Why rare disease clinical trials are rare in themselves

“At the time of my diagnosis, there were only 15 cases known worldwide. The chance of being diagnosed with this disease was one in a million.”

Gabrielle, living with neutral lipid storage disease with myopathy (NLSD-M)*

Rare diseases (RDs) affect approximately 300 million people worldwide, and have a huge impact on the quality of life for both the person with the condition and the people around them.^1-4 Although over 6,000 RDs have now been identified around the world, the general lack of awareness and expertise means these patients are often marginalised and neglected in national health systems.¹

Often causing lifelong disabilities, RDs are characterised by diverse symptoms that not only differ from disease to disease, but also patient to patient.⁵ Alongside the obvious health complications, living with an RD can also be extremely isolating for all involved.⁶

Misdiagnosis is common – patients and their families find themselves stuck in the turmoil of unknowns and uncertainty. Family members often have to become health advocates for their loved one to take control of what feels like an uncontrollable situation. What’s more, finding the right specialist can be tough!

“It’s hard for people to understand what we need to survive.”

Mother of James and Colby, diagnosed with phenylketonuria (PKU)†

Getting the most appropriate treatment is a huge goal for RD patients and their families. But devastatingly, sometimes the condition is so rare, this just isn’t possible.

This is where the hope of clinical trials comes in. Let’s explore this, together.

Rare disease clinical trials are rare in themselves

When it comes to clinical trials, there are many barriers for RD patients.

For example, the low prevalence and dispersed nature of these conditions makes identifying eligible participants very difficult. Patient populations are scattered across wide geographical areas, making recruitment challenging, time-consuming and, unfortunately, costly. It also doesn’t help that many RDs are also often diagnosed late or are left undiagnosed, leading to an even smaller pool of eligible patients.^1,6

“On average, it can take five years – or more – for a rare disease to be correctly diagnosed.”

National Organisation for Rare Disorders‡

Another main barrier to participation is actually getting to the trial clinic, especially as many people with RDs struggle with mobility or have cognitive or physical impairments. Adding to this, the financial aspects of clinical trial logistics can also impact on clinical trial participation.⁷

However, there is a strong commitment by patient advocates and the pharmaceutical industry to tackle these challenges through new legislation.

Let’s get into some of the recent advances in RD care.

1. Patient registries

Establishing patient registries or databases helps to identify individuals with an RD who may qualify for upcoming clinical trials. These registries are key to assessing whether a clinical trial is feasible, and they provide information on trial design and planning. They are often the only way to pool data to achieve a sufficient sample size for epidemiological research and to gather evidence on the effectiveness of an orphan drug.⁸

2. Collaboration with advocacy groups

Partnering with RD organisations extends the number of people you can reach. These groups provide valuable networks and are trusted within patient communities. In addition, they often promote cross-sector collaborations, sharing ideas and advocating for the much-needed funding for research.

3. Digital platforms and social media

Digital tools are increasingly being used to directly identify and connect with patients. Social media platforms and personalised communications can be used for targeted recruitment campaigns in this small patient population.

4. Genetic screening programmes

Advances in genomics allow healthcare providers to identify RD patients via genetic testing, often before symptoms appear. In the UK, for example, the NHS Genomic Network of Excellence for Rare and Inherited Diseases focuses on new working models to improve diagnosis times, reduce genomic health inequalities and roll-out innovative testing approaches. It aims to provide RD patients with fast and accurate diagnosis.⁹

5. Decentralised trials

Participation in clinical studies is becoming more accessible through the use of telemedicine, home visits and wearable health technologies. These measures reduce the logistical burden on patients and their families or carers, especially for geographically isolated individuals.¹⁰

6. Artificial intelligence and digital technologies

Artificial intelligence (AI) is playing a crucial role in optimising trial processes, from patient recruitment to data analysis. Helping to repurpose existing drugs for RDs, AI-driven platforms are enhancing trial efficiency and success rates. However, the potential to generate false positive results in AI means that a highly robust, multidisciplinary framework is necessary to help evaluate any results. Therefore, the integration of AI into drug development, especially for RDs, must be initiated with caution.¹¹

7. International collaboration

Due to the scarcity of patients in individual countries, global partnerships are essential. This ensures access to a larger pool of participants while maintaining compliance across diverse regulatory conditions.

