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FDA seeks feedback on possible analytical standards and approaches to optimize regulation of next-generation sequencing (NGS)-based in vitro diagnostic tests.
On Nov. 12, 2015, FDA held a public workshop, Standards-Based Approach to Analytical Performance Evaluation of Next-Generation Sequencing In Vitro Diagnostic Tests, with the intention of receiving feedback on possible analytical standards and approaches the agency may use to develop and/or revise regulation of next-generation sequencing (NGS)-based in vitro diagnostic tests. FDA hopes to also use comments received from the workshop “to advance the further development of appropriate and relevant performance standards for evaluation of next generation sequencing in vitro diagnostic tests that produce results on variation in the human genome.” According to an FDA discussion paper, the workshop was developed as a way for FDA to consider ways of optimizing the regulation of NGS tests for human genomes and develop a “flexible, adaptive regulatory approach”.
A paper posted by the agency on Feb. 20, 2015 outlined FDA’s strategies for developing this approach, including identifying and implementing analytical standards to ensure NGS tests produce reliably accurate results and develop ways to use databases of genetic variants to guide clinical interpretation of NGS test results. Feedback from the publication of the February paper led FDA to further develop their strategies published in a companion paper, which was discussed at the November workshop.
FDA proposes two approaches to assure the development of analytically valid NGS tests. One approach establishes performance standards that include specific metrics and acceptance criteria that the test would have to satisfy. The other approach would develop design concept standards that would ensure, when complied with, that the manufacturer can achieve the proper design and validation of an NGS test.
The Performance Standards approach would establish the testing metrics and performance criteria and, possibly, prescribed validation studies for establishing the analytical and clinical performance of the test. FDA states that the standards could be developed by FDA or by a FDA-recognized third party. FDA states that the performance standards would not use a specific platform, chemistry, or software, and the developer “would be free to specify intended use, design, and other parameters, as long as the final test could achieve the defined performance metrics.”
The Design Concept Standards approach would use of well-described principles of design to conceptualize a test from beginning to end. Developers would define the intended use of the desired test and then determine the specific test components (e.g., sample collection and processing, sample and library preparation, sequence generation/base calling, mapping and alignment, and variant/genotype calling), test component requirements, and the impact of each component on other design elements. The developer would predefine each component’s specific requirements (e.g., physical, performance, or other requirements). FDA states that, “developers would also need to consider limitations when designing a test, such as the availability of the necessary sample type or the ability of software analytical tools to detect the specific variants of interest. By considering each critical factor in the test development process and their impact on the overall design of the test, developers should be able to consistently generate high-quality NGS-based tests.”
More information on the workshop, including information on obtaining transcripts, can be found on FDA’s website and in the Federal Register.