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Humanized NOG Mice for Intravaginal HIV Exposure and Treatment of HIV Infection
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Active-Controlled Trial Design for HIV Prevention Trials With a Counterfactual Placebo

Fei Gao1, Holly Janes1, Susan Buchbinder2

  • 1Biostatistics, Bioinformatics and Epidemiology Program, Fred Hutchinson Cancer Center, Seattle, Washington, USA.

Statistics in Medicine
|March 5, 2025
PubMed

Insights

New trials for HIV pre-exposure prophylaxis (PrEP) use a novel statistical method comparing active treatments to a theoretical placebo. This approach enhances ethical evaluations and can reduce participant numbers in prevention studies.

Area of Science:

  • Clinical Trials
  • HIV Prevention
  • Biostatistics

Background:

  • Antiretroviral drugs as pre-exposure prophylaxis (PrEP) represent a significant advancement in HIV prevention.
  • Ethical considerations complicate placebo-controlled trials for new PrEP agents when effective options exist.
  • Innovative trial designs are needed to evaluate new PrEP agents ethically and effectively.

Purpose of the Study:

  • To introduce a novel statistical framework for the regulatory approval of new PrEP agents.
  • To design active-controlled trials incorporating a counterfactual placebo estimate for assessing absolute efficacy.
  • To provide a robust methodology for evaluating new PrEP agents amidst ethical and practical challenges.

Main Methods:

  • Development of a statistical framework for regulatory approval assuming a consistent counterfactual placebo estimate.
  • Design of active-controlled trials to assess the absolute efficacy of new PrEP agents relative to active controls.
  • Proposal of a two-step hypothesis testing procedure and methods to mitigate biases in non-randomized comparisons.

Main Results:

  • Demonstration of significantly reduced sample sizes compared to traditional non-inferiority trials.
  • Exploration of various scenarios with different active control effectiveness and counterfactual placebo estimates.
  • Validation of the proposed design's robustness in evaluating new PrEP agents.

Conclusions:

  • The proposed active-controlled trial design with counterfactual placebo estimates offers a viable and ethical approach for evaluating new PrEP agents.
  • This methodology addresses the limitations of traditional placebo-controlled and non-inferiority trials in the context of existing effective PrEP.
  • The framework contributes to the advancement of HIV prevention trial methodology, emphasizing adaptability and statistical innovation.
Keywords:
HIV preventionactive‐controlled trialscounterfactual placebopre‐exposure prophylaxisrelative absolute efficacysample size calculation

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