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

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):  

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.

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

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.

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.

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

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

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,
  • Quality
    – 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,
  • Test
    – 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.

Astrix Technology Group has over 20 years of experience facilitating success in laboratory informatics implementations for pharmaceutical and biotech companies. Our experienced professionals have the experience, skills and knowledge to help you implement innovative informatics solutions for your genomics data management and analytics challenges. Our solutions will allow your organization to turn data into knowledge, increase organizational efficiency, improve quality and facilitate regulatory compliance. If you would like to discuss your laboratory informatics strategy with an Astrix expert, please contact us for a free, no obligations consultation.