Recent developments in improving signal detection and reducing placebo response in psychiatric clinical trials.

Recent (2007-2010) empirical and theoretical literature on associations of trial design features with signal detection and placebo response were investigated, along with data and analytic considerations. Trials with greater percentages of patients randomized to placebo had larger average drug-placebo differences in two comprehensive meta-analyses (MDD and Schizophrenia). Excluding patients with large responses during double-blind placebo lead-ins resulted in small increases in drug-placebo differences. Core factor subscales of the HAMD yielded larger drug-placebo differences than the HAMD total score. Direct likelihood-based (MMRM) and similar analyses provided better control of false positive and false negative results than LOCF and BOCF. Theoretical considerations suggested that the number of sites and number of countries can influence power, depending on the correlation structure in the data and on how sites and countries are chosen. Use of centralized ratings reduced placebo response and improved drug-placebo differences. However, the number of comparisons was too small to draw conclusions. Use of patient ratings and reducing the number of study visits reduced placebo response, but their effects on signal detection were unclear. Practical experience with novel designs such as the sequential parallel approach hold promise for improvements in signal detection. Given the complexities of signal detection and placebo response, no single strategy is likely to fully solve the problem and combinations of approaches may be most useful. Utilizing appropriate analytic techniques and randomizing an adequate fraction of patients to placebo are perhaps the most broadly applicable approaches.