Number Of Clinical Trial Study Sites Impacts Observed Treatment Effect Size: An Analysis Of Randomized Controlled Trials Of Opioids For Chronic Pain
Received 16 January 2019
Accepted for publication 22 October 2019
Published 20 November 2019 Volume 2019:12 Pages 3161—3165
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Katherine Hanlon
Diana S Meske,1 Ben J Vaughn,2 Ernest A Kopecky,3 Nathaniel Katz4,5
1Collegium Pharmaceutical, Inc, Stoughton, MA, USA; 2Rho, Chapel Hill, NC, USA; 3Teva Branded Pharmaceutical Products R&D, Inc, Frazer, PA, USA; 4WCG Analgesic Solutions, Wayland, MA, USA; 5Department of Anesthesia, Tufts University School of Medicine, Boston, MA, USA
Correspondence: Diana S Meske
Collegium Pharmaceutical, Inc, Stoughton, MA, USA
Tel +1 517 712 3087
Background: Many aspects of study conduct impact the observed effect size of treatment. Data were utilized from a recently published meta-analysis of randomized, double-blind, placebo-controlled, clinical trials performed for the United States Food and Drug Administration (FDA) approval of full mu-agonist opioids for the treatment of chronic pain.
Methods: The number of study sites in each clinical trial and standardized effect size (SES) were extracted and computed. Standardized effect size was plotted against number of sites, and a two-piece linear model was fit to the plot. Ten studies were included.
Results: The SES decreased linearly by 0.13 units for every 10 sites (p=0.037), from 0.75 to 0.36, until an inflection point of 60 sites, after which SES did not decline further. The total number of subjects required for 90% power to discriminate drug from placebo increased from 78 to 336 subjects going from 30 to 60 sites.
Conclusion: Results showed that the number of sites was a source of loss of assay sensitivity in clinical trials, which may contribute to the well-known problem of failure to successfully transition from Phase 2 to Phase 3 clinical development. Potential solutions include minimizing the number of sites, more rigorous and validated training, central statistical monitoring with rapid correction of performance issues, and more rigorous subject and site selection.
Keywords: randomized controlled trials, opioids, chronic pain, clinical trials, effect size, study site number
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