The ethical challenges raised in the design and conduct of pragmatic trials: an interview study with key stakeholders

Abstract

Background: There is a concern that the apparent effectiveness of interventions tested in clinical trials may not be an accurate reflection of their actual effectiveness in usual practice. Pragmatic randomized controlled trials (RCTs) are designed with the intent of addressing this discrepancy. While pragmatic RCTs may increase the relevance of research findings to practice they may also raise new ethical concerns (even while reducing others). To explore this question, we interviewed key stakeholders with the aim of identifying potential ethical challenges in the design and conduct of pragmatic RCTs with a view to developing future guidance on these issues.

Methods: Interviews were conducted with clinical investigators, methodologists, patient partners, ethicists, and other knowledge users (e.g., regulators). Interviews covered experiences with pragmatic RCTs, ethical issues relevant to pragmatic RCTs, and perspectives on the appropriate oversight of pragmatic RCTs. Interviews were coded inductively by two coders. Interim and final analyses were presented to the broader team for comment and discussion before the analytic framework was finalized.

Results: We conducted 45 interviews between April and September 2018. Interviewees represented a range of disciplines and jurisdictions as well as varying content expertise. Issues of importance in pragmatic RCTs were (1) identification of relevant risks from trial participation and determination of what constitutes minimal risk; (2) determining when alterations to traditional informed consent approaches are appropriate; (3) the distinction between research, quality improvement, and practice; (4) the potential for broader populations to be affected by the trial and what protections they might be owed; (5) the broader range of trial stakeholders in pragmatic RCTs, and determining their roles and responsibilities; and (6) determining what constitutes "usual care" and implications for trial reporting.

Conclusions: Our findings suggest both the need to discuss familiar ethical topics in new ways and that there are new ethical issues in pragmatic RCTs that need greater attention. Addressing the highlighted issues and developing guidance will require multidisciplinary input, including patient and community members, within a broader and more comprehensive analysis that extends beyond consent and attends to the identified considerations relating to risk and stakeholder roles and responsibilities.

Keywords: Benefit-harm analysis; Comparative effectiveness; Informed consent; Interviews; Pragmatic trial; Qualitative; Randomized controlled trial; Research ethics; Vulnerable participants.