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Oncologists See Clinical Trial Disruptions as Coronavirus Pandemic Continues

NEW YORK – Less than two weeks ago, members of the Jackson Laboratory's Maine Cancer Genomics Initiative (MCGI) were seeing strong enrollment by cancer patients seeking somatic tumor profiling to inform their treatment or potential clinical trial options.

But MCGI Medical Director and Jax medical oncologist Jens Rueter expects that could soon change, as cancer centers and clinical trial sites across the US and beyond respond to the COVID-19 pandemic.

The MCGI is not itself a clinical trial, he explained, but a state-wide precision oncology initiative that provides somatic tumor profiling and molecular tumor board resources for cancer patients treated in five health systems across the state. As of this weekend, one clinical practice in Maine had stopped enrolling patients in the initiative, Rueter said in an email on Sunday.

Along with changes in the way members of MCGI genomic tumor board meets — exclusively online for the moment — the team is keeping an eye on pandemic-related clinical trial changes that may impact current or future enrollment for cancer patients eligible for targeted trials, particularly because patients profiled for the program are often referred to trial sites in Boston.

"This is obviously [going to be] a huge disruption for oncology clinical trials," he said. "I don't see how this couldn't be a huge disruption."

Pandemic preparations

Oncologists, regulatory bodies, trial sponsors, and cancer organizations in the US and beyond are coming to similar conclusions, as the pandemic and preparations for it start to place significant restrictions on the trials that are available to patients and on patients' ability to access those trials.

Beyond concerns around how to manage cancer patient diagnoses and care, hereditary cancer testing, and concerns specific to cancer patients who contract the SARS-CoV-2 virus, experts are being forced to carefully re-evaluate clinical trials that are in development and already underway for uninfected patients, including trials focused on molecularly guided cancer treatments.

The trial situation is still in flux, depending on the location, trial type, sponsor, and patient needs and circumstances. So far, though, much of the available guidance has focused on temporarily curbing new clinical trial enrollment, unless the investigational agent or protocol has a strong chance of success.

Oncologists are prioritizing precision oncology trials, particularly for patients who are receiving, or are eligible for, molecularly targeted treatments that are strongly predicted to benefit them, according to Howard "Skip" Burris, president of the American Society of Clinical Oncology (ASCO).

"To date, we are seeing patients and their physicians seeking investigational new drugs — we're still seeing those patients being referred to clinics wanting to be seen, particularly … if there is a molecular match or some sort of specific therapy that will help them. We're still seeing robust referrals in that regard," explained Burris in an interview a week ago. He is also chief medical officer and president of clinical operations at the Sarah Cannon Research Institute in Nashville.

On the other hand, Burris noted that trials comparing similar, already approved drugs are more likely to be delayed, since the clinical benefit of continuing is more difficult to predict. In those cases, oncologists are prioritizing situations that minimize patients' risk of infection or need to travel.

For his part, Jax's Rueter cautioned that, among other possible impediments to enrollment, clinical trials may not be top of mind for treating physicians, who are juggling a range of other considerations and focused on providing care while limiting cancer patients' potential exposure to the coronavirus.

That may be especially true for oncologists treating patients with compromised immunity related to their conditions or to prior treatments — an issue that's been publicly raised by several cancer organizations and caregivers.

Enrollment is also expected to drop off for early-stage clinical trials with a less clear benefit, according to investigators like Nam Bui, a clinical assistant professor of medicine in oncology at the Stanford Cancer Institute, who specializes in sarcoma and developmental therapeutics, and often works on trials focused on drug safety or dosing.

"Technically, we still can enroll," Bui said in a call on Friday, "but unless we think there's good safety data to justify it — especially for early-phase trials — I would be more apprehensive."

Though the public health crisis in Santa Clara County, California, where Stanford is located, is not as severe as the situation facing institutions in New York City at the moment, Bui and his colleagues are attempting to minimize patient exposure to SARS-CoV-2 as much as possible by reducing trial enrollment.

"With the shelter-in-place [order in California] and knowing how things are exploding in New York City, we want to make sure that cancer patients who are at higher risk, and … [may be] immunocompromised from treatment, are not exposed to greater risk," Bui said.

The situation started changing at Stanford earlier this month. Bui said that the university was starting to place new restrictions. There was already a directive to shut down non-essential research labs. Access to cancer treatment centers at Stanford were restricted to patients, he noted, and the team had received notice that "trials in the [early] stages of opening will not be allowed to open until this virus is under better control."

At Weill Cornell Medicine's Englander Institute for Precision Medicine, Director Olivier Elemento has seen a similar shift toward shutting down non-essential research and marshalling resources toward maintaining crucial research applications, including somatic tumor profiling and other clinical sequencing applications, and off-site computational work.

