Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? Comparison of registered and published primary outcomes in randomized controlled trials. Source of funding and outcome of clinical trials. A cohort study of summary reports of controlled trials. Publication and non-publication of clinical trials: longitudinal study of applications submitted to a research ethics committee. Effect of a US National Institutes of Health programme of clinical trials on public health and costs. Outcome reporting among drug trials registered in ClinicalTrials.gov. Cumulative meta-analysis of therapeutic trials for myocardial infarction.
Cumulative meta-analysis of clinical trials (a Bayesian interpretation for accumulating evidence) will profoundly affect medical care by summarizing evidence in the assessment of technology innovations. Application of the technique to the randomized control trials (RCTs) of streptokinase treatment of acute myocardial infarction, reduction of peri-operative mortality by antibiotic prophylaxis, and prevention of death from bleeding peptic ulcers has revealed efficacy years before it was suspected by any other means. Arrangement of the trials according to event rate in the controls, effect sizes, quality of the trials or according to covariables of interest has supplied unique information. If carried out prospectively the technique supplies invaluable information regarding indications for another trial, the number of patients necessary to determine the validity of past trends, and the type of patients who might be benefitted. Careful examination in a cumulative manner of the prior trials can reduce the need for future large trials. Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions.
                To explore whether the association between funding and conclusions in randomized drug trials reflects treatment effects or adverse events.
                Observational study of 370 randomized drug trials included in meta-analyses from Cochrane reviews selected from the Cochrane Library, May 2001. From a random sample of 167 Cochrane reviews, 25 contained eligible meta-analyses (assessed a binary outcome; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment). The primary binary outcome from each meta-analysis was considered the primary outcome for all trials included in each meta-analysis. The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect, adverse events, and additional confounding factors (methodological quality, control intervention, sample size, publication year, and place of publication).
                Conclusions in trials, classified into whether the experimental drug was recommended as the treatment of choice or not.
                The experimental drug was recommended as treatment of choice in 16% of trials funded by nonprofit organizations, 30% of trials not reporting funding, 35% of trials funded by both nonprofit and for-profit organizations, and 51% of trials funded by for-profit organizations (P<.001; chi2 test). Logistic regression analyses indicated that funding, treatment effect, and double blinding were the only significant predictors of conclusions. Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice (odds ratio, 5.3; 95% confidence interval, 2.0-14.4) compared with trials funded by nonprofit organizations. This association did not appear to reflect treatment effect or adverse events.
                Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results. Readers should carefully evaluate whether conclusions in randomized trials are supported by data. As of 2005, the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrollment as a precondition for publishing the trial's findings in member journals.
                To assess the proportion of registered trials with results recently published in journals with high impact factors; to compare the primary outcomes specified in trial registries with those reported in the published articles; and to determine whether primary outcome reporting bias favored significant outcomes.
                MEDLINE via PubMed was searched for reports of randomized controlled trials (RCTs) in 3 medical areas (cardiology, rheumatology, and gastroenterology) indexed in 2008 in the 10 general medical journals and specialty journals with the highest impact factors.
                For each included article, we obtained the trial registration information using a standardized data extraction form.
                Of the 323 included trials, 147 (45.5%) were adequately registered (ie, registered before the end of the trial, with the primary outcome clearly specified). Trial registration was lacking for 89 published reports (27.6%), 45 trials (13.9%) were registered after the completion of the study, 39 (12%) were registered with no or an unclear description of the primary outcome, and 3 (0.9%) were registered after the completion of the study and had an unclear description of the primary outcome. Among articles with trials adequately registered, 31% (46 of 147) showed some evidence of discrepancies between the outcomes registered and the outcomes published. The influence of these discrepancies could be assessed in only half of them and in these statistically significant results were favored in 82.6% (19 of 23).
                Comparison of the primary outcomes of RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent. Because of recent concerns about conflicts of interest and published research, the author analyzed 107 controlled clinical trials. Studies were classified as favoring either a new therapy or a traditional therapy, and as being supported by a pharmaceutical manufacturer or as being generally supported. Seventy-one per cent of the trials favored new therapies; 43% of these were funded by pharmaceutical firms. Of the 31 trials favoring traditional therapy, only four (13%) were supported by a pharmaceutical firm. There was a statistically significant association between the source of funding and the outcome of the study (p = 0.002). Few trials supported by pharmaceutical manufacturers favored traditional therapy; some reasons for this finding may include selection of drugs likely to be proven efficacious, Type II errors (false-negative studies), and fear of discontinuation of funding should such studies be submitted. Important clinical information may be lost if negative studies are not published. Substantial numbers of clinical trials continue to be reported only in summary reports that present insufficient methodological details to permit informed judgments about the likely validity of the conclusions. Using a cohort of 176 controlled trials reported in summary form, we tested the hypotheses that they would be more likely to be followed by full reports if, on the basis of the information provided in the summary report, (1) the trial was judged to be methodologically sound, (2) the results favored the test treatment, and (3) the sample size was relatively large. The results of univariate and multivariate analyses provided support for only the third of these hypotheses. Investigators, as well as those who fund and sanction the conduct of clinical research, should make greater efforts to ensure that clinical trials are reported properly. Not all clinical trials are published, which may distort the evidence that is available in the literature. We studied the publication rate of a cohort of clinical trials and identified factors associated with publication and nonpublication of results.
                We analysed the protocols of randomized clinical trials of drug interventions submitted to the research ethics committee of University Hospital (Inselspital) Bern, Switzerland from 1988 to 1998. We identified full articles published up to 2006 by searching the Cochrane CENTRAL database (issue 02/2006) and by contacting investigators. We analyzed factors associated with the publication of trials using descriptive statistics and logistic regression models.
