Methodology and design of platform trials: a meta-epidemiological study

doi:10.1016/j.jclinepi.2023.02.010

. 2023 May:157:1-12.

doi: 10.1016/j.jclinepi.2023.02.010. Epub 2023 Mar 8.

Methodology and design of platform trials: a meta-epidemiological study

Tyler Pitre¹, Samantha Cheng², Ellen Cusano³, Nadia Khan⁴, David Mikhail⁵, Gareth Leung⁶, Robin W M Vernooij⁷, Christopher J Yarnell⁸, Ewan Goligher⁹, Srinivas Murthy¹⁰, Anna Heath¹¹, Jasmine Mah¹², Bram Rochwerg¹³, Dena Zeraatkar¹⁴

Affiliations

¹ Division of Internal Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: tyler.pitre@medportal.ca.
² Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
³ Division of Hematology and Hematologic Malignancies, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁴ Schulich School of Medicine and Dentistry, London, Ontario, Canada.
⁵ Faculty of Health Sciences, McMaster University, Canada.
⁶ Faculty of Medicine, University of Ottawa, Canada.
⁷ Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁸ Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada; University Health Network and Sinai Health System, Toronto, Canada; Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Canada.
⁹ Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada; Toronto General Hospital Research Institute, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
¹⁰ Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
¹¹ Child Health Evaluative Science, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Department of Statistical Science, University College London, London, UK.
¹² Department of medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
¹³ Department of Critical Care, Juravinski Hospital, Hamilton, Ontario, Canada; Department of Health Research Methods Evidence and Impact, McMaster University, Hamilton, Ontario, Canada.
¹⁴ Department of Anesthesiology, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods Evidence and Impact, McMaster University, Hamilton, Ontario, Canada.

PMID: 36893990
PMCID: PMC9991927
DOI: 10.1016/j.jclinepi.2023.02.010

Methodology and design of platform trials: a meta-epidemiological study

Tyler Pitre et al. J Clin Epidemiol. 2023 May.

. 2023 May:157:1-12.

doi: 10.1016/j.jclinepi.2023.02.010. Epub 2023 Mar 8.

Authors

Affiliations

¹ Division of Internal Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: tyler.pitre@medportal.ca.
² Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
³ Division of Hematology and Hematologic Malignancies, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁴ Schulich School of Medicine and Dentistry, London, Ontario, Canada.
⁵ Faculty of Health Sciences, McMaster University, Canada.
⁶ Faculty of Medicine, University of Ottawa, Canada.
⁷ Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁸ Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada; University Health Network and Sinai Health System, Toronto, Canada; Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Canada.
⁹ Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada; Toronto General Hospital Research Institute, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
¹⁰ Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
¹¹ Child Health Evaluative Science, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Department of Statistical Science, University College London, London, UK.
¹² Department of medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
¹³ Department of Critical Care, Juravinski Hospital, Hamilton, Ontario, Canada; Department of Health Research Methods Evidence and Impact, McMaster University, Hamilton, Ontario, Canada.
¹⁴ Department of Anesthesiology, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods Evidence and Impact, McMaster University, Hamilton, Ontario, Canada.

PMID: 36893990
PMCID: PMC9991927
DOI: 10.1016/j.jclinepi.2023.02.010

Abstract

Objectives: Adaptive platforms allow for the evaluation of multiple interventions at a lower cost and have been growing in popularity, especially during the COVID-19 pandemic. The objective of this review is to summarize published platform trials, examine specific methodological design features among these studies, and hopefully aid readers in the evaluation and interpretation of platform trial results.

Methods: We performed a systematic review of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov from January 2015 to January 2022 for protocols or results of platform trials. Pairs of reviewers, working independently and in duplicate, collected data on trial characteristics of trial registrations, protocols, and publications of platform trials. We reported our results using total numbers and percentages, as well as medians with interquartile range (IQR) when appropriate.

