European study highlights barriers to multinational clinical trials

European study highlights barriers to multinational clinical trials

A new study by investigators from Europe, including the Netherlands and the United Kingdom (UK), has highlighted key ethical, administrative, regulatory and logistical (EARL) hurdles in conducting multinational randomized clinical trials. The research was the first to comprehensively quantify these barriers to international platform trials and emphasizes the need for urgent improvements, particularly in preparing for future public health crises.

Randomized controlled trials provide the highest level of evidence to inform medical practice. However, conducting such studies presents significant operational challenges and is becoming increasingly difficult. One of the many challenges in conducting high-quality, large-scale clinical research is ensuring compliance with all necessary ethical, administrative, regulatory and logistical (EARL) requirements. In the event of severe infectious disease outbreaks requiring rapid response, EARL requirements and country coordination make clinical trial implementation difficult. The Covid-19 pandemic has highlighted the way countries approached clinical research during a public health emergency. However, the differences in schedules between countries have not been comprehensively quantified.

Comparing schedules

In this study, researchers quantified EARL procedure timelines and compared different European countries. They used data from the Randomized Embedded Multifactorial Adaptive Platform Nonprofit Pneumonia Trial (Remap-CAP), which spanned both the pre-pandemic (2016-2020) and pandemic (2020-2023) periods. Remap-Cap, an international clinical trial with an innovative adaptive platform design, was designed to test multiple drugs for the treatment of pneumonia, including Covid-19, which enabled comparison of a large number of submissions. The new analysis, published this week in JAMA Network Open, included 257 fully signed contracts with study sites in 19 European countries and focused on three key metrics: time to close site contracts, time to regulatory and ethical approval (TTA), and time to first patient enrollment (FPI).

Differences between countries

The results showed that the UK achieved dramatic efficiency gains during the pandemic, with the average completion time falling by 97 percent: from 196 days before the pandemic to just 5 days during the pandemic. In contrast, non-UK countries in Europe only saw an increase of 18 percent, with average times falling from 224 to 183 days. The study also found stark differences in time to ethical and regulatory approvals. The median TTA in the UK during the pandemic was 8 days, compared to 115 days in non-UK countries. The time from approval to first patient enrollment was on average three months faster in the UK (26 days versus 116 days).

These results highlight the striking differences in research infrastructure and interpretation of regulatory guidelines across Europe. For researchers, it is clear that EARL processes in Europe can be a major bottleneck for initiating and executing trials, slowing patient access to potentially life-saving therapies. However, overcoming these challenges requires proactive efforts, including from researchers themselves.”

Denise Van Hout, MD, PhD (Research Program Epidemiology of Infectious Diseases, UMC Utrecht), epidemiologist, first author of the manuscript

Consistent, transparent processes

The researchers also found that while the UK benefited from its established research networks and emergency testing frameworks, other countries continue to face significant challenges. These differences highlight the need to harmonize EARL procedures across countries to reduce delays and maximize the impact of collaborative efforts.

“It is important for researchers planning or conducting multinational studies to recognize how preparation and engagement with ethical processes can contribute early on.” Van Hout emphasized. "Researchers, policymakers, legal experts and regulators must work together to develop consistent, transparent processes that prioritize trial deployment without compromising safety and ethics. This includes more efficient contracting. Greater collaboration and streamlining EARL procedures are important to ensure that patients across Europe, particularly in future pandemic situations, benefit from innovative solutions." Research can benefit.”

Sources: