Of the approximately 7,000 known rare diseases, 95% have no effective treatments. Bringing new treatments to market requires the backing of studies validating their safety and efficacy, but trials in this space are notoriously challenging.

According to a recent study, more than half of rare disease trials are discontinued or remain unpublished four years after completion. Enrolment difficulties account for many orphan disease trials that are terminated early or fail to produce informative findings. Enrolling for rare disease studies is far more challenging than for common diseases, which are typically well understood with a large patient pool. With rare diseases, it tends to be the opposite.

Clinical Trials Arena drew insights from two expert speakers at this week’s virtual Clinical Trials in Rare Diseases Conference 2021 on running successful clinical trials in the rare disease space, overcoming recruitment and retention barriers and the opportunities and challenges brought by the Covid-19 pandemic.

Challenges of rare disease clinical trials

Of the biggest challenges sponsors face when conducting trials in rare diseases, Denmark-based biotech Galecto’s vice president of clinical development Stephen Partridge said:

“I think the main issues in rare diseases stem from the fact that there often isn’t very much information and knowledge about the diseases you’re trying to study.”

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Similarly, rare disease-focused drug developer X4 Pharma’s vice president of patient affairs and advocacy Michele Rhee described “very low disease awareness among healthcare providers [HCPs]” as a frequent barrier in rare diseases. This often means that it falls on the patients, who are often the experts in their disease, to educate their own doctors.

Rhee said that lack of disease awareness among HCPs also impacts sponsors by making it difficult to identify principal investigators (PIs), which then impacts geographic distribution. These geographic issues are amplified by financial burdens for patients, she added.

“A really large proportion of people with rare diseases have to travel over 60 miles for their care,” Rhee said. “When you think of how many people are struggling just to access their care it makes a lot of sense that it’s an even larger issue when they’re trying to enrol in a trial or when we’re trying to approve them for trial.” 

According to the US-based National Organization for Rare Disorders (NORD), 76% of people experienced financial hardship due to their rare disease. Despite this, Rhee said a large proportion of rare disease patients are interested in trying an investigational treatment.

“This is a really large percentage of that patient population that we’re trying to reach,” said Rhee. “This is an amazing opportunity so what we need to do as sponsors is figure out how to meet patients where they are. They’re interested, and we just need to eliminate those barriers, to help them access investigational treatments.”

Covid-19: challenges and opportunities

Over the last 18 months, many of the people working in the life sciences industry would agree that Covid-19 has made their work more challenging but also accelerated the pace of innovation. Necessity, after all, is the mother of invention.

I think almost everybody in the drug development business would say COVID has made the job more difficult,” said Partridge. “I think certainly you need to take into account the risk that Covid has posed to a number of studies. Often in the rare disease setting, people can be quite sick, and therefore the ability to actually run clinical studies has been impacted. I think we’re coming through that now and many health systems have adapted their ways of working to counteract that.”

X4 fielded a number of surveys among its patient communities in April 2020 to ask them about the impact Covid-19 was having on their lives, their willingness to participate in trials, to travel and how risk-averse they were.

“Covid-19 made a really big difference and magnified what everyone was dealing with before,” said Rhee. “We wanted to collect that data to make sure we weren’t just making knee-jerk decisions but were really being informed by what we were hearing from our patients.”

Rhee noted that while Covid-19 was challenging it also presented some amazing opportunities, one being the push to incorporate decentralised clinical trial (DCT) components.

“Covid-19 just accelerated a lot of things that were in process and really [brought us] closer to that decentralised model,” she said. “And what’s interesting is that a lot of the decentralised model components are solutions to some of those larger issues around recruitment and retention.

“You want faster trial enrolment, which reduces costs and improved retention, which can reduce missing data. You want shortened timelines and improved data interoperability and greater control, convenience and comfort for your patients, and greater diversity.”

Going above and beyond with the decentralised model

Michele Rhee, X4 Pharma,
X4 Pharma’s vice president of patient affairs and advocacy Michele Rhee

On the back of the survey results, X4 incorporated several decentralised trial components into all of their trials, mainly telehealth, home nursing, remote monitoring and shipping products to participants’ homes.

“Every barrier we can knock down can improve our chances of success. Every participant, every patient is precious, so understanding what can make this an easier, better process for them is something that we all strive for.”

In one situation, though, due to the pandemic, the X4 had to go above and beyond. In a double-blinded placebo-controlled 52-week study, one patient was nearing the end of the study when Covid-19 hit. Understandably, the participant did not want to travel to the trial site or have a stranger in their home. X4’s solution was a hotel room to conduct the home health visit instead. The participant was more comfortable with this and completed the trial.

“It was really a great success and a really wonderful example that not only do you need to have those [DCT] components in place, but that sometimes even that might not be enough. Sometimes you need to go even further.”

Rhee notes that one downside of DCTs is that when a participant is not coming to the site the relationship isn’t as strong between the site staff, the PI and the participant. “Check in with the participants and make sure they are still engaged and motivated to stay in the trial,” she advised.

Finding patients in the right numbers

Partridge said rare disease studies can be facilitated by active research networks, patient organisations active in the area, and often the activities of a few key experts, but one of the things sponsors really need to understand is the prevalence of the patient population and where to find them.

“That needs some good research in industry databases, in any number of academic or other databases relative to the disease,” he explained. “If you start there, you can find where the patients may be. The next key step is identifying where the actual diagnosis of the patient gets confirmed. Many rare disease patients will be referred, often to just a few specialist centres in a country. It’s [about] identifying those centers that are really important to you.”

Partridge noted that finding large numbers of rare disease patients for a trial is tough but both in the US and Europe, there is great flexibility and collaboration from regulatory authorities in this area owing to the unmet needs of patients.

“You have to negotiate [with the competent authorities] on every single case, on the basis of the disease, and the appropriate sample size to follow,” he said. “The good news is they’re used to this, and they’re very open to being pragmatic. You will have to have a rationale for what you want to do but it’s often a very useful dialogue. Normally it can reach a compromise, and usually it’s based on how difficult it’s going to be to deliver the study.”

Rare disease trials: keys for success

As well as urging sponsors to think very carefully about their choice of contract research organisation or academic group as research collaborator, Partridge said that to be successful, rare disease trials must account for the patient perspective.

“There are a couple of [other] groups that you really need to talk to, to come up with a study which is effective – one is the research coordinators who are working with these patients in their current clinical care and the caregivers to these patients, so you can design a study which is practical and useful for them,” said Partridge.

“The worst thing you can do is over-engineer your study and make it difficult for anybody to take part in.”

Similarly, Rhee advised trial sponsors to always put patients first.

“When we’re looking at how to address the issues that we’re facing around recruitment and retention, it’s really helpful to understand what it’s like to live with the disease that you’re studying,” she said. “And that involves engaging with a patient community.”

“The future is very bright for rare disease studies; they are difficult to do but there’s a great willingness and need to find treatments because most rare diseases don’t have any effective treatment today,” said Partridge.

“The good thing is rare disease studies and research is very well supported in the regulatory authority environment. And certainly, if you have a good early engagement with the payers, for the health technology assessment, you can find exactly what they’re looking for early on, and everybody generally is willing to give you good input on this.”

To access more upcoming clinical trial events, visit the Arena International website.