"The key for everyone in a hospital setting is to make sure that patient safety and patient care is not compromised," Elemento said. "Everything that is affecting the care of patients — all of the patient care and research that involves clinical utility for the patients — is maintained. What is changing a bit is the research aspect."

"It's having a huge, detrimental effect on the ability to conduct clinical trials and maintain the integrity of the trial," said Mary McDermott, a medicine and preventive medicine researcher and physician at Northwestern University, who co-wrote a viewpoint article in the Journal of the American Medical Association on the potential pandemic impacts on clinical trials in general.

Though the piece was not focused on cancer or precision oncology specifically, McDermott and co-author Anne Newman, an epidemiology researcher at the University of Pittsburgh, noted that "creativity and persistence" will be needed to continue with the most crucial trials and to continue collecting as much data as possible to improve the treatment and quality of life of patients in the future.

"Most clinical trials require that you see the participants to do measures, or they come in for a blood test or an assessment," explained McDermott, who specializes in cardiovascular trials. "Recruitment, if it requires an in-person visit, is on hold."

"If it is an oncology patient for whom this is a matter of life or death, they are going to come in [for trial drugs, as needed]," she said. "But if it's not a matter of life and death, most people would probably tell the patient to stay home, and that disrupts the integrity of the trial."

Flexibility for deviations

For trials already underway, meanwhile, oncologists are getting more leeway when it comes to straying from trial protocols to maintain patient treatment and safety, potentially setting aside patient visits to measure a treatment's effectiveness that are not clinically necessary. These changes reflect concerns over patient travel, potential patient quarantines, exposure to the SARS-CoV-2, hospital capacity concerns, and more.

"We have been in constant communication with sponsors and with the FDA and IRBs," Burris said, noting that "all those organizations have been tremendously responsive, for example, to allowing protocol deviations to decrease travel and to promote social distancing."

"It's been consistent across the board that all the sponsors and IRBs have simply asked us to label the protocol deviations related to COVID-19," he explained, "so that they can aggregate those and assess the impact of the pandemic, and also know that that's the primary reason that we're not able to fully comply with the program."

Bui, too, said that he has been seeing "a lot of flexibility from sponsors and the IRB and the institution to prioritize patient safety and to allow the investigator to make judgment calls of what is best for patients.

"In normal settings," he added, "if you take a deviation, it's good to plan ahead with IRBs. But now the IRBs are saying if you have to take deviations for patient safety, that's okay. You don't have to notify them ahead of time to get approvals."

Similarly, he noted that several drug companies have sent out memos outlining strategies for managing cancer patients on existing trials. While he did not divulge the details of those memos, Bui said the guidance provided so far points to increased flexibility — allowing for video follow-up visits with patients, for example, or omitting research-related blood draws that are not clinically necessary.

"They are aware that deviations may happen, or that patient visits may be done remotely instead of having patients coming in, or that a cycle may be delayed," he explained.

Indeed, Rueter said, "If you're a patient on a clinical trial, the institution where you are receiving care and that has enrolled you on the study is going to do everything they have to do to make sure you're safe, and that you're getting the appropriate protocol-driven care."

For trials done at Sarah Cannon, for example, Burris noted that there has been some leeway given to allow extra medications to be dispensed to patients on trial so that they do not have to travel as frequently. And, in some cases, patients may be referred to centers that are not their typical trial sites but are outside of potential hotspots for infection, he added.

"For some patients on investigational drug trials, there is greater latitude in using local labs and having patients go to facilities near their house with less travel and exposure," Burris explained. "Cancer therapy has changed dramatically from the days where the vast majority of patients received chemotherapy."

Burris expects it will be easier to accommodate alternative treatment sites for drugs that are given orally, though he added that some of the treatments administered intravenously are given less frequently, which could help in reducing exposure risk and travel for patients.

"One good piece on the IV therapies nowadays is that with so many of the cancer patients receiving immunotherapies and other types of antibodies, the frequency of administration is much more on the once-every-few-weeks mode," he said.

When patients do need to come in for infusions, Burris added, "we're attempting in the clinic to be aggressive about screening questions, limiting visitors, spacing out infusion rooms."

Ongoing online guidance

Nationally and internationally, oncologists, health centers, cancer-related organizations, and regulatory bodies have been coming up with strategies in real time to maintain cancer patient care during the ongoing COVID-19 pandemic. Some of these changes, which came quickly, have upended travel options for some patients and increased concerns about infection in cancer patients with compromised immunity.

