Challenges In Rare Disease Studies And How Decentralized Trials Can Support

There are more than 7,000 distinct and identifiable rare diseases affecting up to 400 million people worldwide. While individual diseases are uncommon, collectively 5% of the world population suffers from these often-debilitating conditions and patients continue to have high degrees of unmet medical need.

Rare diseases cover a wide spectrum of conditions affecting different organ systems with varying severity, age of onset, and prevalence (see box for more detail on Rare Disease definitions) each with their own individual nuances and challenges.

Getting a diagnosis can be a lengthy process involving many different medical specialties and, as such, these patients tend to be well-informed on their disease. That said, their disease can also have progressed significantly prior to finding a suitable treatment pathway or research study.(1) Many of those suffering from rare diseases possess symptoms that affect their mobility, increasing the burden of traveling to clinical sites – both for standard care and for research study purposes. Limitations from patient symptoms can make clinical trial participation particularly challenging for this already limited number of patients, in turn increasing the difficulty for sponsors seeking to conduct rare disease therapy studies.

With the use of digital platforms and supporting processes, decentralized clinical trials (DCT), can move many aspects of clinical trial participation from the traditional research site to a remote location, most often the participant’s home. The ability to implement DCT elements as a means of reducing the burden of study participation for patients and their caregivers can have a positive impact on the industry’s ability to conduct studies, especially for more challenging therapeutic areas. DCTs offer flexible solutions that can make participation in clinical research easier for patients while maintaining data integrity. Yet, sponsors have been slow to adopt DCT approaches in rare disease trials. Here we will discuss the challenges and common themes in rare disease studies and show why these trials lends themselves to DCT approaches.

Complex studies

Rare diseases are often debilitating and life-threatening, having a significant impact on the daily lives of patients and their families.Most rare diseases have an established genetic link (72%) , however, they can manifest in other ways, such as an immunogenic response, the consequence of an infection, reaction to a toxin, or an adverse drug reaction, for example.

While developing therapies to treat rare diseases is a critical area of clinical research, these studies tend to be more complex than most. This is due to the lack of natural history data and well-established clinical endpoints, as well as an inherently limited number of potential patient candidates. Compounding these challenges, the FDA and EMEA often use different criteria for assessing rare disease studies, causing sponsors to create protocols that attempt to meet both sets of requirements. While these protocols are, of course, designed to achieve the required safety and efficacy data, they can also increase the study burden on patients and their families.

The majority of rare diseases have identified genetic origins, resulting in 50% of all rare patients being children, 30% of whom will die before the age of 5 years. This further complicates rare disease therapy research, as the regulatory environment surrounding pediatric trials calls for a higher level of data and data scrutiny. A child with a debilitating illness adds a different kind of complexity for patients and families, as the whole family, including siblings, can feel the effect and burden of disease management and clinical trial participation; the parents are likely to have many competing demands on their time looking after both ill child but also supporting their siblings. In some instances, there may be more than one child within the family directly affected by the disease.

Decentralized trials offer ways to minimize patient burden by providing a means to conduct study visits remotely using tools including telemedicine, electronic Patient Reported Outcomes (ePROs), patient diaries, wearables, sensors, and other remote data capture methods and for pediatric trials DCT can also support both eConsent and eAssent. DCT approaches may also include home nursing visits that support additional clinical assessments or medication administration for drugs that are more difficult for the patient and caregivers to manage in the home.

Designing a study with decentralized element needs to begin early.Clinical end points need to be established and schedules of events (SoEs) developed that take into account which activities and assessments can be done away from the study site and by whom. Patients and patient groups should be part of these early discussions; if one of the main aims of DCT is being more patient-centric, then we need to hear their voice and not make our own assumptions into the overall design.

Clinical Sites

Rare disease sites are generally highly specialized and relatively low in number. This, compounded by the inherent low number of patients, means that patients and caregivers are likely to live long distances from study sites. For comparison in non-rare disease studies, around 70% of patients live more than two hours from a site4, thus, these patients may need to travel very far – potentially even internationally – for in-clinic visits. For this reason, rare disease studies often necessitate overnight or extended stays, which can be challenging particularly for patients in especially poor health. Remembering that half of rare disease patients are children3 and thus travel is not simple, parents need to make multiple arrangements including time off work and childcare for other siblings. For patients, the illness itself can be an ordeal – an ordeal that is compounded in studies that require frequent visits. Decentralized approaches may not remove the need to entirely, nor should they, but they do offer choices to patients and families, allowing them to better fit the responsibilities of clinical trial participation into their lives.

