What Is Causing the Reduced Drug-Placebo Difference in Recent Schizophrenia Clinical Trials and What Can be Done About It?

Abstract

On September 18, 2007, a collaborative session between the International Society for CNS Clinical Trials and Methodology and the International Society for CNS Drug Development was held in Brussels, Belgium. Both groups, with membership from industry, academia, and governmental and nongovernmental agencies, have been formed to address scientific, clinical, regulatory, and methodological challenges in the development of central nervous system therapeutic agents. The focus of this joint session was the apparent diminution of drug-placebo differences in recent multicenter trials of antipsychotic medications for schizophrenia. To characterize the nature of the problem, some presenters reported data from several recent trials that indicated higher rates of placebo response and lower rates of drug response (even to previously established, comparator drugs), when compared with earlier trials. As a means to identify the possible causes of the problem, discussions covered a range of methodological factors such as participant characteristics, trial designs, site characteristics, clinical setting (inpatient vs outpatient), inclusion/exclusion criteria, and diagnostic specificity. Finally, possible solutions were discussed, such as improving precision of participant selection criteria, improving assessment instruments and/or assessment methodology to increase reliability of outcome measures, innovative methods to encourage greater subject adherence and investigator involvement, improved rater training and accountability metrics at clinical sites to increase quality assurance, and advanced methods of pharmacokinetic/pharmacodynamic modeling to optimize dosing prior to initiating large phase 3 trials. The session closed with a roundtable discussion and recommendations for data sharing to further explore potential causes and viable solutions to be applied in future trials.

Onset and persistence of efficacy by symptom domain with long-acting injectable paliperidone palmitate in patients with schizophrenia

“…The complex nature and increasing magnitude of this phenomenon in the field of antipsychotic medicine [64,65] have resulted in an increasing number of failed trials [64,65]. It appears that methodological factors may in part explain differences in placebo response [64,65]. However, placebo responses of a similar magnitude and pattern to those observed in the trials examined here have been demonstrated in similarly designed PP studies in comparable, ethnically diverse patient populations [66,67].…”

“…The complex nature and increasing magnitude of this phenomenon in the field of antipsychotic medicine [64,65] have resulted in an increasing number of failed trials [64,65]. It appears that methodological factors may in part explain differences in placebo response [64,65].…”

Site-independent confirmation of subject selection for CNS trials: ‘dual’ review using audio-digital recordings

“…Central nervous system (CNS) drug development has been challenged by the frequent failure to achieve signal detection in many clinical trials [1][2][3][4][5][6][7]. Numerous factors affect trial outcomes including the effectiveness of the candidate drug, study design, study completion, and trial execution [6][7][8].…”

“…Numerous factors affect trial outcomes including the effectiveness of the candidate drug, study design, study completion, and trial execution [6][7][8]. Two important trial execution factors are subject selection and ratings precision [6][7][8][9][10][11][12].…”

“…Potential study candidates may be unfamiliar with study procedures and arbitrarily endorse symptoms or exaggerate severity in order to gain entry into the clinical trial. Misplaced site-based incentives (e.g., financial, humanitarian, and competitive interests) may also influence subject selection because clinical trial sites are generally incentivized to enroll rather than reject subjects [6,7,[16][17][18]. Further, there may be concurrent, confounding factors or comorbid conditions that might adversely affect the reliability of symptom severity ratings during the course of the clinical trial [11].…”