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Impact of trial design on the estimation of drug potency and power in clinical trials of haemophilia with inhibitors

机译：试验设计对抑制剂血友病药物效力估算的影响

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Historically, clinical trials of haemophilia with inhibitors (HwI) have been challenged by the small patient population. New approaches to clinical trial methodology and statistical modelling could potentially be used for study optimization. The aim of this work was to evaluate the impact of different trial designs and study conditions on the estimated drug potency and power, and compare traditional statistical methods with repeated time-to-event (RTTE) modelling in terms of power. Bleeding information from a clinical trial of 23 haemophilia patients with inhibitors treated on-demand was used to develop a baseline RTTE model using NONMEM. Clinical trial simulations for a hypothetical anti-haemophilic drug were performed, by adding a drug effect and a literature-derived placebo effect to the baseline RTTE model, using different trial designs (parallel-group, placebo-controlled parallel-group, crossover and placebo-controlled crossover designs) and study conditions, including sample size, study duration and doses. The precision and accuracy of the estimated drug potency (EC50) and power for different trial designs, study conditions and statistical methods (RTTE modelling,t-test and negative binomial regression) were evaluated. The developed baseline RTTE model accurately described the clinical data. The crossover designs displayed up to four-fold higher precision of the estimatedEC50and three-fold higher power relative to the parallel-group trial designs. Furthermore, RTTE modelling provided a higher power relative to the traditional statistical tests. We found that crossover designs in combination with RTTE modelling can reduce the required sample size and study duration, while ensuring high power and precise estimation ofEC50, in clinical trials of HwI.
机译：从历史上看，具有抑制剂（HWI）的血友病患者的临床试验受到小患者人口的挑战。临床试验方法和统计建模的新方法可能用于研究优化。这项工作的目的是评估不同试验设计和研究条件对估计的药物效力和功率的影响，并比较传统的统计方法在权力方面对重复的时间 - 事件（RTTE）建模。来自23例含有抑制剂抑制剂患者的临床试验的出血信息用于使用非谋区开发基线RTTE模型。通过对基线RTTE模型添加药物效果和文献衍生的安慰剂效果来进行假设的抗血友病药物的临床试验模拟，使用不同的试验设计（并联 - 组，安慰剂控制的平行组，交叉和安慰剂 - 控制交叉设计）和研究条件，包括样本大小，研究持续时间和剂量。评估估计的药物效力（EC50）和不同试验设计，研究条件和统计方法（RTTE建模，T检验和阴性二项式回归的功率的精度和准确性。开发的基线RTTE模型精确描述了临床数据。交叉设计显示高达四倍的估计精度，相对于并联组试验设计，估计的三倍高。此外，RTTE建模相对于传统统计测试提供了更高的功率。我们发现，交叉设计与RTTE建模结合可以减少所需的样本大小和研究持续时间，同时确保HWI的临床试验中的550次EREC50的高功率和精确估计。

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