Section Data Science and Methods, Paul-Ehrlich Institut, Langen, Germany.
Department of Medical Informatics, Biometry, and Epidemiology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
J Biopharm Stat. 2024 Aug;34(5):719-736. doi: 10.1080/10543406.2023.2275765. Epub 2023 Nov 21.
Platform trials offer a framework to study multiple interventions in one trial with the opportunity of opening and closing arms. The use of common controls can increase efficiency as compared to individual controls. The need for multiplicity adjustment because of common controls is currently a debate among researchers, pharmaceutical companies, and regulators. The impact of common controls on the type one error in a fixed platform trial, i.e. when all treatments start and end recruitment at the same time, has been discussed in the literature before. We complement these findings by investigating the impact of a common control on the type one error and power in a flexible platform trial, i.e. when one arm joins the platform later. We derived the correlation of test statistics to assess the impact of the overlap and compared the results to a trial with individual controls. Furthermore, we evaluate the power, and the impact of multiplicity adjustment on the power in fixed and flexible platform trials. These methodological considerations are complemented by a regulatory guideline review. With multiple arms, the FWER is inflated when no multiplicity adjustment is applied. However, the FWER inflation is smaller with common controls than with individual controls. Even after multiplicity adjustment, a trial with common controls is often beneficial in terms of sample size and power. However, in some cases, the trial with common controls loses the efficiency gain and it might be advisable to run a separate trial rather than joining a platform trial.
平台试验提供了一种在一次试验中研究多种干预措施的框架，并有机会开放和关闭试验组。与使用个体对照相比，使用共同对照可以提高效率。由于共同对照，需要进行多重性调整，这是研究人员、制药公司和监管机构目前争论的焦点。共同对照对固定平台试验中一类错误的影响，即在所有治疗都在同一时间开始和结束招募时，已经在文献中进行了讨论。我们通过研究共同对照对灵活平台试验中一类错误和功效的影响来补充这些发现，即在一个试验组较晚加入平台时。我们推导出了检验统计量的相关性，以评估重叠的影响，并将结果与个体对照的试验进行了比较。此外，我们还评估了固定和灵活平台试验中的功效，以及多重性调整对功效的影响。这些方法学考虑因素辅之以对监管指南的审查。在存在多个试验组时，如果不进行多重性调整，则 FWER 会增加。然而，与个体对照相比，共同对照的 FWER 增加较小。即使进行了多重性调整，使用共同对照的试验通常在样本量和功效方面是有益的。然而，在某些情况下，使用共同对照的试验会失去效率增益，可能更明智的做法是单独进行试验，而不是加入平台试验。
