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

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. OPEN SCIENCE FRAMEWORK REGISTRATION NUMBER: osf-registrations-yvtjb-v1.

Combination therapies for COVID-19: An overview of the clinical trials landscape.

The COVID-19 pandemic has driven an unprecedented level of global activity in drug discovery and clinical development for effective therapeutics targeting the coronavirus disease. There are currently 744 therapeutics being tested in 2879 clinical trials globally. Almost 90% of these clinical trials are focused on monotherapies. Combination therapies are the mainstay of antiviral therapeutics to increase the potency of the individual compounds and to combat the rapid evolution of resistance, although combination therapies have inherently complex clinical and regulatory development challenges. Increased understanding of the SARS-CoV-2 lifecycle and COVID-19 pathology provides a scientific rationale for evaluating the effectiveness of different combinations. In this paper, we provide an overview of the current clinical trial landscape for combination therapeutics targeting COVID-19 through weekly scanning of national and international clinical trial registries. Our analysis delves specifically into dual combination therapies in what can be defined as "pivotal clinical trials" (active, randomised, controlled and at least phase II), with a focus on new and repurposed therapeutic candidates that have shown positive signals and/or been granted authorisation for emergency use based on positive efficacy and safety data.

Local Inequalities in Health Behaviours: Longitudinal Findings from the Stockton-On-Tees Cohort Study.

This paper provides a longitudinal examination of local inequalities in health behaviours during a period of austerity, exploring the role of 'place' in explaining these inequalities. Data from the Stockton-on-Tees prospective cohort study of 836 individuals were analysed and followed over 18 months (37% follow-up). Generalised estimating equation models estimated the deprivation gap in health behaviours (smoking status, alcohol use, fruit and vegetable consumption and physical activity practices) between the 20% most- and least-deprived neighborhoods (LSOAs), explored any temporal changes during austerity, and examined the underpinning role of compositional and contextual determinants. All health behaviours, except for frequent physical activity, varied significantly by deprivation (p ≤ 0.001). Smoking was lower in the least-deprived areas (OR 0.21, CI 0.14 to 0.30), while alcohol use (OR 2.75, CI 1.98 to 3.82) and fruit and vegetable consumption (OR 2.55, CI 1.80 to 3.62) were higher in the least-deprived areas. The inequalities were relatively stable throughout the study period. Material factors (such as employment, education and housing tenure) were the most-important and environmental factors the least-important explanatory factors. This study suggests that material factors are the most important 'place' determinants of health behaviours. Health promotion activities should better reflect these drivers.