To establish a pharmacological therapy for clinical use, clinical trials are performed in humans that are typically classified into four phases (Friedman et al., 2015): First, in pre-clinical studies pharmacokinetic, toxicity, and efficacy are studied in non-human subjects. In phase I trials, so-called first in human-studies, safety and tolerability of a drug are investigated in healthy volunteers. Phase II trials aim to determine whether a drug can have any efficacy. More specifically, phase IIA trials typically aim at demonstrating clinical efficacy or biological activity (“proof of concept” studies), whereas phase IIB trials are dose-finding studies, performed to reveal optimum dose at which a drug has biological activity with minimal side-effects. Phase III trials investigate effectiveness and the clinical value of a new intervention in a larger patient group. In a randomized controlled trial the effect size of a new intervention is compared with state of the art treatment, if available. Finally, a phase IV trial is a postmarketing surveillance trial, performed e.g., to study whether any rare or long-term adverse effects occur within a much larger patient population and over longer time periods. Individual trials may actually comprise more than only one phase. For instance, there are combined phase I/II or phase II/III trials. Accordingly, given the different purpose of clinical trials, one may also distinguish between early phase studies and late phase trials (Friedman et al., 2015—see above). In principle, this 4-phase pattern also holds for medical technology, e.g., neuromodulation technologies.
Apart from investigating safety and tolerability, it is key to study whether a new therapeutic intervention is superior to pre-existing therapeutic options (Friedman et al., 2015). To this end, one has to take into account non-specific, placebo effects. A placebo effect is a psychobiological phenomenon that causes symptom relief after delivery of inert substances or other types of sham treatment, such as sham surgery or sham stimulation, in combination with verbal instructions suggesting clinical benefit (Price et al., 2008; Benedetti et al., 2011). Note, in clinical trials the terms placebo and sham are basically synonymous, while a placebo typically refers to an inactive substance used in pharmacological trials, whereas a sham stimulation/operation refers to a stimulation/operation without specific therapeutic effect (Price et al., 2008; Benedetti et al., 2011; Friedman et al., 2015). Real placebo effects go beyond spontaneous remission due to the natural history of a disease, regression to the mean induced by selection biases or expectation-related biases of patients and doctors (Benedetti, 2008a).