Topical Article

Rare Disease Clinical Trials | Challenges & Solutions

Posted on by Congenius

In the European Union, a rare disease is defined as one that affects no more than 1 person in 2,000, while in the United States, the Orphan Drug Act defines a rare disease as a disease or condition that affects less than 200,000 people in the US. Whilst rare diseases like cystic fibrosis, haemophilia, and phenylketonuria are broadly familiar, most rare diseases are less well-known.

Although a rare disease affects only a small number of individuals, the cumulative number of affected individuals is high: approximately 6,000-8,000 different clinically defined rare diseases affect an estimated 30 million people in the EU and approximately 300 million people globally. Out of those, 72% have an underlying genetic basis and around 70% affect children.

For many patients with rare diseases and their families, the journey to a correct diagnosis takes at least five years, with countless physician visits and tests along the way. Lack of awareness, disease heterogeneity, and limited data on disease pathology and progression leads to uncertainty and delays. These same problems also pose hurdles for the efficient and effective management of clinical trials, which in turn impedes meeting regulatory requirements for drug or medical device approval.

In this article, our Clinical team introduces the challenges associated with rare disease clinical trials and discusses how Decentralized Clinical Trials (DCTs) or hybrid trials, patient registries, and patient advocacy groups could help to overcome some of these challenges.

What are some of the challenges associated with rare disease clinical trials?

According to ICH-GCP, a clinical trial is any research on human subjects that involves an investigational medicinal product, whereas according to the EU MDR a clinical investigation is any systematic investigation involving one or more human subjects, undertaken to assess the safety or performance of a device.

There are several requirements that clinical studies (trials and investigations) must meet:

  • Appropriate study design including proper research question(s)
  • Appropriate endpoints and their measurement
  • Selection of the correct sample
  • Funds to support the research
  • Knowledgeable study staff
  • Adequate resources to execute the study and address regulatory or ethical concerns

When dealing with rare diseases, the limitations of studying a small population transform these requirements into huge challenges. Below we illustrate the most important challenges associated with clinical studies conducted for rare diseases including:

  • Lack of experts in rare diseases
  • Patient recruitment for clinical trials
  • Patient retention for clinical trials
  • Conducting clinical studies with children

Lack of experts in rare diseases

Some rare diseases are extremely heterogeneous, and the small number of individuals affected results in a lack of scientific expertise and information on the disease. Several studies have shown that lack of rare disease awareness and knowledge amongst physicians could lead to delayed diagnosis or misdiagnosis. It’s therefore important that sponsors work closely with key opinion leaders, patient advocacy groups, patients, and families, because their collective influence on study design helps ensure measurable and meaningful endpoints.

The lack of clinical researchers with interest, training, and experience in the design and execution of trials for rare disorders is evident. A previous study indicated that 78.8% of patients affected by rare diseases have not received proper care because of limited training of health care professionals in this field. Studies in both adults and children have shown that referral by primary paediatric providers to clinical trial centres is vital to ensuring clinical trial recruitment. However, most providers were unaware of community-based paediatric drug trials in progress in which their paediatric patients could potentially participate, so dissemination of information to these providers is an essential step that’s often overlooked.

As Statland et al discuss in their 2012 publication, clinical researchers in academia are challenged with balancing clinical demands and research, navigating regulatory hurdles, the lack of local infrastructure, and the need for training in clinical research. It’s therefore crucial that institutes offer career-training grant opportunities, and provide support, mentorship, and protected time for bench and clinical researchers to develop expertise in the many areas relevant to rare disease research.

Patient recruitment for clinical trials

Perhaps the most frequent problem in clinical studies for rare diseases is the recruitment of a requisite number of study subjects. To be able to draw a statistically significant conclusion on the safety and efficacy of a product, a powered sample size is needed. Already an issue for mainstream clinical studies, this undoubtedly poses a bigger problem when conducting studies for rare diseases. To achieve recruitment targets, studies may need to extend for longer periods. This is not an easy task – especially when dealing with life-threatening diseases.

