Developing a framework for the ethical design and conduct of pragmatic randomized controlled trials

 
 

Overview

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 routine medical care, 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, along with billions in support from governments worldwide, 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 and recent methodological advances can facilitate the conduct of pragmatic RCTs with high internal and external validity.


Pragmatic RCTs raise ethical issues that have not yet been adequately addressed: Should trials of routine medical treatments be regulated as research or practice? What type of consent 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.


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.

 

Members

Principal investigators

Monica Taljaard (Ottawa Hospital Research Institute)

Dean Fergusson (Ottawa Hospital Research Institute)

Terry Klassen (University of Manitoba)

Charles Weijer (Western University)

Co-investigators

Jamie Brehaut (Ottawa Hospital Research Institute)

Marion Campbell (University of Aberdeen)

Allan Donner (Western University)

Sarah Edwards (University College London)

Sandra Eldridge (Barts & the London Queen Mary's School of Medicine)

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

Jess du Toit (Western University)

Cory Goldstein (Western University)

Hayden Peter Nix (Western University)

 
 

Publications

Study protocol

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. Trials 2018; 19: 525.

 

Guidelines

World Health Organization. Ethical considerations for health policy and systems research. Geneva: WHO, 2019.

 

Cluster randomized trials

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.

 

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.

 

McRae AM, Taljaard M, Weijer C. Cluster randomized trials: a closer look. Clinical Trials 2016; 13(3): 294–300.

 

Hemming K, Eldridge S, Forbes G, Weijer C, Taljaard M. How to design efficient cluster randomised trials. British Medical Journal 2017; 358: j3064.

 

Hemming K, Taljaard M, Forbes G, Eldridge SM, Weijer C. Ethical implications of excessive cluster sizes in cluster randomised trials. BMJ Quality and Safety 2018; 27(8): 664-670.

 

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.

 

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.

 

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 Anesthesia 2018; 66(2): 239-240.

 

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 Open 2018; 8(8): e022780.

 

Weijer C, Taljaard M. The ethics of cluster randomized trials: response to a proposal for revision of the Ottawa Statement. J Clin Epidemiol 2019; 116: 140-145.

 

Goldstein CE, Weijer C. A stepwise approach to ethically assess pragmatic cluster randomized trials: implications for informed consent for suicide prevention implementation research. American Journal of Bioethics 2019: 19(10): 101–103.

 

Weijer C, Taljaard M. Ottawa Statement does not impede randomised evaluation of government health programmes. J Med Ethics 2020; 46(1): 31-33.

 

Taljaard M, Goldstein CE, Giraudeau B, Nicholls SG, Carroll K, Hey SP, Brehaut JC, Jairath V, London AJ, Eldridge SM, Grimshaw JM, Fergusson DA, Weijer C. Cluster over individual randomization: are study design choices appropriately justified? Review of a random sample of trials. Clin Trials 2020; 17(3): 253-263.

Al-Jaishi AA, Carroll K, Goldstein CE, Dixon SN, Garg AX, Nicholls SG, Grimshaw JM, Weijer C, Brehaut J, Thabane L, Devereaux PJ, Taljaard M. Reporting of key methodological and ethical aspects of cluster trials in hemodialysis require improvement: a systematic review. Trials. 2020; 21(1): 752. 

 

 

Core ethical concepts

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.

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.

Goldstein CE, Brehaut J, Weijer C. Does consent form follow function? American Journal of Bioethics 2017; 17(12): 29-31.

 

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.

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.

 

Nix HP, Weijer C. Rules of the road for patient-driven consent processes. American Journal of Bioethics 2020; 20(5): 36–37.

Low- and middle-income countries

Mtande TK, Weijer C, Hosseinipour MC, Taljaard M, Matoga M, Goldstein CE, Nyambalo B, Rosenberg NE. Ethical issues raised by cluster randomised trials conducted in low-resource settings: identifying gaps in the Ottawa Statement through an analysis of the PURE Malawi trial. J Med Ethics 2019; 45(6): 388-393.


Joag K, Ambrosio G, Kestler E, Weijer C, Hemming K, Van der Graaf R. Ethical issues in the design and conduct of stepped-wedge cluster randomized trials in low-resource settings. Trials 2019; 20(Suppl 2): 703.

Choko AT, Roshandel G, Conserve DF, Corbett EL, Fielding K, Hemming K, Malekzadeh R, Weijer C. Ethical issues in cluster randomized trials conducted in low- and middle-income countries: an analysis of two case studies. Trials 2020; 21(Suppl 1): 314.

 

 

Pragmatic RCTs

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.

 

Weijer C, Goldstein CE, Taljaard M. TwiC or treat? Are trials within cohorts ethically defensible? Clinical Trials 2017; 15(1): 21-24.

 

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.

 

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, 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.

 

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. 175.    

 

Nicholls SG, Carroll K, Zwarenstein M, Brehaut JC, Weijer C, Hey SP, Goldstein CE, Graham ID, McKenzie J, Grimshaw JM, Fergusson DA, Taljaard M on behalf of the CIHR Ethics of Pragmatic Trials project. The ethical challenges raised in the design and conduct of pragmatic trials. An interview study with key stakeholders. Trials 2019; 20: 765.

 

Goldstein CE, Weijer C. It does not matter whether research interventions are usual care. American Journal of Bioethics 2020; 20(1): 47–48. 

Taljaard M, McDonald S, Nicholls SG, Carroll K, Hey SP, Grimshaw JM, Fergusson DA, Zwarenstein M, McKenzie JE. A search filter to identify pragmatic trials in MEDLINE was highly specific but lacked sensitivity. J Clin Epidemiol 2020; 124: 75-84.

