The Food and Drug Administration (“FDA”) announced a workshop to be held February 20th, 2015, entitled “Optimizing FDA’s Regulatory Oversight of Next Generation Sequencing Diagnostic Tests” to obtain public input regarding its regulation of next generation sequencing (“NGS”). Specifically, the agency seeks public comment and feedback on the issues and questions raised in its discussion paper “Optimizing FDA’s Regulatory Oversight of Next Generation Sequencing Diagnostic Tests – Preliminary Discussion Paper” (“FDA Discussion Paper”) (copy here). This post will highlight FDA’s issues and concerns regarding the analytical performance of NGS. Part II will address the agency’s issues and concerns as they pertain to the clinical performance of NGS.
Personalized medicine relies on reliable and accurate testing of clinically relevant information. Almost all current FDA-approved in vitro diagnostic tests (“IVDs”) measure only a single or a limited number of substances (for example, DNA or proteins). Thus, several patient samples and several tests may be required to evaluate a patient’s clinical status or to select the best therapy for the patient. In contrast, NGS can detect over 3 billion bases in the human genome and may identify almost 3 million genetic variants in a single test. Thus, NGS has the potential to diagnose a number of diseases or conditions in one test.
Historically for traditional IVDs, FDA examines the test for accuracy and reliability (analytic performance) and if the results from the test correctly identifies the relevant disease or condition (clinical or diagnostic performance). The test is approved when FDA determines that an IVD has acceptable analytical and clinical performance. For traditional IVDs, the sponsor seeking FDA-approval provides the data and/or information demonstrating analytical and clinical performance of the test. NGS, in contrast, can potentially evaluate over 3 billion base pairs and therefore evaluating the analytical performance of each data point would take years. In addition,“[b]ecause it is possible to sequence the whole genome, it is not necessary to know what variant one wishes to identify prior to running and successfully interpreting an NGS test – a concept which is very different from how traditional IVDs are used.” See page 2 of FDA Discussion Paper. NGS may identify rare variants for which it may be impractical for test developers to provide conclusive evidence supporting clinical significance. Moreover, how to communicate the significance of some genetic variants to physicians and consumers presents challenges to the agency. See page 2 of FDA Discussion Paper.
FDA acknowledged that any new approach to regulating NGS tests must assure that the public has timely access to tests that have adequate analytical and clinical performance. See page 3 of FDA Discussion Paper. Only one NGS instrument (Illumina MiSeqDx™) and its universal sequencing reagents and two accompanying assays for the diagnosis of cystic fibrosis (Illumina MiSeqDx™ Cystic Fibrosis 139 Variant and Clinical Sequencing Assays) have been FDA- approved. Because it was impractical to detect every possible variant that might exist in a genomic sequence, analytical test performance for the MiSeqDx™ system was demonstrated for a representative number of subsets of types of variants in various sequencing contexts. See page 4 of FDA Discussion Paper. The agency announced that it is considering extending this subset-based approach for other NGS sequencing platforms, but also invites suggestions for other approaches. One such approach that FDA seeks public comment is the development of methodologic quality-based standards that laboratories could meet to establish analytical performance developed by the lab. FDA specifically requests public feedback with regard to: (1) value of a standards-based approach to regulatory review of NGS tests (2) content of standards to be developed that will assure that conformity to the standard will assure test accuracy and reliability, (3) who should develop such standards, and (4) appropriate mechanisms to ensure compliance. See page 5 of FDA Discussion Paper. On page 5 of the FDA Discussion Paper, the agency asks the public ten specific questions relating to analytical performance:
The Workshop will be held from 8:30 am to 5 pm at the Natcher Center at the National Institutes of Health Campus, 9000 Rockville Pike, Bldg. 45 Auditorium, Bethesda, MD 20814. Registration is free and available on a first-come, first-served basis. Persons interested in attending must register on line by 4 pm, February 12th, 2015. Registration is through FDA’s Medical Devices News & Events-Workshops & Conferences at http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/default.htm. The Workshop will be webcast and individuals attending on-line must register by February 12th, 2015.