Institutions are slowly but steadily resuming their investigational efforts, examining both the temporary and lasting effects the pandemic has left on their centers.
From restrictions imposed by pharmaceutical sponsors to suspensions and slowed enrollment, the coronavirus disease 2019 (COVID-19) has affected clinical trial operation in oncology centers across the country. Institutions are slowly but steadily resuming their investigational efforts, examining both the temporary and lasting effects the pandemic has left on their centers.
Declining accrual rates, delays in vital inclusion criteria testing, and social distancing protocols limiting the number of in-person office visits trials often require, are a few examples of the hurdles investigators are currently navigating as operations take steps toward the status quo. In interviews with OncologyLive®, investigators from several cancer centers provide insights on how their operations were affected and the strategies that could be sustained in the future.
In the earliest stages of the COVID-19 pandemic, investigators at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center in Pennsylvania preemptively paused patient enrollment in nontherapeutic clinical studies of pain management and palliative care interventions. Although therapeutic trials were largely permitted to continue accruing patients during this time, like other oncology institutions, UPMC Hillman Cancer Center faced pharmaceutical sponsor-issued limitations on new study initiation and patient enrollment.
“We suspended or reduced activity for around 80 trials over a 1- to 2-week period, and then we were able to reopen them with the help of our institutional review board,” said Robert L. Ferris, MD, PhD, director of UPMC Hillman Cancer Center.
These impediments were further compounded by reduced clinic schedules and social distancing guidelines unique to the COVID-19 health crisis, culminating in a 20% to 30% decrease in accruals.
“Doctors weren’t seeing the same volume of patients, and due to social distancing, you can’t have all of the trials open that you would want to, and if primary care doctors’ offices are not open, then they’re not referring people to the oncologist [as frequently],” Ferris explained.
“Since we are over the peak now in western Pennsylvania, those 10 to 15 trials that were delayed until June have now opened. We see clinical trials as part of cancer treatment, so we’ve tried to keep as many open [as possible],” said Ferris, adding that as primary care doctors’ approach normal operation capacity, “we think we’ll make up that 20% to 30% decline.”
At COVID-19’s apex in mid-April, UPMC, the largest health care network in western Pennsylvania, allocated 2% of its total 5500 hospital beds and 48 of its 750 ventilators to patients with the novel respiratory virus, according to Steven Shapiro, MD, chief medical and scientific officer. On May 7, Shapiro attested that UPMC’s COVID-19–specific admissions have diminished.1
As the number of cases continued to climb over April and May, investigators at Dana-Farber Cancer Institute and Mass General Cancer Center (Mass General), both in Boston, Massachusetts, not only saw a decline in accrual numbers, but also had to navigate the hurdles that came with cancelled qualifying procedures.
Following COVID-19’s spike in Massachusetts in late April,2 Dana-Farber has begun preparations for the return of elective procedures, which will directly benefit the studies that require preliminary biopsies. In early April, the COVID-19 pandemic inhibited Brigham and Women’s interventional radiologists, who perform more than 90% of Dana-Farber’s biopsies, from procuring tumor samples from patients, said BruceE. Johnson, PhD, Dana-Farber’s chief clinical research officer.
“We do about 1000 research biopsies a year, or about 80 a month; it’s a very important scientific piece of what we do,” Johnson said. “On April 1, hospitals stopped doing elective biopsies, [causing us to go] from an average of 80 biopsies a month to 1 in April. This has affected us more than anything.”
Johnson recounted an instance when he was recently considering placing one of his patients on a clinical trial of a bispecific antibody, but was not able to do so, because the eligibility criteria mandated a biopsy to assess EGFR receptor presence on cancer cells.
“They wanted a biopsy so they could correlate the density of the receptors on the cells with how well the agent worked, and we were not able to put anybody on that study because it required the biopsy,” Johnson said. For Dana-Farber, hospitals’ reinstatement of elective procedures will result in a continuation of pretreatment specimen collection for patients who hope to participate in a study that requires one.
Despite COVID-19–related complications to clinical trial operation, preserving therapeutic studies has been, and remains, a key component of Dana-Farber’s clinical ethos, according to Johnson: “Sometimes, the best treatment for people with cancer is a clinical trial, so we were committed to making sure that people who were on a trial could continue on it. We were also committed to continuing to enroll patients onto trials, [while] being mindful of sponsor requirements and minimizing the exposure of our staff and patients to [COVID-19].”
