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Infectious Disease Sequencing Dx Devices to Be Regulated by FDA

NEW YORK (GenomeWeb) – The US Food and Drug Administration today issued a draft guidance on next-generation sequencing-based diagnostic devices for infectious disease.

The guidance, called "Infectious Disease Next Generation Sequencing Based Diagnostic Devices: Microbial Identification and Detection of Antimicrobial Resistance and Virulence Markers," available here, provides industry and FDA staff with recommendations for designing studies to establish the analytical and clinical performance characteristics of NGS diagnostic devices that are intended for use in the diagnosis of microbial infection and selection of appropriate therapies.

It provides detailed information on the types of data FDA recommends to be submitted for a Class II premarket submission, though the inclusion of certain targets — such as hepatitis B, hepatitis C, human papillomavirus, and HIV — could elevate the classification of the device to Class III, according to the agency.

FDA recommends that prior to initiating any clinical or analytical validation studies, developers should contact the agency to discuss whether additional recommendations are available "due to new advancements in this fast moving field."

In contrast to diagnostic devices that sequence the human genome, infectious disease sequencing diagnostics "carry an absolute need for immediate and actionable results, sometimes within hours, as incorrect initial diagnoses potentially leads to fatalities," FDA wrote.

Also, because they analyze a variety of sample types — such as urine, blood, or stool  — and look for a large number of different types of microbes, they cannot use standard assay and analysis processes. "Each unique specimen type may require a different nucleic acid extraction procedure, a different library preparation protocol, and even a different bioinformatics algorithm to generate the final clinical result," according to the authors.

Furthermore, repeat testing is difficult because sample amounts are limited and because treatment decisions often need to be made quickly.

Specifically, the guidance addresses NGS devices that use targeted or agnostic metagenomic sequencing to detect the presence or absence of infectious disease agents or antimicrobial resistance and virulence markers. It does not apply to devices that detect something other than nucleic acids or to devices that are intended to screen donors of blood, cells, or tissues for infectious diseases.

As part of the guidance, FDA proposed the use of a publicly available database of regulatory-grade-quality sequences from a variety of infectious microorganisms for clinical evaluations. FDA established the database, called FDA database for Regulatory Grade microbial Sequences or FDA-ARGOS, in collaboration with the National Center for Biotechnology Information, the Department of Defense, and the Institute for Genome Sciences at the University of Maryland.

Generally speaking, for targeted infectious disease NGS devices, validation concepts similar to those for other multiplexed devices apply, FDA said, pointing to its existing guidance for highly multiplexed microbiological/medical countermeasure in vitro nucleic acid-based diagnostic devices.

For agnostic infectious disease NGS devices that employ metagenomic sequencing, "a representative number of targets (certain agreed on organisms or markers) based on intended use or chosen panel should be validated in the analytical and clinical studies."

Once finalized, the draft guidance will provide "detailed information on the types of studies the FDA recommends to support a premarket application for these devices," according to the document.

Interested parties are invited to submit their comments and suggestions regarding the draft document here by Aug. 11 in order to make sure they can be considered for the final version.

The guidance is likely to affect efforts by a number of manufacturers of next-gen sequencing instrumentation and their customers to establish NGS for infectious disease diagnostics.

Scientists at the University of California, San Francisco, for example, have explored metagenomic sequencing on Illumina's MiSeq to diagnose a variety of infectious diseases, and teams at Columbia University and at Washington University in St. Louis have developed methods to sequence viral genomes from clinical samples.

Also, researchers in the UK published a study last year in which they used Illumina's MiSeq to diagnose tuberculosis, a test they said is faster than standard methods while showing comparable performance.

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