Can placebo controls reduce the number of nonresponders in clinical trials? A power-analytic perspective

There is ongoing debate regarding the ethics of placebo-controlled clinical trials when a moderately effective standard treatment exists. One aspect of the debate--the number of nonresponders--tends to be overlooked. A larger between-group effect size is expected in placebo-controlled trials than in trials with an active comparator. For that reason, substantially fewer subjects need to be enrolled in placebo-controlled trials; consequently, there tend to be far fewer nonresponders in placebo-controlled trials.

This analysis was undertaken to illustrate that the use of placebo as a control can reduce the number of subjects who are unnecessarily exposed to delayed treatment.

Statistical power analyses were used to estimate the sample size required to detect various population treatment differences and the resulting number of nonresponders for 2-tailed chi-square tests.

Empiric evidence of the phenomenon is provided for a wide range of rates of response to placebo, investigational, and comparator treatments. For example, 24 subjects (ie, 12 per group) are needed to detect differences between placebo (10% response rate) and an investigational drug (70% response); 15 of these would not respond. In contrast, if the investigational drug (70% response) is initially compared with a standard therapy (60% response), 752 subjects would be required, 263 of whom would not respond.

This paper shows empirically that placebo controls can reduce the number of nonresponders in a randomized controlled trial. The number of subjects who are exposed to unproven, albeit promising, investigational drugs should be kept to a minimum until placebo-controlled trials support their use.