@article{c5301f4438e44a00a0c38e569a1b0261,
title = "Use of pragmatic and explanatory trial designs in acute care research: lessons from COVID-19",
abstract = "Unique challenges arise when conducting trials to evaluate therapies already in common clinical use, including difficulty enrolling patients owing to widespread open-label use of trial therapies and the need for large sample sizes to detect small but clinically meaningful treatment effects. Despite numerous successes in trials evaluating novel interventions such as vaccines, traditional explanatory trials have struggled to provide definitive answers to time-sensitive questions for acutely ill patients with COVID-19. Pragmatic trials, which can increase efficiency by allowing some or all trial procedures to be embedded into clinical care, are increasingly proposed as a means to evaluate therapies that are in common clinical use. In this Personal View, we use two concurrently conducted COVID-19 trials of hydroxychloroquine (the US ORCHID trial and the UK RECOVERY trial) to contrast the effects of explanatory and pragmatic trial designs on trial conduct, trial results, and the care of patients managed outside of clinical trials. In view of the potential advantages and disadvantages of explanatory and pragmatic trial designs, we make recommendations for their optimal use in the evaluation of therapies in the acute care setting.",
author = "Casey, {Jonathan D.} and Beskow, {Laura M.} and Jeremy Brown and Brown, {Samuel M.} and {\'E}tienne Gayat and {Ng Gong}, Michelle and Harhay, {Michael O.} and Samir Jaber and Jentzer, {Jacob C.} and Laterre, {Pierre Fran{\c c}ois} and Marshall, {John C.} and Matthay, {Michael A.} and Rice, {Todd W.} and Yves Rosenberg and Turnbull, {Alison E.} and Ware, {Lorraine B.} and Self, {Wesley H.} and Alexandre Mebazaa and Collins, {Sean P.}",
note = "Funding Information: SMB reports personal fees from Hamilton for chairing a data safety and monitoring board (DSMB). EG reports grants and research contracts from Philips and Radiometer, consulting fees from Baxter, and speaker's fees from Edwards. MNG reports fees from Regeneron for DSMB participation; she has received support to attend board meetings for the American Thoracic Society. MOH reports fees from Elsevier for statistical peer review, from Berkeley Research Group, Pura Vida Investments, and Guidepoint Advisers for statistical consulting, and from the American Thoracic Society for contributions as a statistical editor of the Annals of the American Thoracic Society. SJ reports fees from Drager, Fisher-Paykel, Baxter, Medtronic, and Fresenius-Xenios for lectures and training courses for physicians and nurses. JCM reports consulting fees from Gilead, and travel support from the Bill and Melinda Gates Foundation. MAM reports research funding from Roche-Genentec; he has received fees from Novartis, Johnson & Johnson, and Citius for DSMB participation. TWR reports personal fees from Sanofi for DSMB participation, and consulting fees and stock options from Cumberland Pharmaceuticals for contributions on a consultancy basis as Director of Medical Affairs. LBW has received research contracts from Boehringer Ingelheim, Genentech, and CSL Behring; she reports consulting fees from Boehringer Ingelheim, Merck, Quark, Citius, and Foresee; she has served on a data monitoring committee for the SIGNET trial and on DSMBs for the INVENT COVID and CounterCovid trials. WHS has received research funding from Endpoint Health and Merck; he reports personal consulting fees from Aerpio Pharmaceuticals, Merck, and Baxter; he has received personal fees for DSMB participation from BioAegis. SPC reports consulting fees from Vir Biotechnology. The other authors declare no competing interests. Funding Information: The 2020 Critical Care Clinical Trialists (3CT) Workshop received unrestricted funding from Abbott Diagnostics and AM-Pharma to partially cover travel and lodging costs, when necessary, but no further payments were made to participants. These organisations had no role in the scientific programme for the conference; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. JDC was supported by the US National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grant K23HL153584. LMB was supported by UL1-TR-002243 from the US National Center for Advancing Translational Sciences. SMB receives research funding from NIH, the Centers for Disease Control and Prevention (CDC), and the Department of Defense (DoD). MNG receives grants from NIH (OT2 HL156812), NHLBI (U01 HL122998), the Agency for Healthcare Research and Quality (ARHQ; R18 HS026188), and CDC (200-2016-91801). MOH was the recipient of grants from NIH (R00 HL141678) and the Patient-Centered Outcomes Research Institute (PCORI; ME-2020C1-19220). WHS receives research funding from NIH (42-312-0217571-66406L; 1OT2HL156812), CDC (75-D-30122-C-12914), DoD (JW190515), and PCORI (1409-24099). TWR was supported by NIH/NHLBI grant U01 HL123033 (K01HL141637). AET was supported by NIH/NHLBI grant K01HL141637. LBW was supported by NIH grants HL103836 and HL135849SPC. SPC receives research funding from NHLBI. The content of this Personal View is solely the responsibility of the authors and does not necessarily represent the official views of ARHQ, CDC, DoD, NHLBI, NIH, the US Department of Health and Human Services, PCORI, or PCORI's Board of Governors or Methodology Committee. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",
year = "2022",
month = jul,
doi = "10.1016/S2213-2600(22)00044-3",
language = "English (US)",
volume = "10",
pages = "700--714",
journal = "The Lancet Respiratory Medicine",
issn = "2213-2600",
publisher = "Elsevier Limited",
number = "7",
}
