The COVID-19 pandemic has proven a major disruption to the clinical trials industry, forcing the delay of many planned studies and driving drug sponsors and researchers to adapt their study methods so that trials can continue. But many adaptations being used to allow trials to move forward ultimately could yield a more nimble industry that can quickly and effectively respond to clinical trial disruptions.
Restrictions imposed by federal, state and local authorities to curb the spread of the coronavirus have had a chilling effect on clinical trial activity. Outside of studies initiated specifically to test potential COVID-19 treatments and vaccines, virtually no new global clinical trials have been initiated, says Ken Getz, deputy director and research professor at the Tufts University Center for the Study of Drug Development (CSDD). Additionally, more than 80 percent of ongoing trials have been delayed or postponed since March, although few have been officially cancelled, he said.
Similarly, in a May 5 draft paper entitled “Clinical trials stopped by COVID-19,” Benjamin G. Carlisle, a researcher at the Berlin Institute of Health (BIH), examined the number of clinical trials terminated, suspended or withdrawn due to COVID-19. According to Carlisle’s data, 44 percent of trials listed on ClinicalTrials.gov that closed between Dec. 1, 2019, and May 5, 2020, gave a reason that explicitly cited COVID-19.
Many CROs have reported decreases — sometimes dramatic — in clinical trial activity due to the pandemic. For instance, PRA Health in a recent financial release announced that it decided to pull its full-year earnings guidance, primarily due to COVID-related challenges and uncertainties. PRA did not reveal how many of its sites had been affected. About the same time, PPD announced that it also would pull its 2020 guidance, noting that in the face of the pandemic, “some customers have delayed new studies and/or paused ongoing studies or certain activities in ongoing studies, such as patient recruitment, patient enrollment, site visits and site monitoring.”
“The industry — like all others — did not anticipate the disruptions from COVID-19,” Getz told The CenterWatch Monthly. “But they have been extremely resilient and responsive, as evidenced by the incredible number of development collaborations and investigational therapies being developed to treat the disease and widespread efforts to transition to virtual and remote activity.”
Certainly, those companies that already had at least pilot-tested novel technologies and procedures were more prepared to deal with the restrictions imposed by the pandemic, said Jill Johnston, president of WCG Clinical’s study planning and site optimization division. Issues faced by researchers operating in the current environment in many ways mirror challenges seen in earlier outbreaks, including COVID-19’s close cousins, SARS and MERS. But after those viral crises subsided, the clinical trial world returned to normal.
“This is a totally different ballgame,” Johnston said, noting that COVID-19 shows signs of being a longer-term problem than the other outbreaks. “I don’t think we’ll ever return to normal. We will move into a new and improved normal that will probably include more acceptance of risk-based approaches, greater use of digital and telehealth components, and a lot more interest in virtual and decentralized trials.”
Some hallmarks of what that new normal might look like already are arising as drug sponsors and researchers scramble to adapt to the demands of conducting research in a COVID-19 environment. And that new normal might also help make researchers and sponsors more agile in their responses to other types of clinical trial disruptions.
Regardless of the reason for a trial interruption, patient safety will always be a paramount concern. In facing down the COVID-19 crisis, researchers and sponsors have had to deal with government-mandated lockdowns and the need to prevent transmission of the virus among their study populations. The resulting boom in use of remote monitoring, virtual doctor visits, wearable technology to track key measurements and other tech-based approaches have been heavily featured in the industry’s response to the pandemic.
Many in the clinical research industry already had been experimenting with some of the innovative approaches being implemented to deal with the COVID-19 disruptions, Getz noted. Approaches such as home-based study participation, mobile and wearable device-enabled trials, remote data collection, risk-based assessment and machine-learning-assisted data analytics have been piloted for years, and the pandemic has acted as a catalyst to accelerate more widespread deployment, he said.
For instance, even as it announced the shuttering of its 2020 guidance, CRO PRA said its mobile health platform and remote monitoring technology had mitigated some of the fallout due to the COVID-19 lockdown. The University of Colorado had reported that its use of telehealth in studies increased more than 200 percent after pandemic-related lockdowns were implemented, Johnston noted.
And many patients will continue to prefer remote options for visits that do not include medical procedures or activities like drawing blood due to the convenience factor. Flexibility associated with the patient’s burden when enrolled in clinical trials is a frequently discussed topic, Johnston explained. And reduced site visits in favor of telehealth options could be an attractive routine option, as well as an effective way to continue operations during disruptions.
