Developing a framework for the ethical design and conduct of pragmatic randomized controlled trials
To make informed decisions, patients, health providers and health system managers need reliable evidence of treatment safety, effectiveness and cost. Pragmatic randomized controlled trials (RCTs) are designed to provide such evidence by evaluating treatments in real-world conditions. But pragmatic RCTs raise difficult ethical issues that challenge researchers and research ethics committees. Our research team, comprising 25 philosophers, trialists and biostatisticians from five countries, will develop guidance for the ethical design and conduct of pragmatic RCTs.
PRINCIPAL INVESTIGATORS:
Monica Taljaard (Nominated Principal Investigator; Ottawa Hospital Research Institute)
Dean Fergusson (Ottawa Hospital Research Institute)
Terry Klassen (Manitoba CIHR SUPPORT Unit)
Charles Weijer (Rotman Institute of Philosophy, Western University)
PROJECT DATES:
2017 – 2021
PROJECT FUNDING:
Canadian Institutes of Health Research
Western University
PROJECT SUMMARY:
The randomized controlled trial (RCT) is a highly reliable method for evaluating treatment in health care. However, most RCTs are conducted under laboratory-like conditions, which limits their applicability to practice. There is therefore an urgent need for pragmatic RCTs, which are undertaken in real-world settings. Pragmatic RCTs provide patients, health providers and health system managers with reliable information on the safety, effectiveness and cost of treatments. Although ethical guidelines exist to protect participants in research, they were not written with pragmatic RCTs in mind. The lack of fit between current guidance and pragmatic RCTs leads to inadequate protections and unnecessary obstacles. In some instances, research participants are left unprotected in research; in other cases, socially important research is hindered.
Our research team, comprising 25 philosophers, trialists and biostatisticians from five countries, will develop guidance for the ethical design and conduct of pragmatic RCTs. Questions addressed include: When stepped wedge RCTs seek to study the roll-out of government policies, ought they be considered research or program evaluation? When pragmatic RCTs compare routinely available medical treatments, should the study interventions be classified as research or practice? Does clinical equipoise apply to pragmatic RCTs evaluating policy, knowledge translation or public health interventions? Must patients in pragmatic RCTs always be informed about trial participation and provide informed consent? When may a waiver of consent be used in pragmatic RCTs and what justifies such use? What is the role of gatekeepers in pragmatic RCTs? We will address these (and other) questions through a combination of ethical analysis and empirical study. This work will feed into a consensus process that will generate ethical guidance for researchers and research ethics committees globally.
Goal: The goal of our international, interdisciplinary collaboration is to develop guidance for the ethical design and conduct of pragmatic randomized controlled trials (RCTs).
Rationale: Pragmatic RCTs are distinct from explanatory RCTs in that they are designed to evaluate treatments in real-world (as opposed to ideal) conditions, directly informing decision-making by patients, health providers and health system managers. They commonly test new treatment strategies against current routine strategies, or different routine strategies head-to-head. The need for more pragmatic RCTs has been identified by the Canadian Institutes of Health Research as an urgent priority. New advances in electronic infrastructure which dramatically lower the cost of pragmatic RCTs (e.g. Institute for Clinical Evaluative Sciences in Ontario, Manitoba Center for Health Policy), along with billions in support from governments worldwide (e.g. Canadian Institutes for Health Research’s Strategy for Patient-Oriented Research, United Kingdom National Institute for Health Research), present an unprecedented opportunity to advance the conduct of pragmatic RCTs, which can ultimately improve the quality and value of health systems and practices. Progress has also been made towards centralized ethics review that permits timely review of multicentre trials (e.g., Clinical Trials Ontario, Health Research Ethics Board of Alberta) and recent methodological advances (e.g., cluster crossovers, stepped wedge, cohort multiple and registry trials) can facilitate the conduct of pragmatic RCTs with high internal and external validity.
However, pragmatic RCTs raise substantial ethical issues that have not yet been adequately addressed: Should trials of routine medical treatments be regulated as research or subsumed under the norms of medical care? What type of consent, if any, is required and what information about risks and benefits should be disclosed to patients? What level of oversight is necessary? The lack of an adequate ethics framework to address these questions is currently a barrier to conducting pragmatic RCTs. Much of the existing literature on pragmatic RCTs appeals to US regulations and lacks convincing arguments grounded in ethical principles. Proposed solutions (e.g. using different regulations in learning healthcare systems) are speculative with no guarantee of improvement over existing oversight procedures. Most importantly, the literature does not reflect a broad vision of protecting core liberty and welfare interests of research participants; novel ethical solutions are required.
