Rare disease landscape: a few initiatives to help you understand the RD environment

Rare diseases (RD) are conditions that have been historically neglected, because of both their complexity and the rarity of their clinical presentations. There are barriers to establishing a timely diagnosis for these patients and unpredictability and challenges when it comes to therapeutic development.

Despite the implementation of specific supportive orphan drug regulations and economic incentives around the globe, aiming at attracting investment in the field, treatments are estimated to be available for less than 5% of RD conditions (source). Therefore, numerous patients suffering from orphan diseases still lack a treatment.

The challenges for research and the development of medicinal products for RDs are myriad:

• The small number of patients affected by a given rare disease may mean that it attracts relatively little attention and funding in the research community, making research and clinical trial studies more difficult.
• The lack of a body of knowledge on the disease and its natural history, the heterogeneity of its clinical presentation, the low, sometimes very low, prevalence make the identification of patients difficult and impact the clinical trial design and methodology.
• The fact that many diseases affect the pediatric population, thus requiring special considerations.

Small clinical trials mean it is riskier to predict the effect on a larger number of patients outside of the inclusion criteria. As real-world efficacy is difficult to predict, regulatory approval and marketing are more challenging and, overall, this makes the investment case less attractive for orphan medicinal products (OMP) developers.

Pharmaceutical companies play a crucial role in the advancement of orphan drug development. Approximately 61% of clinical trials are sponsored by the pharmaceutical industry and 39% by non-commercial sponsors, mainly academia (source).

Given these features, the development of drugs for rare diseases requires the collaboration of many stakeholders (researchers, industry, patients, medical professionals, funders, regulators and payers). One example is in basic research, where collaboration among researchers and between academic researchers and pharmaceutical companies takes place within many initiatives. Basic research by academics and clinical development by companies are the backbone of OMP development. However, for many rare diseases, the scientific base from which drug development can depart from is either non-existent or insufficient, therefore making it difficult to garner pharmaceutical interest. In addition, today, scientific knowledge on rare diseases is still scattered across different institutions and initiatives, and unavailable to many important actors.

Collaborative strategies that pool resources and knowledge are therefore vital in the rare diseases field. The EU has taken great steps in addressing these issues with the creation of several initiatives and resources to help accelerate rare disease research productivity and drug development. These include major initiatives such as:

• The European Joint Programme on Rare Diseases (EJP RD), launched in January 2019, gathers research funders, universities, research organizations and infrastructures, hospitals and patient organizations from more than 135 institutions in 35 countries. Its main objective is to create a research and innovation pipeline “from bench to bedside” ensuring rapid translation of research results into clinical applications and uptake in health care for the benefit of patients.
• The European Reference Networks (ERN), first established in 2017, brings together more than 900 highly-specialized healthcare units from over 300 hospitals in 26 Member States. 24 ERNs are working on a range of thematic issues including bone disorders, childhood cancer and immunodeficiency. They aim to tackle complex or rare diseases and conditions, that require highly specialized treatment and concentrated knowledge and resources.
• The European Rare disease research Coordination and support Action (ERICA), is a new consortium formed in March 2021 to coordinate the clinical research activities of the European Reference Networks (ERNs). It unites the expertise of the 24 ERNs and will create a collaborative platform to share knowledge and good practices through the assembly of transdisciplinary research groups across the different medical areas.
• Orphanet, which was established in 1997 in France gathers information and maintains a central knowledge database of rare diseases and their classification, an inventory of orphan medicines, as well as directories of expert centers and patient organizations, research projects, clinical trials, registries, biobanks and diagnostic laboratories.
• The European Infrastructure for Translational Medicine (EATRIS) offers a broad range of research services for both academia and industry across various research fields. It provides access to a vast array of pre-clinical and clinical expertise and facilities that are available within 115+ top-tier academic centers across Europe for improving and optimizing preclinical and early clinical development of drugs, vaccines and diagnostics.
• The European Clinical Research Infrastructure Network (ECRIN) supports the conduct of multinational clinical trials in Europe. It provides tailored support and tools to facilitate multinational trials preparation and implementation and to overcome the various trial challenges (e.g., regulatory and ethical requirements, management and funding issues).
• The International Rare Diseases Research Consortium (IRDiRC), established in 2011 by the European Commission and the US National Institutes of Health, unites national and international governmental and non-profit funding bodies, companies (including pharmaceutical and biotech enterprises), umbrella patient advocacy organizations, and scientific researchers to promote international collaboration and drive solutions that aim to accelerate diagnosis and therapeutic development for rare diseases worldwide.
• EURORDIS-Rare Diseases Europe is a unique, non-profit alliance of more than 1000 rare disease patient organizations from 74 countries that work together to improve the lives of the 30 million people living with a rare disease in Europe. By connecting patients, families and patient groups, as well as by bringing together all stakeholders and mobilizing the rare disease community, EURORDIS strengthens the patient voice and shapes research, policies and patient services.

To summarize, while a lot of challenges exist, there are also many opportunities such as the regulatory support described in the next step but also the strong supporting role of rare disease patients.