For example, the European Rare Diseases Research Alliance (ERDERA) was formed to improve the health and wellbeing of the 30 million people living with RDs in Europe, making Europe a world leader in RD research and innovation.¹²

A wider global initiative set up by the International Rare Diseases Research Consortium (IRDiRC) is also trying to make sure RD patients achieve an accurate diagnosis and receive appropriate care within a year of seeking medical attention.¹³

8. Adaptive trial designs and patient-centred endpoints

Regulatory bodies like the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are increasingly endorsing adaptive trial designs and patient-centred endpoints. The FDA recently initiated the Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program to help accelerate the development of novel drug and biological products for RDs and provide support to those wanting to run clinical trials in this field.¹⁴

In addition, there is an increased emphasis on patient-reported outcomes and caregiver feedback to ensure trials are more aligned with patient needs. This includes developing new clinical outcome assessments tailored to specific RDs.

9. Genetic variability and personalised medicine

There's a growing focus on genetic variability and personalised medicine, particularly in gene therapy. Innovative approaches like CRISPR and CAR-T therapies are constantly being explored for their potential in RDs.¹⁵

However, novel regulatory approaches are needed to fully realise the therapeutic potential of these new technologies, especially for RDs. The traditional clinical trial pathway for a treatment that might be given to 10 patients a year can’t be the same as for a treatment that will be given to 100,000 patients. The Hospital Exemption Rule stipulated by the EU allows an investigational genetic therapy to be developed at a hospital for use in a single patient, benefiting those individuals with ultra RDs.¹⁵

Overall, robust networks, innovative tools and global collaborations are key to revolutionising clinical trial recruitment for RDs. By embracing these strategies, researchers can drive breakthroughs for those who need them most – people like Gabrielle, James and Colby

Because in the world of RDs, every day without treatment is a day too long. Every breakthrough counts. Every moment matters.

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Quote sources:

* Gabby's Story. Accessed January 2025.

^† Rare Disease Caregivers: You're Not alone. Accessed January 2025.

^‡ A 15-Year Diagnostic Odyssey. Accessed January 2025.

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References

1. EURORDIS. #Resolution4Rare: Global campaign for the first UN Resolution on Persons Living with a Rare Disease. (2021). Accessed January 2025.
2. Haendel M, et al. How many rare diseases are there? Nat Rev Drug Discov. 2020;19(2):77–8.
3. Chung CCY, et al. Rare disease emerging as a global public health priority. Front Public Health. 2022;10:1028545. doi: 10.3389/fpubh.2022.
4. Marwaha S, et al. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Med. 2022;14(1):23.
5. Rare Diseases Europe. What is a rare disease? Accessed January 2025.
6. Priolo M, Tartaglia M. The right to ask, the need to answer – when patients meet research: how to cope with Time. Int J Environ Res Public Health. 2023;20(5):4573.
7. The Association of Clinical Research Professionals. Reducing barriers to participation in clinical trials for rare disease. Accessed January 2025.
8. Orphanet Report Series. Rare disease registries in Europe. Accessed January 2025.
9. NHS England. Rare disease day 2024: harnessing genomic medicine and cutting-edge treatments to improve outcomes for patients with rare conditions. Accessed January 2025.
10. NIHR. Unique capabilities to support the delivery of decentralised clinical trials. Accessed January 2025.
11. MDPI. Using artificial intelligence to advance the research and development of orphan drugs. Accessed January 2025.
12. ERDERA. The European Rare Diseases Research Alliance. Accessed January 2025.
13. IRDiRC. Welcome to IRDiRC. Accessed January 2025.
14. US Food and Drug Administration. Support for clinical Trials Advancing Rare disease Therapeutices (START) pilot program. Accessed January 2025.
15. Innovative Genomics Institute. CRISPR clinical trials: A 2024 update. Accessed January 2025.

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