Gao Fei, Janes Holly, Buchbinder Susan, Donnell Deborah
Biostatistics, Bioinformatics and Epidemiology Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
Stat Med. 2025 Mar 15;44(6):e70022. doi: 10.1002/sim.70022.
In the quest for enhanced HIV prevention methods, the advent of antiretroviral drugs as pre-exposure prophylaxis (PrEP) has marked a significant stride forward. However, the ethical challenges in conducting placebo-controlled trials for new PrEP agents against a backdrop of highly effective existing PrEP options necessitate innovative approaches. This manuscript delves into the design and implementation of active-controlled trials that incorporate a counterfactual placebo estimate-a theoretical estimate of what HIV incidence would have been without effective prevention. We introduce a novel statistical framework for regulatory approval of new PrEP agents, predicated on the assumption of an available and consistent counterfactual placebo estimate. Our approach aims to assess the absolute efficacy (i.e., against placebo) of the new PrEP agent relative to the absolute efficacy of the active control. We propose a two-step procedure for hypothesis testing and further develop an approach that addresses potential biases inherent in non-randomized comparisons to counterfactual placebos. By exploring different scenarios with moderately and highly effective active controls and counterfactual placebo estimates from various sources, we demonstrate how our design can significantly reduce sample sizes compared to traditional non-inferiority trials and offer a robust framework for evaluating new PrEP agents. This work contributes to the methodological repertoire for HIV prevention trials and underscores the importance of adaptability in the face of ethical and practical challenges.
在寻求增强艾滋病病毒（HIV）预防方法的过程中，抗逆转录病毒药物作为暴露前预防（PrEP）的出现标志着向前迈出了重要一步。然而，在已有高效PrEP方案的背景下，针对新的PrEP药物进行安慰剂对照试验面临伦理挑战，这就需要创新方法。本文深入探讨了纳入反事实安慰剂估计（即对没有有效预防措施时HIV发病率的理论估计）的活性对照试验的设计与实施。我们引入了一种用于新PrEP药物监管审批的新型统计框架，该框架基于可获得且一致的反事实安慰剂估计这一假设。我们的方法旨在评估新PrEP药物相对于活性对照的绝对疗效（即相对于安慰剂的疗效）。我们提出了一种用于假设检验的两步程序，并进一步开发了一种方法来解决与反事实安慰剂的非随机比较中固有的潜在偏差。通过探索使用中度和高度有效的活性对照以及来自各种来源的反事实安慰剂估计的不同场景，我们证明了与传统非劣效性试验相比，我们的设计如何能够显著减少样本量，并为评估新的PrEP药物提供一个稳健的框架。这项工作为HIV预防试验的方法库做出了贡献，并强调了在面对伦理和实际挑战时适应性的重要性。
