TY - JOUR
T1 - Hurdles for the Delivery of Multinational Randomized Clinical Trials
AU - van Hout, Denise
AU - Mouncey, Paul
AU - Harrison, David
AU - Bonten, Marc
AU - Derde, Lennie
AU - Angus, Derek C
AU - Anjum, Aisha
AU - Annane, Djillali
AU - Best-Lane, Janis
AU - Brunkhorst, Frank
AU - Cecconi, Maurizio
AU - Ehrmann, Stephan
AU - Gordon, Anthony
AU - Hays, Leanne Marie
AU - Kester, Esmee
AU - Mahon, Niamh
AU - McArthur, Colin
AU - Nichol, Alistair
AU - Peters, Svenja
AU - Pugliese, Sara
AU - Rowan, Kathryn
AU - Torre-Cisneros, Julian
AU - Weis, Sebastian
N1 - Publisher Copyright:
© 2025 American Medical Association. All rights reserved.
PY - 2025/7/1
Y1 - 2025/7/1
N2 - IMPORTANCE: Ethical, administrative, regulatory, and logistical (EARL) procedures can hamper clinical trial delivery. Quantification of these hurdles is rare, prohibiting identification of areas for improvement.OBJECTIVE: To identify and quantify EARL hurdles in trial delivery before and during the COVID-19 pandemic.DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the ongoing Randomized Embedded Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia to enable comparison of EARL procedures for multiple protocols across 19 European countries in the pre-COVID-19 pandemic (February 19, 2016 to March 10, 2020) and COVID-19 pandemic (March 11, 2020, to May 4, 2023) periods. Data were analyzed from November 2024 to March 2025 with contracts and protocol submissions as the units of analysis.MAIN OUTCOME AND MEASURES: Time to (1) site contract completion, (2) regulatory and ethical approval (TTA), and (3) first patient in (FPI). The UK was compared with non-UK countries because of its distinct research infrastructure.RESULTS: There were 257 fully signed first contracts with study sites for analysis. In the UK, contract completion times decreased by 97% (95% CI, 95% to 98%), from a median (IQR) of 196 (154 to 250) days in the pre-COVID-19 pandemic period to 5 (1 to 11) days during the COVID-19 pandemic. In non-UK countries, median (IQR) contract completion times were 224 (119 to 412) days and 183 (62 to 291) days before and during the COVID-19 pandemic, respectively (relative difference, -18%; 95% CI, -43% to 52%). In total, 44 interventions in 16 domains were submitted, yielding 232 protocol approvals for analysis. During the COVID-19 pandemic, median (IQR) TTA was 8 (5 to 31) days in the UK and 115 (47 to 103) days in non-UK countries (median difference, 107 days; 95% CI, 76 to 123 days), with large variation across non-UK countries. Time between approval and FPI during the COVID-19 pandemic was, on average, 3 months faster in the UK compared with non-UK countries (median difference, 90 days; 95% CI, 42 to 141 days).CONCLUSIONS AND RELEVANCE: This study found that EARL procedures were lengthy and variable between countries, reflecting different interpretations of trial regulations, with faster processes in the UK. These findings underscore the need to streamline processes across European countries to improve trial efficiency, in particular during future public health emergencies such as pandemics.
AB - IMPORTANCE: Ethical, administrative, regulatory, and logistical (EARL) procedures can hamper clinical trial delivery. Quantification of these hurdles is rare, prohibiting identification of areas for improvement.OBJECTIVE: To identify and quantify EARL hurdles in trial delivery before and during the COVID-19 pandemic.DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the ongoing Randomized Embedded Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia to enable comparison of EARL procedures for multiple protocols across 19 European countries in the pre-COVID-19 pandemic (February 19, 2016 to March 10, 2020) and COVID-19 pandemic (March 11, 2020, to May 4, 2023) periods. Data were analyzed from November 2024 to March 2025 with contracts and protocol submissions as the units of analysis.MAIN OUTCOME AND MEASURES: Time to (1) site contract completion, (2) regulatory and ethical approval (TTA), and (3) first patient in (FPI). The UK was compared with non-UK countries because of its distinct research infrastructure.RESULTS: There were 257 fully signed first contracts with study sites for analysis. In the UK, contract completion times decreased by 97% (95% CI, 95% to 98%), from a median (IQR) of 196 (154 to 250) days in the pre-COVID-19 pandemic period to 5 (1 to 11) days during the COVID-19 pandemic. In non-UK countries, median (IQR) contract completion times were 224 (119 to 412) days and 183 (62 to 291) days before and during the COVID-19 pandemic, respectively (relative difference, -18%; 95% CI, -43% to 52%). In total, 44 interventions in 16 domains were submitted, yielding 232 protocol approvals for analysis. During the COVID-19 pandemic, median (IQR) TTA was 8 (5 to 31) days in the UK and 115 (47 to 103) days in non-UK countries (median difference, 107 days; 95% CI, 76 to 123 days), with large variation across non-UK countries. Time between approval and FPI during the COVID-19 pandemic was, on average, 3 months faster in the UK compared with non-UK countries (median difference, 90 days; 95% CI, 42 to 141 days).CONCLUSIONS AND RELEVANCE: This study found that EARL procedures were lengthy and variable between countries, reflecting different interpretations of trial regulations, with faster processes in the UK. These findings underscore the need to streamline processes across European countries to improve trial efficiency, in particular during future public health emergencies such as pandemics.
KW - COVID-19/epidemiology
KW - Europe/epidemiology
KW - Humans
KW - Multicenter Studies as Topic
KW - Pandemics
KW - Randomized Controlled Trials as Topic/ethics
KW - SARS-CoV-2
KW - United Kingdom
UR - https://www.scopus.com/pages/publications/105010290231
U2 - 10.1001/jamanetworkopen.2025.18503
DO - 10.1001/jamanetworkopen.2025.18503
M3 - Article
C2 - 40601320
SN - 2574-3805
VL - 8
JO - JAMA network open
JF - JAMA network open
IS - 7
M1 - e2518503
ER -