Dose and Treatment Selection in Clinical Trials

临床试验中的剂量和治疗选择

基本信息

批准号：
7895918
负责人：
Ken Cheung
金额：
$ 35.99万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-08 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895918
关键词：
Acute Adopted Clinical Clinical Data Clinical Trials Complex Conduct Clinical Trials Controlled Clinical Trials Data Dose Effectiveness Enrollment Ethics Funding Goals Gold Herbert Irving Comprehensive Cancer Center Individual Institution Investigation Ischemic Stroke Maximum Tolerated Dose Medical Methodology Methods Neurology New Drug Approvals Outcome Patients Phase Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Placebo Control Procedures Process Randomized Regimen Research Resources Safety Screening procedure Selection for Treatments Staging Statistical Methods Stratification Stroke System Testing Therapeutic Toxic effect Translating Treatment Efficacy Universities Work base clinically relevant design drug development high throughput screening improved nervous system disorder novel phase 3 study placebo controlled study public health relevance response standard care

项目摘要

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.

描述（由申请人提供）：新疗法的临床试验可以通过三个阶段进行。 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 期试验中显示出有希望的治疗方案将被转移到大型、多机构的 III 期研究中，以比较其与标准治疗的有效性。由于有许多候选方案可用，因此必须为昂贵的 III 期测试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导致新化合物数量不断增加，这一点变得越来越重要。在这项研究中，我们提出了新颖的统计设计和策略，以有效的方式利用复杂的临床数据，希望以更少的资源转化为同样准确的临床结论。具体来说，本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个客观约束下具有多个安全终点的 I 期剂量探索试验的方法。现有的设计将终点分解为毒性或无毒性的二分指标，并且可能会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。我们提出的方法将通过使用所有端点来检索信息丢失，并通过适应多个客观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，其中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，并减少接受这些剂量治疗的患者数量。第三，我们提出根据临床和生物学终点在 II 期试验中选择治疗方法的设计。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顺序选择边界的研究。虽然生物学终点通常比临床终点（例如中风患者的改良兰金量表）噪音小，但主要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确保设计具有临床相关性。这些设计将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：尽管在过去十年中做出了努力，但仍然迫切需要针对急性缺血性中风等神经系统疾病的其他治疗方法。成功完成这项研究后，我们将扩大设计新疗法早期研究的能力，并提高各种临床试验环境中选择和筛选过程的统计效率。