Adapting the sample size planning of a phase III trial hased on phase II data
Adapting the sample size planning of a phase III trial hased on phase II data
复制标题
DOI：
10.1002/pst.217
复制
发表时间：
2006-04-01
影响因子：
1.5
通讯作者：
O'Neill, RT
中科院分区：
文献类型：
--
作者：
Wang, SJ;Hung, HMJ;O'Neill, RT
传统上，在临床开发计划中，II 期试验相对较小，预计会导致 III 期试验计划的估计存在很大程度的不确定性。 II 期试验还旨在探索适当的主要疗效终点或患者群体。当疾病的生物学和疾病进展的发病机制得到充分了解后，II 期和 III 期研究可以在具有相同主要终点的相同患者群体中进行，例如，在非胰岛素依赖型糖尿病试验中通过 HbA1c 测量疗效，治疗时间至少为三个月。在分子途径尚未建立良好或短期研究中可能观察不到临床结果终点的疾病领域，例如癌症或艾滋病试验中的死亡率，可以通过在 II 期试验中使用中间替代终点来推测治疗效果。然而，在许多情况下，我们通常会在 II 期试验中探索适当的临床终点。一个重要的问题是，II 期研究中替代终点中观察到的效果有多少可以转化为 III 期试验中的临床效果。另一个问题是第三阶段试验还存在多少不确定性。在这项工作中，我们研究了设计适应（而不是统计测试）的效用，即调整第二阶段信息以规划第三阶段试验。也就是说，我们研究了使用各种 II 期效应大小估计对 III 期试验的样本量规划的影响。一般来说，如果使用 II 期试验的点估计进行规划，建议通过选择较小的 alpha 水平或较高的功率水平来确定 III 期试验的规模。通过使用II期试验的一个标准差置信区间下限进行调整似乎是一个合理的选择，因为如果可以选择低于III期试验真实效果大小的阈值来确定是否启动III期试验，它可以很好地平衡已启动试验的经验力量和未启动试验的比例。 John Wiley & Sons, Ltd 于 2006 年出版
Traditionally, in clinical development plan, phase II trials are relatively small and can be expected to result in a large degree of uncertainty in the estimates based on which Phase III trials are planned. Phase II trials are also to explore appropriate primary efficacy endpoint(s) or patient populations. When the biology of the disease and pathogenesis of disease progression are well understood, the phase II and phase III studies may be performed in the same patient population with the same primary endpoint, e.g. efficacy measured by HbA1c in non-insulin dependent diabetes mellitus trials with treatment duration of at least three months. In the disease areas that molecular pathways are not well established or the clinical outcome endpoint may not be observed in a short-term study, e.g. mortality in cancer or AIDS trials, the treatment effect may be postulated through use of intermediate surrogate endpoint in phase II trials. However, in many cases, we generally explore the appropriate clinical endpoint in the phase II trials. An important question is how much of the effect observed in the surrogate endpoint in the phase II study can be translated into the clinical effect in the phase III trial. Another question is how much of the uncertainty remains in phase III trials. In this work, we study the utility of adaptation by design (not by statistical test) in the sense of adapting the phase II information for planning the phase III trials. That is, we investigate the impact of using various phase II effect size estimates on the sample size planning for phase III trials. In general, if the point estimate of the phase II trial is used for planning, it is advisable to size the phase III trial by choosing a smaller alpha level or a higher power level. The adaptation via using the lower limit of the one standard deviation confidence interval from the phase II trial appears to be a reasonable choice since it balances well between the empirical power of the launched trials and the proportion of trials not launched if a threshold lower than the true effect size of phase III trial can be chosen for determining whether the phase III trial is to be launched. Published in 2006 by John Wiley & Sons, Ltd.