How decentralized trials accelerate rare disease research
By Jena Daniels
Director of Research
Medable
David Fajgenbaum’s life changed forever one summer day in 2010. After experiencing fatigue, his liver, kidneys, bone marrow, heart, and lungs suddenly began to shut down. He was admitted to the intensive care unit where doctors found that he had a retinal hemorrhage that left him blind in his left eye. David drifted in and out of consciousness, was put on a feeding tube, and received blood transfusions. In weeks, the 26-year-old medical student sharply deteriorated and was given last rites.
David was diagnosed with a multi-centric form of Castleman disease (CD), a rare disorder where the immune system attacks and shuts down the body’s vital organs. Like most rare diseases, CD does not discriminate and can occur in people of all ages, genders, races, and ethnicities. After months of hospitalization, David miraculously recovered and returned to medical school. He was prescribed an experimental drug called cetuximab, the first drug to ever undergo a randomized controlled trial for CD – and the only drug in development for a disease that was identified nearly 60 years prior. His prognosis, though, remained unclear.
In the United States, between 6,500 and 7,500 new CD cases are diagnosed each year, compared with 220,000 new cases of lung cancer. Consequently, little research has been done for CD. At the time of David’s first episode, no diagnostic criteria, treatment guidelines, or FDA-approved treatments existed. Worse, no research infrastructure was in place to find a cure; no registries or biobanks, no federal funding, and no collaborative research network to advance understanding.
The story is the same for most rare diseases, even today with scientific advancements that cure cancer. Collectively, 300 to 400 million patients suffer from nearly 7,000 different rare diseases. Currently, 95 percent of rare diseases do not have a single FDA-approved drug treatment, which means more than 30 million people in the United States have few to no options. Many reasons exist for the lack of rare disease research – small patient populations, heterogeneous disease characteristics, lack of scientific knowledge, and absence of historical data – but one of the biggest hurdles is today’s clinical trial model that makes it difficult to recruit enough patients to generate statistically meaningful results.
“In rare disease, it’s difficult to reach a representative sample of patients simply because patients are few and far between … literally. One of the trials that responded to me was based in Belgium, which was simply impractical,” says Alycia James, a healthcare consultant based in Wilmington, N.C., living with myasthenia gravis, a rare neuromuscular disease. “If we could use digital tools to connect to the site without physical visits, more patients could participate in more trials. And the technology is here.”
Indeed, the technologies needed to improve patient access and experiences are here now. The smart application of those technologies can overcome barriers to trial execution and improve data sharing and process efficiency across organizations conducting rare disease research. And, most urgently, those technologies can also be used immediately to ensure progress for thousands of clinical trials during the current COVID-19 pandemic when patients are expected to stay at home.
The need is grave, the technology is here
At a recent congressional hearing, NIAID Director Anthony Fauci, M.D., gave a frank assessment about the shortcomings of the U.S. system for coronavirus testing: It’s “not really geared to what we need right now.”
The same can be said for our traditional clinical trial model. Limiting trials to a handful of physical sites inherently limits patient access, especially those with rare diseases – more than 50 percent of whom are children who depend on their caretakers. Further, limiting interaction to in-person visits is not only grossly inefficient, but it also limits data frequency and quality. And, during a crisis like the COVID-19 pandemic, it’s simply infeasible.
By contrast, decentralized clinical trials are more compelling than ever – and ideal for exactly this type of emergency situation. While some trials are good candidates for a fully decentralized model, others can be managed as a hybrid. Patients can be recruited and consented remotely. Likewise, physician visits can be conducted remotely via telemedicine and data can be captured remotely (and frequently) via medical devices and mobile technology.
The Clinical Trials Transformation Initiative (CTTI) defines decentralized trials as trials executed through telemedicine and mobile/local healthcare providers, using procedures that vary from the traditional clinical trial model. In simplest terms, the trial is conducted remotely so the patient remains at home. These studies often require wearable sensors and mobile health applications that allow the collection of important physiologic data such as respiratory rate, heart rate, temperature, and blood pressure.
For example, a new mobile application called Trial-Fit TeleVisit allows patients worldwide to connect virtually with clinical trial sites. The application enables the following:
• Patient consent for the use of telemedicine in their native language;
• Real-time video capabilities on a single platform that is 21 CFR, Part 11 compliant; and,
• Virtual connections for patients with their site coordinators, investigators, or other care professionals from anywhere in the world.
The industry has been considering decentralized trials for years. Now, as health authorities worldwide struggle to contain the COVID-19 outbreak, there is a renewed push to rapidly implement remote healthcare delivery capabilities. Decentralizing trials has become critical to continue to deliver high-quality healthcare to research participants, while also progressing clinical drug development programs to find treatments for rare and other diseases.
Decentralized benefits to rare disease research
More than 55,000 interventional clinical trials are actively enrolling and providing care for participants worldwide, but only about 3 percent of potentially eligible patients enroll. For many, low enrollment is due to a lack of awareness – this is especially true for rare disease trials. For others, low enrollment is caused by lack of access. Decentralized trials open the door for participation to a much broader audience so that a trial being conducted in Belgium now becomes feasible for rare disease patients like Alycia James living far from that country. Decentralized and hybrid trials increase enrollment and enable greater patient representation that is missing in many rare disease studies.
