Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Assessment of risk of bias among pediatric randomized controlled trials. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. Outcome reporting bias in randomized trials funded by the Canadian Institutes of Health Research. Selection bias in clinical trials. Randomised controlled trial of a theoretically grounded tailored intervention to diffuse evidence-based public health practice [ISRCTN23257060]. Publication bias and meta-analyses: a practical example. An outreach intervention to implement evidence based practice in residential care: a randomized controlled trial [ISRCTN67855475].
To explore whether reported methodologic quality affects estimated intervention effects in randomized trials and contributes to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses.
                Meta-analyses of randomized trials that included at least one large trial (>/=1000 participants) were included, regardless of the therapeutic area. Eligible meta-analyses were identified through electronic searches and bibliographies of relevant articles.
                Full-length randomized trials.
                Methodologic quality was assessed according to reported randomization, double blinding, and follow-up as separate components and by using the Jadad composite scale.
                Fourteen meta-analyses involving 190 randomized trials from eight therapeutic areas were included. Compared with large trials, intervention effects were exaggerated in small trials with inadequate allocation sequence generation (ratio of odds ratios, 0.46 [95% CI, 0.25 to 0.83]; P = 0.011), inadequate allocation concealment (ratio of odds ratios, 0.49 [CI, 0.27 to 0.86]; P = 0.014), and no double blinding (ratio of odds ratios, 0.52 [CI, 0.28 to 0.96]; P = 0.01). Large trials did not differ significantly from small trials with adequate generation of the allocation sequence, adequate allocation concealment, or adequate double blinding. No association was seen between reported follow-up and intervention effects. The Jadad scale provided no additional information because the scale and the quality components overlapped substantially.
                Inadequate generation of the allocation sequence, allocation concealment, and double blinding lead to exaggerated estimates of intervention benefit and may contribute to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses. To determine if inadequate approaches to randomized controlled trial design and execution are associated with evidence of bias in estimating treatment effects.
                An observational study in which we assessed the methodological quality of 250 controlled trials from 33 meta-analyses and then analyzed, using multiple logistic regression models, the associations between those assessments and estimated treatment effects.
                Meta-analyses from the Cochrane Pregnancy and Childbirth Database.
                The associations between estimates of treatment effects and inadequate allocation concealment, exclusions after randomization, and lack of double-blinding.
                Compared with trials in which authors reported adequately concealed treatment allocation, trials in which concealment was either inadequate or unclear (did not report or incompletely reported a concealment approach) yielded larger estimates of treatment effects (P < .001). Odds ratios were exaggerated by 41% for inadequately concealed trials and by 30% for unclearly concealed trials (adjusted for other aspects of quality). Trials in which participants had been excluded after randomization did not yield larger estimates of effects, but that lack of association may be due to incomplete reporting. Trials that were not double-blind also yielded larger estimates of effects (P = .01), with odds ratios being exaggerated by 17%.
                This study provides empirical evidence that inadequate methodological approaches in controlled trials, particularly those representing poor allocation concealment, are associated with bias. Readers of trial reports should be wary of these pitfalls, and investigators must improve their design, execution, and reporting of trials. The goal was to assess the risk of bias among pediatric, randomized, controlled trials (RCTs) reported in 8 high-impact journals.
                We searched PubMed for all pediatric RCTs reported between July 1, 2007, and June 30, 2008, in 8 journals with high impact factors. Using Cochrane Collaboration methods for risk assessment, we evaluated all reports for risk of bias according to domain (ie, randomized sequence generation, allocation concealment, masking, incomplete outcome data, selective outcome reporting, and other). We used multiple logistic regression to test for associations between the presence of a high risk of bias according to domain and funding source, intervention type, trial registration, and multicenter status.
                Industry-funded RCTs were more likely to show a high risk of bias for sequence generation, compared with government-funded RCTs (adjusted odds ratio [aOR]: 6.1 [95% confidence interval [CI]: 1.70- 21.89]), and behavioral/educational trials were more likely to show a high risk of bias for sequence generation (aOR: 2.8 [95% CI: 1.06-7.36]) and allocation concealment (aOR: 4.09 [95% CI: 1.69-9.90]), compared with drug trials. Registered trials were less likely to have a high risk of bias for sequence generation, compared with nonregistered trials (aOR: 0.33 [95% CI: 0.15-0.71]).
