Two Draft FDA Guidelines on NGS Set Foundation for Precision Medicine Initiative

Regulatory NewsRegulatory News | 07 July 2016 |  By 

New next generation sequencing (NGS) technologies that can examine millions of DNA variants at a time and help inform treatment decisions are at the heart of two new draft guidance documents released Wednesday evening by the US Food and Drug Administration (FDA) as part of President Barack Obama’s Precision Medicine Initiative.

FDA says the guidance offers a streamlined approach to the oversight of diagnostics that detect medically important differences in a person’s genomic makeup and can scan a person’s DNA to detect genomic variations that may determine whether a person has or is at risk of disease.

“Targeting the right treatments to the right patients at the right time is the goal of the President’s Precision Medicine Initiative,” said FDA Commissioner Robert Califf. “Soon, patients will have a much more complete picture of their health than in the past, informed by their genetic and genomic makeup. The FDA is preparing for this exciting approach at multiple levels.”

When finalized, the guidance is said to offer a flexible and adaptive regulatory oversight of these tests, allowing for variations in the way companies develop and validate the new technologies.

“FDA values the input we received from genomics experts, industry, health care providers and patients from four public workshops and other outreach opportunities,” said Jeffrey Shuren, director of FDA’s Center for Devices and Radiological Health.

As next-generation sequencing (NGS) costs gradually decline, FDA's Division of Antiviral Products (DAVP) anticipates that more companies will make the switch to NGS for future antiviral drug resistance analyses and other additional uses. An overview of other NGS tests and the companies involved can be found here.

Guidance Specifics

The first draft guidance, titled "Use of Standards in FDA’s Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases" provides recommendations for designing, developing and validating NGS-based tests for rare hereditary diseases, and addresses the potential for using FDA-recognized standards to demonstrate analytical validity, or how well a test predicts the presence or absence of a particular genomic change.

The recommendations in this draft guidance are applicable for NGS-based tests for germline diseases, and whether results are intended to be provided directly to patients or through health professionals. For direct-to-consumer NGS-based tests for germline diseases, FDA says additional recommendations and controls would be needed.

This draft also outlines considerations for possibly classifying certain NGS-based tests for germline diseases in class II and potentially exempting them from premarket notification requirements. Over the longer-term, FDA says it will consider how these recommendations may form the basis for standards that FDA could recognize or whether FDA could establish special controls and/or conditions for premarket notification (510(k)) exemption.

“Additionally, if FDA believes there is a reasonable possibility that the safety and effectiveness of the test can be reasonably assured by general controls or a combination of general and special controls, FDA may identify such a test as a suitable candidate for the de novo process,” the agency notes. “Because FDA believes there is a reasonable possibility that the risks associated with the use of NGS-based tests for germline diseases (e.g., those related to the consequences of a false positive or negative result provided to a patient) may be sufficiently mitigated by a combination of general and special controls, and that the safety and effectiveness of this type of test may be reasonably assured by such controls, FDA believes that an NGS-based test for germline disease can be a suitable candidate for the de novo classification process.”

The agency invites comments on the draft guidance over the next 90 days, and says stakeholders commenting should focus on the guidance in general and the following six questions:

“1. Does the draft guidance content adequately address the analytical performance of targeted and whole exome human DNA sequencing (WES) NGS-based tests intended to aid in the diagnosis of individuals with suspected germline diseases or other conditions (referred to as “NGS-based tests for germline diseases” or “NGS-based tests” in the guidance)? For example, do the recommendations outlined in the draft guidance adequately address the analytical performance of NGS-based tests used as an aid in diagnosis of patients with signs and symptoms of developmental delay or intellectual disability, undiagnosed diseases, or hereditary cancer syndromes? If not, what additional test design, development, or validation activities are necessary for analytical validation of such tests? Are there specific indications within this broad intended use that require different or additional test design, development, or validation activities from those described in the draft guidance?

2. Do the recommendations in the draft guidance adequately address the analytical validation of NGS-based tests that use targeted panels or WES? Targeted sequencing panels? Are there differences between the use of targeted panels and WES that were not adequately distinguished in the recommendations described in the draft guidance?

