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The Food and Drug Administration (“FDA”) announced a workshop to be held February 20^th, 2015, entitled “” 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”) (). My post of highlighted FDA’s issues and concerns regarding the analytical performance of NGS. This post will address FDA’s issues and concerns relating 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 approves a test if it is accurate and reliable (analytical performance), and if the test is shown to correctly identify the relevant disease or condition (clinical or diagnostic 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 in a single test. Thus, establishing analytical performance of a new NGS test could take years – as it would require evaluating the analytical performance of each data point. In addition, it may be unnecessary to know the identity of the variant one wishes to identify prior to running and successfully interpreting an NGS test – a concept which is very different from how traditional IVDs. 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, the agency perceives challenges in communicating the significance of some genetic variants to physicians and consumers. Page 2 of FDA Discussion Paper.

Exploring New Regulatory Approaches for NGS

Clinical Performance

Clinical or diagnostic claims for IVDs are evaluated by FDA based on a sponsor’s submission of adequate data or information in a premarket application. See page 6 of FDA Discussion Paper. Citing Illumina’s NGS-based cystic fibrosis assay as an example of successful FDA review of NGS, FDA allowed Illumina to utilize a well-curated third party database containing evidence from multiple sources to establish clinical significance as an alternative to conducting a new study or using existing literature for two approved tests. As noted by FDA, the two cystic fibrosis assays that were cleared by the agency differ in their indications and approaches to clinical significance: one of the tests reports only a discreet umber of variants with established clinical significance; and the other test reports any variant in the cystic fibrosis gene, regardless of whether any clinical significance is known for the variant. See page 6 of FDA Discussion Paper.

FDA stated that it believes that a similar approach could be applied to establish clinical significance for other NGS tests and indications. As noted in the FDA Discussion Paper, a dialogue between FDA and the National Institutes of Health (“NIH”) has been established with the aim of determining whether the data curated by the ClinGen program (an NIH-funded resource for the development and implementation of a framework for establishing human genomic variants) can be used to support clinical significance. The ClinGen program is noted to be of particular interest due to the NIH’s oversight of the information, and the NIH’ active engagement with clinicians and scientists to establish criteria for the strength of the association between genetic variants and a disease. However, FDA is interested in public comment on the use of other curated databases to support clinical claims for genetic and genomic tests, as well as creating a public process based on important curation criteria. See page 7 of FDA Discussion Paper.

In some instances, the evidence for association between a genetic variant and disease is limited because of the rarity of the variant, or its coexistence with other variants. The agency states that some stakeholders have noted that information regarding genetic variants for which there is limited evidence to establish clear clinical significance may have some value for physicians and patients. In this regard, FDA is seeking public comment on: “1) the value of conveying information about genetic variants for which there is limited evidence of clinical significance, (2) whether some caveat as to the limitations of the available data may be needed, and, 3) if this can be of value, how and under what circumstances the information should be conveyed, to assure the information is effectively communicated, the benefit to medical decision-making is maximized, and risks to patients are minimized.” See page 7 of FDA Discussion Paper. The agency also presents eleven specific questions for public comment:

1. What are current practices for clinical interpretation of variant information from NGS tests?
2. What are the benefits and risks to public health of the use of information from curated databases such as ClinVar/ClinGen in supporting clinical claims made by NGS tests?
3. Would the use of ClinVar/ClinGen or other curated databases by all test developers incentivize data sharing and provide a more efficient way to establish clinical   significance for different variants?  Are there other steps that should be taken to facilitate sharing of this data? Is ClinVar/ClinGen the appropriate resource for FDA to utilize? Are there other resources that FDA should consider?
4. Can curation and evidence evaluation standards be constructed in a manner that would allow interested developers to create databases that could support clinical significance?
5. Can information about the clinical meaning of variants be of value to physicians and patients when there is uncertainty about the strength of the association between the variant and disease? If so, why and under what circumstances?
6. Can information regarding variants of unknown significance or variants with conflicting evidence regarding significance be of value to providers and patients?  If so, why and under what circumstances?
7. How should FDA ensure that laboratories are accurately reporting the strength of variant-disease associations?
8. How can FDA incentivize test developers and clinical laboratories to deposit their information in ClinVar to improve the ability of the community to understand the genetic basis of disease?
9. What controls should be in place, if any, for laboratories who wish to implement their own interpretive process, rather than relying on FDA-recognized evidence assessments?
10. What measures should be put in place to monitor progress and impact, both positive and negative, of the proposed use of well curated databases?
11. What other options should FDA consider to assure that the clinical significance of variants reported by NGS tests is accurate?

See page 8 of FDA Discussion Paper.

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 . The Workshop will be webcast and individuals attending on-line must register by February 12^th, 2015.

NGS is promised to reduce the cost of health care by leveraging diagnostic analysis for multiple diagnostic and prognostic indications. However, any test that directs therapeutic intervention must be safe and reliable. FDA, consistent with its mission to both protect and promote public health, is seeking the public’s assistance with evaluating and regulating this new technology. While the agency’s workshop is specifically directed to diagnostic innovators, those that develop and manufacture therapeutics that are linked to a genetic variant are advised to monitor these proceedings as well.