“We are definitely seeing a jolt to the industry and a lot of interest around remote monitoring, remote visits, remote auditing and the technology supporting that,” Johnston agreed. “The pandemic took everyone by surprise, but I think the companies already actively looking at and pursuing these options were in a much better position to pull the trigger.”
Companies that had not put as much effort toward some of these technologies and approaches were “a bit surprised and might have been a bit behind the eight-ball,” she added.
But that doesn’t mean that companies have remote approaches all figured out. Some questions remain around critical issues like accountability; any ongoing trials during the pandemic still must keep track of investigational products even if research staff and monitors cannot check those supplies manually at the research sites.
Source document verification (SDV) has also proven a thorny issue when investigational sites are shut down. Industry is beginning to develop approaches to verify documentation, Johnston said. For instance, monitors may want to coordinate with sites to receive remote, temporary and restricted access to electronic medical records (EMRs), with quality review conducted off-site. Remote monitoring visits might include SDV if source documents are provided in redacted format. Questions and queries about source data may also be resolved remotely, she added, by phone or online meeting software, for instance.
But technology and flexible options for patient participation are just part of the story. Drug sponsors likely will become more receptive to even higher levels of customization in protocol designs, with the ultimate goal of offering study participants myriad options — including traditional site visits plus home-based, remote and virtual approaches — to participate, Getz suggested. These approaches can potentially help researchers to weather myriad interruptions.
“There are fundamental areas that have been impacted by the pandemic response that we expect will be permanently changed,” Getz said. “These relate less to specific tactics and solutions that might be implemented and more to strategic shifts.”
These shifts could include more development collaboration in the private sector and between public and private entities, Getz suggested, along with more master protocol designs — including umbrella and platform trials — where multiple sponsors are involved to share development risk, allowing multiple therapies to be tested simultaneously to save time and promote efficiency.
In a late April WCG Clinical webinar, Getz also suggested that the post-COVID clinical trial environment will include a greater number of hybrid clinical trials that make greater use of remote monitoring and risk-based assessments. Self-administered procedures and diagnostic assessments might also become more common.
And Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), agreed that the pandemic is a spur to industry to reinvent itself in some ways. During a Clinical Trials Transformation Initiative (CTTI) webinar in April, she suggested that she would like to see sponsors and researchers shift to conducting more master protocols — trials that look at multiple products in tandem, rather than the traditional approach of each trial reviewing a single investigational drug.
“We think that there is urgent need for master protocols to be put together, particularly for all the repurposed agents that are not going to need a lot of early work,” said Woodcock, noting that trials of early-phase COVID-19 vaccine candidates or treatments could benefit from rapid elimination of less-promising agents.
While COVID-19 is the current concern, researchers and sponsors need to be cognizant that any clinical trial could be affected by various types of interruptions, including not only disease, but natural or human-caused disasters or severe weather events. For example, any supply chain disruption — due to weather events, biological disasters or even just localized manufacturing or transport issues — can impact an organization’s ability to obtain biological specimens, safety or lab equipment or other supplies, noted CITI Program, an online training program about issues involving clinical trials in humans, in a March 11 blog entry.
What goes into an effective disaster plan? To a degree, some responses will be emergency-specific. A disease emergency like COVID-19, for instance, might limit patient and staff access to research sites in the interest of social distancing, but those sites will be ready to inhabit again when the crisis is past. Fire, flooding, earthquakes or other natural disasters, on the other hand, can decimate facilities and equipment, destroying samples and records as well, and render them unusable for years.
An important first step is for research organizations to routinely back up all servers and technology systems, including email servers, financial and credentialing systems, and other key databases, CITI advised.
The CITI Program’s and the University of North Carolina’s clinical trial emergency preparedness guidelines recommend that organizations consider partnerships with other research facilities to share resources and information. This is often standard for organizations that do a lot of multisite research. But crisis communication plans often are mistakenly considered to be solely a function of the public relations department; this is not true. A solid disaster plan should include strategies for addressing not only patients and the public, but also collaborating organizations, regulatory agencies, vendors and suppliers, and accreditation organizations.
UNC recommended that disaster plans include coordinating an alternative site to conduct study visits if feasible and establishing partnerships with other sites or academic institutions to provide for collaborative emergency sites in the event of emergency.
And, importantly, any emergency preparedness plan must not exist in a vacuum. SOPs aimed at handling trial disruptions are intrinsically linked to everyday operations like patient interactions, recordkeeping, investigative product handling, equipment maintenance and storage and data handling. SOPs for all of these types of activities can tie back into the idea of always being ready to respond quickly to any event that might interrupt normal research activities.