Results: We identified 15,277 unique search records and screened 14,403 titles and abstracts after duplicates were removed. We identified 98 unique randomized platform trials. Sixteen platform trials were sourced from a systematic review completed in 2019, which included platform trials reported prior to 2015. Most platform trials (n = 67, 68.3%) were registered between 2020 and 2022, coinciding with the COVID-19 pandemic. The included platform trials primarily recruited or plan to recruit patients from North America or Europe, with most subjects being recruited from the United States (n = 39, 39.7%) and the United Kingdom (n = 31, 31.6%). Bayesian methods were used in 28.6% (n = 28) of platform RCTs and frequentist methods in 66.3% (n = 65) of trials, including 1 (1%) that used methods from both paradigms. Out of the twenty-five trials with peer-reviewed publication of results, seven trials used Bayesian methods (28%), and of those, two (8%) used a predefined sample size calculation while the remainder used pre-specified probabilities of futility, harm, or benefit calculated at (pre-specified) intervals to inform decisions about stopping interventions or the entire trial. Seventeen (68%) peer-reviewed publications used frequentist methods. Out of the seven published Bayesian trials, seven (100%) reported thresholds for benefit. The threshold for benefit ranged from 80% to >99%.

Conclusion: We identified and summarized key components of platform trials, including the basics of the methodological and statistical considerations. Ultimately, improving standardization and reporting in platform trials require an understanding of the current landscape. We provide the most updated and rigorous review of platform trials to date.

Keywords: Adaptive randomization; COVID-19; Methods; Platform trials; Systematic review; Trials.

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Figures

**Fig. 1**
Systematic inclusion and exclusion flow diagram.

**Fig. 2**
Incidence in platform trial registrations from 2004 to 2022.

See this image and copyright information in PMC

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References

1. Park J.J.H., Harari O., Dron L., Lester R.T., Thorlund K., Mills E.J. An overview of platform trials with a checklist for clinical readers. J Clin Epidemiol. 2020;125:1–8. - PubMed
1. Granholm A., Alhazzani W., Derde L.P.G., Angus D.C., Zampieri F.G., Hammond N.E., et al. Randomised clinical trials in critical care: past, present and future. Intensive Care Med. 2021;48:164–178. - PMC - PubMed
1. Woodcock J., LaVange L.M. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377:62–70. - PubMed
1. Berry S.M., Connor J.T., Lewis R.J. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA. 2015;313:1619–1620. - PubMed
1. Adaptive platform trials: definition, design, conduct and reporting considerations. Nat Rev Drug Discov. 2019;18(10):797–807. - PubMed

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[1] Park J.J.H., Harari O., Dron L., Lester R.T., Thorlund K., Mills E.J. An overview of platform trials with a checklist for clinical readers. J Clin Epidemiol. 2020;125:1–8. - PubMed

[2] Park J.J.H., Harari O., Dron L., Lester R.T., Thorlund K., Mills E.J. An overview of platform trials with a checklist for clinical readers. J Clin Epidemiol. 2020;125:1–8. - PubMed

[3] Granholm A., Alhazzani W., Derde L.P.G., Angus D.C., Zampieri F.G., Hammond N.E., et al. Randomised clinical trials in critical care: past, present and future. Intensive Care Med. 2021;48:164–178. - PMC - PubMed

[4] Granholm A., Alhazzani W., Derde L.P.G., Angus D.C., Zampieri F.G., Hammond N.E., et al. Randomised clinical trials in critical care: past, present and future. Intensive Care Med. 2021;48:164–178. - PMC - PubMed

[5] Woodcock J., LaVange L.M. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377:62–70. - PubMed

[6] Woodcock J., LaVange L.M. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377:62–70. - PubMed

[7] Berry S.M., Connor J.T., Lewis R.J. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA. 2015;313:1619–1620. - PubMed

[8] Berry S.M., Connor J.T., Lewis R.J. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA. 2015;313:1619–1620. - PubMed

[9] Adaptive platform trials: definition, design, conduct and reporting considerations. Nat Rev Drug Discov. 2019;18(10):797–807. - PubMed

[10] Adaptive platform trials: definition, design, conduct and reporting considerations. Nat Rev Drug Discov. 2019;18(10):797–807. - PubMed

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Methodology and design of platform trials: a meta-epidemiological study

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Methodology and design of platform trials: a meta-epidemiological study

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