Operational complexities in international clinical trials: a systematic review of challenges and proposed solutions

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Abstract

Objective

International trials can be challenging to operationalise due to incompatibilities between country-specific policies and infrastructures. The aim of this systematic review was to identify the operational complexities of conducting international trials and identify potential solutions for overcoming them.

Design

Systematic review.

Data sources

Medline, Embase and Health Management Information Consortium were searched from 2006 to 30 January 2023.

Eligibility criteria

All studies reporting operational challenges (eg, site selection, trial management, intervention management, data management) of conducting international trials were included.

Data extraction and synthesis

Search results were independently screened by at least two reviewers and data were extracted into a proforma.

Results

38 studies (35 RCTs, 2 reports and 1 qualitative study) fulfilled the inclusion criteria. The median sample size was 1202 (IQR 332–4056) and median number of sites was 40 (IQR 13–78). 88.6% of studies had an academic sponsor and 80% were funded through government sources. Operational complexities were particularly reported during trial set-up due to lack of harmonisation in regulatory approvals and in relation to sponsorship structure, with associated budgetary impacts. Additional challenges included site selection, staff training, lengthy contract negotiations, site monitoring, communication, trial oversight, recruitment, data management, drug procurement and distribution, pharmacy involvement and biospecimen processing and transport.

Conclusions

International collaborative trials are valuable in cases where recruitment may be difficult, diversifying participation and applicability. However, multiple operational and regulatory challenges are encountered when implementing a trial in multiple countries. Careful planning and communication between trials units and investigators, with an emphasis on establishing adequately resourced cross-border sponsorship structures and regulatory approvals, may help to overcome these barriers and realise the benefits of the approach.

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osf-registrations-yvtjb-v1.

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Most cited references 60

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The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

Matthew J L Page, Joanne E McKenzie, Patrick Bossuyt … (2024)

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

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Ethical and scientific implications of the globalization of clinical research.

Seth W Glickman, John G McHutchison, Eric Peterson … (2009)

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The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design

Derek C Angus, Scott Berry, Roger J. Lewis … (2020)

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled “a randomized embedded multifactorial adaptive platform.” The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas. Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open

Journal ID (iso-abbrev): BMJ Open

Journal ID (hwp): bmjopen

Journal ID (publisher-id): bmjopen

Title: BMJ Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2044-6055

Publication date Collection: 2024

Publication date (Electronic): 15 April 2024

Volume: 14

Issue: 4

Electronic Location Identifier: e077132

Affiliations

[1 ] departmentTranslational and Clinical Research Institute , Ringgold_5994Newcastle University , Newcastle upon Tyne, UK

[2 ] Ringgold_6072Northumbria Healthcare NHS Foundation Trust , Northumbria, UK

[3 ] departmentNIHR Innovation Observatory, Population Health Sciences Institute , Ringgold_5994Newcastle University , Newcastle upon Tyne, UK

[4 ] departmentPopulation Health Sciences Institute , Newcastle University , Newcastle upon Tyne, UK

[5 ] departmentNewcastle Clinical Trials Unit , Newcastle University , Newcastle upon Tyne, UK

[6 ] departmentMusculoskeletal Unit , Ringgold_5983Newcastle Upon Tyne Hospitals NHS Trust , Newcastle Upon Tyne, UK

Author notes

[Correspondence to ] Dr Arthur G Pratt; arthur.pratt@ 123456newcastle.ac.uk

Author information

Leher Gumber http://orcid.org/0000-0003-0154-1207

James MS Wason http://orcid.org/0000-0002-4691-126X

Arthur G Pratt http://orcid.org/0000-0002-9909-8209

Article

Publisher ID: bmjopen-2023-077132

DOI: 10.1136/bmjopen-2023-077132

PMC ID: 11029458

PubMed ID: 38626966

SO-VID: 8634b705-2e85-4709-b80b-29da850c91c9

License:

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

History

Date received : 26 June 2023

Date accepted : 27 February 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000272, National Institute for Health and Care Research;

Award ID: NIHR153955

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ScienceOpen disciplines: Medicine

Keywords: clinical trial,randomized controlled trial,systematic review

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ScienceOpen disciplines: Medicine

Keywords: clinical trial, randomized controlled trial, systematic review

Operational complexities in international clinical trials: a systematic review of challenges and proposed solutions

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Abstract

Objective

Design

Data sources

Eligibility criteria

Data extraction and synthesis

Results

Conclusions

Open science framework registration number

Related collections

Drug Repurposing

Most cited references 60

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

Ethical and scientific implications of the globalization of clinical research.

The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Funding

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