Because there are fewer rare disease studies compared to more common diseases and conditions, sites involved in rare disease research can be less experienced with trials. They may not be as familiar with elements such as good clinical practice (GCP) nor the extra systems and necessary regulatory requirements that need to be in place when compared to large study centers. Thus,these sites often require more intense training and ongoing support, including how to introduce and advocate for DCT elements to their patients. This needs to be built into the site training plan from the first contact. Enhanced training and support should be made available throughout the course of the study. Work can be done to capture where each site’s pain points are, which DCT elements they might be hesitant about and other concerns these sites may have about their role in the decentralized study. Knowing this at the outset of the study can greatly reduce problems during the trial. Having readily accessible and easily comprehensible training materials can greatly alleviate site burden, support them to be DCT advocates, which in turn will help with DCT uptake by their patients.

Hybrid vs Fully decentralized trials

Since rare diseases tend to be severe and life-threatening, and indeed this is part of the European Union definition of rare disease, clinical oversight for these patients is critical. This is why fully-decentralized studies for rare disease are extremely unlikely. Instead, these studies are likely to contain element of both site-based studies and DCTs, or hybrid clinical studies. Such approaches maintain the value of site-based clinical visits while using DCT approaches to improve the participant experience along with the quality of data captured by:

• Eliminating the need for some clinical visits by capturing data remotely
• Providing purpose-built channels for remote engagement and communications between patients and the clinical team
• Capturing important data points between visits, providing site teams with more insight into patient health and challenges, allowing them to make quicker, more informed decisions designed to keep patients on track

While it is easy to get excited about the ability of various technologies to capture data remotely, we must not overlook the value trial sites bring to research, particularly with rare diseases. The clinical teams at these sites often have long-term, deep connections with participants. As a result, they are often deeply vested in their health journey and wellbeing. This can mean that site teams are very protective of their patients and these relationships, which can make some sites reticent to promote decentralized approaches. Likewise, rare disease patients often want direct contact with sites, indeed being connected to a specific clinician may be the primary reason for them joining a clinical study in the first place. Taken together, hybrid study approaches that serve to reduce patient burden while preserving the roles of the clinicians can help convince rare disease sites to get involved with research and grant access to their patients.

Drug delivery challenges and DCT approaches

While the issue is not unique to rare disease studies, the mode of drug delivery (e.g., by mouth, sub cutaneous (sub-cut), intravenous (IV), infusion) influences our DCT approach. While pills can be shipped directly to patients, and technologies can be employed to ensure drug adherence, other types of medication require the help of a medical professional either at the clinic or at home.Sub-cut, IV or infusion administration need not rule out in-home drug administration as home health nurses may be a viable option to do the drug administration – although some countries do have stringent regulatory environments regarding modes of drug administration and thus a visit that can be conducted remotely in one country may not be feasible in another. Home nurse visits can be accompanied with a telehealth visit allowing the principal investigator (PI) to be part of the process – this helps reduce patient stress and the PI continues to have direct line of sight of their patient. All this said, there are some kinds of medications that will require in-clinic administration. With these, DCT elements can be employed to gather other data (ePROs, readings through mobile and/or wearable medical devices, etc.) remotely, allowing sites to optimize the patient’s time in clinic, allowing them to have a more relaxed experience while they get their medication.

Patient Recruitment & Retention

By definition, rare diseases mean a very limited number of patients that can potentially participate in clinical trials. With a recent study citing that approximately 25% of all rare disease for therapies for these patients with clinical trials often being their only healthcare option, strongly suggests that providing more options for how and importantly where they can engage with clinical research will increase their both recruitment and allowing them to stay in the study for the long term.

Traditionally patients are recruited through the study sites that know them, or they are referred through their clinicians’ professional networks. DCT approaches can help by expanding the way we engage with these patients. For example, rare disease patients are often highly engaged with patient advocacy groups. These groups can be influential; engaging with them early in the protocol development stage can help develop protocols that are easier for patients to adhere to along with providing opportunities to pressure test the DCT elements, such as wearables and other technology.At the other end, patient advocacy groups can help promote the study, while adding built-in credibility to the drug development program.Patients visiting these advocacy groups online can easily be directed to a study landing page where they can find out more about the study, self-pre-screen and be directed to a participating site and eConsent (either at site or remotely - local regulations permitting). Making this process simple and intuitive can be an effective way of getting interested and likely eligible candidates to get enrolled quickly.

