This survey was conducted as part of a five-year project studying ethical issues in CRTs . Following a series of empirical studies (including this survey), an in-depth ethical analysis, and an extensive consensus process, the Ottawa Statement ─ the first comprehensive ethics guidelines specific to CRTs ─ was published in November 2012 . Although the survey was fielded before development of the Ottawa Statement, it is informative to interpret the results of the survey in light of the recommendations in the Ottawa Statement.
The first aim of the survey was to determine the need for research ethics guidelines for CRTs among research ethics chairs internationally. We found that 84% of research ethics chairs overall recognized the need for ethics guidelines for CRTs and 92% the need for education of ethics committees about ethical issues in CRTs. The perceived need for guidelines was not significantly associated with experience reviewing CRTs, which suggests that the need remains widespread and is not declining with experience. In our survey of 182 trialists (authors of CRTs) conducted as part of the five-year project, 74% (95% CI 67 to 80%) agreed or strongly agreed that there is a need to develop ethics guidelines for CRTs and 70% (95% CI 63 to 77%) that ethics committees could be better informed about distinct ethical issues surrounding CRTs . Surprisingly, the proportions of research ethics chairs indicating the need for ethics guidelines were higher than the corresponding proportions of trialists.
Our second aim was to investigate research ethics review procedures for three different kinds of CRTs. We found that there was little agreement among committees in the type of ethics reviews required in the cluster-cluster and professional-cluster scenarios, both among and within countries. Whereas regulatory differences may explain differences among countries, it does not explain within-country variability. Whereas there was more agreement in the individual-cluster scenario, cluster-cluster trials and professional-cluster trials often evaluate public health programs or quality improvement initiatives, and it is not always clear if such trials ought to be considered research and undergo research ethics review. According to Recommendation 1 in the Ottawa Statement, all CRTs involving human research participants must be submitted to a research ethics committee. This includes CRTs evaluating quality improvement and knowledge translation interventions, and those in education or public health research. The type of ethics review is subject to the discretion of the committee; research ethics committees ought to undertake a proportional approach to the review of study protocols such that CRTs that pose substantial risk or involve vulnerable participants ought to receive intensive scrutiny, whereas CRTs that pose low risk and do not involve vulnerable participants may be eligible for an expedited or delegated review. Although the majority of respondents in all three scenarios agreed that some type of review is required (as opposed to no review), variability in the type of review required is an important finding as it reflects fundamental differences among committees with respect to the perceived level of risk associated with each scenario and the perceived vulnerability of those who might be considered participants. The type of review may have implications with respect to the level of scrutiny a protocol will receive during the review process, the number of reviewers assessing a protocol, and the time required to complete the review process.
Our third aim was to characterize the views of research ethics chairs on the identification of research subjects. The proper identification of research subjects is of considerable importance, as only those cluster members who are research subjects properly fall under the protection of research ethics committees and the regulations under which they operate. We observed substantial variability among chairs in all three countries with respect to the identification of research subjects in the cluster-cluster and professional-cluster scenarios. The individual-cluster scenario, which most resembles a standard randomized controlled trial, presented less disagreement. According to the Ottawa Statement [17, 18] a research participant is defined as any individual whose interests may be affected as a result of study interventions or data collection procedures; that is, any individual who is the recipient or the direct target of a study intervention (whether an individual level or cluster level intervention), with whom researchers interact for study purposes, or about whom identifiable private information is collected. In the cluster-cluster scenario, fewer than one-third of chairs would consider residents in intervention and control communities to be research subjects, even though study interventions are targeted at them. It is a unique characteristic of CRTs that there can be participants at both individual and cluster levels. Surprisingly, in agreement with the Ottawa Statement, two-thirds of chairs indicated that they would consider health professionals to be research subjects. On the other hand, nearly 40% would consider patients whose health professionals participate in a knowledge translation intervention and who contribute only aggregate data (that is, practice-level imaging rates) to be research subjects. It is possible that those respondents who were broadly inclusive in identifying individuals who may be subjects in a CRT were doing so because they believed that the study required full ethics review and this would be one way to that end. Furthermore, although the need to seek informed consent is a separable issue , it is possible that chairs conflated the identification of research participants with the need to seek informed consent. The Ottawa Statement may help to avoid conceptual confusion by providing clarity on these important questions.
To the best of our knowledge, this is the first study to compare deliberations and decisions among research ethics committees in the review of CRTs. Although the scenarios were hypothetical, they represent three common settings where CRTs are used and are based on published CRTs. Participants in our survey provided perspectives from chairs in three countries: Canada, the United States, and the United Kingdom, and represented a variety of institutions: universities, hospitals, non-profit and for-profit, and varying degrees of experience. Our study provides empirical data of variability among committees both within and among countries in key decisions about the ethics review and conduct of CRTs. Although variability among ethics committees is not necessary morally problematic , these decisions have clear repercussions for the ability of research ethics committees to fulfill their purpose which includes protecting the rights and wellbeing of all research participants and to provide independent, competent, and timely review of the ethics of proposed studies .
Our study has two main limitations. First, our response rate was low and results may therefore not be representative. There can be many reasons for the low response. One is that our sampling frame was imperfect. Despite our best efforts at obtaining updated contact information and screening out ineligible committees prior to sampling, 105 of the 647 sampled committees (16%) either indicated that they were ineligible (that is, were nonbiomedical or did not review randomized controlled trials) or had invalid email addresses. Our stated response rate is conservatively calculated, meaning that all non-respondents are assumed to be eligible and included in the denominator of the response rate. The type of contact information varied: in some cases we had an email address for a named chair, while for others, only a central contact was available. Our analyses of response rates showed that response rates were higher among committees with more recent contact information; it was also higher among committees at NIH-funded institutions (more likely to be biomedical). Finally, our survey was relatively long and presented three complex scenarios; research ethics chairs are busy professionals and may simply not have had the time to complete the survey. Although we do not have any information that would allow us to investigate differences between respondents and non-respondents, we have no reason to expect answers of non-respondents to differ substantially from those observed in this survey.
A second limitation is that the descriptions of the scenarios were necessarily brief. In practice, ethics committees would have access to the full study protocol. It is possible that at least some of the variability observed is due to the lack of clarity or incompleteness of the information provided. However, we believe that the most relevant information was presented in each scenario, and the results are in line with findings from our survey of CRT investigators, which suggested that there are substantial challenges in practice. We were pleasantly surprised by the level of detail and thoughtfulness put into the open text responses. It was apparent that the majority of respondents paid careful consideration to the details provided in the scenarios and presented well-articulated and clear responses. This suggests that respondents understood that the scenarios were intended to trigger reflection on a certain class of study, rather than limit their consideration to those details provided in the survey alone.