Strategies to minimize placebo effects in research investigations

Placebo-controlled trials are the research standard to evaluate new interventions for which there is no standard of care. While lessening performance and detection bias, such design provides a direct mode of comparison against the probed intervention. Still, using placebo arms may pose new challenges to the design, conduct and analysis of clinical trials. This is particularly relevant in circumstances of non-additivity between the therapeutic and the placebo effects, if the outcome of interest has floor or ceiling effects, or when the predicted effect size of the intervention is large and leads to small sample sizes. There are several possible strategies to mitigate the confounding effects of the placebo, each relevant to specific clinical trial designs. This chapter puts into context the new challenges created by the placebo effect, discusses possible ways around them, and explores the future of the field.