The US FDA's Project Optimus initiative that emphasizes dose optimization prior to marketing approval represents a pivotal shift in oncology drug development. It has a ripple effect for rethinking what changes may be made to conventional pivotal trial designs to incorporate a dose optimization component. Aligned with this initiative, we propose a novel Seamless Phase II/III Design with Dose Optimization (SDDO framework). The proposed design starts with dose optimization in a randomized setting, leading to an interim analysis focused on optimal dose selection, trial continuation decisions, and sample size re-estimation (SSR). Based on the decision at interim analysis, patient enrollment continues for both the selected dose arm and control arm, and the significance of treatment effects will be determined at final analysis. The SDDO framework offers increased flexibility and cost-efficiency through sample size adjustment, while stringently controlling the Type I error. This proposed design also facilitates both Accelerated Approval (AA) and regular approval in a "one-trial" approach. Extensive simulation studies confirm that our design reliably identifies the optimal dosage and makes preferable decisions with a reduced sample size while retaining statistical power.

翻译：美国FDA的"Optimus项目"倡议强调在上市批准前进行剂量优化，这代表了肿瘤药物开发的一个关键转变。它产生了连锁效应，促使人们重新思考如何修改传统的关键试验设计以纳入剂量优化部分。与此倡议相一致，我们提出了一种新颖的剂量优化无缝II/III期设计框架。该设计始于随机化设置下的剂量优化，随后进行一项中期分析，重点是最佳剂量选择、试验继续决策以及样本量重新估计。基于中期分析的决定，患者入组将在选定的剂量组和对照组中继续进行，治疗效果的显著性将在最终分析时确定。SDDO框架通过样本量调整提供了更高的灵活性和成本效益，同时严格控制了I类错误。这一拟议设计还有助于在"单试验"方法中实现加速批准和常规批准。大量的模拟研究证实，我们的设计能够可靠地识别最佳剂量，并以减少的样本量做出更优的决策，同时保持统计功效。