Reimagining the clinical trial paradigm for rare disease patients

Elizabeth Sachnoff from ProPharma considers the landscape of clinical trials for rare diseases, and how these could be improved
According to the European Commission (EC) there are more than 6,000 rare diseases, and more are identified each year.1 While definitions vary across the globe, the US defines a rare disease as a condition impacting less than 200,000 individuals and the EU fewer than five in 10,000 people. Ultra-rare diseases are less defined but are tracked by the NIH with a prevalence of one per 50,000 people.2
An estimated 36 million individuals in the EU and more than 30 million Americans are living with a rare disease – highlighting the urgency for solutions. The US passed The Orphan Drug Act to advance research on rare diseases, with similar legislation in the EU. However, despite the market need and demand, the development of treatments and therapies for rare diseases face significant hurdles, including the complexities of conducting clinical trials with limited patient populations.
Patient enrolment is one of the primary obstacles to conducting an effective clinical trial. Globally, 55% of clinical trials are terminated because of low accrual, meaning not enough patients complete the study.3 Further, nearly 80% of clinical trials fail to meet their enrolment targets, leading to an extended timeline and costly delays.3
Additionally, when dealing with such small patient populations, as are typical with rare diseases, there are added challenges in understanding disease progression, selecting appropriate clinical endpoints and managing the considerable burden placed on patients and caregivers.
Working in partnership with regulatory bodies and patient advocacy groups while taking an empathetic approach is critical to the evolution of the effective treatment of rare diseases. Patient advocacy groups in rare diseases are tight-knit communities of individuals who share knowledge and often information about clinical trials available and eligibility criteria.

Understanding the disease

Natural history studies provide keen insights into the progression of a disease, especially for genetic disorders. These studies are often started by pharmaceutical companies or small biotechs, academic and private institutions, and even patient advocacy groups. What natural history studies provide researchers with is the ability to look at the progression of the disease with the current standard of care, demographic information and current treatment modalities (eg, physical therapy, occupational therapy).
However, natural history information is not always readily available, or the data does not contain all the information pertinent to determining the progression of the disease. With the increased use of biomarkers, existing natural history studies may not have sufficient information for identified biomarkers.
Understanding expressivity is crucial – it refers to how a disease affects each individual differently. Essentially, it’s about figuring out why the disease impacts some people more severely than others. Natural history studies help researchers by providing a reference group to compare how much a disease impacts different people. This comparison is vital for those developing new treatments to gauge their effectiveness.
In conditions with high mortality rates, researchers often look back at medical records and gather information through surveys. For diseases affecting children, information provided by parents and/or caregivers is essential. This retrospective approach aims to fill gaps in data, combining formal medical records – which detail diagnoses and changes in tests – with personal observations not captured in clinical settings, such as a child’s responsiveness to their name or the sounds made by nonverbal individuals. This comprehensive view can sometimes allow for the exclusion of a placebo group in clinical trials for rare and ultra-rare diseases, though such decisions are subject to approval by regulatory bodies and ethics committees.

Selecting appropriate clinical endpoints

Choosing the right measure or endpoint is crucial for the success of clinical trials. This endpoint is the result that shows if the treatment being tested is effective. However, selecting the wrong endpoint can lead to trial failure and delay the approvals of treatments. This is especially tricky in rare disease research where there are fewer patients, making each person’s response to the treatment and continuation in the clinical trial vital. Often, the goal in studies of life-threatening diseases is to see if the treatment can extend life beyond what’s expected without it.
In first-in-human trials, the main focus is usually building a safety profile for the treatment. While studies in more common conditions might enrol healthy volunteers, rare disease research often involves treating directly into the patient population. These early trials might explore many different potential benefits of the treatment, helping to shape future studies. Although animal tests can predict how humans might react, only testing in humans can truly show if the treatment offers real improvements.
Collaboration with patient advocacy groups is essential in rare disease research, not just for recruiting participants but also for understanding what matters most to patients and their families. Insights from these groups can highlight important aspects of the disease that hadn’t been considered before, leading to the inclusion of new types of assessments in clinical trials. In the US, the US Food and Drug Administration (FDA) has developed a series of guidelines for patient-focused drug development (PFDD). With this guidance, drug developers should collect data that patients find meaningful to help guide regulatory and drug development decisions. Accounting for individual feedback through surveys, interviews and focus groups has led to development of newer measures such as the Observer-Reported Communication Ability Measure (ORCA) used to gather communication ability of individuals with Angelman Syndrome created by Duke University, US.
Clinical trials can be overwhelming with the number of assessments required, sometimes requiring visits to be spread out over several days and covering a wide range of tests from blood work to imaging. It’s important to remember the physical and emotional strain on patients and their caregivers, who are already dealing with the challenges of chronic illness or disability. To avoid adding to their burden and prevent patient fatigue, especially in diseases like neuromuscular disorders, performing tests in a specific sequence is recommended. This helps ensure consistent results and reduces the impact of external factors on the scoring of the outcomes.

