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ORACLE II – Optimal Rules for Adaptive Designs with reCalculation of sampLE size

ORACLE II â 重新计算样本量的自适应设计的最佳规则

基本信息

批准号：
387053251
负责人：
Professor Dr. Meinhard Kieser, Ph.D.
金额：
--
依托单位：
Institut für Medizinische Biometrie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/387053251?language=en
关键词：
ORACLE II Optimal Rules Adaptive

项目摘要

In standard clinical trial designs, all design parameters must be fixed during the planning stage. Thereby, in particular the choice of the sample size is a crucial issue. It is based on the assumed treatment effect size, the chosen level of significance, the desired power, and the distribution of the applied test statistic. However, the common uncertainty on the true underlying effect size in the planning stage of a trial may result in wrong planning assumptions and, therefore, imply misspecification of the sample size. Adaptive designs provide the possibility to modify the trial design during the ongoing trial and allow correcting for wrong planning assumptions. At the interim analysis, it is decided whether the trial should be stopped for futility or efficacy, respectively, or whether the trial enters the second stage. In the latter case, many design parameters can be adapted, in particular the required sample size. Thereby, the second stage sample size is usually determined by predefined rules and is usually provided as a function of the interim result.The question of a sensible choice of the specific adaptive trial design arises intuitively. There are several challenges related to adaptive designs. The overall aim of this joint proposal between Heidelberg and Berlin is to continue the successful work of the previous DFG-funded project ORACLE. Within the ongoing ORACLE project, recalculation rules were improved and optimized with respect to different optimization and performance criteria. Within the new ORACLE II project, the results and methods of the previous project should be further improved an extended, in particular with respect to non-normally distributed outcomes, designs with more than one interim analysis, and designs with more than two groups. Whereas the ORACLE project exclusively focused on the aspect of sample size in adaptive designs, the focus of the new project ORACLE II is broader: An adequate sample size recalculation rule only has a relevant impact for practical applications if other challenges related to adaptive designs are addressed simultaneously. The most prominent requirements are adequate, unbiased treatment effect estimators and confidence intervals along with corresponding p-values. The above objectives will be addressed within the following work packages and time frames:• Work package 1 (Month 1-12, Berlin): Assessing performance of sample size recalculation • Work package 2 (Months 1-12, Heidelberg): Point estimators, confidence intervals, p-values for adaptive designs with sample size adaptions• Work package 3 (Months 13-24, Berlin & Heidelberg): Sample size recalculation in designs with more than two arms or stages• Work package 4 (Months 25-36, Berlin & Heidelberg): Extensions to binary and time-to-event endpoints

在标准临床试验设计中，所有设计参数必须在计划阶段固定。因此，特别是样本量的选择是一个至关重要的问题。它基于假设的治疗效应量、选择的显著性水平、期望的把握度和应用的检验统计量的分布。然而，在试验的计划阶段，真实的潜在效应量的常见不确定性可能导致错误的计划假设，因此，意味着样本量的错误指定。适应性设计提供了在正在进行的试验期间修改试验设计的可能性，并允许纠正错误的计划假设。在中期分析时，决定是否应分别因无效或有效而停止试验，或试验是否进入第二阶段。在后一种情况下，可以调整许多设计参数，特别是所需的样本量。因此，第二阶段的样本量通常由预定义的规则确定，并且通常作为中期结果的函数提供。直观地出现了对特定适应性试验设计进行明智选择的问题。有几个与自适应设计相关的挑战。海德堡和柏林之间的这一联合提案的总体目标是继续之前DFG资助的项目ORACLE的成功工作。在进行中的ORACLE项目内，根据不同的优化和性能标准改进和优化了重算规则。在新的ORACLE II项目中，应进一步改进前一个项目的结果和方法，特别是在非正态分布结果、具有一个以上中期分析的设计和具有两个以上组的设计方面。尽管ORACLE项目专门关注自适应设计中的样本量方面，但新项目ORACLE II的关注点更广泛：只有在同时解决与自适应设计相关的其他挑战时，适当的样本量重新计算规则才对实际应用产生相关影响。最突出的要求是充分、无偏的治疗效应估计值和置信区间沿着以及相应的p值。上述目标将在以下工作包和时间框架内实现：（第1-12个月，柏林）：评估样本量重新计算的性能·工作包2（第1-12个月，海德堡）：样本量自适应设计的点估计量、置信区间、p值·工作包3（第13-24个月，柏林和海德堡）：两组或两个以上阶段设计中的样本量重新计算·工作包4（第25-36个月，柏林和海德堡）：二进制和至事件时间终点的扩展