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Ultra-Rare Diseases: Decentralized Solutions to Tackle Challenging Clinical Studies

What is a rare disease? The answer seems obvious, yet there is not a universally agreed-upon definition. In fact, there are almost 300 different definitions from over 1,100 organizations with interest in rare diseases.(1) So it isn’t surprising that there is even less certainty about what constitutes an ultra-rare disease.

What Is an Ultra-Rare Disease?

As per the case with rare disease in general, there is no single definition of what constitutes an ultra-rare disease. That said, there are some guidelines that provide insight:

  • In Europe, a disease is generally considered to be ultra-rare if it affects one patient per 50,000 people (or fewer than 20 patients per million of population). (2,3) This is the definition used at THREAD
  • Other scholarly sources use < 1 patient per 100,000 as the definition (4)
  • Others define ultra-rare as even more scarce. For instance, The n-Lorem Foundation (5) defines ultra-rare as a disease that occurs either when a patient has a mutation unique to them or has a mutation that has been identified as causing disease in fewer than 30 patients worldwide and is therefore out of the reach of traditional commercial drug programs

The total number of patients affected with ultra-rare diseases runs into the millions and that number grows each year as advances in genome sequencing improves the ability to diagnose them. Whatever definition is used, the extreme rarity of such patients presents unique challenges to their diagnosis and treatment paradigms. Further, the diseases that these patients experience are typically severe, often fatal, and frequently cause developmental delays, mobility difficulties, and other healthcare issues. In short, these patients are desperate and underserved.

Difficult Research Challenges

Drug development for ultra-rare diseases is inherently challenging. In many respects, rare and ultra-rare drug development has been shoehorned into an ill-fitting framework that needs to be overhauled. Indeed, compared to drugs for common indications, on average, rare disease compounds take four years longer for product launch. For ultra-rare diseases the timeline is even longer, taking an additional 2 years.(5) This additional time not only increases costs, but also increases uncertainty for biopharmaceutical companies as to what the landscape will look like once they reach market authorization.

Small patient population sizes inherent in ultra-rare disease studies provide challenges to the collection and analysis of efficacy data. These challenges are compounded alongside ethical considerations around study design and the use of placebo or standard of care in patients with life limiting or debilitating diseases. Additionally, given that studies in ultra-rare diseases often require a global footprint to recruit patients, there can be additional complications associated with differences in standard of care between countries and regions. Furthermore, market access plays a large role in ultra-rare drug development success in that not only do sponsors need to build into their overall strategy the means to provide the relevant data to meet stringent regulatory approval, they also need to have the data to support why payers should approve reimbursement. While this applies to all drugs, it is heightened for ultra-rare disease therapy development as the cost per patient can be exceptionally high.

Potential study participants are often difficult to identify for a variety of reasons, including:

  • Scarcity: There are fewer individuals that are spread across the globe
  • Condition: Patients are often dealing with life-limiting and/or debilitating illness which may affect mobility, cognition, etc.
  • Diagnosis: Diagnostic journey can be long and many patients remain mis-diagnosed or undiagnosed
  • Pediatric component: Approximately 50% of all patients with rare disease are children
  • Economic burden: Patients and families with rare and ultra-rare disease can often have financial challenges due to the disease impacting work, impacting access to transportation, other out of pocket expenses

Due to the limited number of patients, potentially eligible participants are more likely to be spread out internationally. This means that participants in ultra-rare disease studies often must interact with clinical sites located in other parts of the world. The necessity of cross-border travel must be considered, this can take the form of air ambulance given the severity of many of these diseases along with the steps to ensure that the patient can legally be treated in a given country or state, not to mention the regulatory requirements for all countries involved.

Decentralized Approaches Can Help

For all the reasons outlined thus far, traditional site-based study designs offer numerous obstacles for patients with ultra-rare diseases. Decentralized clinical trial (DCT) elements can help make research participation more accessible and realistic for patients, regardless of where they live in the world. DCT elements help to collect data from the patient in their home, reducing – and in some cases eliminating – the burden of travel for participants and their families. Additionally, for patients suffering from severe illness that impairs their mobility and/or leaves them with little energy, DCTs allow for the use of mobile medical devices and even wearable devices that collect data with minimal ask of the participant.

Despite the small numbers of people impacted by ultra-rare diseases, as compassionate healthcare professionals, we know that every patient deserves hope. Using DCT approaches, we can make ultra-rare disease studies more accessible to eligible patients, support participating sites, and make studies more efficient for all stakeholders. This provides patients with the knowledge that the medical community continues to make them a priority and gives them hope for a healthier future, both for themselves and others living with the same conditions.

For more information on how to employ decentralized approaches in your rare disease drug development program, visit THREADresearch.com


(1) P. Wicks:From A to Zebra: Data-driven strategies for training AI to understand rare diseases | MobiHealthNews


(3) REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/ EC. Accessed at: http://eur-lex.europa.eu/legal-content/EN/TXT/ PDF/?uri=CELEX:32014R0536&qid=1421232837997&from=EN. Accessed online May 28, 2020.

(4)Characteristics of drugs for ultra-rare diseases versus drugs for other rare diseases in HTA submissions made to the CADTH CDR | Orphanet Journal of Rare Diseases | Full Text (biomedcentral.com)

(5) The n-Lorem Foundation is a non-profit group focused on supporting the development of therapies for patients suffering from ultra-rare diseases caused by genetic mutations that affect approximately fewer than 30 patients in the world.

Joyce Moore
Head of Rare Disease Solutions, THREAD

Joyce brings over 22 years of clinical drug development expertise where she has worked effectively across multiple disciplines, therapeutic areas, and clinical stakeholders. For the last 16 years, she has focused on patient engagement and has a deep understanding of the Rare Disease and pediatric clinical trial space.

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