Rare Disease Decentralized Clinical Trials and Registries: Four (4) considerations for your internal business case

I was speaking with a potential THREAD client/sponsor reviewing their protocol to support a clinical trial with rare disease patients and caregivers. We reviewed the strategy options, patient/caregiver insights, and decentralized approaches available to support their upcoming study. Based on some of the questions asked, I recognized that several baseline considerations for why decentralized approaches are the right fit for rare disease studieswerenotclearly known by some of the study stakeholders. This moment quickly reminded me that each rare disease clinical trial strategy required the fundamentals to be included so that every stakeholder had the same context.

Hundreds of rare disease studies have now been conducted globally with decentralized approaches(including some fully decentralized registry designs) over the last eight (8) years. Continuing to recognize the fundamentals of the business case remains important to continuing this positive trend for research sites, patients and their caregivers.

If you are exploring what or how to add decentralized clinical trial (DCT) approaches to your upcoming rare disease clinical trial or registry,please consider the following in your internal business caseas many of the stakeholders you need buy-in from may need this important context.

Rare Diseases Studies Introduce Different Complexities

Research on rare diseases is critical to support the millions of people that suffer from these debilitating conditions. While developing therapies to treat rare diseases is a critical area of clinical research, these studies tend to be more complex than most. These complexities are typically due to the lack of natural history data, disease-appropriate clinical endpoints, caregiver inclusion and an inherently limited number of patients.

Global regulatory agencies often use different criteria for assessing rare disease studies, causing sponsors to create protocols that attempt to meet both sets of requirements. While rare disease protocols are designed to achieve the required safety and efficacy data, the complex nature of rare disease protocols can also significantly increase the study burden on patients, caregivers and their families.

Patients in rare disease populations face more barriers in terms of access to medical research studies and ongoing care than patients with more commonly treated diseases. Rare disease patients and their families consistently report care inadequacies, such as diagnostic delays and lack of disease knowledge amongst primary care physicians.

It is also important to recognize that a high-percentage of rare diseases affect children.Pediatric and adolescent clinical trials require a tailored variety of solutions for children and their caregivers. These research trials for children with rare diseases experience increased challenges given that they affect the entire family’s daily routine.

Children's clinical trials can often be the only healthcare option available creating a significant burden for the whole family. Travel alone can be significant and tiring as participation means parents are challenged to find a balance between the needs of the patient and other family members.Parents of children with rare diseases have multiple roles: caregiver, consenter, travel agent, appointment coordinator and primary advocates for their children’s health. Designing a rare disease study requires us to plan for both the pediatric patient and their caregivers.

As there are fewer clinical trials in individual rare diseases,research sites participating in rare disease trials are often newer to clinical research, may not have a clinical research focused practice, and may need additional support to navigate clinical trial operations. This especially includes study monitoring, using eClinical technologies and navigating local regulatory requirements. Providing this context internally can be materially important especially in sponsor companies that have a wide portfolio of assets.Sometimes we assume that our colleagues have worked in a rare disease study or registry beforeand understand this requirement.

Consideration #1:The internal business case should clarify that this rare disease studycannotbe conducted like all other study designs. Decentralized approaches were added to serve the complex and unique elements of participation to achieve timelines, provide a competitive study design that is attractive to patients, meet recruitment targets and enable quality data capture over the life of the study.

Common Challenges in Rare Disease Clinical Trials

Rare disease studies are complex and participation is often difficult for patients and their families. Although this may be challenges for some non-rare disease studies, the combination of all these challenges in a single study is critical to address in planning. The challenges are numerous and include the following key barriers to clinical trials participation for rare diseases patients:

• Distance:Almost 40% of rare disease patients travel over 60 miles for healthcare. Study participants often travel longer distances, sometimes across borders, for study visits.
• Time: Even if they can reach clinics, participation can require long durations and be tiring to the family. Participants must adhere to strict visit schedules over the treatment period which often go on for many years. Each visit often require substantially more testing and time than a normal doctor’s visit. Time required in a research study adds a commitment burden to participants and their families and is a key barrier to participation.
• Access:Many of those suffering from rare diseases are living with symptoms that are debilitating and may affect their mobility, making travel to clinical sites difficult 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. This can increase the difficulty for sponsors seeking to conduct rare disease studies. Children may have requirements to participate during hours they are in school which may require research study visits at school.
• Long-Term Follow-Up:Rare disease clinical research studies are often followed by open-label extension studies allowing patients to continue receiving the drug for an extended period and/or up until market authorization. This impacts both the ability to recruit patients and also allows for sponsors to collect additional data points that can support their regulatory applications. Long-term follow-up can continue for many years following initial treatment and can extend long beyond the timeframe patients would normally be engaged with the participating site.

Consideration #2:The internal business case should specifically highlight and include a plan to address each (and all) challenges in this rare disease study such as distance/travel, time, access and long-term retention requirements.