Methods: To address this gap, our project will combine empirical and conceptual work, and a consensus process.
Empirical work will 1) identify a comprehensive list of ethical issues through in-depth interviews with experts (trialists, ethicists, research ethics committee chairs), 2) document practice by reviewing a random sample of pragmatic RCTs and surveying authors; 3) elicit views of research ethics chairs through surveys in Canada, UK, US, France, Australia and 4) elicit views and experiences of patients and decision-makers through focus groups and surveys.
The conceptual work will be an in-depth analysis of the identified ethical issues from the empirical work. This will result in a series of background publications outlining proposed solutions with principles, policy options and rationale. Both the empirical and ethical workstreams will inform a consensus process.
The consensus process will involve convening an international Expert Panel and a consensus conference. We will engage in an e-consultation with the broader research community, funders, regulators and patient groups. The Expert Panel will produce the final guidance document which will be disseminated internationally.
Study team: Includes philosophers, trialists, methodologists, social scientists, knowledge users and patients.
Outcomes: Background papers, educational materials and tailored guidance documents to inform and support researchers, research ethics committees, regulators and funders in the ethical design and conduct of pragmatic RCTs.
Faculty:
| Monica Taljaard (Ottawa Hospital Research Institute) | Dean Fergusson (Ottawa Hospital Research Institute) |
| Terry Klassen (University of Manitoba) | Charles Weijer (Western University) |
| Jamie Brehaut (Ottawa Hospital Research Institute) | Marion Campbell (University of Aberdeen) |
| Allan Donner (Western University) | Sarah Edwards (University College London) |
| Sandra Eldridge (Barts and the London School of Medicine and Dentistry) | Christopher Forrest (University of Pennsylvania) |
| Bruno Giraudeau (Université François-Rabelais de Tours) | Ian Graham (Ottawa Hospital Research Institute) |
| Jeremy Grimshaw (Ottawa Hospital Research Institute) | Karla Hemming (University of Birmingham) |
| Spencer Hey (Harvard University) | Vipul Jairath (Western University) |
| Alex London (Carnegie Mellon University) | Susan Marlin (Clinical Trials Ontario) |
| John Marshall (University of Toronto) | Lauralyn McIntyre (Ottawa Hospital Research Institute) |
| Joanne McKenzie (Monash University) | Alison Paprica (University of Toronto) |
| Merrick Zwarenstein (Western University) |
Trainees:
| Cory Goldstein (Western University) |
| Austin Horn (Western University – Former trainee) |
Articles:
Core ethical concepts
Hey SP, Weijer C, Taljaard M, Kesselheim AS. Research ethics for emerging trial designs: does equipoise need to adapt? British Medical Journal 2018; 360: k226.
Hey SP, London AJ, Weijer C, Rid A, Miller F. Is the concept of clinical equipoise still relevant to research? British Medical Journal 2017; 359: j5787.
Goldstein CE, Brehaut J, Weijer C. Does consent form follow function? American Journal of Bioethics 2017; 17(12): 29-31.
Horn AR, Weijer C. Clinical Equipoise. Encyclopedia of Global Bioethics 2016: 1–11.
Hey SP, Weijer C. What questions can a placebo help answer? Monash Bioethics Review 2016; 34(1): 23–36.
Weijer C, Miller PB, Graham M. The duty of care and equipoise in randomized controlled trials. In: Arras JD, Kukla R, Fenton E (eds.). Routledge Companion to Bioethics. Routledge: New York, 2015: pp. 200–214.
Pragmatic RCTs
Nicholls SG, Carroll K, Brehaut JC, Weijer C, Hey SP, Goldstein CE, Zwarenstein M, Graham I, McKenzie JE, McIntyre L, Jairath V, Campbell MK, Grimshaw JM, Fergusson DA, Taljaard, M. Stakeholder views regarding ethical issues in the design and conduct of pragmatic trials: Study Protocol. BMC Medical Ethics 2018; 19: 90.
Taljaard M, Weijer C, Grimshaw JM, Ali A, Brehaut JC, Campbell MK, Carroll K, Edwards S, Eldridge S, Forrest CB, Giraudeau B, Goldstein CE, Graham I, Hemming K, Hey SP, Horn AR, Jairath V, Klassen TP, London AJ, Marlin S, Marshall JC, McIntyre L, McKenzie JE, Nicholls SG, Paprica PA, Zwarenstein M, Fergusson DA. Developing a framework for the ethical design and conduct of pragmatic trials to improve patient health and health system outcomes: Study protocol for a mixed methods study. Trials2018; 19: 525.
