STATISTICAL METHODS FOR COMPLEX CANCER TRIALS

复杂癌症试验的统计方法

• 批准号: 6514238
• 负责人: PETER F THALL
• 金额: $ 11.13万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-03 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514238
• 关键词: clinical research; clinical trials; experimental designs; health care model; human subject; human therapy evaluation; method development; model design /development; neoplasm /cancer therapy; statistics /biometry

DESCRIPTION (Adapted from the Applicant's Abstract): When patient outcome in a clinical trial includes both adverse and efficacy events, it is ethically and scientifically desirable to account for both types of treatment effects. Current typical practice, however, is to formally design such clinical trials based on a single efficacy or time-to-event outcome, while including additional, often informal provisions for safety monitoring. This may misrepresent the scientific goals of the trial, including the power of the test for efficacy. Moreover, informal safety monitoring procedures often have very undesirable properties. The long-term objective of this research is to provide models and methods for the design, conduct and analysis of clinical trials involving multivariate outcomes that include adverse events. The aim is to provide a more realistic and reliable basis for treatment evaluation while also formalizing safety monitoring by making early stopping rules for adverse events explicit. While each of the three research projects described below was motivated by one or more clinical trials at M.D. Anderson Cancer Center, the proposed methods will be broadly applicable to similar clinical trials, both in oncology and in other areas involving adverse treatment effects. To facilitate application, portable computer software to implement the proposed methods will be developed and freely distributed. Three different but related clinical settings will be considered: (1) In the first setting, treatment effect is characterized by a two-dimensional (efficacy, safety) parameter. This parameter may arise from multinomial or bivariate discrete outcomes, including such events as 50 percent shrinkage of a solid tumor, complete remission of leukemia, toxicity, or death; or from a bivariate non-negative valued random variable, such as disease-free survival time and an index of treatment-related morbidity. Using the two-sample, one-sided test proposed by Thall and Cheng (1998) to quantify efficacy-safety trade-offs, the specific goals are to derive optimal and minimax two stage designs and more general group-sequential designs, and to extend the test by allowing smooth decision boundaries and two-sided alternatives. (2) In the second setting, each patient receives multiple treatment courses according to the common medical practice of repeating a treatment that is successful and otherwise switching to a different treatment. The research goals are (a) to extend the model and multi-course treatment evaluation and selection methods of Thall, Millikan and Sung (1998) from binary to trinary outcomes, thus incorporating adverse events, and (b) to extend the method to accommodate dose-finding. (3) The third setting deals with short-term treatment-related adverse events, "toxicity,'' that affect long-term survival. We propose to develop mixture models, estimates and group-sequential tests for survival time that use toxicity data together with the usual right censored event times. The aim is to provide a basis for safety monitoring in phase III trials that is part of the formal test, rather than an additional ad hoc procedure.

描述（改编自申请人的摘要）： 临床试验包括不良事件和功效事件，从道德上讲， 从科学上讲，可以考虑两种类型的治疗效果。 但是，当前的典型实践是正式设计此类临床试验 基于单一功效或事件的结果，包括 安全监控的其他通常非正式的规定。这可能 歪曲了试验的科学目标，包括测试的力量 用于功效。此外，非正式的安全监控程序通常非常有 不良属性。这项研究的长期目标是提供 设计，进行和分析临床试验的模型和方法 涉及包括不良事件的多元结果。目的是 为治疗评估提供更现实和可靠的基础 通过制定不良事件的早期停止规则来对安全监控进行正式监控 显式。虽然下面描述的三个研究项目中的每一个是 由M.D. Anderson癌症中心进行的一项或多项临床试验的动机， 建议的方法将广泛适用于类似的临床试验 肿瘤学和其他涉及不良治疗效果的领域。促进 应用程序，便携式计算机软件以实现所提出的方法将 可以开发和自由分发。 将考虑三种不同但相关的临床环境：（1） 第一个设置，治疗效果的特征是二维 （功效，安全）参数。此参数可能来自多项式或 双变量离散结果，包括诸如50％收缩的事件 实体瘤，白血病完全缓解，毒性或死亡；或来自一个 双变量非负值随机变量，例如无病生存 时间和与治疗相关的发病率指数。使用两个样本， Thall and Cheng（1998）提出的单侧测试量化疗效安全 权衡，具体目标是获得最佳和最小值两个阶段 设计和更一般的小组序列设计，并通过 允许平稳的决策边界和双向替代方案。 （2）在 第二个设置，每个患者都会根据多个治疗课程 重复成功治疗的常见医学实践 否则切换到不同的治疗方法。研究目标是（a） 扩展模型和多道菜的治疗评估和选择方法 Thall，Millikan和Sung（1998）从二进制到三级结果，因此 合并不良事件，（b）扩展该方法以适应 剂量找到。 （3）第三个设置涉及短期治疗相关的 不利事件，“毒性，影响长期生存”。我们建议 开发混合模型，估计和小组序列测试以生存时间 使用毒性数据以及通常的正确审查事件时间。这 目的是为第三阶段试验提供安全监控的基础 正式测试的一部分，而不是额外的临时程序。