Clinical Research and the Challenge for Rare Diseases

Last year, I was unexpectedly thrust into the world of rare diseases. My sister, Annie, was diagnosed with Pseudomyxoma peritonei (PMP), a rare type of appendix cancer. Given PMP’s rarity, Annie’s doctor was less than optimistic about the prognosis. But there was a glimmer of good news: A pioneering surgical procedure recently had been developed. The bad news, however, was that the procedure was only available at two centers in the country and, even if Annie was accepted, it would be considered a last resort, with inconsistent reports of success.

I asked about clinical trials. The doctor didn’t know of any. I turned to the Internet and to There were just three trials listed for PMP, although the nearest one was 3,000 miles away in a different country. In principle, we would do anything to get my sister the right treatment. But taking part in a trial under these circumstances simply wouldn’t be feasible. If this is typical, it paints a distressing picture.

It also raises questions. Even setting aside the traumatic experiences of the patient and her family, what does this imply for the industry? Is enough being done to find cures for rare diseases? What is the clinical research landscape? How can we do a better job to attract people into rare disease clinical trials? What are the unique issues? What are the barriers? What do we even mean by a rare disease?

Setting the Context

The FDA and EMA define rare diseases as conditions affecting less than one in two thousand people. That would equate to around 200,000 people or fewer in the United States and 250,000 or fewer in the European Union. At last count, it is estimated that around 4,500 drugs are in development for 447 rare diseases.

It’s worth noting that among the global total of 350 million patients with rare diseases, half are young children. Around 30% won’t see their fifth birthdays. Moreover, their journey to the correct diagnosis may already have been long and painful. At first glance, it may appear that rare conditions are of limited appeal to the pharma industry. Doesn’t a smaller target population represent a smaller revenue opportunity?

On the contrary, rare diseases are a natural area of interest for pharma businesses because there is clear unmet need. Furthermore, NIH research shows insights from investigators in rare diseases can help improve understanding of more common diseases. Thus, these conditions are attracting increasing interest from clinical researchers. The number of clinical research studies has increased by 56% in the last three years.

But research into rare diseases presents a particular set of challenges. While patients and their families tend to be highly engaged and motivated, and take proactive roles in researching treatment options, the patient population is, by definition, small. Also, it is likely to be geographically diverse. Study sites will be highly specialized and there will be very few of them. This immediately throws up a host of practical issues.

When we’re recruiting volunteers for any clinical research, there are certain perennial challenges. Even for trials dealing with common conditions, large patient populations, and an abundance of trial sites, enrollment is a recurring concern.

Clinical Trial Recruitment Challenges

Awareness of clinical research is low and for the few who are considering participating, there are barriers—inconvenience, mistrust, concerns about safety, the burden and duration of the trial, and the possibility of receiving a placebo. Estimates vary but it’s frequently cited that more than 80% of studies are delayed due to problems with recruitment. Only 4% of Americans have ever participated in a study.

With rare diseases, it is even more challenging. Where should we start in figuring out how to navigate the obstacles? Part of the answer lies in the same good practices that apply to all clinical trial recruitment. Success rests on finding the right people, making enough of them aware of relevant studies and minimizing the burden for them to participate.

The awareness challenge can be addressed in a number of ways. A “broadcast” approach isn’t directly relevant to these small niche groups—though raising the public’s appreciation of clinical research generally would be a good thing. For small patient populations, the key tools are social media, patient communities, and advocacy groups. Patients and families tackling rare diseases often feel isolated and turn to the Internet to find information and to share experiences online.

Today, we can employ sophisticated online media buying strategies such as programmatic, search optimization, geo-targeting, and “look-a-like” profiles to create highly targeted campaigns. These have made online media planning a front-line tool to pinpoint hard-to-find patients. Organizations such as NORD (National Organization for Rare Disorders) have a significant role to play here, as do the industry bodies with which they collaborate, such as the Center for Information and Study on Clinical Research Participation, CenterWatch, and

Recognizing Awareness Opportunities

Occasionally, a rare condition is catapulted into the public consciousness through a high-profile news story—say, a celebrity is diagnosed with the condition—or a campaign, such as the ALS Ice Bucket Challenge, which captures the public imagination. This gives a fleeting opportunity to tell people about clinical research when it is “front of mind,” but we need to be agile to exploit these opportunities. They are, by nature, unpredictable.

