Personalized or Precision Medicine needs reliable and accurate diagnostic tests to guide clinical intervention and treatment decisions. Traditional testing of germline variants is site-specific and therefore only provides information on one or at most, several variants at a time. Advances in DNA sequencing technology, notably Next Generation Sequencing (NGS), permit the analysis of millions of variants at a time. As a result, one test will provide clinically relevant and actionable data on a multitude of conditions, some of which are unknown until the test has been completed.

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. This post will review the first draft guidance, “Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases” (Guidance).

The Guidance provides 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 intended to aid in the diagnosis of individuals with suspected germline diseases or other conditions. Guidance at page 1. FDA notes that for the purpose of the Guidance, the term” germline diseases or other conditions” encompasses those genetic conditions arising from inherited or de novo germline variants.

Recommendations for Design, Development, and Validation of NGS-based Tests for Germline Diseases

The Guidance provides recommendations regarding how a NGS-based test should be designed, developed, and validated. As a general principle, test developers should first define the indications for use statement of their test, and this statement will then determine how the test should perform. Guidance at page 7. Test developers are encouraged to prospectively determine the types of studies that should be conducted as well as the thresholds that should be met for a minimum and target value of performance. Subsequent validation studies should indicate if the predefined performance values have been met. If the test does not meet any one of the predefined performance specifications, the test should be modified and revalidated. Id. The cycle of design, development and validation should be repeated until the test meets the predefined performance specifications.

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.