FDA, along with editors at peer-reviewed journals and even payors, encourage labs and researchers to deposit variant data in public repositories. National insurer Aetna requires newly contracted labs to deposit variant data into a database called ClinVar if they want to be in network for BRCA1 and BRCA2 genetic testing. Medicare contractor Palmetto doesn't require it, but encouraged labs to submit data to ClinVar when it outlined the analytical performance by which it will evaluate coverage for circulating tumor DNA tests. 

ClinVar is a freely available archive of genotype and phenotype relationships the National Institutes of Health launched three years ago, and more than 500 submitters have contributed data to the repository so far. Simultaneously, the National Human Genome Research Institute has also funded ClinGen, which aims to create a central resource for clinically relevant genes and variants that can be used for precision medicine.

"When you look at what's going on in the community and see the development of databases like ClinVar and the evidence evaluation program ClinGen, it's really infrastructure being developed that the FDA, as well as test developers, physicians, and patients, can all leverage … [and] will give us a common understanding of evidence and produce high-quality interpretation," Litwack said.

The agency has also discussed with stakeholders the pros and cons of advancing predefined analytical performance standards or creating a so-called design concept standard. The design concept standard would be a more flexible approach, while performance standards would prescribe more specific requirements.

Based on public feedback, Litwack indicated at the Festival of Genomics this week that the FDA is learning toward a design concept approach where it delineates the process, "but [does] not say you have to have x, y, or z," Litwack said. "Once we have some idea of the standards in place, we'll be able to accommodate many different test designs and uses and begin to fit it into our regulatory structure."

Litwack added that the agency is committed to working with the life sciences community to advance regulation for NGS-based tests. "All of these things we're talking about are things we view as a collaboration … to develop the science and standards of databases and other tools that will inform the regulatory system," he said.