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This week’s blog was written by Rosaline de Koning, a 4th year medical student from Oxford University. Rosaline entered The 2020 Student Voice Prize and was shortlisted for her brilliant essay “Perks of a pandemic: lessons in improving the delivery of clinical rare disease research”

Read her essay below and be sure to enter The 2021 Student Voice Prize when it returns this Autumn!

Entering my fourth year of medicine at the University of Oxford with an interest in rare disease, I was looking to gain a first-hand understanding of patients’ experiences. I signed up for SVP’s patient group pairing scheme and met Helen Bedford-Gay, the mother of a fibrodysplasia ossificans progressiva (FOP) patient and co-founder of FOP friends. We talked about what it’s like to live with the disease, the effect of COVID, and the impact of the pandemic on the FOP research community.

With Helen’s help, I got in touch with the FOP research team in Oxford and the clinical investigators at the STOPFOP Amsterdam trial centre, and was inspired to write an essay on how COVID has affected rare disease research.

I learned about the challenges they faced; how patients, their families, and research staff have fought to provide care despite these challenges; and I thought about what we could learn from this experience to improve research going forward.

I’m immensely grateful to the people who took the time to talk to me and share their experiences of FOP, and am looking forward to engaging in rare disease medicine throughout my training and career.

Perks of a pandemic: lessons in improving the delivery of clinical rare disease research

The global COVID-19 pandemic has forced a new way of life: one of shielding, caution, and constant worry. Sadly, this is nothing new for Jasper (pseudonym) and his family. Jasper suffers from Fibrodysplasia Ossificans Progressiva (FOP), a rare, untreatable disease characterised by the transformation of soft tissue into bone that affects only about 900 people worldwide and 30 patients in the UK. Patients often experience their first flare-ups before the
age of 10, marked by painful swellings that leave behind ectopic bone. This formation of a second skeleton progressively restricts the patient’s ability to move and slowly strips them of their independence, before an often premature death. As flare-up triggers include minor trauma – simply falling off a bike or catching a cold – Jasper was shielding long before COVID-19 ever hit.

Fifteen years ago, the causative gene mutation for FOP was discovered: a gain of function mutation on the ACVR1 gene encoding ALK2, a receptor in the bone morphogenic protein-signalling pathway, leading to hypersensitive and ectopic BMP signalling that triggers heterotopic ossification. Since these discoveries, the field has been looking for kinase inhibitors that can selectively bind to this receptor to disrupt the pathological signalling and inhibit bone growth. Five years ago, the FOP research team at Oxford was screening shelved pharmacological agents and found a hit. Saracatinib, a dual kinase inhibitor originally developed for cancer patients, flagged as an active and selective inhibitor of ALK2, and subsequently proved effective in animal models.

This drug could be the key to stopping the disease in its tracks, and a clinical trial could be life changing. However, just as the STOPFOP clinical trial was announced, the pandemic hit, and all clinical research was brought to a halt. Soon, it became a matter of balancing the risk of contracting the virus against the certainty of disease progression the further this treatment was delayed. The STOPFOP trial is one of many that turned this unprecedented situation into an opportunity to deliver truly patient-centric care to clinical trial participants. I’ve distilled my conversations with patients, researchers, and clinical trial investigators into three domains in which the virus has driven improvements to research: patient empowerment, centralisation of expertise, and use of technology.

Patient Empowerment

A recent international survey conducted by EURORDIS, the European Organisation for Rare Diseases, revealed that the main factor contributing to patient satisfaction is a quality relationship with researchers involved in the trial. This becomes crucial in the light of the pandemic, where trust that the patient’s safety is the top priority through an open and honest line of communication between the patient and clinician is vital. Accordingly, STOPFOP trial investigators contacted each trial participant and asked what could be done to make them feel safe and have a positive experience. This patient-centricity can and should be applied beyond the virus – patients always need to feel like more than just a number. Going forward, standard practice should allow patients to provide feedback on the hurdles and concerns that come with trial participation, to optimise the patient experience.

Let’s take this one step further. It’s good to listen to patients: to design a trial with your participants in mind. It’s better to empower patients: to design a trial with your participants. The rare disease community is at a major advantage in this field, with small, tight-knit communities and strong patient-clinician relationships. Additionally, rare disease patients often have a unique expertise and understanding of their condition, providing insights into the potential physical and emotional implications of trial participation that might otherwise never be considered or acknowledged. This can be harnessed. Patient advocacy groups and advisory boards can be involved in writing consent forms and information leaflets, and can improve study protocols and outcome measures. During COVID-19, involving patients improves their safety. Beyond COVID-19, involving patients can improve recruitment, retention, and experience, and therefore trial success.

