Optimal sample size allocation and go/no‐go decision rules for phase II/III programs where several phase III trials are performed
Optimal sample size allocation and go/no‐go decision rules for phase II/III programs where several phase III trials are performed
复制标题
进行多项 III 期试验的 II/III 期项目的最佳样本量分配和通过/不通过决策规则
DOI：
10.1002/bimj.201700241
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发表时间：
2019
影响因子：
1.7
通讯作者：
Kirchner
中科院分区：
文献类型：
--
作者：
Preussler;Kieser;Kirchner
二期和三期项目的实施成本高、耗时长，而且由于后期开发阶段的高失败率，风险很大。II期和III期试验之间有很强的联系，因为进行/不进行的决定和III期选择的样本量是基于II期观察到的结果。因此，第二期和第三期的综合规划是合理的。二期/三期项目的成功关键取决于二期和三期的资源分配，包括样本量，以及决定是否停止或继续进行三期项目所采用的规则。最近，提出了一种基于效用的方法，其中通过考虑药物开发计划的固定和可变成本以及成功上市后的潜在收益来实现II/III期项目的最佳规划。然而，该方法仅限于单个III期试验项目，而监管机构通常要求在两个或多个III期试验中具有统计显著性。我们将此程序推广到进行两个或多个III期试验的项目。最佳II期样本量和进行/不进行的决策规则提供了时间-事件结果和案例，其中至少有一个，两个或三个III期试验需要成功。在这些不同的病例中比较不同的药物开发计划策略（例如，一个大型与两个III期试验）。在肿瘤临床试验中的应用说明了所提出的方法。
The conduct of phase II and III programs is costly, time‐consuming and, due to high failure rates in late development stages, risky. There is a strong connection between phase II and III trials as the go/no‐go decision and the sample size chosen for phase III are based on the results observed in phase II. An integrated planning of phase II and III is therefore reasonable. The success of phase II/III programs crucially depends on the allocation of the resources to phase II and III in terms of sample size and the rule applied to decide whether to stop or to proceed with phase III. Recently, a utility‐based approach was proposed, where optimal planning of phase II/III programs is achieved by taking fixed and variable costs of the drug development program and potential gains after a successful launch into account. However, this method is restricted to programs with a single phase III trial, while regulatory authorities usually require statistical significance in two or more phase III trials. We present a generalization of this procedure to programs where two or more phase III trials are performed. Optimal phase II sample sizes and go/no‐go decision rules are provided for time‐to‐event outcomes and cases, where at least one, two, or three phase III trials need to be successful. Different drug development program strategies (e.g. one large vs. two phase III trials) are compared within these different cases. Application to practical examples typically met in oncology trials illustrates the proposed method.
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期刊：
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作者：
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1995
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发表时间：
1932
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