                451 study protocols and 375 corresponding articles were analyzed. 233 protocols resulted in at least one publication, a publication rate of 52%. A total of 366 (81%) trials were commercially funded, 47 (10%) had non-commercial funding. 346 trials (77%) were multi-centre studies and 272 of these (79%) were international collaborations. In the adjusted logistic regression model non-commercial funding (Odds Ratio [OR] 2.42, 95% CI 1.14-5.17), multi-centre status (OR 2.09, 95% CI 1.03-4.24), international collaboration (OR 1.87, 95% CI 0.99-3.55) and a sample size above the median of 236 participants (OR 2.04, 95% CI 1.23-3.39) were associated with full publication.
                In this cohort of applications to an ethics committee in Switzerland, only about half of clinical drug trials were published. Large multi-centre trials with non-commercial funding were more likely to be published than other trials, but most trials were funded by industry. Few attempts have been made to estimate the public return on investment in medical research. The total costs and benefits to society of a clinical trial, the final step in testing an intervention, can be estimated by evaluating the effect of trial results on medical care and health.
                All phase III randomised trials funded by the US National Institute of Neurological Disorders and Stroke before Jan 1, 2000, were included. Pertinent publications on use, cost to society, and health effects for each studied intervention were identified by systematic review, supplemented with data from other public and proprietary sources. Regardless of whether a trial was positive or negative, information on use of tested therapies was integrated with published per-use data on costs and health effect (converted to 2004 US dollars) to generate 10-year projections for the US population.
                28 trials with a total cost of 335 million dollars were included. Six trials (21%) resulted in measurable improvements in health, and four (14%) resulted in cost savings to society. At 10 years, the programme of trials resulted in an estimated additional 470,000 quality-adjusted life years at a total cost of 3.6 billion dollars (including costs of all trials and additional health-care and other expenditures). Valuing a quality-adjusted life year at per-head gross domestic product, the projected net benefit to society at 10-years was 15.2 billion dollars. 95% CIs did not include a net loss at 10 years.
                For this institute, the public return on investment in clinical trials has been substantial. Although results led to increases in health-care expenditures, health gains were large and valuable. Clinical trial registries are in widespread use to promote transparency around trials and their results.
                To describe characteristics of drug trials listed in ClinicalTrials.gov and examine whether the funding source of these trials is associated with favorable published outcomes.
                An observational study of safety and efficacy trials for anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006.
                ClinicalTrials.gov, a Web-based registry of clinical trials launched in 1999.
                Publications resulting from the trials for the 5 drug categories of interest were identified, and data were abstracted on the trial record and publication, including timing of registration, elements of the study design, funding source, publication date, and study outcomes. Assessments were based on the primary funding categories of industry, government agencies, and nonprofit or nonfederal organizations.
                Among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations. Trials funded by industry were more likely to be phase 3 or 4 trials (88.7%; P < 0.001 across groups), to use an active comparator in controlled trials (36.8%; P = 0.010 across groups), to be multicenter (89.0%; P < 0.001 across groups), and to enroll more participants (median sample size, 306 participants; P < 0.001 across groups). Overall, 362 (66.3%) trials had published results. Industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization-funded trials (P < 0.001). Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%; P = 0.013). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization-funded trials without industry contributions (P = 0.005 across groups).
                The publication status of a trial could not always be confirmed, which could result in misclassification. Additional information on study protocols and comprehensive trial results were not available to further explore underlying factors for the association between funding source and outcome reporting.
                In this sample of registered drug trials, those funded by industry were less likely to be published within 2 years of study completion and were more likely to report positive outcomes than were trials funded by other sources.
                National Library of Medicine and National Institute of Child Health and Human Development, National Institutes of Health. The large volume of published randomized, controlled trials has led to a need for meta-analyses to track therapeutic advances. Performing a new meta-analysis whenever the results of a new trial of a particular therapy are published permits the study of trends in efficacy and makes it possible to determine when a new treatment appears to be significantly effective or deleterious. We describe the use of such a procedure, cumulative meta-analysis, to assess therapeutic trials among patients with myocardial infarction.
                We performed cumulative meta-analyses of clinical trials that evaluated 15 treatments and preventive measures for acute myocardial infarction.
                An example of this method is its application to the use of intravenous streptokinase as thrombolytic therapy for acute infarction. Thirty-three trials evaluating this therapy were performed between 1959 and 1988. We found that a consistent, statistically significant reduction in total mortality (odds ratios, 0.74; 95 percent confidence interval, 0.59 to 0.92) was achieved in 1973, after only eight trials involving 2432 patients had been completed. The results of the 25 subsequent trials, which enrolled an additional 34,542 patients through 1988, had little or no effect on the odds ratio establishing efficacy, but simply narrowed the 95 percent confidence interval. In particular, two very large trials, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico trial in 1986 (11,712 patients) and the Second International Study of Infarct Survival trial in 1988 (17,187 patients) did not modify the already established evidence of efficacy. We used a similar approach to study the accumulating evidence of efficacy (or lack of efficacy) of 14 other therapies and preventive measures for myocardial infarction.
                Cumulative meta-analysis of therapeutic trials facilitates the determination of clinical efficacy and harm and may be helpful in tracking trials, planning future trials, and making clinical recommendations for therapy.
Most trials have been designed and reported poorly, resulting in a lack of evidence for potentially beneficial treatments. There is a desperate need for large well conducted studies that evaluate long-term effects of current therapies. We suggest the creation of an international platform to improve quality and standardization of future trials in order to inform clinical practice.