Dose and Treatment Selection in Clinical Trials

描述(申请人提供)：一种新疗法的临床试验可能会经过三个阶段。I期试验通常是评估毒性并确定安全剂量范围的小规模研究。具体的任务通常是确定最大耐受量。一旦选择了安全剂量的治疗，其治疗效果将在第二阶段试验中进行测试。在第二阶段试验中显示有希望的方案将被转移到大型、多机构第三阶段研究，将其有效性与标准治疗进行比较。在许多方案可能是大型III阶段研究的候选方案，但相对于标准评估每一种方案的资源太少的情况下，必须设置优先顺序，仅选择那些有望在III阶段试验中成功评估的方案。在这项研究中，我们提出了新的统计设计和策略，有效地利用了观察到的临床数据，希望用更少的资源转化为同样准确的临床结论。具体地说，该应用程序涵盖以下三个临床场景。首先，我们提出了基于多个重复安全终点的I期剂量发现试验的方法，并将这些方法应用于重新设计当前的卒中试验。现有的设计将端点分解为毒性或无毒性的二分指示器，并且这样做的代价可能是没有利用所有可用的信息。我们提出的方法有望通过在试验过程中使用所有端点来恢复信息损失。其次，我们提出了第二阶段剂量发现疗效试验的方法，在该试验中，患者将分两个阶段进行登记。有了中期分析，我们可以关闭无效剂量，并减少使用这些剂量治疗的患者数量。第三，我们提出了在第二阶段试验中选择或筛选治疗方法的设计。目前的设计比较僵化，在试点的规划和实施过程中存在很大的实际难度。例如，我们的方法在中期分析的日程安排和优先选择处理方法方面提供了灵活性。这些设计将被应用于设计神经疾病患者的各种临床试验。尽管在过去十年中做出了努力，但对急性缺血性中风和肌萎缩侧索硬化症(ALS)的额外治疗仍是迫切需要的。在这项研究成功完成后，我们将扩大我们的能力，以支持新疗法的早期研究，并提高各种临床试验环境下选择和筛选过程的统计效率。

DESCRIPTION (provided by applicant): Clinical trials of a new treatment may proceed through three phases. Phase I trials are typically small studies that evaluate toxicity and determine a safe dosage range. The specific task is usually to determine the maximum tolerated dose. Once a safe dose of the treatment is chosen, its therapeutic efficacy will be tested in a phase II trial. Regimens shown promising in phase II trials will then be moved to large, multi- institutional phase III studies that compare their effectiveness to standard treatments. In situations when many regimens are possible candidates for a large phase III study, but too few resources are available to evaluate each relative to the standard, priority must be set to select only those with promise for successful evaluation in phase III trials. In this research, we propose novel statistical designs and strategies that utilize the observed clinical data in an efficient manner, which is hoped to translate into equally accurate clinical conclusions with fewer resources. Specifically, this application covers the following three clinical scenarios. First, we propose methods for phase I dose-finding trials based on multiple and repeated safety endpoints, and apply the methods to re-design a current stroke trial. Existing designs collapse the endpoints into a dichotomized indicator of toxicity or no-toxicity, and may do so at the expense of not utilizing all information available. Our proposed methods are expected to retrieve the information loss by using all endpoints in the conduct of a trial. Second, we propose methods for phase II dose-finding efficacy trials, in which patients will be enrolled in two stages. Having an interim analysis, we can shut down ineffective doses and reduce the number of patients treated at these doses. Third, we propose designs to select or screen treatments in phase II trials. Current designs are rigid and impose great practical difficulty during the planning and the implementation of a trial. Our methods provide, for instance, flexibility in the scheduling of interim analyses and the prior preference of treatments. These designs will be applied to design various clinical trials in patients with neurological disorders. Despite the efforts in the past decade, additional therapies for acute ischemic stroke and amyotrophic lateral sclerosis (ALS) are sorely needed. Upon successful completion of this research, we will extend our capacity to support early phase investigation of new treatments and enhance the statistical efficiency of selection and screening process in a variety of clinical trial settings.