Active placebo control interventions in pharmacological trials: a scoping review of the development process and a terminological analysis

OBJECTIVES: Randomised trials with active placebo control groups rarely report details about the development process of the active placebo control intervention, and the terminology is inconsistent. We therefore wanted 1) to review studies on the development process of active placebo control interventions for pharmacological randomised clinical trials, and 2) to analyse variations in the meaning and subtype classification of the term "active placebo" in pharmacological research publications. STUDY DESIGN AND SETTING: In a scoping review, we searched ten bibliographic databases and identified studies addressing the development process of active placebo control interventions. We conducted a qualitative content analysis of quotes about the development process. In a terminological analysis, we identified publications using the term "active placebo" and analysed variations in its meaning as well as principles for classifying active placebo controls into subtypes. RESULTS: We included 15 studies addressing active placebo development, mostly randomised trials. The studies covered five phases of the development process: 1) specification of criteria for a satisfactory active placebo control intervention, 2) identification of candidates, 3) selection of a specific active placebo, 4) dose finding, and 5) evaluation of the active placebo. The studies typically addressed evaluation and less frequently the other four phases. Meanings of the term "active placebo" varied, e.g., a control mimicking perceptible effects of an experimental drug without being therapeutic (our core definition), a therapeutically active control, or a placebo control with unintended therapeutic effects. We suggested a classification scheme of four subtypes of active placebo controls based on content and matching quality. CONCLUSION: We propose a framework of five phases to describe the development process of active placebo control interventions in pharmacological randomised clinical trials, and we provide a conceptual clarification of the term "active placebo". This may inspire trialists in development and reporting of an active placebo control intervention and provides context for readers of trial reports and researchers conducting systematic reviews.