Preliminary biopsies are just one of the study sponsor prerequisites that prompted consideration during the pandemic. Regarding pharmaceutical sponsors’ trial protocols, Johnson explained that the standard procedures for pharmacokinetic (PK) study procession also posed a challenge, due to the need for multiple patient visits. “The first day, patients start treatment, and then sometimes, they’ll come back for a day 5 or a week 1 [follow-up visit],” Johnson said.
Fortunately, through collaboration with its sponsors, Dana-Farber was able to temporarily waive these repeated trips to the center, as well as PK assessment in studies where PKs is not a primary safety end point.
As states including Massachusetts move to reopen, factors that could potentially limit a patient’s ability to participate in a clinical trial, such as biopsy collection, or have an impact on the aggregation of patient data are expected to have less of an effect on clinical trial operation at Dana-Farber, Johnson said. This sentiment is bolstered by the cancer center’s enrollment of patients on therapeutic studies through April.
“We keep close track of the number of people who enroll in therapeutic trials every month, and in 2018 and 2019, the median was about 200 patients a month. That started going down in early 2020, and we ended up putting 83 patients on protocol in April. Now you can think of that as a glass half full or half empty. It’s a little less than half of what we normally do, but we’re proud that we were able to maintain that through the month of April,” Johnson said.
The disruption to patient enrollment that Dana-Farber Cancer Institute and UPMC Hillman Cancer Center have encountered throughout the evolution of the COVID-19 pandemic is not specific to either institution. New data from the Cancer Research Institute and IQVIA show that just 20% of United States–based centers continued to enroll patients at the usual rate, while 20% halted new patient enrollment altogether. The hardship faced by oncology institutions globally mirrored that of United States oncology institutions: 20% of centers in Asia suspended enrollment, and although the European sites surveyed did not stop enrolling patients, 86% said the enrollments proceeded at a lower rate (Figure).3
Mass General also saw a decline in patient accruals during the early evolution and peak of the COVID-19 pandemic, according to Rebecca Heist, MD, MPH, an expert in lung malignancies at the cancer center and an associate professor of medicine at Harvard Medical School. “New accrual numbers decreased significantly during this time, so we are planning now to expand those numbers,” Heist said.
At Mass General, clinical trial operations slowed, but never came to a full halt. “As a cancer center, it was really important to us to be able to continue to offer clinical trials for our patients, and we worked very hard to do that,” Heist said. “The only studies that were truly closed were [those for which] the sponsor suspended accrual,” she added.
During this time, the cancer center permitted patients who were already on clinical trials to continue receiving their investigational interventions and prioritized patient enrollment on therapeutic studies “with either potentially lifesaving or truly disease-altering treatments,” Heist explained. “There was a kind of self-regulation involved, where we knew that it wouldn’t be great for the system, operationally, if we flooded it with tons of new patient accruals because so many resources had to be redirected toward COVID-19,” she said.
As Mass General and other oncology institutions across the nation resume their clinical routine amid COVID-19, in thecontext of its clinical study offerings, Mass General will continue to give preference to trials “with truly disease-altering potential.”
The practice of giving preference to the studies that may hold the most promise is not unique to Mass General. The Mayo Clinic Cancer Center adopted a similar approach, said Steven R. Alberts, MD, chair of the Division of Medical Oncology and deputy director for Clinical Research at the Mayo Clinic Cancer Center, which has sites in Rochester, Minnesota; Jacksonville, Florida; and Phoenix/Scottsdale, Arizona.
“Like any institution, COVID-19 certainly had a big impact on Mayo’s 3 main campuses in Minnesota, as well as in Phoenix and Jacksonville. When COVID-19 hit, it really caused us to greatly slow down our clinical trials,” Alberts said. “We didn’t put a complete stop to them, but it [prompted] us to look carefully at which trials were really critical to patients, and in general, our [feeling] was if there were no reasonable standard-of-care options for a patient, we would offer a clinical trial if that trial had some meaningful chance of benefiting a patient.”
