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Rare disease clinical research: it is time to tackle what matters most to patients

13 June 2024

Supporting the development and evaluation of new treatments for rare diseases has become a key priority of the 21st century. Over 7,000 distinct rare diseases, affecting around 36 million people in Europe and between 25 to 30 million Americans, constitute the largest unmet medical need across the globe!

Rare disease patients suffer from a huge variety of rare and ultra-rare conditions (89.1% of rare diseases are ultra-rare!), for which scientific knowledge, medical information and therapeutic options are sadly lacking. Rare diseases are also characterized by a wide diversity of signs and symptoms, which vary not only between diseases but also between patients suffering from the same disease.

Despite the large number of patients and families who are collectively affected by rare diseases internationally, the general lack of public awareness, the lack of scientific knowledge, and the significantly limited expertise have marginalized rare diseases populations in both health systems and health- and social-care policies. Governments, independent organizations, and patient advocacy groups have started to address this challenge and have deployed significant efforts to shed light on the desperate need for more patient-centric rare disease research.

What is the specific position of regulatory agencies in rare diseases clinical trials? How does engaging with patient organizations improve rare disease drug development? How important do Patient Reported Outcomes need to become to improve the success of rare disease clinical trials?

1- The position of regulatory agencies towards drug development for rare diseases has evolved

Since the Orphan Drug Act in 1983, regulatory agencies have launched numerous initiatives and collaborative efforts to support rare disease drug development. The EMA and FDA have worked closely together on the designation and assessment of orphan medicines. These agencies also share information on orphan medicines with each other under their confidentiality arrangement, and both authorities have developed common procedures for applying for orphan designation and for submitting their reports on the status of the development of designated orphan medicines.

2- Patient organizations and non-profit organizations play an instrumental role in steering rare disease drug development​

As incentives to support orphan designation application, the agencies:

  • Provide solid scientific advice.
  • Promote access to research grants.
  • Propose streamlined processes.
  • Offer several years of market exclusivity.

Beside deploying efforts to encourage industry stakeholders to increase their investments in rare disease R&D, national and international agencies recommend collaborating with non-profit organizations and patient organizations, which have become key in drawing attention to rare diseases and mobilizing the rare disease community.

Having a rare disease presents specific questions that need to be answered in a specific manner:

  • The question of individual symptomatology: Rare diseases are characterized by a wide range of symptoms, which vary not only between diseases, but also between patients with the same disease. Therefore, understanding the individual symptomatology, and focusing on addressing the symptoms that matter most to patients, is a particular challenge.
  • The question of diagnosis: Patients experience significant delays in access to robust diagnoses: in Europe, 25% of rare disease patients had to wait between 5 to 30 years from disease onset to receiving a genetic diagnosis for their condition. Wide variations in age of onset and natural history of the disease complicate and significantly extend the diagnosis process.
  • The question of treatment: As well as the long wait for a robust diagnosis, rare disease patients and their families also often experience the the harsh reality of a lack of appropriate care, with 95% of rare diseases having no cure at all.
  • The question of the socioeconomic impact: Both patients and caregivers highlight the challenges in maintaining employment and education, due to frequent medical follow-ups and the uncertain nature of their condition. Rare Disease UK reports that 66% of rare disease patients and caregivers in the UK indicate an impact on their ability to find and maintain paid employment.

Local and international non-profit organizations as well as patient organizations have raised these specific concerns, and are now recognized for the very important role they play in tackling them:

  • Patient organizations have grown and structured themselves in the rare disease field. While active across many therapeutic areas, the role of patient groups is particularly important in the context of rare diseases: with scarce medical knowledge, families affected by these conditions come together to provide each other with support and to share experiences. Recent research suggests that patient organizations play an important role in steering research efforts in rare disease. This research also highlights that the presence of patient organizations and the mobilization of rare disease patients are fundamental prerequisites for conducting efficient clinical research.
  • National and international non-profit organizations have become very active.
    Of these, the European Organization for Rare Diseases (EURORDIS) ran a particularly insightful survey showing, amongst other things, that it is necessary to consider other specific challenges that rare disease patients must face, such as the distance to centers of reference, the link to local structures, the differences that exist between countries and between patients themselves. EURORDIS called for several actions to face these problems including a more patient-centered approach to research and care that should encompass the development of PRO tools to support evidence of treatment benefits, and increased funding for patient quality of life research.

