  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 necessitates 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 comparison 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.
