Why is drug development for rare diseases so challenging?

UpdatedSeptember 26, 2019

Drug development for any disease is a complex, expensive and slow process. Layer on top of that developing drugs for a condition that impacts a limited population, and we as a rare-disease community are up against some unique challenges.

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The limited number of patients for trials

Let’s start with the obvious. Although the definition of a rare disease in the U.S. is a condition that affects fewer than 200,000 people, most rare diseases affect far fewer people.

Why is having a small number of patients a disadvantage when it comes to clinical trials? In the world of clinical studies, the gold standard is randomized clinical trials. In a randomized clinical trial, participants are randomly assigned to either an experimental or a control group to eliminate any population bias. It is considered the most effective way to find out if there is a cause-and-effect relationship between a drug intervention and an outcome.

Studies for rare diseases have smaller patient populations to recruit from and randomized trials are not always an option. Researchers may have to find the next best alternative for clinical trial design, however this is also an opportunity for creative approaches and collaboration.

For example, at AllStripes we are working towards a future where quality natural history studies may be able to take the place of a control group. Reducing the need for placebo control would mean that more patients could access the trial drug, something we know is important to many people in the rare community.

Limited knowledge of the history and progression of the disease

The challenges of having a limited number of patients extend to researchers’ existing knowledge of a condition. In some cases, even the top experts in the world with knowledge of a given rare disease may not know enough about the natural progression to make fully informed recommendations on what to track in a trial or how a trial should be designed.

The few clinical experts who know each rare condition deeply, combined with the limited knowledge available on the condition makes it difficult to jumpstart research in a given condition, even if patients and communities are driven and well organized. This again points to the need for efforts like AllStripes’ to recruit, organize and structure as much available data on a given rare disease as possible, to help fill in those gaps of knowledge.

Disease heterogeneity in the patient population

Even when patients are able to participate in a rare disease trial, there is the challenge of disease heterogeneity, meaning differences in the disease in terms of how it affects different patients. This range of differences can be seen in symptoms, severity, progression or exposure to prior treatment.

About 80% of rare diseases are genetic disorders and many have a wide range of disease heterogeneity. These many “versions” of a disease present a challenge in deciding how to measure the outcome of a drug trial.

Serving pediatric populations

About 50% of rare diseases affect pediatric populations (birth to 16 years of age). Research in pediatric populations is unique because children are under the care of parents or guardians and cannot give consent by themselves.

Researchers also need to take on additional ethical considerations and restrictions for pediatric populations. For example the use of certain procedures may be okay for research with adults but not for children.

Protections for children involved in research are unquestionably critical, but add another layer of consideration when a team is designing a treatment trial.

The need to standardize the collection and handling of data

Standardization of data is a challenge faced by all clinical trials, not just in trials that involve rare diseases.

However, due to the limited number of patients in rare disease clinical trials, it is even more crucial to standardize the collection and handling of data in such studies. AllStripes’ work to abstract research-grade data from rare disease patient records could be a big step forward for researchers facing this challenge, and we take on maintaining the data as well by keeping it up to date each year.

Efforts to address challenges in developing drugs for rare disease

There is some good news, we promise! In recent years, we’ve seen a growing effort to address some of the challenges in developing drugs for rare diseases. Below are some of the highlights.

Orphan Drug Designation

The Orphan Drug Act (ODA) was created in 1983 to encourage the development of drugs for rare diseases by making sponsors eligible for certain financial incentives. Before the ODA, less than one drug a year was approved for rare diseases in the U.S. Decades later, in 2018 there were 35 novel drugs and biologics approved in 2018 with orphan drug designation.

Incentivizing more companies in this space

The ODA provides certain financial benefits to incentivize more companies in the space of rare disease drug research. Incentives associated with orphan drug designation include the following:

  1. Tax credit for 25% of qualified clinical trial costs
  2. Waiver of fees under the Prescription Drug User Fee Act
  3. Eligibility for a 7-year period of market exclusivity

Flexibility in the application of regulatory standards

Due to the need for more research in the area of rare diseases, the U.S. Food and Drug Administration (FDA) provides some flexibility in applying regulatory standards to this group.

Take for instance the kind and quality of data. The FDA uses scientific judgment to determine if the data provided by a rare disease study is sufficient.

The availability of expedited programs

Since many rare diseases are life-threatening with unmet medical needs, the FDA has made it possible for sponsors to apply for certain expedited programs if they qualify.

Such programs include fast-track designation, breakthrough therapy designation, priority review designation and accelerated approval.

Addressing the need for more knowledge about rare conditions

In addition to making rare diseases more appealing for drug companies to work on, there have been new efforts to collaborate across the rare-disease space and share knowledge.

We will continue to highlight efforts that are working to address these challenges and celebrate all who endeavor to collaborate more actively for rare disease patients.

As more and more patients join AllStripes, we are excited to grow a truly robust source of real-world evidence for rare conditions that can be accessed freely by academic researchers and is never exclusive to any one company. To learn more visit allstripes.com


  1. FAQs About Rare Diseases | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases. Accessed August 30, 2019.

  2. Kaplan W, Wirtz VJ, Mantek-Teeuwisse A, Stolk P, Duthey B, Laing R. Priority Medicines for Europe and the World - 2013 Update. World Health Organization; 2013:148-150. https://www.who.int/medicines/areas/priority\_medicines/MasterDocJune28\_FINAL\_Web.pdf?ua=1

  3. RARE Facts. Global Genes. https://globalgenes.org/rare-facts/. Accessed September 1, 2019.

  4. Day S, Jonker AH, Lau LPL, et al. Recommendations for the design of small population clinical trials. Orphanet J Rare Dis. 2018;13. doi:10.1186/s13023-018-0931-2

  5. Whicher D, Philbin S, Aronson N. An overview of the impact of rare disease characteristics on research methodology Orphanet J Rare Dis. 2018;13(1):14. doi:10.1186/s13023-017-0755-5

  6. 15 for 15: Rare Genetic Diseases. Genome.gov. https://www.genome.gov/dna-day/15-for-15/rare-genetic-diseases Accessed September 1, 2019.

  7. Research C for DE and. Rare Diseases: Common Issues in Drug Development Guidance for Industry. U.S. Food and Drug Administration. http://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-common-issues-drug-development-guidance-industry-0. Published May 14, 2019. Accessed September 3, 2019.

  8. CFR - Code of Federal Regulations Title 21. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.105. Accessed September 3, 2019.

Originally posted at September 26, 2019

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