Dean Fergusson

Cluster randomization is an increasingly important trial design that can help advance the agenda of the pragmatic trial and provide essential information about the effectiveness and comparative effectiveness of interventions used routinely in medical practice. In addition to the parallel-arm design, cluster cross-over and stepped wedge designs are becoming increasingly popular. When such designs are embedded within routine clinical practice with waivers of informed consent, they have several methodological and logistical advantages over traditional patient randomized designs. However, these trials raise ethical issues that challenge researchers, research ethics committees, regulators, and sponsors as they seek to responsibly fulfill their respective roles. This workshop will use the FLUID and TRACTION trials to illustrate these issues, stimulate discussion, and inform the development of proposed solutions. FLUID is an ongoing pragmatic comparative effectiveness cluster cross-over trial currently taking place ─ with waived consent ─ at hospitals in Ontario. FLUID compares the effects of two commonly used resuscitation fluids: Normal Saline versus Ringer’s Lactate, on death and hospital readmissions. TRACTION is a pragmatic trial currently being planned at hospitals in Ontario and Manitoba, to evaluate whether a hospital policy of universal use of tranexamic acid during major surgeries safely reduces red blood cell transfusions. The methodological and ethical implications of cluster versus individual randomization will be discussed. Both FLUID and TRACTION raise several challenging ethical issues: What is an appropriate justification for cluster randomization? When individual-level interventions are implemented institution-wide as a policy in a cluster randomized trial, may one proceed without patient consent? Do patients need to be notified about the trial; if so, how? How should risk be evaluated given prior efficacy and safety data in other settings? After a series of presentations by trialists, methodologists and ethicists, we will engage in interactive discussions with the audience using a web-based audience response system.

Background: Pragmatic RCTs are intended to provided results that are directly relevant to clinical or health policy decisions, with designs concordant with this aim. While their intent to more closely align research with real-world applications may address concerns regarding the disconnect between research and practice they may also raise new ethical concerns. Methods: We conducted interviews with key stakeholders (methodologists, clinical investigators, ethicists, regulators, lay members of study teams). Interviewees were identified through published articles, funding decisions, centers known to be engaged in the design or conduct of pragmatic trials, and our investigator network. Results: We conducted 45 interviews between April-September 2018, with interviewees largely from the USA (16), Canada (10), UK (10) and mainly patient partners within study teams (16), clinical investigators (10), methodologists (7) and ethicists (7). Issues that were deemed to be more relevant or enhanced in relation to the oversight of pragmatic trials were: Risk identification and what counts as minimal risk?; The distinction (and relevance) between research, quality improvement, and practice; The potential for expanded populations affected by the trial and protections owed; The broader range of stakeholders in relation to the trial and determining their roles and responsibilities; Determining and reporting interventions or comparators as usual care, and; Determining when alterations to traditional informed consent approaches are appropriate. Discussion: To date the literature is dominated by discussion of consent and the research-practice distinction. Risk evaluation in this space was felt to be an area in need of development, particularly in relation to trials of routinely used interventions and whether these constitute research. The question of whether equal obligations are owed to all individuals affected by the trial has largely not been addressed. Each of these issues have substantive implications for the oversight of pragmatic trials. Keywords: consent, clinical trials