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

Randomized 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 randomized clinical trials and 2) to analyze variations in the meaning and subtype classification of the term "active placebo" in pharmacological research publications.

In a scoping review, we searched 10 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 analyzed variations in its meaning as well as principles for classifying active placebo controls into subtypes.

We included 15 studies addressing active placebo development, mostly randomized trials. The studies collectively 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, for example, a nontherapeutic control with perceptible effects (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.

We propose a framework of five phases to describe the development process of active placebo control interventions in pharmacological randomized clinical trials, and we provide a conceptual clarification of the term "active placebo". These may inspire trialists when developing and reporting an active placebo control intervention and provides context for readers of trial reports and researchers conducting systematic reviews.

Randomized trials are used to investigate the effects of drugs in a fair and unbiased manner. The drugs are often compared against a similarly looking placebo control so that trial participants and personnel can be blinded. This means that they do not know if the tablet or injection given is the drug or the placebo. For drugs with clear side effects, some of the participants may later guess that they were given the drug and not the placebo. This is called unblinding. For example, some drugs for depression and pain may cause dry mouth or sedation that is readily felt. Unblinding may lead to overstating the benefits of the drug. Active placebo control groups are a possible way to prevent this, by having added one or more ingredients that have some of the same side effects as the drug. For example, atropine causes dry mouth similarly to older antidepressants. Despite their potential, few trials use active placebo controls, and the trial publications rarely describe how the active placebo was selected or developed. They may not even call it active placebo, and at the same time, other research papers may use the term "active placebo" but in a different meaning. In this study, we wanted to look at studies that described the development of active placebos. We found 15 such studies. Many of the studies investigated active placebo controls for psychedelic drugs, such as psilocybin. The studies rarely described how to find and select possible active placebos, but rather how an actual active placebo was evaluated afterwards, for example, whether participants could guess if they were given the drug or the placebo. We also analyzed meanings of the word "active placebo" in research papers. Some researchers meant the same as us, while others used the word when comparing a drug to another therapeutically active drug. In total, we found 15 distinct meanings of the term. Finally, we suggested different subtypes of active placebo controls, for example, whether the active placebo contained another ingredient or a low dose of the drug not suspected to be therapeutic.