On April 13, 2018, FDA issued the final guidance documents “Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS) – Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases” (hereinafter the NGS Guidance, available here) and “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics” (hereinafter the Databases Guidance, available here). We previously blogged on the draft guidance documents issued in July 2016 here. As we discussed in our earlier post, these guidances have the possibility to be incredibly important to the IVD industry given the tremendous potential that sequencing holds.
The two guidances could hardly have undergone more different degrees of revision since their drafts were issued. The Databases Guidance received no substantive changes as compared to the draft. On the other hand, the NGS Guidance has undergone significant changes as compared to its draft, including its name. The draft NGS Guidance was originally named the “Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases.” NGS test developers will want to ensure they closely read the final NGS guidance to understand the full extent of its changes. Below we discuss several of the significant substantive changes to the NGS Guidance.
It is important to note that FDA provided no explanation for the changes to the NGS Guidance. Unlike the case with regulations, where FDA describes the reasons for revisions, guidances keep readers guessing as to why FDA’s thinking has shifted.
One of the major changes to the scope of the guidance is that it now applies only to NGS-based IVDs intended to diagnose suspected germline diseases in symptomatic patients. The guidance specifically states that it “does not address tests intended for use in the sequencing of healthy individuals.” The original guidance did not limit the scope of the guidance to only symptomatic individuals. This is an important change that will limit the scope and impact of the guidance to industry.
The guidance does, however, include several new helpful sections, including one regarding recommendations for reviewing changes to device design and production. This section pertains to all changes, including those that may or may not require premarket review. The guidance provides general guidance regarding assessing changes, including revalidation. The guidance also includes a new Appendix A. This appendix includes illustrative examples to aid in the guidance’s recommendations regarding analytical tests.
Finally, the NGS Guidance includes a notably shorter discussion of the possible exemption of NGS-based tests for germline diseases as compared to the draft. The draft had a full section regarding the possibility of an exemption for such tests. The final NGS Guidance still leaves open the potential for NGS-based tests being exempt from premarket notification. But, with a much more limited discussion in the final guidance it may be a signal that the Agency believes it is less likely that these tests will actually be exempt once classified. The guidance continues to state that it anticipates that the de novo pathway is the appropriate premarket pathway for these IVDs.
The extent of changes to the final NGS Guidance likely reflect that the Agency’s understanding and view regarding these tests is continuing to evolve. That will almost certainly remain the case for years to come. This is an area we will continue to watch closely and look forward to seeing FDA’s first de novo authorization for an NGS test to diagnose a germline disease.