Informants responded to questions addressing main pre-identified categories of: (1) ethical issues in CRTs; (2) experiences with the ethics review process for CRTs; and (3) the need for, and input on, possible ethics guidelines for CRTs. Responses were categorized into sub-headings that best described the issues addressed by informants.
Ethical issues in CRTs
The need for informed consent
Informants’ answers to the question of ‘In which circumstances is informed consent required from individual research participants?’ varied widely. For many informants, whether or not informed consent was required in a particular CRT depended on the kind of intervention being evaluated, specifically on whether it was an individual clinical treatment or a health service or other cluster level intervention.
‘The type of intervention that is being trialed is… of crucial importance. So, for example, whether… you are changing the way the entire service is delivered, or whether you are intervening at an individual level and you are just randomizing at a higher level for convenience… it is about which level… the intervention [is] being targeted at…’ (Informant 11, Primary Care Researcher)
The type of data collection procedures used in a CRT could also determine the need for consent from cluster members. Researchers almost universally obtained consent from cluster members if they interacted with these cluster members or intervened upon them to collect data.
‘If we interact with the participant we get consent first. If we are making observations in a public setting, we are not required to get consent… Those activities don’t require consent.’ (Informant 3, Public Health Researcher)
Many informants related concerns over the effect of obtaining informed consent on the validity of a CRT’s findings. In particular, informants worried that disclosure of the nature of the interventions under study in CRTs of behavioral interventions may lead to bias if research participants modify their behavior as a result of information disclosed during consent negotiations rather than as a result of the study interventions.
‘One of the things I am concerned about is bias. If you get really informed consent from people in trials it results in either bias or contamination.’ (Informant 5, Statistician)
With respect to studies of health services or quality improvement interventions, in which the only involvement of individual patients is the use of their health information for data collection, informants expressed concern that requiring informed consent may make such CRTs logistically unfeasible. Several informants felt that these methodological challenges were sufficient to justify a waiver of informed consent for cluster members.
‘Wherever people propose that [requiring individual patient consent], it is the death of those kinds of studies. It is the death of health services research. You can quote me on that. If you require consent to use the data… to look at the performance of a system, it will be a complete disaster.’ (Informant 1, Hospital Care/ Quality Improvement (QI) Researcher)
With respect to CRTs in healthcare implementation research, informants had different perspectives on when, if ever, consent or permission from healthcare professionals is required. Investigators often asked permission, either from individual healthcare professionals or from a group practice, to enrol these professionals in their study.
‘Normally [permission would be obtained] at a general practice level. That would have been done at a partner level, so there would be a discussion within the practice and then agreement at a practice level. There would have been consensual agreement between the partners, between the individual general practitioners that their practice would take part.’ (Informant 11, Primary Care Researcher)
Other informants proceeded with practice-based CRTs without securing the agreement of all healthcare professionals in the practice who might be affected by the intervention.
‘For the ones targeted at practitioners, we had to install software in their electronic medical records systems and computers in their offices so that it would have been GPs in the practice who gave consent. Within a practice, they didn’t all have to agree.’ (Informant 2, Primary Care Researcher)
Some informants argued that healthcare professionals have a professional obligation to participate in CRTs involving a knowledge translation or quality improvement intervention, which therefore overrides any requirement to obtain consent.
‘I would argue that [there is a] professional responsibility to practitioners to take part in research that involves clinical knowledge.’ (Informant 9, Primary Care Researcher)
Role of the cluster gatekeeper or decision-maker
Informants identified several ethical challenges related to the role of the gatekeeper: the individual who makes a decision with respect to CRT participation on behalf of a cluster. Informants noted challenges identifying the appropriate gatekeeper for certain kinds of groups, particularly municipalities. Opinions varied on whether municipal leaders had the appropriate authority to allow their community to participate in a CRT.
‘In some instances there really is no party to go to for permission when we are doing a community study for example and we are randomly assigning counties or cities. There really isn’t anybody that gives permission for that kind of thing. Even in a city where there is a mayor, the mayor can’t give permission for a city to participate in something. At least that has always been my view.’ (Informant 3, Public Health Researcher)
Informants also recognized that some clusters, such as schools and hospitals, may have multiple gatekeepers because of the organizational structure of these institutions.
‘First off you have to have the district agree that you can even work in this district. Then you have to get the principal to agree that they want to participate in the project. And then we had… the president of the local parent leadership group.’ (Informant 16, Public Health Researcher)
In situations in which researchers had difficulty identifying the appropriate gatekeeper for community-based research, they typically sought the approval of some local advisory committee.
‘Our approach in virtually every instance was to organize a local community advisory board made up of community residents in the city if we were working with cities or in the county if we were working with counties. We would get their input on a variety of things though the basic design was set.’ (Informant 3, Public Health Researcher)
Another ethical challenge concerning gatekeepers related to the scope of the gatekeeper’s decision-making authority. Responses varied on whether the gatekeeper possessed sufficient authority to provide consent on behalf of all cluster members, or whether the gatekeeper was simply permitting access to individual cluster members who would subsequently provide consent for CRT participation.
‘I think the main issues for me still stem around the issue of consent. Who [gives] consent? Whether consent needs to be achieved at every level of cluster or whether almost guardian consent is acceptable and that has been where the most discussion has happened really about in the ethical issues of cluster trials for me.’ (Informant 11, Primary Care Researcher)
Some informants seemed comfortable accepting a gatekeeper’s consent on behalf of an entire cluster for studies that were evaluating cluster-level interventions, such as educational or quality improvement interventions targeted at healthcare systems or practitioners.
