In a recent forum, oncology professionals explored how precision medicine can help cancer patients by ensuring that diagnostic tests for somatic mutations in oncology are accurate and meet certain analytical performance standards. Organized by the Friends of Cancer Research (FOCR) and Alexandria Real Estate Equities, Inc., in Washington, DC, the event was the sixth "Blueprint for Breakthroughs" forum on which the two groups have collaborated.
As more and more genetic tests become available to clinicians, the accuracy and reliability of these tests become increasingly important, because if a diagnostic test is wrong and a cancer patient receives the wrong treatment, "the patient will be hurt dramatically," said Ellen V. Sigal, PhD, Founder and Chairperson of the FOCR. Both physicians and patients need to trust the diagnostic tests being used. So do insurers who pay for the tests.
Expanding Diagnostic Testing Use
In a keynote address, FDA Commissioner Scott Gottlieb, MD, stated, "I think there's broad appreciation of how diagnostic testing can help patients." But, he noted, "It's relatively recently that we've seen companion diagnostics coupled specifically to treatment." Because this trend is so recent, he stated the economic case for companion diagnostics is just now evolving.
"Right now, we don't really have a bar; we really need to set the bar" for proficiency in diagnostic mutation testing, said Lisa M. McShane, PhD, Acting Associate Director for the Division of Cancer Treatment & Diagnosis, Biometric Research Program, NCI. She noted that the entire history of modern medicine has been about raising the performance bar, and that setting quality metrics-proficiency testing standards-is part of ensuring that the upward progression in medicine continues.
One effective way to ensure a diagnostic mutation test meets certain agreed-upon quality standards would be to couple use of the test with reimbursement, suggested Erasmus Schneider, PhD, Associate Director for Research and Technology, Wadsworth Center, New York State Department of Health. "Insurance companies can say, 'We will only pay if the test meets certain standards,'" he noted.
Policy & Standards
The FOCR released a pre-meeting draft white paper, "Charting the Course for Precision Medicine: Adopting Consensus Analytical Standards and Streamlining Approval Pathways for Post-Market Modifications for NGS Tests in Oncology." That white paper, whose key points were discussed at the forum, provides a list of policy opportunities for precision medicine in establishing minimum analytical performance characteristics for somatic mutation testing in oncology, especially for next-generation sequencing (NGS) panels (see list on page 19).
The white paper also makes the point that "due in part to the fragmented regulatory landscape for diagnostic tests in the U.S., physicians and patients relying on these tests often do not know whether the test went through the FDA-approval process or is being offered as a [laboratory-developed test]." The paper poses the following questions on analytical standards for diagnostic tests:
* What are the core performance metrics and how can we get the necessary groups to reach consensus on the necessary performance standards?
* Who/what sets the benchmarks for diagnostic tests?
* Should a standards development organization, such as the Clinical & Laboratory Standards Institute, be charged with developing an internationally recognized format for collecting data and a rigorous but reasonable method for establishing minimal analytical performance metrics and assuring cutoffs (decision points) have been adequately set?
* Where should these standards be published to encourage adoption and should there be an enforcement strategy?
* How should the claims and limitations of a test be reported to patients and physicians?
Currently there are more than 30 in vitro diagnostics (IVDs) approved by the FDA as companion diagnostics, noted the white paper. Companion diagnostics are not only a key feature of personalized medicine, but they are also "changing our traditional testing paradigm," said Adam C. Berger, PhD, Senior Staff Fellow in the FDA's Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health (CDRH). As this new testing paradigm evolves, he noted that the FDA is "developing a nimble regulatory approach for genetic tests."
At the FDA, Berger explained that staffers are looking at technical/analytic standards for NGS and the use of curated databases to provide clinical evidence on NGS. When a diagnostic test goes through regulatory review at the FDA, the agency uses performance standards when they are available and validated, added Reena Philip, PhD, Director of the FDA's Division of Molecular Genetics and Pathology, Office of In Vitro Diagnostics and Radiological Health, CDRH. She noted that standards are important for each intended use of a given test.
