The Ottawa Ethics of Cluster Trials Consensus Group sets out 15 recommendations for the ethical design and conduct of cluster randomized trials.

Objective To assess the impact of the 2004 extension of the CONSORT guidelines on the reporting and methodological quality of cluster randomised trials.Design Methodological review of 300 randomly sampled cluster randomised trials. Two reviewers independently abstracted 14 criteria related to quality of reporting and four methodological criteria specific to cluster randomised trials. We compared manuscripts published before CONSORT (2000-4) with those published after CONSORT (2005-8). We also investigated differences by journal impact factor, type of journal, and trial setting. Data sources A validated Medline search strategy.Eligibility criteria for selecting studies Cluster randomised trials published in English language journals, 2000-8.Results There were significant improvements in five of 14 reporting criteria: identification as cluster randomised; justification for cluster randomisation; reporting whether outcome assessments were blind; reporting the number of clusters randomised; and reporting the number of clusters lost to follow-up. No significant improvements were found in adherence to methodological criteria. Trials conducted in clinical rather than non-clinical settings and studies published in medical journals with higher impact factor or general medical journals were more likely to adhere to recommended reporting and methodological criteria overall, but there was no evidence that improvements after publication of the CONSORT extension for cluster trials were more likely in trials conducted in clinical settings nor in trials published in either general medical journals or in higher impact factor journals. ConclusionThe quality of reporting of cluster randomised trials improved in only a few aspects since the publication of the extension of CONSORT for cluster randomised trials, and no improvements at all were observed in essential methodological features. Overall, the adherence to reporting and methodological guidelines for cluster randomised trials remains suboptimal, and further efforts are needed to improve both reporting and methodology. IntroductionIn recent years, increasing attention has been paid to the importance of good reporting practices as they relate to the potential utility of a manuscript. 1 The CONSORT (consolidated standards of reporting trials) statement, originally published in 1996 and updated in 2001 and 2010, provides authors and editors with a checklist for a minimum set of recommendations for RESEARCHreporting the trial design, analysis, and results. 2 Although certain inadequacies remain common, the quality of reporting of randomised controlled trials in medical journals seems to be improving over time. 3 A recent systematic review indicated that the CONSORT statement has played an important role in this progression. 4 Unfortunately, reviews of published cluster randomised trials (see box 1) have repeatedly found important shortcomings in their methodological conduct and reporting. [5][6][7][8][9][10][11][12][13][14][15][16][17][18] For example, a review of 152 c...

BackgroundCluster randomized trials (CRTs) pose ethical challenges for investigators and ethics committees. This study describes the views and experiences of CRT researchers with respect to: (1) ethical challenges in CRTs; (2) the ethics review process for CRTs; and (3) the need for comprehensive ethics guidelines for CRTs.MethodsDescriptive qualitative analysis of interviews conducted with a purposive sample of 20 experienced CRT researchers.ResultsInformants expressed concern over the potential for bias that may result from requirements to obtain informed consent from research participants in CRTs. Informants suggested that the need for informed consent ought to be related to the type of intervention under study in a CRT. Informants rarely expressed concern regarding risks to research participants in CRTs, other than risks to privacy. Important issues identified in the research ethics literature, including fair subject selection and other justice issues, were not mentioned by informants. The ethics review process has had positive and negative impacts on CRT conduct. Informants stated that variability in ethics review between jurisdictions, and increasingly stringent ethics review in recent years, have hampered their ability to conduct CRTs. Many informants said that comprehensive ethics guidelines for CRTs would be helpful to researchers and research ethics committees.ConclusionsInformants identified key ethical challenges in the conduct of CRTs, specifically relating to identifying subjects, seeking informed consent, and the use of gatekeepers. These data have since been used to identify topics for in-depth ethical analysis and to guide the development of comprehensive ethics guidelines for CRTs.

The cluster randomized trial (CRT) is used increasingly in knowledge translation research, quality improvement research, community based intervention studies, public health research, and research in developing countries. However, cluster trials raise difficult ethical issues that challenge researchers, research ethics committees, regulators, and sponsors as they seek to fulfill responsibly their respective roles. Our project will provide a systematic analysis of the ethics of cluster trials. Here we have outlined a series of six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation:1. Who is a research subject?2. From whom, how, and when must informed consent be obtained?3. Does clinical equipoise apply to CRTs?4. How do we determine if the benefits outweigh the risks of CRTs?5. How ought vulnerable groups be protected in CRTs?6. Who are gatekeepers and what are their responsibilities?Subsequent papers in this series will address each of these areas, clarifying the ethical issues at stake and, where possible, arguing for a preferred solution. Our hope is that these papers will serve as the basis for the creation of international ethical guidelines for the design and conduct of cluster randomized trials.

