同时考虑响应和毒性的Ⅱ期临床试验设计(英文)

Alternative Designs of PhaseⅡTrials Considering Response and Toxicity

肿瘤学研究常通过Ⅱ期临床试验设计来初步评价一个新的治疗方案的疗效,目前流行的方法是Simon的两阶段试验设计。不过他只关注反应率,即对肿瘤有抑制作用的病人比率。而在实际临床中,人们既想控制肿瘤的生长,也不希望毒性的副作用大。Conaway和Petroni基于治疗方案的疗效和安全性,提出一种Ⅱ期临床试验设计方法,对响应与毒性给以相同的权重。本文提出新的想法来处理安全性与疗效之间的平衡关系,主要思想是分开控制反应率和毒性的第一类错误。在Ⅱ期临床试验阶段,由于样本量较小的缘故不大可能同时控制反应率和毒性的第一类错误,我们可以根据实际临床需要将这两个第一类错误分别确定在不同的显著性水平。比如,如果我们更关注治疗方案的毒性多过疗效,可以将毒性的第一类错误定在较低的水平(如5%),而将反应率的第一类错误定在较高的水平(如10%或15%)。基于上面的思想,本文给出了寻找停止域和拒绝域的准则和样本量大小的确定公式。我们的方法较其它设计方案更稳健,而且能准确地控制感兴趣的参数(反应率或毒性)的第一类错误。另外,本文思想在概念上很直观,易于临床操作,尤其符合Ⅱ期临床试验设计小样本量的要求。

Phase Ⅱclinical trials in oncology are used to initially evaluate the therapeutic efficacy of a new treatment regimen. Simon＇ s two stage design is commonly used for such trials. However, he only focused on the＂ response rate＂, the proportion of patients experiencing tumor regression. In Clinical practice, it is preferred of a sequential design to monitor antitumor activity as well as toxicity. Conaway and Petroni proposed a method for designing phase Ⅱ trials on the basis of both treatment efficacy and safety,which imply an equal weighing of response and toxicity. In this paper, we developed an alternative test to cope with the trade - off between safety and efficacy. The main idea is to control for the marginal type Ⅰ errors of response rate and toxicity rate separately. We provide guides on searching the stopping and rejecting regions and determination of sample size. The proposed method has advantage over other designs, including those of Conaway and Petroni＇ s and Bryant and Day＇ s, that it can definitely control one type Ⅰ error of the interests such as treatment antitumor activity or safety and is robust against the real association parameter. Furthermore, it is conceptive intuitive, very simple to implement, and also feasible for the requirement of small sample size in a phase Ⅱ trial.