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Myron Cohen has run clinical trials through hurricanes and civil unrest. Now, the infectious disease researcher at the University of North Carolina, Chapel Hill, says he and his colleagues are in a new situation: trying to carry out large, international trials in the midst of coronavirus lockdowns. Cohen co-leads a network of HIV prevention trials, some of which have paused during the pandemic. But for other studies, he says, “stopping would be of grave consequence” to participants. So study teams have bought and shipped protective equipment to personnel at clinical trial sites, secured special permits where necessary for trial participants to leave their homes for medical visits, and arranged their private transportation to avoid public buses.
Not all clinical trials have had to go through such logistical gymnastics. But across diverse fields, investigators have managed to keep treating patients who might benefit from experimental therapies. Slowdowns and pauses in recruiting new participants will delay results—but for many studies, data are still flowing in.
Now, research teams are contemplating the ways the pandemic might insert itself into their trial results. Could changes induced by the pandemic—including less consistent follow-up visits, reduced movement, poorer mental or physical health, or infection with the novel coronavirus itself—blur the statistical signals of a treatment’s risks and benefits?
“We’re all going to have to plan for how we account for the impact of COVID,” says Janet Dancey, a medical oncologist at Queens University in Kingston, Canada. Many concerns remain hypothetical. Until researchers finish collecting and analyzing their data, they won’t know whether coronavirus-related disruptions will undermine results. “But I’m worried about it,” Dancey says.
Though medical centers around the world have shifted staff and resources to COVID-19, they also continue to bring in patients with other life-threatening diseases. Many institutions have stratified their ongoing clinical studies and halted any in which patients didn't stand to benefit directly. But for many cancer patients, participating in a clinical trial can provide the best available treatment, says Monica Bertagnolli, a cancer researcher at Harvard Medical School. “Everybody who is already on a clinical trial is there because they have cancer or some serious condition, and this is a really important part of their treatment,” she says. “You don’t want to deny that to patients.”
The Alliance for Clinical Trials in Oncology, which conducts clinical trials across the United States and Canada, has not withdrawn any participants from treatment during the pandemic, says Bertagnolli, who chairs the organization. But, she adds, “I won’t say that the treatment hasn’t been changed a little bit.” In some cases, the pandemic has delayed imaging appointments and biopsies that can guide treatment plans and gauge how a tumor is changing. As a result, researchers might not be able to document how much a cancer has grown or spread at the exact time points specified in the trial design. (The U.S. Food and Drug Administration has indicated that deviations from study protocol to protect patients’ safety during the pandemic are justified.)
“I’m already seeing many more deviations,” says Howard Burris, an oncologist and chief medical officer of Sarah Cannon, the Cancer Institute of HCA Healthcare, and president of the American Society of Clinical Oncology. He’s optimistic that small data gaps won’t change big-picture trial results. “Hopefully, in a randomized trial, those things sort of sort themselves out,” he says. “I think we’ll be able to adjust.”
But trial data might become muddied if some participants are sickened by the novel coronavirus or die from it, Dancey notes. Presumably, SARS-CoV-2 infections would be distributed randomly between a study’s treatment and control groups. But they could still make it harder for researchers to pick up signals of benefit or to disentangle negative side effects of the experimental treatment. “If there are competing causes of death that are going on, then it will be harder to show differences in outcomes,” Dancey says. “It reduces our power.”
Other effects of the coronavirus pandemic on trial participants might be more subtle. For example, the results of HIV prevention trials depend in part on participants’ risk of contracting the virus, Cohen notes, and social distancing orders that limit intimacy might change that underlying risk. The researchers will have to take into account the fact that getting an experimental drug was far from the only change in participants’ lives over the course of the trial.
Trials focused on mental health could face other complications, says Lynnette Averill, a psychologist at the Yale School of Medicine, who is studying the anesthetic ketamine as a potential treatment for post-traumatic stress disorder (PTSD). “A global pandemic where you’re isolated and potentially have fears of you or your family being ill … those things are highly stressful, and potentially traumatic,” she says. “This experience may be significant enough that there has to be some sort of analysis of the pandemic effect. … We may in fact have entirely different cohorts pre- and postpandemic.”
Averill also wonders whether investigators running trials of PTSD, anxiety, and depression will see a shift in the demographics of trial participants. The mental health effects of caring for COVID-19 patients in overstretched hospitals may make more health care workers eligible for such trials, for example.
Dancey, who directs both a research network that runs cancer trials and a funding organization that supports them, has been helping develop guidance for researchers on how to adapt studies during the pandemic. The best they can do, she says, is focus on a study’s primary endpoint, make data collection as complete as possible, and document any deviations from the study plan. “We have to make sure that people are looked after—whether they’re patients with or without cancer, or health care professionals,” she says. “And then we’ll look after the trial.”
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