FDA Watch: Agency Issues New Guidance to Ease Approval of NGS Tests & IVD Devices

April 13 was a red letter day for FDA guidance with the agency issuing a pair of final guidances on the design, development and validation of next-generation sequencing (NGS) tests, as well as a draft guidance outlining a proposed new voluntary, streamlined submission process for evaluating the risks of investigational in vitro diagnostics (IVDs) being codeveloped alongside a trial cancer drug. Here is the lowdown on all three sets of guidance:

Final Guidance 1: Using Public Genetic Variant Repositories to Show Clinical Validity of NGS Tests
The two final guidances are designed to make it easier and more efficient to develop NGS tests. The first final guidance, which bears the catchy title “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic & Genomic-Based In Vitro Diagnostics,” explains how test developers can rely on FDA-recognized public genetic variant repositories to support the accuracy of their tests and related marketing claims.

A “genetic variant database” means a publicly accessible database of human genetic variants that aggregates and curates reports of human genotype-phenotype relationships to a disease or condition with publicly available documentation of evidence supporting those linkages, the guidance explains. While as a best practice, such databases should follow an open-access model, databases that use licensing models and charge fees for commercial use may also qualify and be used to support clinical validity of genetic or genomic tests, the guidance continues.

Criteria of reliability includes a genetic variant database that:

• Operates so as to provide sufficient information and assurances regarding the quality of source data and its evidence review and variant assertions;

• Offers transparency regarding its data sources and operations, particularly on how variant evidence is evaluated;

• 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; and

• Houses genetic variant information generated by validated methods.

Final Guidance 2: Design of NGS Tests for Diagnosing Germline Diseases
The other final guidance (“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”) explains to test developers the types of data the FDA is looking for in premarket submissions for such tests. Such tests do not include NGS-based tests for aid in the diagnosis of microbial infection, cell-free DNA testing, direct-to-consumer uses, fetal testing, microbial genome identification and detection of antimicrobial resistance and virulence markers, pre-implantation embryo testing, risk assessment, risk prediction, RNA sequencing, screening, stand-alone diagnostic purposes, tumor genome sequencing or use as a companion or complementary diagnostic, the guidance explains.

The guidance then lists recommendations covering different aspects of NGS test development and quality including:

• NGS test design considerations;
• Test performance and accuracy;
• Test run quality metrics;
• Performance and evaluation studies;
• Supplemental procedures;
• Variant annotation and filtering;
• Presentation of test performance in labeling; and
• Test reports.

Draft Guidance: Determining Risk of Investigational IVDs
The new draft guidance lays out a streamlined process for evaluating investigational IVDs in oncology drug trials, specifically whether the investigational IVD is considered significant risk (SR), nonsignificant risk (NSR) or exempt. The guidance says that the FDA device division would make this risk determination alongside the drug division’s evaluation of the investigational new drug application. It also calls on sponsors to submit information on how the test results will be used in the clinical trial, discuss the prevalence of the biomarker in the patient population and any risks the biopsy collection process has on study subjects.

If the drug and device divisions find that an investigational IVD in a particular study confers non-significant risk, the FDA will issue a letter instructing sponsors to proceed with the trial ensuring that biopsy procedures do not carry significant risks and report any unanticipated adverse events. If the test is found to carry significant risks, FDA will tell the sponsor to submit an IVD exemption application and wait to start the trial until it is approved. Trials of invasive biopsy procedure presenting serious health risk to study participants would not be eligible for the new streamlined submission process, the guidance notes.

The deadline to comment on the draft guidance is 60 days from the April 13 publication date.

New FDA Approvals
Meanwhile, here’s a rundown of the key new FDA approvals announced from late March through mid-April:

NEW FDA APPROVALS

During the period, the following FDA CLIA waiver was announced:

NEW FDA CLIA WAIVERS

New CE Marks & Global Certifications
Notable European CE certifications:

NEW CE CERTIFICATIONS

Other international clearances announced in the past month: