The FDA released two final guidance documents related to next-generation sequencing (NGS) and one draft guidance on investigational in vitro diagnostics (IVDs) in oncology trials. All three documents offer test developer recommendations for a more efficient path to market.

The two final guidance documents provide NGS test developers with recommendations for designing, developing and validating tests, as well as using genetic variant databases to support clinical validity.

The first guidance, Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics, encourages developers to use clinical evidence found in FDA-recognized public databases to support clinical claims for their tests. The agency said this will ensure accurate clinical evaluation while providing developers with an efficient means of gaining marketing clearance or approval for new tests.

The guidance describes the FDA’s considerations for recognizing publicly accessible genetic variant databases as sources of valid scientific evidence during premarket review, and also spells out how database administrators can apply to the FDA for inclusion in the program.

FDA Commissioner Scott Gottlieb said the agency “recognizes the tremendous potential of NGS technology to guide and improve patient outcomes” and said the agency is “developing a policy approach to keep pace with fast-moving NGS technologies that give patients and clinicians confidence in these panels’ analytical and clinical validity, while still allowing these sequencing systems to be efficiently updated as new genes, or gene variants, or improved algorithms come online.”

According to Gottlieb, “We believe that this guidance will encourage expert-based crowd sourcing of NGS evidence generation, curating and data sharing—which can all advance the development of high-quality precision medicine treatments and diagnostics.”

The second guidance, “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,” provides recommendations for designing, developing and validating NGS-based tests used to diagnose individuals with suspected genetic diseases. The guidance describes how the FDA evaluates premarket submissions to determine how accurate a test is at detecting a particular genomic change.

The FDA developed the guidelines because current regulatory approaches are “appropriate for conventional diagnostics” that measure a limited number of chemical substances, while new sequencing technologies can examine millions of DNA variants at a time, and require a more “flexible approach to oversight that is adapted to the novel and evolving nature of these tests.”

In providing regulatory oversight for NGS in vitro diagnostic tests, the agency hopes to encourage the development of the rapidly evolving technology while ensuring that the devices are safe and effective.

Draft Guidance

The draft guidance introduces an optional submission process for determining the risks or non-risks of using an investigational in vitro diagnostic in a clinical trial involving an oncology investigational drug.

According to the guidance, Investigational In-vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination, the submission process determines whether the use of an investigational IVD in a clinical trial for an oncology therapeutic is a significant risk (SR), nonsignificant risk (NSR) or exempt. The trial may require an investigational device exemption (IDE) approval if it is found to be a SR, the guidance stated, in addition to an investigational new drug application (INDA).

A single sponsor should be prepared to hold communications with the FDA about the IND and should submit information about the oncology development program to either CBER or CDER, who will consult CDRH to determine its risk factor.

That information includes how the sponsor will apply investigational IVD results to the clinical trial, what they know about the prevalence of the biomarker in the patient population, and the specimen type that will be collected for investigational IVD testing, the guidance stated. In addition, if a biopsy is required for the IIVD testing, the sponsor should note any potential risks.

FDA Commissioner Scott Gottlieb stated that the guidance will “encourage greater innovation and accelerate the adoption of tools that can increase the productivity of clinical research and improve the delivery of cancer care.”