Design and Analysis of three- and multi-armed "gold-standard" non-inferiority trials

由于开发更有效的治疗方法的局限性，非劣效性试验在临床研究中变得越来越重要。如果新治疗具有其他优势，如更低的成本、更好的安全性或在次要终点方面提高的疗效，则非劣效性的证明特别有趣。非劣效性试验的一个主要困难是缺乏测定敏感性的问题，即在特定试验中治疗效果的可能性通常很小，例如由于不满意的依从性或纳入了高比例的反应不足的患者。因此，有积极参考和安慰剂组的试验设计，通常被称为“三臂金标准设计”，被认为比包括安慰剂的双臂非劣效性设计更可取。在本研究建议中，安慰剂对照非劣效性试验的统计方法学将得到加强，并扩展到多治疗组的设计或可能同时检测次要终点的设计。该项目的一个特别重点是构建合适的同时置信区间。具有绝对和相对非劣效裕度的设计都将被考虑。对于具有绝对非劣效边际的设计，同时测试和间隔估计非劣效和有效性的方法将是一个主要主题。目标是开发方法，说明非劣效性声明的临床相关性取决于观察到的活性比较剂的疗效。为此目的，将考虑固定样本量的设计，以及顺序和适应性设计，其中在参考文献不够有效的情况下，有可能将焦点从非劣效性转移到治疗效果的量化到安慰剂。

Due to limitations in the development of more efficient therapies, non-inferiority trials are becoming increasingly important in clinical research. The proof of non-inferiority is of particular interest if the new treatment has other advantages like lower costs, better safety profiles or an increased efficacy with regard to secondary endpoints. A major difficulty with non-inferiority trials is the problem of lack of assay sensitivity, i.e. the potential that in the specific trial treatment effects is generally small, e.g. due to unsatisfactory compliance or the inclusion of a high proportion of insufficiently responding patients. Therefore trial designs with active reference and placebo groups, often denoted as ``three-armed gold-standard designs'', are considered preferable to two-armed non-inferiority designs whenever it is ethical to include the placebo. In this research proposal the statistical methodology for placebo controlled non-inferiority trials will be enhanced and extended to designs with multiple treatment arms or designs with the possibility of testing also secondary endpoints. A particular focus of the project is the construction of suitable simultaneous confidence intervals. Designs with absolute and relative non-inferiority margins will both be considered. For designs with absolute non-inferiority margins, methods for simultaneous testing and interval estimation of non-inferiority and efficacy will be a major theme. The goal is to develop methods that account for the fact that the clinical relevance of the non-inferiority claim depends on the observed efficacy of the active comparator. To this end fixed sample size designs, as well as sequential and adaptive designs, will be considered in which there is the possibility of switching the focus from non-inferiority to the quantification of the treatment's efficacy to placebo in cases where the reference is not sufficiently efficient.