FDA offers strategies to streamline schizophrenia drug trials

Regulatory NewsRegulatory News
| 11 November 2020 | By Mary Ellen Schneider 

Shortening the length of clinical trials and simplifying the symptom scale are two strategies that could help make schizophrenia drug trials less costly and more efficient, according to study findings from scientists at the U.S. Food and Drug Administration (FDA).
Schizophrenia drug developers face several obstacles when evaluating treatments, including high patient dropout rates in trials, modest treatment effects, high placebo response, and uncertainty about which endpoints capture the drug’s impact on disease symptoms.  “Given these obstacles, it may not be surprising that several larger pharmaceutical companies appear to have scaled back their developmental efforts in regard to schizophrenia, despite its toll on patients and their families,” the FDA wrote in a recent Regulatory Science Impact Story.
In a study published in JAMA Psychiatry, researchers from the FDA’s Center for Drug Evaluation and Research and the University of Maryland in Baltimore evaluated the impact of study design changes using clinical trial data from 32 placebo-controlled randomized controlled trials of atypical antipsychotic drugs approved by the FDA.
Standard clinical trials of schizophrenia treatments typically last 6 weeks and patients are assessed using the Positive and Negative Syndrome Scale (PANSS), which measures 30 individual symptoms. The researchers set out to evaluate shortening these trials and reducing the number of symptoms measured by the PANSS. When looking at shortening trials, they examined the concordance of treatment effects at each week of the trial with subsequent treatment outcomes and the course of treatment-related adverse effects. When looking at simplification of the PANSS, they examined which of the symptoms was strongly correlated with the overall PANSS in pooled subjects.
The study showed that by week 4, treatment response was 88% of that seen at week 6. Additionally, 93% of treatment groups produced similar outcomes at week 4, compared with week 6. Four weeks also appeared sufficient for detecting adverse events. Trends in the occurrence of adverse events were evident by the first week and appeared similar over the duration of the 6-week trials for akathisia, extrapyramidal symptoms, agitation, and tachycardia. The total number of adverse events, however, was higher in week 6 than in weeks 3 or 4, the researchers reported.
“The researchers reasoned further that the shorter trial (i.e., lasting four weeks) could also reduce patient dropout, an important source of bias in drug trials that can make interpretation more difficult, because patients completing a longer trial may differ from non-completers in important respects; this potential advantage would likely offset any minor decrease in statistical power that might arise from the shortened (i.e., four-week) trial,” the FDA wrote.
Researchers also tested a simplified version of the PANSS – with 19 items instead of 30 – and found that it had similar results to the full version of the instrument. The overall concordance rate between the two versions of the PANSS was 93% at week 4 and 97.7% at week 6. “The modified measure also decreased overall variability in patient response, presumably because noninformative items had been removed, and this would have the effect of reducing the trial size needed to see a statistically significant effect of a drug,” the FDA wrote.
Taken together, the two trial design changes could help accelerate drug develop, agency scientists concluded. They encouraged drug developers to consult the FDA early when planning clinical trials.
The study was supported in part by the Oak Ridge Institute for Science and Education Research Participation Program at the FDA’s Center for Drug Evaluation and Research.
JAMA Psychiatry


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Tags: clinical, FDA, trials, US

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