According to the U.S. Food and Drug Administration (FDA), there are more than 30 million people living with a rare disease in the country, around half of whom are children. An analysis by Allucent indicated that in 2025, rare disease studies accounted for more than a quarter of clinical trial activity
Ten years ago, it would have been fair to assume that most of these studies took place in a conventional setting, with patients attending a clinical research site for all visits and assessments. The burdens associated with this model—travelling hundreds of miles, taking time off work, and, for families, repeatedly moving a seriously ill or disabled child—can be significant
Nowadays, many rare disease trials incorporate decentralized elements, allowing patients to participate either from home or closer to where they live
“Decentralized approaches are delivering value across many therapeutic areas, but in rare disease, the return can be particularly significant,” said Missy Taylor, vice president of global clinical operations at Veristat. “Small, geographically dispersed patient populations make access a critical challenge, and patient-centric trial models can help ensure that eligible patients can participate.”
To put it differently, instead of perceiving rare diseases as being particularly suited to decentralization, it is likely that much of rare disease research may not be possible without decentralization
“I think that plays a part in why we have not had many rare disease drug approvals in the past,” said Pamela Tenaerts, MD, CMO at Medable. “In some ways, it was just not possible to do the research.”
Evolution, not revolution
The concept of moving research activities away from the traditional trial site is not new. Tenaerts points out that using local laboratories, local physicians, eConsent, and electronic data collection in trials all predate the current decentralized clinical trial (DCT) terminology
“A lot of this has been converging and taken under this umbrella of DCT, but it’s not all new,” she said. “It has been evolutionary rather than revolutionary.”
That said, the COVID-19 pandemic rapidly accelerated remote trial deployment with the use of digital technologies, but these were implemented through necessity rather than by choice
“When companies aggressively implemented decentralized approaches during the pandemic, it was a stopgap measure,” said Craig Lipset, co-chair of the Digital Trials and Research Alliance. “Those were not fully baked solutions that were meant to sustain and scale in an organization. Coming out of the pandemic, a lot of companies had to retreat [from DCTs] a bit and regroup.”
Post-pandemic, researchers are increasingly considering which DCT elements are appropriate for a particular study and the outcome they want to achieve
“We’ve gotten past the assumption that this is an all or nothing,” said Lipset
A trial may use eConsent, electronic clinical outcome assessments (eCOA), home nursing, telehealth, wearables, mobile research units, or direct-to-patient shipments without becoming fully virtual
Building the evidence base
However, understanding the impact of these individual elements on trial success rates remains difficult. “Unfortunately, we still are running largely on anecdote,” said Lipset
There are individual studies showing how DCTs can boost enrollment, diversity, and other outcomes, but sponsors have not consistently tracked which decentralized elements have been used in which trials
One initiative attempting to address this evidence gap is the Partnership for Advancing Clinical Trials (PACT) Consortium
The consortium was established following work by Tufts University researchers, in collaboration with Medable, that examined the financial value of decentralized methods. Although the calculations suggested that DCTs offer substantial value, it was difficult to establish which decentralized elements were responsible
PACT now includes more than 30 biopharmaceutical organizations that work together to gather data on the impact of DCT solutions on clinical trial performance
One of the consortium’s recent outputs is the DCT Element Impact Matrix (see table). It assesses 13 DCT features against a range of clinical trial performance measures like patient satisfaction and retention
One of the strongest signals in the PACT data is patient satisfaction, with 10 of the 13 elements rated as having a high impact
“In almost every area … patient satisfaction is the highest,” said Tenaerts. “It’s clearly something that patients really appreciate.”
Although the matrix reflects a move away from viewing complete decentralization as the only alternative to standard trials, the data is based on a small sample size and should be considered an early signal, cautioned Lipset
The “holy grail” of patient choice
Patient insight is also important. “It’s now common for most major drug developers to include input from patients when they’re planning and designing their studies,” said Lipset
He described meaningful choice as the “holy grail” for clinical trials: giving patients flexibility based on where they are in their patient journeys and their lives
For example, a patient concerned that they have experienced an adverse event may actively want to attend a specialist research center. For those able to reach a site, Lipset noted, the experience is often overwhelmingly positive
“But that’s not the issue,” he said. “The issue is who can actually get to the site to have that experience.”
On the other hand, Taylor pointed out that not everyone wants <a href="https://healthylife7.com/okla-hospitals-seek-funding-to-strengthen-rural-ems-healthcare/” title=”Okla. hospitals seek funding to strengthen rural EMS, healthcare”>healthcare workers visiting their homes to carry out assessments. “I think that’s where I’m seeing things evolve, the choice,” she said
Meaningful choice therefore needs to be built into trial design rather than added after a study is underway, but existing clinical research systems are not always set up to manage the host of options patients may like
In a truly flexible trial, Lipset said, “some patients may opt for visit five in the clinic, and some may opt for visit five to happen at home or by video. I don’t think we are ready for that type of flexibility yet, but the patients are.”
When burden shifts
Even so, moving an activity into a patient’s home does not automatically remove the burden associated with it
“Burden in trials is like matter and energy; it never goes away, it just takes on different forms,” said Lipset. “Burden doesn’t magically vaporize if we decentralize—burden shifts, and we can’t let burden shift from the site to the patient.”
Apps, passwords, Bluetooth pairing, charging wearables, electronic patient-reported outcomes reminders, home sampling kits, courier collections, and nursing schedules can all create new tasks. For families dealing with rare diseases and already coordinating complex care, a DCT risks becoming another management responsibility
Creating a “digital divide” is also a risk. Many older patients and those from marginalized populations may not have the digital literacy needed to manage DCT tools. But Lipset stressed that “DCTs done right should not leave people behind.”
