In-person cooking classes. Group exercise classes. A weekend afternoon spent inside a room socializing with others. Today, these may seem like fiction, but earlier this year they were components of Cook and Move for Your Life, a study designed to see what kind of support helps breast cancer survivors maintain healthy nutrition and exercise after treatment.
The trial was fully enrolled and ready to go when the first trickle of novel coronavirus cases became a firehose.
“The first class session [for the trial] went beautifully, there was a wonderful engagement,” recalled Meghan Lyle, a dietitian in Fred Hutchinson Cancer Research Center’s Prevention Center who also administers cancer prevention clinical trials. The Cook and Move trial, run by Hutch public health researcher Dr. Heather Greenlee, drew on all three resources offered by the Prevention Center: the clinic, exercise lab and nutrition lab.
“All of the cancer survivors engaged in the study were just really excited about it,” Lyle said. “And then it all had to stop.”
Clinical trials are a key step in the process of bringing new, improved treatments or lifestyle interventions to patients. Often, trials of potential new treatments offer a last hope for patients whose disease has resisted standard treatment regimens, making clinical trial access an important component of patient care.
When enrolling a patient in a clinical trial, researchers and clinicians are accustomed to weighing the potential risks with the potential benefits — for the patient.
The SARS-CoV-2 pandemic upended the usual calculations by adding dire new risks for patients, unprecedented risks for trial staff members, and an unexpected need to work local healthcare resources into the equation. Already accustomed to weighing the potential benefits of a new treatment against its potential risks for patients, researchers were suddenly faced with weighing the risks of administering the trials themselves.
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“We had to evaluate [clinical trials] in ways we never had to before,” said Kristi Stiffler, the associate vice president of clinical research at Fred Hutch.
And in early 2020, many of the risks, carried by a little-understood pathogen, were unknown. Researchers and study administrators needed to make decisions about how to keep patients and staff safe in an environment of rapidly evolving knowledge.
Not surprisingly, clinical trials took a big hit in the early days of the pandemic. Dr. Joe Unger, a Hutch biostatistician in the SWOG Cancer Research Network recently published work in the JAMA Network Open showing that new enrollment in cancer clinical trials dropped precipitously in the early weeks of the pandemic.
“Enrollment is critical to enable us to complete the trials and develop new treatments for patients,” Unger said. “A slowdown in enrollment … that could result in fewer new treatments. It's important for patients to have good access to clinical trial participation as an option for their care. The pandemic introduced some added barriers to clinical trial participation, in addition to the many that already exist.”
Top of mind as the pandemic unfolded was safety.
“Our very first thoughts were, of course, about the patients. We want to do what's best for the patients,” said Dr. Fred Appelbaum, a bone marrow transplant specialist who is the executive vice president and deputy director of the Hutch and holds the Metcalfe Family/Frederick Appelbaum Endowed Chair in Cancer Research.
Ensuring the safety of staff who administer clinical trials was also a top consideration, he said.
When the first few cases of COVID-19 were diagnosed in the Seattle area in January, few suspected they were the preliminary rumblings of a landslide. But epidemiologists who track viruses, including at Fred Hutch, were worried.
Oncology clinical trials run by Hutch scientists occur under the auspices of the Fred Hutch/University of Washington Cancer Consortium, which also includes the Seattle Cancer Care Alliance, the center’s clinical care partner, and Seattle Children’s.
Spurred to action by epidemiologists’ predictions, those involved in administering the Consortium’s clinical trials jumped into action.
“Right off the bat, even well in advance of the stay-at-home order, [the Prevention Center] instituted a symptom screen,” Lyle said.
There are many categories of interventional clinical trials. Treatment trials, which test a potential treatment regimen, and trials that test lifestyle interventions that may help prevent cancer or its recurrence, or improve life quality for survivors of cancer, such as those run out of the Hutch’s Prevention Center, are two trial categories.
Clinical trials are organized into three phases: Phase 1 trials, in which a drug is first administered to humans to assess its safety, side effects and dosing; Phase 2 trials, which are designed to assess the new drug’s efficacy; and larger Phase 3 trials, in which the new regimen is compared to standard of care for the disease. A successful cancer treatment progresses through all three phases before being approved for general use by the Food and Drug Administration.
