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FDA Offers Guidance on Submitting NGS Data in Support of Antiviral Drugs

NEW YORK – The US Food and Drug Administration this week issued final guidance concerning the submission of next-generation sequencing data from resistance assessments performed in the development of antiviral drugs.

The FDA's Division of Antiviral Products independently analyses all resistance studies associated with antiviral drugs "to ensure that the emergence of resistance is carefully characterized and explained in the label," the agency said.

The new technical specifications document provides nonbinding recommendations on acceptable NGS platforms and the types of information the FDA is looking for sponsors to submit, including NGS protocols and data analysis methods.

The FDA will accept data from "most standard NGS platforms provided the sponsor submits the appropriate details for the sequencing platform, the protocols used for sample preparation, the raw NGS data in fastq format, and the methods used to analyzed the data," the agency wrote, adding that it recommended early communication, before data are submitted.

Acquired resistance to antiviral drugs is a concern for several reasons. According to the US Centers for Disease Control and Prevention, constantly changing genetic makeup, as seen in influenza viruses, can lead viruses to become less susceptible to antiviral drugs during treatment. And according to reports from the World Health Organization, drug-resistant viruses can develop in immunocompromised or immunosuppressed patients.

"Providing accurate resistance information is imperative for protecting public health to prevent the emergence of novel resistant and cross-resistant viral variants that have the potential to infect others and cause major outbreaks of disease that cannot be controlled by approved drug products," the FDA said in its new guidance. Resistance information, which FDA includes in drug product information, is also useful to healthcare professionals who oversee the use of antiviral drugs, and FDA can request sequence analysis of host genes targeted by the virus to determine if "population-based alleles have an effect on efficacy."

The guidance is intended to help address complexities to the resistance analysis process introduced by NGS, including the fact that NGS provides sequence information for individual viruses within a viral population, instead of an average sequence, as provided by Sanger sequencing.

"The complexity of the data makes it challenging for reviewers to analyze and validate sequence information particularly because there are currently no standardized bioinformatics analysis approaches for analyzing these large datasets," the agency said.

In addition to submitting Fastq files, sponsors can submit assembled read mappings in .fas, .ace, .sam, or .bam formats.

The FDA said sponsors should provide a frequency table "reporting all amino acid substitutions that differ from baseline and frequencies greater than or equal to 1 percent," and summary tables for each study.

NGS protocols should include design elements, including performance characteristics of the NGS platform, target gene regions, attempted coverage levels, nucleic acid extraction methods, library preparation methods, and multiplexing methods, if applicable.

The FDA noted that "any protocol that uses a PCR amplification step before NGS should provide evidence that amplifications are representative of the target population and minor variants would still be present in the NGS data."

For analysis, FDA recommended reports contain summary statistics for each sequencing run, contig and mapping reports, and multiple items for de novo assembly.

Files may be submitted via portable hard drive or the Center for Drug Evaluation and Research electronic gateway.

The FDA is continuing to accept public comments on the document.

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