Jeremy Grimshaw

Randomized controlled trial trial designs exist on an explanatory-pragmatic spectrum, depending on the degree to which a study aims to address a question of efficacy or effectiveness. As conceptualized by Schwartz and Lellouch in 1967, an explanatory approach to trial design emphasizes hypothesis testing about the mechanisms of action of treatments under ideal conditions, whereas a pragmatic approach emphasizes testing effectiveness of two or more available treatments in real-world conditions. Interest in, and the number of, pragmatic trials has grown substantially in recent years, with increased recognition by funders and stakeholders worldwide of the need for credible evidence to inform clinical decision-making. This increase has been accompanied by the onset of learning healthcare systems, as well as an increasing focus on patient-oriented research. However, pragmatic trials have ethical challenges that have not yet been identified or adequately characterized. The present study aims to explore the views of key stakeholders with respect to ethical issues raised by the design and conduct of pragmatic trials. It is embedded within a large, four-year project that seeks to develop guidance for the ethical design and conduct of pragmatic trials. As a first step, this study will address important gaps in the current empirical literature with respect to identifying a comprehensive range of ethical issues arising from the design and conduct of pragmatic trials. By opening up a broad range of topics for consideration within our parallel ethical analysis, we will extend the current debate, which has largely emphasized issues of consent, to the range of ethical considerations that may flow from specific design choices. Semi-structured interviews with key stakeholders, across multiple jurisdictions, identified based on their known experience and/or expertise with pragmatic trials. We expect that the study outputs will be of interest to a wide range of knowledge users including trialists, ethicists, research ethics committees, journal editors, regulators, healthcare policymakers, research funders and patient groups. All publications will adhere to the Tri-Agency Open Access Policy on Publications.

Pragmatic comparative effectiveness randomized controlled trials evaluate the effectiveness of one interventions under real-world clinical conditions. The results of ceRCTs are often directly generalizable to everyday clinical practice, providing information critical to decision-making by patients, clinicians, and healthcare policymakers. The PRECIS-2 framework identifies nine domains that serve to score a trial on a continuum between very explanatory to very pragmatic. According to the framework, pragmatic trials may have one or more of the following features: there are fewer eligibility criteria for participants, in an...

The ethics of the Flexibility In duty hour Requirements for Surgical Trainees trial have been vehemently debated. Views on the ethics of the FIRST trial range from it being completely unethical to wholly unproblematic. The FIRST trial illustrates the complex ethical challenges posed by cluster randomised trials of policy interventions involving healthcare professionals. In what follows, we have three objectives. First, we critically review the FIRST trial controversy, finding that commentators have failed to sufficiently identify and address many of the relevant ethical issues. The 2012 Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides researchers and research ethics committees with specific guidance for the ethical design and conduct of CRTs. Second, we aim to demonstrate how the Ottawa Statement provides much-needed clarity to the ethical issues in the FIRST trial, including: research participant identification; consent requirements; gatekeeper roles; benefit-harm analysis and identification of vulnerable participants. We nonetheless also find that the FIRST trial raises ethical issues not adequately addressed by the Ottawa Statement. Hence, third and finally, we raise important questions requiring further ethical analysis and guidance, including: Does clinical equipoise apply to policy interventions with little or no evidence-base? Do healthcare providers have an obligation to participate in research? Does the power-differential in certain healthcare settings render healthcare providers vulnerable to duress and coercion to participant in research? If so, what safeguards might be implemented to protect providers, while allowing important research to proceed?

Pragmatic randomized controlled trials are designed to evaluate the effectiveness of interventions in real-world clinical conditions. However, these studies raise ethical issues for researchers and regulators. Our objective is to identify a list of key ethical issues in pragmatic RCTs and highlight gaps in the ethics literature. We conducted a scoping review of articles addressing ethical aspects of pragmatic RCTs. After applying the search strategy and eligibility criteria, 36 articles were included and reviewed using content analysis. Our review identified four major themes: 1) the research-practice distinction; 2) the need for consent; 3) elements that must be disclosed in the consent process; and 4) appropriate oversight by research ethics committees. 1) Most authors reject the need for a research-practice distinction in pragmatic RCTs. They argue that the distinction rests on the presumptions that research participation offers patients less benefit and greater risk than clinical practice, but neither is true in the case of pragmatic RCTs. 2) Most authors further conclude that pragmatic RCTs may proceed without informed consent or with simplified consent procedures when risks are low and consent is infeasible. 3) Authors who endorse the need for consent assert that information need only be disclosed when research participation poses incremental risks compared to clinical practice. Authors disagree as to whether randomization must be disclosed. 4) Finally, all authors view regulatory oversight as burdensome and a practical impediment to the conduct of pragmatic RCTs, and argue that oversight procedures ought to be streamlined when risks to participants are low. The current ethical discussion is framed by the assumption that the function of research oversight is to protect participants from risk. As pragmatic RCTs commonly involve usual care interventions, the risks may be minimal. This leads many to reject the research-practice distinction and question the need for informed consent. But the function of oversight should be understood broadly as protecting the liberty and welfare interest of participants and promoting public trust in research. This understanding, we suggest, will focus discussion on questions about appropriate ethical review for pragmatic RCTs.