Beyond creating awareness, the key to enrollment lies in understanding the patient’s perspective and designing a patient-friendly experience up-front. The criteria for selecting volunteers begins with the study protocol design, but we should also consider what motivates people to join. Sometimes participation is a last resort, but equally, it might be a desire to understand their condition or to help others. A “one-size” recruitment method does not necessarily fit all.

We can use qualitative research and ethnography, early in the planning process, to enrich our understanding of patients’ lives and put ourselves in their shoes. With rare diseases, we are typically dealing with widely dispersed people, so that might mean doing a small number of home visits and interviews on the phone or via Skype. Even this kind of small-scale research can throw up insights and surprises, giving crucial learnings to design the right methods that appeal to people more effectively and to promote adherence later in the study.

Minimizing the Patient Burden

Geography is a particular barrier. Frequent site visits, over long distances—sometimes even in another country—are a major obstacle to volunteering, especially when involving children. Like all research designs, there is much we can do to make the experience as simple as possible: Minimizing travel, making visits as pleasant as they can be, making sure the process is organized around the volunteer, their welfare, and comfort. This should be best practice anyway, but for rare diseases, doubly so.

There is significant interest in designing research that does not depend on site visits. “Site-less,” “remote,” or “virtual” trials are particularly attractive for rare diseases with clear advantages: These trials remove the obstacles associated with long and inconvenient travel to sites, so they make volunteering more attractive—so much so that Craig Morgan of software company goBalto refers to conventional site-based research as “a dying paradigm.”

Site-less research works two ways. First it is facilitated by technology (“eHealth” or “mHealth” in the jargon), where volunteers are engaged through a combination of video communication (e.g., FaceTime or Skype), with HCPs where human contact is required, and smart devices like Fitbit, smartwatches, and apps that take measurements. This approach is especially relevant for younger, more digitally native populations, although it is also used increasingly in neurological conditions such as Alzheimer’s and Parkinson’s. mHealth can bring additional benefits in speed and in streamlining collaboration between study teams. It has limitations for more complex studies or those involving older people.

The second approach employs “home-based” methods. Rather than the volunteer coming to visit us, we go to them. Homecare facilitated by nurse experts is becoming more mainstream across medical specialties as inpatient beds are increasingly at a premium. This approach is especially pertinent for older populations. The two approaches—mHealth and homecare—can be complementary.

Another promising solution employs a “concierge” approach to remove the financial and logistical burden from volunteers and their family. We can create a system that takes care of everything, managed by an expert operational team. They talk directly to patients and caregivers to reduce their anxiety. They pick them up and travel with them—accompanied by physicians when necessary. They arrange visas and translators. If accommodation is needed, they ensure all the relevant creature comforts are at hand.

This kind of support is resource-intensive, but it can make the difference between keeping a trial fully enrolled and preventing drop-outs or having a trial fail. Hence, it can deliver a significant return on investment.

The Way Forward

In many ways, rare diseases represent the quintessential version of the challenge we face in clinical research recruitment and retention. They embody all of the issues that we typically face in finding the right people and educating and attracting them, while removing the obstacles to volunteering—only more so. They are a kind of ultimate clinical research “torture test.” Nevertheless, rare conditions are attracting more attention than ever before, so they could provide a hothouse or testing ground for innovative recruitment methods. It would not be surprising if some of the measures discussed above ushered in a new generation of better trial designs with more targeted and innovative awareness campaigns.

In the true spirit of patient-centeredness, this should pave the way for trial designs and campaigns that are better constructed around people’s lives. mHealth and concierge services are great examples of this. At a time when patients and their families are feeling anxious, exposed, and at their most vulnerable, it is our responsibility to do everything we can to make the research experience more transparent, friendlier, and less onerous for them. In this respect, advances in rare disease research methods can point the way forward.

  • Kate Spencer

    Kate Spencer is Managing Partner at Langland USA. Kate established U.K.-based Langland’s Clinical Trial Recruitment (CTR) communications offering and successfully led the CTR team in support of more than 400 trials across the world. In 2016, she established Langland’s first U.S. office where she continues to scale the business and replicate the Langland brand internationally.


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