Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland.
Center for Translational Medicine, University of Maryland, Baltimore.
JAMA Psychiatry. 2020 Oct 1;77(10):1064-1071. doi: 10.1001/jamapsychiatry.2020.1596.
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.
促进安全有效的精神分裂症药物的开发是公共卫生的当务之急。
评估缩短随机临床试验（RCT）持续时间与阳性和阴性综合征量表（PANSS）的修改之间的关联，以设计精神分裂症药物的 RCT，并为接受历史上认可的试验持续时间和反应评估的替代监管途径提供视角。
创建了一个数据库，其中包括 2001 年 1 月 1 日至 2015 年 12 月 31 日期间美国食品和药物管理局（FDA）批准的 8 种非典型抗精神病药物的 32 项安慰剂对照 RCT 的临床试验数据。该数据库包括总和个体 PANSS 项目评分、人口统计学特征、处置和不良事件（AE）的信息。
选择了提交给 8 种新型抗精神病药物的所有临床试验。
进行了质量控制检查，以确保收集的数据与每项试验报告的结果一致。数据于 2015 年 3 月 15 日至 2015 年 9 月 30 日收集。数据分析于 2015 年 10 月 1 日至 2016 年 6 月 20 日进行。
进行了以下分析：（1）从基线到第 6 周总 PANSS 评分的纵向评估，（2）第 6 周与更早时间点之间总 PANSS 评分变化的相关性分析，（3）使用总 PANSS 和修改后的 PANSS 在第 6 周和更早时间点进行跨试验结果的一致性分析，（4）治疗出现的 AE 的时间过程分析。
最终数据库包含了来自 32 项药物试验的 14219 名参与者的数据；14219 名参与者中有 9805 名（69.0%）为男性，他们要么是白人（7183 名[50.5%]），要么是黑人（4346 名[30.6%]）。治疗期间的平均（SD）年龄为 38.9（10.9）岁，精神分裂症诊断时的平均（SD）年龄为 25（8.5）岁。在治疗后 1 周观察到治疗反应与安慰剂反应之间的显著分离。治疗组之间的总体一致性率从第 1 周稳步增加到第 4 周（第 1 周为 68.0%，第 2 周为 74.0%，第 3 周为 83.0%，第 4 周为 93.0%）。第 1 周时 AE 发生的趋势明显，第 3、4 和 6 周时的 AE 百分比相似。在第 4 周时，修改后的 PANSS 评分与总 PANSS 评分的基线变化之间的总体一致性率为 93.0%（86 个治疗组中的 80 个），在第 6 周时为 97.7%（86 个治疗组中的 84 个）。将试验持续时间缩短至 4 周会增加 502 名参与者所需的样本量。使用修改后的 PANSS 作为终点，4 周试验的样本量为 402 名参与者，6 周试验的样本量为 296 名参与者。
这项分析的结果表明，有可能简化精神分裂症药物临床试验的设计。试验赞助商可能会考虑采用这些策略，并鼓励他们在药物开发过程的早期与 FDA 进行咨询。
