Cluster Randomized Trials Lainie Friedman Ross MD Ph

Cluster Randomized Trials Lainie Friedman Ross, MD, Ph. D Carolyn & Matthew Bucksbaum Professor of Clinical Ethics University of Chicago © Ross, 2013

What is a cluster randomized trial (CRT)? l A cluster randomized controlled trial is a type of trial in which groups of subjects (as opposed to individual subjects) are randomized. l So, we randomize different communities, clinics, or cities to either get or not get a particular intervention (or for one cluster to get treatment A and one to get treatment B. l In contrast with a traditional clinical trial in which we randomize individuals. © Ross, 2013

Who is the research subject? l Cluster randomized trial to improve adherence to guidelines for hypertension drug prescribing l Providers were randomized to receive l general guideline education l General guideline education plus patient-specific reminders l Outcomes l Overall compliance with guidelines l Adequacy of patient’s BP as ascertained by review of patients’ charts l Questions: l Who are the subjects? l Whose consent is needed? © Ross, 2013

Who is the research subject? l COMMIT: Community Intervention Trial for Smoking Cessation l 22 cities in US and Canada randomized to l Either a community-level antismoking intervention delivered through mass media, health care professionals and worksites or l No intervention l Investigators interacted with the community by forming a board of community representatives. l Individual respondents not aware they were involved in a trial, although they provided verbal consent to complete a telephone survey l Questions l l l Who are the subjects? Whose consent is needed? What role can/should community board play? l Are Community Reps morally necessary? l Are they morally sufficient? © Ross, 2013

Randomized Control Trial (RCT) vs. Cluster Randomized Trial (CRT) l What question does the trial seek to answer? l RCT: is drug A superior to drug B l CRT: Questions are typically more complex and inherently pragmatic than those in conventional RCTs l the effectiveness of multicomponent strategies intended to promote health or to prevent disease, l to encourage the adoption of uncontentious processes of care; and l to evaluate the efficacy of certain explicit algorithms designed to influence the delivery of care. l When do you want to use CRT for pragmatic and logistical reasons? l Intervention at community level (*fluoride in the water) l Specialized resources (specially programmed devices such as computer based clinical decision support tools) l To minimize contamination bias which occurs… l When providers assigned to deliver the innovative intervention also treat individuals randomized to the control group; or l When providers consciously or unconsciously adopt aspects of the comparator intervention because of proximity to, or informal interaction with, others delivering the intervention; or l When patients modify their behavior after interacting with patients receiving the innovative interventions © Ross, 2013

Problems with CRT l Interventions intended to influence at one level whereas outcomes measured at another level l Attempt to change doctors behaviors; determine if successful by measuring patient outcomes. l The level of outcome data analysis—best termed the level of inference-determines what data must be obtained, about whom, and the statistical analyses employed (and whose consent is necessary). l CRTs reduce the statistical efficiency relative to RCTs that randomize the same number of individuals l The threshold for determining the magnitude of an effect necessary to have public heath significance may be quite different than the threshold for “clinical significance”, a consequence of the prevention paradox: l Low intensity interventions that are less efficacious but can be delivered to a large number of people may have a more pervasive impact © Ross, 2013

Weijer et al. Ethical issues posed by cluster randomized trials (CRTs) in health research. Trials 2011; 12: 100 1) Who is a research subject? 2) From whom, how and when must informed consent be obtained? 3) Does clinical equipoise apply to CRTs? 4) How do we determine if the benefits outweigh the risks of CRTs? 5) How ought vulnerable groups be protected in CRTs? 6) Who are gatekeepers, and what are their responsibilities? © Ross, 2013

References l Eldridge SM, Ashby D, Feder GS. Informed patient consent to participation in cluster randomized trials: an empirical exploration in primary care. Clinical Trials 2005; 2: 91. On the web at: http: //ctj. sagepub. com/content/2/2/91. long l Mann H, Reyes M. Identifying the Human Research subject in cluster randomized Controlled Trials. IRB: Ethics and Human Research 2008; 30 (5): 14 -18 l Medical Research Council (UK). Cluster randomised trials: Methodological and ethical considerations. 2002. On the web at: http: //www. mrc. ac. uk/Utilities/Documentrecord/index. htm? d=MRC 002406 l Weijer C, Grimshaw JM, Eccles MP, et al. (2012) The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials. PLo. S Medicine. 9(11): e 1001346. On the web at: http: //www. plosmedicine. org/article/info%253 Adoi%252 F 10. 1371%252 Fjournal. pmed. 10 01346 l Weijer C, Grimshaw JM, Taljaard M, et al. Ethical issues posed by cluster randomized trials in health research. Trials. 2011; 12: 100. On the web at: http: //www. trialsjournal. com/content/12/1/100. This is the 1 st in a series of articles in Trials by a group of Canadians who had a grant to study the issues. © Ross, 2013