Dealing with rare diseases

It’s one of the paradoxes of rare disease research: while each individual disease is rare by definition, they are surprisingly common when taken as a whole. Around 300–400 million people worldwide are thought to live with rare diseases, including more than 30 million in Europe and 30 million in the US. That’s as much as 6–8% of the population.

Within the EU, rare diseases are defined as those that affecting less than one person in every 2,000. That applies to nearly 8,000 diseases, ranging from well-known conditions like Ehlers Danlos Syndrome, cystic fibrosis and haemophilia, to genetic conditions afflicting only a handful of people. The rare disease population, then, is a diverse group with highly individualised needs.

If there is a common denominator, it’s the fact those needs are often underserved. Patients can struggle for years to receive a diagnosis, and even once they do know what they’re dealing with they can face feelings of loneliness and isolation. They may lack suitable medications, due largely to a lack of market incentive – why develop a drug if there’s such a limited patient pool? In fact, only 10% of rare diseases have a treatment and significantly fewer than that have a cure.

Even when a drug has been approved, patients may lack appropriate drug delivery devices, often limited to standardised syringes and vials.

“On the one hand, we see that there is a growing number of drug-device combination products,” says Dr Anneliene Jonker, a researcher in rare diseases therapeutic innovation at the University of Twente in the Netherlands. “On the other hand, we see more and more challenges, both on the regulatory side and in ways that are specific to rare diseases.”

Jonker is the vice chair of the Therapies Scientific Committee at the International Rare Diseases Research Consortium (IRDiRC), for which she heads up different working groups and taskforces. One such working group, established in 2022, investigated the role and value of medical devices in rare diseases. As part of their remit, they mapped out different countries’ approaches to device development and explored how those approaches could be harmonised. They also set up a framework for the off-label use of devices.

Building on this research, the team is now moving on to look at drug-device combination products. These might include transdermal patches, drug-eluting stents, infusion pumps and inhalation devices.

“When we presented at pharmaceutical conferences, a lot of people came to us and said, this is fantastic work, but our issue is combining the worlds of drugs and devices,” recalls Jonker. “Knowing that this is a specific need in rare diseases, it is really something that we hope to focus on starting this year.”

Regulatory roadblocks

Governments have long been aware of the problems faced by rare disease patients. The Orphan Drug Act in the US (1983) and the EU orphan drug designation (2000) were enacted to stimulate drug development in the field. Since then, over 1,100 rare disease drugs have been approved by the FDA, with nearly half the new drugs approved in 2022 indicated for such a purpose. Meanwhile, many researchers believe that drug repurposing – finding new uses for existing medicines – could be key to developing orphan drugs more quickly.

Unfortunately, devices remain something of a sticking point. Only two countries worldwide (the US and Japan) have an orphan device regulation that would boost the market in a similar way to those for orphan drugs. The EU lacks any framework of this kind. Even within the US, which launched its Humanitarian Use Device programme in 1990, there is broad consensus that more needs to be done.

In 2016 FDA study of 588 clinicians, almost two-thirds (64%) expressed dissatisfaction with the existing devices for rare diseases, while more than three-quarters (77%) said that repurposing existing devices was insufficient. A similar proportion (74%) saw the lack of profitability to industry as a large impediment.

Jonker comments that many devices on the market were developed without much patient input. There is also a major problem in Europe with what she calls ‘disappearing devices’ – devices that were once available for rare disease patients but have been withdrawn due to unforeseen effects of the EU Medical Devices Regulation. This applies to some urgently needed products, such as a catheter used to perform life-saving heart surgery on newborns.

“We’ve written a letter to the EU Health Commissioner Stella Kyriakides, signed with over 60 organisations throughout Europe, to say that we really need to focus on this,” she says.

Regarding drug delivery devices specifically, she notes that the industry faces several roadblocks. First, how is the product classified – as a device or as a drug? It may not always be obvious, and EU-based manufacturers need to navigate a particularly complex system involving two separate bodies. There is also a lack of specific market incentives or guidance related to rare diseases. The IRDiRC will be looking at what can be done to make things easier.

“We’re hoping to gain a better understanding of the regulatory basis and how we can stimulate development, as well as learning from the FDA,” she says.

Specific needs

So what do rare disease patients actually need in terms of drug delivery devices, be they combination products or otherwise? A big part of the equation, remarks Jonker, is the fact that many of these patients are children. Around 70% of rare diseases start exclusively in childhood (another 18% can start during childhood or adulthood), and the majority of these have a typical onset under the age of six.

That means that devices need to be adapted for a paediatric population – which most obviously means shrinking them down.

“If you have an implant [for prolonged drug delivery] or drug-eluting stent, it will need to be smaller to actually fit in children,” says Jonker. “That can be quite limiting, because you might need a certain dose of drug, but it needs to fit into a much smaller stent or implant.”

It doesn’t stop there, however. As paediatricians are fond of saying, a child is not just a small adult. For instance, young children have a different fat and muscle distribution to adults, meaning any intramuscular injection device will need to account for these differences.

Young children also have immature kidney and liver function, which may entail delivering the drug in smaller doses more frequently. There are differences in immune function, with implications for how certain drugs are injected, and differences in metabolism, with implications for dosage. “Children’s metabolism can be faster, so the release of the medication needs to be faster,” comments Jonker. Side effects may also be more pronounced.

There can be challenges, too, when it comes to usability. Very young children may struggle to swallow a pill, meaning a different form of administration (such as a drug-device combination) is required. Even as children get older, they may have a hard time operating their devices for one reason or another. If it’s their parent or carer who will be administering the drug, the design needs to reflect that too.

“How can the patient or the family handle the drug device combination?” says Jonker. “In some cases, like implants, you don’t have to do anything. But if you have to get a transdermal patch, the question is does this stick? Are you as a patient able to handle that easily?”

In the FDA study of clinicians, 44% reported that paediatric intrathecal ports for drug delivery were an unmet need. One orthopaedic surgeon added that there was a need for ‘drug delivery devices that are controlled by feedback from physiologic sensors’. This, they added, would be suitable for ‘virtually every rare disease where a drug/dose relationship to the severity of disease is known’.

These kinds of considerations, however, are far from exhaustive – and it would be fair to say this topic has been historically under-explored. As the IRDiRC’s work gets under way, it should be possible to establish more areas of unmet need. It should also be possible to find solutions – places that industry and regulators can focus their efforts, in order to make a meaningful difference to patients’ lives.

“The question is really can we not only see it as a challenge, but also as a fantastic learning opportunity to bring all these fields together?” says Jonker. “We see fantastic progress in the field of drug development, we see fantastic progress in field of device development. I think the rare disease world is blooming. Can we truly see it as an opportunity to learn from each other and bring those strengths together? So, for me, the glass is half full.”