摘要：We argue that cluster-randomized trials are an important methodology, essential to the evaluation of many public health interventions. However, in the case of at least some cluster-randomized trials, it is not possible, or is incompatible with the aims of the study, to obtain individual informed consent. This should not necessarily be seen as an impediment to ethical approval, providing that sufficient justification is given for this omission. We further argue that it should be the institutional review board’s task to evaluate whether the protocol is sufficiently justified to proceed without consent and that this is preferable to any reliance on community consent or other means of proxy consent. THE PARADIGM CASE FOR RE search testing the effectiveness of medical interventions is the randomized controlled trial (RCT), in which individual patients are randomly allocated to 1 of 2 or more different interventions to test their relative effect on a predetermined outcome variable. The randomization process, together with other features of the design of RCTs, controls for extraneous factors that could plausibly influence the outcome variable and thereby lead to confounding. 1 This focus on RCTs and the ethical issues that they create has also influenced the development of research ethics, in which the RCT seems well established as the assumed methodology of choice. However, other methods are often used, and we focus on the cluster-randomized trial. A cluster-randomized trial randomizes at the social group level (e.g., village, hospital, school)—hence “cluster”—rather than at the level of individual patients. Cluster-randomized trials are popular in the assessment of organizational change and social, behavioral, and community-level interventions in public health. 2 They retain the element of randomization and thus have many of the benefits of RCTs in terms of seeking to avoid confounding, and this is why many hold them to be superior to the obvious alternative method of cohort studies. Cluster-randomized trials are not merely an alternative to RCTs but are used when an RCT is inappropriate or impossible. This alternative design might be indicated for the following reasons. First is the nature of the intervention. Some interventions that we wish to assess are delivered at the cluster rather than the individual level, such that it is not possible to randomly assign individual patients to interventions. Kumar et al. 3 studied 3 different approaches to behavior change management relating to childbirth, delivered through a community education approach; the unit of randomization was the village rather than individual community members. Second is the nature of the delivery of the intervention. For example, on some occasions, the target of the intervention is not the patient directly but the care provider. If the intervention involves the education of practitioners or a change in their practice, then the results of such an intervention cannot be applied selectively to certain patients in that practitioner’s caseload. Hence Figueiras et al. 4 used a cluster-randomized trial design when testing educational outreach visits relating to Portuguese physicians’ reporting of adverse drug reactions. Third is obtaining a clear and consistent answer to the chosen research question. For example, some treatments (e.g., certain behavioral or educational interventions) are susceptible to contamination, whereby individuals who have not been allocated to the intervention in question may nonetheless be exposed to it through interaction with those who have been allocated to it. Therefore, Peri et al. 5 adopted a cluster-randomized trial design when evaluating functional activity in residential care facilities. Although activity programs were individually designed, there would be a risk in an individually randomized trial that residents allocated to the control intervention might observe and thereby come to adopt the activities in these programs. Similarly, Smith et al. 6 used a cluster design to evaluate the use of antibiotics and dry mopping for otitis media among Kenyan schoolchildren. The studies cited as examples illustrate a basic distinction that can be drawn between “cluster-cluster” and “individual-cluster” cluster-randomized trials, 7 depending on where the intervention is delivered and where randomization occurs. In cluster-cluster trials, intervention is delivered and the units are randomized at the cluster level. 3,4 In individual-cluster trials, the intervention is delivered at the individual level, whereas units are randomized at the cluster level. 5,6 This is an important distinction, as shown in the next section. The cluster-randomized trial presents several methodological challenges, at the level of both design and statistical analysis. 8 It also has been recognized that cluster-randomized trials pose certain ethical challenges. 7,9–11 We consider the specific ethical issues raised by such trials in relation to informed consent. We argue that a different perspective needs to be taken on this issue from that commonly taken in respect of the conventional RCT 12 and that research ethics guidelines and regulations should allow sufficient flexibility to permit the use of cluster-randomized trials when appropriate.
