Generating Evidence for Genomic Diagnostic Test Development Workshop Summary (2011) / Chapter Skim
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3 Approaches to Evidence Generation
3 Approaches to Evidence Generation
Pages 25-42
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From page 25... ...
• More efficient methodologies for generating evidence need to be developed to expedite decision-making. • Researchers need to collect and store biospecimens from pro spective clinical trials with future analysis and use in mind.
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From page 26... ...
. Retrospective trials can provide useful Marker + Retrospective Responder Marker – DRUG A Marker + Nonresponder Marker – ALL Marker + Responder Marker – DRUG B Marker + Nonresponder Marker – Prospective Stratified Drug A Marker Positive Drug B Test Drug A Marker Negative Drug B Prospective Screened Marker + Drug A Genotype Guided Marker – Drug B ALL Drug A Usual Care Non Guided Drug B FIGURE 3-1 Pharmacogenomic trial designs, including retrospective, prospective Figure 3-1.eps stratified, and prospective screened.
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To foster the adoption of genomics-based interventions, it will be important to increase the generalizability of clinical trial designs and results to include clinical practice settings; to demonstrate improvement in health outcomes as well as the cost effectiveness of testing versus not testing; and to establish evidence-based guidelines. Lerman offered several reasons for the reduced generalizability and lack of translation of classic randomized clinical efficacy trials into clinical practice.
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Population Selective, homogeneous Diverse, heterogeneous Setting Specialized, controlled Clinical practice Intervention Fixed, protocol-driven Flexible, clinician judgment Comparator Placebo or active Usual care, least $ Compliance Closely monitored, high Highly variable Assessments Elaborate, complex Simple outcomes Goal FDA approval Adoption in practice SOURCE: Lerman, IOM workshop presentation on November 17, 2010. One approach to addressing these issues, Lerman suggested, is a practical clinical trial model (also called a pragmatic clinical trial; [Brass, 2010]
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From page 29... ...
Lerman and her colleagues obtained evidence of association by a retrospective analysis of four clinical trials, and they then established the clinical validity of the nicotine metabolism ratio test in a prospective stratified RCT. Next Lerman discussed a hypothetical practical clinical trial of genotypeguided versus non-guided nicotine therapy, comparing a nicotine patch (low cost, low toxicity)
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Varenicline 0.50 C NRT Patch Varenicline 35% 0.45 0.40 0.35 Test 0.30 Efficacy Placebo 19% 0.25 D hypothesis 0.20 Slowest 25 50 75 Fastest Percentile of 3HC Ratio N=675 Patch 28% E Normal Metabolizers (NMs) F Varenicline 46% FIGURE 3-3 Prospective stratified RCT scheme.
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Once clinical validity has been established in a prospective trial, a practical clinical trial could be part of the validation pathway to help facilitate the transition into practice. USE OF ARCHIVED SAMPLES TO EVALUATE GENOMIC TESTS Richard Simon of the National Cancer Institute (NCI)
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Clinical utility can take into account costs or advantages and disadvantages, but he said that the key factor in utility is whether the result of the test is actionable and informs treatment selection to the benefit of the patient. The optimal designs for evaluating the clinical utility of a prognostic marker include prospective clinical trials and retrospective analysis of archived specimens from a prospective trial.
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in which the results were consistent. In conclusion, analysis of archived tissues for prognostic and predictive biomarkers can provide either a higher or a lower level of evidence in support of clinical utility depending upon several key factors: the analytical validation of the assay; the nature of the study from which the specimens were archived; the number and condition of the specimens; and whether a focused, written plan for analysis of the specified biomarker was developed before assaying any tissue.
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As one part of the larger structure, a field evaluation program was developed to collect primary data in order to address uncertainties identified in the systematic reviews and to perform post-market assessment of real Professional, Ontario Health MOHLTC public, and System industry feedback loop Physicians Requests Requests Schedule of Benefits Recommendations Knowledge Transfer LHINs – Implementation: OHTAC Hospitals, Community Stakeholder Agencies, etc.... Engagement Field Outcomes Tracked by MAS Evaluations MOHLTC with GIS Uncertainty • Post-market technology evaluation • POC/INR through PATH, THETA, Intermediate care ICES • Cardiac Expert PATH (McMaster Univ.)
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. It has insured PET scanning for staging lung cancer, but field studies have not shown clinical utility for head and neck cancer or in staging breast cancer, and these applications of PET are not insured.
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analysis Endovascular PATH and single Prospective Safety assessment of No endoleak; Funded for high but not abdominal aortic AHSC observation endoleak CE only for high low surgical risk aneurysm repair surgical risk (160) Multifaceted PATH, with Before-after Prioritize Most CE were Bariatric program funded primary care Oxford University study using micro investments bariatric surgery, and additional funding diabetes program simulation economic according to MDT; Least, for MDT; Insulin infusion model downstream effects insulin infusion pumps for type 2 on hold and CE following pumps for type II systemic review of diabetes strategy 64-slice CT PATH, with Patients for CA also Uncertainty Sensitivity lower OHTAC recommended angiography cardiologists, underwent CTA regarding than reported, slow diffusion until (CTA)
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biopsy PET for colorectal OCOG RCT Clinical utility Accrual completed Awaiting results cancer metastatic in decision for February 2010 to liver (400) metastatectomy PET for head and OCOG Prospective cohort Clinical utility pre- No clinical utility Not insured neck cancer (400)
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MAS looked at the predictive value of mutated EGFR based on a retrospective subgroup analysis of archived specimens from a RCT of first-line treatment with gefitinib versus chemotherapy. The results of the analysis suggested a statistically significant improvement in progressionfree survival for gefitinib versus chemotherapy in EGFR-mutation-positive patients, but not in EGFR-mutation-negative patients (Zhu et al., 2008)
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A primary issue is what questions should be in the chain. Analytic Framework Ransohoff said that established analytic frameworks should be used to develop chains of evidence for genomic tests, and he referred to a presentation that Steven Woolf had given to the roundtable at its March 2010 workshop.
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In many cases the rate-limiting step is funding, infrastructure, or informatics, but in generating evidence for genomic test development, the ratelimiting step is formulating the key clinical questions and designing a study that provides strong evidence or a link in the chain. The question that needs to be addressed, Ransohoff said, is whether existing data can be used in a strong design.
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Rather, the focus should be on answering specific clinical questions and opportunistically designing strong research studies in different settings. DISCUSSION Archived Specimens A participant noted that "you can't test specimens if you don't have the specimens to test." Some fields, such as breast cancer research, collect tissues prospectively when conducting clinical trials, Dan Hayes said.
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From page 42... ...
Ransohoff noted that the system rewards clinicians for getting grants and publishing papers, as opposed to producing products or expanding general knowledge. Simon said that, in his experience, industry is extremely interested in new clinical trial designs that use predictive biomarkers or candidate predictive biomarkers in new drug development.
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