As COVID-19 infections mounted, leadership, trial administrators, infections disease experts and clinicians from all the partner institutions formed a steering committee to assess all trials run through the Consortium. They made a different risk/benefit assessment for each trial phase. Trials that did not have proven clinic benefit or trials with an approved alternative were among the first trials targeted to temporarily suspend, Stiffler said.
“We realized that there were certain trials that would put patients at increased risk and were not necessarily of benefit to them,” Appelbaum said. “In Phase 1 studies, we're looking at a drug for which we have no proof of utility. Those studies meant that the patients had to come in, make more visits, be more in public — we didn't think it was necessarily in their best interest to be on Phase 1.”
Similarly, said Lyle, many of the trials conducted through the Prevention Center are exploratory protocols that don’t necessarily offer participants direct clinical benefit. Any trials that relied on in-person visits were halted when King County, Washington — where Fred Hutch is located — instituted its stay-at-home order in late March. Phase 3 treatment trials were also put on hold because patients in these trials had standards of care they could receive instead of the experimental treatment.
In cases where Phase 2 clinical trials were deemed in the best interest of the patient, they continued, and most of the Consortium’s Phase 2 cancer clinical trials have remained open to enrollment. This decision was echoed in guidelines later published by the National Cancer Institute to help cancer centers navigate the pandemic.
“The NCI has tried to encourage those sites that have sufficient resources to prioritize those studies that are enabling patients to get access to new treatment, which I think was the right decision,” Unger said.
Balancing a patient’s need to enroll in a clinical trial with their pandemic risk sometimes took creativity and patience. Providers tried to find ways to delay enrollment for some patients, in the hopes that COVID-19 infection rates would be under control in time for the patient to receive the experimental therapy, Stiffler said.
In some trials, only certain components were paused, she said.
Along with monitoring safety and measuring whether the treatment works against cancer, some trials include ancillary studies designed to help scientists better understand how the drug works or how cancer progresses and responds to treatment.
“First of all, we needed to press pause on any research that required additional or prolonged patient visits just for sample collection,” she said, to limit the potential exposure of patients and staff.
Some trials modified certain components instead of stopping completely, switching from in-person visits to video conferencing and shipping oral drugs to patients when possible.
Telemedicine and new procedures for remote participation became important for many trials.
The WEBS study, a prevention trial conducted by UW public health researcher Dr. Ellen Schur and Hutch nutrition researcher Dr. Mario Kratz, is investigating how the damage response of glial cells in the hypothalamus may impact weight regulation. The study, which implements a group behavioral intervention based on the Diabetes Prevention Program curriculum, was quickly able to transition from in-person groups sessions to Zoom-based virtual sessions.
Greenlee’s Cook and Move study will restart soon, as well, switching its in-person nutritional education sessions, exercise sessions and cooking demonstrations to Zoom.
Regulations governing the clinical trial consent process also changed to accommodate the pandemic. The FDA published guidance specific to clinical trial conduct during the pandemic, providing acceptable alternatives and allowances to ensure patient safety and compliance with study protocols. The agency also provided free online access to a new tool that made it possible for some patients to consent remotely instead of in-person.
“Regulators and researchers had to get innovative so we could continue to offer patients these potentially life-saving treatments. The pandemic forced research to better integrate technology into our work,” Stiffler said.
Many prevention trials require blood draws to look at how interventions affect health markers like cholesterol and blood glucose. Some of these were able to go remote, too. Several trials run through the Prevention Center switched from blood drawn by a phlebotomist to sending patients an at-home device that can take a smaller amount of blood. Validation work to understand what the device can and can’t be used for is still underway, Lyle noted.
For institutions running cancer clinical trials, another key part of the safety equation was preserving resources, including protective equipment, hospital capacity and staff time.
At the start of the pandemic, personal protective equipment was scarce. Appelbaum and other leaders hoped to conserve the small amount of available supplies for care providers on the front lines of the COVID-19 crisis.
“We wanted to be careful about using very, very dear resources,” Appelbaum said. It’s one of the reasons that the Prevention Center immediately shut down operations for all in-person trials as the pandemic ramped up, Lyle said.
Hospital resources were also a concern. As Italy and New York provided terrifying cautionary tales, the Consortium’s COVID-19 clinical trial response team tracked the number of open ICU beds around the Seattle area.