The ability to collect data remotely can also encourage researchers to collect more of it, but “just because you can doesn’t mean that you should,” said Tenaerts. She argued that trials should be approached through a “data minimization lens” to avoid pushing excessive collection onto participants. They should only collect what is required to answer the scientific question, address errors that matter, and protect participants
Managing complexity with AI
Behind the scenes, the management of DCTs is complex, with elements of training vendors like home healthcare providers (HCPs), labs, and logistics, and coordination with regulatory standards. Various computer-based systems are also needed to manage the different types of digital data collected
To address this complexity, Medable has built an agentic artificial intelligence (AI) platform that connects clinical systems, data, and workflows. Unlike generative AI, which responds to a prompt, an AI agent can operate within an authorized workflow, review connected information, identify a potential issue, and help initiate the next action
Tenaerts gave the example of an agent identifying a new medication recorded in an electronic data capture system but finding no corresponding adverse event, which she said would be unusual. The system could flag the discrepancy and prepare a query for review
“Normally the human would have [to] make all those connections, but now a system can connect these,” she said. Importantly, the processes are carried out with human oversight and compliance with regulatory systems
For rare disease research, the potential is significant. Small patient populations can still generate highly complex, heterogeneous, and longitudinal data. AI agents may help absorb some of the operational burden generated by increasingly distributed trials
Natural history from a distance
Although DCTs have some challenges, support from patients is overwhelmingly positive. In the Center for Information and Study on Clinical Research Participation’s 2023 Perceptions & Insight Study, 80% of 12,017 participants said they were either somewhat or very willing to participate in a fully remote clinical trial. For a mobile nurse model, this figure was 81%, and for a hybrid model, it was 86%. In addition, 66% of respondents said that the ability to complete study visits closer to home, such as at a local laboratory, was one of the most important factors for keeping someone enrolled during a three-to five-year follow-up period.
Retaining patients for extended periods can be particularly important for rare diseases, for which natural history studies are needed to understand how a condition progresses over time
“When we’re thinking about natural history studies, in many cases they are inherently decentralized opportunities,” said Lipset
Patients may provide access to electronic health records and self-captured data remotely, allowing registry-based natural history studies to collect information from geographically dispersed patients. This can make studies more affordable and scalable for patient groups and smaller sponsors
One example of decentralization being used to build longitudinal information comes from a non-interventional pediatric neurological natural history study described by Taylor. The study involved seriously ill children and a small number of sites in the U.S. and Germany, creating a significant travel burden for families
“We shifted it from a standard, traditional site-based [study] into remote with virtual assessments, and then really focused on minimizing the travel,” she said
Caregivers were guided through neurological and motor assessments traditional in-person assessments to validate the remote approach
“That really served as the pilot test for the decentralized capabilities,” said Taylor
The approach was subsequently incorporated into a Phase I/II pediatric Canavan disease gene therapy study involving four U.S. sites and targeting 26 participants. The trial uses eConsent and virtual DCT tools, with follow-up continuing to 2032
THREAD Research has also applied decentralized approaches to natural history studies through its work with Parent Project Muscular Dystrophy on The Duchenne Registry. The mobile platform incorporates eConsent, eCOA, surveys, and decentralized research tools, allowing data to be collected remotely from patients and caregivers. According to THREAD, in the first year of the mobile app, the Registry collected nearly 50% more surveys than in previous years and additional data from more than 1,000 registrants worldwide. The platform also supported recruitment for 12 clinical trials.
Bridging care and research
While decentralized approaches can bring research closer to patients, the HCPs already involved in their day-to-day care have traditionally remained outside the clinical trial infrastructure. New regulatory guidance, however, points to a potentially greater role for local HCPs in supporting trial-related activities
“We’re starting to see the description of a new role in clinical trials of a healthcare provider who is not an investigator and not a sub-investigator,” said Lipset
The FDA’s guidance on clinical trials with decentralized elements specifically describes HCPs who perform trial-related activities but are not trial personnel. For rare disease patients, this could create a clearer role for local physicians and nurses who are already involved in their care while the specialist investigator is possibly based hundreds of miles away
“Healthcare providers are becoming increasingly important in our model … bridging the remote activities and the clinical oversight,” she said
The role of local HCPs is another indication that decentralization is becoming less about recreating the clinical trial site in a patient’s home and more about building trials around the existing lives and care pathways of participants
“We do this for the patients, right?” said Taylor. “I mean, the patients matter.”
For rare disease, the potential to widen access, reduce travel, and support longer-term participation is difficult to ignore. However, decentralization “is not a silver bullet for recruitment,” cautioned Lipset. “We still have to make patients aware of trials. [Decentralization] makes it easier for them to find a pathway to say yes, but it doesn’t add them to the top of the funnel.”
Nor is there a single decentralized model that will work for every disease, study, or patient population. Instead, the future may lie in applying the same principles of precision that increasingly underpin drug development to the design of clinical trials themselves
“Precision medicine needs to apply to the clinical trial methodologies as well,” said Tenaerts
For rare disease research, this means considering which decentralized elements are appropriate for a particular study, where individual activities should take place, and how much data is needed to answer the research question. Above all, it means designing trials that give patients a realistic pathway for participation
Laura Cowen is a freelance medical journalist who has been covering healthcare news
for over 10 years. Her main specialties are oncology and diabetes, but she has written
about subjects ranging from cardiology to ophthalmology and is particularly interested
in infectious diseases and public health
News & FeaturesArtificial intelligenceRare diseasesTreatment outcomeUnited States Food and Drug Administration
