In drug development programs, proof‐of‐concept Phase II clinical trials typically have a biomarker as a primary outcome, or an outcome that can be observed with relatively short follow‐up. Subsequently, the Phase III clinical trials aim to demonstrate the treatment effect based on a clinical outcome that often needs a longer follow‐up to be assessed. Early‐phase outcomes or biomarkers are typically associated with late‐phase outcomes and they are often included in Phase III trials. The decision to proceed to Phase III development is based on analysis of the early‐Phase II outcome data. In rare diseases, it is likely that only one Phase II trial and one Phase III trial are available. In such cases and before drug marketing authorization requests, positive results of the early‐phase outcome of Phase II trials are then likely seen as supporting (or even replicating) positive Phase III results on the late‐phase outcome, without a formal retrospective combined assessment and without accounting for between‐study differences. We used double‐regression modeling applied to the Phase II and Phase III results to numerically mimic this informal retrospective assessment. We provide an analytical solution for the bias and mean square error of the overall effect that leads to a corrected double‐regression. We further propose a flexible Bayesian double‐regression approach that minimizes the bias by accounting for between‐study differences via discounting the Phase II early‐phase outcome when they are not in line with the Phase III biomarker outcome results. We illustrate all methods with an orphan drug example for Fabry disease.

中文翻译：

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孤儿药开发早期和晚期结果的综合评估

在药物开发项目中，概念验证 II 期临床试验通常将生物标志物作为主要结果，或者可以通过相对较短的随访观察到的结果。随后，III期临床试验旨在根据临床结果证明治疗效果，该临床结果通常需要更长的随访时间才能评估。早期结果或生物标志物通常与晚期结果相关，它们通常包含在 III 期试验中。进行 III 期开发的决定是基于对 II 期早期结果数据的分析。在罕见病中，很可能只有一项 II 期试验和一项 III 期试验可用。在这种情况下，在药品上市许可申请之前，II 期试验早期结果的积极结果可能被视为支持（甚至复制）晚期结果的积极 III 期结果，没有正式的回顾性综合评估，也没有考虑研究之间的差异。我们使用应用于 II 期和 III 期结果的双回归模型来数值模拟这种非正式的回顾性评估。我们为导致校正双回归的总体效应的偏差和均方误差提供了分析解决方案。我们进一步提出了一种灵活的贝叶斯双回归方法，该方法通过在 II 期早期结果与 III 期生物标志物结果结果不一致时对 II 期早期结果进行贴现，从而将研究间差异最小化。