Association of study design features and treatment effects in trials of chronic medical conditions: a meta-epidemiological study

Abstract

ObjectivesTo evaluate the association of study design features and treatment effects in randomised controlled trials (RCTs) evaluating therapies for individuals with chronic medical conditions.DesignMeta-epidemiological study.SettingRCTs from meta-analyses published in the 10 general medical journals with the highest impact factor published between 1 January 2007 and 10 June 2019 and evaluated a drug, procedure or device treatment of chronic medical conditions.Main outcome measuresThe association between trial design features and the effect size, reporting a ratio of ORs (ROR) and 95% confidence interval (CI).ResultsWe included 1098 trials from 86 meta-analyses. The most common outcome in the trials was mortality (52%), followed by disease progression (16%) and adverse events (12%). Lack of blinding of patients and study personnel was associated with a larger treatment effect (ROR 1.12; 95% CI 1.00 to 1.25). There was no statistically significant association with random sequence generation, allocation concealment, blinding of outcome assessors, incomplete outcome data, whether trials were stopped early, study funding, type of interventions or with type of outcomes (objective vs subjective).ConclusionThe meta-epidemiological study did not demonstrate a clear pattern of association between risk of bias indicators and treatment effects in RCTs in chronic medical conditions. The unpredictability of the direction of bias emphasises the need to make every attempt to adhere to blinding, allocation concealment and reduce attrition bias.Trial registration numberNot applicable.

Commercial funding and estimated intervention effects in randomized clinical trials: Systematic review of meta‐epidemiological studies

“…We included eight meta-epidemiological studies in our review (Figure 1, Supplementary file B). [10][11][12][13][14][15][16][17] The eight meta-epidemiological studies were published between 2013 and 2021 (Table 1) and investigated a total of 264 meta-analyses (range 12-86) and 2725 trials (range 82-1098). All eight meta-epidemiological studies investigated meta-analyses and trials from specific clinical areas (e.g., critical care and neonatal care).…”

“…Commercially funded trials frequently have surrogate primary outcomes 28 . In contrast, four of the included meta‐epidemiological studies (154 meta‐analyses of 1613 trials) mainly included meta‐analyses with mortality outcomes 10,12–14 . The trial outcomes included in the meta‐analyses may therefore in some cases be secondary outcomes not used for framing trial conclusions.…”

“…In our pooled analysis, the seven included metaepidemiological studies had different approaches to handling trials with unreported funding source. In one meta-epidemiological study, trials with unreported funding source were excluded from the analysis, 12 in another meta-epidemiological study these trials were grouped with noncommercially funded trials, 11 and in the remaining five meta-epidemiological studies these trials were grouped with trials with commercial funding 13 or a high risk of commercial funder influence. [14][15][16][17] Finally, in line with previous systematic reviews of meta-epidemiological studies we did not formally assess risk of bias in the included studies.…”

“…28 In contrast, four of the included meta-epidemiological studies (154 meta-analyses of 1613 trials) mainly included meta-analyses with mortality outcomes. 10,[12][13][14] The trial outcomes included in the metaanalyses may therefore in some cases be secondary outcomes not used for framing trial conclusions. Still, if we interpret our findings to indicate a less dramatic association between commercial funding and trial results than that of the Cochrane Review, this would be in accordance with the comparatively lower risk of confounding in meta-epidemiological studies.…”

Different meta-analysis methods can change judgements about imprecision of effect estimates: a meta-epidemiological study

“…The detailed literature search and method of study selection and data extraction were reported in a previous study 12. The same database has been used in a previous publication, while the current manuscript intends to address different objectives 13 14. With different inclusion/exclusion criteria and updated literature search till 10 June 2019, different datasets were included in the analyses.…”