Considerations in rare disease study design

Designing a clinical trial is a complex and challenging process. There are several key factors that researchers have to consider, from patients, costs, practicalities, risk measures and much more.

Designing clinical trials for rare disease studies can be especially challenging.

Rare disease research comes with its own unique challenges, making it particularly important to overcome potential study barriers with the right clinical trial design. From low disease prevalence, patient heterogeneity, and paediatric populations, there are several elements of rare disease that make it necessary to approach research with an agile study design. 

As an area of research that requires intricate planning, rare disease study designs often follow different formats to traditional trial designs.

Rare disease trial designs have to balance the need to investigate unique products within the parameters of valid and regulated clinical research, while navigating the challenges of rare disease research that make clinical trial management more difficult.

This article discusses the best study designs for rare diseases, with methods for overcoming the particular challenges presented in rare disease research. 

What we’ll cover

Why should we study rare diseases?

Very little is known about how rare diseases should be treated. Despite affecting more than 3 million people worldwide, there are only licensed medicines available for 500 of these known rare diseases. These figures highlight the highly unmet need to develop effective treatments for the rare disease patients that need them – which can only be achieved through effective study design.

As well as developing new treatments, rare disease studies help make broader discoveries about the functions of genes and gene products that interact with the disease. As a result, studying rare diseases also develops our wider medical understanding of other diseases. 

In order to fulfil these needs, study designs need to carefully consider the many challenges and opportunities of rare disease clinical trials.

The main challenges in rare disease study design

Rare disease study designs often have to navigate difficult challenges in order to be effective. The design must incorporate solutions that address the challenges of small patient populations, geographical disparity, lack of existing treatments, and many other factors. 

Here are just some of the main challenges to consider in rare disease study designs.

Low disease prevalence

One of the biggest challenges in rare disease research is low disease prevalence. By EU definition, a rare disease is considered rare if it affects less than 1 in 2000 people. By nature, rare diseases affect fewer people, which has major implications on rare disease study design.

Study designers have to plan the research so that it is viable with smaller patient groups, incorporating efficient trial designs relevant to small populations. The research may encounter logistical problems that are often associated with small numbers of patients and specialist centres, such as patient drop out having a more significant impact on the study.

Geographical disparity

Another implication of low disease prevalence is geographical disparity. Researchers cannot assure that the target patient populations are geographically concentrated. It is likely that patients are dispersed across different regions and countries, presenting logistical challenges in rare disease study designs.

As a result, many rare disease studies have undertaken a decentralised approach, which is discussed further in this article. 

Patient population heterogeneity

Patient heterogeneity refers to the natural variation in factors and characteristics amongst patient population groups. Heterogeneous variations may include age, genetic differences, disease stage, molecular differences, and more.

Rare diseases are often formed as a result of atypical genetic, immunologic or oncologic mutations – each of which may involve different underlying mechanisms amongst patient groups. What’s more, clinical parameters of rare diseases are hard to define, since so many are under-researched without definitive characteristics. 

It can therefore be difficult to obtain a clinically relevant study population in rare disease research. When considering the best study design for rare disease trials, investigators must acknowledge patient heterogeneity within the methodology, specifying and distinguishing subgroups where possible.

Benefits of common rare disease trial study designs

Case-control studies

Case-control study designs have been used in several rare disease clinical trials. A case control study compares patients who have the rare disease (cases) with a similar group of patients who do not have the disease (controls).

Case-control studies are suitable for small population sizes, making it possible to investigate rare diseases with this kind of study design. Case-control studies are less concerned with the frequency of the disease amongst patient groups, instead focusing on the common exposures amongst the case group in comparison to the control group. 

For example, researchers may look at Ehlers-Danlos syndromes, a group of rare conditions affecting 1 in 20,000 people worldwide. The case-control study would find a group of patients with Ehlers-Danlos syndromes (cases) and compare this group with similar patients who do not have Ehlers-Danlos syndromes (controls).

The aim of the case-control study would be to identify common exposures in the control group. Researchers investigate medical and lifestyle histories, working retrospectively to uncover common factors associated with the disease.

The reason that this study design is so suitable for rare disease trials is because it is achievable with smaller and scarce patient groups. It allows for researchers to select patient cases themselves, helping overcome the issues of low disease prevalence and patient population heterogeneity in randomised sampling.

This study design’s retrospective approach makes it highly suitable for rare disease research, since this eliminates the need for long follow-up periods. For diseases that occur very infrequently, long follow-up periods can be highly impractical, time-consuming and expensive. 

