NGS Guidances Lay Foundation for Precision Medicine Initiative

The FDA is creating a new flexible regulatory pathway for genomic tests that sequence the human genome as part of President Obama’s Precision Medicine Initiative.

The agency released two complementary draft guidances that set a foundation for the pathway by streamlining submission and review of data supporting clinical validity of next-generation sequencing (NGS)-based in vitro diagnostics.

The agency sought feedback from industry stakeholders during four public meetings before crafting the guidances, which explain how the agency might consider exempting certain NGS-based tests from premarket review, Assistant Commissioner Heidi Marchand said.

The move represents FDA’s commitment to harness technology and share genomic findings pouring out of clinical research, she said.

“This system would be efficient and flexible: as technology advances, standards can be updated to help ensure test accuracy,” the FDA said. “Similarly, as clinical evidence improves, new interpretations could be supported.”

The first draft guidance, “Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases,” provides recommendations for designing, developing and validating NGS-based tests for hereditary diseases, and addresses the potential for using FDA-recognized standards to demonstrate analytical validity.

Standards for Analytical Validation

Stakeholder feedback indicated that conforming to standards for analytical validation of NGS-based tests would allow for differences in development but could accommodate evolution of newer technology.

“Upon finalization of this guidance, test developers will be able to follow these recommendations when preparing a premarket submission,” the guidance said. It stressed that the guidance is limited to targeted and whole exome human DNA sequencing (WES) NGS-based tests to aid in diagnosing suspected germline diseases or other conditions. It does not apply to NGS-based tests intended for stand-alone diagnostic tests. Additional recommendations or controls would also be required for direct-to-consumer NGS-based tests for germline diseases.

The agency said it would be seeking stakeholder comments on expanding the scope but wanted to hear from industry first.

Although the FDA has cleared a few single-gene, disease-specific, targeted NGS-based diagnostics, it has not classified NGS-based tests with a broad intended use for suspected germline diseases. Hence, an NGS-based test would automatically be classified as a Class III device under current regulations. The agency said it would consider de novo requests for NGS tests, and that if such a request is granted, then the test could serve as a predicate for future 510(k) submissions.

The FDA could even exempt certain tests from premarket notification requirements. Regardless, NGS tests must demonstrate analytical validity, and using a standards approach could streamline how this validity is demonstrated.

The guidance lays out the typical elements of an NGS-based test for germline diseases, as well as recommendations for design, development and validation of those tests.

The FDA recommends the following test design considerations:

• Indications for use statement that prospectively defines and documents the specific clinical need driving development of the test;
• Specific user needs for the test;
• Specify and document the acceptable specimen types to be used for the test;
• Specify and document the region of the genome that will be interrogated;
• Demonstrate performance needs by defining and documenting a minimum set of metrics and performance thresholds, as well as possible limitations to test performance; and
• Specify and document all test components.

For FDA Recognition

The FDA’s second draft guidance, entitled “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics” describes an approach for test developers to use data from public genomic databases to gain FDA recognition.

The guidance notes that administrators of databases can voluntarily apply to FDA for recognition, and it describes how the agency would review those applications. Administrators seeking recognition of their genetic variant database should contact the FDA through the pre-submission program.

The guidance stresses the importance of public databases because much of the data that could be used to support clinical validity of NGS-based tests are not publicly accessible. Aggregation of clinical genotype-phenotype associations and evaluating that evidence would promote rapid translation of genetic information into useful clinical evidence.

The agency defines a “genetic variant database” as a publicly accessible database that aggregates and curates reports of phenotype-genotype relationships to a disease with publicly available documentation of evidence supporting those linkages.

In interpreting data, the guidance stresses the importance of using qualified experts to make informed conclusions about genetic variants and their meaning for clinical decisions.

The guidance draws parallels between the use of evidence standards with the types of evidence to support FDA premarket submissions. As such, clinical validity is based on the “totality of available evidence” and not on isolated case reports or summary literature.

Comments are due Oct. 6. Read the guidances here: www.fdanews.com/07-13-16-NGSpublicdatabase.pdf and here www.fdanews.com/07-13-16-NGSclinicalguidance.pdf. — Tamra Sami