When Christina Brennan initially planned a clinical trial to test the use of famotidine for treating mild COVID-19, she wrote a protocol that involved participants occasionally coming in for lab work at an internal medicine clinic. Enrollment in trials run by Brennan and her colleagues on hospitalized COVID-19 patients was waning following last spring’s surge, so she’d shifted her focus to studying COVID-19 patients who were fighting the disease at home. But in speaking with the clinic’s doctors last summer, she learned that patients who had tested positive for SARS-CoV-2 would not be allowed in the clinic of the nonprofit provider Northwell Health, New York’s largest healthcare system.
“This gave us pause,” says Brennan, the vice president of clinical research at Feinstein Institutes for Medical Research, Northwell’s research arm. After hearing stories from patients who had experienced COVID-19 and told her how exhausting the illness was, she also realized that patients might appreciate not having to travel, not to mention the fact that many “patients were fearful to come back in,” Brennan says. “All in all, we thought the best decision [was to do the trial] in the comfort of a patient’s home—that we could do this fully remote.”
Brennan, her Northwell colleagues, and their Cold Spring Harbor Laboratory collaborators rewrote the protocol for the new trial of famotidine—a drug sold under the brand name Pepcid for treating stomach ulcers, acid reflux, and heartburn—and started lining up what was needed to switch to a remote setup. “The pandemic was forcing all of this to be at rapid speed,” Brennan recalls.
Her team is far from alone. Although researchers had begun exploring the use of modern technology to move certain trials partially or entirely out of the clinic long before the pandemic hit, the lockdowns enforced in the face of COVID-19 threw many trial investigators into the deep end. In 2020, 76 percent of more than 200 clinical trial sponsors said they conducted most or all of their patient monitoring remotely, up from only 18 percent of respondents the previous year, according to the 2021 State of the Industry Report from Florence Healthcare. And in a survey conducted by Oracle Health Sciences of more than 250 professionals at biopharma and medical device companies as well as contract research organizations, 76 percent of respondents said that the pandemic had accelerated their adoption of methods for remotely conducting clinical trials.
As we move out of the pandemic, we hope that this becomes a new normal.—Richard Moscicki, Pharmaceutical Research and
Manufacturers of America
“Sponsors had to scramble” to find other ways to continue ongoing trials and begin new ones, says Richard Moscicki, executive vice president of science and regulatory advocacy and the chief medical officer at the Pharmaceutical Research and Manufacturers of America (PhRMA). “We had a generation of new medicine at risk for patients around the world with the pandemic. We’re lucky we could adapt and the tools were available.” Clinical researchers embraced the digital age and treaded water. Now, they’re learning to swim.
Even after the immediate threat of COVID-19 has passed, remote trials—often called virtual or decentralized trials—are here to stay, predict experts who spoke with The Scientist. And even those that aren’t entirely remote will likely maintain some virtual components, they say. While there are regulatory and logistical hurdles to overcome, remote approaches offer sponsors and investigators numerous advantages, from efficiency and cost effectiveness to improved patient compliance and datasets that capture a broader population. And perhaps most importantly, they help reduce the burden for taking part, moving toward a more patient-focused approach—a trend that has been called a “democratization of clinical trials.”
“One important piece I take away is patient centricity,” says Brennan. “We’re able to bring the trial to the patient.”
Modern technology helps clinicians collect data from afar
Participants in Brennan’s COVID-19 famotidine trial, which started in mid-January this year, are gifted an iPad for filling out daily questionnaires, and Bluetooth-enabled technology for recording their own vitals. These gadgets include a pulse oximeter to measure oxygen saturation in the blood, a scale, a thermometer, and a spirometer to measure breathing. On four separate occasions over the course of a month, a phlebotomist comes to the patients’ homes to draw blood and take nasal swabs for COVID-19 testing.
Harvard Medical School’s JoAnn Manson, chief of the Division of Preventive Health at Brigham and Women’s Hospital, turned to similar technologies when she and her colleagues launched an entirely remote study testing vitamin D for treating COVID-19 and preventing transmission. The trial includes a mix of COVID-19–positive people and their household members, and officially launched last fall. For blood samples, the team chose a more socially distanced option than Brennan’s team did: shipping out the materials for participants to prick a finger and dot the blood drop onto filter paper to be mailed back. “Doing a trial remotely doesn’t even preclude having blood sampling,” Manson says.
Among the advantages of remote setups is high patient compliance, says Brennan. “Sometimes compliance [in a traditional study] drops off as the years of the trial goes on,” she says, but in her most recent trial, she says that all patients have sent the data that investigators have requested and have agreed to the schedule of at-home blood draws. “We have nearly 100 percent compliance.”
Scott Weidley, CEO of ClinCapture, a California-based company that sells virtual data collection software, adds that remote monitoring of participants allows investigators to “collect data in real time, and over extended time, in ways you can’t do in the clinic.” In fact, he argues, it’s perhaps the most likely part of the clinical trial process to remain virtual after the threat of COVID-19 is no longer forcing the issue. “You could make the argument it’s superior to deliver the treatment in some cases on site, but I think there’s a very strong argument that collecting the data actually has many advantages remote.”
