Until recently, the design and analysis of clinical trials to evaluate HIV prevention interventions was relatively straightforward. Participants would be randomised to receive the intervention of interest or to receive no intervention (placebo under the most robust design). The analysis would compare HIV incidence rates between the groups, yielding an estimate of the effectiveness – the proportionate reduction in incidence – achieved by the intervention. This model of experimental simplicity was ended with the discovery of the remarkable effectiveness of oral pre-exposure prophylaxis (PrEP) using TDF-FTC. This meant it became ethically unacceptable to include a no intervention group in most study populations. Current studies of novel PrEP agents have instead been designed as non-inferiority trials in which the experimental arm is compared with an active-control TDF-FTC arm. The challenges in analysing and interpreting such trials will be discussed, pointing out the need to collect additional contextual information. A different perspective is required for the evaluation of other prevention interventions, including vaccines. Here, the primary interest may be in estimating biological efficacy rather than a direct comparison with oral PrEP. Nevertheless, the ethical requirement to offer PrEP complicates trial design and interpretation, as well as potentially requiring much larger studies. This session will attempt to illuminate key, basic concepts, keeping statistical detail to a bare minimum.