1

Introduction1

The sequencing of the human genome has greatly accelerated the process of linking specific genetic variants with disease. These findings have yielded a rapidly increasing number of molecular diagnostic tests designed to guide disease treatment and management. Many of these tests are aimed at determining the best treatments for specific forms of cancer, making oncology a valuable testing ground for the use of molecular diagnostic tests in medicine in general.

Nevertheless, many questions surround the clinical value of molecular diagnostic tests, and their acceptance by clinicians, payers, and patients has been unpredictable. A major limiting factor for the use of these tests has been the lack of clear evidence of clinical utility. Barriers to the generation of evidence of clinical utility include a lack of consensus among stakeholders regarding both the level of evidence needed to move a test into clinical practice and the acceptable methodologies to collect and validly demonstrate that evidence.

Capturing the benefits of molecular diagnostics will require stakeholders to help shape and define methodologies for efficiently generating reliable information about which tests will improve health outcomes for patients. Sustained dialogue among stakeholders is needed to help close the current

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1 The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Institute of Medicine, and they should not be construed as reflecting any group consensus.



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1 Introduction1 The sequencing of the human genome has greatly accelerated the pro- cess of linking specific genetic variants with disease. These findings have yielded a rapidly increasing number of molecular diagnostic tests designed to guide disease treatment and management. Many of these tests are aimed at determining the best treatments for specific forms of cancer, making oncology a valuable testing ground for the use of molecular diagnostic tests in medicine in general. Nevertheless, many questions surround the clinical value of molecular diagnostic tests, and their acceptance by clinicians, payers, and patients has been unpredictable. A major limiting factor for the use of these tests has been the lack of clear evidence of clinical utility. Barriers to the generation of evidence of clinical utility include a lack of consensus among stakehold- ers regarding both the level of evidence needed to move a test into clinical practice and the acceptable methodologies to collect and validly demon- strate that evidence. Capturing the benefits of molecular diagnostics will require stakehold- ers to help shape and define methodologies for efficiently generating reliable information about which tests will improve health outcomes for patients. Sustained dialogue among stakeholders is needed to help close the current 1  The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Institute of Medicine, and they should not be construed as reflecting any group consensus. 1

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2 GENOME-BASED DIAGNOSTICS evidence gaps and foster the development of clinically valuable tests that can inform both clinical and policy decision making. PRIOR ROUNDTABLE WORKSHOPS The Roundtable on Translating Genomic-Based Research for Health held two previous workshops examining barriers to the development and use of genomic-based diagnostic tests. At the first workshop, held in November 2010, it became clear, said Robert McCormack, head of technol- ogy, innovation, and strategy for Veridex LLC, that multiple stakeholders are involved and that their multiple needs are not always aligned (IOM, 2011a). To move forward, he said, these needs have to be combined and reconciled, which will require dialogue and coordination. Participants at the 2010 workshop also emphasized the need for rules demonstrating that clinical utility has been achieved, both for future tests and for those in use today. Demonstrating clinical utility is a higher hurdle to meet for diagnostic tests than technical feasibility, analytic validation, or clinical validation, said McCormack. To overcome this hurdle, he argued, the concept of clinical utility needs to be better defined. In addition, the evidence generated and analyzed to demonstrate clinical utility needs to be adapted to the clinical setting, and clinical utility needs to be matched with the indication to make the task manageable. Finally, McCormack said, the workshop demonstrated that the full picture is much bigger than most stakeholders imagine. The challenge of establishing clinical utility extends throughout the diagnostic discovery and development process, encompassing not only evidence development but also reimbursement and regulatory hurdles. “You cannot just fix one element,” said McCormack. “It all has to come in line for the [system] to work.” The second workshop, held in November 2011, focused on this broad- ened landscape and emphasized the many changes needed to develop, regu- late, and reimburse for genomic tests (IOM, 2012a). The involvement of providers is essential to creating short- and long-term change by enabling access and demonstrating value for genomic tests, McCormack said. At the same time, payers are the most important stakeholder in changing the overall climate for tests. The venture capital perspective was a “sobering” example at the workshop, according to McCormack. Venture investment in biotechnology has decreased precipitously over the last 10 years, and it is apparent, said McCormack, that in order for venture capitalists to continue investing their dollars in the United States, they will “need to see a seamless path from FDA [U.S. Food and Drug Administration] to CMS [Centers for Medicare & Medicaid Services] to the private payer. Until they see that, they are taking their money offshore.” In addition, many participants at the

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INTRODUCTION 3 workshop called for greater oversight by the FDA of genomic test develop- ment, particularly for laboratory-developed tests (LDTs), though this call was not unanimous. THE CURRENT EFFORT On May 24, 2012, the Roundtable on Translating Genomic-Based Research for Health and the Center for Medical Technology Policy co- hosted a workshop in Washington, DC, to foster the identified need for fur- ther sustained dialogue between stakeholders regarding the clinical utility of molecular diagnostics. Titled Evidence for Clinical Utility of Molecular Diagnostics in Oncology, the workshop brought together a wide range of stakeholders, including patients, health care providers, policy makers, pay- ers, diagnostic test developers, researchers, and guideline developers, to identify the challenges and opportunities in advancing the development and use of molecular diagnostic tests designed to guide the treatment and man- agement of patients with cancer.2 Box 1-1 lists the goals of the workshop. BOX 1-1 Workshop Goals •  ssess the evidentiary requirements for clinical utility of molecular diagnostics A used to guide treatment decisions for patients with cancer. •  iscuss methodologies, including innovative models, related to demonstrating D these evidentiary requirements that meet the needs of all stakeholders. •  onsider innovative, sustainable research collaborations for generating evi- C dence of clinical utility involving multiple stakeholders. This summary document describes the presentations and rich discus- sions that occurred at the workshop. Chapter 2 establishes a framework for the discussion by examining the history and broad issues associated with the development and use of molecular tests in oncology, the chal- lenges that requiring clinical utility evidence generation for molecular tests poses, the potential impact molecular diagnostics could have on medicine, and the difficulties in establishing evidence standards that satisfy all stake- holders. Chapter 3 presents the perspectives of five different stakeholder groups—clinical guideline developers, health care providers, payers, aca- 2  Theworkshop agenda, speaker biographical sketches, full statement of task, and registered attendees can be found in Appendixes A-D.

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4 GENOME-BASED DIAGNOSTICS demic health systems, and patients—demonstrating both the common- alities and differences in their positions. Chapter 4 looks at the tools that have been and are being developed for use in assessing clinical utility, including a recommended framework for evaluating omics-based tests, comparative-effectiveness research, randomized controlled clinical trials, and observational studies. This chapter also provides considerations for determining whether a test is useful from statistical and economic perspec- tives. Chapter 5 examines possible paths forward to apply those tools to the many challenging issues associated with the use of molecular tests in medi- cine. The role of establishing successful partnerships to overcome challenges encountered during test development and the importance of the availability of biospecimens and data are discussed. This final chapter also provides a summary of the proposals suggested by individual speakers to advance the development of clinical utility measures for molecular diagnostics.