On December 29, 2014, FDA issued a public workshop notice and associated discussion paper entitled “Optimizing FDA’s Regulatory Oversight of Next Generation Sequencing Diagnostic Tests–Preliminary Discussion Paper.”  The Discussion Paper describes opportunities and regulatory challenges presented by next-generation sequencing (NGS) tests, and requests public comment on possible new approaches to demonstrating analytical performance and clinical performance of NGS tests.

NGS, also called “high throughput sequencing,” refers to technologies that can perform sequencing of large segments of an individual’s DNA, and even the individual’s entire genome.  A single NGS test can identify thousands or millions of genetic variants that an individual may have, in contrast to laboratory tests that identify a single or a defined number of substances.  The NGS test results can be used to diagnose or predict an individual’s risk of developing many different diseases or conditions.  NGS tests pose regulatory challenges to FDA, because they can “generate large amounts of data and consequently may have relatively broad or undefined intended uses or indications.”  79 Fed. Reg. 78092, 78093 (Dec. 29, 2014).

For purposes of considering the questions posed about possible new regulatory approaches for NGS tests, FDA’s Discussion Paper defines an NGS test as “a human DNA sequencing assay performed on a particular NGS instrument (e.g., MiSeqDx) with a workflow defined by standard operating procedures that specify all materials and procedures.”  FDA’s definition covers the patient sample type through computational processing of sequencing data.  It also includes “any portion of interpretation of the clinical meaning of individual variants identified in that patient that is performed within the test system (including software) rather than by a healthcare professional.”

FDA’s Discussion Paper describes how the agency applied a subset-based approach in authorizing, through the de novo process, the marketing of the MiSeqDx™ instrument (DEN130011) and Universal Kit sequencing reagents (DEN130042).  Analytical test performance for the system was “demonstrated for a representative subset of types of variants in various sequence contexts.”  FDA intends to use this subset-based approach for other NGS platforms.  But the agency is also considering whether a standards-based approach to FDA regulatory review of NGS tests would be valuable, and requests public feedback on this issue.

In evaluating in vitro diagnostic (IVD) devices, FDA reviews the clinical performance of the test — that is, whether the test results correctly identify the relevant disease or condition.  This might be impractical for NGS tests because they detect rare variants, and because the rare mutations coexist with other possible causative variants.  FDA is exploring the use of genetic databases that would provide information on genetic variants and their association with disease, including disclosing the strength of the evidence regarding the association.

FDA’s Discussion Paper focuses on two databases supported by the National Institutes of Health (NIH): ClinVar and ClinGen.  ClinVar is a public database of reports of human variants and their relationship to phenotypes.  ClinGen is a resource for expert evaluation of research data and genetic test results to determine which variants are most relevant to patient care.  Important factors regarding these databases are that they are accessible to the public, transparent, and updated with new evidence curated by the scientific community.  FDA is seeking public comment regarding whether other databases that meet these criteria could be used to support clinical claims for genetic and genomic tests.

FDA’s Discussion Paper also requests comment on whether and how to communicate to physicians information about genetic variants whose clinical significance is not well understood.  In this regard, FDA is seeking to assure that test information will benefit medical decision-making while minimizing risks to patients.

The Discussion Paper lists ten specific questions regarding analytical performance, and eleven specific questions regarding clinical performance.  The public can comment on these questions at the public workshop being held on February 20, 2015, and in written comments that should be submitted to the docket by March 20, 2015 (Docket No. FDA-2014-N-2214).