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

Abstract

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.

KEYWORDS:

• Active-controlled trial
• Compliance
• Generalizability
• HIV prevention
• Intention-to-treat effect
• Post-randomization event

Acknowledgments

We appreciate all the constructive feedback from the editor, associate editor, and two anonymous reviewers. We are grateful to the study participants, study staff and investigators on HPTN 084 and Partners PrEP who provided the data for this analysis.

Disclosure Statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

We acknowledge the funders and sponsors of the trials. We are grateful to the HPTN Manuscript Review Committee for helpful feedback. This work was supported by the U.S. National Institutes of Health grants R01AI177078 and UM1AI068617 (Fei Gao) and by the VIDD Faculty Initiative Award at the Fred Hutchinson Cancer Center (Fei Gao and Bo Zhang). Oliver Dukes received support from the Research Foundation Flanders (1222522N).