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Rare Disease Clinical Research Trials

Understanding Rare Diseases

There are more than 7,000 distinct and identifiable rare and orphan diseases affecting up to 400 million people worldwide. More “common” rare diseases are likely to be well known, including cystic fibrosis or hemophilia, whereas ultra-rare diseases (those the EU considers to be less than 1 in 50,000) will be less well known. Due to advances in genomics, there are around 250 new rare diseases being identified annually, most likely with only a few individuals or families affected worldwide. Rare disorders 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 - 80%), 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, as examples. While this category of diseases is often referred to collectively, rare diseases span across all therapeutic areas and often affect multiple organs. Even for those that study rare diseases, understanding causes, impacts and how to gather data through clinical studies is often challenging.

Why Should We Study Rare Diseases?

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. This is, in part, due to the lack of natural history data and disease-appropriate clinical endpoints, as well as an inherently limited number of patients. 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 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 and their families.

Patients in the rare disease population face more barriers in terms of access to medical research studies and ongoing care than patients with more common diseases. Rare disease patients and their families consistently report care inadequacies, such as diagnostic delays (it can take on average 4-5 years and visiting multiple specialists to get a diagnosis) and lack of disease knowledge amongst primary care physicians. Traditionally, clinical trials for rare diseases haven’t favored the rare disease community for a host of reasons, travel, limited study sites, trial burden and fewer research trials among them. Because there are fewer clinical trials in individual rare diseases, sites participating in rare disease trials are often clinical research naïve and thus may need additional support to navigate good clinical practice (GCP), new technologies and the regulatory environment. Even given these challenges, drug development for rare diseases is paramount for those affected, their families and scientific advancement in general. According to the NIH, investigating the underlying mechanism for rare and undiagnosed diseases can yield some of the most interesting scientific discoveries and studying the role of a gene(s) in a rare or undiagnosed disease can help our understanding of related common diseases.

Spotlight on Rare Disease Research for Children

Up to 80% of rare diseases are genetic in origin, and 70%, of those, have exclusive pediatric onset which means that rare disease disproportionately affect children - 50% of rare disease patients are children. Pediatric and adolescent clinical trials are therefore critically important for this patient population and the biopharmaceutical industry. However, research trials for children with rare diseases also come with increased challenges given that they affect the entire family’s day-to-day routine. Children's clinical trials, while often the only healthcare option available, can also create a significant burden for the whole family. Travel alone can be significant and tiring and 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 and appointment coordinator and primary advocates for their children’s health. Often a clinical study is the only healthcare option available for children with rare diseases so ensuring they are designed with patient and family needs in mind is critical.

Rare & Orphan Disease Drug Development

Rare disease drug research development often follows a different path compared to conventional drugs. A variety of factors contribute to this including the rarity of patients, severity of rare diseases, ethical considerations, regulatory landscape and new modalities of drugs in development:

  • Natural History studies can be an important first step to support a better understanding of the disease. These can also positively impact the design of clinical studies and, when well-designed, the data can contribute to the marketing authorization submissions.
  • Rare disease clinical research studies are often followed by open-label extension studies allowing patients to continue the drug for an extended period and, in some instances, up until market authorization. This both positively impacts the ability to recruit patients and also allows for sponsors to collect additional data points that can support their marketing authorization applications.
  • Long-term follow-up for regenerative medicines can continue for many years following initial treatment and can extend long beyond the timeframe patients would normally be engaged with the participating site.

According to experts from the US FDA, new approaches in current clinical trials may offer valuable solutions to overcome hurdles seen in traditionally designed studies, streamlining both clinical studies and regulatory processes to bring much-needed treatments to the market more quickly. By appropriately deploying a variety of decentralized approaches, patient engagement can be maintained via telehealth and rigorous data collection can continue remotely via eCOA, ePRO or devices and sensors.

Common Challenges in Rare Disease Clinical Trials

Rare disease studies are complex and participation is often difficult for patients and their families. Challenges are numerous but those below constitute the major 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 long distances, sometimes across borders, for study visits.
  • Time: Even if they can reach clinics, participation can be long and tiring. Participants must adhere to strict visit schedules over the treatment period – anywhere from six months to many years. Each visit requires 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, which in turn, increases the difficulty for sponsors seeking to conduct rare disease studies.

Is There A Study Design That Can Best Support Rare Disease Research?

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 and 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 and remote-access technologies.

