Clinical Trials for Rare Diseases: Problems and Perspectives, part 1

Part 1, financial and organizational challenges.

Rare diseases (RD) are a heterogeneous group of over 6,000 disorders. There is no single official definition of RD, and different countries define them in their own way relying on different prevalence rates.



   Definition of rare disease according to prevalence

   European Union

   ≤ 5/10,000


   < 200,000 individuals (equivalent to ~6/10,000)


   < 50,000 individuals (equivalent to ~4/10,000)


   < 2,000 individuals (equivalent to ~4/10,000)

   South Korea

   < 20,000 individuals (equivalent to ~4/10,000)


   ≤ 1/10,000


   ≤ 1/10,000


RD are often called “orphan diseases” because of being neglected by researches, funding agencies, and pharmaceutical companies. Small potential market and limited basic knowledge on RD pathophysiology make them unprofitable and risky targets for therapeutics development. Meanwhile, despite the rarity of each disease, their cumulative impact on public health is huge. Most RD are chronic, debilitating or even life-threatening, and more than half affect children. An urgent need to encourage RD research and orphan drug discovery was realized in the early 1980s. The first law aimed at raising attention of potential sponsors to RD was the US Orphan Drug Act of 19831. It was succeeded by similar legislation in other countries, including the European Union (the EU Regulation 141/20002). The incentives provided to clinical trialists in frame of these regulatory initiatives include:

  • simplification of marketing authorization procedures
  • extended market exclusivity
  • protocol assistance and scientific advice from regulatory bodies
  • tax credits, regulatory fee reductions or waivers

Introduction of RD legislation was generally fruitful. In the USA, nearly 250 orphan drugs have received marketing authorization from 1983 to 2004. By contrast, less than 10 RD medicinal products for RD treatment reached the USA market during the decade prior to 1983. 

Today, financial and informational support also comes from grants and other programs. Some of them are listed below:

  • Orphan Products Clinical Trials Grants Program3 (encourages clinical development of products for use in rare diseases or conditions. Provides funding)
  • Orphan Products Natural History Grants Program4 (supports studies that promote medical product development through characterization of RD natural history. Provides funding)
  • Therapeutics for Rare and Neglected Diseases Program5 (supports pre-clinical development of therapeutic candidates for RD treatment. Provides project management and drug development operational support)

Lack of funding is undoubtedly not the only barrier challenging the development of orphan drugs. A serious problem can be recruiting a sufficient number of patients to provide an adequate sample size for a clinical study.

  • Patients with RD are often few and geographically dispersed. Those with severe RD can hardly travel to research centers to participate in a trial.
  • RD are poorly represented in medical nomenclatures (such as ICD-10), that hampers patients identification.
  • Insufficient knowledge on the disease natural history, clinical signs and symptoms underlies significant delays in diagnosis, and some RD patients may remain undiagnosed throughout all their lives. Moreover, inappropriate previous treatment can make such individuals ineligible for forthcoming trials.

Thus, the time needed to enroll participants can be extremely long, and in some cases executing a trial is impossible without international collaboration. Multination trial, in turn, could be difficult to conduct due to differences in regulatory and ethical requirements, language and cultural barriers, different standards for RD diagnostics, and variable availability of treatment options.

In the European Union, multinational cooperation in clinical research will be facilitated by the upcoming Regulation (EU) No 536/20146 that will harmonize both the rules for conducting clinical trials and the assessment processes.

Collaboration across multiple centers throughout the world as well as recruiting individuals with RD in clinical trials can be ameliorated by establishing research networks and consortia and partnership with patient organizations.

  • The Rare Diseases Clinical Research Network7 (RDCRN) provides support for clinical studies in RD, facilitates collaboration between research groups and patient organizations, promotes participation in trials, and enhances data sharing.
  • The National Organization for Rare Disorders8 (NORD) is a RD patient advocacy organization that supports patients and their families, RD patient organizations, medical professionals, and all stakeholders involved in the development of new diagnostics and treatments. In particular, NORD shares information about opportunities to participate in clinical trials.
  • EURORDIS-Rare Diseases Europe9 is a non-profit alliance of 808 RD patient organizations. One of its goals is advancing scientific and clinical RD research.
  • Orphanet10 is a portal for RD and orphan drugs. It facilitates exchange of knowledge and offers a wide range of freely accessible services. These services include inventories of RD and orphan drugs at all stages of development, a collection of thematic reports, and the Orphanet Rare Disease Ontology - a structured vocabulary for RD derived from the Orphanet database. Moreover, Orphanet maintains the Orphanet rare disease nomenclature (ORPHAnumber) that helps to improve the visibility of RD in health and research information systems.
  • The International Rare Diseases Research Consortium11 (IRDiRC) is a consortium of nearly 50 funding and patient organizations aimed at fostering international research collaboration and investment. One of its goals for the decade 2017-2027 is contributing to the development of 1000 new RD therapies.



[1] The Orphan Drug Act of 1983. Accessed 23 July 2018.

[2] Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products. Accessed 23 July 2018.

[3] Orphan Products Clinical Trials Grants Program. Accessed 23 July 2018.

[4] Orphan Products Natural History Grants Program. Accessed 23 July 2018.

[5] National Institutes of Health’s Therapeutics for Rare and Neglected Diseases (TRND) program. Accessed 23 July 2018.

[6] Regulation (EU) No 536/2014 of the European Parliament and of the Council on clinical trials on medicinal products for human use. Accessed 23 July 2018.

[7] Rare Diseases Clinical Research Network (RDCRN). Accessed 24 July 2018.

[8] National Organization for Rare Disorders (NORD). Accessed 24 July 2018.

[9] EURORDIS-Rare Diseases Europe. Accessed 24 July 2018.

[10] Orphanet. Accessed 24 July 2018.

[11] International Rare Diseases Research Consortium (IRDiRC). Accessed 24 July 2018.