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      Number Of Clinical Trial Study Sites Impacts Observed Treatment Effect Size: An Analysis Of Randomized Controlled Trials Of Opioids For Chronic Pain

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          Abstract

          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.

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          Most cited references 18

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          Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials.

          The US Food and Drug Administration (FDA) has issued warnings that use of antidepressant medications poses a small but significantly increased risk of suicidal ideation/suicide attempt for children and adolescents. To assess the efficacy and risk of reported suicidal ideation/suicide attempt of antidepressants for treatment of pediatric major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and non-OCD anxiety disorders. PubMed (1988 to July 2006), relevant US and British regulatory agency reports, published abstracts of important scientific meetings (1998-2006), clinical trial registries, and information from authors. Studies were published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone, venlafaxine, and mirtazapine) in participants younger than 19 years with MDD, OCD, or non-OCD anxiety disorders. Information was extracted on study characteristics, efficacy outcomes, and spontaneously reported suicidal ideation/suicide attempt. Twenty-seven trials of pediatric MDD (n = 15), OCD (n = 6), and non-OCD anxiety disorders (n = 6) were selected, and risk differences for response and for suicidal ideation/suicide attempt estimated by random-effects methods. Pooled risk differences in rates of primary study-defined measures of responder status significantly favored antidepressants for MDD (11.0%; [95% confidence interval {CI}, 7.1% to 14.9%]), OCD (19.8% [95% CI, 13.0% to 26.6%), and non-OCD anxiety disorders (37.1% [22.5% to 51.7%]), corresponding to a number needed to treat (NNT) of 10 (95% CI, 7 to 15), 6 (4 to 8), and 3 (2 to 5), respectively. While there was increased risk difference of suicidal ideation/suicide attempt across all trials and indications for drug vs placebo (0.7%; 95% CI, 0.1% to 1.3%) (number needed to harm, 143 [95% CI, 77 to 1000]), the pooled risk differences within each indication were not statistically significant: 0.9% (95% CI, -0.1% to 1.9%) for MDD, 0.5% (-1.2% to 2.2%) for OCD, and 0.7% (-0.4% to 1.8%) for non-OCD anxiety disorders. There were no completed suicides. Age-stratified analyses showed that for children younger than 12 years with MDD, only fluoxetine showed benefit over placebo. In MDD trials, efficacy was moderated by age, duration of depression, and number of sites in the treatment trial. Relative to placebo, antidepressants are efficacious for pediatric MDD, OCD, and non-OCD anxiety disorders, although the effects are strongest in non-OCD anxiety disorders, intermediate in OCD, and more modest in MDD. Benefits of antidepressants appear to be much greater than risks from suicidal ideation/suicide attempt across indications, although comparison of benefit to risk varies as a function of indication, age, chronicity, and study conditions.
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            Once-daily OROS hydromorphone ER compared with placebo in opioid-tolerant patients with chronic low back pain.

             P M Hale,  A Khan,  M Kutch (2010)
            This multicenter, double-blind, placebo-controlled study using a randomized withdrawal design evaluated the efficacy and safety of once-daily OROS hydromorphone ER in the treatment of opioid-tolerant patients with chronic moderate-to-severe low back pain (LBP).
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              Bias caused by sampling error in meta-analysis with small sample sizes

               Lifeng Lin (2018)
              Background Meta-analyses frequently include studies with small sample sizes. Researchers usually fail to account for sampling error in the reported within-study variances; they model the observed study-specific effect sizes with the within-study variances and treat these sample variances as if they were the true variances. However, this sampling error may be influential when sample sizes are small. This article illustrates that the sampling error may lead to substantial bias in meta-analysis results. Methods We conducted extensive simulation studies to assess the bias caused by sampling error. Meta-analyses with continuous and binary outcomes were simulated with various ranges of sample size and extents of heterogeneity. We evaluated the bias and the confidence interval coverage for five commonly-used effect sizes (i.e., the mean difference, standardized mean difference, odds ratio, risk ratio, and risk difference). Results Sampling error did not cause noticeable bias when the effect size was the mean difference, but the standardized mean difference, odds ratio, risk ratio, and risk difference suffered from this bias to different extents. The bias in the estimated overall odds ratio and risk ratio was noticeable even when each individual study had more than 50 samples under some settings. Also, Hedges’ g, which is a bias-corrected estimate of the standardized mean difference within studies, might lead to larger bias than Cohen’s d in meta-analysis results. Conclusions Cautions are needed to perform meta-analyses with small sample sizes. The reported within-study variances may not be simply treated as the true variances, and their sampling error should be fully considered in such meta-analyses.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                JPR
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                20 November 2019
                2019
                : 12
                : 3161-3165
                Affiliations
                [1 ]Collegium Pharmaceutical, Inc , Stoughton, MA, USA
                [2 ]Rho , Chapel Hill, NC, USA
                [3 ]Teva Branded Pharmaceutical Products R&D, Inc , Frazer, PA, USA
                [4 ]WCG Analgesic Solutions , Wayland, MA, USA
                [5 ]Department of Anesthesia, Tufts University School of Medicine , Boston, MA, USA
                Author notes
                Correspondence: Diana S Meske Collegium Pharmaceutical, Inc , Stoughton, MA, USATel +1 517 712 3087 Email dsmeske@gmail.com
                Article
                201751
                10.2147/JPR.S201751
                6875508
                © 2019 Meske et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 2, Tables: 1, References: 28, Pages: 5
                Categories
                Original Research

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