Generating Evidence for Genomic Diagnostic Test Development Workshop Summary (2011) / Chapter Skim
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2 Stakeholder Perspectives on Evidence
2 Stakeholder Perspectives on Evidence
Pages 5-24
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Enabling the validation and utilization of genomic-based diagnostic tests involves understanding the views of these interested parties. Stakeholders representing regulators, payers, evidence-based review groups, and providers shared their perspectives on evidence (summarized in Box 2-1)
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6 GENOMIC DIAGNOSTIC TEST DEVELOPMENT BOX 2-1 Stakeholder Perspectives on Evidence FDA • Regulatory decision to approve or clear a diagnostic device for marketing • Focused on safety and effectiveness o nalytical validity: sufficiently accurate and precise measurement of the A analyte o linical validity: the biological and medical significance of the test result C • Risk-based classification approach to regulation of devices • ore complex, higher-risk devices require more substantial levels of M evidence • ound by law to declare or decline approval/clearance based on evidence B submitted by product sponsor (i.e., no mechanism for provisional approval) Payers • Insurer decision to cover and reimburse the use of a diagnostic device • Focused on outcomes • linical utility: the impact of the test on patient management and outcomes C compared with usual care • ay choose to provisionally cover a test pending collection of further evi M dence of utility (coverage with evidence development)
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Performance Claims The performance claims and risk-based classification of a diagnostic test are based on how well the test supports the intended use. FDA requires evidence of analytical validity, the accuracy in and reliability of measuring the analyte of interest, and clinical validity, the accuracy and reliability of the test in identifying or predicting the biological and medical significance of the test result.
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Becker highlighted some of the challenges associated with establishing analytical and clinical validity of diagnostic devices (Box 2-2)
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There may also be limits to the "diagnostic truth" of the test results if information is limited on the patient's underlying condition, and follow-up and outcome studies may be difficult and costly to perform. Diagnostic tests may be submitted to FDA as stand-alone tests or in association with a drug.
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described the evaluation criteria that TEC uses for its assessment of genetic test evidence. Established in 1985, TEC is housed within the Blue Cross and Blue Shield Association, which is the membership organization for Blue Cross and Blue Shield Plans.
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and is described by measures of association, such as sensitivity, specificity, and predictive value as well as odds ratios, risk ratios, and logistic regression analyses, that describe whether a genetic test retains significance when analyzed along with other criteria. Clinical validity is concerned with the significance of the test for populations of patients.
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. Again, this evidence was primarily supportive of clinical validity and was not sufficient to meet TEC criteria, Piper said, but the TEC medical advisory panel asked if a better analysis had been done on the existing data.
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would have received chemotherapy. Since the reclassification analysis was done using retrospective data from completed clinical trials, outcomes were known.
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As only erlotinib is available in the United States, the TEC medical advisory panel requested independent assessment of erlotinib, and the subsequent assessment concluded that EGFR mutation testing to predict response to erlotinib treatment does meet TEC criteria. Outcomes for progression-free survival and overall survival showed a much better separation between responders and nonresponders, and showed that patients with the wild-type EGFR gene were not likely to respond to erlotinib, thus, indicating it is best for them to move to an alternative treatment (TEC, 2011)
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. In these cases, EGAPP uses the ACCE criteria to develop an indirect chain of evidence to address key questions of analytic validity, clinical validity, and clinical utility.
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Moderate certainty means that there are some questions about the evidence and some risk that future research could lead to a change in the recommendation, but in the judgment of the EGAPP working group the evaluation of net benefit has met the criteria for making the recommendation. Finally, low certainty is when there is inadequate evidence of a net benefit to make a recommendation.
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Finally, BRAF mutation testing is based on single-gene mutation sequencing, and analytic validity in that setting is high. Based on existing clinical studies, EGAPP also found adequate evidence of clinical validity for all three tests.
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In this case, after a review of the Oncotype DX, MammaPrint, and H:I ratio tests, EGAPP "found insufficient evidence to make a recommendation for or against the use of tumor gene expression profiles to improve outcomes in defined populations of women with breast cancer." This insufficient evidence conclusion was classified as encouraging, however, as EGAPP "found preliminary evidence of a potential benefit of testing results to some women who face the decisions about treatment options (reduced adverse events due to low risk women avoiding chemotherapy) but could not rule out the potential for harm for others (breast cancer recurrence that could have been prevented)
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HEALTH-CARE PROVIDER PERSPECTIVE A Focus on Value As an oncologist, Daniel Hayes of the University of Michigan Comprehensive Cancer Center looks at genomic diagnostic tests from the perspective of value. The goal is to improve cancer outcomes by focusing the "right therapy on the right patient," thereby increasing the chances of cure, survival, or palliation and decreasing exposure to toxicity from unnecessary or inappropriate therapy.
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SOURCE: Berry et al., 2005; Peto et al., 2000. Figure 3-2.eps To help guide decisions regarding the value of genomic diagnostic tests, the American Society of Clinical Oncology (ASCO)
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Tumor marker utility is poorly valued, which leads to the low level of reimbursement. This means lower funding for tumor marker research and little incentive to do properly designed and controlled clinical studies.
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Calonge noted that the potential value of information is included in the EGAPP outcomes set, but understanding the actual value is difficult. If ending the diagnostic odyssey provides a health benefit to an individual,
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A health outcome would instead be a case when the information reduces the diagnostic odyssey or is useful for reproductive decision making. However, if the information predicts the risk of a disease for which there is no preventive or ameliorative treatment, then there is no health outcome.
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One does not stop at clinical validity and associational evidence, Piper said. Becker agreed that there is a fair amount of commonality about the kind of evidence that helps in reaching a decision.
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