Goldstein CE, Weijer C, Brehaut J, Campbell M, Fergusson D, Grimshaw JG, Hemming K, Horn AR, Taljaard M. Accommodating quality and service improvement research within existing ethical regulations. Trials 2018; 19: 334.
Horn AR, Weijer C, Grimshaw JM, Brehaut JC, Fergusson D, Goldstein CE, Taljaard M. An ethical analysis of the SUPPORT trial: addressing challenges posed by pragmatic comparative effectiveness randomized controlled trials with interventions routinely used in medical practice. Kennedy Institute of Ethics Journal 2018; 28(1): 85-117.
Goldstein CE, Brehaut J, Fergusson D, Grimshaw J, Horn AR, Taljaard M, Weijer C. Ethical issues in pragmatic randomized controlled trials: a review of the literature identifies gaps in ethical argumentation. BMC Medical Ethics 2018; 19(1): 14.
Weijer C, Goldstein CE, Taljaard M. TwiC or treat? Are trials within cohorts ethically defensible? Clinical Trials 2017; 15(1): 21-24.
Campbell MK, Weijer C, Goldstein CE, Edwards SJ. Do doctors have a duty to participate in pragmatic randomised trials? British Medical Journal 2017; 357: j2817.
Cluster randomized trials
McIntyre L, Taljaard M, McArdle T, Fox-Robichaud A, English SW, Martin C, Marshall J, Menon K, Muscedere J, Cook DJ, Weijer C, Saginur R, Maybee A, Iyengar A, Forster A, Graham ID, Hawken S, McCartney C, Seely AJ, Stiell IG, Thavorn K, Fergusson DA. FLUID trial: a protocol for a hospital-wide open-label cluster crossover pragmatic comparative effectiveness randomised pilot trial. BMJ Open2018; 8(8): e022780.
Goldstein CE, Giraudeau B, Weijer C, Taljaard M.In reply: when and how should we cluster and cross over: methodological and ethical issues (letters 1 and 2).Canadian Journal of Anesthesia2018; 66(2): 239-240.
Goldstein CE, Giraudeau B, Weijer C, Taljaard M. When and how should we cluster and cross over: methodological and ethical issues. Canadian Journal of Anesthesia 2018; 65(7): 760-765.
Horn AR, Weijer C, Hey SP, Brehaut JC, Fergusson D, Goldstein CE, Grimshaw JM, Taljaard M. Thinking clearly about the FIRST trial: Addressing ethical challenges in cluster randomized trials involving health providers. Journal of Medical Ethics 2018; 44(9): 593-598.
Hemming K, Taljaard M, Forbes G, Eldrige SM, Weijer C. Ethical implications of excessive cluster sizes in cluster randomised trials. BMJ Quality and Safety 2018; 27(8): 664-670.
Hemming K, Eldridge S, Forbes G, Weijer C, Taljaard M. How to design efficient cluster randomised trials. British Medical Journal 2017; 358: j3064.
McRae AM, Taljaard M, Weijer C. Cluster randomized trials: a closer look. Clinical Trials 2016; 13(3): 294–300.
Taljaard M, Weijer C, Grimshaw JM. Ethical implications of cluster randomized trials. International Encyclopedia of the Social and Behavioral Sciences (2nd ed.) 2015: 897–905.
Taljaard M, Chaudhry SH, Brehaut JC, Weijer C, Grimshaw JM. Mail merge can be used to create personalized questionnaires in complex surveys. BMC Research Notes 2015; 8: 574.
Stepped wedge trials
Hemming K, Taljaard M, McKenzie JE, Hooper R, Copas A, Thompson JA, Dixon-Woods M, Aldcroft A, Doussau A, Grayling M, Kristunas C, Goldstein CE, Campbell MK, Girling A, Eldridge S, Campbell MJ, Lilford RJ, Weijer C, Forbes AB, Grimshaw JM. Reporting of stepped wedge cluster randomised trials: extension of the CONSORT 2010 statement with explanation and elaboration. BMJ2018; 363: k1614.
