Ethical issues in the design and conduct of cluster randomised controlled trials

British Medical Journal, May 22, 1999 by Sarah J L Edwards, David A Braunholtz, Richard J Lilford, Andrew J Stevens

Summary points

Need for cluster trials will increase with concern over health service evaluation, but issues of ethics and guardianship must be addressed

In some cluster trials the intervention can be targeted at individuals (individual-cluster); where this would be too difficult or expensive the intervention is targeted at the whole group (cluster-cluster)

Autonomy is important in individual-cluster trials, while the utilitarian welfare of the cluster as a whole is of paramount importance in cluster-cluster trials

In individual-cluster trials the participants should give consent; cluster-cluster trials need procedural safeguards appropriate to the risks carried by the cluster intervention

Guardians should sign a consent form that sets out their duties before they volunteer a cluster for a trial

In most randomised controlled trials, individual patients are randomised to a treatment or control group, but sometimes this is undesirable or even impossible and groups (clusters) of people may be randomised instead. These are called cluster randomised controlled trials, and although they have been around for a long time, the need for them is likely to increase in line with growing concern to evaluate the delivery of health services, public education, and policy on social care.

Ethical context

The ethical aspects of medical practice and medical research are most often discussed in the context of two main moral traditions--utilitarianism and Kantian ethics. Broadly speaking, utilitarianism is concerned with increasing social utility (value), which usually means that the individuals maximise their expected utility and so act in their own best interests. In the long run social utility will not be served by demanding that individuals be self sacrificing for the common good. This leads to matters of distributive justice whereby utility and disutility, benefits and costs, are distributed as fairly and evenly as possible across society. The Kantian tradition shows why we are duty bound to respect a person's autonomy.

There is some harmony between these traditions as competent patients are in the best position to know how they value possible consequences (utilities) and, equipped with the relevant probabilities, they are best placed to make decisions that concern them directly.[1] This takes the form of informed consent from individual participants. In cluster randomised controlled trials, however, informed consent for trial entry (that is, for randomisation) cannot be obtained individually because one person's choice will impinge on another's. The question then is, under what, if any, circumstances are cluster trials ethical? Here we discuss why a cluster trial might be mounted, who has a duty of care to the people who form the cluster in question and should make the decision to participate on its behalf, and how this duty of care should be discharged.

Why randomise by cluster?

There are two widely used arguments for randomisation by cluster. Firstly, the intervention itself may be administered to and affect entire clusters of people as opposed to individuals within that cluster. Examples include interventions that are diffuse (for example, information technology) or area wide (for example, promoting lifestyle changes on local radio). Secondly, although the intervention or treatment is given to individuals, it may also affect others within that cluster. This may be because it "leaks," contaminating those who are not supposed to receive it, thereby weakening any estimate of treatment difference. For example, people who are receiving a behavioural intervention to reduce smoking may talk it over with control subjects, who may in turn adopt the experimental practice. Some interventions, despite being limited to individuals, may affect others through a "herd effect." For example, people in a cluster that has been vaccinated not only have more resistance to the illness against which they have been vaccinated, but they are also less likely to be exposed to the illness in the first place.

Who consents to trial entry?

In the normal research process, a researcher (trialist) and sponsor decide to launch a trial; they are generally interested in the scientific results of the trial, perhaps to influence policy. However, the decision about whether a particular cluster participates in the trial is taken by an agent, whom we call a guardian and who has the power to "deliver" that cluster. Examples of guardians include the chief executive of a hospital, managing partner of a primary care practice, or head teacher. Guardians may be democratically elected or appointed, though not necessarily with this specific role in mind. In deciding to volunteer the cluster for an experiment that is not routine, the guardian, as advocate, must act in the best interests of the cluster; this may or may not be his or her habitual role. It should be noted that guardians, like doctors in conventional trials, have some potential conflicts of interest. They may, for example, have a scientific interest in the results as well as a benevolent concern tot the welfare of the cluster, or they may receive financial incentives. Consequently, safeguards, like ethics committee approval, are desirable.