Clinical OMICs - Volume 3, Issue 9 - 18

(continued from previous page) available. All of this information-and much more-must be submitted to FDA before the agency will recognize the database. But database recognition is not necessarily permanent. Once a database is recognized, the operator will need to remain in good standing. FDA has said that it will review the databases "on a set schedule to verify" that they continue to comply. The draft guidance does not explain what happens if FDA finds issues; how a database operator can respond; or what happens to applicants relying on the database. Many questions abound. FDA does not say how a database operator could challenge a decision not to recognize it, nor does the document talk about the notice to database operators before their database loses its recognition. Even so, the concept of reliance on curated databases in lieu of sponsor-generated data is a step forward. Also issued July 8, the second draft guidance addresses the use of standards for NGS-based IVDs diagnosing germline mutations. FDA stresses the narrow scope: the document excludes, for example, standalone diagnostics, screening, fetal testing, or multiple other applications. Nevertheless, the draft guidance does cover a significant clinical area. Many mutations will not have predicate devices, i.e., there is no FDAcleared IVD for the mutation. The agency, though, held out the strong possibility of tests undergoing review through the de novo process, rather than the more stringent pre-mar18 Clinical OMICs September 2016 ket approval process. The de novo is more akin to the 510(k) notification, and offers significant advantages to both FDA and sponsors, both in the initial review and once the test is on the market. Furthermore, FDA held out the possibility that future IVD NGS tests that fall within the classification may not need to undergo any FDA review. This could mean that a single NGS IVD germline mutation test could enable other companies to enter the market without prior FDA review. FDA did not explicitly say that it would use the de novo process. Rather, it said these tests would be good candidates for de novo. Given that FDA cannot guarantee a device will be reviewed de novo until the data are submitted, this is about the strongest favorable signal that FDA can grant. Furthermore, FDA held out the possibility that future IVD NGS tests that fall within the classification may not need to undergo any FDA review. This could mean that a single NGS IVD germline mutation test could enable other companies to enter the market without prior FDA review. That is, in fact, what happened to a class of tests when FDA granted de novo status to 23andMe's genetic tests. However, FDA will establish "special controls." Later entrants will need to meet these special controls, even if they bypass FDA review. FDA does provide a considerable amount of guidance as to the contents of these submissions. These include, among other elements, accuracy, precision, limit of detection, analytical specificity, and test run quality metrics. The draft guidance also describes the information needed for test reports, including a summary of the performance tests and the use of "clear, consistent language that can be easily understood." While it is still unclear what will be the fate of FDA's proposal to regulate laboratory developed tests, this may give some insights into what would be expected in lab reports if FDA did regulate LDTs. The two draft guidances collectively represent progress in understanding FDA's expectations for NGS tests. While hardly complete, they are a start. All interested parties have the opportunity to comment, with a 90-day comment period. Given the complexity of the two topics, the different perspectives of potential applicants, and the ongoing technological changes in the NGS arena, FDA will have a lot to consider before it issues these documents in final. In the meantime, NGS-based IVD manufacturers will consider how this affects their FDA strategy, and laboratories offering NGS testing will be evaluating not only these documents, but waiting to see what happens with a guidance document of even greater importance to them: FDA's guidance on laboratory-developed tests. www.clinicalomics.com http://www.clinicalomics.com

Table of Contents for the Digital Edition of Clinical OMICs - Volume 3, Issue 9