FDA Advances Precision Medicine Initiative by Issuing Two Draft Guidances on NGS-Based Tests

Creating a regulatory framework to support rapid evolution of NGS technologies

In support of the President’s Precision Medicine Initiative, the US Food and Drug Administration (FDA) issued on 6 July 2016 two draft guidances on use of standards in FDA regulatory oversight of next generation sequencing (NGS)-based in vitro diagnostics used for diagnosing germline diseases and use of public human genetic variant databases to support clinical validity for NGS-based in vitro diagnostics.  

Many advances in precision medicine will depend on the safe and effective use of NGS technology. As part of the Precision Medicine Initiative, FDA has been focused on optimising FDA’s regulatory oversight for NGS in vitro diagnostic tests to help accelerate research and the clinical adoption of precision medicine while assuring the safety and effectiveness of these tests.

While current regulatory approaches are appropriate for conventional diagnostics that measure a limited number of substances associated with a disease or condition, the new sequencing technologies can examine millions of DNA variants at a time, and thus require a flexible approach to oversight that is adapted to the novel nature of these tests.

The field of genetic and genomic testing is dynamic, and the agency understands that there is a need to encourage innovation while assuring that NGS-based tests provide accurate and useful results. When the guidances are finalised, 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.

The FDA values the input received from genomics experts, industry, health care providers and patients from four public workshops and other outreach opportunities. Based on this input, they crafted draft recommendations that they believe will encourage innovation and advance the goal of precision medicine. 

Regulatory oversight of NGS for diagnosing germline diseases

As part of the Precision Medicine Initiative effort, the draft guidance document provides FDA’s proposed approach on the content and possible use of standards in providing oversight for whole exome human DNA sequencing (WES) or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 (hereinafter referred to as “NGS-based tests for germline diseases” or “NGS-based tests”).

This document provides recommendations for designing, developing, and validating NGS-based tests for germline diseases, and also discusses possible use of FDA recognised standards for regulatory oversight of these tests. These recommendations are based on FDA’s understanding of the tools and processes needed to run an NGS-based test and the design and analytical validation considerations appropriate for such tests.

Upon finalisation of this guidance, test developers will be able to follow these recommendations when preparing a premarket submission. The recommendations in the draft guidance document are applicable for NGS-based tests for germline diseases, whether results are intended to be provided directly to patients or through healthcare professionals; however, for direct-to-consumer NGS-based tests for germline diseases additional recommendations and controls would be needed.

This draft guidance document also outlines considerations for possibly classifying certain NGS-based tests for germline diseases in class II and potentially exempting them from premarket notification requirements. Over the longer term, FDA will consider how these recommendations may form the basis for standards that FDA could recognise or whether FDA could establish special controls and/or conditions for premarket notification exemption.

The considerations and recommendations in the draft guidance are limited to targeted and WES NGS-based tests intended to aid in the diagnosis of individuals with suspected germline diseases or other conditions. 

The document does not apply to NGS-based tests intended for stand-alone diagnostic purposes. Additionally, the document is not intended to apply to NGS-based tests intended for screening, microbial genome testing, risk prediction, cell-free DNA testing, foetal testing, pre-implantation embryo testing, tumour genome sequencing, RNA sequencing, or use as companion diagnostics, as these may have other analytical characteristics not addressed by the recommendations in the document.

FDA intends to provide recommendations and discuss pathways for additional intended uses of NGS-based tests in future guidance documents. In the interim, the public may contact FDA with questions about these issues.

Use of public human genetic variant databases to support clinical validity for NGS-based in vitro diagnostics

This draft guidance document describes one part of FDA’s effort to create a flexible and adaptive regulatory approach to the oversight of NGS-based tests as part of the Precision Medicine Initiative. The goal of this effort is to help ensure patients receive accurate and meaningful results, while promoting innovation in test development. This draft guidance document describes 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.

This draft guidance document describes FDA’s considerations in 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. This draft guidance further outlines the process by which administrators of publicly accessible genetic variant databases could voluntarily apply to FDA for recognition, and how FDA would review such applications and periodically reevaluate recognised databases.

The genetic variant databases discussed in the draft guidance only include those that contain human genetic variants, and do not include databases used for microbial genome identification and detection of antimicrobial resistance and virulence markers. This draft guidance does not apply to software used to classify and interpret genetic variants, but instead, only regards use of curated databases using expert human interpretation.

The FDA encourages public comments on these two draft guidances during the 90-day comment period.

FDA's guidance documents, including these two guidance documents, do not establish legally enforceable responsibilities. Instead, guidance documents describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance documents means that something is suggested or recommended, but not required.