Decentralized Approaches for Rare Disease Trials

The Rare Disease research community is beginning to understand the potential of a decentralized approach for the populations they serve. The shift to remote and hybrid studies is helping sponsors and sites capture rare disease patient data remotely during, between and in lieu of in-clinic visits. Many rare diseases tend to be severe and life-threatening. Clinical oversight for these patients is critical so these studies are likely to contain elements of both on-site and remote visits. Such approaches maintain the value of site-based clinical visits while using DCT to improve the participant experience. This approach eliminates the need for some clinical visits by capturing data remotely while providing purpose-built channels for remote engagement and communications between patients and the site team.

There are many benefits of hybrid trials and decentralized trials for both researchers and people with rare diseases. With the use of digital platforms and supporting processes, virtual clinical trials can move many aspects of clinical trial participation from the traditional research site to a remote location, which opens up engagement possibilities for patients with rare diseases. The ability to implement remote clinical trials 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.

DCT and hybrid study designs features support rare disease trials in a number of ways:

  • eConsent can support a robust consenting process, improve trial data quality and mitigate audit risks.
  • Telehealth, or telemedicine, allows for remote visits between patients and clinicians. They allow for both scheduled and ad hoc meetings and provide a necessary connection for rare disease patients and the physicians they trust. While some in-person visits will be necessary, many conversations done via telemedicine are sufficient and allow patients to remain in their homes. Further, telehealth 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) are validated outcome assessments and can be conducted by clinicians (eClinRo), by patients (ePRO), or caregivers/ observers (eObsRO). The majority of these assessments can be done remotely either through dedicated smart device applications in combination with telehealth or home health visits. Rare disease studies tend to be complex with many assessments partly due to the lack of well-established clinical endpoints and thus having the ability to do some of the assessments remotely is beneficial for all. ePROs can be of particular importance in rare disease studies and together with other assessments provide data that give site teams insight into the patient’s condition and progress.
  • eDiaries and patient surveys similar to eCOA 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 sites to identify issues or challenges quickly and act on them to keep patients safe and on track.
  • Wearables, sensors and mobile medical devices (e.g. blood pressure monitors, ECG, airflow cytometers, spirometers, 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 or is it suitable for 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 are able to send dosing or activity reminders to patients; schedule either telehealth or in-clinic visits; facilitate eConsent/eAssent; support eCOA/ePRO, diary or survey submissions; and allow on-demand outreach by a patient to the study team – or vice versa.

Increasing Participation in Rare Disease Clinical Trials

Rare diseases, inherently, mean that the pool of potential study candidates will be small which causes challenges to recruitment, as does the fact that these participants are often managing debilitating conditions. A recent study revealed that approximately 25% of all rare disease trials terminate due to insufficient recruitment. All of this increases pressure on the site and study team to keep enrolled participants engaged and to try to minimize dropouts. Decentralized and hybrid studies have the potential to recruit patients via digital channels from a broad geography, maintain engagement throughout the study and thus minimize the potential for drop-out. DCT models increase opportunities for participant communication and connection, supporting protocol adherence and patient retention.

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 life-cycle. They can support patient insights to ensure drugs and protocols are developed with patients in mind. Engaging advocacy groups and patients also opens up the possibility of recruiting patients through advocacy groups and other digital means. These 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 be directed to a participating site. Thus patient engagement can help get patient insights, find qualified candidates and help support them through the trial.

Increasing participation in rare disease research also extends to clinical trial sites. Fewer rare disease studies compared to common diseases means there are fewer sites with extensive clinical expertise. Clinical research naive sites 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. Options like remote data collection provide frequent updates on patients that sites can monitor in near real-time. This allows them to make informed decisions and to support patients in a timely fashion.

Best Practices for Rare Disease Trial Success

Rare disease clinical trials are complex and the potential pool of study candidates and trial sites is small. By reducing the burden for rare disease study participants and giving sites the tools they need to manage these complicated studies, DCTs can facilitate better study experiences and more successful rare disease trials. Designing a study with decentralized elements needs to begin early. Clinical endpoints need to be explored 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. DCT approaches can help by allowing for remote data collection and streamlining processes for sites. The ability to set up an automated process in a platform can significantly decrease rare disease study time both on the initial study set up and throughout trial execution. Automated processes decrease human error, lessen process time and capture aligned data more efficiently and accurately. Looking forward, while DCTs are expected to increase across all therapeutic areas, rare disease is one of the areas poised to lead that growth.

THREAD helps biopharma and life science organizations capture data from participants and sites remotely during, between, and in lieu of in-clinic visits. The company’s mission seeks to make trials five times more inclusive and 30% more efficient through one comprehensive technology platform. Driven by this mission, THREAD has become a reliable global partner for an industry looking to help people with rare diseases.