Exploratory Analyses of Efficacy Data From Schizophrenia Trials in Support of New Drug Applications Submitted to the US Food and Drug Administration

Division of Psychiatry Products, Office of Drug Evaluation I, Office of New Drugs, Food and Drug Administration, Silver Spring, MD, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 05/2012; 73(6):856-64. DOI: 10.4088/JCP.11r07539
Source: PubMed


There has been concern about a high rate of placebo response and a decline in treatment effect over time in schizophrenia trials as well as the implications of increasing conduct of such trials outside North America. This report explores differences in efficacy data over an 18-year period from randomized placebo-controlled trials submitted in support of new drug applications (NDAs) for the treatment of schizophrenia and differences in results between trials conducted in North America and elsewhere.
Clinical trial data that were submitted to the US Food and Drug Administration (FDA) as part of NDAs for the indication of schizophrenia between 1991 and 2009.
Efficacy data were compiled from 32 clinical trials with 11,567 evaluable patients with schizophrenia. Data from completed, randomized, multicenter, double-blind, placebo-controlled, 4- to 8-week clinical trials in adult patients diagnosed with schizophrenia according to DSM-III or DSM-IV criteria were included.
Baseline demographic and disease characteristics, including mean Positive and Negative Syndrome Scale (PANSS) total scores, were summarized and compared between North American and multiregional trials. Mean change from baseline to endpoint in PANSS total scores was utilized as the primary outcome of interest. We explored differences in treatment effect and success rate of these trials based on when and where the studies were conducted, sample size, trial duration, and baseline patient characteristics.
Twenty-one of the 32 trials were conducted solely in North America, and 11 were carried out in multiple regions. Of those 11 multiregional trials, 2 were conducted exclusively in foreign countries. Although the observed responses (change from baseline) in placebo and drug-treated groups in multiregional trials tended to be larger than in North American trials, the treatment effects (drug-placebo difference) were -9 and -8 PANSS units for North American and multiregional trials, respectively. When time of trial conduct was taken into account, an increasing placebo response and a diminishing treatment effect over time were observed in North American trials from -10.8 PANSS units for the first period (1991-1998) to -6.0 PANSS units for the later period (1999-2008). The overall trial success rate over the almost 2 decades was 78%, declining slightly in trials conducted after 1999, the time period during which multiregional trials were first conducted (74% for 1999-2008 vs 85% for 1991-1998), despite increasing sample sizes in the later period. The mean baseline PANSS total score was in the range of 87-100 for most of these trials. Trials in patients with higher mean baseline PANSS total scores tended to show larger treatment effects than those in patients with lower scores. The mean body weight and body mass index (BMI) were higher in patients in North American trials and North America-predominant multiregional trials compared to those in foreign-predominant multiregional trials (mean body weights of 85 kg and 81 kg vs 72 kg, and BMIs of 29 and 27 vs 25, respectively). Treatment effects decreased as body weights increased, especially in North American trials. In foreign-predominant multiregional trials, there were higher proportions of women than in North American trials and North America-predominant multiregional trials (40% vs 22% and 27%, respectively) and a relatively larger proportion of Asians (21% vs 1% and 8%, respectively).
A high and increasing placebo response and a declining treatment effect are of great concern in schizophrenia trials conducted in North America. In this era of global clinical trials, close attention is needed to the design and conduct of these trials.

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    • "In a recent meta-analysis, the all-cause discontinuation parallels the efficacy in that the most effective drugs have the lowest discontinuation rates (Leucht et al., 2013). In randomized controlled trials in patients suffering schizophrenia, more participants withdraw because of inefficacy than because of side effects (Khin et al., 2012). "
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    ABSTRACT: Background: Few studies have investigated the relationship between the use of different generations of antipsychotics and mortality with contradictory results. The aim of this study is to compare mortality among patients suffering schizophrenia taking different generations of antipsychotics in a nationwide population-based cohort study in Taiwan. Methods: A total of 812 patients suffering newly diagnosed schizophrenia under monotherapy of second generation antipsychotics (SGAs) comprised the group of cases. The matched controls were under monotherapy of first generation antipsychotics (FGAs). Each case was matched individually with their initial antipsychotics prescription calendar year and month, gender, and age. Cox regression analyses were applied to estimate survival time, adjusting for gender, age, residence, insurance premium, Charlson comorbidity index, hospital admission days, and hospital admission times. An analysis including the number of antipsychotic prescriptions, a proxy indicator of adherence, into the fully adjusted model to reveal the effect of adherence on survival of patients served as a sensitivity analysis. Results: Subjects receiving SGAs had lower admission times and inpatient days, more antipsychotic prescriptions, and longer follow-up time than FGAs. Compared with the FGAs group, the adjusted hazard ratio of mortality was 0.58 (95% confidence interval =0.34-0.96, p=.034) for SGAs group. After controlling for the number of antipsychotic prescriptions, the difference in mortality between antipsychotic generations was non-significant. Conclusions: The results of this study suggest that SGAs were better than FGAs in mortality among patients suffering schizophrenia. The difference in mortality can be explained by the better medication adherence of SGAs.
    Schizophrenia Research 10/2015; DOI:10.1016/j.schres.2015.10.005 · 3.92 Impact Factor
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    • "Our use of 10-point differences might thus not seem to represent clinically important differences. However, as we noted previously, we report results for ten point reductions because they represent the average placebo-corrected response to antipsychotic treatment from 32 registration trials submitted to the FDA (Khin et al., 2012), and, as we have Table 3 Three-month adjusted average total (unconditional) number of psychiatric hospitalizations and number of nights in the hospital for psychiatric hospitalizations. "
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    Schizophrenia Research 06/2015; 166(1-3). DOI:10.1016/j.schres.2015.05.021 · 3.92 Impact Factor
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    • "Similar differences were previously reported by Khin et al. (2012). However there are contradicting results regarding the impact of race on efficacy of pharmacological treatment of schizophrenia (Teo et al., 2013; Bersani et al., 2011; Bigos et al., 2011; Stauffer et al., 2010; Ciliberto et al., 2005). "
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    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2014; 24(7). DOI:10.1016/j.euroneuro.2014.02.006 · 4.37 Impact Factor
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