FDA's 2015 Regulatory Targets in Genetic Testing: Laboratory-Derived Tests and Next-Generation Sequencing

The FDA is holding two upcoming public workshops in the next several months that consider several areas of genetic test regulation which may be the subject of upcoming FDA actions. The FDA derives authority for any proposed oversight of genetic testing from its general mandate to regulate medical devices; one category of device is the in vitro diagnostic (IVD), a term that generally captures tests and assays that are used in the diagnosis (or treatment) of disease, including genetic tests. The ongoing issue of whether laboratory-derived tests (LDT) should be directly regulated by the agency continues to be unresolved. Because LDTs constitute the majority of commercially available genetic tests in the U.S., the absence of regulation regarding the utility and/or validity of these tests means that most of the genetic tests in the U.S. are not subject to FDA oversight (however, general certification of laboratories does occur under the Clinical Laboratory Improvement Amendments (CLIA). The FDA published its Framework for Regulatory Oversight of Laboratory Developed Tests last fall, and generally proposed a risk-based classification and regulatory structure for LDTs. The agency’s rationale for increasing its involvement in this genetic testing sector was provided: 

LDT’s are important to the continued development of personalized medicine, but it is important that in vitro diagnostics are accurate so that patients and health care providers do not seek unnecessary treatments, delay needed treatments, or become exposed to inappropriate therapies.The FDA has generally not enforced premarket review and other applicable FDA requirements because LDTs were relatively simple lab tests and generally available on a limited basis. But, due to advances in technology and business models, LDTs have evolved and proliferated significantly since the FDA first obtained comprehensive authority to regulate all in vitro diagnostics as devices in 1976.

The public workshop for discussion of the LDT framework will be held on January 8-9, 2015; public comments to the online document can still be filed until until February 2, 2015.

The FDA is also considering how it might interface with the field of next generation sequencing (NGS), a term applied to high-throughput methods for generating multiple DNA sequences in parallel; such methods can produce whole-genome or exome-only DNA sequences efficiently and quickly. Typically, the sequencing operation does not start with a particular clinical goal in mind or a particular gene or mutation of interest; the approach is clinically neutral and aims to produce genome-wide DNA sequences. NGS sequencing therefore creates high-volume data that requires serious computational analysis in order to create meaningful, useful results for clinical application. NGS can generate data that reveals rare and previously unknown genetic variants. Because of the broad-brush nature of whole-genome sequencing, it has the potential to reveal incidental (undirected) findings; the ethical management of such information by medical personnel has been the subject of bioethical and academic debate. The FDA has issued a discussion paper which highlights specific concerns and possible standardization for NGS technologies: 

NGS tests are unique among existing IVDs in the amount of data that can be generated, the lack of an a priori definition of what will be detected, and the number of clinical interpretations that can be made from a single patient sample. In order to continue to support the development of useful medical information, FDA believes the most efficient possible approaches to regulating NGS tests should be considered. Among the possibilities, a standards-based approach to analytical performance of NGS tests and the use of centralized curated databases containing up-to-date evidence to support clinical performance are under discussion.

The public workshop on NGS regulation will be held on February 20, 2015; the agency will  receive comments until March 20, 2015.