Nicholls SG, Zwarenstein M, Hey SP, Giraudeau B, Campbell MK, Taljaard M. The importance of decision intent within descriptions of pragmatic trials. J Clin Epidemiol 2020; 125: 30-37.

Stepped wedge trials

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.

 

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.

 

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. British Medical Journal 2018; 363: k1614.

 

Hemming K, Taljaard M, Marshall T, Goldstein CE, Weijer C. Stepped-wedge trials should be classified as research for the purpose of ethical review. Clinical Trials 2019; 16(6): 580-588.

 

Presentations

Workshops and panels

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 

 

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.

 

Fergusson D, McIntyre L, Taljaard M, Horn A, Weijer C. Ethical challenges in pragmatic comparative effectiveness trials (Invited panel). Society for Clinical Trials. Montreal. May 15, 2016.

 

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.

 

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.

 

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.

 

Saginur R, Fergusson D, Karanicolas P, Weijer C. Innovation and ethical considerations in clinical trial design. Clinical Trials Ontario Conference. Toronto. March 27, 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.

 

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.

 

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.

 

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.

 

Hey SP, Brehaut J, Fergusson D, Gillies K, Merz J, Weijer C. Safeguarding public and patient trust in pragmatic trials without written informed consent (Invited panel). Society for Clinical Trials. New Orleans, USA. May 21, 2019.

 

Hemming K, Taljaard M, Heels-Ansdell D, Weijer C, Fergusson D. The multiple-period cluster randomised cross-over design for comparative effectiveness research: statistical and ethical issues (Invited panel). Society for Clinical Trials. New Orleans, USA. May 22, 2019.

 

Weijer C, Melsop S, Shoben A. The ethics of community engaged research. Conversations About Research ethics (CARE) Panel. Ohio State University, Columbus, USA. January 28, 2020.


 

Individual talks

Weijer C. Recent advances in research ethics: developing the first ethical guidelines for cluster randomized trials. Western Research Forum. London. March 21, 2015.

 

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.

 

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. May 17, 2016.

 

Goldstein CE, Taljaard M, Weijer C. Ethics of pragmatic randomized controlled trials. Meeting of the Society for Clinical Trials. Montreal. 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. Canadian Bioethics Society. Toronto. May 27, 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. American Society for Bioethics and Humanities. Washington, DC, USA. October 10, 2016.

 

Weijer C, Taljaard M. The ethics of pragmatic trials. Ottawa Hospital Research Institute Clinical Research Week. Ottawa. October 18, 2016.

 

Taljaard M, Weijer C. The ethics of cluster randomized trials. Public Health Agency of Canada Research Ethics Board. Ottawa. January 12, 2017.

 

Taljaard M, Weijer C. Pragmatic randomized controlled trials: interplay between design and ethics. Clinical Epidemiology Program Rounds. Ottawa. January 27, 2017.

 

Weijer C. Models of informed consent in pragmatic trials. Ontario SPOR Support Unit (OSSU) Workshop on Pragmatic Trials. Toronto. March 7, 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.

 

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.

 

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. Canadian Bioethics Society. Montreal. May 25, 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, 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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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 C. Ethical considerations in pragmatic cluster randomized trials. Clinical Trials Ontario Conference. Toronto. March 28, 2019.

 

Weijer C. Getting real about real world evidence: ethical issues in pragmatic trials. 8th Annual Lilly Grand Rounds in Bioethics. Eli Lilly & Company. Indianapolis, USA. May 29, 2019.

 

Weijer C. FIRST principles: an ethical analysis of a randomized trial of work hours for trainee surgeons. Surgical Society Lecture, University of Cape Town. Cape Town, South Africa. July 25, 2019.

 

Weijer C. The ethical challenges of “real world” randomized controlled trials. Bioethics Symposium, University of Cape Town. Cape Town, South Africa. July 29, 2019.

 

Weijer C. Ethics and novel research design. R2HC Research Forum. Royal Holloway University, London, United Kingdom. September 11, 2019.

 

Weijer C. Cluster headaches: the contested role of informed consent in cluster randomized trials. Health Sciences Research Ethics Board, Western University. September 17, 2019.

 

Weijer C. Ethical challenges of comparative effectiveness RCTs using routinely collected data. Medical Grand Rounds, University Hospital. London, Canada. September 19, 2019.

 

Weijer C. Cluster headaches: the contested role of informed consent in cluster randomized trials. Health Research Methods, Evidence and Impact (HEI) Rounds. McMaster University, Hamilton, Canada. October 16, 2019.

 

Weijer C. Ethical challenges of comparative effectiveness RCTs using routinely collected data. Medical Grand Rounds, Victoria Hospital. London, Canada. October 18, 2019.

 

Nicholls SG, Carroll K, Brehaut JC, Zwarenstein M, Hey SP, Weijer C, Grimshaw JM, Fergusson DA, Taljaard M. What ethical challenges do pragmatic trials pose for the oversight of human subjects’ research? An interview study with key stakeholders (Poster). PRIM&R Advancing Ethical Research Conference. Boston, USA. November 17-20, 2019.

 

Weijer C. The FLUID trial: Ethical and design issues in a pragmatic comparative effectiveness trial. Bioethics Grand Rounds. College of Medicine, Ohio State University, USA. January 27, 2020. 

 

Goldstein CE, Weijer C. Is cluster randomization used to avoid obtaining patient informed consent? World Congress of Bioethics. June 18-21, 2020.

 

©2020 Charles Weijer