Rare disease drug development is a rapidly expanding field with growing pressure for getting a more orphan drugs approved to treat rare diseases. There is a vast consensus among patients, health care bodies, governments, etc. to expedite drug development in this field.

Some wonderful numbers that attest to growing interest in rare diseases and orphan drugs are as follows.

  1. The growth of the orphan drug market is double that of the overall prescription drug market, which is set to grow by 5.3% over the period 2017-2022.
  2. Orphan drugs are set to account for 21.4% of global prescription sales in 2022, excluding generics, up from 6% in 2000.
  3. In 2016 orphan drug sales increased 12.2% to $114bn vs. 2015, while non-orphan drug sales increased by 2.4% to $578bn. [1]

What is Rare Disease?

Rare diseases (RD) are complex diseases with a very low prevalence [11]. A disease is considered rare if fewer than 1 out of 2000 in the EU, 1500 in the US, and 2500 in Japan are affected and these are not defined officially but just for reference.

Below are the countries with the criteria for the disease to be considered as rare

The majority of rare diseases currently have no approved treatments available for patients, despite the fact that research related to rare diseases has expanded significantly in the past 20 years.

A key reason for this may be the unique challenge researchers face while developing drugs to treat rare diseases, including difficulties designing and executing effective and appropriate clinical trials. [2][3]

How many people are affected by Rare Diseases?

Data show that collectively 350-400 million people worldwide are affected by rare diseases and rare diseases affect approximately 6-10% of the population and 3-4% of births.

In U.S health care there are almost 7,000 rare diseases, affecting more than 25 million Americans and their families.

What are the causes of Rare Disease?

Most about 80% of rare diseases are genetic and the rest may occur as a result of viral or bacterial infections, allergies, and other environmental causes [2]

How many Rare Diseases are identified?

  • There are about 5,000-8,000 rare diseases and new rare diseases are being discovered every time.
  • These diseases can affect people very differently for example people with the same condition can have very different signs and symptoms, or there may be many subtypes of the same condition.
  • Rare cancers are a sub-group of rare diseases, and there are 198 estimated types of rare cancer.
  • In the European Union, rare cancers account for 22% of all cancer diagnoses [2]

Rare Disease Day, takes place on the last day of February every year which was initiated in Europe by EURORDIS (European Organisation for Rare Diseases) and over 80 countries participate in awareness raising activities and events with aim to raise awareness and increase understanding of rare diseases among the general public, researchers and policymakers across the globe.

Some Rare Disease facts

  • 50% of rare diseases affect children
  • 80% of rare diseases are linked to genetic mutations
  • Rare diseases are responsible for 35% of deaths in the first year of life
  • 30% of children with rare diseases will not live to see their 5th birthday
  • In the U.S 30 Million people are living with Rare Disease
  • If all the people with rare disease lived in one country then it would be the world’s 3rd populous country in the world [2][5][6]

The leading market for Orphan Drugs by Therapeutic area, Indication & Geography

By Therapeutic area

  • Oncologic Diseases
  • Metabolic Diseases
  • Hematologic and Immunologic Diseases
  • Infectious Diseases
  • Neurologic Diseases

By Indication

  • Non-Hodgkins Lymphoma
  • Acute Myeloid Leukemia
  • Cystic Fibrosis
  • Glioma
  • Pancreatic Cancer
  • Ovarian Cancer

By Geography

  • Asia Pacific
  • Europe
  • North America
  • Middle East & Africa
  • Latin America

Key Pharma Players in Rare Disease

  • Novartis AG
  • Hoffman-La Roche Ltd
  • Celgene Corporation
  • Bristol Myers Squibb
  • Shire
  • Pfizer Inc
  • Sanofi S A
  • Bayer [4][5]


  • The National Institutes of Health (NIH) established the Rare Diseases Clinical Research Network I (RDCRN I) to address the unique challenges of research on rare diseases.
  • In 2009, the NIH funded 19 continuing and new clinical research consortia to strengthen the ongoing clinical research in rare diseases.

