Active-Controlled Trial Design for HIV Prevention Trials with a Counterfactual Placebo

TL;DR

This paper proposes a novel active-controlled trial design using a counterfactual placebo estimate to ethically and efficiently evaluate new HIV PrEP agents, reducing sample sizes and addressing biases.

Contribution

It introduces a new statistical framework for HIV prevention trials that incorporates counterfactual placebo estimates to assess absolute efficacy of new PrEP agents.

Findings

Significantly reduces required sample sizes compared to traditional trials.

Provides a robust method for evaluating new PrEP agents ethically.

Addresses biases in non-randomized comparisons to counterfactuals.

Abstract

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.