Background Pragmatic randomized controlled trials are designed to evaluate the effectiveness of interventions in real-world clinical conditions. However, these studies raise ethical issues for researchers and regulators. Our objective is to identify a list of key ethical issues in pragmatic RCTs and highlight gaps in the ethics literature. Methods We conducted a scoping review of articles addressing ethical aspects of pragmatic RCTs. After applying the search strategy and eligibility criteria, 36 articles were included and reviewed using content analysis. Results Our review identified four major themes: 1) the research-practice distinction; 2) the need for consent; 3) elements that must be disclosed in the consent process; and 4) appropriate oversight by research ethics committees. 1) Most authors reject the need for a research-practice distinction in pragmatic RCTs. They argue that the distinction rests on the presumptions that research participation offers patients less benefit and greater risk than clinical practice, but neither is true in the case of pragmatic RCTs. 2) Most authors further conclude that pragmatic RCTs may proceed without informed consent or with simplified consent procedures when risks are low and consent is infeasible. 3) Authors who endorse the need for consent assert that information need only be disclosed when research participation poses incremental risks compared to clinical practice. Authors disagree as to whether randomization must be disclosed. 4) Finally, all authors view regulatory oversight as burdensome and a practical impediment to the conduct of pragmatic RCTs, and argue that oversight procedures ought to be streamlined when risks to participants are low. Conclusion The current ethical discussion is framed by the assumption that the function of research oversight is to protect participants from risk. As pragmatic RCTs commonly involve usual care interventions, the risks may be minimal. This leads many to reject the research-practice distinction and question the need for informed consent. But the function of oversight should be understood broadly as protecting the liberty and welfare interest of participants and promoting public trust in research. This understanding, we suggest, will focus discussion on questions about appropriate ethical review for pragmatic RCTs.

Owing to unique features of their design, cluster randomized trials complicate the interpretation of standard ethics guidelines. The recently published Ottawa statement on the ethical design and conduct of cluster randomized trials provides researchers and research ethics committees with detailed guidance on the design, conduct and review of cluster trials. The Ottawa statement sets out 15 recommendations, including guidance on the justification of study design, the need for research ethics committee review, the identification of research participants, obtaining informed consent, the role of gatekeepers in protecting cluster interests, the assessment of benefits and harms, and the protection of vulnerable participants

Owing to unique features of their design, cluster randomized trials complicate the interpretation of standard ethics guidelines. The recently published Ottawa statement on the ethical design and conduct of cluster randomized trials provides researchers and research ethics committees with detailed guidance on the design, conduct, and review of cluster trials. The Ottawa statement sets out 15 recommendations, including guidance on the justification of study design, the need for research ethics committee review, the identification of research participants, obtaining informed consent, the role of gatekeepers in protecting cluster interests, the assessment of benefits and harms, and the protection of vulnerable participants.

Objective Cluster randomised trial (CRT) investigators face challenges in seeking informed consent from individual patients (cluster members). This study examined associations between reporting of patient consent in healthcare CRTs and characteristics of these trials. Study design Consent practices and study characteristics were abstracted from a random sample of 160 CRTs performed in primary or hospital care settings that were published from 2000 to 2008. Multivariable logistic regression was used to examine associations between reporting of patient consent and methodological characteristics, as well as publication features such as date and journal of publication. Results 82 (53.8%) of 160 studies reported obtaining informed consent from individual patients. Reporting of patient consent was independently and positively associated with: smaller cluster size, the evaluation of experimental interventions targeted at patients, data collection from individual patients, publication later than 2004 and publication in higher-impact journals. Conclusions Reporting of consent practices in published CRTs should be improved. Consent practices in published CRTs appear to be related to the type of interventions under study, as well as journal impact and trends in research ethics practices. These findings will inform best practices in trial conduct and ethics review, remediation of errors in consent practices and ethics review and the development of regulatory guidance for CRTs

Quality and service improvement (QSI) research employs a broad range of methods to enhance the efficiency of healthcare delivery. QSI research differs from traditional healthcare research and poses unique ethical questions. Since QSI research aims to generate knowledge to enhance quality improvement efforts, should it be considered research for regulatory purposes? Is review by a research ethics committee required? Should healthcare providers be considered research participants? If participation in QSI research entails no more than minimal risk, is consent required? The lack of consensus on answers to these questions highlights the need for ethical guidance. Three distinct approaches to classifying QSI research in accordance with existing ethical principles and regulations can be found in the literature. In the first approach, QSI research is viewed as distinct from other types of healthcare research and does not require regulation. In the second approach, QSI research falls within regulatory guidelines but is exempt from research ethics committee review. In the third approach, QSI research is deemed to be part of the learning healthcare system and, as such, is subject to a different set of ethical principles entirely. In this paper, we critically assess each of these views. While none of these approaches is entirely satisfactory, we argue that use of the ethical principles governing research provides the best means of addressing the numerous questions posed by QSI research.