Adaptive enrichment designs for confirmatory trials

Lai, Tze Leung; Lavori, Philip W.; Tsang, Ka Wai

doi:10.1002/sim.7946

Cited by 19 publications

(25 citation statements)

References 36 publications

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“…Finally, the cost-effectiveness study was derived from the UK Biobank, a longitudinal population study rather than a randomised controlled trial which would otherwise overestimate the incremental benefits. 46–48…”

Section: Discussionmentioning

confidence: 99%

Cost-Effectiveness of Polygenic Risk Scores to Guide Statin Therapy for Cardiovascular Disease Prevention

Kiflen

et al. 2022

Circ: Genomic and Precision Medicine

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BACKGROUND: Atherosclerotic cardiovascular diseases (CVDs) are leading causes of death despite effective therapies and result in unnecessary morbidity and mortality throughout the world. We aimed to investigate the cost-effectiveness of polygenic risk scores (PRS) to guide statin therapy for Canadians with intermediate CVD risk and model its economic outlook. METHODS: This cost-utility analysis was conducted using UK Biobank prospective cohort study participants, with recruitment from 2006 to 2010, and at least 10 years of follow-up. We included nonrelated white British-descent participants (n=96 116) at intermediate CVD risk with no prior lipid lowering medication or statin-indicated conditions. A coronary artery disease PRS was used to inform decision to use statins. The effects of statin therapy with and without PRS, as well as CVD events were modelled to determine the incremental cost-effectiveness ratio from a Canadian public health care perspective. We discounted future costs and quality-adjusted life-years by 1.5% annually. RESULTS: The optimal economic strategy was when intermediate risk individuals with a PRS in the top 70% are eligible for statins while the lowest 1% are excluded. Base-case analysis at a genotyping cost of $70 produced an incremental cost-effectiveness ratio of $172 906 (143 685 USD) per quality-adjusted life-year. In the probabilistic sensitivity analysis, the intervention has approximately a 50% probability of being cost-effective at $179 100 (148 749 USD) per quality-adjusted life-year. At a $0 genotyping cost, representing individuals with existing genotyping information, PRS-guided strategies dominated standard care when 12% of the lowest PRS individuals were withheld from statins. With improved PRS predictive performance and lower genotyping costs, the incremental cost-effectiveness ratio demonstrates possible cost-effectiveness under thresholds of $150 000 and possibly $50 000 per quality-adjusted life-year. CONCLUSIONS: This study suggests that using PRS alongside existing guidelines might be cost-effective for CVD. Stronger predictiveness combined with decreased cost of PRS could further improve cost-effectiveness, providing an economic basis for its inclusion into clinical care.

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Section: Discussionmentioning

confidence: 99%

Cost-Effectiveness of Polygenic Risk Scores to Guide Statin Therapy for Cardiovascular Disease Prevention

Kiflen

et al. 2022

Circ: Genomic and Precision Medicine

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“…Our study stresses the need for continuing research into possible applications of adaptive designs in diagnostic accuracy research. Recent endeavors concerning late phase diagnostic trials on patient benefit, which are beyond the focus of this study, dealt with multiplicity issues in exploratory subgroup analysis, including adaptive biomarker‐driven designs and specified the application of an enrichment design comparing a new endovascular treatment with standard of care for ischemic stroke patients . The following questions might be subject to future research: How can adaptive designs be applied with possible early stopping due to efficacy or futility as well as seamless designs? Can adaptive designs for the reestimation of PPV and NPV be transferred to the reestimation of the sensitivity and specificity? What is the optimal time point for an interim analysis—as early as possible, or as late as necessary?…”

Section: Discussionmentioning

confidence: 99%

Adaptive trial designs in diagnostic accuracy research

Zapf

Stark

Gerke

et al. 2019

Statistics in Medicine

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The aim of diagnostic accuracy studies is to evaluate how accurately a diagnostic test can distinguish diseased from nondiseased individuals. Depending on the research question, different study designs and accuracy measures are appropriate. As the prior knowledge in the planning phase is often very limited, modifications of design aspects such as the sample size during the ongoing trial could increase the efficiency of diagnostic trials. In intervention studies, group sequential and adaptive designs are well established. Such designs are characterized by preplanned interim analyses, giving the opportunity to stop early for efficacy or futility or to modify elements of the study design. In contrast, in diagnostic accuracy studies, such flexible designs are less common, even if they are as important as for intervention studies. However, diagnostic accuracy studies have specific features, which may require adaptations of the statistical methods or may lead to specific advantages or limitations of sequential and adaptive designs.In this article, we summarize the current status of methodological research and applications of flexible designs in diagnostic accuracy research. Furthermore, we indicate and advocate future development of adaptive design methodology and their use in diagnostic accuracy trials from an interdisciplinary viewpoint. The term "interdisciplinary viewpoint" describes the collaboration of experts of the academic and nonacademic research.

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“…Notably, these designs explicitly factor in the possibility that the new drug might differentially benefit distinct biomarker subgroups, and allow data-dependent mid-course enrichment with preservation of type I error. In terms of application, both Rosenblum and Hanley ( 65 ) and Lai et al ( 66 ) have applied their adaptive enrichment designs to the setting of stroke trials. This does not restrict its relevance of this to deal with trial designs for precision oncology.…”

Section: Adaptive Enrichment Designsmentioning

confidence: 99%

Challenges, opportunities, and innovative statistical designs for precision oncology trials

Yin¹,

Shen²

2022

Ann Transl Med

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In the era of precision oncology, improved understanding of tumor heterogeneity, particularly at the molecular level, has caused a shift from traditionally histology based cancer drug development to molecularly targeted drug development. The shift to the molecular view of cancer leads to increasingly small cancer populations for clinical trials which may be underpowered using traditional statistical designs. This paradigm shift lead to the recent developments of innovative clinical trial designs to address the challenges from precision oncology clinical trials. Hence, this paper reviewed and described innovative trial designs for precision oncology. Different strategies were discussed to account patient and treatment effect heterogeneity, including precision dose-finding designs that tailor the optimal dose to different patients at different time points, master protocol designs that match patients' molecular alterations with specific targeted agents, and adaptive enrichment designs that dynamically modify eligibility criteria and enroll patients that are most likely to benefit from the novel agents. Despite their superior performance, better understanding of practical barriers is needed to widen their implementation for precision oncology trials. Therefore, this paper also reviewed the practical challenges regarding the implementation of precision oncology clinical trials, along with the strength and weakness of various approaches of precision oncology clinical trial designs.

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Adaptive enrichment designs for confirmatory trials

Cited by 19 publications

References 36 publications

Cost-Effectiveness of Polygenic Risk Scores to Guide Statin Therapy for Cardiovascular Disease Prevention

Cost-Effectiveness of Polygenic Risk Scores to Guide Statin Therapy for Cardiovascular Disease Prevention

Adaptive trial designs in diagnostic accuracy research

Challenges, opportunities, and innovative statistical designs for precision oncology trials

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