Addressing Regional Variation in Clinical Trial Risks

For years, regulatory agencies like the FDA and EMA have required monitoring of the conduct and the progress of clinical trials to ensure patient protection and the reliability of trial results.^1,2 However, as clinical trials have become increasingly global, oversight has become increasingly complicated and risk increasingly diverse. To overcome regional variations in clinical trial risks, we need to understand them—and take prospective measures to reduce them based on the data we can unearth from central monitoring.

Central monitoring methods

Central monitoring (CM) is a core component of risk-based quality management (RBQM). It allows study teams to proactively detect emerging quality-related risks, address confirmed issues and drive higher quality outcomes.³ A variety of methods may be applied to support CM, but the two most used are key risk indicators (KRIs) and statistical data monitoring (SDM).

KRIs are metrics for pre-identified risks in specific targeted areas of study conduct. Sites that deviate from the expected range of values for a given KRI are flagged as ‘at risk.’ SDM represents a more holistic approach to quality oversight, applying several statistical tests on all the data collected during the conduct of a clinical trial. The goal of SDM is to identify atypical data patterns at sites that may represent various systemic issues or, in some rare cases, reveal fraud.⁴

Using KRIs or SDM, sponsors can detect a variety of emerging risks, including inadequate adverse-event reporting, protocol deviations or delays in data entry. Importantly, these risks can be flagged at different levels—site, country or region—providing a structured way to monitor and remediate data quality concerns.⁵

The challenges of global clinical trials

Clinical trials today span diverse cultural, medical and regulatory environments. This diversity brings benefits, including broader representation of patients. However, it also creates challenges for consistent trial conduct. Regional differences in language, medical practice, experience with clinical research and good clinical practice (GCP) guidance may influence trial processes and data quality.

Patient-facing materials such as consent forms and patient questionnaires must not only be accurately translated but also adapted to the target culture. For example, in most emerging countries patients hold their physicians in high regard.⁶ This can lead them to accept a recommendation to enroll in a trial without fully understanding the implications. Foreign sponsors need to ensure they have informed consent while also respecting cultural differences.

The level of adverse event (AE) reporting also varies significantly by region. This again can be driven by cultural differences to, for example reporting and dealing with pain.⁷ Similarly, some countries display greater levels of patient compliance with doctor instructions, which may also be associated with higher rates of enrollment and retention.⁸

Such variations can introduce diversity in trial outcomes and complicate oversight.

Analyzing regional variation in clinical trial risks

To examine regional variation in clinical trial risk monitoring around the world, researchers analyzed a large dataset covering 585 trials conducted by 46 sponsors and contract research organizations (CROs) worldwide.⁹ The data came from a CM platform. More than 56,000 sites trial sites were grouped into seven geographic regions—North America, Central/South America, Western Europe, Eastern Europe, Africa/Middle East, Asia and Pacific—to assess regional differences in monitored clinical trial risks.

The primary outcome was the relative KRI risk score, defined as the relative risk in the selected region in comparison to the expected risk computed using data across all regions globally. Ten KRIs used across numerous clinical development organizations and trials were selected for comparison. They covered a variety of risk categories including safety, compliance, data quality and enrollment and retention. The detection of abnormal data patterns used mixed effects statistical models that allowed centers or countries to differ from each other, so only deviations that exceeded the expected variability in the data were flagged.

The analysis, published in October 2025, found region was the primary source of diversity. In contrast, study phase, therapeutic area and study size did not contribute meaningfully to between-study variation. The four risks with the largest distribution across regions were: off-schedule visit rate, protocol deviation rate, screen failure rate and serious AE rate. However, other risks, including visit-to-entry cycle time and missed assessment rate, had a very narrow distribution.

These results highlight the need to take corrective actions to ensure specific risks remain controlled given the circumstances of each region.

Perceptions and countries in crisis

As well as looking at predefined regions, the 2025 research also includes two illustrative use cases to test common perceptions of data quality and the impact of an ongoing crisis, such as a war or pandemic, on trial conduct.

