Clinical Trial Regulations and Guidelines & Quality in Clinical Trials (Canadian Cancer Trials Group, 2019): 25-slide presentation.

• Summary: A broad overview of clinical trial regulations in Canada, including a brief description of the Nuremburg Code, the Declaration of Helsinki, the Tri-Council Policy Statement (TCPS), relevant Food and Drug regulations in Canada, and ICH-Good Clinical Practice (E6). * Note: The regulatory approval requirements for pragmatic trials depend on the specific nature of the trial. Researchers are encouraged to consult Health Canada guidance documents (conveniently hyperlinked throughout this summary website), seek advice from their local REBs, and to contact Health Canada directly if future clarification is needed.

NIH Pragmatic Trials Collaboratory - Ethical and Regulatory Oversight Considerations (May 14, 2021): 13-min webinar (28-slide presentation)

• Summary: Dr. Stephanie Morain introduces ethical and regulatory oversight considerations related to, e.g., consent, data monitoring, defining minimal risk, the research/quality improvement distinction, vulnerable participants, REB harmonization, identifying direct and indirect participants, gatekeepers, (FDA)-regulated projects, the nature of interventions tested in pragmatic trials, and privacy. While some terminology mentioned is specific to the United States, the considerations are similar in the Canadian landscape.

Califf RM, Sugarman J. Exploring the ethical and regulatory issues in pragmatic clinical trials. Clin Trials. 2015 Oct;12(5):436-41. (9-page paper)

• Summary: The integration of research and practice (as often observed in pragmatic trials) poses questions about appropriate ethical and regulatory oversight. By examining pragmatic trials in the United States, it became apparent that long-term success in implementing innovative clinical trials would also require a reexamination of existing ethical and regulatory approaches. This paper sets the stage for a series of open access articles discussing: (1) the role of gatekeepers, (2) harmonization of institutional review boards (REBs), (3) distinctions between research and quality improvement activities, (4) the nature of interventions in pragmatic trials, (5) identifying direct and indirect subjects, (6) determining what constitutes “no more than minimal risk” research, (7) the use of waiver or modification of informed consent, (8) engaging vulnerable subjects, (9) investigations involving the use of regulated products, (10) privacy, and (11) the role of data monitoring.

NIH Pragmatic Trials Collaboratory - Ethics and Regulatory Challenges and Lessons Learned (May 9, 2024): 6-min webinar.

• Summary: Drs. Stephanie Morain and Pearl O’Rourke discuss ethics and regulatory challenges and lessons learned during the NIH Pragmatic Trials Collaboratory's 2024 Annual Steering Committee Meeting.

Goldstein CE, et al. Ethical issues in pragmatic randomized controlled trials: a review of the recent literature identifies gaps in ethical argumentation. BMC Med Ethics. 2018 Feb 27;19(1):14. (10-page paper)

• Summary: Given that pragmatic trials raise unique ethical complexities for researchers and regulators, this scoping review describes ethical considerations in these studies and highlights gaps in the ethics literature. Four major themes were revealed: (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. It is noted that the current discussion about the ethical considerations related to pragmatic trials is overwhelmingly taking place in the United States.

Kim SY, Kimmelman J. Practical steps to identifying the research risk of pragmatic trials. Clin Trials. 2022 Apr;19(2):211-216. (10-page paper)

• Summary: Pragmatic trials that compare two or more purportedly “within the standard of care” interventions may provide real-world evidence for informing policy and practice decisions. However, there is debate regarding their research “risk status” which in turn could lead to confusion about appropriate regulatory and consent requirements. Using a variety of examples of “standard of care” pragmatic trials, a four-step-process illustrates how a researcher can evaluate the additional research risk associated with their planned study.

Sugarman J, Califf RM. Ethics and regulatory complexities for pragmatic clinical trials. JAMA. 2014 Jun 18;311(23):2381-2. (2-page paper) * As this is an optional resource, an institutional login (e.g., university or research institute e-mail address) is required to access this material. 

• Summary: Based on experiences from select pragmatic trials in the United States, a description of ten ethical and regulatory complexities that “must be unraveled in ways that enable vital research while also protecting the rights, interests, and welfare of research participants” is provided. These include: (1) Consent, (2) Risk determination, (3) Nature of interventions, (4) Identifying research participants, (5) Regulated products, (6) Institutional review boards (/REBs), (7) Research and quality improvement, (8) Vulnerable subjects, (9) Data monitoring, and (10) Gatekeepers.