Session Topic: Strategies for Successful Rare Disease Clinical Trials


In the United States, a disease is defined as rare if it affects fewer than 200,000 individuals. According to the NIH Office of Rare Diseases Research (ORDR), more than 25 million people in the United States have a type of rare disease1. The National Organization for Rare Disorders estimates that there are nearly 7000 rare genetic or acquired diseases. Effective treatments exist for only a few.

There are many rare diseases in the NIAMS mission including musculoskeletal diseases (e.g. chondrodysplasias, genetic rickets, muscular dystrophies, nemaline myopathies, osteogenesis imperfecta), rheumatic diseases (e.g. inflammatory myopathies, pediatric rheumatic diseases, scleroderma, vasculititis) and skin diseases (e.g. cutis laxa, epidermolysis bullosa, pachyonychia congenita, pemphigus, pseudoxanthoma elasticum).

Clinical trials for rare diseases, whether funded by NIAMS or others, often encounter challenges. These include a small number of patients able to participate in studies, a limited availability of established outcome measures and natural history data upon which to base the study, and a lack of research infrastructure, such as collaborative networks of clinical research sites. Despite these obstacles, investigators have conducted meaningful clinical trials for rare diseases. Strategies that have facilitated successful studies have included using innovative trial designs (e.g., adaptive designs), partnering strategically with advocacy groups, industry and academic networks, and leveraging resources from research on common diseases (e.g., repurposing of drugs, outcome measures, infrastructure).

Goals of the Session

Participants will discuss obstacles that researchers have encountered and strategies that have led to success in rare diseases clinical trials. The session will provide NIAMS attendees with an understanding of practices that will enhance a trial’s likelihood of being informative and impactful, as well as insights into how to avoid potential pitfalls associated with studies of rare diseases.

Key Questions

Participants will be instructed to discuss the scenarios below and address the following questions:

  • What are the major obstacles that the investigator(s) will likely encounter in planning and conducting these trials, and what strategies do you suggest to address them?
  • What barriers will the researchers face when accessing essential resources (e.g. access to drug/placebo, biostatistical and data management support, support for regulatory approvals), and how can NIAMS enhance the trials’ likelihood of success?
  • Are there important differences between these investigator-initiated trials/self-assembled networks and trials conducted through NIH-established infrastructures [e.g., CTSAs, Rare Disease Clinical Research Network (RDCRN), NeuroNEXT]?
  • Is there an evaluation process and criteria that NIAMS should consider applying to determine whether these are high priority, potentially impactful trials appropriate for our support?

The following general questions also will guide the discussion:

  • What are some of the metrics of success for rare disease clinical trials supported by NIAMS?
  • How could NIAMS contribute to disseminating the results of successfully completed trials in rare diseases so these advances might influence clinical practice?


  • A clinical researcher has access to a cohort of rare disease patients and is interested in conducting a trial testing a repurposed drug. However, this investigator has limited clinical trial experience. Previous clinical trials of drugs that target the same biochemical pathway have been inconclusive, but this new drug is more potent, and anecdotal reports suggest it may be efficacious for patients with this rare disease. As with many rare diseases, there is some knowledge of the natural history of the disease, but there are no well-established outcome measures.
  • A network of clinical investigators at multiple institutions has been focusing on a specific rare disease for about ten years, conducting natural history studies and a few pilot trials with small numbers of patients. The results of clinical trials that they have conducted so far have been encouraging, resulting in moderate impact publications, but not sufficient for seeking approval of any new drugs/biologics or significant changes in clinical practice. One of the participating investigators just published exciting results demonstrating efficacy in an animal model for this rare disease by treating with a new chemical compound. Partnering with a small biotechnology company, the investigator has generated strong pharmacology and toxicology data. They have developed a method for producing sufficient amounts of the compound, and submitted an investigational new drug application. The other investigators in the network would like to test this compound in their patient cohort.



Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, Nguyen T, Paulus K, Merkel PA, Rare Diseases Clinical Research Network. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009 Jan;96(1):20-6. doi: 10.1016/j.ymgme.2008.10.003. Epub 2008 Nov 13. PMID: 19013090

Last Reviewed: 09/04/2013