Rare disease clinical development requires more than scientific innovation. Because patients are few, expertise is fragmented and clinical pathways are often complex, successful trial execution depends on the ability to build integrated, cross-border research ecosystems.
Over the past decade, Europe has become one of the world’s most strategic regions for rare disease clinical development. By combining research investment, specialized clinical networks and progressive regulatory harmonization, the European Union has created an ecosystem designed to reduce fragmentation, support collaboration and make clinical research more feasible in rare and ultra-rare diseases.
Europe’s response to this challenge has been to move from isolated research efforts towards a more coordinated rare disease ecosystem.
ERDERA, ERNs, JARDIN, and CTR 536/2014: Europe’s Strategy for Rare Disease Clinical Research
As of today, ERDERA, the European Rare Diseases Research Alliance, is one of the clearest examples of this ambition: a Horizon Europe partnership designed to make Europe a global leader in rare disease research. This organization unites more than 170 public and private organizations across 37 countries, focused on improving prevention, diagnosis and treatment for the 30 million Europeans living with a rare disease.
Another fundamental strategic adoption made by Europe to respond to the complexity in the rare disease clinical research field is the European Reference Networks (ERNs), founded in 2017 to address the challenges through cross-border cooperation. The ERNs are a unique network at global level, bringing together centers of excellence across different European countries and enabling the sharing of highly specialized expertise. As of today, there are 24 active networks that involve more than 1600 specialized centers in around 380 hospitals across 27 EU Member States and Norway. This structure allows clinical and scientific expertise to be concentrated and shared, improving diagnostic and therapeutic capacity for rare and ultrarare diseases. ERNs cover a broad spectrum of rare diseases, grouped across different clinical areas, such as neuromuscular, metabolic, oncological, and congenital conditions.
The value of ERNs is particularly significant if we focus on clinical trials in Europe, because they can support trial feasibility by increasing visibility of specialized centers and facilitating expert collaboration, potentially leading to easier recruitment and referral of patients. Additionally, ERNs facilitate the sharing of clinical data and the adoption of common clinical practices, that help improve the studies, reduce fragmentation and increase research quality.
To further strengthen the ERNs collaboration, in 2024 the European Commission launched the JARDIN initiative, aimed at integrating ERNs more closely into national healthcare systems and to create a closer connection between European networks and local healthcare facilities, facilitating inclusion in clinical trials. Together with the creation of collaborative initiatives, EU has made very important changes in its regulatory system in order to have a more competitive and attractive clinical research. One fundamental step consists in the adoption of the Clinical Trials Regulation (CTR 536/2014), in place since 2022, that introduces a centralized system with a single application for multicentric studies in the European Union, reducing administrative burden and approval times. Although the Regulation entered into force in 2014, the timing of its application depended on the development of a fully functional EU clinical trials portal and database. Among many positive effects on the clinical studies in Europe, this new regulation also allows to increase patient recruitment across different European countries.
The Spanish Case
Among the European countries, there is one that was (and still is) particularly able to integrate in its system all these changes: Spain. This country stands out as a model example, having emerged as one of the global leaders in clinical research and the top European country for clinical studies, including the ones for rare diseases. And here we would like to discuss several key factors that contributed to this success.
First, Spain was early and proactive in adopting the European regulatory framework, introducing a national regulation aligned with the European Regulation as early as 2015. This allowed the simplification and harmonization of procedures, making the country particularly attractive to international sponsors and supporting the development of clinical studies, even in early stages (I-II phases). In addition, the Spanish Agency for Medicines and Health Products (Aemps), under the Ministry of Health, which is the competent authority for the authorization of clinical trials, has a very proactive approach in maintaining ongoing dialogue with the pharmaceutical industry that sponsors the studies, promoting the fast advance of the clinical research activity.
Second, Spain’s healthcare system is very efficient and harmonized. With an extensive network of hospitals and research centers, the country offers an ideal environment for conducting complex clinical trials. Furthermore, the strong collaboration between basic research and clinical applications makes the shift “from bench to bed” even faster.
Another key element is the significant investment made by the pharmaceutical industry, as Spain’s model is based on a strong collaboration between the public and private sectors. Health authorities, hospitals, universities, researchers, pharmaceutical industry, and patient associations work together in a coordinated manner, creating an efficient system for the development of clinical research. In addition, a substantial portion of resources invested by the private industry goes to clinical trials, enabling an increasing number of patients to access innovative therapies early on. This is particularly relevant in the field of rare diseases, where therapeutic options are often limited.
To put this success into numbers, between January 2022 and February 2024, 2491 clinical trials have been authorized in the European Union, with Spanish centers participating in 1136 of them (45.6% of the total).
In the rare disease field specifically, Spain’s contribution is equally significant: in 2025, 207 of the 929 clinical trials authorized in the country were focused on rare diseases, representing more than the 22% of all authorized studies.
In conclusion, the European Union represents as a key strategic territory for conducting clinical trials. Within the EU, countries like Spain, which have successfully adopted European directives and enhanced them with strong and coordinated national healthcare systems, represent a very important center for investing in the clinical development for rare disease therapies.