Association of End Point Definition and Randomized Clinical Trial Duration in Clinical Trials of Schizophrenia Medications

Abstract

Facilitating the development of safe and effective medications for schizophrenia is a public health imperative. To evaluate the association of shortening randomized clinical trial (RCT) duration with the modification of the Positive and Negative Syndrome Scale (PANSS) for the design of RCTs of medications for schizophrenia and to offer perspective on an alternative regulatory pathway to the historically accepted trial duration and response assessment. A database was created consisting of clinical trial data from 32 placebo-controlled RCTs of 8 atypical antipsychotic drugs approved by the US Food and Drug Administration (FDA) between January 1, 2001, and December 31, 2015. The database included information on total and individual PANSS item ratings, demographic characteristics, disposition, and adverse events (AEs). All clinical trials submitted to 8 new drug applications of atypical antipsychotic drugs were selected. Quality control checks were performed to ensure that the collected data were consistent with the reported results of each trial. Data were collected from March 15, 2015, to September 30, 2015. Data analysis was conducted from October 1, 2015, to June 20, 2016. The following analyses were performed: (1) longitudinal assessment of mean change from baseline in total PANSS score, (2) correlation analyses between change from baseline in total PANSS score at week 6 and earlier time points, (3) concordance analyses of outcomes across trials between week 6 and earlier time points using total PANSS and modified PANSS, and (4) analyses of time course of treatment-emergent AEs. The final database contained data from 14 219 participants enrolled in 32 drug trials; 9805 of 14 219 participants (69.0%) were male and were either white (7183 [50.5%]) or black (4346 [30.6%]) individuals. The mean (SD) age during treatment was 38.9 (10.9) years, and the mean (SD) age at schizophrenia diagnosis was 25 (8.5) years. Statistically significant separation between treatment response and placebo response was observed after 1 week of treatment. The overall concordance rate across treatment groups steadily increased from week 1 to week 4 (68.0% for week 1, 74.0% for week 2, 83.0% for week 3, and 93.0% for week 4). Trends in AE occurrence were evident by week 1 and percentage of AEs were similar across weeks 3, 4, and 6. The overall concordance rate between change from baseline in the modified PANSS score and change from baseline in the total PANSS score was 93.0% (80 of 86 treatment groups) at week 4 and 97.7% (84 of 86 treatment groups) at week 6. Shortening the trial duration to 4 weeks increased the required sample size to 502 participants. Using the modified PANSS as the end point, the sample size for a 4-week trial was 402 participants and 296 participants for a 6-week trial. Findings from this analysis suggest that there is the potential to streamline the design of schizophrenia drug clinical trials. Trial sponsors may consider incorporating these strategies and are encouraged to consult with the FDA early in the drug development process.