A three-stage clinical trial design for rare disorders

Many clinical trials of uncommon diseases are underpowered because of the d ifficulty of recruiting adequate numbers of subjects. We propose a clinical trial design with improved statistical power compared to the traditional r andomized trial for use in clinical trials of rare diseases. The three-stag e clinical trial design consists of an initial randomized placebo-controlle d stage, a randomized withdrawal stage for subjects who responded, and a th ird randomized stage for placebo non-responders who subsequently respond to treatment. Test level and power were assessed by computer-intensive exact calculations. The three-stage clinical trial design was found to be consist ently superior to the traditional randomized trial design in all cases exam ined, with sample sizes typically reduced by 20 per cent to 30 per cent whi le maintaining comparable power. When a treatment clearly superior to place bo was considered, our design reached a power of 75 per cent with a sample of 21 patients compared with the 52 needed to attain this power when only a randomized controlled trial was used. In situations where patient numbers are limited, a three-stage clinical trial design may be a more powerful des ign than the traditional randomized trial for detecting clinical benefits. Copyright (C) 2001 John Wiley & Sons, Ltd.