Overcoming Challenges in Rare Disease Clinical Research

September 15, 2021

Current Landscape of Rare Disease Clinical Research

Rare diseases affect an estimated 3-6% of the global population,\(^1\) which may in fact be an underestimate, given the difficulty of diagnosing such diseases.\(^2\) The definitional prevalence of rare disease varies by region, in the European Union, a disease is defined as rare when it affects fewer than 1 in 2,000 people, but in the U.S. the Orphan Drug Act of 1983 defined it as a condition with a prevalence of less than 200,000 in the U.S.\(^3\) Currently, there are an estimated 300 million people around the world suffering from a rare disease.\(^4\) Among the 6,000-7,000 known rare diseases, the most common rare diseases are multiple sclerosis, narcolepsy, and primary biliary cholangitis.\(^5\) As diagnostic technology continues to advance, new rare diseases are continuously being identified and reported in the medical literature.

Rare diseases present a unique diagnostic challenge because of a lack of disease awareness in the medical community, limited medical specialization in rare diseases, and symptom overlap with other diseases.\(^6\) Given that relatively few patients are affected by each rare disease, there is limited data about disease pathology and progression of each rare disease. This results in a lack of evidence-based treatments for rare diseases, often rendering them incurable conditions. Efforts to provide better therapeutic options for patients with rare diseases are rooted in clinical trials, which is emphasized by the recent the FDA proposal for Rare Disease Clinical Trial Networks.\(^7\) 

Some challenges are unique to rare disease research. One is the small patient population, such that clinical trials compete for enrollment of the same patients. This population is geographically dispersed around the globe, and within different countries there is a different model of healthcare for rare disease patients, which poses a challenge to patient recruitment. Yet another challenge is the disease heterogeneity, including subtype, symptom presentation, stage, and prior treatment. For paediatric patients there are additional ethical and legal considerations, which constitute half of rare disease patients, and these logistical challenges can slow the recruitment timelines.

Overcoming Challenges in Rare Disease Trials

To successfully overcome these rare disease research challenges, clinical trials should make specific accommodations, especially as it relates to patient recruitment, patient retention, and clinical outcomes. An effective patient recruitment strategy should operate on three key levels. First it should engage investigators and key opinion leaders, to build referral networks. It should then utilize existing rare disease patient registries and communicate with disease-specific patient support groups. After that, it should employ a digital engagement strategy that provides information on current clinical trials, to connect patients to ongoing trials while they search online for information about their diagnosis.

Successful patient recruitment should be paired with effective patient retention strategies which employ a patient-centric approach. The clinical research staff members should make study participation as easy as possible for patients, to reduce barriers to study completion.\(^8\) Such barriers will be study- and context-dependent and may even be patient-dependent. For example, a patient may have transportation and accommodation needs that preclude their ability to participate in the study, and the clinical research staff should assist in arranging these services. Borrowing from best practices in customer service, clinical research staff should proactively think through the process of study participation, anticipate and address any identified pain points, and remain responsive to patient feedback throughout the trial.

The success of the trial also depends on study design, which includes appropriate and informative clinical outcomes. The U.S. FDA Roadmap to Patient-Focused Outcome Measurement in Clinical Trials consists of three main tenets: understanding the disease or condition, conceptualizing treatment benefit, and selecting or developing the outcome measure.\(^9\) Optimizing clinical outcomes in rare disease research will often require the adaptation of existing data collection instruments, which may have been developed for other diseases in the field or for general use that is not disease-specific.\(^{10}\) Modification of existing instruments is time-consuming but is still more efficient than developing new instruments, and it may require a more creative approach to functionally adapt them to the trial needs.

Dokumeds as your Rare Disease CRO

Dokumeds is a global clinical trials organization with experience operating trials as a rare disease CRO. Critical to the success of Dokumeds in rare disease research and other clinical trials is the in-house expertise of the Dokumeds medical science liaison (MSL). The MSL plays a central role in successful patient enrollment, by educating the investigator and staff at study sites, and by tapping into the network of healthcare providers that can refer potential patients. Dokumeds’ track record includes clinical trials for a variety of rare diseases, such as: idiopathic pulmonary fibrosis, mastocytosis, alpha-mannosidosis, systemic sclerosis, giant cell arteritis, palmoplantar pustulosis, pediatric rhabdomyosarcoma, and neuroectodermal tumors. The success of patient enrollment in these trials relied upon Dokumeds’ site selection strategy using the extensive global clinical network that Dokumeds has developed during more than 25 years in business. Dokumeds looks forward to further opportunities to work with partners on rare disease research.


  1. Nguengang Wakap, S., Lambert, D.M., Olry, A. et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 28, 165–173 (2020). https://doi.org/10.1038/s41431-019-0508-0
  2. Templeton, Lisa. Rare diseases more common than we think. Medical News Today. Published 01 Nov 2019. https://www.medicalnewstoday.com/articles/326879. Accessed 15 Jul 2021.
  3. National Center for Advancing Translational Sciences. FAQs about rare diseases. Last updated 26 Jan 2021. https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases. Accessed 15 Jul 2021.
  4. Joszt, Laura. Not so rare: 300 million people worldwide affected by rare diseases. AJMC. Published 07 Nov 2019. https://www.ajmc.com/view/not-so-rare-300-million-people-worldwide-affected-by-rare-diseases. Accessed 16 Jul 2021.
  5. Ghosh, Iman. Infographic: Which rare diseases are the most common? Visual Capitalist. Published 11 Sep 2019. https://www.visualcapitalist.com/which-rare-diseases-are-the-most-common/. Accessed 17 Jul 2021.
  6. The National Organization for Rare Disorders. Barriers to rare disease diagnosis, care and treatment i6n the US: a 30-year comparative analysis. (2020) https://rarediseases.org/wp-content/uploads/2020/11/NRD-2088-Barriers-30-Yr-Survey-Report_FNL-2.pdf
  7. FDA in brief: FDA requests input on rare disease clinical trial networks. Published 29 May 2020. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-requests-input-rare-disease-clinical-trial-networks. Accessed 17 Jul 2021.
  8. Deward SJ, Wilson A, Bausell H, Volz AS, Mooney K. Practical aspects of recruitment and retention in clinical trials of rare genetic diseases: the phenylketonuria (PKU) experience. J Genet Counsel 23, 20-28 (2014). https://doi.org/10.1007/s10897-013-9642-y
  9. U.S. Food and Drug Administration: Center for Drug Evaluation and Research. Roadmap to patient-focused outcome measurement in clinical trials. https://www.fda.gov/media/87004/download. Accessed 18 Jul 2021.
  10. Benjamin K, Vernon MK, Patrick DL, Perfetto E, Nestler-Parr S, Burke L. Patient-reported outcome and observer-reported outcome assessment in rare disease clinical trials: an ISPOR COA emerging good practices task force report. Value in Health 20, 838-855 (2017). https://dx.doi.org/10.1016/j.jval.2017.05.015

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