There is no universally accepted definition of what constitutes a rare disease. In the United States, the term applies to any disease, or a subset of common diseases, affecting fewer than 200,000 people. The European Union uses a definition of less than five per 10,000, whilst Japan defines a rare disease as being prevalent in less than 50,000 of the general population. There are an estimated 6,000 – 8,000 different rare diseases with new conditions continually identified with advances in research: an average of 260 new diseases are described each year.

Although rare diseases are individually uncommon, the cumulative impact is substantial, affecting between 6% and 8% of the European population – the equivalent of 300 – 400 million people globally. Whilst 80% of rare diseases have an identified genetic origin, other rare diseases manifest due to degenerative and proliferative causes.

Over 50% of rare diseases are life-limiting, and disproportionately affect children. Approximately 70% of genetic rare diseases start in childhood and more than 30% of children with a rare disease die before the age of five.

There is a large unmet need for both the diagnosis and treatment of rare diseases. Patients on average experience a delay of six and eight years between symptom onset and diagnosis. Diagnostic challenges are compounded by the lack of effective treatments as 95% of all rare diseases are currently without single approved therapy. Furthermore, the burden of rare diseases is not limited to patients, but also to caregivers, who often face a lifetime of complex care.

Orphan drug legislation

The regulatory landscape has been a catalyst for accelerating drug approvals for rare diseases. A ground-breaking precedent was set by the United States when the 1983 Orphan Drug Act incentivised investment in the research and development of rare diseases. Following the initial success of the 1983 Orphan Drug Act, similar incentives were introduced by Japan and Australia. In 2000, the European Union adopted Regulation (EC) No 141/2000 on orphan medicinal products ‘to provide incentives for the research, development and placing on the market of designated orphan medicinal products’.

Since the introduction of the rare disease drug legislation, more than 6,200 and 2,300 treatments have been given orphan drug designation by the FDA (Food and Drug Administration) and EMA COMP (European Medicines Agency Committee for Orphan Medicinal Products) respectively. However, approval rates are low – only 17% (1,036) orphan candidates were approved by the FDA between 1983 and 2021, and 8% (191) by the EMA COMP between 2000 and 2020.

Furthermore, orphan designation applications are often withdrawn (14% FDA and 28% EMA). Encouragingly, the number of drugs granted orphan designation has remained at pre-pandemic levels over the last two years.

In addition to these incentives for rare disease research, global health authorities have recommended the adoption of innovative trial designs to accelerate approvals of safe and effective medicines. These include the use of natural history studies, disease registries, and previous clinical trial results for external control arms, patient identification using existing data from electronic health records (EHR), alternative endpoint generation using EHR and emerging data sources, like wearable technology, and simulation studies, among others.

COVID-19 and patients with rare disease

The COVID-19 pandemic is having an enormous impact globally, with worldwide confirmed cases reaching more than 460 million with total COVID-19-related deaths surpassing 6million in March 2022.

As well as vulnerability to severe infection, the rare disease community has been disproportionally affected by the COVID-19 pandemic due to unprecedented impact on diagnostic services, treatment delays, suspended research, and displacements within the patient pathway. A large quantitative survey (N = 6,945) conducted by Rare Barometer investigated the impact of COVID-19 in rare disease. The survey found that, during the first peak of the pandemic, 83% of patients’ care was disrupted across Europe with 21% of patients reporting that they were unable to access treatments. In addition, a large proportion of patients with rare disease – 66% – reported worsening mental health and depression.

Clinical trials during the COVID-19 era

Clinical trial research was severely impacted during the first wave of the COVID-19 pandemic due to shortages of medical and support staff, inadequate monitoring, travel restrictions, interruptions of supply chains, shortages of medical equipment, uncertainty over continued funding, and imposed restrictions. This resulted in the disruption of over 1,200 clinical trials in 2020, and a greater than 500% increase in suspended trials throughout 2020 compared to 2019. After June 2020, the number of clinical trials suspended or with delayed initiation due to COVID-19 slowly started to recover.

However, there are an increasing number of trials reporting that the slow enrolment of participants continues to be a major disruptor. Many hospitals that serve as trial sites were inundated with COVID-19 patients and may still not be available due to the continued high prevalence of COVID-19 owing to the emergence of the highly contagious Omicron variant.

In addition, investigators may have been reassigned to COVID-19 trials or to treating patients with COVID-19, while non-COVID trials have in some cases been deprioritised. Indeed, the volume of non-COVID clinical trials has decreased 18% (2,556) in 2020 and 5% (668) in 2021 compared to before the pandemic across the United States and Europe.

Trials for orphan drugs during the COVID-19 pandemic

Conducting clinical research in rare diseases is challenging regardless of the challenges presented by the COVID-19 pandemic. These challenges are largely due to small, underdiagnosed patient populations dispersed across geographic large regions.

In a recent review of non-completed rare disease clinical trials, patient accrual was found to be the most common reason for trial termination. Heterogeneity in clinical presentation, and potential ethical implications due to high medical unmet need seen in many rare diseases, can also make it difficult to identify suitable cohorts of sufficient size to power traditional study designs.

The usual challenges of rare disease research have been compounded by the COVID-19 pandemic, including the ability or willingness of patients and caregivers to travel, and reduced access to specialist medical care resulting in diagnosis and treatment delays.

Despite these challenges, the average number of marketing-authorisation applications to the EMA for orphan medicinal products during COVID-19 was higher compared to before the pandemic. Cancer, haematology and neurology remain the indications with the highest volume of EMA recommendations for the authorisation of new medicines. In addition, over 50% of all novel drug approvals by the FDA CDER are for the treatment of rare disease.

Has anything positive come from the COVID-19 pandemic for orphan drug development?

The COVID-19 pandemic has brought unprecedented challenges to clinical trial research and the rare disease community. It has in turn catalysed the development, use and deployment of digital technology within health systems due to the need to reduce person-to-person contacts, and to support remote data gathering.

These digital advances have aided the paradigm shift towards more efficient decentralised and non-traditional trial designs that circumvent many of the challenges traditionally faced for rare disease studies. These innovations, despite being developed out of necessity, have contributed to the number of new drug approvals outpacing expectations, especially for rare diseases.

As the pandemic becomes endemic and restrictions are lifted, it is paramount that this momentum for innovation is continued.