EndoCompass Project: Rare Diseases in Endocrinology

Abstract

Background

Endocrine science remains underrepresented in European Union research programmes despite the fundamental role of hormone health in human well-being. Analysis of the CORDIS database reveals a persistent gap between the societal impact of endocrine disorders and their research prioritization. At national funding level, endocrine societies report limited or little attention of national research funding towards endocrinology. The EndoCompass project – a joint initiative between the European Society of Endocrinology and the European Society of Paediatric Endocrinology – aimed to identify and promote strategic research priorities in endocrine science to address critical hormone-related health challenges.

Methods

Research priorities were established through comprehensive analysis of the EU CORDIS database covering the Horizon 2020 framework period (2014–2020). Expert analysis evaluated the European rare disease research landscape, including European Reference Networks, ERICA, and emerging research infrastructures to identify structural needs and opportunities.

Results

Research priorities focus on leveraging established frameworks to advance rare disease research through harmonized data capture and registries; standardization of patient-centred outcome measures; development of innovative trial methodologies for small populations; enhancement of diagnostic capabilities through genomic innovation; and creation of sustainable research networks. Special emphasis is placed on bridging the gap between paediatric and adult care while fostering public-private partnerships.

Conclusions

This component of the EndoCompass project provides an evidence-based roadmap for developing rare disease research infrastructure. The analysis demonstrates the need for coordinated European approaches to rare disease research, combining expertise across centres, age groups, and specialities. The findings support strategic investment in sustainable rare disease research networks.

Background

Despite the inherent unusualness of a rare disease, it is far from uncommon to have a rare disease. In 2022, the European Commission reported that, in the European Union, approximately 36 million people live with a rare condition, and more than 6,000 different rare diseases have already been identified. While one rare condition may affect only a handful of patients worldwide (so being considered an ultra-rare condition), another may impact as many as 250,000 patients.

According to the European Registries for Rare Endocrine Conditions [1], more than 440 distinct rare diseases affect the endocrine system. However, to date, the number of patients with rare endocrine conditions in Europe is still not known. Currently, around 80% of rare conditions are found to be of genetic origin, and of those, 70% start in childhood [2].

While, historically, the key focus on rare conditions has been in paediatrics, this has changed recently. Due to advances in care and therapy, many conditions now have an extended or even normalized lifespan, so that age-appropriate care practices in adult medicine are needed. Furthermore, some rare conditions have been overlooked in childhood and may primarily present in adulthood, due to the time points of certain symptoms. Lastly, adult medicine has realized the importance of acquired rare conditions during adult life.

Therefore, the care of patients with rare (endocrine) conditions requires: (1) knowledge gain across many medical specialist areas, (2) the concept of management over the lifetime, and (3) the availability of diagnostic and therapeutic options, including participation in translational and clinical research for all age groups.

The lack of experience and scattered knowledge regarding rare diseases leads to diagnostic delays. There is a need for increased awareness among the public and for the establishment, funding, and sustainability of centres of expertise to enable earlier and correct diagnosis, as well as optimal management, treatment, and care. Many additional hurdles, however, still need to be overcome as there are no treatment options for the vast majority of cases. Furthermore, there might be lesser interest from pharmaceutical companies, due to difficulties in conducting appropriate clinical trials and lower chances for economic success. The phrasing and structuring of research needs and opportunities in rare diseases constitute challenges that are pursued vigorously by the European Union.

Development of a Research Network and Platform

The following have been realized by the European Union and the European Reference Networks (ERNs) to develop the prerequisite framework for rare disease research.

European Reference Networks and ERICA

In 2017, the European Commission installed 24 ERNs under EU Directive 2011/24/EU on the application of patients’ rights in cross-border healthcare and the EU4Health programme. In 2023, the ERNs included more than 1 400 centres of expertise within 400 healthcare providers in the European Union and Norway which, altogether, capture all rare disease domains.

