Following the U.S. Food and Drug Administration’s (FDA) workshop addressing proposed regulation of laboratory developed tests (LDTs) in January (see NIR, Jan. 26, 2015, p. 1), the FDA recently turned to the similar topic of evaluating next-generation sequencing (NGS). Recognizing both the expanding clinical applications of NGS tests and the challenges of overseeing such testing, the FDA held a day-long workshop in February, seeking advice from the industry on how best to regulate NGS. An FDA discussion paper released in anticipation of the workshop explains that oversight of NGS testing can be difficult given the ability to sequence the whole genome and identify a potentially unlimited number of variants. The FDA acknowledges it is impractical to require analytical and clinical performance be demonstrated for every possible variant. Panel presentations consumed most of the workshop with far fewer individual public comments than occurred during the January LDT workshop. As with the LDT comments, some commenters asserted that regulation of NGS could stifle innovation and delay access to critical testing capabilities. The bulk of the discussion, however, focused on the issues raised by the unique nature of NGS and difficulties concerning demonstration of analytical and clinical performance. During three sessions, panels of […]
Following the U.S. Food and Drug Administration’s (FDA) workshop addressing proposed regulation of laboratory developed tests (LDTs) in January (see NIR, Jan. 26, 2015, p. 1), the FDA recently turned to the similar topic of evaluating next-generation sequencing (NGS). Recognizing both the expanding clinical applications of NGS tests and the challenges of overseeing such testing, the FDA held a day-long workshop in February, seeking advice from the industry on how best to regulate NGS. An FDA discussion paper released in anticipation of the workshop explains that oversight of NGS testing can be difficult given the ability to sequence the whole genome and identify a potentially unlimited number of variants. The FDA acknowledges it is impractical to require analytical and clinical performance be demonstrated for every possible variant.
Panel presentations consumed most of the workshop with far fewer individual public comments than occurred during the January LDT workshop. As with the LDT comments, some commenters asserted that regulation of NGS could stifle innovation and delay access to critical testing capabilities. The bulk of the discussion, however, focused on the issues raised by the unique nature of NGS and difficulties concerning demonstration of analytical and clinical performance. During three sessions, panels of individuals representing a broad spectrum of stakeholders addressed development of standards for evaluating NGS tests, implementation of such standards, evidence and database curation for demonstrating clinical performance, communication of results and test reliability to providers and patients, and other factors to consider regarding the FDA’s regulatory approach.
An often cited challenge to evaluating NGS was the fact that it can have different clinical utility in different contexts—for example, whether utilized for cancer treatment or identification of hereditary disease. Reference was made to the FDA’s authorization of Ilumina’s MiSeqDX testing based on demonstration of the analytical test performance for a “representative subset of types of variants in various sequence contexts.” In its discussion paper, the FDA expressed an intent to continue that subset-based approach to analytical performance evaluation but welcomed suggestion of other methods.
With regard to demonstrating clinical performance of NGS, attendees were asked to comment on the use of “highly curated genetic databases that provide information on genetic variants and their association with disease.” Several attendees supported the use of shared databases, with some suggesting participation in publicly shared databases should be mandatory.
The FDA moderators asked panelists whether they thought standards were feasible and, if so, who should develop them, who should implement them, and how compliance with the standards could be verified. Panelists advised the FDA to involve multiple stakeholders in crafting any standards and pressed for flexibility in the standards to accommodate the rapidly developing nature of the technology. More than one speaker emphasized the urgency of these issues noting that NGS is already in use and significant numbers of patients are already relying on this testing. Attendees agreed that patients and physicians need to know about the reliability of these tests to make informed decisions. Panelists also discussed issues concerning informed consent and the need to understand how much the patient does and doesn’t want to know about their genetic information.
A transcript of the workshop will be available on the FDA’s website. Written comments should respond to the questions raised in the discussion paper and must be submitted by March 20, 2015. For instructions with regard to submission of written comments, see the FDA’s announcement of the workshop in the Dec. 29, 2014 Federal Register.
Takeaway: Like LDTs, next-generation sequencing tests raise unique challenges for regulators charged with protecting patient safety. Recognizing these challenges, the FDA is again soliciting industry comment on how best to protect safety without stifling innovation.
