On April 13, 2018, FDA issued final guidance on the Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics. The guidance is based on draft guidance dated July 8, 2016. The guidance is part of FDA’s efforts to create a flexible and adaptive regulatory approach for overseeing next generation sequencing tests. According to FDA, genetic variant databases that comply with the guidance may provide valid scientific evidence to support clinical validity in a premarket submission and thus be recognized by FDA for such use.

For example, FDA recommends that genetic variant database administrators create and document standard operating procedures (SOPs) for data evaluation and make certain information about them and data sources publicly available. Administrators should also take steps to ensure the preservation, integrity, and security of data, and use commonly accepted data formats and consistent nomenclature. FDA also states that variant data should be accompanied by metadata indicating, for example, information about the analytical performance of the test used to detect the variant.

In addition, FDA recommends that each variant evaluation follow a publicly available and validated protocol and be performed by at least two professionals. FDA recommends that the protocols incorporate and weigh multiple lines of evidence, use a tiered system of assertions, and incorporate unique details of the gene/disease or condition being evaluated.

The guidance describes a three-step process for genetic variant databases to obtain recognition from FDA: (1) voluntary submission of detailed information about the database, (2) FDA review of genetic variant database policies and procedures for maintaining data and making variant assertions, and (3) maintenance of FDA recognition of a database. Once a genetic variant database is recognized, FDA may allow its assertions to be relied on in a premarket submission without additional scientific evidence.