In addition, due to the small number and geographical dispersion of patients, most of the studies require set-up as multicentric studies with multiple centres in different countries. A benefit of this, is that multicentric studies help increase diversity. But on the other hand, multicentric studies often mean a higher financial investment from the sponsor, slower study start-up caused by multiple submissions to national competent authorities and Ethic Committees, multiple study protocol amendments, language barriers, and the involvement of more clinical research organisations with rare disease specialties.

Patient retention for clinical trials

Besides patient recruitment, a big challenge when performing clinical research for rare diseases is the high lost-to-follow-up rate. Results of a recent study revealed that 19% of paediatric trials were discontinued early, with patient accrual difficulty (37%) as the most common reason for discontinuation. Amongst the main reasons patients gave for dropping out of the clinical trials were factors such as lack of time, lengthy travel distance, technical complications with study procedures, too many doctor appointments, and family concerns.

Participating in a clinical study is a significant commitment for patients and their families, especially when multiple on-site visits are deemed necessary by the study protocol. To help overcome this challenge, sponsors should ease the burden of participation by, for example:

  • Limiting the frequency and duration of study visits
  • Limiting the number of assessments
  • Offering off-site or home health visits for evaluations, such as for vital signs, which do not have to be performed at the research site
  • Eliminating any upfront or out-of-pocket expenses for patients and their families

Children in Clinical Studies

Approximately three quarters of affected patients with rare diseases are children. According to ICH-GCP, children are defined as a vulnerable population who cannot consent for themselves to be included in clinical studies and who therefore need to be protected when participating in a clinical study.

Historically, children were not included in clinical studies because of a misperception that excluding them from research was in fact protecting them. This resulted in many approved, licensed, cleared, or authorised drugs, biological products, and medical devices lacking paediatric-specific labelling information. As a result, in cases with no alternative, doctors had to use a product off-label and extrapolate the medication dose or treatment largely from adult data. Unsurprisingly, this has historically raised the risk of unexpected adverse events. In 2008, 211,209 emergency room visits in the US were by children 12 or younger due to adverse drug reactions.

It is widely accepted now, that for drugs and biologics, children can demonstrate unique characteristics that differ from adults – for example, regarding absorption, distribution, metabolism, and excretion. Furthermore, the performance characteristics of a medical device used on a child may differ from adult use. Because of these differences, it is vital to study treatment options directly in children – but with additional safeguards to protect them during clinical studies.

Some countries have a supportive regulatory framework in place when it comes to performing paediatric clinical research for rare diseases. In 2022 the FDA released a draft guidance which describes ethical considerations for including children in clinical trials and helps investigators, sponsors, and Institutional Review Boards (IRBs) understand and interpret the regulations that apply to children as human subjects within the context of a paediatric clinical study. The FDA guidance asks for a thorough benefit / risk assessment to determine whether it’s appropriate for children to enrol in a clinical trial. It outlines the limit on the allowed risk based on the child’s direct benefit from the treatment. In cases where there’s no predicted benefit, the risk to the child must be low, or only a minor increase above minimal risk. In addition, the knowledge gained via the trial should be deemed critical for the understanding of, or improvement of, the child’s condition.

A controversial ethical topic is the use of placebos in paediatric randomized clinical trials (RCTs). An RCT in clinical research typically compares a proposed new treatment against an existing standard of care treatment; these are then termed the ‘experimental’ and ‘control’ treatments, respectively. When no such generally accepted treatment is available, a placebo may be used in the control group so that participants are blinded to their treatment allocations.

Double-blind and placebo-controlled RCTs are still thought to be the “gold standard” of clinical studies since they are the most methodologically rigorous approach to assess the effect size of prospective new medicines. For children enrolled in the active arm of a placebo-controlled study, there is a direct benefit foreseen from the product which in turn allows a higher risk. However, for children in the placebo arm this prospect is absent, and therefore the risks should be low.

The risk of withholding effective known therapy for children receiving a placebo in a clinical trial also needs consideration. Whilst the clinical evaluation may be straight forward if no other treatments exist for the condition, if there are existing treatments, the evaluation can become more problematic. This could be addressed by maintaining the standard of care therapies in the placebo arm, with the placebo used as an add on. If there are scientific reasons for needing to withhold known effective therapy, the time that the treatment is withheld should be limited to the shortest time needed to evaluate the effect and it should be established that withholding the therapy won’t exceed the minor increase over minimal risk threshold or result in any irreversible harm to the children in the study. It’s no surprise that parents are more reluctant to provide consent for the participation of their child in a placebo RCT, meaning that alternatives like the so-called comparator studies (which typically focus on efficacy relative to a drug that is already on the market rather than a placebo), are all the more important.

