Regional Disparities in Clinical Trial Risks and Representation Highlight Global Challenges
Analysis of 585 clinical trials reveals region is the primary driver of risk variation, with North America showing 29% higher screen failure rates. Heart failure trials show severe underrepresentation, with only 14.5% of participants from outside Europe and North America despite Asia having 50% of global heart failure cases. Central monitoring methods and representativeness indices are proposed to address these disparities.
The globalization of clinical trials has revealed significant regional disparities in both risk management and participant representation, with data showing wide variations in key risk indicators and persistent underrepresentation of certain global populations in pivotal studies. An analysis of 585 trials, 46 sponsors and CROs, and more than 56,000 sites across seven global regions found that region was the primary driver of key risk indicator variation, while study phase, therapeutic area, and study size showed minimal impact.
Four key risk indicators showed the widest regional spread: off-schedule visit rate, protocol deviation rate, screen failure rate, and serious adverse event rate. North America demonstrated a 29% higher risk of screen failures compared with the global average, while Japan showed statistically lower risk across four compliance-related KRIs, including missed assessments and protocol deviations. Ukraine's relative KRI risk score rose to 32% above average in 2022 and 121% above average in 2023 following the start of the war.
Regional differences in language, medical practice, experience with clinical research and good clinical practice guidance may influence trial processes and data quality. The level of adverse event reporting also varies significantly by region, which can be driven by cultural differences in reporting and dealing with pain. Patient-facing materials such as consent forms and patient questionnaires must not only be accurately translated but also adapted to the target culture.
In heart failure randomized controlled trials, regional enrollment of participants often does not represent the regional distribution of cardiovascular diseases. Over the past four decades, trials have enrolled participants primarily from North America and Europe, limiting the global generalizability of findings. Among 157,416 participants in 414 heart failure RCTs published in high-impact journals, only 14.5% were enrolled outside Europe and North America.
In 2021, there were 55.4 million people with heart failure worldwide, with the greatest population in Asia (50%), followed by Europe (18%), Africa (14%), North America (10%) and Central & South America (8%). Representation index and participant-to-prevalence ratio revealed similar estimates of geographic representation relative to disease prevalence, with overrepresentation in Europe and North America and gross underrepresentation in Asia and Africa.
To improve regional representativeness, targeted strategies are needed that address barriers faced at the national, regulatory, sponsor or funder, institution and patient level. Researchers recommend the use of a representativeness index during trial planning and site selection to enhance regional representativeness. Expanding trial participation beyond historically dominant regions could be a key step in improving trial efficiency, external validity and global health equity.
Central monitoring methods, including key risk indicators and statistical data monitoring, allow study teams to proactively detect emerging quality-related risks, address confirmed issues and drive higher quality outcomes. These methods can detect a variety of emerging risks, including inadequate adverse-event reporting, protocol deviations or delays in data entry, and can be flagged at different levels—site, country or region—providing a structured way to monitor and remediate data quality concerns.