‘I would say most of them have been looking towards a cluster guardian… consent because most of the interventions I have been involved in have been mainly around management interventions where the real intervention is at the level of either the practitioner, the health professional or the healthcare organization and this specific intervention hasn’t really been targeted at the lower level of the cluster, the patient level.’ (Informant 11, Primary Care Researcher)
Other informants expressed a different opinion. They felt it was important to obtain consent from individual patients in healthcare CRTs, regardless of whether consent for cluster enrolment was obtained from a gatekeeper.
‘So there is… consent for the patient and… consent for, in our case, the practice, so there are two levels of consent if you like. If there wasn’t patient consent involved, then obviously there would be very significant ethical issues but I have come to the view that if patients are given information and they consent, then that is fine.’ (Informant 9, Primary Care Researcher)
Risks and potential benefits
Our interview guide included items addressing the risks posed by CRT participation. Informants had few concerns regarding the risks posed to cluster members by CRTs.
‘Risks were none. I think we came up with some for the ethics committee.’ (Informant 14, Primary Care Researcher)
The interventions under evaluation in CRTs were commonly perceived as standard care with little or no incremental risk to cluster members.
‘None of the interventions that we have evaluated have put anyone at any kind of risk… there is certainly little risk involved.’ (Informant 3, Public Health Researcher)
For healthcare CRTs that evaluated the effect of interventions on health professionals using patients’ health information, informants identified threats to privacy as the sole risk.
‘I think the core risk is loss of privacy. That really is the only issue because we weren’t studying… a therapeutic intervention.’ (Informant 8, Hospital Care/QI Researcher)
Some informants voiced concern that members of clusters assigned to control groups may not benefit from an experimental intervention.
‘The dilemma and the tension again was this trial that is basically about the QI where the controlled practices got nothing. They didn’t get anything but normal care.’ (Informant 14, Primary Care Researcher)
One commonly employed solution to address this dilemma was to offer the experimental intervention to the control clusters after the CRT had been completed.
‘Sometimes we are so concerned about the control arm feeling that they don’t get anything that it might affect recruitment, that we offer them the intervention once the trial is over.’ (Informant 14, Primary Care Researcher)
An additional risk identified by one informant was that CRT enrolment may entail an increased clinical or administrative workload for participating medical practices.
‘The only risk I feel in doing a lot of research here is practices become overburdened by having to do research.’ (Informant 5, Statistician)
Experiences with the ethics review process
Many of the informants noted wide variability among research ethics committees, and across jurisdictions, in both the ethics review process and in ethics committees’ decisions. Informants noted that this variability has made it more difficult to do multicenter CRTs.
‘Cluster… trials of hospitals randomize independent institutions, each of which has a [research ethics committee]. Each [research ethics committee], with its slightly different application procedures, forms, and timelines has been a separate and trying process.’ (Informant 7, Primary Care Researcher)
Several informants commented that the ethics review process was easier in the past, and has become more cumbersome in recent years.
‘… Generally it hasn’t been too bad up until the last 5 years. Beforehand we were quite comfortably able to get ethics approval… but it is different now.’ (Informant 13, Primary Care Researcher)
However, other informants commented that as research ethics committees become familiar with the CRT design, the review process has gone more smoothly.
‘… Now CRTs are widely accepted research methods, particularly in primary care studies, primary care settings. Ethics committees are now actually quite comfortable with them.’ (Informant 14, Primary Care Researcher)
Informants’ opinions varied on the effect of the ethics review process and regulatory requirements on the validity of a CRT. Half of the informants reported a positive impact of the ethics review process on the quality of their studies, while the other half reported negative effects. Perceived negative effects included threats to validity from consent processes, and diminished enrolment because of consent requirements.
‘As the participation rates drop… then the results are less generalizable and less helpful. There is no question that the higher hurdles for consent in school studies and certainly in clinic based studies have made it more difficult to do the work and to get high participation rates.’ (Informant 3, Public Health Researcher)
Perceived positive effects included requirements for greater methodological rigor and thoughtfulness in study design, and improved protections for research participants.
‘I am a great believer that [research] ethics committee[s] do ask… searching questions… Just the process of thinking about the ethical implications of your design is something that we might not do if we didn’t have to go to ethics committees… I think I would say for all my research, it is improved the quality of what we do.’ (Informant 14, Public Health Researcher)
Developing ethics guidelines for CRTs
Informants were asked explicitly about the need for guidelines for the ethical conduct of CRTs. Generally, informants were supportive of efforts to develop ethics guidelines for the design, conduct, and review of CRTs, and identified informed consent as an ethical challenge for which investigators and ethics committees are in particular need of guidance.
‘I think there does still need to be a discussion document… on when is individual level consent an absolute requirement.’ (Informant 11, Primary Care Researcher)
When asked for suggestions for the content of ethics guidelines, another common response was to suggest inclusion of educational material for research ethics committees on the ethical and methodological aspects of CRTs that make CRTs distinct from individually randomized trials.
‘I think that there are issues which make cluster trials different to the sort of trials that [research ethics committees] normally see and that it would give me confidence as an investigator if I knew that they fully understood the difference.’ (Informant 20, Hospital Care/QI Researcher)