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Methods for planning and analysis of clinical phase II trials in oncology

肿瘤学临床 II 期试验的计划和分析方法

基本信息

批准号：
151327791
负责人：
Professor Dr. Meinhard Kieser, Ph.D.
金额：
--
依托单位：
Radiologische Klinik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/151327791?language=en
关键词：
Methods planning analysis clinical phase

项目摘要

Within the current funding period of the project, two-stage adaptive designs were developed for clinical phase II studies in oncology that, during the course of the trial, allow for arbitrary (especially: data-driven) modifications of the initial sample size fixed in the planning phase while controlling the significance level. These designs allow for addressing unforeseen or unpredictable changes occurring during the study conduct without compromising the specified type I error rate. For example, assumptions regarding the treatment effect made in the planning stage might be put into question by the results of an interim analysis. It would then be a promising option either to reduce or to increase the sample size. Currently, however, it is still an open question which one of the various possible strategies for sample size recalculation is "optimal" in such a situation. This problem will be examined in the continuation phase of the project. Based on the results of these investigations, recommendations shall be provided about the choice of an appropriate design or sample size recalculation strategy in the respective situation at hand. Moreover, methods are to be developed that allow to adequately deal with over- or underrunning of the sample size planned for the interim analysis. Such a situation arises quiet often in practice, for example due to a too late or too early stop of patient recruitment. All currently available methods show serious deficits; amongst others, they do not control the pre-specified significance level.Furthermore, there are currently no methods available for calculating valid p-values, point estimates andconfidence intervals in phase II oncology trials with an adaptive design. It is well-known that an application of methods developed for the respective one-stage designs lead to distorted results and, consequently, to a biased interpretation of the study. When our project is being continued, it is our aim to develop analysis methods for phase II oncology trials with adaptive design that take into account the sequential and flexible nature of the study design leading to unbiased results. The characteristics of the created methods will be examined, and recommendations will be given about which of the methods are to be preferred.The developed methods will be implemented in an R software package with a user-friendly user interface. This will lead to a direct transfer of the project results into practice.

在项目的当前资助期内，为肿瘤学临床II期研究开发了两阶段自适应设计，在试验过程中，允许对计划阶段固定的初始样本量进行任意（特别是：数据驱动）修改，同时控制显著性水平。这些设计允许在不影响规定的I类错误率的情况下解决研究实施期间发生的不可预见或不可预测的变化。例如，中期分析的结果可能会对计划阶段的治疗效果提出质疑。因此，减少或增加样本量将是一个有希望的选择。然而，目前，它仍然是一个悬而未决的问题，其中的各种可能的策略重新计算样本量是“最佳”在这种情况下。这个问题将在项目的继续阶段加以审查。根据这些调查的结果，应提供关于在各自情况下选择适当设计或样本量重新计算策略的建议。此外，还将制定方法，以充分处理中期分析计划的样本量过量或不足的情况。这种情况在实践中经常出现，例如由于患者招募的太晚或太早停止。所有现有的方法都显示出严重的缺陷;除其他外，它们不能控制预先规定的显著性水平。此外，目前还没有方法可用于计算具有自适应设计的II期肿瘤学试验中的有效p值、点估计值和置信区间。众所周知，应用为相应的一阶段设计开发的方法会导致结果失真，从而导致对研究的偏倚解释。当我们的项目继续进行时，我们的目标是开发具有适应性设计的II期肿瘤学试验的分析方法，该方法考虑到研究设计的顺序性和灵活性，从而获得无偏倚的结果。所创建的方法的特点将被检查，并建议将给出哪些方法是prefered.The开发的方法将在一个R软件包中实现与用户友好的用户界面。这将导致项目成果直接转化为实践。