Rare disease patients and families experience extraordinary healthcare, psychosocial, and economic burdens. As their direct involvement in clinical research rises, patient concerns and quality of life should be a key focus area for rare disease clinical researchers.

3- Measuring and improving the quality of life of patients and their families has become paramount in rare disease clinical trials

Rare diseases are typically disabling, and the quality of life of a person living with a rare disease is severely affected by several parameters, including:

  • The lack of autonomy, due to the chronic, progressive, and degenerative aspects of the disease.
  • The psychological impact of the whole journey, due to the extended diagnosis, the lifetime disease duration, and the frequently life-threatening aspects of the disease.
  • The lack of information and lack of therapeutic management.

Notably, 75% of rare diseases affect children, and 70% of rare diseases have their onset during childhood. This means that many patients suffering from a rare disease do so from a young age, and for their entire life. As such, rare diseases affect not only the individual who is diagnosed, but also their  families, friends, caregivers, and society as a whole.

Combining the severity and the disabling aspects of the condition, the lack of existing treatments, and the scarcity of adequate scientific data, the barriers to advance scientific research in rare disease are high, and it is time for researchers to develop creative and innovative approaches.

Rare disease clinical trials need to go beyond traditional clinical trial designs. They need pragmatic additions to conventional measures that will allow the breadth of observations and information collected to be expanded and target aspects of the disease that are relevant to patients.

Modern clinical research has several ways to capture treatment effects from patient perspectives, and can ensure the measurement of meaningful outcomes, symptoms, and aspects of the disease that matter to patients and families.

  • Increase the use of Patient Reported Outcomes (PRO) measures to bring a different, patient-centered perspective on the efficacy of a treatment and its impact on quality of life. While administering PRO measures for rare diseases poses unique challenges because of small patient populations and disease heterogeneity, they are the only way to ensure the measurement of meaningful outcomes.
  • Develop new, disease specific PRO measures to support evidence of treatment benefits in specific diseases or conditions. It is expected that well-designed PRO measures will support clinical endpoints, which are often challenging to measure and not necessarily relevant in rare disease clinical research; they should also contribute to reducing the large number of aspects that are important to patients but not captured with existing measures.
  • Increase funding for research on patient quality of life, through patient-centered approaches and research projects that are run in collaboration with patient advocates and associations.
  • Include eDiaries in rare disease clinical trials as a further means of capturing the patient perspective. The eDiary questionnaires can be specifically designed to track several aspects of the disease or treatment impact on a daily basis, e.g., symptom severity or pain, and to monitor the evolution of a symptom throughout the trial.
  • Widen the clinical outcomes assessments to include caregiver evaluations (Observer-Reported Outcomes, ObsRO) and clinician assessments (Clinician-Reported Outcomes, ClinRO). Including caregivers and healthcare providers will allow the perspectives to be broadened and will expand the knowledge on both the disease and the individual symptomatology. This will also allow situations where patients are unable to respond themselves to be managed, e.g when patients are significantly debilitated or with pediatric populations.


It is time to enhance the use of alternative, patient-centered measures in rare disease clinical research. By using both standard quality of life scales as well as newly designed, disease-specific PRO measures, and by involving caregivers and healthcare providers, the rare disease clinical research community will be able to target meaningful outcomes and shift the focus to what we all need to understand most: what matters to patients and their families.


Estelle Haenel, Chief Medical Officer @Kayentis

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