                Overall, we found a large proportion of pediatric RCT reports with a high risk of bias for sequence generation and allocation concealment. Factors associated with a high risk of bias included industry funding and assessment of behavioral/educational interventions, whereas trial registration was associated with a lower risk of bias. Selective reporting of outcomes within published studies based on the nature or direction of their results has been widely suspected, but direct evidence of such bias is currently limited to case reports.
                To study empirically the extent and nature of outcome reporting bias in a cohort of randomized trials.
                Cohort study using protocols and published reports of randomized trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg, Denmark, in 1994-1995. The number and characteristics of reported and unreported trial outcomes were recorded from protocols, journal articles, and a survey of trialists. An outcome was considered incompletely reported if insufficient data were presented in the published articles for meta-analysis. Odds ratios relating the completeness of outcome reporting to statistical significance were calculated for each trial and then pooled to provide an overall estimate of bias. Protocols and published articles were also compared to identify discrepancies in primary outcomes.
                Completeness of reporting of efficacy and harm outcomes and of statistically significant vs nonsignificant outcomes; consistency between primary outcomes defined in the most recent protocols and those defined in published articles.
                One hundred two trials with 122 published journal articles and 3736 outcomes were identified. Overall, 50% of efficacy and 65% of harm outcomes per trial were incompletely reported. Statistically significant outcomes had a higher odds of being fully reported compared with nonsignificant outcomes for both efficacy (pooled odds ratio, 2.4; 95% confidence interval [CI], 1.4-4.0) and harm (pooled odds ratio, 4.7; 95% CI, 1.8-12.0) data. In comparing published articles with protocols, 62% of trials had at least 1 primary outcome that was changed, introduced, or omitted. Eighty-six percent of survey responders (42/49) denied the existence of unreported outcomes despite clear evidence to the contrary.
                The reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with protocols. Published articles, as well as reviews that incorporate them, may therefore be unreliable and overestimate the benefits of an intervention. To ensure transparency, planned trials should be registered and protocols should be made publicly available prior to trial completion. The reporting of outcomes within published randomized trials has previously been shown to be incomplete, biased and inconsistent with study protocols. We sought to determine whether outcome reporting bias would be present in a cohort of government-funded trials subjected to rigorous peer review.
                We compared protocols for randomized trials approved for funding by the Canadian Institutes of Health Research (formerly the Medical Research Council of Canada) from 1990 to 1998 with subsequent reports of the trials identified in journal publications. Characteristics of reported and unreported outcomes were recorded from the protocols and publications. Incompletely reported outcomes were defined as those with insufficient data provided in publications for inclusion in meta-analyses. An overall odds ratio measuring the association between completeness of reporting and statistical significance was calculated stratified by trial. Finally, primary outcomes specified in trial protocols were compared with those reported in publications.
                We identified 48 trials with 68 publications and 1402 outcomes. The median number of participants per trial was 299, and 44% of the trials were published in general medical journals. A median of 31% (10th-90th percentile range 5%-67%) of outcomes measured to assess the efficacy of an intervention (efficacy outcomes) and 59% (0%-100%) of those measured to assess the harm of an intervention (harm outcomes) per trial were incompletely reported. Statistically significant efficacy outcomes had a higher odds than nonsignificant efficacy outcomes of being fully reported (odds ratio 2.7; 95% confidence interval 1.5-5.0). Primary outcomes differed between protocols and publications for 40% of the trials.
                Selective reporting of outcomes frequently occurs in publications of high-quality government-funded trials. Of 90 patients with intermediate or high-grade sarcoma eligible for a randomized trial of adjuvant doxorubicin (Adriamycin, Adria Laboratories, Columbus, Ohio), 48 were not entered: 24 (27%) by physician's choice and 24 refused randomization. Sixty-five percent of lower stage patients were randomized compared with 37% of those with higher stage (P = .02). Patients with extremity lesions were more frequently offered participation in the study (P = .07). Patients with lower stage lesions accepted randomization more readily than those with higher stage lesions (P = .01). As predicted by the higher stage and percentage of central lesions, the disease-free survival of nonrandomized patients was inferior to that of randomized patients (P = .15). Thus, patients at high risk appeared to avoid randomization and adjuvant doxorubicin in this trial, resulting in an inferior disease-free survival for the nonrandomized control group. Important questions generally require randomized trials that reliably determine relative treatment differences. If, however, the patients in a clinical trial are not representative of the entire patient population because of patient and physician selection biases, the generalizability of the results to the entire patient population may be compromised. For example, the prognosis of the general population cannot necessarily be inferred from the selected group in the study. In this study, the randomized and nonrandomized series yielded differing conclusions regarding treatment efficacy, even when an adjustment was made for known prognostic facts. Previous studies have shown that Norwegian public health physicians do not systematically and explicitly use scientific evidence in their practice. They work in an environment that does not encourage the integration of this information in decision-making. In this study we investigate whether a theoretically grounded tailored intervention to diffuse evidence-based public health practice increases the physicians' use of research information.
