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期试验是通过确定最大耐受量的特定任务来评估毒性的小型研究。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。由于有许多候选方案可用，迫切需要为昂贵的III阶段测试确定最有希望的疗法。这一点变得越来越重要，因为有限的主题和资金来源，以及由于高通量筛选而不断增加的新化合物数量。在这项研究中，我们提出了新的统计设计和策略，高效地利用复杂的临床数据，希望用更少的资源转化为同样准确的临床结论。具体地说，此次续签申请涵盖以下三个临床场景。首先，我们提出了在异方差和多目标约束下具有多个安全终点的I期剂量发现试验方法。现有的设计将终点压缩为毒性或无毒性的二分法指标，这样做的代价可能是没有利用所有可用的信息，并过度简化复杂的临床目标。我们提出的方法将通过使用所有端点来恢复信息损失，并通过适应多个目标约束来实现临床相关性。其次，我们提出了基于安全性和有效性终点的II期剂量发现试验方法，在该试验中，患者将分两个阶段入选。有了中期分析，我们可以关闭无效或不安全的剂量，并减少接受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根据临床和生物终点选择治疗方案的设计。这项工作扩展了我们正在进行的具有单一生物终点的试验的序贯选择边界的研究。虽然生物学终点通常比中风患者的临床终点(如改良的Rankin评分)噪音更小，但主要的治疗目标是改善临床结果。我们的双变量方法将通过使用噪音较小的生物终点来提高治疗选择的效率，同时通过使用临床结果来确保设计与临床相关。这些设计将被应用于设计神经疾病患者的各种临床试验。与公共卫生相关：尽管在过去十年中做出了努力，但仍迫切需要对急性缺血性中风等神经疾病进行额外的治疗。在这项研究成功完成后，我们将扩大我们的能力，以设计新疗法的早期调查，并在各种临床试验环境中提高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 small studies that evaluate toxicity with a specific task 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. With many candidate regimens available, it is imperative to identify the most promising therapies for the expensive phase III testing. This has become increasingly important because of the limited subject availability and funding resources, and an ever increasing number of new compounds due to high throughput screening. In this research, we propose novel statistical designs and strategies that utilize the complex clinical data in an efficient manner, which is hoped to translate into equally accurate clinical conclusions with fewer resources. Specifically, this renewal application covers the following three clinical scenarios. First, we propose methods for phase I dose-finding trials with multiple safety endpoints under heteroscedasticity and multiple objective constraints. 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 and over-simplifying the complex clinical objectives. Our proposed methods will retrieve the information loss by using all endpoints and achieve clinical relevance by accommodating multiple objective constraints. Second, we propose methods for phase II dose- finding trials based on both safety and efficacy endpoints, in which patients will be enrolled in two stages. Having an interim analysis, we can shut down ineffective or unsafe doses and reduce the number of patients treated at these doses. Third, we propose designs to select treatments in phase II trials based on both clinical and biologic endpoints. This work extends our ongoing research on sequential selection boundaries for trials with a single biologic endpoint. While a biologic endpoint is typically less noisy than a clinical endpoint such as the modified Rankin scale in stroke patients, the primary therapeutic objective is to improve the clinical outcomes. Our bivariate approach will improve the efficiency in treatment selection by using the less noisy biologic endpoint while assuring the design is clinically relevant via its use of the clinical outcomes. These designs will be applied to design various clinical trials in patients with neurological disorders. PUBLIC HEALTH RELEVANCE: Despite the efforts in the past decade, additional therapies for neurological disorders such as acute ischemic stroke are sorely needed. Upon successful completion of this research, we will extend our capacity to design early phase investigation of new treatments and enhance the statistical efficiency of selection and screening process in a variety of clinical trial settings.