For instance, direct-to-patient decentralized trial technology allowed one mid-sized pharmaceutical company to not only conduct reverse feasibility for site selection, reducing the projected number of sites from 100 to 25, but also saved the company more than $20M in study-related costs. The study needed to pre-screen more than 11,000 patients with a rare genetic variant that only affects roughly 2 percent of the population. By utilizing decentralized solutions, patient enrollment increased two-fold – in half the time – and reached underrepresented populations, improved patient data capture, decreased patient and site burden, and enabled real-time data capture.
Another benefit of decentralized trials is that they provide more and higher quality data, as noted in the previous example. Trial participants that track progress using a diary or recounting specific events that are pertinent to the trial at their next office visit create retrospective bias and inaccurate data capture. Decentralized trials enable patient reporting in real time for increased accuracy. For example, if the patient had an adverse event like a headache, she can capture the event at that specific moment while experiencing it. Patients can also capture a broader set of contextual data, such as their location when they had the episode or whether they were sleep deprived, hungry, et cetera, with digital tools. Researchers can use the contextual data to better understand the triggers around the adverse event.
An additional advantage for rare disease research is the ability to continuously collect data about a treatment over time – this is particularly important with rare disease research since so little is known about its various forms, like David’s CD. Remote technologies like wearable devices, in conjunction with mobile health applications, can track symptoms without pause.
“Many rare disease patients have good days and bad days, and it’s often unpredictable. Many of the treatments, too, take months to work,” explains James. “Digital technologies can automatically track and measure the impact of an experimental treatment over time as patients may not realize results right away. I have to actively think what my physical abilities were two months ago to realize whether I’m seeing any benefit from a new medication because improvement occurs so subtly and gradually.”
Untether from the past for a brighter future
Decentralized trials expand and accelerate the industry’s ability to conduct research by untethering it from physical sites. This is critical today as people around the world are being told to stay home due to the COVID-19 pandemic while trials need to continue without the risk of pathogen exposure. Yet, this model is just as critical for future rare disease research that involves small patient populations far-flung around the globe and enabling research continuity in the inevitable event of future pandemics.
Shifting to decentralized trials will require changes to study design or regulatory approvals and other important considerations will arise regarding data collection – there’s no “One size fits all” solution. However, if there is a silver lining to the recent pandemic, it’s the opening of our collective eyes to the great potential for better clinical trial execution with decentralized trial technologies. While that’s no small task, it’s an urgent one for many clinical trial leaders right now.
With all of this in mind, an immediate opportunity is at hand for decentralized and hybrid trials to help us through these challenging times, using digital and mobile technologies to improve patient access, experience, and outcomes. Let’s work together as a community to drive forward faster, whether it’s streamlining trials for COVID-19 vaccines, reducing timelines for other therapies, or initiating new trials to address rare diseases.
Fortunately, a large number of new development programs for drugs targeting a wide range of rare diseases are in process. According to a 2019 Tufts University study, rare disease drug development is one of the fastest-growing areas in research and development, accounting for as much as one-third of products in the pipeline. BIO also reports that almost every pharmaceutical company has, or is opening, a rare disease division. The path to overcoming the anticipated research hurdles runs through new remote and digital technologies.
David Fajgenbaum, tenuously stable, understands this better than most. After graduating from medical school, he embarked on a mission to find a cure – knowing that his symptoms could return at a moment’s notice. He established the Castleman Disease Collaborative Network (CDCN) and his volunteer army has taken back momentum in the war against the disease. The CDCN is using technology and other resources to crowdsource the most promising research questions and recruit world-class researchers to tackle them.
Decentralized trials are no longer a nice-to-have. Reducing trial timelines has to be a long-term industry imperative, and digital technology can help valuable research continue to move forward while keeping participants safe. Let’s start now, and let’s move faster together.
If you want to join this effort, please contact [email protected] or reach out to anyone on the Medable team at www.medable.com. We’re working closely with regulators, pharma sponsors, biotech sponsors, clinical research organizations and other tech companies worldwide in an effort to mobilize and accelerate decentralized trial adoption.
About the author
As director of research at Medable and part of the Digital Science Team, Jena Daniels addresses persistent problems, disconnects in care, and disparities in various therapeutic areas through collaborative projects that use innovative methods to connect patients, clinical teams, patients, and caregivers. In 2019, Daniels co-established Medable’s Patient Advisory Council, which engages and empowers patient advocates to assist product development and research teams to develop meaningful, actionable, and patient-focused solutions. Daniels is responsible for completing milestones for Medable’s NIH NCI SBIR awards and assists in developing strategic partnerships. Prior to joining Medable, Daniels was a clinical research manager at Harvard Medical School and Stanford University School of Medicine. Daniels can be reached at [email protected].
