将活性对照相对于安慰剂的意向治疗效应从历史安慰剂对照试验推广到活性对照试验：HPTN 084 研究中每日口服 TDF/FTC 疗效的案例研究
Generalizing the intention-to-treat effect of an active control against placebo from historical placebo-controlled trials to an active-controlled trial: A case study of the efficacy of daily oral TDF/FTC in the HPTN 084 study
AI总结：
本文提出在潜在结果框架下，利用历史安慰剂对照试验数据推断活性对照的意向治疗效应，并通过 HPTN 084 案例估计 TDF/FTC 的疗效，强调依从性、混杂因素及敏感性分析。
摘要：
在许多临床场景中，活性对照试验设计（如非劣效性或优效性设计）常用于将试验药物与活性对照（如 FDA 批准的标准疗法）进行比较。一个突出的例子是最近的 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，将新型 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）进行比较。解读像 HPTN 084 这样的活性对照试验结果的一个关键复杂因素是，没有安慰剂组，活性对照（以及试验药物）相对于安慰剂的疗效只能通过利用其他数据源来推断。在本文中，我们在潜在结果（PO）框架下，研究利用相关历史安慰剂对照试验数据对活性对照的意向治疗（ITT）效应进行统计推断。我们强调了依从性和未测量的混杂因素的作用，详细讨论了识别假设和两种推断模式（点识别与部分识别），提出了在允许点识别的识别假设下的估计量，并提出了放松识别假设所需的敏感性分析。我们将我们的框架应用于使用早期 3 期、安慰剂对照的每日口服 TDF/FTC 试验（Partners PrEP）数据，估计 HPTN 084 中每日口服 TDF/FTC 相对于安慰剂的意向治疗效应。
英文摘要：
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. \bz{In this article, we study statistical inference for the intention-to-treat (ITT) effect of the active control using relevant historical placebo-controlled trials data under the potential outcomes (PO) framework}. 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).
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