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Abstract
The rapid emergence and clinical translation of novel high-throughput sequencing technologies created a need to clarify the regulatory pathway for the evaluation and authorization of these unique technologies. Recently, the US FDA authorized for marketing four next generation sequencing (NGS)-based diagnostic devices which consisted of two heritable disease-specific assays, library preparation reagents and a NGS platform that are intended for human germline targeted sequencing from whole blood. These first authorizations can serve as a case study in how different types of NGS-based technology are reviewed by the FDA. In this manuscript we describe challenges associated with the evaluation of these novel technologies and provide an overview of what was reviewed. Besides making validated NGS-based devices available for in vitro diagnostic use, these first authorizations create a regulatory path for similar future instruments and assays.
Disclaimer
The views expressed in this article are those of the authors and do not necessarily reflect the official policy of the US FDA.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
FDA has granted the first marketing authorizations to next-generation sequencing -based technology, making available validated next-generation sequencing-based devices for in vitro diagnostic use and creating a regulatory path for similar future instruments and assays.
General use (non-disease-specific) platforms can be granted marketing authorization through demonstration of analytical performance across claimed genetic variant types and genomic contexts.
The novel regulatory path created for the platform, without specific clinical indications, should allow decreased development timelines for specifically indicated assays and uses.
Disease-specific assay systems can be granted marketing authorization by demonstrating analytical and clinical performance, which may include using a clinical grade database(s), a path similar to the one employed for the cystic fibrosis 139-variant assay using Clinical and Functional Translation of CFTR (CFTR2) Project database.
Notes
†Special controls are regulatory requirements for class II devices established to provide reasonable assurance of the safety and effectiveness of the device and are usually device specific Citation[21]. The classification regulations in the Code of Federal Regulations that apply to a specific class II device will state the type of special controls that are applicable. To find the applicable regulation, one can search FDA’s device classification database Citation[22,23].
Depending on the regulation, special controls can include performance standards, special labeling requirements, premarket data requirements and guidance documents.
*For the purposes of this article ‘clinical grade’ databases are defined that are considered to be of sufficient quality, for example, are curated according to some agreed-upon levels of standard, to be used clinically.