“For the most part, we tried to suspend enrollments on trials that required in-patient hospital stays,” Stiffler said. This included some cellular immunotherapy and bone marrow transplant trials that include treatment regimens that suppress a patients’ immune systems and could make them even more vulnerable to coronavirus infection. Thanks to precautionary measures, so far none of the patients participating in Hutch and SCCA blood stem cell transplant trials have contracted COVID-19, Appelbaum noted.
Another precious but limited resource was staff.
Even as some cancer clinical trials were put on hold, the center launched several new COVID-19-focused trials to help add to the growing body of knowledge about the new virus.
“We didn't have a way to suddenly quadruple our administrative staff,” Appelbaum said. “We still have the same Institutional Review Board and we still have the same clinical trial support group. It took a lot to do all these other studies and make all the changes we wanted to make [to existing cancer trials] — but they stepped up to the challenge.”
When it became clear that the Seattle-area peak of COVID-19 had passed, the Hutch began reopening paused trials in phases. Each clinical research disease group assessed its portfolio of trials to reopen in each phase.
Groups chose trials to reopen in the initial phase “based on which trials they felt were the most compelling. Which were the ones that they felt they could do most safely,” Appelbaum said. “Everyone, from physicians to nurses to administrative staff, were part of the decision-making process.”
Prevention trials that only needed short interactions with staff “generally were able to come back online quicker than those that were, say, more intensive and needed several hours of more direct, sustained interaction with staff,” said Dr. Eric Chow, the director of the Prevention Center.
Prevention trials that included an exercise component where heart or lung function were measured — tests that require deep breathing on the part of the participant and close contact between participants and trial staff — didn’t make the initial cut, Lyle said. But Prevention Center staff are working to make it possible to safely do these studies: The center has purchased a DLCO box, an enclosed space in which study participants perform their pulmonary testing with less exposure to staff.
Safety measures have evolved in line with the evolving understanding of SARS-CoV-2 transmission, and there's more available personal protective equipment, Lyle said.
Right now, Prevention Center staff wear face masks and face shields or other eye protection. When an intervention requires reduced physical distance, study participants wear a surgical mask, which provides more protection than a cloth mask.
Fewer participants are scheduled for in-person visits at the same time, to reduce potential contact between trial participants and allow staff more time for safety protocols. Signs emphasize physical distancing, and HEPA-outfitted air filters have been installed in the exercise testing room.
Staff thoroughly sanitize equipment between interventions.
Screening trial participants for COVID-19 has also evolved from the earliest days before tests were available and understanding of potential symptoms were more limited. Infectious disease experts helped craft a safety plan and new screening guidelines as the pandemic progressed.
Now, those who complete VO2 max testing or spirometry (a lung function test) as part of their study visit must also test negative for SARS-CoV-2 infection within three days prior to their visit and conduct two extensive symptom screens, one before their study booking, and one at arrival. They’re able to swab their own sinuses and the sample is subjected to the gold standard for tests of active coronavirus infection, the PCR test.
The Prevention Center “ended up subsidizing or subsidizing a portion of that test just because that was a new cost that studies had to bear,” Chow noted. “We wanted to help studies get back on track as much as we could, knowing that for some participants, coming in in advance may be a barrier.”
Some of the changes the COVID-19 crisis forced on clinical trial operation may remain even after the pandemic is gone, researchers said — and to the benefit of trial participants.
Chief among these were the switch to electronic records and to telemedicine, trends that were already underway but accelerated during the pandemic. Remote participation could be a boon in the future to certain participants who currently have significant barriers to participating in trials, including those who live far away from the dedicated cancer centers that administer most cancer clinical trials, Unger said.
“Many patients face numerous indirect costs of trial participation, such as having to take time off work or get access to day care, that can be prohibitive. These challenges may be potentially mitigated by the kinds of flexibilities in trial participation that are being considered for the long term,” he said.
But telemedicine is not a guaranteed panacea to enrollment barriers, Unger noted.
Not all patients are tech savvy enough; some may not have the internet access needed to connect to care providers and a clinical trial team remotely. Researchers are studying the changes COVID-19 brought to trials to determine which are the most beneficial to patients and may take hold long term.
“I think that our learnings around administering virtual behavioral interventions is definitely going to be something that study groups take forward,” Lyle said. “The efficiencies and improvements that lower the barriers to study participation is something that all investigators are looking at really closely.”
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at firstname.lastname@example.org.
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