FDA Workshops and Stakeholder Engagement Culminate in Draft Guidance on NGS-Based Testing

Promoting flexibility and efficiency, the U.S. Food and Drug Administration (FDA) issued two draft guidance documents in early July, addressing oversight of next generation sequencing (NGS)-based tests and the databases that support clinical claims for these tests.

Acknowledging input from genomics experts, providers, patients and other industry stakeholders via public workshops and other efforts, Jeffrey Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health said in a statement that the agency believes the guidance documents “will encourage innovation and advance the goal of precision medicine: to speed the right individualized treatments to patients sooner.”

Public Input
The FDA explained that “current regulatory approaches are appropriate for conventional diagnostics that measure a limited number of substances associated with a disease or condition,” but a more “flexible approach to oversight” is needed for sequencing technologies that “examine millions of DNA variants at a time.”

That need for flexibility was emphasized by participants in a February 2015 FDA workshop addressing potential NGS standards (See National Intelligence Report, March 9, 2015, p. 1). At that workshop when asked whether standards for NGS tests were feasible and, if so, who should develop them, who should implement them, and how could compliance be verified, panelists recommended the FDA involve multiple stakeholders in crafting any standards and advised that given the rapidly developing nature of the technology, the standards’ flexibility was critical. Two more workshops held in November 2015 addressed NGS standards and use of databases to establish clinical relevance of genetic variants. The FDA at the time said it sought “sufficiently flexible assay performance standards that can accommodate innovation, including test modifications, while assuring NGS test safety and effectiveness.”

The draft guidance documents just released are intended to provide that flexibility. The FDA explained in its announcement of the documents’ release: “When the guidances are finalized, adherence to them will offer appropriate flexible and adaptive regulatory oversight of these tests, while allowing for variations in development and validation and accommodating the rapid evolution of NGS technologies.”

NGS Test Guidance
“Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases”— provides the FDA’s proposed recommendations for “designing, developing, and validating NGS-based tests for germline diseases, and also discusses possible use of FDA-recognized standards for regulatory oversight of these tests.” The guidance informs test developers how they can get their NGS tests for germline diseases classified as class II devices and potentially exempt from premarket notification. NGS tests have not been classified by the FDA so they would normally fall into Class III device category under existing law. That means the developer would need to submit an application for premarket approval rather than premarket notification under Section 510k, because there are no similar predicate devices already approved by the FDA.

The guidance is limited to targeted and whole exome sequencing NGS-based tests that diagnose germline diseases or other conditions. It doesn’t apply to NGS tests for “stand-alone diagnostic purposes” or for “screening, microbial genome testing, risk prediction, cell-free DNA testing, fetal testing, pre-implantation embryo testing, tumor genome sequencing, RNA sequencing, or use as companion diagnostics,” which could have different analytical characteristics not addressed by the guidance. The guidance sets forth test design considerations, test performance characteristics, test run quality metrics and general recommendations for performance evaluation studies.

Genetic Variant Databases Guidance
“Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing(NGS)-Based In Vitro Diagnostics—details the FDA’s thinking on “how publicly accessible databases of human genetic variants can serve as sources of valid scientific evidence to support the clinical validity of genotype- phenotype relationships in FDA’s regulatory review of NGS-based tests.”

One of the FDA’s objectives for this guidance is to promote use of publicly accessible databases of genetic variant data to help determine clinical validity of NGS-based tests and thus advance precision medicine. So the guidance sets standards for determining “whether a genetic variant database is a source of valid scientific evidence” that could support the clinical validity of an NGS-based test in a premarket submission. The FDA addresses the quality of the data contributed as well as the privacy and security of information in the databases and transparency as to the sources of data in the databases. As to data quality, the guidance recommends genetic variant databases use consistent nomenclature “that is widely accepted by the genomics community for gene names and/or symbols, genomic coordinates, variants, described clinical and functional characteristics and classifications.” The FDA also recommends that metadata accompany the variant data in the databases, demonstrating the number of independent laboratories and names of laboratories reporting variant classifications and the name of the test used to detect the variant, and when possible, technical characteristics of such tests.

The guidance also indicates how publicly accessible databases can apply for FDA recognition and how the FDA will evaluate such databases. The recognition process would be voluntary and similar to the standards recognition process under Section 514 of the Food, Drug and Cosmetic Act for standards assuring safety and effectiveness of medical devices. But, the FDA explains in a footnote, it won’t be conducted under Section 514. Databases that receive recognition will be reviewed regularly to ensure they continue to meet the requirements of the guidance.

Next Steps
The two draft guidance documents have a 90-day comment period and were published in the July 8 Federal Register. Public comments can be submitted at any time for FDA guidance documents but to have comments considered before these draft guidance documents are finalized, comments must be submitted by Oct. 6, 2016 for each guidance.

The FDA is also hosting two webinars focusing on the guidance documents on July 27. The first webinar, from 12 noon to 1 p.m. EST, focuses on the technical and regulatory aspects of the guidance documents. The second webinar, 1:30 to 2:30 p.m. EST, will discuss the significance of the guidance documents for patients and health care providers. Click here for more information about the webinars. Transcripts of the webinars and the slide presentations will be available for review after the webinars for those who don’t attend.

Takeaway: Workshops and stakeholder input yield results with draft FDA guidance on how to get FDA approval for NGS tests and the databases that support their clinical validity.