Dose and Treatment Selection in Clinical Trials

描述（由申请人提供）：新疗法的临床试验可分为三个阶段。一期试验通常是评估毒性和确定安全剂量范围的小型研究。具体的任务通常是确定最大耐受剂量。一旦选择了安全的治疗剂量，其治疗效果将在II期试验中进行测试。在II期试验中表现出希望的方案将被转移到大型、多机构的III期研究中，将其与标准治疗的效果进行比较。在许多方案都可能用于大型III期研究的情况下，但相对于标准，可用于评估每个方案的资源太少，必须优先选择那些有希望在III期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，以有效的方式利用观察到的临床数据，希望以更少的资源转化为同样准确的临床结论。具体来说，该应用程序涵盖以下三种临床场景。首先，我们提出了基于多个和重复安全终点的I期剂量寻找试验方法，并应用这些方法重新设计当前的卒中试验。现有的设计将终点分解为毒性或无毒性的二分类指标，并且可能以不利用所有可用信息为代价。我们提出的方法有望通过在试验中使用所有端点来检索信息丢失。其次，我们提出了II期剂量寻找疗效试验的方法，其中患者将分为两个阶段。通过中期分析，我们可以关闭无效剂量，并减少用这些剂量治疗的患者人数。第三，我们提出在II期试验中选择或筛选治疗的设计。目前的设计是刚性的，在规划和实施试验过程中存在很大的实际困难。我们的方法提供了，例如，在安排中期分析和治疗的优先选择的灵活性。这些设计将应用于设计各种神经系统疾病患者的临床试验。尽管在过去的十年中做出了努力，急性缺血性中风和肌萎缩侧索硬化症（ALS）仍然迫切需要额外的治疗方法。一旦成功完成这项研究，我们将扩大我们的能力，以支持新疗法的早期研究，并提高在各种临床试验环境中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.