The Food and Drug Administration (“FDA”) announced a workshop to be held February 20^th, 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.

The Promise of NGS in Personalized Medicine

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.

The Challenges of Regulating NGS

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.

Exploring New Regulatory Approaches for NGS

Analytical Performance

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:

1. How are labs currently developing NGS tests and assessing their analytical performance?
2. What are the benefits and risks to public health of having FDA independently evaluate the analytical performance of NGS tests and/or platforms using data submitted by the developer on an agreed upon subset of data points for the test?
3. What are the benefits and risks to public health of a standards-based approach to regulating NGS analytical performance?
4. Would a standards-based approach limited to NGS tests that use FDA cleared or approved components encourage continued development and consumer access to NGS tests with appropriate analytically performance?
5. To what extent could computational approaches be used to assess analytical performance? If possible, who should develop such approaches, how could FDA facilitate their development, and how could they be validated?
6. Are the concepts for standards outlined above adequate to ensure that NGS tests have appropriate analytical performance? If not, what else should be included? Alternatively, are some of the concepts for standards listed above unnecessary, and if so, which ones and why?
7. How should changes or advances in technology be managed utilizing a standards-based approach? What types of changes in technology pose the most concern and what are the best standards to address those concerns?
8. Who should develop the standards: FDA, an ad hoc committee of experts, a Standards Development Organization, others, or a combination of these approaches?
9. What measures should be put in place to monitor progress and impact, both positive and negative, if a standards-based approach were adopted?
10. How should conformity with standards be assessed?

Attending the Public Workshop

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 12^th, 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 12^th, 2015.

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