Managing patient and caregiver burdens

Participating in clinical trials for rare diseases brings extra challenges for patients and their caregivers. Those with severe cognitive, mobility or respiratory issues face even more obstacles, including transporting medical devices like ventilators, mobility aids and feeding tubes to trial sites. Since clinical trials for rare diseases often have few locations, participants may need to travel far, even abroad, adding to the complexity of the need to transport medical equipment.
“ As we continue to refine our approaches and leverage innovative solutions, the hope for discover ing life-changing treatments for rare diseases shines brighter than ever 
To ease these challenges, trials are increasingly adopting more flexible designs. Not all procedures need to happen at the trial site and some, like blood draws or checking vital signs, can be done at home by healthcare professionals. This approach, however, depends on local laws and the qualifications required for healthcare providers in different countries.
Another innovative strategy is a regional treatment centre model, sometimes referred to as a bespoke model, for complex therapies, including gene therapy. Patients receive treatment at these centres and then return home for follow-up care locally, reducing travel burdens. Additionally, concierge services offer logistical support, helping with visas, transport, lodging and local information to make the trial process less stressful for participants and their families.

Overcoming challenges

Navigating the complexities of conducting and recruiting for clinical trials in the realm of rare diseases is fraught with challenges, yet it remains an immensely rewarding endeavour. The path to success requires meticulous planning and collaboration with regulatory strategy and protocol design experts. Engaging with these professionals early on is crucial to circumvent potential obstacles and streamline the trial design process.
A proactive approach, including consultations with regulatory agencies, especially those concerning orphan drugs, can significantly reduce the need for revisions and enhance the trial’s efficiency. Recently, there has been a marked shift towards prioritising the selection of meaningful clinical endpoints and enriching the patient experience within these trials. This focus aims to ensure the scientific validity and relevance of the research and also underscores a commitment to patient-centricity. By emphasising outcomes that genuinely matter to patients and their families and by making clinical trial participation as accessible and as least burdensome as possible, the field is moving towards more empathetic and effective research methodologies.
The journey of rare disease clinical trials embodies a delicate balance between scientific rigour and human compassion. It’s a testament to the resilience and dedication of the research community, patients and their caregivers. As we continue to refine our approaches and leverage innovative solutions, the hope for discovering life-changing treatments for rare diseases shines brighter than ever. The collective efforts to overcome these hurdles advance medical science and offer hope to those affected by rare conditions, affirming the invaluable impact of persistence, innovation and collaboration in the quest to improve lives.

Elizabeth Sachnoff is clinical project director at ProPharma and executive board member of the Syngap1 Foundation.Elizabeth is an accomplished clinical trial professional with nearly 20 years of experience in the biopharmaceutical and eCOA industry. She oversees teams running all aspects of clinical trials including project management, data management, regulatory affairs, vendor management, pharmacovigilance and medical monitoring navigating the complexities of running global clinical trials in rare disease.Elizabeth has held various positions within clinical operations, clinical compliance and commercial. She has worked across various phases of clinical trials from first-in-human to post-observation studies. Elizabeth has a wealth of knowledge across project management, data privacy and system implementation. Her therapeutic experience includes gene therapy, rare disease, CNS, rheumatology, dermatology, endocrinology, oncology, gastroenterology, women’s health, infectious disease and nephrology.