Decline in Treatment Effect, Increase in Placebo Response in Clinical Trials of Schizophrenia

Over the past decade, concerns have grown during the increased placebo response and decreased treatment effect observed in clinical trials for schizophrenia. These concerns were confirmed in a survey of clinical trial data from New Drug Applications (NDAs) submitted to the US Food and Drug Administration (FDA) from 1991 to 2009.² Of even greater concern, this trend has continued in recent years, according to 2009 to 2015 NDA data published in the Journal of Clinical Psychology. In both studies, the trend was most pronounced in clinical trials conducted in North America.

The pre-2009 and post-2009 studies used randomized, multicenter, double-blind, placebo-controlled clinical trials conducted in adults diagnosed with schizophrenia. The researchers noticed a shift from the majority of clinical trials being conducted exclusively in North America to the majority being conducted multiregionally. The pre-2009 study used NDAs for 12 antipsychotics drugs tested in 21 North American trials and 11 multiregional trials (N=11,567). NDAs for 3 drugs were submitted to the FDA from 2009 to 2015. In the post-2009 study, the majority of the trials were conducted internationally, with 4 North American trials and 10 multiregional trials (N=6434). The researchers quantified mean placebo response as mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total scores, which constituted the primary outcome of interest.

The results of the current study confirmed a continuation of the trend identified in the pre-2009 study for elevated placebo response (increase of −6.4 to −10.5 mean change in PANSS score) and reduced treatment effect (decrease of −8.6 to −5.8 mean score change). In the North American trials, mean placebo response changed from −4.3 in the pre-2009 study to −8.5 in the post-2009 study. In the multiregional studies, the change in mean placebo response was −10.0 to −11.3 from pre-2009 to post-2009 studies.

Changes in mean drug response remained stable from the pre-2009 to post 2009 studies in the North American trials (−13.1 to −13.0) and the multiregional trials (−18.0 to −18.0). Mean treatment effect, calculated as mean drug response minus mean placebo response, changed between the pre-2009 study and the post-2009 study, going from −9.0 to −3.4 in the North American studies and −8.1 to −6.4 in the multiregional trials.

Notably, the clinical trial success rate dropped from 78% to 57% during the 2 periods, even as sample sizes generally increased by nearly 30 participants and baseline disease severity remained the same. The researchers suggested that the higher placebo response in North American trials may be prompting sponsors to exclusively use multiregional trials for drug approval to improve success rates.

Variations in healthcare standards could lead to greater heterogeneity in drug and placebo responses, and thus dropout patterns. The researchers called for the reexamination of study design for future trials, as well as close observation of trial conduct.

In an accompanying commentary, Thomas P. Laughren, MD, from the Massachusetts General Hospital Clinical Trials Network and Institute in Boston, concluded that the post-2009 study severely understates the effect of reduced treatment effect in schizophrenia trials.³ Dr Laughren indicated that the study may be limited by the failure to stratify trials by program and noted that examining regional differences could contribute additional insight. He also expressed concern that pharmaceutical companies may abandon North American clinical trials altogether.³

Dr Laughren called for the creation of a large shared patient-level database from all placebo-controlled clinical trials, although he warned that pharmaceutical companies would be unlikely to fund or contribute data. “The one thing that is clear is that this is a serious problem that is going to have a negative impact on schizophrenia research and ultimately on public health. We should all be concerned about that,” Dr Laughren concluded.³

References

1. Gopalakrishnan M, Zhu H, Farchione TR, et al. The trend of increasing placebo response and decreasing treatment effect in schizophrenia trials continues: an update from the US Food and Drug Administration. J Clin Psychiatry. 2020;81(2):19r12960.

2. Khin NA, Chen YF, Yang Y, Yang P, Laughren TP. Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration. J Clin Psychiatry. 2012;73(6):856–864.

3. Laughren TP. A Growing crisis in schizophrenia drug development: failing signal detection at north american and other clinical trial sites. J Clin Psychiatry. 2020;81(2):19com13110.