NEW DESIGNS AND STATISTICAL METHODS FOR NIDDK STUDIES

描述（改编自申请人的摘要）：国家 糖尿病、消化和肾脏疾病研究所（NIDDK） 长期赞助新疗法的临床研究。 这 应用程序为NIDDK提出了新的设计和统计方法 临床研究。 此应用程序的主要重点是 开发用于临床试验和剂量反应的新设计 研究，这将更好地有利于个人参与者， study. 这些新设计是响应驱动的;也就是说，响应来自 使用研究中以前的受试者以确保更高的概率 未来的受试者将被分配到治疗或剂量水平 目前为止“表现”更好。 响应驱动的设计具有丰富的 生物统计学研究的历史，对临床医生有吸引力，但 由于现有统计数据的局限性， 技术. 本申请的大部分内容涉及补救措施， 将使响应驱动设计在更多的I-III期临床试验中变得可行 对NIDDK感兴趣的疾病进行新疗法的试验。 以前很少有方法学工作涉及到反应的使用- 剂量反应或毒性研究的驱动设计。 这个项目 提出了一类基于广义Polya urn模型，允许以特定分位数为目标， 剂量反应关系的描述，同时保护 患者被分配到高毒性剂量水平。 这个类 的设计基本上是非参数的，并允许各种各样的 设计选择。 这样的设计将是感兴趣的预测试阶段 新疗法的明显的伦理利益，但也 适用于联合疗效/毒性反应，通常关注 在第二阶段试验中。 估计和推断的问题 在设计的实际执行中进行检查。 比较 与现有的其他方法。 提出了其他响应驱动设计，包括全顺序 剂量反应研究设计，滴定或剂量范围设计 实验，适合III期临床试验的设计， 多个治疗组和适合生存试验的设计。 这些设计中的每一个都是由现实的研究场景所激发的， 道德利益与实际问题沿着权衡 执行;处理潜在的批评，并努力 提出解决方案。 大多数NIDDK试验采用组序贯监测技术。 两 其他主题，一本关于分组顺序监测数据的专著， 临床试验，以及三个连续监测的设计 标准随机化设计时，临床试验中的治疗组 也被开发出来了。

DESCRIPTION (adapted from the applicant's abstract): The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) has a long history of sponsoring clinical studies of new therapies. This application proposes new designs and statistical methods for NIDDK clinical studies. The primary emphasis of this application is the development of new designs for clinical trials and for dose-response studies which will better benefit the individual participant in the study. These new designs are response-driven; that is, responses from previous subjects in the study are used to ensure a higher probability that future subjects will be assigned to treatments or dose levels "performing" better thus far. Response-driven designs have a rich history in biostatistical research and are attractive to clinicians, but are not utilized very often due to limitations of existing statistical techniques. A large part of this application addresses remedies which will make response-driven designs feasible for more Phase I-III clinical trials of new therapies for diseases of interest to the NIDDK. Little previous methodological work has addressed the use of response- driven designs for dose-response or toxicity studies. This project presents a randomized class of designs based on the generalized Polya urn model which allows targeting of a particular quantile and description of the dose- responsive relationship while protecting patients from being assigned to highly toxic dose levels. This class of designs is essentially nonparametric and allows a wide variety of design choices. Such designs will be of interest for pre-testing stages of new therapies for the obvious ethical benefits, but are also applicable to combined efficacy/toxicity responses, often of interest in Phase II trials. Problems with estimation and inference and issues in the practical implementation of the design are examined. Comparison with other existing methodology is proposed. Other response-driven designs are proposed, including a fully sequential design for dose-response studies, a design for titration or dose ranging experiments, a design appropriate for Phase III clinical trials with multiple treatment arms, and a design appropriate for survival trials. Each of these designs is motivated by realistic study scenarios, and ethical benefits are weighed along with issues of practical implementation; potential criticisms are addressed, and efforts made to propose solutions. Most NIDDK trials employ group sequential monitoring techiques. Two other topics, a monograph on group sequential monitoring of data in clinical trials, and a design for sequential monitoring of three treatment arms in a clinical trial when a standard randomization design is used, are also developed.