Roughly 7,000 diseases meet the definition of a rare disease. Combined, they affect about 400 million people worldwide.Although much progress has been made in developing scientific knowledge and conducting clinical research in rare diseases, serious challenges remain. Three key hurdles significantly affect clinical research in rare diseases: (1) heterogeneity among patients; (2) the physical, logistical and time burden on patients; and (3) low patient participation and retention – with as many as 30% of 659 clinical trials  interrupted mainly due to poor participation rate, according to a study conducted in 2019.

Patient-centric solutions and greater use of digitalisation can improve the success rate of clinical trials in rare diseases. These include: partnering with patients and ensuring that their voices are heard; strengthening knowledge-based networks to enable more shared data around the globe; and embracing greater digitalisation in the communication and rollout of clinical trials. Qualitative research undertaken in the past few months also noted insights from a cross-section of patients and experts into some of these solutions. Industry stakeholders should be encouraged to adopt these critical steps to help offset the hurdles patients experience in clinical research in rare diseases.

Hurdle 1: Heterogeneity among patients delays disease diagnosis

As 70% of rare diseases affect several organs at the same time, healthcare providers can face difficulties in developing a diagnosis. The potential delay in fully establishing the diagnostic criteria, in addition to only a small number of experts being available, means that misdiagnoses are not uncommon. It takes an average of almost five years for a patient to be correctly diagnosed.

When asked about the diagnosis process, Justine Hill, rare disease research patient advocate, UK, commented: “You can’t imagine the number of times that members of the rare disease community would go back and forth to general practice, specialists and hospitals! No-one is really trained to expect the rare.” The significant variability in a patient’s age and onset of the disease as well as in the signs and symptoms, are characteristic of rare diseases. “The first time I heard about my disease was from my ophthalmologist, who identified ophthalmic symptoms amongst several others; my pain and my joints issues could have been part of many other diseases,”confirmed interviewed respondent Sheila K., acromegaly patient in Italy.

Mutations occurring in the same gene can be associated with different clinical diagnoses and thus pose obstacles to narrowing down the patient population. Duchenne Muscular Dystrophy (DMD) is an example of a genetic disease that results from a mutation in the dystrophin gene, for which over 1,000 different mutations can occur. This makes creating a one-size-fits-all treatment very challenging.

Hurdle 2 - Significant patient burden negatively impacts the ability of patients to enter and remain in a clinical study

In rare diseases, patients live with what can be very debilitating conditions. The physical and logistical difficulties that patients and families go through can make their trial participation arduous. Keeping them in the study – often in the absence of a significant treatment benefit – is a huge challenge. Moreover, as the medical expertise is not widely accessible, this reduces the number of clinical trial sites available, requiring patients to potentially travel very long distances. According to Richie K, a rare disease patient in the US: “The number of visits and the distance we have to travel make it very difficult. This year, I was more hesitant to come to the clinic during the pandemic. Now I’ve come to the point that I’m comfortable with coming for procedures that have to happen on site, but I wouldn’t be comfortable to come for visits that are not justified.”

Hurdle 3 - Low patient participation and retention – a threat to clinical trial success

A rare condition is defined by affecting fewer than 400,000 people worldwide. It is well established that finding and enrolling patients in a rare disease clinical trial is extremely problematic. Maintaining such a sparsely spread geographic population becomes the next obstacle. As more than 50 % of rare diseases affect the paediatric population,the obstacles accumulate: child recruitment and retention challenges add to the paucity and scattered rare disease patient population issues that impede patient recruitment.

Another obstacle is obtaining sufficient amounts of reliable data; as options such as extending the study duration (which can have a severe financial impact) or expanding the number of research sites (which is difficult in the absence of research expertise) may not always be feasible.

How to overcome these hurdles to facilitate rare disease clinical research

Improve communication and patient partnering

Tailoring communications and engaging patients in designing the research is a vital part of the rare disease research optimisation efforts. As patient populations are limited, maximising communication efforts is even more critical. Clinical trial stakeholders must ensure that patients understand their condition and fully appreciate what it means to participate in a clinical trial. Using adapted communication channels, such as patient association forums, referrals and social media, will increase patient awareness and participation in research.

Commenting on patient engagement, Justine Hill, rare disease patient advocate, UK, said:“The rare disease translational research collaboration, where I worked, had 12 workstreams engaging patients. All the workstreams had early involvement from patients in the design throughout the whole process; they were sitting  on committees and working on questionnaires.”

Meanwhile steps to address the lack of trial transparency for patients and caregivers have improved:“Things have really moved from a few tokenistic people with limited input to patients even having paid positions into the research,”she emphasised.

Reducing this opacity requires further efforts. These include spending more time with patients and caregivers and explaining the causes of the disease, the objective of the study and what to expect in the upcoming days, weeks and months. Patients and caregivers also need – and deserve – to know what their data will be used for. Justine added: “Clinicians could not, in my experience, develop the research without their patients' and carers' help.”

Strengthen knowledge-based network

Creating networks of excellence, which constitute an avenue for sharing knowledge, best practice and diagnosis information, is key to supporting rare disease research. Europe is gradually attempting to maximise the potential of scattered data that, if brought together, should help improve the diagnosis and treatment of rare disease patients. The recently created European platform will maximise the potential of this information and will also make it easier to compare information collected in the future, across Europe. Equally, in the US, the National Institute of Health (NIH) has created a global registry project for rare diseases, providing a simple and inexpensive system for specific registry development for any given rare disease.

Increase digitalisation of clinical trials

One way to reduce patient’s burden is to take advantage of the exponential progress made in patient-facing technologies, as Richie remarked: “I would not understand having to go to site when everything could be done remotely thanks to technology.” Proposing targeted tele-visits and moving the patient’s data capture outside of the clinical site via various electronic data capture methods (eConsent, eCOA, e-diaries, wearables) opens the door to virtualisation of the clinical trial, that facilitate reducing the number of journeys clinical participants need to take.

Virtualisation methods need to be well thought through and adapted to the specifics of the protocol. Their potential impacts on patients and sites should be considered early in the set-up process. With this and the input of all the relevant stakeholders, digital methods are likely to contribute to study success and reduce patient burden. Patients have been responding positively: I am passionate of  technology; this has been instrumental into improving mine and many patients’ lives,” said Sheila.

The challenges in developing the scientific knowledge and clinical research in the area of rare diseases must be overcome. Partnering with patients and expanding networks and access to clinical research are fundamental steps, but not the only ones. The move to hybrid clinical trials and remote approaches that the unprecedented sanitary crisis has brought about is already reported by patients as improving their clinical research experience. By embracing these changes, clinical trial stakeholders will improve research for those who need them most.

Estelle Haenel is medical director at Kayentis