INSERM CIC P-0802, University Hospital of Poitiers, France.
Stat Med. 2011 Apr 15;30(8):801-11. doi: 10.1002/sim.4148. Epub 2011 Jan 12.
The primary goal of phase II studies is to assess the efficacy of the new treatment in order to decide whether it has sufficient activity to warrant further evaluation in a phase III comparative trial. However, many adequately conducted phase II trials are negative leading to termination of drug development. Heterogeneity of the population is often considered to be a cause of treatment effect dilution. One approach to determine the sensitive subpopulation is to conduct several phase II trials, one in each specific subset of patients. This option might unethically increase the number of non-sensitive patients under evaluation. Adaptive two-stage designs have been recently proposed. London and Chang proposed a global one-sample test for response rates for stratified phase II clinical trials, whereas Jones and Holmgren proposed an adaptive design that allows preliminary determination of efficacy that may be restricted to a specific subpopulation defined by biomarker status. These two methods do not allow early termination for efficacy in one or several subgroups as they are extensions of the Simon design. The authors propose an alternative method to deal with stratification in phase II clinical trials and identification of the best target population. This method is based on the multiple-stage Fleming design allowing for early stopping rules for either efficacy or inefficacy. It also integrates a procedure testing whether treatment effects are similar or heterogeneous between the two groups. The operating characteristics of this method were compared with those of a standard Fleming design using exact binomial probabilities.
二期研究的主要目标是评估新治疗方法的疗效，以确定其是否具有足够的活性，从而值得在三期比较试验中进一步评估。然而，许多充分进行的二期试验结果为阴性，导致药物开发终止。人群的异质性通常被认为是治疗效果稀释的原因。一种确定敏感亚群的方法是进行几项二期试验，每个试验在特定的患者亚群中进行。这种选择可能不道德地增加了正在评估的非敏感患者的数量。适应性两阶段设计最近已经提出。London 和 Chang 提出了一种用于分层二期临床试验的响应率的全局单样本检验，而 Jones 和 Holmgren 提出了一种适应性设计，允许初步确定疗效，该疗效可能仅限于由生物标志物状态定义的特定亚群。这两种方法都不允许因一个或几个亚组的疗效而提前终止，因为它们是 Simon 设计的扩展。作者提出了一种替代方法来处理二期临床试验中的分层和确定最佳目标人群。该方法基于多阶段 Fleming 设计，允许针对疗效或无效性进行早期停止规则。它还集成了一个程序，用于测试两组之间的治疗效果是否相似或异质。使用精确二项式概率比较了该方法的操作特性与标准 Fleming 设计的操作特性。
