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. 2025 Jul 1;8(7):e2518503.
doi: 10.1001/jamanetworkopen.2025.18503.

Hurdles for the Delivery of Multinational Randomized Clinical Trials

Denise van Hout  1 , Paul Mouncey  2 , David Harrison  2 , Marc Bonten  1   3 , Lennie Derde  1   4 ; REMAP-CAP European Regional Investigators; Derek C Angus  5 , Aisha Anjum  6 , Djillali Annane  7 , Janis Best-Lane  6 , Frank Brunkhorst  8 , Maurizio Cecconi  9 , Stephan Ehrmann  10   11 , Anthony Gordon  6 , Leanne Marie Hays  12 , Esmee Kester  13 , Niamh Mahon  12 , Colin McArthur  14 , Alistair Nichol  12 , Svenja Peters  13 , Sara Pugliese  9 , Kathryn Rowan  2 , Julian Torre-Cisneros  15 , Sebastian Weis  16   17   18
Affiliations

Hurdles for the Delivery of Multinational Randomized Clinical Trials

Denise van Hout et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bonten reported receiving grants from the European Union (HORIZON EU funding RECOVERY, HORIZON EU funding ECRAID-PRIME, and HORIZON EU funding CoMeCT); having research collaborations with Merck, GSK, Sanofi, Sequiris, TechnoPhage, Attea Pharmacy, Phaxiam, Janssen Vaccines (all payments to University Medical Center Utrecht [UMCU] or Ecraid); having served on advisory boards for Merck, GSK, Janssen Vaccines (all payments to UMCU); and serving on a data safety and monitoring board for Sanofi (all payments to UMCU) outside the submitted work. Dr Derde reported being a CoVice chair of the European Society of Intensive Medicine, steering committee member of the Surviving Sepsis Campaign Guidelines on the Management of Adults, and member of the international trial steering committee of Randomized Embedded Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP; chair 2021-2023) outside the submitted work. Dr Ehrmann reported receiving grants from Aerogen Ltd and Fisher & Paykel, personal fees from Aerogen Ltd, and nonfinancial support from Aerogen Ltd and Fisher & Paykel outside the submitted work. Dr Gordon reported receiving nonfinancial support from National Institute for Health and Care Research Imperial Biomedical Research Centre (infrastructure support), National Institute for Health and Care Research (senior investigator grant), personal fees from AstraZeneca, and serving as director for the National Institute for Health and Care Research National Research Collaboration Programme outside the submitted work. Dr McArthur reported receiving grants from the Health Research Council of New Zealand outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Site Contract Completion Time, Time to Approval, and Time From Approval to First Patient In
The boxplot displays the distribution of data, with the end of the boxes representing the first quartile and third quartile (ie, the IQR) and the median represented by the middle line. Whiskers extend to the smallest and largest values within 1.5 times the IQR. Any values outside these lines are plotted as outliers. Two outliers for site contract completion time (1195 and 1733 days for pre–COVID-19 pandemic period and non-UK) were included in analyses but omitted from this plot for visibility reasons. See the Table for results by country.
Figure 2.
Figure 2.. Variation in Time to Approval of Identical Protocols Across Different European Countries
The 6 protocols with the largest variation in time to approval are displayed. Each data point represents time to approval in a different country. An X indicates pre–COVID-19 pandemic submission, while all others were submitted during the COVID-19 pandemic.
See this image and copyright information in PMC

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