Schizophrenia clinical trials have exhibited a trend of increasing placebo responses and decreasing treatment effects over a 24-year period, particularly North American trials, according to study results published in Journal of Clinical Psychiatry.
Researchers noted that this trend is “of great concern,” and because of the current global nature of drug development, future trials should focus on trial conduct and reexamine design elements.
“Drug development has now become a global process, and multiregional trials for regulatory submission purposes have become the norm,” Mathangi Gopalakrishnan, MS, PhD, of the Center for Translational Medicine at University of Maryland School of Pharmacy, and colleagues wrote. “Global clinical trials may reduce time to drug approval, facilitating earlier patient access to new and innovative treatments. In future decades, therefore, continuing globalization of drug development is inevitable, and efforts to understand global and regional differences in placebo response and treatment effect are essential for efficient drug development.”
The researchers noted that this increasing placebo response and declining treatment effect began being reported for new drug applications during the “pre-2009 period” from 1991 through January 2009. They also referenced current exploratory analyses, which provide an update in the trends observed in treatment effect, placebo response and dropout rates for NDAs submitted to the FDA from February 2009 to 2015, or the “post-2009 period.”
In their analysis, Gopalakrishnan and colleagues collected clinical trial data from all acute schizophrenia trials submitted as part of NDAs during both periods. They included aggregate trial-level efficacy data from 4- to 8-week, fixed- and flexible-dosed, multicenter, multiregional, randomized, placebo-controlled trials among adult patients with schizophrenia. Pre-2009, there were 12 NDAs with 32 trials and 11,567 patients, and post-2009, there were three NDAs with 14 trials and 6,434 patients. The researchers summarized and compared baseline demographic and disease variables and scores on the Positive and Negative Syndrome Scale (PANSS) for the two time periods. Mean change from baseline to endpoint in total PANSS score obtained by last-observation-carried-forward analysis served as the primary efficacy measure. Investigators also explored regional differences in treatment effect and placebo response for the two time periods based on dropout rates, patient characteristics and sample size.
Results showed trials were mostly multiregional during the post-2009 period (71%) compared with the pre-2009 period (34%).
The post-2009 period had an overall trial success rate of 57% vs. 78% during the pre-2009 period. The researchers compared the two periods and found that the mean placebo response, defined as change from baseline in PANSS score, increased from 6.4 to 10.5, and the mean treatment effect, defined as drug response-placebo response, declined from
8.6 to 5.8. They observed substantial differences especially in North American trials, in which placebo response increased from 4.3 pre-2009 to 8.5 post-2009. Moreover, treatment effect decreased from 9 in the pre-2009 period to 3.4 in the post-2009 period. The difference in placebo response in the pre- and post-2009 periods was 10 and 11.3, respectively. Treatment effect pre- and post-2009 was 8.1 and 6.4, respectively, in multiregional trials for the two time periods, and the researchers considered this effect minimal. In both time periods, baseline disease severity remained similar, with PANSS scores ranging between 85 and 100. Irrespective of region and time period, trials with higher mean baseline PANSS scores tended to show higher treatment effect. Post-2009 dropout rates were higher (55%) in North American trials than in multiregional trials (33%), comparable with the pre-2009 trend.
“Overall, our updated analyses using post-2009 trials have demonstrated similar findings — increasing placebo response and diminishing treatment effect — to those for the pre-2009 trials,” the researchers wrote. “With more pharmaceutical sponsors embracing multiregional clinical trials for regulatory submissions, trial design and conduct that incorporates mechanisms to minimize placebo response need to be carefully considered to increase the efficiency of drug development in schizophrenia.” – by Joe Gramigna
Disclosures: The authors report no relevant financial disclosures.