TY - JOUR

T1 - Randomised clinical trials in critical care

T2 - past, present and future

AU - Granholm, Anders

AU - Alhazzani, Waleed

AU - Derde, Lennie P.G.

AU - Angus, Derek C.

AU - Zampieri, Fernando G.

AU - Hammond, Naomi E.

AU - Sweeney, Rob Mac

AU - Myatra, Sheila N.

AU - Azoulay, Elie

AU - Rowan, Kathryn

AU - Young, Paul J.

AU - Perner, Anders

AU - Møller, Morten Hylander

N1 - Publisher Copyright: © 2021, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2022

Y1 - 2022

N2 - Randomised 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.

AB - Randomised 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.

KW - Clinical trials

KW - Critical care

KW - Intensive care

KW - Randomized clinical trials

U2 - 10.1007/s00134-021-06587-9

DO - 10.1007/s00134-021-06587-9

M3 - Review

C2 - 34853905

AN - SCOPUS:85120379859

VL - 48

SP - 164

EP - 178

JO - European Journal of Intensive Care Medicine

JF - European Journal of Intensive Care Medicine

SN - 0935-1701

IS - 2

ER -