                148 self-selected public health physicians were randomised to an intervention group (n = 73) and a control group (n = 75). The intervention group received a multifaceted intervention while the control group received a letter declaring that they had access to library services. Baseline assessments before the intervention and post-testing immediately at the end of a 1.5-year intervention period were conducted. The intervention was theoretically based and consisted of a workshop in evidence-based public health, a newsletter, access to a specially designed information service, to relevant databases, and to an electronic discussion list. The main outcome measure was behaviour as measured by the use of research in different documents.
                The intervention did not demonstrate any evidence of effects on the objective behaviour outcomes. We found, however, a statistical significant difference between the two groups for both knowledge scores: Mean difference of 0.4 (95% CI: 0.2-0.6) in the score for knowledge about EBM-resources and mean difference of 0.2 (95% CI: 0.0-0.3) in the score for conceptual knowledge of importance for critical appraisal. There were no statistical significant differences in attitude-, self-efficacy-, decision-to-adopt- or job-satisfaction scales. There were no significant differences in Cochrane library searching after controlling for baseline values and characteristics.
                Though demonstrating effect on knowledge the study failed to provide support for the hypothesis that a theory-based multifaceted intervention targeted at identified barriers will change professional behaviour. Publication bias is widely appreciated, but considerable time and effort are needed to locate and obtain data from unpublished randomized controlled trials (RCTs), those published in non-English language journals or those reported in the gray literature; for this publication, we will call this collection of trials the "gray+literature." However, excluding such trials from systematic reviews could introduce bias and give rise to misleading conclusions.
                We aimed to explore and quantify the impact of inclusion of gray+ literature on the results of all completed individual patient data (IPD) reviews coordinated by our group (13 meta-analyses). For each IPD review, results were calculated for RCTs fully published in English language journals and RCTs fully published in English language journals and the gray+literature.
                The IPD meta-analyses based only on RCTs that were fully published in English language journals tended to give more favorable results than those that included RCTs from the gray+literature. Although in most cases the addition of gray+data gave less encouraging results, moving the estimated treatment effect toward a null result, the direction of effect was not always predictable.
                We recommend that all systematic reviews should at least attempt to identify trials reported in the gray+literature and, where possible, obtain data from them. The aim of this project was to assess whether outreach visits would improve the implementation of evidence based clinical practice in the area of falls reduction and stroke prevention in a residential care setting.
                Twenty facilities took part in a randomized controlled trial with a seven month follow-up period. Two outreach visits were delivered by a pharmacist. At the first a summary of the relevant evidence was provided and at the second detailed audit information was provided about fall rates, psychotropic drug prescribing and stroke risk reduction practices (BP monitoring, aspirin and warfarin use) for the facility relevant to the physician. The effect of the interventions was determined via pre- and post-intervention case note audit. Outcomes included change in percentage patients at risk of falling who fell in a three month period prior to follow-up and changes in use of psychotropic medications. Chi-square tests, independent samples t-test, and logistic regression were used in the analysis.
                Data were available from case notes at baseline (n = 897) and seven months follow-up (n = 902), 452 residential care staff were surveyed and 121 physicians were involved with 61 receiving outreach visits. Pre-and post-intervention data were available for 715 participants. There were no differences between the intervention and control groups for the three month fall rate. We were unable to detect statistically significant differences between groups for the psychotropic drug use of the patients before or after the intervention. The exception was significantly greater use of "as required" antipsychotics in the intervention group compared with the control group after the pharmacy intervention (RR = 4.95; 95%CI 1.69-14.50). There was no statistically significant difference between groups for the numbers of patients "at risk of stroke" on aspirin at follow-up.
                While the strategy was well received by the physicians involved, there was no change in prescribing patterns. Patient care in residential settings is complex and involves contributions from the patient's physician, family and residential care staff. The project highlights challenges of delivering evidence based care in a setting in which there is a paucity of well controlled trial evidence but where significant health outcomes can be attained.
Due to the high level of risk of bias in the two included trials there is insufficient evidence to conclude that one intervention is superior to another.