• Anders Granholm, Waleed Alhazzani, DerdeLennie P GLPGDepartment of Intensive Care Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.Julius Center for Health Sciences and Primary Care, Utrecht, The Netherlands., Derek C Angus, Fernando G Zampieri, Naomi E Hammond, SweeneyRob MacRMRegional Intensive Care Unit, Royal Victoria Hospital, Belfast, Northern Ireland, UK., Sheila N Myatra, Elie Azoulay, Kathryn Rowan, Paul J Young, Anders Perner, and MøllerMorten HylanderMHDepartment of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark..
• Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark. andersgran@gmail.com.
• Intensive Care Med. 2022 Feb 1; 48 (2): 164-178.

AbstractRandomised clinical trials (RCTs) are the gold standard for providing unbiased evidence of intervention effects. Here, we provide an overview of the history of RCTs and discuss the major challenges and limitations of current critical care RCTs, including overly optimistic effect sizes; unnuanced conclusions based on dichotomization of results; limited focus on patient-centred outcomes other than mortality; lack of flexibility and ability to adapt, increasing the risk of inconclusive results and limiting knowledge gains before trial completion; and inefficiency due to lack of re-use of trial infrastructure. We discuss recent developments in critical care RCTs and novel methods that may provide solutions to some of these challenges, including a research programme approach (consecutive, complementary studies of multiple types rather than individual, independent studies), and novel design and analysis methods. These include standardization of trial protocols; alternative outcome choices and use of core outcome sets; increased acceptance of uncertainty, probabilistic interpretations and use of Bayesian statistics; novel approaches to assessing heterogeneity of treatment effects; adaptation and platform trials; and increased integration between clinical trials and clinical practice. We outline the advantages and discuss the potential methodological and practical disadvantages with these approaches. With this review, we aim to inform clinicians and researchers about conventional and novel RCTs, including the rationale for choosing one or the other methodological approach based on a thorough discussion of pros and cons. Importantly, the most central feature remains the randomisation, which provides unparalleled restriction of confounding compared to non-randomised designs by reducing confounding to chance.© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.

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