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What should the ethical protections be in cluster trials?

This week I was delighted to listen in to a consensus conference of researchers, ethicists, editors and other interested parties, aiming to produce a set of guidelines for the ethical conduct and review of cluster randomized trials.

A cluster trial has been defined as a trial in which “the study,┬árandomize[s] interventions to groups of patients (e.g., families, medical practices) rather than to individual patients”.

The group coordinating this consultation has developed a set of wiki pages, and has published a series of papers in the open-access journal Trials outlining what the issues are (each of the papers is accessible via the group’s wiki site above, as well as the journal website itself).

The consultation is dividing its efforts into defining and discussing each of six key ethical problems, each of which affects cluster trials in unique ways.

“Firstly, who is the research subject in a cluster trial? Secondly, when, and from whom, is informed consent needed in a cluster trial? Thirdly, does clinical equipoise apply in cluster trials? Fourthly, how should benefits and harms be assessed in cluster trials? Fifthly, do gatekeepers have a role to play in protecting the interests of those affected by cluster trials? Finally, what are the issues for cluster trials in vulnerable populations?”

These are important issues, as convincingly set out in the conference and in the introductory papers. Data presented in the webcast showed that a sizeable proportion (up to 30%) of published reports of cluster trials do not provide information on the ethical oversight, or consent procedures for the study. The chairs of research ethics boards consider the issues raised to be important, but do not apply protections consistently, and there’s a risk of both over- and under-regulating participants in cluster trials. For example, if ethics committees require consent from everyone affected in the randomized communities, for some types of cluster trials this may make the study unfeasible or consent meaningless (eg if interventions are applied at a community level, exposing everyone in a particular setting to the intervention, it may be completely unfeasible to avoid exposing individuals to the intervention even if they decline consent). The series of papers give some great real life examples highlighting what the problems and questions are.

So, what are the solutions on the table? The consultation sets out possible definitions for the research “subject” (or perhaps, more accurately, the research participant) in cluster trials. Specifically, this definition proposes:

“A research subject is an individual whose interests may be compromised as a result of interventions in a research study”

This definition would include individuals who are directly intervened upon by investigators for research purposes; individuals who are intervened upon by manipulation of their environment by investigators for research purposes; individuals who interact with investigators for the collection of data; and individuals from whom investigators obtain identifiable private information for the purpose of collecting data.

The guidelines under development also distinguish, as previous work has done, between different types of cluster trials, and this helps define at what level, and which individuals should be protected as research participants. Three types of cluster trials are defined – “cluster-cluster” trials (interventions are applied to entire clusters and not to individuals); “physician-cluster” trials (interventions are intended to affect the process of care offered by physicians, and thus their patients are indirectly affected); and “individual-cluster” trials (in which groups of individuals are randomized, but interventions are applied to individuals within those groups). Defining these different types makes it easier to work out whose interests need to be protected in the trial, and how. It’s also clear that editors need to do a much better job of encouraging authors to explain how they viewed the ethical implications of their cluster study, and at what level they applied specific protections such as consent, and why.

The guidelines group is still keen to hear from interested parties and you can post your discussion questions via the wiki pages – so if these issues are important to you, read the papers and get involved with the group. A summary of the webcast will also be posted on the site.

Recent cluster trials published in PLoS Medicine include:

Roca A, Hill PC, Townend J, Egere U, Antonio M, et al. (2011) Effects of Community-Wide Vaccination with PCV-7 on Pneumococcal Nasopharyngeal Carriage in The Gambia: A Cluster-Randomized Trial. PLoS Med 8(10): e1001107.

Cuevas LE, Yassin MA, Al-Sonboli N, Lawson L, Arbide I, et al. (2011) A Multi-Country Non-Inferiority Cluster Randomized Trial of Frontloaded Smear Microscopy for the Diagnosis of Pulmonary Tuberculosis. PLoS Med 8(7): e1000443.

Kangwana BP, Kedenge SV, Noor AM, Alegana VA, Nyandigisi AJ, et al. (2011) The Impact of Retail-Sector Delivery of ArtemetherÔÇôLumefantrine on Malaria Treatment of Children under Five in Kenya: A Cluster Randomized Controlled Trial. PLoS Med 8(5): e1000437.

Luoto R, Kinnunen TI, Aittasalo M, Kolu P, Raitanen J, et al. (2011) Primary Prevention of Gestational Diabetes Mellitus and Large-for-Gestational-Age Newborns by Lifestyle Counseling: A Cluster-Randomized Controlled Trial. PLoS Med 8(5): e1001036.

My 2010 competing interests are on the PLoS Medicine site.

  1. Fascinating questions here… You seem to be more or less considering what happens when the unit of observation in a trial is moved up the spectrum from individual-level randomisation, which is fine.

    However, I think it is also interesting to approach the issue from the other end of the spectrum. Let’s suppose a health authority decides to consider a new therapeutic strategy by just choosing one or a few districts for intial roll-out, testing and evaluation.

    An example is http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3156.2009.02447.x/pdf

    Is this a trial? It’s not fundamentally different from randomised intervention by GP practice, except for the scale of the unit of observation. But in reality the individuals in the districts chosen as intervention and control districts in such a situation have no say in whether to participate – and if this kind of activity is initiated within routine health services, what are the ethical issues and what is the responsible ethical authority?

    Personally I think it is reasonable for a health authority to roll-out new therapies in a controlled and evaluatable way, and would argue this is better than just adopting a new strategy on a blanket basis without evaluation – which also often happens: for example, foetal ultrasound in routine antenatal care?

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