Once enrolled, DCT elements help to keep participants engaged and retained. In-home medical devices, wearables and smart device applications can allow patients and caregivers to submit data from home or meet with clinicians virtually via telehealth which, again, can help to reduce the number of necessary in-clinic visits. These same applications used for data capture and submission can be used for on-demand outreach to the site team, or to access a library of support and guidance materials. The ability to remain in the home more, with a sense of support and access to their clinicians can help many patients overcome day-to-day challenges over the course of a trial and remain enrolled.

DCT features support rare disease trials in a number of ways. Following is a breakdown of common DCT elements and how they benefit rare disease studies.

Telehealth

Telehealth, or telemedicine, allows for remote visits between patients and clinicians. They allow for both scheduled and ad hoc meetings and provide a necessary tether for rare disease patients and the physicians they trust. While some in-person visits will almost certainly be necessary, many conversations done via telemedicine are sufficient and allow patients to remain in their homes more often. Further, telehealth can be combined with other DCT elements to expand the number and scope of validated assessments that can be done remotely.

eCOA/ePROs

Electronic clinical outcome assessments (eCOA) are validated outcome assessments submitted by patients (ePRO), caregivers/observers (eObsRO), and clinicians (eClinRo). The majority of these assessments can be done remotely either through dedicated smart device applications and / or in combination with telehealth or home health visits. These are particularly important in rare disease studies due to the historical lack of well-established clinical endpoints. ePROs and other assessments provide a trackable source of frequent data that give study teams ongoing insight into the patient’s condition.

eDiaries and Patient Surveys

Similar to eCOA submissions, patient eDiaries and surveys are an effective way to collect study-specific data without the need for an in-clinic visit. These elements provide valuable data on how patients are doing day-to-day, allowing study teams to identify issues or challenges quickly and act on them to keep patients on track. They also can provide valuable clues as to potential new clinical endpoints for rare disease.

Wearables and Medical Devices

Mobile medical devices (e.g. blood pressure monitors, ECG, airflow cytometers, etc.) and wearable sensors can be utilized in DCTs for periodic or continuous data collection. Consideration should be given to the patient usability of the wearable device or sensor, i.e. can it be easily incorporated into their daily life and/or is it usable by patients with the particular indication. Set up and training can be done, depending on complexity and patient situation, via a smart device application, in the home by a home health professional, or during an in-clinic visit.

Patient Apps and/or Websites

As mentioned before many assessments, such as eCOA, can be captured via a smart device application. But they are capable of a great deal more during DCTs. These apps/DCT platforms have a number of uses, such as (but not limited to):

• Sending dosing or activity reminders to patients/caregivers
• Scheduling visits – either telehealth or in-clinic
• Submitting eConsent/eAssent
• Facilitating ePRO, diary or survey submissions
• On-demand outreach by patient to the study team – or vice versa

While all phases of a pipeline can benefit from DCT features, certain stages of the pipeline stand to benefit more. Which DCT features are right for a particular study is largely driven by the protocol, patient population, disease stage etc. For example, early stages and first-in-human studies, understandably, lend themselves less to the use of DCT approaches because PIs need to have close follow-up with patients during these scenarios. However, all other stages of development lend themselves well to the integration of DCT elements; which elements will be deployed will depend on the protocol and the specific study requirements at each stage.

At the start of the drug development pathway, natural history studies and registries are often required to help understand the natural course of the rare disease and help distinguish patient subgroups and explore clinical endpoints. Phase I/Phase IIa rare disease studies are commonly combined. Later stage studies often have an open label extension allowing patients access to the IP through till market authorization (this can be a big incentive for participation) and Phase III can be substituted by post-approval registry. Expanded Access programs help widen the availability of the IP to the patient population pre-approval, while simultaneously supporting safety data for submissions. The figure below shows alignment with DCT implementation by study stage.

Rare disease trials present numerous challenges to research. These studies tend to be complex and the potential pool of study candidates is inherently small. Because these conditions are rare the number of study sites and clinicians with research experience is similarly limited. Further, the patients most likely to qualify for a given study tend to present with severe illness, making the responsibilities of clinical trial participation such as travel to clinical sites a burden for many.

DCT approaches that allow for remote data collection can help to improve how rare disease studies are conducted in several ways. Utilizing technology to capture and submit data from the patients’ homes helps to reduce the number of necessary clinical visits and lighten the study burden for patients and caregivers.