Growth in Diagnostic Testing
Complicating the case for diagnostic testing standards is that today the market is flooded with genetic tests, said Julie Dixon, PhD, Director of Global Regulatory Sciences at Bristol-Myers Squibb. She noted that more than 69,000 genetic testing products are available and, on average, 10 new products enter the market every day. Dixon noted that among the benefits of NGS testing is that it can determine patients who might benefit from a "wait-and-see" approach rather than immediate treatment; help select patients who might benefit from immunotherapies and combinations of these drugs; and enable tumor-agnostic drug development. On the last point, she cited the example of pembrolizumab, the first drug approved for multiple cancerous tumors regardless of where they appear in the body.
On the downside, Dixon noted there are barriers to NGS testing that include the availability of a test, cost of the test, reimbursement for the test, turnaround time for test results, tissue requirements, and lack of standardized reporting of results. "Collaboration will be required to address NGS standardization to realize its full potential," she emphasized.
Agreeing was Jason D. Merker, MD, PhD, Assistant Professor of Pathology and Co-Director of the Stanford Medicine Clinical Genomics Service at Stanford University School of Medicine. "It really does need to be a partnership," he said.
"We need to have analytical standards so everyone is reading from the same book," stressed Dara L. Aisner, MD, PhD, Director of the Colorado Molecular Correlates Laboratory-which is devoted to personalized medicine-and Associate Professor in the Department of Pathology at the University of Colorado in Aurora. She added that professional societies need to be a major player in setting proficiency standards for diagnostic tests.
NGS has changed how patients are treated in the clinic, leading to a regulatory conundrum-innovation versus keeping patients safe, said Rasika Kalamegham, PhD, Group Director for U.S. Regulatory Policy at Genentech. Referring to test variability, she said the last thing patients should have to worry about is whether they can trust their diagnostic test results. "That's our responsibility," she said. "Let's convene on a minimum standard [of proficiency]," she suggested. "That doesn't mean you can't exceed it." She added, "If you do have standards, it makes it that much easier when it comes to interpreting the results."
Peggy Eastman is a contributing writer
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Defining Standards for Next-Generation Sequencing
1. A survey should be performed of existing guidelines for establishing agreed-upon analytical performance parameters to avoid redundant standards and to build upon existing consensus standards.
2. FDA should describe which materials are acceptable for validation of modifications to a diagnostic test given that clinical samples from clinical trials will not be widely available.
3. Adopting analytical standards requires standardized reference material. Standard setting bodies such as the National Institute of Standards and Technology and others should be encouraged to develop reference materials such that they are made available to sponsors and laboratories for use to assure standardization of test results across test platforms.
4. A designated professional organization such as the College of American Pathologists or the Association for Molecular Pathology should develop a curated list of high-quality reference materials available for establishing analytical performance characteristics, as well as develop a submission process to evaluate additional reference material for inclusion.
5. Incentives should be identified and fostered for demonstrating analytical validation across laboratories.
6. Where possible, real-world evidence should be gathered about test performance and patient outcomes through expanded use of registries and databases (clinical claims). This is in keeping with the FDA's draft guidance on the "Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based in Vitro Diagnostics" use of databases.
7. Organizations overseeing proficiency testing should make results widely available so there is a better understanding for the state of the agreement of testing performance across test platforms and sites.
8. FDA expertise should be leveraged to develop innovative regulatory strategies for regulatory review and approval of modifications to NGS-based tests. The FDA is familiar with reducing review burden in a variety of methods, including use of special 510(k)s, migration studies for introducing new versions of old tests, and the replacement reagent protocol to reduce redundant review. While these strategies do not directly fit the regulatory paradigm currently being proposed, they may serve as the basis for creating a reliable but efficient mechanism for addressing the data opportunities and burdens of NGS technologies.
9. There should be standardization of the information reported to patients and physicians, and the interpretability of laboratory report information should be ensured.
10. In addition to diagnostic modifications, stakeholders should be encouraged to propose novel approaches to the process of modifications to use of approved drugs. For example, if additional variants are shown to be clinically relevant to the use of an approved drug, patients and physicians would benefit from an expansion of not only the diagnostic label but also the drug label to reflect the expanded intent-to-treat population.
11. There are reimbursement and coverage challenges. The extensive efforts of sponsors that have demonstrated clinical validity of their IVDs via FDA review should be recognized in some way such that it provides an incentive for sponsors to submit modifications to the FDA after initial approval of the test (e.g., differential reimbursement).