Decentralized Approaches for Rare Disease Trials

Ensuring clinical trials are truly patient-centered is critical. This is especially true for rare disease clinical research studies. Adopting a patient-centered study design means acknowledging that every patient comes in with differing backgrounds, needs and expectations. The best study design for rare diseases is one that gives patients and families flexibility with choices as to how they engage with clinical research sites. Given the increased expectation to collect clinical data outside of a traditional clinical setting, many rare disease studies are employing a hybrid approach to collect data through telehealth, home health visits, at-school visits and remote-access technologies.

The shift to hybrid study designs (visits in clinicandin home) is helping sponsors and sites capture rare disease patient data during on-site visits, at home in between these visits and in lieu of in-clinic visits. The ability to implement remote clinical trial approaches for rare diseases can reduce the burden of study participation for patients and their caregivers and can have a positive impact on the industry’s ability to conduct studies, especially for more challenging therapeutic areas. Advances in healthcare technologies, such as wearables and sensors, mean many clinical trial procedures can take place virtually, and data can be collected from wherever the patient is at any time.

Decentralized design approaches include and are not limited to the following technology solutions. I provided a short definition on each of the below examples as may be helpful context for internal stakeholders to be clear on what they can offer in a study.

• eConsent- conduct consent (and assent) via a digital education workflow and/or paper signed version upload. Ensuring the patient and their caregivers always have access to the consents/agreements signed is critical.
• Telehealth Virtual Visits- allows for remote visits between patients and clinicians. They allow for both scheduled and on-demand (i.e. ad-hoc) appointments providing a necessary connection for rare disease patients and the physicians they trust. While in-person visits will be necessary, many conversations done via telemedicine are sufficient and allow patients to remain in their homes. Telehealth Virtual Visits can be combined with other DCT elements to expand the number and scope of validated assessments that can be performed remotely.
• Electronic Clinical Outcome Assessments (eCOA)- validated outcome assessments and include instruments that can be conducted by clinicians (ClinRo), by patients (ePRO), or caregivers/ observers (ObsRO). The majority of these assessments can be conducted remotely either through dedicated smart device applications in combination with telehealth or home health visits. Rare disease studies tend to be complex with many eCOA assessments partly due to the lack of well-established clinical endpoints. Including the capability to do some of the assessments remotely is beneficial for research sites and patients.
• eDiaries- specific data without the need for an in-clinic visit. These elements provide valuable data on how patients are doing day-to-day, allowing sites to identify issues or challenges quickly and act on them to keep patients safe and on track.
• Digital Health Technology (DHT)- includes a variety of sensors and wearables for active, periodic or continuous data collection. Consideration should be given to the patient usability of the wearable device/sensor, what feedback is given back to the participant and how the device is maintained (i.e. tech support, charging requirements, etc.).
• Activity Alerts- patient apps help study participants to manage the larger variety of visits, assessments, and other logistics required to support rare disease programs. These often include activity reminders to patients to schedule the next visits (i.e. in-clinic, virtual, home health, school, etc.), facilitate the next step in an eConsent/eAssent process, alert when a critical ePRO needs completion by a specific time today, respond to open messages from the research site and more.

Consideration #3:The internal business case should include the specific decentralized approaches planned with their strategic purpose and a short definition of what each tactic means, how it will be used and why it will be critical to support this rare patient population.

Recruitment Strategies for Rare Disease Clinical Trials

Most of study stakeholders recognize that the "rare" in rare disease means that the pool of potential study candidates will be small and make clinical trial recruitment challenging. This obviously increases pressure on the research site and study team to advertise the clinical trial, keep enrolled participants engaged and minimize dropouts. The recruitment strategy requires a robust plan and the addition of "non-traditional" approaches to properly advertise the study specific to the patient population.

When consulting experts to help the study team develop a recruitment plan, it may be helpful to consider the following tactics as a small part of it:

• Expand Geography to Recruit- Decentralized study approaches have the potential to supplement and support recruitment via offering research sites a broader geographic area around their center to recruit from (depending on the in-clinic visit, travel distance, site location, etc.).
• Advocacy Group Engagement- Patients with rare diseases are often highly engaged with patient advocacy groups. These groups can support study participation at multiple stages through the drug development lifecycle. Engaging advocacy groups can help promote the study while adding built-in credibility for their audience. Patients visiting advocacy groups’ online sites can be directed to a study-specific web page where they can find out more about the study, self-pre-screen, and/or be directed to a participating site.
• Research Site Support- Increasing participation in rare disease research also extends to clinical trial sites. Fewer rare disease studies compared to common diseases means there will be fewer sites with extensive clinical expertise in this specific patient population. Clinical research naive sites are often required and will need more extensive training, tools and 24/7/365 support to participate. By reducing the burden for rare disease study participants and giving sites the always available tools they need to manage these complicated studies, DCTs can facilitate a better experience for both experienced and new researchers.

Consideration #4:The internal business case should include the non-traditional recruitment strategies planned, why they are needed and how the specific decentralized approaches can support the recruitment plan's successful implementation in the study.

THREAD helps biopharma and life science organizations conduct the most complex rare disease studies with decentralized approaches in 60+ countries and 100 languages. If you want to learn more or want consulting support with your DCT design, please message me or email us at sales@threadresearch.com