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. ? ? ?
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