2-in-1 design (Chen et al. 2018) is becoming popular in oncology drug development, with the flexibility of using different endpoints at different decision time. Based on the observed interim data, sponsors choose either to seamlessly advance a small phase 2 trial to a full-scale confirmatory phase 3 trial with a pre-determined maximum sample size, or to remain in a phase 2 trial. This approach may increase efficiency in drug development but is rigid and requires a pre-specified fixed sample size. In this paper, we propose a flexible 2-in-1 design with sample size adaptation, while retains the advantage of allowing intermediate endpoint for interim decision. The proposed design reflects the needs of recent FDA's Project FrontRunner initiative to encourage using an earlier surrogate endpoint to potentially support accelerated approval with conversion to standard approval with long term endpoint from the same randomized study. Additionally, we identify the interim decision cut-off to allow conventional test procedure at the final analysis. Extensive simulation studies showed the proposed design require much smaller sample size and shorter timeline than the simple 2-in-1 design, while achieving similar power. A case study in multiple myeloma is used to demonstrate the benefits of the proposed design.
翻译:2-in-1设计(Chen等人,2018年)在肿瘤药物开发中越来越受欢迎,灵活地在不同的决定时间使用不同的终点。根据观察到的临时数据,赞助者选择将小规模的2阶段试验顺利地推进到全面确认阶段3试验,并预先确定最大样本规模,或者继续处于第2阶段的试验。这种办法可能提高药物开发的效率,但是僵硬的,需要事先确定固定的样本规模。在本文件中,我们提议采用灵活的2-in-1设计,同时保留允许中间端点作临时决定的优势。拟议的设计反映了林业发展局最近的项目FrontRunner倡议的需要,即鼓励使用早期的代理端点,以便鼓励使用早期的代理端点,以便可能支持加速批准,从同一随机研究中长期的端点转换为标准批准。此外,我们确定了临时决定的截止点,以便在最后分析中允许采用常规测试程序。广泛的模拟研究表明,拟议的设计需要比简单的2-in-1设计要小得多的样本规模和较短的时间期限,同时取得类似的权力。在多处进行个案研究时,以显示拟议的设计的好处。