As discussed in March 31 issue of IBO (see IBO 3/31/18), recent FDA decisions have signaled the Agency’s increasing attention to the regulation of NGS IVDs. Last week, these efforts continued as the FDA released two guidance documents for genomic testing. FDA Commissioner Scott Gottlieb, MD described the documents as providing “a modern and flexible framework to generate data needed to support the FDA’s review of NGS-based tests, and give developers new tools to support the efficient development and validation of these technologies.” The guidance documents finalize draft versions released in 2016. Although adherence to the guidance is not required by test makers, the guidelines indicate the FDA’s position on the subject and its formation of future regulatory policies. The following article highlights pertinent aspects of the guidance but is not intended as a comprehensive summary.

Genetic Variant Databases for PMA Submissions

On April 12, the FDA released its final guidance on the role of genetic variant databases in the regulatory environment; specifically, the guidance regards the use of such databases to determine the clinical validity of genomic and genetic-based tests, including but not limited to NGS tests, as part of a premarket submission.

The guideline supports the use of such databases as part of premarket submissions, citing their conformity to professional guidelines and use of evidence from a range of sources, among other factors. It specifies how variant databases can be submitted to the FDA for recognition and the criteria for such recognition. The guidance applies to both open-access and commercial variant databases. The FDA is also considering the use of third-party reviewers for the databases, according to the document.

In particular, the guidance emphasizes public access to database procedures and operations, including data sources and standard operating procedures (SOPs). This is inline with the guidance’s recommendations for ongoing database review and updates. As the guidelines states, “The FDA may also ‘spot-check’ assertions about genetic variants to assure they continue to be supported and that the genetic variant database continues to follow its SOPs for evaluation.”

The guidance also specifies how database assertions can be used. “In order to be FDA-recognized, a genetic variant database should not include any recommendations regarding clinical treatment or diagnosis. However, an assertion that states that a variant is clinically significant as an actionable mutation may be found within an FDA-recognized genetic variant database.”

Design, Development and Analytical Validation of NGS-based IVDs for Diagnosing Suspected Germline Diseases

This guidance document addresses NGS test development for whole-exome human sequencing and targeted human sequencing for diagnoses related to germline diseases (diseases resulting from inherited or de novo germline variants) in symptomatic individuals. In particular, the FDA views the guidance as assisting the development of consensus standards. By contributing to Special Controls, such standards could eventually aid in the submission of NGS-based germline tests as Class II devices under the De Novo process, opening the door for them to be used as predicate devices for 510(k) submissions. Beyond this, the FDA’s stance suggests additional standards development, stating, “[the] FDA is particularly interested in the development of standards that address considerations beyond what is described in this guidance.”

“…FDA believes that it may be possible, in the future, to develop special controls that could provide a reasonable assurance of the safety and effectiveness of NGS-based tests intended to aid in the diagnosis of suspected germline disease, possibly under certain conditions of exemption, without the need for 510(k) premarket review.”

Furthermore, these developments could result in new test classifications, according to the guidelines, and, perhaps, no requirement for 510(k) approval. As the guideline states, “As the Agency gains more experience with these devices, FDA believes that it may be possible, in the future, to develop special controls that could provide a reasonable assurance of the safety and effectiveness of NGS-based tests intended to aid in the diagnosis of suspected germline disease, possibly under certain conditions of exemption, without the need for 510(k) premarket review.”

Among the submission requirement recommended to establish analytical validity are bioinformatics documentation, library preparation and enrichment, and multiplexing, among others. Notably, in regard to accuracy, “When clinical samples, cell lines or biosynthetic materials are not available, in silico constructed sequences containing known sequence variants of various claimed types (e.g., SNVs, indels, duplications, repeat expansions, CNVs, structural variants) may be used in addition to biological specimens to assess performance of the bioinformatics pipeline.” In addition, the guidance recommends documentation of variant annotation and filtering and how to present the test performance in labeling.