Randomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a “7 + 3” induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81–1.69), 1.05 (95% CI 0.86–1.30), 1.00 (95% CI 0.84–1.19), and 1.02 (95% CI 0.87–1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR < 0.76, as assumed in the statistical analysis plan) was very low at the first interim analysis (1.2%, 0.6%, 0.4%, and 0.1%, respectively). Similar observations were made for low probabilities of any benefit regarding CR. Therefore, Bayesian analysis significantly adds to conventional methods applied for interim analysis and may thereby accelerate the performance and completion of phase III trials.
随机对照试验（RCTs）是评估新药获益风险比的金标准。然而，对其成熟结果的评估往往需要多年时间。我们假设，在中期分析时间点结合贝叶斯推断方法可能加速并强化此类试验所能产生的认知。为验证这一假设，我们回顾性地将贝叶斯方法应用于HOVON 132试验。该试验将800名年龄在18至65岁的新诊断急性髓系白血病患者随机分配至含或不含来那度胺的"7+3"诱导治疗方案。在首例患者入组五年后，最终传统分析显示该试验主要终点为阴性，实验组与对照组在无事件生存期（EFS）上无差异（风险比[HR] 0.99，p=0.96）。我们采用贝叶斯方法回顾性模拟了入组150例、300例、450例和600例患者后的中期分析，以早期识别疗效缺乏信号。在四次中期分析中，来那度胺组与对照治疗组的EFS风险比分别为1.21（95% CI 0.81-1.69）、1.05（95% CI 0.86-1.30）、1.00（95% CI 0.84-1.19）和1.02（95% CI 0.87-1.19）。来那度胺组的完全缓解率较低，早期死亡更频繁。贝叶斯方法发现，在首次中期分析时，EFS获得临床相关获益（HR<0.76，符合统计分析计划假设）的概率极低（四次分析分别为1.2%、0.6%、0.4%和0.1%）。对完全缓解率的任何获益概率也观察到类似低值。因此，贝叶斯分析显著补充了传统中期分析方法，可能加速III期临床试验的执行与完成。
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