Placebo-free designs for evaluating new mental health treatments: the use of adaptive treatment strategies.

The dominant pre-marketing clinical trial in psychopharmacology is a non-equivalence design that randomizes patients to one of three treatments: an accepted standard, the innovation (new drug), or placebo, with the main efficacy comparison being innovation vs placebo. The reasons behind the choice of placebo control in new drug development include anticipated small effect size for active-controlled comparisons and the sufficiency of demonstrated treatment effect (new drug vs placebo) for regulatory approval. These reasons have led to great reliance on placebo control in drug evaluation studies, despite the ethical controversy over the use of placebo when there are known effective standard treatments. While the use of placebo controls has been widely debated, a less considered aspect of the usual placebo-controlled non-equivalence design is the disparity between the decisions that it supports and those that pervade clinical practice. We propose an alternative approach that randomizes one group of patients to an adaptive treatment strategy that exemplifies the adaptive nature of clinical decision-making in the treatment of ongoing mental health disorders. The basic idea is to compare the adaptive strategy, which uses a patient's outcomes to date to determine when to switch from an initial treatment (e.g. an accepted standard) to an alternative (e.g. the new) treatment, to fixed trials of either treatment option. We state the conditions under which the adaptive treatment RCT is attractive to implement and the requirements for doing so. 2004 John Wiley & Sons, Ltd.