Challenges And Opportunities In Rare Disease Clinical Trials: Putting The Patient First

Clinical research helps develop new evidence-based approaches to treating health conditions, resulting in better, safer and more effective treatments.

However, in the case of studying rare disease treatments, clinical research can be particularly challenging. This can be for a number of reasons, such as the rare disease not being fully understood, a lack of awareness for the condition, as well as there being fewer patients able to participate in clinical trials. Read more on ‘Rare diseases: everything you need to know‘.

The challenges of rare disease clinical trials require new approaches in order to effectively tackle the difficulties associated with developing rare disease treatments and orphan drugs. Potential solutions from experts in orphan drug development include better engagement with patients and a specifically tailored trial design. 

When identifying opportunities to improve trial designs, it is first important to understand the key challenges in rare disease clinical trials.

What Are the Main Challenges In Rare Disease Research?

The challenges of rare disease clinical trials begin with understanding the condition itself. As an orphan disease, there is often very little medical knowledge surrounding the condition’s causes and impacts on the human body. 

By definition, a condition is considered rare if it affects fewer than 1 in 2,000 people and, as a result, knowledge is neither well defined nor well spread.

Additionally, there is often very little known about how the condition affects the patient’s quality of life. With knowledge generally lacking in areas of orphan disease, this can lead to many challenges in rare disease clinical trials. 

From awareness, funding, patient enrollment and working with small data samples, the complications in rare disease clinical trials present researchers with unique challenges. However, this only makes it more important to advocate for research and improve the lives of rare disease patients.

Read the full reportPutting The Patient First: The Challenge and Opportunities To Improve Rare-Disease Therapy Development

Awareness Of Rare Diseases

When considering the main challenges in rare disease clinical trials, most of the major difficulties arise from the lack of public and medical awareness for the condition itself. 

Awareness for rare diseases is often much lower than awareness for more common conditions, and many rare diseases are often poorly understood by medical professionals. This lack of understanding can complicate the clinical trial process.

With little definition surrounding the disease, there is often a lot of debate and discussion amongst researching bodies, authorities and agencies before the clinical trial can proceed. 

Whilst it is important that the condition is understood from the outset, this uncertainty can prolong the time it takes for clinical research to begin. 

Raising Funds

Clinical trials can only go ahead with the support of funding from sponsors and advocating bodies. Funding is often encouraged by a heightened awareness for a disease or condition, for instance, more common types of cancer research are supported by high profile awareness campaigns and influential non-profit organisations.

With rare diseases sadly lacking the levels of awareness that more common conditions have, this can lead to challenges in obtaining the necessary funding to support the research.

As pointed out by Oved Amitay, Chief Business Officer of Centogene, venture capitalists may unfortunately be ‘disinterested in supporting the trial’s funding if the patient population is too small’, and the ‘investment may not seem like a viable commercial opportunity’.

While the opportunities present in clinical development should not be focused on commercial viability – they should be proactively focused on improving patient lives – money is an important factor and commercial viability is therefore always at play. This challenge can feel frustrating for campaigners, researchers and, of course, the patients themselves.

Niche Populations

Since rare diseases affect fewer individuals than common diseases, the population groups are often much smaller. Niche populations can complicate clinical trial designs, making it more challenging for researchers to effectively test new treatments on suitable volunteer sample sizes.

With a smaller patient volunteer group, there is a smaller amount of data in rare disease research. This can limit the extensiveness of clinical trial data, making it more challenging for researchers to identify important safety aspects of test treatments, such as rare side effects.

Patient Enrollment

Patient enrollment can be demanding in rare disease research. With a smaller patient population size, it is more difficult to reach potential volunteers.

As well as a reduced patient population size, the patient population might also be geographically dispersed. Researchers are therefore met with the challenge of devising a suitable clinical trial enrolment plan that effectively reaches the right patients.

One way in which Clinical Research Organisations (CROs) are improving rare disease patient enrolment and retention is by improving patient engagement. It ensures that the trial is designed in a way that puts the needs of rare disease patients first.

Diagnostics and Tools

In the effort to increase awareness and reach more potential patient volunteers, early diagnostic capability can play an important part. 

By developing more advanced diagnosis capabilities prior to the clinical trial’s launch, researchers can identify new patients with a rare disease who may otherwise be undiagnosed until later years.

This may involve qualitative analysis of health records, as well as campaigning through social media networks. 

Managing Expectations

Due to the lack of awareness and knowledge surrounding rare diseases, expectations about the research process and its endpoints may not be clearly defined.

Understanding the condition early on can help smooth out the process. This might include defining the disease’s natural history and identifying which endpoints are the most important, as highlighted by Dr. Eleanor Perfetto at the US National Health Council. It is also encouraged to gain early insights from patients themselves.

With a stronger understanding of the condition, research organisations are able to put forward a stronger rare disease development proposition to key agencies. By understanding the complexities involved, as well as the pros and cons, agencies know they have a partner to talk with. 

The main advantage of this is that key players know more about what to expect from the research, which helps accelerate the process. 

As well, patients themselves need to understand exactly what the rare disease research can do for them, with information on how it may benefit them, how the trial design will cater for their needs and what is required on their behalf. 


Rare disease clinical trials are amongst some of the most challenging research processes. From lacking awareness or having a lack of patients, to the disease simply not being fully understood, there are many practical hurdles that can prolong the clinical process. 

However, with a genuinely patient-centric approach that clearly defines the potential challenges and endpoints of the research, CROs can propose a much stronger argument for rare disease therapy developments.

This provides the patient with confidence from the outset, as well as defining clear expectations for key sponsors, partners and authorities.

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