Abstract

Recent successes of antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV infection have raised questions whether further placebo controlled trials of new HIVprevention technologies are ethically justifiable. A trial with active agent(s) in the comparator group can be designed either as a superiority or non-inferiority trial. In a non-inferiority trial the hypothesis tested is that the intervention is not inferior to, by a predefined clinically relevant amount, or at least as effective as, the comparator. Noninferiority trials pose challenges in data interpretation. Firstly it is possible to show equivalence of two non-effective interventions. If the active comparator intervention is ineffective, the new intervention would be shown to be noninferior to this inactive intervention, while neither intervention is superior to placebo or no intervention. The second challenge is that any effect that dilutes the true efficacy of an intervention in a trial, such as non-adherence, loss to follow-up or protocol violations, makes it easier for the two interventions to be declared equivalent. Nondifferential low adherence is unlikely to lead to the conclusion that an inferior intervention is non-inferior. However, differential adherence between study arms, which is more likely in non-blinded trials, is likely to bias the results and lead to incorrect conclusions. Investigators conducting non-inferiority trials will have to pay special attention to supporting, measuring and maintaining high adherence. The goal in future noninferiority trials should be to maintain similar levels of high adherence in all study arms, but at a minimum to reduce the likelihood of differential adherence across study arms. 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2012, 26:000‐000

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