Do Smaller Trials Overestimate the Benefits of Biomedical Interventions? Insights from Mega-Trials study

Sep 22
In the world of medical research, the accuracy and reliability of clinical trial outcomes are very important to guide decision making. Small-scale trials are often the first to provide insights into the effectiveness of treatments, but how reliable are these findings compared to large-scale studies, or "mega-trials," involving over 10,000 participants? Our new study published in JAMA Network Open dives into this question, offering important findings for clinicians, researchers, and healthcare policymakers.
This comprehensive meta-research analysis, led by researchers from the University of Bern, Epistudia and Stanford University, along with contributions from colleagues from University of Utrecht, Graz, Lausanne, German Centrefor Diabetes Research,  and Duke University School of Medicine, explored how the results of small trials align with those from mega- trials.

Key Findings:
Impact on Mortality and Primary Outcomes
In an analysis of 120 mega-trials, for critical measures such as all-cause mortality and primary outcomes, mega-trials often failed to show statistically significant effects, especially on mortality. Of the 120 mega-trials identified, only 34% of the interventions showed a significant result for the primary outcome and 18% showed a significant result for all-cause mortality.

Mega-Trials vs. Smaller Trials
The study analyzed 82 mega-trials and corresponding meta-analyses of smaller trials. The findings showed that results of meta-analyses of small trials in general align with the results of mega-trails exploring the same intervention. However, smaller trials conducted before the mega-trials reported more beneficial results than the mega-trial and subsequent smaller clinical trials, suggesting that early smaller trials might overestimate the benefits of treatments. This reinforces the necessity of larger, well-powered studies to confirm the efficacy of treatments.

Why This Matters
Most biomedical interventions do not show significant effects in large-scale trials, particularly for critical endpoints like mortality. The findings challenge the reliance on early-phase small trials, underscoring the potential risks of overestimating the benefits of new treatments.
For Epistudia, committed to advancing rigorous evidence synthesis and research methods, these results highlight the crucial role of large, well-conducted studies in shaping reliable scientific conclusions. This study, with contributions from leading universities and researchers across Europe and the U.S., highlights the need for caution in interpreting early trial results and calls for a greater focus on conducting and supporting mega-trials to ensure the highest standards of evidence-based medicine.
Read the Full Study
For a detailed exploration of the data and its implications, you can access the full publication in JAMA Network Open here.