Chen Cong, Huang Mo, Zhang Xuekui
Biostatistics and Research Decision Sciences, Merck & Co., Inc, Rahway, New Jersey, USA.
Pfizer Inc, Collegeville, Pennsylvania, USA.
Pharm Stat. 2025 Nov-Dec;24(6):e70031. doi: 10.1002/pst.70031.
Adaptive Phase 2/3 designs hold great promise in contemporary oncology drug development, especially when limited data from Phase 1 dose-finding is insufficient for identifying an optimal dose. However, inconsistent results between Phase 2 and Phase 3 may raise regulatory and practical concerns. The imperfection in dose selection further complicates the issue. In this paper, we explicitly incorporate the concerns about inconsistency into the statistical analysis under three hypothesis testing strategies (conservative, aggressive, and neutral) by specifying an inconsistency cutoff and accounting for the probability of "picking-the-winner." This investigation illustrates how to balance regulatory caution, sponsor interests, and practical considerations in adaptive Phase 2/3 designs with dose optimization, which paves the way for further research in a less explored area.
适应性2/3期设计在当代肿瘤学药物开发中具有巨大潜力，特别是当1期剂量探索获得的有限数据不足以确定最佳剂量时。然而，2期和3期结果不一致可能会引发监管和实际方面的担忧。剂量选择的不完善使问题进一步复杂化。在本文中，我们通过指定不一致临界值并考虑“选出优胜者”的概率，在三种假设检验策略（保守、激进和中性）下，将对不一致性的担忧明确纳入统计分析。本研究说明了如何在具有剂量优化的适应性2/3期设计中平衡监管谨慎、申办方利益和实际考虑因素，为在一个较少探索的领域开展进一步研究铺平了道路。