Hemming K, Taljaard M, Forbes A. Modeling clustering and treatment effect heterogeneity in parallel and stepped-wedge cluster randomized trials. Statistics in Medicine 2018; 37(6): 883-898.
Taljaard M, Hemming K, Shah L, Giraudeau B, Grimshaw JM, Weijer C. Inadequacy of ethical reporting and conduct of stepped wedge cluster randomised trials: results from a systematic review. Clinical Trials 2017; 14(4): 333-341.
Presentations:
Workshops and panels
Weijer C, Taljaard M, Goldstein CE. Workshop on the ethics of cluster randomized trials. Pragmatic Clinical Trials Unit, Queen Mary University London. London, United Kingdom. November 21, 2018.
Taljaard M, Weijer C, Hey SH, Goldstein CE, Fergusson D. Developing a framework for the ethical design and conduct of pragmatic trials: consultation with the clinical trials community. Society for Clinical Trials. Portland, USA. May 22, 2018.
Hey SH, Renfro L, Taljaard M, Weijer C. Developing a framework for the ethical design and conduct of pragmatic trials: consultation with the clinical trials community. Society for Clinical Trials. Portland, USA. May 21, 2018.
Saginur R, Fergusson D, Karanicolas P, Weijer C. Innovation and ethical considerations in clinical trial design. Clinical Trials Ontario Conference. Toronto, CA. March 27, 2018.
Naganathan V, Travison T, Allore H, Taljaard M, Weijer C. International, Pragmatic and Multisite Trials: Design, Implementation and Ethical Considerations (Invited Panel). 21st IAGG World Congress of Gerontology and Geriatrics. San Francisco, USA. July 24, 2017.
Weijer C, Borio LL, Gertz BJ, Miller JE, Troxel A. Beyond RCTs: Assessing the need for alternatives (Invited panel). New York Academy of Sciences Conference on “The Direction of Clinical Trials”. New York, USA. June 21, 2017.
Eldridge S, Grimshaw JM, Goldstein CE, Hey SP, Weijer C. The pragmatic randomized controlled trial at 50: past successes; future challenges (Invited panel). International Clinical Trials and Methodology Conference and Society for Clinical Trials. Liverpool, UK. May 9, 2017.
Fergusson D, McIntyre L, Taljaard M, Horn A, Weijer C. Ethical challenges in pragmatic comparative effectiveness trials (Invited panel). Society for Clinical Trials. Montreal, CA. May 15, 2016.
Dijkgraaf R, Alberts B, Nordling L, Mair D, Weijer C, Soror S. Interplay between science advice, politics and the media (Invited panel). Interacademy Partnership Conference on Science Advice. Hermanus, South Africa. March 1, 2016.
Hemming K, Taljaard M, Weijer C, Matei M, Eldridge S, Giraudeau B. Variations in Regulatory Requirements and Implications for Consent Procedures in Cluster Randomized Trials (Invited Workshop). Society for Clinical Trials. Arlington, USA. May 18, 2015
Individual talks
Taljaard M, Weijer C. Ethics in cluster randomized trials. Center for Evaluation, London School of Hygiene and Tropical Medicine. London, United Kingdom. November 19, 2018.
Weijer, Taljaard M. The ethics of cluster randomized trials: A response to van der Graaf and colleagues. CEP 2nd Biennial Workshop on Ethics & Public Policy. Pittsburgh, USA. November 2, 2018.
Goldstein CE, Weijer C. “Do patients have a moral obligation to participate in research?” Meeting of the American Society for Bioethics and Humanities, Disneyland, California, US. October 19, 2018.
Taljaard M, Weijer C. Ethical issues in cluster randomized trials. INSERM Workshop 254: Principles and Methods of Population Health Intervention Research. Bordeaux, France. October 19, 2018.
Weijer C. Ethical issues in pragmatic trials in hemodialysis units in Ontario. Gardener’s Grove 2018: Growing Knowledge to Live Well. Mississauga, June 3, 2018.
Goldstein CE, Weijer C. Ethical implications for pragmatic trials involving head-to-head comparisons of usual care interventions: an ethical analysis of the MINT trial. Society for Clinical Trials. Portland, USA. May 22, 2018.
Goldstein CE, Weijer C. The learning health care system and conscription into research: the content and limits of a Rawlsian common good. American Society for Bioethics and Humanities. Kansas City, USA. October 20, 2017.
Weijer C. Origins and evolution of equipoise. Research Ethics for the 21st Century: Does Clinical Equipoise Need to Adapt? Harvard Medical School. Boston, USA. September 28, 2017.