Researchers would have to follow a large patient group across a long period of time in order to gather the relevant data, which is made difficult due to the scarcity and geographical disparity associated with rare diseases.

Adaptive designs

Adaptive clinical trials make suitable study designs for rare disease research. In contrast to traditional trial designs, researchers continually assess and modify adaptive trials, using accumulated data to adapt the course of the trial as it progresses. 

This allows for greater flexibility, which in turn helps overcome the challenges presented in rare disease research and optimise for success in real-time. Adaptive decisions are based on empirical evidence to maintain the integrity and validity of the research.

Adaptive designs also have the benefit of shorter overall timelines. This is a major advantage in cases of rare disease research, where longer study periods are often particularly impractical and expensive due to small and dispersed patient populations.

Adaptations to the trial are sanctioned under regulations, meaning the study achieves the highest scientific integrity, while adapting original trial protocols in order to benefit patients and product development.

In rare disease research, studying an orphan drug with a view to treat wider populations is not always plausible. Alternatively, adaptive rare disease trials may primarily aim to treat patients within the trial as successfully as possible, and adaptations to the process allow this to happen.

For example, resources and study routes that were not effective during phase I research would be removed from the trial, instead focusing on routes that have shown positive clinical response. In effect, this increases the chances of seamless phase II and phase III clinical trial design, which maximises the potential for successful patient outcomes.

Decentralised trials

Decentralised trials (DCTs) are studies that take place without the use of centralised study sites. Instead, decentralised trials use integrated technologies and local healthcare providers to engage with patients. This makes it easier for patients to take part in the study, removing the need to travel to study sites.

As an integrally patient-centric study design, decentralised trials put the patient first. For rare disease patients especially, traditional centralised trials can be difficult to engage with and participate in.

Firstly, it is unlikely that the entire patient population is located near to a single potential study test site. Traditional designs almost always involve travel, but decentralised trial designs allow the research to take place at the patient’s home, or at a local healthcare facility.

Secondly, many orphan diseases have debilitating effects on patients, making travel not only impractical, but in some cases impossible. This is a common study design used in rare disease research, and is just one way that modern research is meeting the needs of rare disease patients.

Decentralised rare disease study designs also help to reduce costs and risks to patients, both of which are key considerations in rare disease research. Learn more about balancing budget and risk with decentralised clinical trial designs

Translational research

Translational research aims to turn existing scientific findings into new targeted treatments for rare diseases. This study approach takes findings from broader patient settings, and applies them to the context of the rare disease study, establishing a bridge between basic research and clinical practice.

Translational studies play an important role in drug discovery. With so few treatments available, this study approach is particularly useful for rare diseases. 

Very little is known about rare diseases. Many are the result of genetic disorders, and atypical immunologic or oncologic diseases, all of which present aberrant cases of human pathology and physiology.

As a result, there is usually a lack of existing scientific knowledge in the specific mechanisms of the study disease, making it difficult to understand exactly how a new treatment would work. Translational studies can bridge the gap in this knowledge, providing insights and discovery routes into new rare disease treatments.

Multi-arm trials

Multi-arm clinical trials are used to compare different treatments within the same single study. Each treatment is tested for similar indications, typically tested against a common control drug. This trial design presents an opportunity in rare disease research to develop new treatments more time and cost effectively, allowing researchers to investigate multiple treatments within the scope of a single study. 

Multi-arm trial designs are also highly suited to rare disease research in that they allow researchers to test new treatments on smaller patient populations, since only one control group is usually required.

Additionally, multi-arm trials may consider an adaptive approach, where ineffective treatments can be eliminated from the trial as it progresses in order to focus on more promising treatments.

Not only does this increase the effectiveness of the trial, this approach also increases the potential for rare disease patients within the trial to receive effective treatments. 

The patient’s view

Patients are at the heart of rare disease research. When considering which clinical trial design is best for rare disease studies, the patient must come first.

Trial designers have a responsibility to consider which trial design aspects are considered important by patients, specifically in the context of rare diseases and the afflictions they may have on patients’ day-to-day lives.

One thing that must remain the same throughout any type of rare disease clinical trial design is a patient centric approach. It is vital to consider how patient engagement strategies can improve the experience for those taking part in the study, benefiting not only the patients, but the success of the therapy development itself.

An agile CRO for complex clinical studies

At Simbec-Orion, we specialise in rare diseases as a therapeutic area of study, offering full-service CRO solutions for complex clinical studies. We respond to the needs of rare disease research with agile study designs, providing clinical trial management across phase II, II and III research. Speak to our experts to learn how we can help. 

Contact us to get in touch or submit an RFI/RFP.

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