Next Generation Sequencing (NGS) permits the analysis of millions of genetic variants at a time and has proven to be invaluable for the development of personalized or precision medicine. Analysis of whole genomes is providing insight into the diagnosis, prediction and treatment of disease, and will continue to do so as more genetic information is collected and analyzed.

The FDA, in partnership with President Obama’s Precision Medicine Initiative (PMI), is working to take advantage of NGS for the development of new personalized therapies while maintaining quality and safety. FDA issued two draft guidances designed to streamline regulatory oversight for NGS tests. The first guidance discussed FDA’s proposed approach on the content and possible use of standards in providing oversight for whole exome human DNA sequencing (WES) or targeted human DNA sequencing NGS-based tests and was reviewed in my prior post of August 1, 2016. This post will review the second draft guidance, “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics” (Guidance).

The Guidance notes that while the industry understands the value of reliable genetic data to support clinical validity of NGS-based tests, the FDA believes that much of this data is not publicly accessible. The data that is accessible to the public will require controls and standards to establish its reliability so that it can be translated into useful clinical evidence. The second Guidance is provided by FDA to recommend standards that will promote the aggregation, curation and interpretation of clinical genotype-phenotype associations in publicly accessible genetic variant databases into clinically useful evidence. Guidance at page 2. The Agency also hopes that the recommendations noted in the Guidance will encourage the deposition of variant information in public databases, reduce regulatory burden on test developers and encourage advancements in the implementation of precision medicine. Id.

Recommendations to Support Recognition of Publicly Accessible Genetic Variant Databases of Human Genetic Variants as Sources of Valid Scientific Evidence Supporting Clinical Validity of NGS Tests

In brief, FDA recommends that the genetic variant database should: “(1) operate in a manner that provides sufficient information and assurances regarding the quality of source data and its evidence review and variant assertions; (2) provide transparency regarding its data sources and its operations, particularly around how variant evidence is evaluated and interpreted; (3) collect, store, and report data and conclusions in compliance with all applicable requirements regarding protected health information, patient privacy, research subject protections, and data security; and (4) house sequence information generated by validated methods.” Guidance at pages 4 and 5.

In addition, the Guidance states that if the data and assertions from genetic variant databases follow the FDA’s recommendations, the data would be considered as valid and supportive of clinical validity in a premarket submission. Guidance at page 8. FDA announced its intention to implement a recognition process for publicly accessible databases and their assertions to stream line FDA premarket review of NGS tests. Evidence from the validated databases could be submitted by NGS-test developers as part of their premarket review submission, and in some instances, without submission of additional clinical data regarding the variant. Id.

Comments, Suggestions and Questions

Comments and suggestions regarding the draft Guidance may be submitted within 90 days from the July 8, 2016 publication date of the Guidance in the Federal Register. Comments may be submitted electronically to or in writing to the Division of Docket Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville Maryland 20852. All comments must be identified with the docket number listed in the Federal Regiser notice.

The public can submit questions about this Guidance concerning devices regulated by CDRH by contacting the Personalized Medicine Staff at 301-796-6206 or at For questions regarding the Guidance as applied to devices regulated by CBER, the public is invited to contact the Office of Communication, Outreach and Development in CBER at 1-800-835-4709 or by email at ocod@fda.hhs. gov.