Goldstein CE, Horn AR, Taljaard M, Weijer C. Ethical issues in individual-cluster trials: beyond the Ottawa Statement. Canadian Bioethics Society. Montreal, CA. May 25, 2017.
Goldstein CE, Horn AR, Taljaard M, Weijer C. Ethical Issues in individual-cluster trials: beyond the Ottawa Statement. Ethox Centre. Oxford, UK. May 10, 2017.
Goldstein CE, Horn AR, Taljaard M, Weijer C. Ethical Issues in individual-cluster trials: beyond the Ottawa Statement. International Clinical Trials and Methodology Conference and Society for Clinical Trials. Liverpool, UK. May 9, 2017.
Weijer C. Inadequacy of ethical conduct and reporting of stepped wedge cluster randomized trials: Results from a systematic review. The CONSORT extension for stepped-wedge cluster randomised trials (SW-CRT): Liverpool consensus meeting. Liverpool, UK. May 7, 2017.
Weijer C. Models of informed consent in pragmatic trials. Ontario SPOR Support Unit (OSSU) Workshop on Pragmatic Trials. Toronto, CA. March 7, 2017.
Taljaard M, Weijer C. Pragmatic randomized controlled trials: interplay between design and ethics. Clinical Epidemiology Program Rounds. Ottawa, CA. January 27, 2017.
Taljaard M, Weijer C. The ethics of cluster randomized trials. Public Health Agency of Canada Research Ethics Board. Ottawa, CA. January 12, 2017.
Weijer C, Taljaard M. The ethics of pragmatic trials. Ottawa Hospital Research Institute Clinical Research Week. Ottawa, CA. October 18, 2016.
Horn AR, Taljaard M, Weijer C. An ethical analysis of the SUPPORT study: addressing challenges posed by a randomized controlled trial comparing standard treatments used in medical practice. American Society for Bioethics and Humanities. Washington, DC, USA. October 10, 2016.
Horn AR, Taljaard M, Weijer C. An ethical analysis of the SUPPORT study: addressing challenges posed by a randomized controlled trial comparing standard treatments used in medical practice. International Association of Bioethics. Edinburgh, UK. June 15, 2016.
Horn AR, Taljaard M, Weijer C. An ethical analysis of the SUPPORT study: addressing challenges posed by a randomized controlled trial comparing standard treatments used in medical practice. Canadian Bioethics Society. Toronto, ON. May 27, 2016.
Goldstein CE, Taljaard M, Weijer C. Ethics of pragmatic randomized controlled trials. Meeting of the Society for Clinical Trials. Montreal, CA. May 17, 2016.
Horn AR, Taljaard M, Weijer C. An ethical analysis of the SUPPORT study: addressing challenges posed by a randomized controlled trial comparing standard treatments used in medical practice. Society for Clinical Trials. Montreal, CA. May 17, 2016.
Weijer C. Ethical issues in cluster randomized trials in health research. International Working Group, U.S. Office for Human Research Protections. Washington, DC, USA. April 13, 2016.
Weijer C. Recent advances in research ethics: developing the first ethical guidelines for cluster randomized trials. Western Research Forum. London, CA. March 21, 2015.
Previous Projects:
Ethical and Policy Issues in Cluster Randomized Trials
Previous Trainees:
Ariella Binik (Ethox Center, University of Oxford)
Spencer Hey (Center for Bioethics, Harvard University)
Andrew McRae (Division of Emergency Medicine, University of Calgary)
Andrew Peterson (Institute for Philosophy and Public Policy, George Mason University)
Our research project offers an outstanding training opportunity for graduate students in applied ethics, philosophy of science (clinical trials) and epidemiology. The ethical and policy challenges posed by pragmatic RCTs are complex and, as such, solutions will require scholarship at the interface between philosophy and the medical sciences.
As full members of an internationally recognized research team, trainees will learn how to collaborate with scholars from other disciplines, write papers for philosophy, clinical trials and medical journals, present work to diverse audiences, participate in crafting policy to guide the design and conduct of pragmatic RCTs, and engage the public through education and social media. Core members of our research team have worked together for a decade, and our trainees have gone on to research and faculty positions at Harvard University, the University of Oxford and other excellent institutions.
If you are interested in getting involved with our project, there are funded opportunities for graduate students available. Those interested are encouraged to contact Charles Weijer.
Photo credit: The physician by Adrian Clark (license)