Next-Generation Sequencing: FDA Offers Guidance to Streamline Path to Market

Regulatory NewsRegulatory News
| 12 April 2018 | By Zachary Brennan 

The US Food and Drug Administration (FDA) on Thursday finalized two guidance documents related to next-generation sequencing (NGS) and drafted new guidance on investigational in vitro diagnostics (IVDs) in oncology trials – all of which offer recommendations to provide test developers with a more efficient path to market.

The finalized 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.

“The rapid adoption of NGS technologies in research and clinical settings is helping to identify countless new genetic variants. However, information about genetic variants is generally stored in a manner that is not publicly accessible,” explained Jeffrey Shuren, director of FDA’s Center for Devices and Radiological Health. “Today’s release of the FDA’s final guidance on genetic variant databases will help change this paradigm by encouraging data sharing and the accumulation in public databases of evidence supporting the clinical validity of genomic tests to help provide an even more efficient path to market.”

The 7-page draft guidance, meanwhile, describes how sponsors of certain oncology trials can use an optional streamlined submission process to determine whether use of an investigational IVD -- including those that incorporate NGS technology -- in a trial of investigational cancer drug or biological products is considered significant risk, nonsignificant risk or exempt from review.

“This is a step toward our goal of having a common filing for a drug and diagnostic system where the drug is co-developed with a diagnostic test,” FDA Commissioner Scott Gottlieb said in remarks on Thursday.


NGS can enable doctors to look across millions of DNA changes that may determine whether a person has or is at risk of developing a genetic disease, or to inform treatment decisions, FDA explained.

“The rapid adoption of NGS-based tests in both research and clinical practice is leading to identification of an increasing number of genetic variants (e.g., pathogenic, benign, and of unknown significance), including rare variants that may be unique to a single individual or family,” FDA said.

To date, FDA has authorized three NGS onco-panels:
  • FoundationOne CDx, which was approved in November 2017, and can detect genetic mutations in 324 genes;
  • MSK-IMPACT, also approved in November 2017, which can detect genetic mutations in 468 genes; and
  • Oncomine Dx Target Test, approved in June 2017, which can detect genetic mutations in 23 genes.
“Other tests using NGS technology authorized by FDA to date include: Praxis Extended RAS Panel (detects two genes) and FoundationFocus BRCA (also detects two genes),” an FDA spokesperson told Focus.
“These panels can accelerate cancer drug development and improve clinical outcomes by reducing patient screening time and costs. These technologies can help reduce the risks associated with the need for multiple tissue biopsies. And these platforms can be rapidly updated to detect new oncogenes or gene variants as these markers are identified by researchers,” Gottlieb explained.

In 2017, FDA also took several actions to streamline the development and review of a variety of genetic-based tests – authorizing a third-party option for authorizing tumor profiling tests, and outlining standardized development criteria for consumer carrier screening tests to allow for their marketing without prior agency review. FDA also established such criteria for genetic health risk tests and proposed to allow their marketing after a one-time agency review.

Final Guidance

One 41-page guidance finalized Thursday, known as “Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS)–Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases,” provides recommendations for designing, developing and validating NGS-based tests.

The guidance offers perspective on what the agency looks for in premarket submissions to determine a test’s analytical validity, including how well the test detects the presence or absence of a genomic change.

The other 16-page guidance issued Thursday, titled “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics,” describes how test developers may rely on clinical evidence from FDA-recognized public databases to support clinical claims.

The guidance describes how product developers can use these databases to support the clinical validation of NGS tests that they are developing. These public databases may include resources like ClinGen, which is maintained by the National Institutes of Health (NIH). Using FDA-recognized databases will provide test developers with an efficient path for marketing clearance or approval of a new test.

On 26 April, FDA will hold a webinar on the two final guidance documents.


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