by Daryl Pritchard, Ph.D., PMC Vice President, Science Policy

Next-generation sequencing (NGS) holds great promise for advancing personalized medicine in cancer care. NGS diagnostics will allow for the identification of all the genetic variants an individual or tumor can have. This information can be used to make health care decisions based on the molecular characteristics of each individual patient’s disease, thus truly personalizing health care strategies. Today’s FDA Public Workshop — Next Generation Sequencing-Based Oncology Panels, advances public engagement with FDA on novel approaches to regulatory oversight of these tests.

Future investment and technological advancements in NGS depend on clear, predictable guidelines. Developing those guidelines will require a careful, calculated approach. The Coalition’s current thinking on that topic is presented here.

The recommendations below are informed by conversations with Coalition members and FDA as well as the insights generated by today’s public workshop and the previous meetings FDA has convened on the subject. They are applicable to the oversight of NGS oncology panels as well as NGS tests in other disease states.

As FDA continues to develop its approach to NGS oversight, the Coalition recommends that the agency:

Seize the opportunity to devise a new oversight framework that allows for meaningful evaluation of tests with dynamic evaluative capabilities.

NGS tests represent a new frontier in regulatory processes. Unlike traditional companion Dx assays that assess a single analyte, an NGS panel may identify multiple genetic variants concurrently, and the results of the test could lead to useful information about many different biomarkers. In devising regulatory oversight schemes, FDA should seize the opportunity to provide meaningful oversight of novel technical diagnostic platforms with dynamic clinical evaluative capabilities.

Develop clear standards for the level of clinical evidence necessary to establish the significance of genetic variants.

NGS panels may report on variants over a spectrum of clinical claims, but it is important to determine an appropriate level of clinical evidence to provide a reasonable assurance of safety and accuracy for included variants. Important factors in clinical decision making, such as the risk level associated with a biomarker, whether it is a rare or co-existent variant, and whether there is conflicting data regarding a clinical claim, should be considered.

Provide a mechanism by which FDA can update the purposes and applications of NGS tests.

New paradigms in oversight of clinical performance must allow for flexibility in analysis of information. While the NGS test itself might not change, the general intended uses of a panel, the biomarkers included in clinical assessment and the clinical application of the information provided by the panel may change over time with additional knowledge about individual biomarkers and their clinical significance.

We recognize that this can be a challenge. While we cannot assume that the detection of additional mutations provides new or improved clinically actionable information, FDA should describe and then be willing to accept what is considered a reasonable level of evidence to explore additional or expanded purposes for clinical applications.

Continue to Engage the Community

FDA has the opportunity to build a functional new oversight paradigm for NGS that recognizes changes regarding potentially actionable information in the least burdensome manner while ensuring patient safety and access. As the agency considers new oversight processes that recognize modifications/additions to clinical data and leverage large database information to inform clinical endpoints, it is important to continue to work with all stakeholders to develop important details on how such a database would be resourced, standardized and administered.

Moving forward, we recommend that FDA continue developing discussion drafts and/or draft guidance documents describing current thinking on these issues and incorporating feedback from this workshop and other forums. FDA draft documents should be updated regularly to reflect evolving thought and emerging best practices.

We appreciate the high level of engagement FDA is having with stakeholders, and look forward to working with the agency going forward.