Genome-Based Diagnostics Demonstrating Clinical Utility in Oncology: Workshop Summary (2013) / Chapter Skim
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4 Tools for Generating and Synthesizing Evidence
4 Tools for Generating and Synthesizing Evidence
Pages 29-50
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From page 29... ...
• Studies of clinical utility should be conducted in settings that are relevant to more real-world clinical decisions. • Focusing more on value than on cost-effectiveness in assess ments of molecular diagnostics will enable analyses to be descriptive in addition to prescriptive and will allow consider ation of the full context of care.
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From page 30... ...
It also was asked to apply these criteria to omics-based tests used in the three cancer clinical trials conducted by the Duke investigators and to recommend ways to ensure adherence to the developed framework. A Recommended Framework An omics test is defined as being composed of or derived from multiple molecular measurements and interpreted by a fully specified computational model to produce a clinically actionable result (IOM, 2012b)
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The test development and validation should be performed in a Clinical Laboratory Improvement Amendments (CLIA) accredited clinical laboratory if the test is intended to direct patient management.
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NOTE: FDA, U.S. Food and Drug Administration; IDE, investigational device exemption; IRB, institutional review board; LDT, laboratory-developed test.
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Prospective or retrospective studies can be conducted using archived specimens from previously conducted clinical trials. Also, prospective clinical trials can be performed where either the test does or does not direct patient management.
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In cancer genomics, the goal is to figure out, for patients with a similar diagnosis, what tumor markers or genomic markers predict who will respond to treatment, who will not respond to treatment, and who will have adverse effects. The methods used in CER are typically the same as in traditional genomic studies (see Table 4-1)
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TOOLS FOR GENERATING AND SYNTHESIZING EVIDENCE 35 TABLE 4-1 Comparative-Effectiveness Research Versus Traditional Studies of Genomic Tests for Cancer Comparative-Effectiveness Feature of Research Research Traditional Studies Priority of study among Determined by multiple Opportunity as dictated by alternatives stakeholders, using criteria expert assessment of emerging such as disease burden or technology cost, lack of information, variability in care Study design Retrospective or Retrospective analysis of prospective analysis existing tumor specimens; occasional prospective analysis of observational data Comparisons Direct comparisons of new Direct comparisons of therapy with usual care competing therapies, often not considering usual care Topics Prevention, treatment, In most cases, prediction of monitoring, and other narrow effects such as serious broad topics drug interactions, response to treatment, tumor recurrence Perspectives Multiple, including Clinician and patient clinician, patient, purchaser, and policy maker Study populations and Representative of clinical Highly selected settings practice Data elements Patient characteristics, Patient characteristics, clinical quality of life, safety end points of treatment, resource use and costs, patients' preferences Funding "Coverage with evidence Private investors, research development" programs, grants from federal sources public–private partnerships such as the National Institutes of Health SOURCE: Ramsey et al., 2011.
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One or more decision points are built into the trial design for analysis of outcomes and associated patient or disease characteristics to identify subgroups that are responding favorably. Pragmatic clinical trials -- also called practical clinical trials, effectiveness trials, or large simple trials -- are designed to help decision makers choose between options for care in routine clinical practice.
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These studies are nonrandomized and include retrospective analysis of biospecimens from RCTs, retrospective and prospective cohort designs, studies based on registries, and studies with case-control designs. The strength of the evidence increases in the progression from observational studies to pragmatic RCTs to explanatory RCTs.
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High-quality observational study designs and evidence of underlying biological mechanisms can contribute to the evidentiary framework. For example, large prospective cohort studies with very large effects and compelling data can make a convincing argument for clinical utility even if the evidence was only generated with observational studies.
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When is a prognostic test clinically useful? McShane asked.
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To determine when a predictive test is clinically useful, a treatmentby-marker interaction can be assessed, but care needs to be taken in inter
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Retrospective studies can provide a high level of evidence if they are performed properly. For example, a prospective-retrospective study can produce high levels of evidence for the value of a test if specimens were collected carefully in a clinical trial, if a sufficient number of representative specimens were collected, if the assay was analytically validated, if an analysis plan was prespecified, and if results were validated in one or more similar but separate studies (Simon et al., 2009)
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Randomized clinical trials adequately powered to detect treatment effects are often not sufficiently powered to establish predictive marker effects. For example, the nonsignificance of a treatment effect in a "marker negative" subgroup is often misinterpreted as no treatment effect, even though the test may not be adequately powered to exclude a treatment benefit.
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But representative specimen collections from populations for which the tests might be used, along with data on treatment, outcome, the handling of specimens, and so on, are an important place to start. Adequate funding for collection and storage of annotated specimens from clinical trials and other carefully followed cohorts would also be very helpful, she added.
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About half have a reasonable incremental costeffectiveness ratio, but only about 10 percent of the analyses demonstrate that these interventions save money, Phillips said. Another 10 percent of the studies concluded that the interventions cost more and provide less health benefits than the standard of care, and these studies generally were done before the recent increase in high-cost diagnostics and cancer drugs.
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(2011) demonstrated that few costeffectiveness analyses of breast cancer diagnostics explicitly evaluated the relationships among the methods of targeting, the accuracy of the test, and
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Advancing the Utility of Oncology Diagnostics As Robert Bast did in the previous session, Noel Doheny, chief executive officer of Epigenomics, used a specific disease to make several general points about the tools available to assess the clinical utility of molecular diagnostics in oncology. Colorectal cancer is the second largest cancer killer in the United States, causing 50,000 deaths and 140,000 new cases each year, or 15 to 20 deaths per 100,000 inhabitants (ACS, 2012)
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A Blood Test for Colorectal Cancer The availability of a blood test could promote higher rates of screening by providing the ability to evaluate patients who would not otherwise have been screened, said Doheny. In a survey of more than 1,300 adults, 75 percent said they were more likely to get screened more frequently if a blood test were available.3 Epigenomics has been developing a blood test for colorectal screening based on a circulating marker called methylated Septin9.
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About 1,000 tests per week are being done in the United States currently, which means that about five patients each week are being detected by a blood test as having colorectal cancer that would not have been detected if that test had not been done. "That, in our eyes, is a very positive position to be in," said Doheny.
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TOOLS FOR GENERATING AND SYNTHESIZING EVIDENCE 49 cifically for personalized medicine assays to overcome the extended and biased review cycles in traditional publications. Finally, real-world LDT performance should be linked to FDA filings, he said.
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