Advancing rare disease clinical trials on an international scale: Barriers and emerging solutions

Rare diseases affect over 300 million people worldwide, yet only 5% of these conditions have approved treatments. A key obstacle to rare disease drug development is designing clinical trials that can accommodate small patient populations and high disease heterogeneity. Increasingly, rare disease clinical trials are being conducted across multiple countries, which improves patient recruitment and therapeutic validity. However, international clinical trials introduce complex regulatory, financial, legal, and ethical challenges. These challenges can impede trial execution and ultimately delay access to treatment, particularly in low- and middle-income countries (LMICs). In this review, we explore the evolving landscape of international rare disease clinical trials. We discuss current barriers and strategies to harmonize global regulations, incentivize financial investment, adapt intellectual property frameworks, and enhance LMIC participation. By identifying both structural gaps and promising initiatives, we aim to provide a resource that supports more effective and globally inclusive rare disease research.