2023/04/07 by Qijia He, Fei Gao, He, Qijia +7 · 1 citation
Mathematics · Medicine · #Advanced Causal Inference Techniques #Alternative medicine #Clinical endpoint #Clinical trial #Double blind #Emtricitabine #FOS: Computer and information sciences #Family medicine #Human immunodeficiency virus (HIV) #Internal medicine #Medicine #Methodology (stat.ME) #Pharmacology #Placebo #Placebo-controlled study #Population #Randomized controlled trial #Statistical Methods and Bayesian Inference #Statistical Methods in Clinical Trials #Viral load
paper · pdf · doi:10.48550/arxiv.2304.03476
published in arXiv (Cornell University) (Cornell University)
openalex publication_date 2023/04/07 · openalex created_date 2023/04/11 · openalex updated_date 2026/07/28
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. \bzIn 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 versus 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).