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In many clinical settings, an active-controlled trial design (e.g., anon-inferiority or superiority design) is often used to compare an experimentalmedicine to an active control (e.g., an FDA-approved, standard therapy). Oneprominent example is a recent phase 3 efficacy trial, HIV Prevention TrialsNetwork Study 084 (HPTN 084), comparing long-acting cabotegravir, a new HIVpre-exposure prophylaxis (PrEP) agent, to the FDA-approved daily oral tenofovirdisoproxil fumarate plus emtricitabine (TDF/FTC) in a population ofheterosexual women in 7 African countries. One key complication of interpretingstudy results in an active-controlled trial like HPTN 084 is that the placeboarm is not present and the efficacy of the active control (and hence theexperimental drug) compared to the placebo can only be inferred by leveragingother data sources. \bz{In this article, we study statistical inference for theintention-to-treat (ITT) effect of the active control using relevant historicalplacebo-controlled trials data under the potential outcomes (PO) framework}. Wehighlight the role of adherence and unmeasured confounding, discuss in detailidentification assumptions and two modes of inference (point versus partialidentification), propose estimators under identification assumptions permittingpoint identification, and lay out sensitivity analyses needed to relaxidentification assumptions. We applied our framework to estimating theintention-to-treat effect of daily oral TDF/FTC versus placebo in HPTN 084using data from an earlier Phase 3, placebo-controlled trial of daily oralTDF/FTC (Partners PrEP).

Generalizing the intention-to-treat effect of an active control against  placebo from historical placebo-controlled trials to an active-controlled  trial: A case study of the efficacy of daily oral TDF/FTC in the HPTN 084  study