For many rare diseases with no approved preventive interventions, promising interventions exist, yet it has been difficult to conduct a pivotal phase 3 trial that could provide direct evidence demonstrating a beneficial effect on the target disease outcome. When a promising putative surrogate endpoint(s) for the target outcome is available, surrogate-based provisional approval of an intervention may be pursued. We apply the Causal Roadmap rubric to define a surrogate endpoint based provisional approval causal roadmap, which combines observational study data that estimates the relationship between the putative surrogate and the target outcome, with a phase 3 surrogate endpoint study that collects the same data but is very under-powered to assess the treatment effect (TE) on the target outcome. The objective is conservative estimation/inference for the TE with an estimated lower uncertainty bound that allows (through two bias functions) for an imperfect surrogate and imperfect transport of the conditional target outcome risk in the untreated between the observational and phase 3 studies. Two estimators of TE (plug-in, nonparametric efficient one-step) with corresponding inference procedures are developed. Finite-sample performance of the plug-in estimator is evaluated in two simulation studies, with R code provided. The roadmap is illustrated with contemporary Group B Streptococcus vaccine development.

翻译：对于许多尚无获批预防干预措施的罕见疾病，虽然存在有前景的干预手段，但开展能够提供直接证据证明对目标疾病结局具有有益效果的关键性3期试验一直存在困难。当存在可用于目标结局的有前景的假定替代终点时，可寻求基于替代终点的干预措施临时批准。我们应用因果路线图框架，定义了一个基于替代终点的临时批准因果路线图。该路线图将估计假定替代指标与目标结局之间关系的观察性研究数据，与收集相同数据但检验治疗对目标结局效果效力严重不足的3期替代终点研究相结合。其目标是通过两个偏倚函数，在考虑替代指标不完美以及观察性研究与3期研究中未治疗组条件性目标结局风险迁移不完善的前提下，实现对治疗效果的保守估计/推断，并提供估计的下限不确定性边界。我们开发了两种治疗效果估计量（插件式、非参数高效一步法）及相应的推断程序。通过两项模拟研究评估了插件式估计量的有限样本性能，并提供了R代码。本文以当代B族链球菌疫苗研发为例对该路线图进行了说明。