One of the other big advantages of going virtual, experts agree, is that it allows clinical trial investigators to broaden their reach. For Brennan and her colleagues, that meant opening up enrollment in their famotidine trial to COVID-19 patients throughout the New York metropolitan area, rather than restricting it to patients who could easily get to Long Island. In Manson’s study of vitamin D for treating and preventing COVID-19, her team recruited patients from around the country, allowing them to recruit more people more quickly than they could have done with a local study. That was critical, Manson says, because enrollment was time sensitive—the protocol involved treating patients within a week following diagnosis.
More vital than efficiency of enrollment, though, is the ability to capture a more diverse group of participants. “The most important thing for a clinical trial to show is both safety and efficacy in a representative sample of the population,” says Christoph Koenen, executive VP and chief medical officer at Japanese pharma company Otsuka, which has done remote and hybrid (partially remote) trials before. Currently, most trials fall short of this goal, he says, in large part because they pull from surrounding areas to the sites hosting the study, and clinical trial centers in the US tend to be located in urban centers on the East and West coasts and are more likely to be affiliated with academic institutions than rural practices. “With that, you bias your patient population,” he says.
With remote trials able to reach a greater geographic area, they are also reaching populations of different ethnic backgrounds and socioeconomic statuses—the key to good quality data, Koenen notes. “We are opening participation up to parts of the country, to parts of society that have not been able to participate in the past. And by doing that, we do believe we will be able to get a more representative sample of the overall population.” Brennan agrees. “The beauty of going virtual is it makes the care accessible and equitable.”
An uncertain future
Moscicki notes that there are logistical challenges to be worked out when it comes to remote clinical trial regulation by the US Food and Drug Administration (FDA). The agency has supported the use of digital technologies to allow trials to be partly or fully virtual since SARS-CoV-2 began circulating in the country, but it remains to be seen how these approaches will be regulated post-pandemic, he says. “While I think FDA was terrific and speedily tried to provide some guidance that would be helpful to sponsors who were dealing with this change, there’s still some lack of clarity . . . particularly around the data collection efforts.”
Another issue that requires careful consideration in the transition to a remote setup is how to properly recruit participants. “That’s the first piece of any clinical trial, to have informed consent to make sure that these patients, who are volunteers, are willing participants,” says Brennan. This has traditionally been done in the clinic, where researchers and healthcare providers can explain what the trial entails and answer any questions a prospective participant might have. Moving this process online requires taking precautions to ensure that the consent was informed and genuine. Just any e-sign software wouldn’t do, Brennan says. “The FDA regulates anytime you’re using electronic signatures with their Code of Federal Regulations.” When she launched the famotidine trial, she ensured with their electronic data capture system, Redcap, was compliant, she says.
Koenen of Otsuka, which just launched a fully remote nationwide trial of so-called digital therapeutics such as mobile apps for people with major depressive disorder, says that the FDA has been accommodating of the shift toward virtual in the face of COVID-19. The agency, he says, has been “allowing us to use virtual visits, virtual assessments, because physical interaction was simply not possible.” In March 2020, the FDA released guidance for how clinical trial investigators should work to ensure patient safety during the pandemic, and it has updated that guidance several times since then, most recently in December. It did so “to assist sponsors and trial sites in addressing these challenges for the duration of the COVID-19 public health emergency,” agency spokesperson Lindsey O’Keefe writes in a statement emailed to The Scientist. FDA spokesperson Amanda Turney adds, “We believe that trials will gradually become more reliant on remote procedures.”
But it remains to be seen how regulations play out post–COVID-19, Koenen notes. “The big question mark is going to be how much of that is going to revert to the old normal, versus how much of that will the agency allow us to keep virtual.” Moscicki agrees that there are details to be worked out concerning regulatory oversight of clinical trials in the digital age. “We haven’t got it all down perfect yet,” he says. “As we move out of the pandemic, we hope that this becomes a new normal. But to help it become that new normal, we do have to solve these questions.”
When it comes to broadening patient representation, investigators will have to take into account differences in people’s access to the necessary tools. While remote trials may reach many more people than they could if only recruiting locally, they could miss those without smartphones, internet, or other tools needed to participate. Related issues may crop up with non-native English speakers, adds Andrea Bastek, director of innovation at Florence Healthcare, an online platform for management of remote clinical research. “You have to be careful to make sure that your solutions or remote capabilities are inclusive of all different types of groups.”
But with appropriate attention to the many factors involved, everyone who spoke with The Scientist agreed the trend of clinical trials going remote—spurred along by COVID-19—will continue. “We think this truly can be a meaningful advance even outside of the pandemic,” Moscicki says. “We’re looking forward to a brave new world as the silver lining that can come out of the hardship that this last year has brought upon us all.”