The Rare Disease Clinical Research Network II (RDCRN)

  • Currently, the RDCRN consists of 19 Rare Diseases Clinical Research Consortia in addition to a Data Management Coordinating Center (DMCC).
  • The RDCRN studies approximately 90 rare diseases at over 97 academic institutions with several hundred investigators in the United States and in other countries.
  • The RDCRN enables the collaboration of scientists from multiple disciplines and provides shared access to geographically distributed research resources and patient populations.
  • Each consortium studies a group of related rare and sometimes fatal diseases.
  • The DMCC develops and introduces novel technologies for data collection, information sharing, and the performance of studies.
  • The RDCRN leads an effort for the incorporation of standard data which allows RDCRN researchers to integrate their data with other clinical networks and scientists, enabling the development of new diagnostic tools, treatments, and preventive strategies.
  • Each consortium in the RDCRN includes active participation by patients and investigators have made progress in every aspect of clinical research of rare diseases being studied in the network.
  • Each consortium conducts longitudinal natural history studies and clinical trials of new medications, often in collaboration with industry sponsors and patient advocacy groups, and training future leaders in the field.
  • Currently, there are over 26 clinical studies actively enrolling patients.
  • The RDCRN web site provides key information about rare diseases for physicians, investigators, patients, and the public.  The site lists all of the studies and the participating sites.
  • The RDCRN has also developed a unique web-based contact registry for patients who wish to learn about their disease and participation in clinical studies. [10]

Clinical Trials in Rare Diseases

The process of drug development and approval is expensive and time-consuming and poses specific challenges for rare diseases, ultimately affecting patients’ access to new treatments.

To encourage pharmaceutical companies to conduct research and develop drugs for rare diseases, the special designation of ‘orphan drugs’ has been given to medicines that are used to treat rare diseases

Many principles and theories have been found to improve drug development in Rare Disease.

Challenges in Clinical Trials of Rare disease

  • Small populations, limited opportunity for study and replication in clinical trials, few treating physicians and treatment centers are the cons for clinical trials in rare diseases
  • Disease history is often poorly understood and the ability to detect clinically meaningful outcomes requires an understanding of their rate of occurrence and variability, both of which contribute to difficulties in powering a study.
  • Clinical parameters are difficult to define because many rare diseases are poorly characterized and under‐researched.
  • Identification of affected patients can be difficult, especially early in the course of their disease, are generally geographically dispersed.
  • The difficulty of estimating the expected effect size of therapy and to decide on the most appropriate duration of the study because of the limited knowledge about the natural cause of the disease
  • Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients and often lacking endpoints, outcome assessment tools
  • Trials are frequently conducted on an international scale and may be subject to complex or multiple regulatory agency oversights and may be affected by local customs. [7][8]

Study Design aspects

  • There is a considerable amount of information in rare diseases from observational studies like self‐ controlled observational studies, case‐control studies, and prospective inception cohort studies
  • Registries serve as an important tool of information to study the natural history of a disease as well as to improve in designing a clinical trial from various aspects.

Key Points to Consider for Clinical Trials in Rare Disease

Budget Planning

  • Accurate per patient budget estimation
  • Regulatory approvals costs
  • Insurance
  • Exchange rate of a particular country
  • Site overheads

Country Set up considerations

  • Identify local expert contact for regulatory navigation
  • Translation

Study Set up: Accurate assessment of timeline Site set up in various regions

  • Sub-agreements with contracting partners
  • Licencing, Drug Procurement, and Manufacturing
  • Investigator Brochure
  • Patient Recruitment etc

Challenges for multicenter clinical trials

Clinical researchers in rare diseases face many challenges when conducting trials in small populations.

  • Difficulty to set up multiple sites in different countries to achieve recruitment targets
  • The diverse landscape of clinical trial regulations in those countries and Issues related to drug supply
  • NIH requirements regarding contracting with non-US sites,
  • lack of national harmonization with contracting and the requirement to negotiate terms and contract individually with each site and
  • Diversity of languages needed for study materials. [7][8][9][10]

Looking to conduct clinical trials in rare diseases? Credevo can help you!


  1. https://www.pharmaworldmagazine.com/rare-diseases-orphan-drug-market/
  2. https://study-volunteers.iconplc.com/__uuid/35914204-fbff-4622-8455-eae2a916a2d9/Rare-Disease-Brochure.pdf
  3. https://www.ifpma.org/wp-content/uploads/2017/02/IFPMA_Rare_Diseases_Brochure_28Feb2017_FINAL.pdf
  4. https://www.maximizemarketresearch.com/global-orphan-drugs-market-key-trends/
  5. https://issuu.com/healthcaretrends/docs/global_rare_disease_drugs_market
  6. https://www.weforum.org/agenda/2017/01/the-future-of-treating-rare-diseases/
  7. https://www.ncbi.nlm.nih.gov/pubmed/28815894
  8. http://www.rarediseasesjournal.com/articles/design-and-analysis-of-clinical-trials-for-small-rare-disease-populations-raredis-1-1054.php
  9. https://www.researchgate.net/publication/284142252_Challenges_of_the_set-up_process_for_academic_led_international_studies_of_rare_diseases
  10. https://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=126&key=R
  11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068991/