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:从历史性的安慰剂对照试验到活性对照试验,推广活性对照的意向治疗效应
翻译后的摘要:在许多临床环境中,常常采用活性对照试验设计(例如非劣效或优越性设计)比较实验性药物和活性对照(例如FDA批准的标准疗法)。一个显著的例子是最近的第3期疗效试验,HIV Prevention Trials Network Study 084(HPTN 084),在7个非洲国家的异性恋女性中比较长效卡博替格韦新的HIV预防性预防(PREP)药物和FDA批准的每日口服替诺福韦/恩替卡韦(TDF/FTC)。在像HPTN 084这样的活性对照试验中解释研究结果的一个关键复杂问题是,安慰剂组没有出现,并且只能利用其他数据源来推断与安慰剂相比,活性对照(以及实验药物)的有效性。在本文中,我们提出了一个严谨的因果推断框架,利用相关历史安慰剂对照试验数据推断活性对照的意向治疗(ITT)效应。我们强调依从性和未被测量的混淆的作用,详细讨论识别假设和两种推理模式(点推理与部分识别),提出了在允许点识别的识别假设下的估计器,并阐述了需要进行的灵敏度分析以放松识别假设。我们运用我们的框架,利用早期Phase 3,每日口服TDF/FTC的安慰剂对照试验数据(Partners PrEP),估计每日口服TDF/FTC相对于安慰剂在HPTN 084中的意向治疗效应。