The mission of the ERNs is to reduce present health inequalities across Europe, focussing on the following milestones: (1) demonstration of an added value of (cross-border) virtual consultations by multidisciplinary expert boards, (2) standardization of care for rare conditions (using transparency, guideline conformity, and patient involvement), and (3) development of structural pathways into science. For this purpose, in 2021, an ERN Research Working Group set up the ERICA project (European Rare Disease Research Coordination and Support Action, funded by Horizon 2020), in which all 24 ERNs participate [3]. ERICA has created a platform that integrates all ERN research and innovation capacities, with a focus on: (1) effective data collection strategies via the ERN registries, (2) patient-reported outcome measures, and (3) translation and research innovation.

A research priorities survey of the ERN Research Working Group mapped the research priorities across all ERNs. The integrated results of this survey formed the basis for the strategic positioning, structure, and actions of the ERICA project (2021–2025). These research priorities were harmonized data capture, patient-centred outcome measures, legal issues, investigator-initiated trial planning and execution, pragmatic (registry-based) clinical trials, and advanced experimental therapies (Fig. 1a). A pivotal role is given to the ERN registries, which are regarded as unique platforms linking care to research under the umbrella of, and in line with, the vision of the European Health Data Space [4]. The registries have developed from assessment of quality of care by numbers and have progressed through standardization of what is collected as assessment of quality by clinical outcomes [3]. Thus, they are benchmarking clinical outcomes and acting as a platform for quality improvement with active patient participation (with the patient as co-owner of her/his data).

Fig. 1.

a ERICA project stated priorities for ERN research (https://erica-rd.eu/). b Patient-rated priorities for research in rare diseases, reproduced from de Graaf, J.P., de Vries, F., Dirkson, A. et al. Patients with rare endocrine conditions have corresponding views on unmet needs in clinical research. Endocrine 71, 561–568 (2021). https://doi.org/10.1007/s12020-021-02618-z.

Rare Disease Research Infrastructures and Programmes

Despite the enormous availability of expertise in rare disease research, the rare disease research landscape in Europe has been scattered until recently. Multiple European research infrastructures harbouring specific rare disease expertise have been launched. These include Connect for Children (C4C), the European Clinical Research Infrastructure Network (ECRIN), the European Infrastructure for Translational Medicine (EATRIS), and biobanks, such as the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI), in the presence of the European Medicines Agency, industry partnerships, the European Commission (DG Research and +DG Sante), and the Board of Member States.

In 2019, the European Joint Programme on Rare Diseases (EJP RD) was launched [5]. This was the first overarching rare disease research consortium, bringing together 130 institutions (including the 24 ERNs) from 35 countries to create a comprehensive and sustainable ecosystem, allowing a virtuous circle between research, care, and medical innovation [6].

The successor to EJP RD under Horizon Europe is even more ambitious and will run from 2024 to 2034. Called the European Rare Disease Research Alliance (ERDERA), it aims to be maximally inclusive by supporting robust patient need-led research. It will do this by utilizing and maximizing the power of health and research data and by engaging and coordinating regional, national, EU, and international alignment, to accelerate the development of new treatments and diagnostic pathways [7].

ERDERA includes 171 organizations from 36 countries (26 in the European Union, 7 associated countries, and 3 non-EU countries). Its structure encompasses, in addition to funding (such as joint transnational calls), the development of a European Clinical Research Network (CRN). This CRN will implement research activities targeting the clinical trial readiness of rare conditions around 4 pillars:

• 1.Diagnostic research (data readiness, genome reanalysis research pipeline, genomic innovation to shorten time to diagnosis)
• 2.Outcome research (real-world data, clinical outcome assessment)
• 3.Innovative therapies (advanced therapeutic medicinal products, trial methodologies, to name a few)
• 4.Task forces (drug trials, non-pharmacological interventions).

