Exploratory Analyses of Efficacy Data From Schizophrenia Trials in Support of New Drug Applications Submitted to the US Food and Drug Administration
ABSTRACT 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.
SourceAvailable from: Anncatherine M Downing[Show abstract] [Hide abstract]
ABSTRACT: Background Pomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia.Methods Enrolled adult patients (ages 18¿65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry. Patients (N¿=¿1013) were randomized 2:2:2:1 to treatment with placebo, LY40 mg twice daily (BID), LY80 mg BID, or risperidone (RIS) 2 mg BID for 6 weeks after a one-week blinded placebo lead-in. The primary outcome assessed change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score in an overall schizophrenia population and a predefined subpopulation which excluded non-Hispanic white patients with the A/A genotype at the HTR2A SNP rs7330461.ResultsNeither LY2140023 dose showed significant improvement compared to placebo on PANSS total in either population (1-sided p-value [significance level], overall: LY40, p¿=¿.154 [0.01]; LY80, p¿=¿.698 [0.01], subpopulation: LY40, p¿=¿.033 [0.0025]; LY80, p¿=¿.659 [0.0025], MMRM analysis). RIS statistically separated from placebo in both populations (p¿<¿.001 [0.05]). There were no statistically significant differences in the incidence of serious adverse events, and no seizures on LY2140023.ConclusionLY2140023 treatment did not demonstrate efficacy in populations studied. Overall, LY2140023 treatment was generally well tolerated with no new adverse safety findings compared to previous trials. Further understanding of the role of glutamate as a therapeutic target in schizophrenia is needed.Clinical trials registrationA Phase 2, Multicenter, Double-Blind, Placebo-Controlled Comparator Study of 2 Doses of LY2140023 Versus Placebo in Patients With DSM-IV-TR SchizophreniaClinicalTrials.gov identifier: NCT01086748.BMC Psychiatry 12/2014; 14(1):351. DOI:10.1186/s12888-014-0351-3 · 2.24 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: In the last half-century, randomized, placebo-controlled, double-blind design has become the norm for clinical trials and has created a windfall for the drug manufacturers. It has also created extra headaches for the statisticians measuring study outcomes. When compared with the placebo pill, there has been a steady decline in the effectiveness of new agents during last 25 years, whereas placebo responsiveness has increased in studies lasting less than 8 weeks. Placebo effect rates have risen approximately 7% per decade during the last 30 years, and more recent trials have shown an approximate 1.6-fold greater risk for placebo effects. There is a high, unpredictable, and heterogeneous responsiveness in many psychiatric conditions. True placebo effects can only be separated from non-specific treatment effects if a no-treatment control group is included; however, such trials are rarely performed in psychiatric conditions for ethical reasons. In clinical practice, the positive-care effect can increase the magnitude of placebo component of the pharmacodynamic response of the drug. It is difficult to apply a placebo condition to psychotherapy as the therapist knows what "brand" of therapy is given, and some of the essential ingredients (ie, hope, belief, expectations, healing ritual, and emotionally charged interaction with an expert) are also common to placebo condition. It has been shown that the therapeutic relationship itself can produce benefits in psychotherapy, independent of the specific techniques employed. Experimental conditions affect both the subjects and the researchers in different and unpredictable ways. Blinded, randomized, controlled trials may be impartial and truth-seeking, but they are still vulnerable to measurement and reporting bias, and some scholars are in favor of replacing them with well-designed observational studies because their results do not overestimate the magnitude of therapeutic effect as once thought.Psychiatric Annals 02/2014; 44(2):84-88. DOI:10.3928/00485713-20140205-06 · 0.71 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: High placebo response is widely believed to be one major reason why many psychiatric clinical trials fail to demonstrate drug efficacy. In order to alleviate this problem, research has developed several enrichment designs, including the parallel design with a placebo lead-in phase, the sequential parallel design, and a recently proposed two-way enriched design. While these designs have been evaluated and discussed individually, their effectiveness against each other has not been rigorously compared. The current study examines the various enrichment designs simultaneously. Building on their strengths, we introduce a new improved design named ‘sequential enriched design’ (SED) aimed at removing not only patients with high placebo response but also patients who do not respond to any treatment from the study. The SED begins with a double-blind placebo lead-in phase followed by a traditional parallel design in the first stage. Only patients who respond to the drug in the first stage are re-randomized to the drug or placebo at the second stage. We simulate data for a mixed population composed of four subgroups of patients who are predetermined as to whether they respond to drug or not as well as to placebo or not. By focusing on the target patients whose responses reflect the drug's efficacy, we evaluate the bias, mean squared error, and power for different designs. We demonstrate that the SED produces a less biased estimate for the target treatment effect and yields reasonably high power in general compared with the other designs. Copyright © 2014 John Wiley & Sons, Ltd.Statistics in Medicine 02/2014; 33(17). DOI:10.1002/sim.6116 · 2.04 Impact Factor