Rare disease and clinical trials: what challenges do researchers and companies have to overcome?

It is no surprise that tackling rare diseases comes with many challenges. Research and drug development process standards are not adapted to the field. Yet, the number of people living with rare diseases represent the equivalent of the third largest country on the planet and they need help. Over the past decade, despite great market barriers, influential players in the industry have been moving into action. The future is filled with new possibilities, from collaborations to innovations in clinical trial design. In this article, Alcimed decrypts the current challenges researchers face when organizing clinical trials with rare disease patients and the solutions to overcome these challenges.

Rare diseases are receiving growing attention from researchers and industries

Over the past decades, the knowledge of rare diseases has been expanding, leading to field expertise, specialized research centers, and patient associations. In fact, the number of newly registered rare diseases has been dropping, whereas newly registered clinical trials went up 5-fold in less than two decades[1][2]. To some extent, we are becoming more aware of what rare diseases exist globally, and more ready to deploy research efforts to investigate them.

In 2021, the 193 United Nations member states adopted, for the first time, a resolution to increase the visibility and support of people living with a rare disease. In 2022, the French Rare diseases foundation, which was born by the will of five major players in France, completed 10 years of supporting clinical research and patient associations and hosting yearly symposiums since 2019. Similarly, in March 2023, Greece will be hosting the third international conference on rare diseases challenging the status quo with different stakeholders, from health policy professionals to patients.

With this growing need for solutions and therapies in these niche markets, stakeholders are positioning themselves in the race where the first challenge is to choose amongst approximately 7000 diseases, which disease(s) to address[3]. As the treatment market projection is set to double between 2020 and 2030[4], rare diseases are becoming a major axis of action for pharmaceutical companies and other players in nearby industries.

Recruitment of patients with a rare disease poses challenges for clinical trials

An inherent lack of participants for clinical trials on rare diseases

By definition, there is a low prevalence of each rare disease. The lack of patients who can participate in clinical trials will crumble the robustness of the trial design and the significancy of its results, decreasing the attraction of sponsors and thus leading to less clinical trials. With less means to investigate, researchers cannot improve pathogeneses and diagnoses knowledge, the expertise stagnates and, with it, the promise of treatment for these patients. Patients end up with little options available, if any. Also, compared with non-rare diseases, rare diseases trials usually enroll fewer participants and are more likely to be single-armed (i.e. no control), non-randomized and open-label. Also, there is a higher drop off proportions, and even a larger number are early termination[1].

Eligibility criteria that exclude many potential participants of clinical trials from the start

The above context of small sample sizes brings more restrictions. Once a patient finds a clinical trial in which to enroll, the next challenge is becoming a participant. The eligibility criteria can be as restrictive as the population size of the disease is small. With the numerous conditions to pass on clinical history, age, co-morbidity, side effects, and family history, many potential candidates remain only that and go back to square one.

A conflict arising between research and actual treatment

Finally, complying with the statistical need for controls is a battle in the case of rare diseases. Particularly, there is a difficult question of ethics behind the control by placebo. In some diseases, the rapid progression of the condition, quickly life-threatening, will urge any relative or patient to enroll in active treatment options as part of the interventional arm, rather than betting on getting assigned to the reference study arm.

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2 solutions to overcome the challenges linked to clinical trials on rare diseases

Solution n°1: capitalizing on the rare disease communities to find potential participants for clinical trials

Fewer patients per disease allows companies to directly impact patients’ lives more intimately. This improves communication between medical professionals, clinical professionals, and patients, addressing their real needs and burdens. It can inspire new workflows to advance action on rare diseases. For instance, patients’ relatives now leverage social media to gain attention for urgent clinical trial searches. These emotionally engaged social circles offer great opportunities for impactful change.

Solution n°2: exploiting new research and opportunities for collaboration

There is an undeniable global momentum for action, seducing the established players of the healthcare industry with interesting startups to watch such as Keros Therapeutics, Imara, or Dyne Therapeutics. Opportunities remain to be seized with new collaborations and new programs to refresh the rare diseases treatment and research landscape. Precisely, new research approaches are being analyzed. Recent publications suggest an innovative thinking to bypass the limited number of subjects available and the standard approval process of drugs. For example, showing ”non ineffectiveness” instead of effectiveness but also adopting a two-stage adaptive seamless trial design.

Patients, together with their relatives and medical teams are constantly proving that the need for innovation in the field is real and growing. Can clinical trial designs be adapted to the little number of rare diseases patients? What new funding programs can be created to make science move forward? What new collaborations can be imagined to refresh the research landscape? And these are only a few of the questions to be asked. Alcimed is there to help the different players, established and new ones, to find out how to take position in this race and explore their way to innovation. Don’t hesitate to contact our team!

[1] Sakate, R., Fukagawa, A., Takagaki, Y., Okura, H., & Matsuyama, A. (2018). Trends of clinical trials for drug development in rare diseases. Current Clinical Pharmacology, 13(3).
[2] Chang, X., Zhang, J., Jiang, Y., Shang, M., & Wu, Y. (2022). A survey of registered pharmacological clinical trials on rare neurological diseases in children in 2010–2020. Frontiers in Pediatrics, 10.
[3] Wakap, S. N., Lambert, D., Olry, A., Rodwell, C., Gueydan, C., Lanneau, V., Murphy, D. N., Cam, Y. L., & Rath, A. (2019). Estimating cumulative point prevalence of rare diseases : Analysis of the Orphanet Database. European Journal of Human Genetics, 28(2).
[4] BioSpace. (2022, août 25). Rare Diseases Treatment Market Size, Share, Growth, Trends | Report 2022-2030. BioSpace.

About the author, 

Thaïs, Consultant in Alcimed’s Life Sciences team in Switzerland