Roche Pharma AG, Grenzach-Wyhlen, Germany.
Roche Pharma AG, Grenzach-Wyhlen, Germany; Medical School of Hanover, Hanover, Germany.
Value Health. 2018 Jun;21(6):698-706. doi: 10.1016/j.jval.2017.09.010. Epub 2017 Nov 7.
In oncology clinical trials, crossover is used frequently but may lead to uncertainties regarding treatment effects.
To investigate the handling of evidence from crossover trials by the European Medicines Agency (EMA) and the German Federal Joint Committee (G-BA).
For oncology medicines with early benefit assessments before January 2015, presence of crossover, clinical data, EMA requests for additional data, and G-BA benefit ratings/evidence levels were analyzed from manufacturers' dossiers, G-BA appraisals, European Public Assessment Reports, and original publications.
Eleven of 21 benefit assessments included crossover trials. Significant intergroup differences (P < 0.05) in overall survival (OS) were noted in 7 of 11 trials with and 7 of 10 without crossover. For 6 of 11 medicines with crossover, these were demonstrated before crossover. Treatment effects generally worsened with increasing proportions of crossover. The EMA requested additional data more frequently if crossover was performed, particularly if no OS data were available before crossover. The G-BA granted a considerable benefit to 73% of medicines with crossover and 40% of those without. Evidence levels were intermediate for 50% and 75%, respectively. None of the medicines received the highest evidence level.
In G-BA appraisals, oncology medicines with crossover received better additional benefit ratings, but were assigned lower evidence levels, than those without. The five medicines with crossover after progression were assigned lower evidence levels than the six medicines with crossover after demonstration of superior OS, indicating that the way in which crossover is implemented may be one factor influencing the assignment of evidence levels by the G-BA.
在肿瘤学临床试验中，交叉设计经常被使用，但可能会导致对治疗效果的不确定性。
调查欧洲药品管理局（EMA）和德国联邦联合委员会（G-BA）如何处理交叉试验的证据。
对于 2015 年 1 月前进行早期获益评估的肿瘤学药物，如果存在交叉设计，分析制造商文件、G-BA 评估、欧洲公共评估报告和原始出版物中的临床数据、EMA 要求额外数据的情况，以及 G-BA 获益评定/证据等级。
21 项获益评估中有 11 项包含交叉试验。在 11 项有交叉设计的试验和 10 项无交叉设计的试验中，有 7 项观察到总生存期（OS）的组间差异有统计学意义（P < 0.05）。在 6 项有交叉设计的药物中，这些差异在交叉之前就已经显现。随着交叉比例的增加，治疗效果通常会恶化。如果进行了交叉设计，EMA 更频繁地要求提供额外的数据，特别是如果在交叉之前没有 OS 数据。G-BA 对 73%的有交叉设计的药物和 40%的无交叉设计的药物给予了相当大的获益。证据等级分别为中级和高级的 50%和 75%。没有一种药物获得了最高的证据等级。
在 G-BA 的评估中，与没有交叉设计的药物相比，有交叉设计的肿瘤学药物获得了更好的额外获益评定，但被分配了较低的证据等级。在有交叉设计的 5 种药物中，有 3 种是在疾病进展后进行的，而在有交叉设计的 6 种药物中，有 4 种是在 OS 得到改善后进行的，这表明交叉设计的实施方式可能是影响 G-BA 分配证据等级的一个因素。
