Implementation of the ICH E9 (R1) addendum in vaccine efficacy studies: the hypothetical and principal stratum strategies

Over the past decades, the primary interest in vaccine efficacy evaluation has mostly been on the effect observed in trial participants complying with the protocol requirements (per protocol analysis). The ICH E9 (R1) addendum provides a structured framework to formulate the clinical questions of interest and formalize them as estimands. In this paper, the estimand framework is retrospectively implemented in a human papillomavirus (HPV) phase 3 trial, where the vaccine efficacy was originally estimated on the per protocol set. We focus on two strategies for dealing with the presence of intercurrent events: the hypothetical and the principal stratum strategies. We address the interpretation of these two estimands, their estimation as well as articulation of the underlying identifiability assumptions. Finally, we leverage the results of the HPV application to formulate general considerations regarding the implementation of the ICH E9 (R1) addendum in vaccine efficacy studies.

过去数十年来，疫苗效力评估的核心研究重点大多集中于符合试验方案要求的受试者中观察到的效应（符合方案分析，per protocol analysis）。人用药品注册技术要求国际协调会（ICH）E9(R1)附录提供了结构化框架，用于明确相关临床问题并将其形式化为效应量（estimand）。本文回顾性地将该效应量框架应用于人乳头瘤病毒（HPV，human papillomavirus）III期临床试验——该试验原本基于符合方案集估算疫苗效力。我们重点关注两种处理并发事件的策略：假设策略与主层策略（principal stratum strategies）。本文阐述了这两种效应量的解读方式、估算方法，以及相关可识别性假设的明确表述。最后，我们借助该HPV试验的研究结果，就疫苗效力研究中实施ICH E9(R1)附录的通用考量要点展开探讨。