The earliest time point where a treatment outcome could be observed was 1 week after initiation of medication compared to placebo.
Islam R. Younis, PhD
As researchers struggle to develop new treatments for schizophrenia, 1 group is suggesting a reduced approach to clinical trials could yield more treatments.
A team, led by Islam R. Younis, PhD, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), examined whether a shortened version of the Positive and Negative Syndrome Scale (PANSS) and shorter randomized clinical trial duration either in isolation or in combination, can facilitate the development of new schizophrenia drugs.
The analysis included 32 randomized, placebo-controlled clinical trials of 8 atypical antipsychotic drugs approved by the FDA between 2001-2015 involving 14,219 patients. The investigators created a database that included information on total and individual PANSS item rating, demographic characteristics, disposition, and adverse events.
The mean age during treatment was 38.9 and the mean age at schizophrenia diagnosis was 25 years old.
The investigators performed quality control checks to ensure the collected data was consistent with the reported results of each trial.
The team also performed longitudinal assessments of the mean change from baseline in total PANSS score, correlation analyses between change from baseline in total PANSS score at week 6 and earlier time points, concordance analyses of outcome across trials between week 6 and earlier time points using total PANSS and modified PANSS, and analyses of time course of treatment—emergent adverse events.
The investigators found the overall concordance rate between the change from baseline scores in the modified Positive and Negative Syndrome Scale and changes from baseline scores in the total Positive and Negative Syndrome Scale was 93.0% at week 4 and 97.7% at week 6.
The overall concordance rate across treatment groups rose from week 1-4 (68.0% for week 1, 74.0% for week 2, 83.0% for week 3, and 93.0% for week 4).
The earliest time point where a treatment outcome could be observed was 1 week after initiation of medication compared to placebo. Trends in adverse events were evident by week 1 and the percentage of events were similar across weeks 3, 4, and 6.
By shortening the trial duration to 4 weeks, the investigators suggested increasing the required sample size to 502 participants.
By using the modified PANSS at the end point, the sample size for a 4-week trial was 402 participants and 296 participants for a 6-week trial.
Overall, the study suggests a streamlined approach to designing schizophrenia drug clinical trials. The researchers also suggest trial sponsors consider incorporating the strategies and are encouraged to consult with the FDA early in the drug development process.
“Results of this analysis suggest that the combination of the modified version of the Positive and Negative Syndrome Scale and a shortened drug trial duration may provide an alternative regulatory pathway to the development of new drugs for schizophrenia,” the authors wrote.
There is currently a need for safe and effective schizophrenia treatments. Treatment in response to antipsychotic agents is highly variable, making drug development challenging.
There are other issues also making it difficult to make new drugs for schizophrenia, including an incomplete understanding of the underlying disease biology and challenges in clinical trial design and conduct.
About 25% of schizophrenia drug trials do not show the therapeutic benefit of the drug or the treatment effect diminished over time.
The study, “Association of End Point Definition and Randomized Clinical Trial Duration in Clinical Trials of Schizophrenia Medications,” was published online in JAMA Psychiatry.