Clinical trials have traditionally relied on efficacy outcomes measured in the clinic, such as mobility tests and clinician assessments of disease activity. But researchers are now devising digital endpoints to remotely collect data in real time, offering a more complete picture of a patient’s health.
Digital endpoints refer to clinical outcomes gathered outside of the clinical setting, usually through devices like wearable sensors. These can range from mobility measures for patients with amyotrophic lateral sclerosis (ALS) to smartphone-based cough detection for children with asthma.
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Despite the high potential of digital endpoints, their uptake remains relatively low among most major pharma players, explains Adam Cohen, PhD, a clinical pharmacologist researching digital endpoints at Leiden University, Netherlands. Complex regulatory barriers and inadequate funding pose significant implementation challenges.
“The opportunities for digital endpoints are enormous,” Cohen says. “Unfortunately, the barriers are almost greater.”
Measuring mobility
In the central nervous system (CNS) disease space, there is a growing emphasis on using activity trackers to measure patients’ real-world mobility, explains Dr. Laurent Servais, a neuroscientist at the University of Oxford. Activity trackers, such as wearable sensors and pedometers, can better capture the daily impact of disease than many traditional outcomes in clinical trials.
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The actual development of a digital endpoint, however, can take up to five years, and many trial sponsors are reluctant to adopt novel approaches, Servais says. Over the past decade, the uptake of activity trackers in CNS clinical trials has only slowly increased, according to GlobalData’s Clinical Trials Database.
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By GlobalDataRegulators have shown slightly more willingness to accept digital endpoints, which could spur increased uptake in the coming years. Servais successfully developed the digital endpoint Stride Velocity 95th Centile (SV956), which received EMA approval as a secondary endpoint for trials of Duchenne muscular dystrophy in 2019.
SV956 uses a wearable device to measure the speed of the fastest strides taken over a period of 180 hours. Meanwhile, most trials for Duchenne muscular dystrophy currently use the outcome 6-Minute Walk Test (6MWT), which measures the distance a patient can cover in six minutes in a clinical setting.
Uncontrollable factors, such as fatigue from travelling to the clinic, could influence how a patient performs in the 6MWT. A digital endpoint like SV956, however, could better capture a patient’s mobility in their daily lives by measuring data over a longer time period in a real-world setting.
Digital endpoints like 9V956 are still mostly relegated to secondary or exploratory outcomes in trials. “There’s not enough confidence to use digital endpoints as primary outcomes in pivotal studies, but that confidence could come with experience,” Servais says.
Overcoming regulatory barriers
Most patients support digital endpoints as a tool for better capturing and monitoring their own health, explains Dr. Ruben van Eijk, a biostatistician at University Medical Center Utrecht, Netherlands. However, digital endpoints still face significant delays and even resistance from regulatory bodies. “Until digital endpoints are accepted by regulators, I think the uptake will always remain low,” van Eijk says.
For example, van Eijk worked with a pharma company to incorporate a device that assesses lung function into clinical trials, both remotely and in the clinic. Although European regulators supported using the device during site visits, they would not accept data recorded remotely. Regulators said they could not guarantee that the patient—and not a family member or caregiver—was blowing into the device.
Digital endpoint researchers need to show regulators that data collected with devices outside of the clinic and inside of the clinic have a high correlation without systemic biases, van Eijk says.
Unfortunately, regulators in the US and Europe have key operational differences that can complicate the approval process. The EMA asks researchers to collect significant data before beginning discussions, while the FDA focuses on establishing a process for data collection first. As a result, researchers working with the FDA risk collecting different data than what regulators are seeking, Servais explains.
In either case, Servais and van Eijk agree that early data collection is key to developing a successful digital endpoint. This is particularly true for Servais’s own experience with SV95C in Duchenne muscular dystrophy. “If we had more money or could do it again, we would have invested more money and time into data collection,” he says.
Pharma investment falters
To increase the uptake of digital endpoints, pharma will have to invest more resources into including these novel outcomes in late-stage trials, Cohen explains. Currently, pharma pours huge sums of funding into running clinical trials, while comparatively little funding goes into validating clinical endpoints. Additionally, CROs that implement clinical trials are heavily driven by precedence, making the pharma industry as a whole conservative in adopting changes.
In the past decade, pharma companies sponsored fewer than one-third of all Phase II and Phase III trials using activity monitors, according to GlobalData’s Clinical Trials Database. Meanwhile, institutions such as academic research centers and government organizations accounted for the majority of trial activity.
What's next for digital endpoints?
Going forward, it is also unclear what role artificial intelligence (AI) will play in analyzing data from digital endpoints. Many pharma companies are already investing in digital biomarkers, which could use AI to analyze granular data on measures such as disease progression and drug response.
However, according to Servais, AI may not play a major role in the future of digital endpoints. Regulatory bodies like the FDA make it clear that any outcome measures used in registrational clinical trials must be anchored to a patient’s perspective, he explains. “If an endpoint is based on an AI algorithm, good luck convincing regulators that it is clinically significant for patients,” Servais says.
Still, despite many uncertainties and implementation barriers, experts say the number of validated digital endpoints is likely to jump in the coming years. “New endpoints introduced in the space today are the consequence of decisions made five years ago,” Servais says. “I expect that the number of digital outcomes in use will dramatically increase over the next two years.”
