Generalizing the Intention-to-Treat Effect of an Active Control from Historical Placebo-Controlled Trials: A Case Study of the Efficacy of Daily Oral TDF/FTC in the HPTN 084 Study

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 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 vs. 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). Supplementary materials for this article are available online, including a standardized description of the materials available for reproducing the work.

在诸多临床场景中，活性对照试验设计（如非劣效性或优效性设计）常被用于将试验药物与活性对照（如美国食品药品监督管理局（Food and Drug Administration，FDA）批准的标准疗法）进行对比。其中一个典型案例为近期一项Ⅲ期疗效试验——艾滋病预防试验网络（HIV Prevention Trials Network，HPTN）084研究（HPTN 084），该研究在7个非洲国家的异性恋女性人群中，对比了长效卡博特格拉韦（一种新型艾滋病病毒暴露前预防（Pre-Exposure Prophylaxis，PrEP）制剂）与FDA批准的每日口服富马酸替诺福韦二吡呋酯+恩曲他滨（Tenofovir Disoproxil Fumarate plus Emtricitabine，TDF/FTC）的疗效。此类活性对照试验（如HPTN 084）在解读研究结果时存在一项关键难点：试验未设置安慰剂对照组，因此活性对照（进而试验药物）与安慰剂相比的疗效，仅能通过整合其他数据源进行推断。本文基于潜在结果（Potential Outcomes，PO）框架，利用相关历史安慰剂对照试验数据，针对活性对照的意向治疗（Intention-to-Treat，ITT）效应展开统计推断研究。本文着重阐明依从性与未测混杂的作用，详细讨论识别假设与两类推断模式（点识别与部分识别），提出满足点识别条件的识别假设下的估计量，并梳理了放宽识别假设所需的敏感性分析方法。我们利用一项早期开展的每日口服TDF/FTC安慰剂对照Ⅲ期临床试验（伴侣PrEP试验（Partners PrEP））的数据，将本文提出的框架应用于HPTN 084中每日口服TDF/FTC与安慰剂相比的ITT效应估计。本文的补充材料可在线获取，其中包含可用于复现研究成果的标准化材料说明。