In many clinical settings, an active-controlled trial design (e.g., a non-inferiority or superiority design) is often used to compare an experimental medicine to an active control (e.g., an FDA-approved, standard therapy). One prominent example is a recent phase 3 efficacy trial, HIV Prevention Trials Network Study 084 (HPTN 084), comparing long-acting cabotegravir, a new HIV pre-exposure prophylaxis (PrEP) agent, to the FDA-approved daily oral tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) in a population of heterosexual women in 7 African countries. One key complication of interpreting study results in an active-controlled trial like HPTN 084 is that the placebo arm is not present, and the efficacy of the active control (and hence the experimental drug) compared to the placebo can only be inferred by leveraging other data sources. In this article, we propose a rigorous causal inference framework to infer the intention-to-treat (ITT) effect of the active control using relevant historical placebo-controlled trial data of the active control. We highlight the role of adherence and unmeasured confounding, discuss in detail identification assumptions and two modes of inference (point versus partial identification), propose estimators under identification assumptions permitting point identification, and lay out sensitivity analyses needed to relax identification assumptions. We applied our framework to estimating the intention-to-treat effect of daily oral TDF/FTC versus placebo in HPTN 084 using data from an earlier Phase 3, placebo-controlled trial of daily oral TDF/FTC (Partners PrEP).

翻译：在许多临床场景中，主动对照试验设计（如非劣效性或优效性设计）常用于比较试验药物与主动对照药物（如FDA批准的标准疗法）。一个典型案例是近期开展的3期疗效试验——HIV预防试验网络研究084（HPTN 084），该试验在7个非洲国家的异性恋女性人群中，比较新型HIV暴露前预防（PrEP）药物长效卡博特韦与FDA批准的每日口服替诺福韦酯/恩曲他滨（TDF/FTC）的疗效。解读HPTN 084这类主动对照试验结果的关键难点在于缺乏安慰剂组，主动对照药物（进而试验药物）相对于安慰剂的疗效只能通过其他数据源推断。本文提出一个严格的因果推断框架，利用主动对照药物的相关历史安慰剂对照试验数据，推断其意向性治疗（ITT）效应。我们重点阐述依从性与未测量混杂的作用，详细讨论识别假设与两种推断模式（点识别与部分识别），提出在允许点识别的识别假设下的估计量，并设计用于放宽识别假设的敏感性分析方法。我们利用早期每日口服TDF/FTC的3期安慰剂对照试验（Partners PrEP）数据，将该框架应用于估计HPTN 084中每日口服TDF/FTC相对于安慰剂的意向性治疗效果。