Götte Heiko, Schüler Armin, Kirchner Marietta, Kieser Meinhard
Merck KGaA, Darmstadt, Germany.
Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
Pharm Stat. 2015 Nov-Dec;14(6):515-24. doi: 10.1002/pst.1717. Epub 2015 Sep 28.
In recent years, high failure rates in phase III trials were observed. One of the main reasons is overoptimistic assumptions for the planning of phase III resulting from limited phase II information and/or unawareness of realistic success probabilities. We present an approach for planning a phase II trial in a time-to-event setting that considers the whole phase II/III clinical development programme. We derive stopping boundaries after phase II that minimise the number of events under side conditions for the conditional probabilities of correct go/no-go decision after phase II as well as the conditional success probabilities for phase III. In addition, we give general recommendations for the choice of phase II sample size. Our simulations show that unconditional probabilities of go/no-go decision as well as the unconditional success probabilities for phase III are influenced by the number of events observed in phase II. However, choosing more than 150 events in phase II seems not necessary as the impact on these probabilities then becomes quite small. We recommend considering aspects like the number of compounds in phase II and the resources available when determining the sample size. The lower the number of compounds and the lower the resources are for phase III, the higher the investment for phase II should be.
近年来，观察到III期试验的高失败率。主要原因之一是由于II期信息有限和/或对实际成功概率缺乏认识，导致对III期试验规划的假设过于乐观。我们提出了一种在事件发生时间设置中规划II期试验的方法，该方法考虑了整个II期/III期临床开发计划。我们推导了II期后的停止边界，该边界在II期后正确的继续/终止决策的条件概率以及III期的条件成功概率的附带条件下，使事件数量最小化。此外，我们给出了关于II期样本量选择的一般建议。我们的模拟表明，II期观察到的事件数量会影响继续/终止决策的无条件概率以及III期的无条件成功概率。然而，在II期选择超过150个事件似乎没有必要，因为那时对这些概率的影响变得相当小。我们建议在确定样本量时考虑II期化合物数量和可用资源等方面。II期化合物数量越少且III期资源越少，II期的投入就应该越高。
