Statistical Methods in Trials with Sequential Parallel Design for Trials with High Placebo Response

Strong placebo response has been problematic in central nervous system (CNS) clinical trials, leading to a reduced drug effect and thus resulting in decrease in probability of finding an effective drug. The ideal situation is to have comparative data collected only from subjects who are placebo non-responders. Stringent trial procedures together with enrichment of placebo non-responders are some of the ways to decrease placebo response in clinical trials. 

Fava et al. (2003) proposed a SPD where subjects are only randomized during Period 1. Accordingly, some placebo non-responders in Period 1 continue on placebo in Period 2 and others switch to drug in Period 2; and subjects who are treated with drug in Period 1 would continue to receive drug in Period 2. Treatment sequences for all subjects are all pre-specified prior to trial start; and data from Period 2 for subjects who are on drug in both periods are for safety evaluations only.