PMID- 32609294 OWN - NLM STAT- MEDLINE DCOM- 20210212 LR - 20210702 IS - 2168-6238 (Electronic) IS - 2168-622X (Print) IS - 2168-622X (Linking) VI - 77 IP - 10 DP - 2020 Oct 1 TI - Association of End Point Definition and Randomized Clinical Trial Duration in Clinical Trials of Schizophrenia Medications. PG - 1064-1071 LID - 10.1001/jamapsychiatry.2020.1596 [doi] AB - IMPORTANCE: Facilitating the development of safe and effective medications for schizophrenia is a public health imperative. OBJECTIVES: 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. DATA SOURCES: 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). STUDY SELECTION: All clinical trials submitted to 8 new drug applications of atypical antipsychotic drugs were selected. DATA EXTRACTION AND SYNTHESIS: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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. FAU - Younis, Islam R AU - Younis IR AD - Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. FAU - Gopalakrishnan, Mathangi AU - Gopalakrishnan M AD - Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. AD - Center for Translational Medicine, University of Maryland, Baltimore. FAU - Mathis, Mitchell AU - Mathis M AD - Division of Psychiatry Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. FAU - Mehta, Mehul AU - Mehta M AD - Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. FAU - Uppoor, Ramana AU - Uppoor R AD - Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. FAU - Zhu, Hao AU - Zhu H AD - Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. FAU - Farchione, Tiffany AU - Farchione T AD - Division of Psychiatry Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. LA - eng PT - Journal Article PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - JAMA Psychiatry JT - JAMA psychiatry JID - 101589550 RN - 0 (Antipsychotic Agents) SB - IM CIN - JAMA Psychiatry. 2020 Oct 1;77(10):999-1000. PMID: 32609302 MH - Adult MH - Aged MH - Antipsychotic Agents/adverse effects/*therapeutic use MH - Cause of Death MH - Cohort Studies MH - Cost of Illness MH - Depressive Disorder/drug therapy/mortality/psychology MH - Duration of Therapy MH - *Endpoint Determination MH - Female MH - Humans MH - Male MH - Middle Aged MH - *Randomized Controlled Trials as Topic MH - Risk Factors MH - Schizophrenia/*drug therapy/mortality MH - *Schizophrenic Psychology PMC - PMC7330825 COIS- Conflict of Interest Disclosures: Drs Younis and Mathis contributed to this work while employees of the US Food and Drug Administration. Dr Younis reported receiving personal fees from Astellas Pharma outside the submitted work. Dr Mathis reported receiving personal fees from Allergan outside the submitted work. No other disclosures were reported. EDAT- 2020/07/02 06:00 MHDA- 2021/02/13 06:00 PMCR- 2021/07/01 CRDT- 2020/07/02 06:00 PHST- 2020/07/02 06:00 [pubmed] PHST- 2021/02/13 06:00 [medline] PHST- 2020/07/02 06:00 [entrez] PHST- 2021/07/01 00:00 [pmc-release] AID - 2767296 [pii] AID - yoi200035 [pii] AID - 10.1001/jamapsychiatry.2020.1596 [doi] PST - ppublish SO - JAMA Psychiatry. 2020 Oct 1;77(10):1064-1071. doi: 10.1001/jamapsychiatry.2020.1596.