3. The recommendations in this document focus on WES and targeted NGS-based tests for germline diseases. Are the recommendations outlined in the guidance sufficient to address analytical validation for whole genome sequencing (WGS) NGS-based tests for germline diseases? If not, what additional test design, development, and validation activities are needed to address the analytical validation of such tests?

4. Accuracy is generally described using an agreement, typically positive and negative percent agreement (PPA and NPA), between a new test and an accepted reference method. For NGS-based tests, positive predictive value (PPV) may be a more meaningful metric than NPA when calculating the likelihood that a variant call detected by the test is a true positive. If PPV is calculated using only analytical results without taking into account prevalence in a population, it is sometimes called 'technical' PPV (TPPV) to distinguish it from prevalence-based PPV. What are the benefits and weaknesses to assessing NGS-based test accuracy using TPPV in addition to PPA and NPA, or instead of NPA?

5. Are the minimum performance thresholds presented in this draft guidance appropriate, or are alternative thresholds more appropriate? Are there 'best ways' to determine acceptable thresholds for each metric? Are there performance metrics that do not require minimum thresholds? Are there test scenarios where minimum thresholds are not useful or relevant?

6. How can bias and over-fitting be minimized or accounted for if known 'reference' samples are used as comparators in accuracy studies?”

The second draft guidance, titled "Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics," describes an approach where test developers may rely on clinical evidence from FDA-recognized public genome databases to support clinical claims and provide assurance of accurate clinical interpretation of results, which is part of what FDA says is “an easier path for marketing clearance or approval.” 

This draft guidance also describes FDA’s considerations in determining whether a genetic variant database is a source of valid scientific evidence that could support the clinical validity of an NGS-based test in a premarket submission.

The agency is looking to further outline the process by which administrators of publicly accessible genetic variant databases could voluntarily apply to FDA for recognition, and how FDA would review such applications and periodically reevaluate recognized databases.

The genetic variant databases discussed in this draft guidance only include those that contain human genetic variants, and do not include databases used for microbial genome identification and detection of antimicrobial resistance and virulence markers, FDA says. This draft guidance also does not apply to software used to classify and interpret genetic variants, but instead, only regards use of curated databases using expert interpretation.

In terms of comments, FDA is requesting a response on the following five questions in particular:

“1. Should the quality recommendations outlined in the guidance apply equally to databases of somatic variants and to germline variants?

2. While this document applies to NGS-based tests, FDA expects that it may also be relevant to genetic tests that use other technologies (e.g., polymerase chain reaction, Sanger sequencing, etc.). Are any additional considerations necessary to support the use of these databases in the premarket review of tests using technologies other than NGS, should FDA decide to apply this approach more broadly in the future?

3. FDA recognizes that the evidence linking specific variants to diseases or conditions will change over time, and as such, assertions about those variants may also change. If an assertion regarding a variant changes over time, how should FDA assess what regulatory actions may be appropriate with respect to in IVDs supported by such assertions? How often should FDA conduct ongoing review of an FDA-recognized database?

4. FDA notes that databases may have 'discordant calls' with other databases, where the assertions for a variant in each database vary. While FDA believes that these discordant calls often arise because one database has information the other does not and our proposed policy will mitigate these issues over time; what, if any, action should FDA take when it learns about discordant calls between two databases with respect to database recognition or IVDs supported by such calls in FDA-recognized databases?

5. FDA has requested information regarding conflicts of interest for curators and personnel of databases seeking FDA recognition. FDA acknowledges that many personnel involved with variant curation and interpretation may have some connection to NGS test developers. What type of information should FDA collect and what policies should it implement to mitigate such potential conflicts of interest in FDA-recognized databases?”


This approach to regulating NGS-based tests is part of FDA’s engagement in the Precision Medicine Initiative (PMI), launched by Obama in early 2015.

Also as part of the PMI, the National Institutes of Health announced on Wednesday evening the offering of $55 million to begin work on a million-patient study.

“Building in strong privacy and security protections from the start, NIH is teaming up with regional health care providers and community-based health clinics to sign up a million or more volunteers from all walks of life,” Obama wrote in an op-ed in the Boston Globe. “The health, environmental, and lifestyle information this diverse group will provide will be analyzed by qualified scientists to generate new insights and one day bring us closer to curing diseases like cancer and diabetes.”


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