FDA’s Guidance for Genetic Testing: What are the implications?

Author: Lynn Griffin, PhD

In April of this year, the FDA finalized guidelines on two topics related to genetic testing: (1) how to address clinical validity through the use of databases; and (2) how to address analytical validity for next-generation sequencing (NGS)-based diagnosis of germline diseases. The guidelines make recommendations and outline processes that may increase the speed of innovation and create a more efficient path to market for genetic tests.

In the guideline that focuses on clinical validity, the FDA provides standards and best practices for managing genetic databases and outlines a process by which public databases can apply for FDA recognition. For a company developing a genetic test, being able to use the vast amount of information available in public genetic databases may mean a more rapid path to FDA marketing clearance. To be FDA-recognized, database hosts must meet standards and submit documentation as outlined in the guidance document.

FDA recognition only applies to public databases and the application for recognition is voluntary. After approval for FDA recognition, public databases will need to maintain recognition through regular reviews. Although proprietary databases are not eligible for FDA recognition, information from these databases can still be used to support the clinical validity of a diagnostic test. This guideline is an important starting point for all database developers because it gives key insights into the features the FDA is evaluating. By providing guidance on best practices for genetic databases, the FDA hopes to accelerate the premarket approval process by allowing applicants to leverage public databases to support the clinical validity of genetic- and genomic-based in vitro diagnostics.

The second FDA guideline outlines best practices for tests involving NGS for germline diseases. It’s important to specifically address NGS-based tests because they differ from traditional (single gene) testing; NGS-based tests can yield thousands to millions of genetic variants in a single test, and it’s not always possible to evaluate each variant individually. The new FDA guideline provides guidance for NGS-based germline tests; some NGS tests may be exempt from premarket review if they fit within the guidelines.

The FDA document provides guidance on the following aspects of NGS-based germline tests:

• Design, performance characteristics, and quality metrics (such as indications, specimen requirements, accuracy, methods, coverage, and bias)
• Performance evaluation (such as validation, test limits, sample preparation)
• Labeling (such as aspects of test design, performance information, limitations)
• Test report features (such as information on the genetic basis of the disease)
• Modifications (such as addition/removal of new genetic markers)

What do these guidelines signal to the genetic testing community and what impact will it have on patients and management of genetic testing? These guidelines are a great step in providing a level of consistency for developing and accessing specific aspects of genetic tests, which has been lacking in this field. However, they are guidelines, and not requirements; thus, the developers of laboratory-based genetic tests do not have to follow them and are not required to go through PMA or 510(k) clearance. Furthermore, while analytical validity and clinical validity are important aspects when assessing a genetic test, neither of these guidelines address the clinical utility of genetic testing. Does it matter if a genetic test has strong analytical validity and clinical validity if it does not show clinical utility?

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