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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 Jun; 73(6):856-64.JC

Abstract

OBJECTIVE

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.

DATA SOURCES

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.

STUDY SELECTION

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.

DATA EXTRACTION

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.

RESULTS

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).

CONCLUSIONS

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.

Authors+Show Affiliations

Division of Psychiatry Products, Office of Drug Evaluation I, Office of New Drugs, Food and Drug Administration, Silver Spring, MD, USA. ni.khin@fda.hhs.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

22687813

Citation

Khin, Ni A., et al. "Exploratory Analyses of Efficacy Data From Schizophrenia Trials in Support of New Drug Applications Submitted to the US Food and Drug Administration." The Journal of Clinical Psychiatry, vol. 73, no. 6, 2012, pp. 856-64.
Khin NA, Chen YF, Yang Y, et al. 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):856-64.
Khin, N. A., Chen, Y. F., Yang, Y., Yang, P., & Laughren, T. P. (2012). Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration. The Journal of Clinical Psychiatry, 73(6), 856-64. https://doi.org/10.4088/JCP.11r07539
Khin NA, et al. 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):856-64. PubMed PMID: 22687813.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration. AU - Khin,Ni A, AU - Chen,Yeh-Fong, AU - Yang,Yang, AU - Yang,Peiling, AU - Laughren,Thomas P, Y1 - 2012/05/15/ PY - 2011/11/15/received PY - 2012/02/15/accepted PY - 2012/6/13/entrez PY - 2012/6/13/pubmed PY - 2012/9/27/medline SP - 856 EP - 64 JF - The Journal of clinical psychiatry JO - J Clin Psychiatry VL - 73 IS - 6 N2 - OBJECTIVE: 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. DATA SOURCES: 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. STUDY SELECTION: 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. DATA EXTRACTION: 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. RESULTS: 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). CONCLUSIONS: 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. SN - 1555-2101 UR - https://www.unboundmedicine.com/medline/citation/22687813/Exploratory_analyses_of_efficacy_data_from_schizophrenia_trials_in_support_of_new_drug_applications_submitted_to_the_US_Food_and_Drug_Administration_ L2 - http://www.psychiatrist.com/jcp/article/pages/2012/v73n06/v73n0620.aspx DB - PRIME DP - Unbound Medicine ER -