  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. \bz{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 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).