Expectations of Patients and Society

The development of a well-structured rare disease research ecosystem requires that all rare disease research stakeholders can participate. Identification of the right partners for coordinated research initiatives will be key, including initiation of new public-private partnerships and alignment of research strategies with professional societies, as well as with international networks, such as the ERNs that represent both academia and patients. Partners will need to be prepared and equipped to demonstrate readiness for the initiation of international and translational clinical trials, ranging from phases 1 to 4.

The expectations of patients and society with regard to research on rare endocrine conditions have recently been mapped [8]. In this survey-based study, the specific themes related to rare endocrine conditions were prioritized by patients and highlighted, in particular, the need for more research on the ability to work and to participate in social activities (Fig. 1b). The study provided clear recommendations for clinical experts on how to incorporate its results into the design of future studies on rare endocrine conditions and especially the utilization of the results in designing patient-reported outcome measures for the disease areas covered by the ERN on Rare Endocrine Conditions (Endo-ERN). This is exemplary for many chronic conditions that require lifelong therapy and have an overall good life expectancy and, thus, may be relevant to all ERNs.

Utilizing the Established Framework

Overall, the now established framework will allow the development of healthcare provision for complex and rare conditions to attain a new, expertise-driven quality, based on knowledge generation, transparency, and networking. Furthermore, connection to a combined research environment will open possibilities for exponential growth and competitive science in human biology and medicine and will provide the European partnership with a world-leading role. For many rare conditions, networking activities are mandatory in research, whether this is the reliance on adequate patient cohorts, modern techniques and methodology, or the exchange of experts in robust consortia that allow for transparent (albeit competitive) scientific activities. Similarly, optimal management of complex and rare conditions relies on both knowledge and benchmarking of best practice in healthcare provision. Ultimately, connecting research and healthcare will provide the basis for the European success in a worldwide competitive environment.

Focus Areas for Research into Rare Conditions

The following are examples of specific topics that should be considered when deciding on a research grant. They have been incorporated into the Endo-ERN Quality of Care Improvement and Research Counsel:

• 1.Diagnostic research readiness:

  • Assessment of data readiness, standardization, and harmonization

  • Genome reanalysis pipeline application, variant interpretation, and translation to endocrinology departments or clinics

  • Genomic innovation to shorten time to diagnosis

• 2.Clinical trial readiness:

  • Multinational patient inclusion and collaboration

  • Disease progression modelling

• 3.Clinical outcome assessment:

  • Estimating the socio-economic impact of rare endocrine diseases

  • Digital tool and pathway development

  • Develop/implement disease-specific clinical outcome assessment tools

• 4.Innovative therapies:

  • Advanced therapeutic medicinal products need assessment/mapping in Endo-ERN

  • Analysis of specific therapy and treatment availability across EU member states

• 5.Unique clinical resource development/pilot:

  • Disease-specific patient journey development

  • Rare endocrine disease patient pathway development/application

  • Mapping of European patient referral pathways/channels in Endo-ERN

The overall research framework needs to be used specifically for rare conditions, for reasons including the importance of sharing data (especially from genomics), the specifications for clinical trials and development of novel therapeutic approaches, and overall new care models. The latter have been developed through the ERNs and will be introduced into the different member states via the JARDIN programme. JARDIN is a joint action of the European Union to increase the effective integration of the ERN process into national healthcare systems. This, in turn, will lead to effective future research strategies as outlined above.

Conflict of Interest Statement

Alberto M. Pereira and Olaf Hiort are the coordinator and deputy coordinator of Endo-ERN.

Funding Sources

Endo-ERN is funded by the European Union under the framework of the EU4Health Programme, Grant Agreement No. 101084921.

Author Contributions

Alberto M. Pereira: investigation, methodology, project administration, visualization, writing – original draft, and writing – review and editing. Olaf Hiort: investigation, methodology, project administration, writing – original draft, and writing – review and editing.

Funding Statement

Endo-ERN is funded by the European Union under the framework of the EU4Health Programme, Grant Agreement No. 101084921.