Dose and Treatment Selection in Clinical Trials

描述（由申请人提供）：新治疗的临床试验可能会通过三个阶段进行。I期试验是小型研究，通过特定任务评估毒性，以确定最大耐受剂量。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期试验中显示有希望的方案将被转移到大型的多机构III期研究中，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，因此必须为昂贵的III期试验确定最有希望的疗法。由于受试者可用性和资金资源有限，以及由于高通量筛选而产生的新化合物数量不断增加，这变得越来越重要。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。具体而言，本次续期申请涵盖以下三种临床场景。首先，我们提出了异方差和多目标约束下多个安全性终点的I期剂量探索试验方法。现有的设计将终点分解为毒性或无毒的二分法指标，并且可能以不利用所有可用信息和过度简化复杂的临床目标为代价。我们所提出的方法将通过使用所有端点来恢复信息损失，并通过容纳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期剂量探索试验的方法，患者将分两个阶段入组。通过中期分析，我们可以关闭无效或不安全的剂量，减少接受这些剂量治疗的患者数量。第三，我们提出了在II期试验中根据临床和生物学终点选择治疗的设计。这项工作扩展了我们正在进行的关于单一生物学终点试验的序贯选择边界的研究。虽然生物学终点通常比临床终点（如卒中患者中的改良兰金量表）噪音小，但主要治疗目标是改善临床结局。我们的双变量方法将通过使用噪声较小的生物学终点来提高治疗选择的效率，同时通过使用临床结局来确保设计具有临床相关性。这些设计将应用于设计神经系统疾病患者的各种临床试验。公共卫生相关性：尽管在过去的十年中的努力，其他治疗神经系统疾病，如急性缺血性中风是迫切需要的。在成功完成这项研究后，我们将扩大我们的能力，以设计新治疗的早期研究，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 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.