Centralisation of Expertise

Many clinical trials, including STOPFOP, require specialist imaging equipment, physical examinations, or samples that mean appointments can’t be missed or conducted remotely in the light of the pandemic. This has forced clinicians to think creatively about how to minimise risk when vulnerable patients have to enter their clinic. Appointments can be scheduled to optimise efficiency: advising participants to arrive at their exact appointment time and ensuring they’re seen immediately. Where patients need to undergo multiple procedures with multiple specialists (i.e. blood samples, imaging, and physical examinations), they should be conducted in the same department to avoid unnecessary movement. Beyond COVID-19, maintaining this system of minimising time spent and distance travelled can significantly improve the rare disease patient’s trial experience, especially for those with compromised mobility as in FOP.

Possibly more significant than travel distance within a trial centre is travel to the trial centre. In rare diseases, the small patient population and limited expertise means that there are few expert centres to which patients can travel for trials, an accessibility hurdle further exacerbated in the current climate. Thus, in the last few months, there has been a global conversation about the decentralisation of clinical trials. Theoretically, distributing data collection at remote sites could allow clinical trial appointments to be conducted closer to home – or even at home – significantly reducing both burden and risk to participants.

Despite these advantages, this system is not suited to rare diseases. In FOP, every medical procedure comes with risk of irreversible bodily harm, and clinicians handling patients need to be adequately trained to avoid this. Due to the rarity of the disease, it can’t be expected that trial staff at distributed centres would fulfil these requirements. Additionally, from a mental health perspective, visiting a specialist centre can provide temporary relief and support from the frustrating widespread lack of knowledge that comes with having a rare disease, where patients like Jasper can be around people who have dedicated their lives to helping their specific condition. 

Lastly, EURORDIS has prioritised a multi-disciplinary approach for rare disease research, which is promoted through centralisation of expertise rather than its distribution. Beyond COVID, cultivating these specialist centres can streamline progress and improve research delivery.

Use of Technology

Depending on the trial, data can be gathered through virtual means. Some have successfully conducted virtual appointments for the administration of cognitive assessments10; others suggest remote monitoring strategies using digital tools and wearable technologies – a promising avenue for continuous data collection to improve study power11. Future trial design should consider these methods of data collection and analysis, where there are alternatives to physical appointments. In ongoing trials like STOPFOP, where technology doesn’t yet allow virtual scanning or at-home PET-CTs, online consent systems can be set up, as suggested by the EMA.

The STOPFOP trial is already a model for how technology can be utilised to improve recruitment, as a multi-national collaborative clinical trial. With expert centres in the UK, the Netherlands, and Germany, STOPFOP has been able to recruit FOP patients across Europe to break down geographical constraints and allow more patients access to this promising treatment – another example of patient-centricity. Multi-national collaboration and communication helps overcome one of the biggest challenges in rare disease research: the lack of patient population and funding to conduct randomised controlled trials, the gold standard for establishing efficacy.

Indirectly, advocacy for rare diseases is crucial to the delivery of clinical research, as public attention and awareness often translates to funding and project approval. The mass movement to the online and virtual world is an opportunity to get creative with informing the general public and the medical profession about conditions that have such a major impact on patients like Jasper. For example, STOPFOP has held an online, internationally accessible webinar about the trial, and the Oxford team researching FOP has participated in virtual science fairs. This pandemic is an example of how much can be accomplished with enough public attention and resources, and even a fraction of that public interest directed at FOP and other rare diseases could mean the difference between life and death for 400 million rare disease patients worldwide.

Concluding Comments

This pandemic has delayed promising trials, disrupted those ongoing, and has robbed many rare disease patients of valuable time to experience life without the constant fear and anxiety of this virus. Still, all stakeholders have determinedly worked to progress clinical rare disease research despite all challenges, providing lessons we can take from this situation into the future.

We can empower our patients and harness their unique expertise for trial design and conduction; we can centralise clinical expertise to maximise efficiency and optimise participant experience; and we can capitalise on technology to increase accessibility, improve study design, and advocate for rare disease patients.

COVID-19 has forced the patient into the forefront of all research considerations, paving the way for the development of true patient-centricity in research, and revolutionising our approach to clinical trials. Improving participant experience, and therefore recruitment and retention, will lead to successful trials and progress the clinical rare disease research field, providing hope that there will soon be a treatment for FOP, to save patients like Jasper.

Perks of a pandemic: lessons in improving the delivery of clinical rare disease research

by Guest Contributer time to read: 11 min