In 2021 Ukraine had a lower relative KRI risk score than the average across all countries. However, after the beginning of the war, in 2022 the relative KRI risk score increased to 32% higher than the average risk across all countries. It became even worse in 2023 with a KRI risk score 121% higher than the average across all countries. The most significantly impacted KRIs unsurprisingly focused on data issues with missed assessments and delays in data reporting. This is clear evidence of a significant disruption to clinical trial operations since the start of the war.

Japan, which has a reputation for excellent data quality, had a strikingly low relative KRI risk score for four different KRIs without any overlap with other regions. These were missed assessment rate, off-schedule visit rate, protocol deviation rate and early-termination rate. These may be explained by cultural traits that are particular to Japan, including a greater emphasis on procedural compliance and precision. For example, previous analysis has observed that clinical trials conducted in Japan experience a lower patient drop-out rate and compliance with protocol and GCP is relatively high in Japan.¹⁰ This is in line with the 2025 analysis which found Japan had a statistically better performance overall across four compliance-related risks, including fewer issues with missed assessments, protocol deviations, early patient terminations and off-schedule site visits.

Overcoming regional variations in risk

The results of the study above highlight that, even when sites receive the same protocol and other study documentation, there are relative differences in commonly monitored risks. Acknowledging this may help study teams to better understand what to expect and how to interpret the KRI results in each region.

Providing KRI risk oversight at region or country level should not exclude countries from participating in clinical research. Instead, it should help sponsors take the corrective action needed to ensure risks remain controlled given the circumstances specific to each region or country.

For instance, if a trial is planned in North America, there is a 29% higher risk related to the rate of screen failures.⁹ Sponsors should consider control strategies to take this risk into account. For example, it may be appropriate to recruit additional sites to ensure patient enrollment targets in the region are achieved or to pro-actively monitor and assess the reasons for screen failures.

As another example, if an investigational product is new with a lack of prior safety knowledge, it will be key to balance sites to ensure that diversity of the patient population and the quality of the reporting are both well controlled. Additionally, before and during the conduct of the study, other actions should be implemented like site staff training and enhanced safety monitoring.

Clinical development organizations must also develop strategies to deal with the impact on quality when a country is in crisis. For example, if there is missing data because of missed assessments, enrollment or study discontinuation, the sponsor may need to consider modifications of the study protocols in some cases. Continuously assessing trends of KRI risks in a country or a region impacted by a severe crisis would help sponsors to take corrective actions to control trial risks in real time.

For example, in Ukraine, most of the risk metrics except safety reporting deteriorated after the start of the war so sponsors and CROs should consider how to overcome this. Crucially, we must not abandon trials in countries experiencing crisis situations. Clinical research is a necessity, and we have an ethical imperative to protect patients.

Conclusion

Successful conduct of clinical research is essential regardless of regional differences—or indeed the presence of crises such as pandemic or war.

To ensure consistency in risk management, clinical trial sponsors must implement risk planning and risk control strategies. These include continuous risk assessment, to ensure regional variations are quickly identified and mitigated, and the ability to modify protocols to consider cultural differences and extreme changes in a region or country’s circumstances.

By understanding regional differences in risk, and putting in place effective measures to mitigate them, we can protect data integrity, increase the likelihood of study success and ensure patients get the care they need.

Sylviane de Viron, data and knowledge manager at CluePoints

References

1. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-risk-based-quality-management-clinical-trials_en.pdf
2. https://www.fda.gov/media/116754/download
3. https://link.springer.com/article/10.1007/s43441-024-00613-w
4. https://link.springer.com/article/10.1007/s43441-021-00341-5
5. https://link.springer.com/article/10.1007/s43441-022-00470-5 
6. https://www.appliedclinicaltrialsonline.com/view/language-culture-global-clinical-trials
7. https://journals.lww.com/cancernursingonline/abstract/2008/05000/asian_american_cancer_patients__pain_experience.16.aspx
8. https://link.springer.com/article/10.1177/2168479014529573
9. https://bmjopen.bmj.com/content/15/10/e094950.full
10. https://link.springer.com/article/10.1177/2168479014529573