This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation. This paper addresses the second of the questions posed, namely, from whom, when, and how must informed consent be obtained in CRTs in health research? The ethical principle of respect for persons implies that researchers are generally obligated to obtain the informed consent of research subjects. Aspects of CRT design, including cluster randomization, cluster level interventions, and cluster size, present challenges to obtaining informed consent. Here we address five questions related to consent and CRTs: How can a study proceed if informed consent is not possible? Is consent to randomization always required? What information must be disclosed to potential subjects if their cluster has already been randomized? Is passive consent a valid substitute for informed consent? Do health professionals have a moral obligation to participate as subjects in CRTs designed to improve professional practice?We set out a framework based on the moral foundations of informed consent and international regulatory provisions to address each of these questions. First, when informed consent is not possible, a study may proceed if a research ethics committee is satisfied that conditions for a waiver of consent are satisfied. Second, informed consent to randomization may not be required if it is not possible to approach subjects at the time of randomization. Third, when potential subjects are approached after cluster randomization, they must be provided with a detailed description of the interventions in the trial arm to which their cluster has been randomized; detailed information on interventions in other trial arms need not be provided. Fourth, while passive consent may serve a variety of practical ends, it is not a substitute for valid informed consent. Fifth, while health professionals may have a moral obligation to participate as subjects in research, this does not diminish the necessity of informed consent to study participation.

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IMPORTANCEThe management of patients with syncope in the emergency department (ED) is challenging because no robust risk tool available has been recommended for clinical use.OBJECTIVE To validate the Canadian Syncope Risk Score (CSRS) in a new cohort of patients with syncope to determine its ability to predict 30-day serious outcomes not evident during index ED evaluation. DESIGN, SETTING, AND PARTICIPANTSThis prospective multicenter cohort study conducted at 9 EDs across Canada included patients 16 years and older who presented to EDs within 24 hours of syncope. Patients were enrolled from March 2014 to April 2018. MAIN OUTCOMES AND MEASURES Baseline characteristics, CSRS predictors, and 30-day adjudicated serious outcomes, including arrhythmic (arrhythmias, interventions for arrhythmia, or unknown cause of death) and nonarrhythmic (myocardial infarction, structural heart disease, pulmonary embolism, or hemorrhage) serious outcomes, were collected. Calibration and discrimination characteristics for CSRS validation were calculated. RESULTS A total of 3819 patients were included (mean [SD] age 53.9 [22.8] years; 2088 [54.7%] female), of whom 139 (3.6%) experienced 30-day serious outcomes, including 13 patients (0.3%) who died. In the validation cohort, there were no differences between the predicted and observed risk, the calibration slope was 1.0, and the area under the receiver operating characteristic curve was 0.91 (95% CI, 0.88-0.93). The empirical probability of a 30-day serious outcome during validation was 3.64% (95% CI, 3.09%-4.28%) compared with the model-predicted probability of 3.17% (95% CI, 2.66%-3.77%; P = .26). The proportion of patients with 30-day serious outcomes increased from 3 of 1631 (0.3%) in the very-low-risk group to 40 of 78 (51.3%) in the very-high-risk group (Cochran-Armitage trend test P < .001). There was a similar significant increase in the serious outcome subtypes with increasing CSRS risk category. None of the very-low-risk and low-risk patients died or experienced ventricular arrhythmia. At a threshold score of −1 (2145 of 3819 patients), the CSRS sensitivity and specificity were 97.8% (95% CI, 93.8%-99.6%) and 44.3% (95% CI, 42.7%-45.9%), respectively. CONCLUSIONS AND RELEVANCEThe CSRS was successfully validated and its use is recommended to guide ED management of patients when serious causes are not identified during index ED evaluation. Very-low-risk and low-risk patients can generally be discharged, while brief hospitalization can be considered for high-risk patients. We believe CSRS implementation has the potential to improve patient safety and health care efficiency.

This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the first of the questions posed, namely, who is the research subject in a CRT in health research? The identification of human research subjects is logically prior to the application of protections as set out in research ethics and regulation. Aspects of CRT design, including the fact that in a single study the units of randomization, experimentation, and observation may differ, complicate the identification of human research subjects. But the proper identification of human research subjects is important if they are to be protected from harm and exploitation, and if research ethics committees are to review CRTs efficiently.We examine the research ethics literature and international regulations to identify the core features of human research subjects, and then unify these features under a single, comprehensive definition of human research subject. We define a human research subject as any person whose interests may be compromised as a result of interventions in a research study. Individuals are only human research subjects in CRTs if: (1) they are directly intervened upon by investigators; (2) they interact with investigators; (3) they are deliberately intervened upon via a manipulation of their environment that may compromise their interests; or (4) their identifiable private information is used to generate data. Individuals who are indirectly affected by CRT study interventions, including patients of healthcare providers participating in knowledge translation CRTs, are not human research subjects unless at least one of these conditions is met.