During this period, Mayo Clinic halted translational data collection and primarily provided phase 2 and phase 3 trial offerings, and “very limited” phase 1 studies. In lieu of suspending studies, Mayo Clinic asked clinicians to internally consult with the clinical research chairs on a new patient enrollment to a given trial and obtain approval from the research chair. This method allowed Mayo Clinic to ensure that only patients who did not have viable therapeutic alternatives were being enrolled on the cancer center’s clinical trials without wholly shutting down study operations. Unsurprisingly, Mayo Clinic saw a dip in patient accruals: “[at] the lowest point, our enrollment dropped to probably a third of our normal enrollment,” Alberts said.
In what was a welcome change to Mayo Clinic’s clinical milieu, the cancer center has resumed a more normalized state of study operation and began to open “most” of its clinical trials the week of May 11. Already, Mayo Clinic has seen an increase in the number of patients seeking care and clinical trial opportunities, according to Alberts.
“We expected there to be some increase in patients coming back just for general care, including clinical trials, but our numbers have gone up more quickly than what we thought. At the end of this week, our normal volume of patients is at about 85% of what it had been prior to COVID-19, and if we add in the virtual visits, we’re up to about 95%, so the practice has ramped up very quickly, and along with that, we’re definitely seeing an increase in the number of patients going on to clinical trials,” Alberts said.
Moving forward, Mayo Clinic will continue to temporarily limit its menu of phase 1 studies that are visit or procedure intensive to minimize the number of patients who repeatedly come through the institution’s doors in this early stage of reopening, Alberts added.
Broadly, the clinicians agreed that although COVID-19 hindered some facets of study operation, they also indicated that some of the strategies that were implemented amid the pandemic could not only be sustained in the aftermath but also streamline the facilitation of clinical trials in the future.
“Like a lot of other large institutions, Mayo Clinic is slow to change and, and COVID-19 made us change very quickly in a lot of ways,” Alberts said. “The lessons [we] learned will help us design the next generation of trials.”
Specifically, the use of telemedicine and remote assessments, when possible, may allow cancer centers to reach a broader network of patients who might not have elected to pursue treatment at a certain institution due to distance, Alberts observed. In addition to the digital collection of data from study participants in the instances when it was feasible, Mayo Clinic also worked with the National Cancer Institute and pharmaceutical companies to ship drugs to patients within a prespecified radius. “In the past, nobody would have ever considered sending an oral drug to a patient on a clinical trial through the mail, outside some selected situations,” Alberts said, adding that akin to telehealth services, this practice could possibly endure.
At Mass General, virtual visits and evaluations have also been of value, especially in securing informed consent from patients who are about to enroll on a clinical trial, according to Heist, who said clinicians will video call patients and go page by page through the emailed consent form. “It’s something I would like to see continue after the pandemic,” Heist said. “It allows us to broaden access to patients, who are sometimes limited by the amount of travel that it takes to go on a clinical trial.”
Visiting the treating institution to physically sign the consent form and then subsequently returning for screening and treatment can be laborious and costly for patients at a distance from the cancer center, Heist explained. Obtaining consent remotely could reduce travel for study participants in the long run, minimizing the amount of travel that accompanies enrollment in a clinical trial. Acquiring consent electronically is also of interest at Dana-Farber, Johnson said.
In the months, and perhaps even the years to come, telemedicine will remain a key component of clinical trial coordination at UPMC Hillman Cancer Center, attested Ferris, who said the institution can be expected to take more advantage of remote monitoring in its commitment to affording its patients the timely care that they need, COVID-19 or no COVID-19. “We have to remind everybody that 700,000 or 800,000 people are going to die from cancer this year, so we believe continuing cancer treatment and research is crucial,” Ferris concluded.
1. Heyl E. UPMC seeing decrease in coronavirus patients. Patch. Published May 7, 2020. Accessed May 14, 2020. https://patch.com/pennsylvania/pittsburgh/upmc-seeing-decrease-coronavirus-patients
2. Ellison A. Updated COVID-19 peak dates, state by state. Becker’s Hospital Review. Published April 29, 2020. Accessed May 14, 2020. https://www.beckershospitalreview.com/patient-flow/updated-covid-19-peak-dates-state-bystate.html
3. Upadhaya S, Yu JX, Olivia C, Hooton M, Hodge J, Hubbard-Lucey VM. Impact of COVID-19 on oncology clinical trials. Nat Rev Drug Discov. Published May 18, 2020. Accessed May 19, 2020. https://www.nature.com/articles/d41573-020-00093-1