What are some solutions to these challenges?

The challenges outlined above cannot be solved solely with existing or new legislation – other concepts and ideas are essential to minimise their impact.

Decentralized Clinical Trials

As defined by the FDA, a decentralized clinical trial (DCT) is a clinical trial where some or all of the trial-related activities occur at locations other than traditional clinical trial sites.

In fully decentralized clinical trials, all activities take place at locations other than traditional trial sites, such as in the patient’s home or in local health care facilities that are convenient for trial participants. However, this is not possible for all trial types; for example, because the trial participants cannot be sufficiently monitored remotely, or there are trial procedures, such as scans or assessments of important parameters / endpoints that require the physical attendance of trial participants.

A DCT is termed a hybrid trial if the trial adopts decentralized elements in parallel with the physical attendance of the trial participants at the clinical site. The concept of DCTs or hybrid trials is not new but whilst previously only one or a few decentralized elements have been used, in 2020, COVID-19 and the associated lockdowns – as well as advancing tech – dramatically accelerated the use of virtual, decentralized, and hybrid trials.

Hybrid trials are thought to promote greater inclusivity, diversity, and equitable access to research participation by reducing the number of on-site visits. Beyond facilitating access and participation, they can ease recruitment, decrease delays, enhance participant retention, and lower overall costs. In addition, telehealth / virtual follow-up visits can make experts in the field of the specific rare disease available to each and every trial participant independent of their geographical location.

Partnership with patient organisations & patient contact registries, and clinical education

Effective recruitment can be further supported through partnership with patient organisations and patient contact registries, as well as by thorough clinician education, to increase disease recognition and decrease time to diagnosis. Patient registries can help with the limitations of small numbers in numerous ways. First, a comprehensive knowledge of the disease natural history can provide information about the efficacy of a therapeutic intervention and subsequently help with benchmarking. This could allow the use of a single-arm clinical study without a placebo or other concurrent control group.

To cite an example, the evidence submitted to support FDA approval of alglucosidase alfa (Myozyme) for infantile-onset Pompe disease included a comparison of outcomes for 18 pivotal trial participants with outcomes for infants followed in a natural history study. The number of individuals with a rare disease able to participate in the treatment arm of a clinical study can be significantly increased if the division of research participants into test and control groups can be avoided. Arguably, there are numerous advantages to this, including the enablement of informative, planned comparisons of study participant subgroups. Also, patients may be more willing to participate in a trial if assured they will receive the test drug, particularly when no standard therapy exists. The continued development of inclusive patient registries and natural history studies is therefore crucial.


The several requirements that clinical studies must meet are transformed into huge challenges when dealing with rare diseases. Lack of scientific expertise, training, and information on rare diseases often leads to delayed diagnosis or misdiagnosis. Patient recruitment and retention can be hampered by small patient populations, geographical dispersion of patients, as well as time and financial constraints for patients, technical complications with procedures, and family concerns. And the lack of relevant historical data for paediatric clinical studies, and ethical issues around the use of placebos in paediatric RCTs present significant hurdles for clinical trials involving children.

Whilst these challenges are too complex to be solved with one concept, the increased adoption of decentralized clinical trials and hybrid trials is certainly a good starting point to improve trial accessibility. Effective collaboration between sponsors, patients, and their families can facilitate more measurable and meaningful clinical study endpoints. And with partnership between sponsors, key opinion leaders, patient organisations, and patient contact registries, together with improved clinician education, rare disease clinical trial recruitment can be further supported by increased disease recognition and decreased diagnosis time.

By combining these concepts, the industry can work towards improved treatment solutions, and reduce the burden for the 300 million people affected by rare diseases globally.

Should you have a challenge regarding clinical studies, feel free to get in touch – our Clinical team is ready and happy to help.

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