Laboratory Compliance

FDA’s Guidance on Genetic Testing: What You Need to Know

Laboratory Compliance

December 19, 2021

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In traditional medical care, diseases are typically detected via chemical changes associated with a particular condition and all patients receive a similar dose of a medication as treatment. While this one-size-fits-all approach has led to great advancements in medicine, it has by no means been successful for all patients.

Over the last decade, a new technology known as next generation sequencing (NGS) has been paving the way for precision medicine (PM) – a more personalized approach where disease prevention and treatment is tailored to the individual based on their genetics, environment and lifestyle. The goal of PM is to be able to prescribe the right treatments to the right patients at the right time.

Unlike traditional diagnostics which measure a limited number of analytes, NGS can identify millions of DNA variants in a single test, allowing scientists to identify or ‘sequence’ large sections of a person’s DNA in just a couple of hours. Access to human genetic profiles is allowing researchers to identify disease-causing variants and develop treatments, and clinicians to match patients to suitable treatments with increasing precision. Advances in PM have already led to a variety of FDA-approved treatments that are tailored to an individual’s genetic profile, or the genetic profile of a tumor.

Over the past several years, the FDA has been working with stakeholders from across the genomics community to develop regulations that encourage innovation and ensure that genetic tests provide accurate and meaningful results for patients. On April 13, 2018, the FDA issued two separate finalized guidance documents related to next-generation sequencing (NGS):  

These 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.

With these new guidance documents, the FDA has laid out a flexible and adaptive regulatory approach that accommodates the rapidly evolving nature of NGS technologies, streamlined the regulatory pathway for NGS-based tests, and provided a reasonable assurance of testing safety and effectiveness. Let’s take a look at some of the key parts of these guidance documents.  

Guidance on Public Genetic Variant Databases to Support Clinical Validity

Increasing use of NGS technologies in both research and clinical settings is supporting the identification of many new genetic variants that can hold much clinical significance. Unfortunately, this information is often stored in a manner that is not accessible to researchers. The new FDA guidance encourages the creation of FDA-recognized public genetic variant databases to promote data sharing of evidence that supports the clinical validity of genetic and genomic-based tests. Such databases will aggregate and curate reports of human genotype-phenotype relationships to a disease or condition and include publicly available documentation of evidence supporting such linkages.

To become an FDA-recognized publicly available human genetic variant database that can be used to support clinical validity of genetic variant assertions, the database must meet the following criteria:

  • Operates in a manner which provides sufficient information and assurances to assess the quality of its source data, evidence review, and assertions regarding variants
  • Provides transparency regarding its data sources, how it operates, and how it evaluates variant evidence
  • Collects, stores, and reports data and conclusions in compliance with all applicable requirements regarding protected health information, patient privacy, research subject protections, and data security
  • Contains genetic variant information generated using validated methods.

The new Guidance outlines a three-step process for genetic variant databases to gain recognition from the FDA:

  • Voluntary submission of detailed information (outlined in the Guidance) about the database to the FDA
  • FDA reviews genetic variant database policies and procedures for maintaining data and making variant assertions
  • The database must be maintained in a way that satisfies FDA standards for recognition and undergoes regular reviews.

Once a genetic variant database is recognized by the FDA, its assertions can be relied on in a premarket submission without requiring any additional scientific evidence. For companies developing genetic tests, being able to rely on the vast information available in public databases to verify clinical validity of the test means a faster path to FDA marketing clearance. The FDA hopes that this guidance will encourage crowdsourcing of clinical evidence, curating and data sharing in order to advance the development of high-quality PM treatments and diagnostics.

Guidance on Design, Development and Validation of NGS-Based In Vitro Diagnostics

This guidance document is part of the FDA’s efforts to create a flexible and adaptive approach to regulation of next generation sequencing (NGS)-based tests that will serve to foster innovation and also assure that the tests are accurate and meaningful. In this guidance, the FDA outlines important considerations for designing, developing and establishing the analytical validity of NGS-based tests intended to aid in diagnosis of germline diseases (conditions arising from inherited or de novo germline variants). This guidance does not apply to NGS-based tests designed for other purposes.   

The FDA intends the recommendations in this guidance to assist test developers directly. Additionally, given that the FDA has a widely used standards recognition program that facilitates use of consensus standards to meet premarket submission requirements for devices, and since standards can more rapidly evolve with changes in technology, the FDA intends the recommendations in this guidance to inform and hopefully spur the development of consensus standards by experts in the genomics community.

The FDA believes the recommendations in this guidance may serve to reasonably assure the safety and effectiveness of these tests, which would allow NGS-based tests intended to aid in the diagnosis of suspected germline diseases to be candidates for classification as Class II (moderate risk) devices via the de novo process. If classified as class II, subsequent NGS-based tests would be reviewed through the 510(k) program, significantly streamlining the review process. The hope is that, with adherence to the recommendations in this guidance (or consensus standards that address them), along with the utilization of FDA-recognized publicly available human genetic variant databases as described in previous section, the FDA can consider exempting these kinds of NGS-based tests from premarket review in the future.

The specific recommendations in this guidance for NGS-based germline tests are extensive. Some of the aspects addressed include:

  • Test Design Considerations – design standards to ensure a test consistently meets performance metrics appropriate for the indications for use of the test (e.g., define the specific indications for use for a given test, document specific test features that are needed to assure development of a test that meets users’ needs, document acceptable specimen types to be used for the test, etc.)
  • Test Performance Characteristics – set of performance metrics that should be assessed when analytically validating NGS-based tests intended to aid in the diagnosis of suspected germline diseases (e.g., test accuracy, test reproducibility and repeatability, limit of detection, analytical specificity, etc.)
  • Quality Metrics – suggested test run quality metrics used to determine if tests should be accepted (e.g., coverage thresholds, performance thresholds, specimen quality, strand bias, etc.)
  • Recommendations for Performance Evaluation Studies – features to incorporate when evaluating test performance (e.g., perform validation studies, evaluate and document accuracy by comparison to a method identified as appropriate comparator by FDA, use specimens that reflect actual specimen type and population test is indicated for, assess test limits, etc.)
  • Presentation of Test Performance in Labeling – describes what information should be included in labeling to document test performance (e.g., aspects of test design, specimen type, results for test accuracy and precision/reproducibility, probability of test failure, limitations, etc.)
  • Test Reports – describes information that should be included in test reports (e.g., relationship between reported variants and the clinical presentation, description of genomic and chromosomal regions detected by the test, performance study summary, etc.)
  • Modifications – provides guidelines for documentation, validation and resubmission when modifications are made to approved 501(k) devices)


The new field of genomic testing and research is experiencing dramatic growth due to a rapidly evolving technology base. The new FDA guidance documents described above provide a flexible framework to generate the data needed to facilitate the FDA’s review of NGS-based tests. As such, these guidance documents help to ensure that NGS-based tests provide accurate and meaningful results, while at the same time lowering the barrier to innovation by giving developers new tools that support efficient test development and validation. Ultimately, it is patients who will benefit, as these FDA recommendations will be utilized to speed the development of high-quality precision medicine treatments and diagnostics that will improve patient outcomes.

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