"At this time, we do not know how [the] COVID-19 pandemic will evolve, or the extent to which it will place stress on cancer patients, their families, and their caregivers," the National Cancer Institute (NCI) wrote in a statement on March 19, noting that the "healthcare team taking care of a patient is best suited to evaluate that individual's unique situation and advise on the safest course of action."

"During this challenging situation, we understand that healthcare system resources will be limited, and this may affect cancer clinical trial operations. We do, however, believe that there are circumstances (e.g. in order to get access to potentially life-saving therapy) where patients with cancer should enroll or continue on a clinical trial even during the COVID-19 pandemic," the NCI continued. "Advice given to patients participating in clinical trials should be tailored to the individual patient based on their clinical circumstances."

The institute said it is continuing to track NCI-supported trials and attempting to accommodate principal investigators, as needed, so that patients could continue on trials to the extent possible. It is encouraging trial sites to contact NCI if they are making policy or practice changes that differ from those outlined by the National Institutes of Health.

For its part, the US Food and Drug Administration (FDA) issued clinical-trial related guidance on March 18, which was updated on Friday.

For clinical trials, most recommendations from the FDA and other cancer or physician groups line up with experiences being shared by oncologists in the field — namely, strategies to ensure access to clinical trial agents deemed most likely to have an impact, while putting off new clinical trial enrollment for more experimental or early-stage treatments.

An FDA spokesperson told Precision Oncology News that while it "does not regulate routine healthcare delivery or practice of medicine, we are fully supportive of interventions that may improve the safety of patients in the context of the COVID-19 pandemic."

Referring to the administration's trial guidance, the FDA suggested sponsors consider and evaluate strategies to replace or reduce in-person visits.

"In making the decision to continue use or administration of the investigational product, the sponsor should consider whether the safety of trial participants can be assured with the implementation of the altered monitoring approach," the FDA told PON. "If that involves using different sites to deliver the investigational product, an assessment will need to be made regarding whether the alternative site can provide skilled personnel and other resources necessary to appropriately deliver the investigational product."

Organizations such as ASCO and its patient information site Cancer.Net, the SWOG, the UK's National Health Service (NHS), Cancer Research UK, and others have shared information with their members as it becomes available.

Meanwhile, in an article published in the Journal of the National Comprehensive Cancer Network on March 20, investigators with the Seattle Cancer Care Alliance, the Fred Hutchinson Cancer Research Center, and the University of Washington noted that "[e]nrollment in clinical trials for all diseases will have to be limited to those that are most likely to benefit our patients."

"To what extent we can prioritize the therapies given to individual patients to reduce the burden on our system under stress is an ongoing challenge," they wrote. "Cancer centers should make it their mission to do all [things] possible to continue to keep their doors open to provide care, unless there comes a time when staff and patient safety are no longer tenable."

Telemedicine's time

Burris said federal agencies are also providing flexibility around telemedicine so that clinicians can do follow-up visits with patients by phone, Skype, or video messaging, even in settings where the IT infrastructure and HIPAA-compliant privacy safeguards cannot be put in place quickly enough.

"Many of the oncology clinics, if not all, have moved to taking patients who come in on surveillance every six to 12 months, and pushing their visits out and connecting with them by telephone to reduce the volume at the cancer clinics for patients who are currently needing therapy," he explained.

While some of these methods are being put together on the fly during the pandemic, there are investigators who have been incorporating telemedicine into their trials for several years to address barriers such as geography that keep patients from taking part in trials in general.

In a paper published in the Journal of Clinical Oncology in 2017, for example, Icahn School of Medicine at Mount Sinai's Matthew Galsky and his co-authors presented findings from a telemedicine-based clinical trial of oral metformin treatment in 15 patients with castration-naïve prostate cancer.

"The challenges we're facing now are in part unique, but they're in part just a function of the lack of pragmatism in clinical cancer research," noted Galsky, who directs the genitourinary medical oncology department and the novel therapeutics unit at Icahn School of Medicine, and co-directs the MSSM and Tisch Cancer Institute's Center of Excellence in Bladder Cancer.

"Even in the absence of a viral pandemic there are barriers to patients participating in cancer clinical trials," Galsky said, noting that remote and decentralized trials have the potential to overcome some of these challenges and may help cancer patients who are currently enrolled in trials.

"There's certainly been some communication from institutional review boards and from other oversight organizations that visits conducted by a local physician could be substituted for visits at the main study center, whereas typically that's not allowed because of regulatory barriers," he said.

In the longer term, some oncologists are hopeful that approaches being used to preserve treatment availability for patients on targeted or other key treatment trials may influence future clinical trial design to increase access for patients in geographically remote or rural locations.

"The situation has forced us to really think about how we can optimize processes, especially with respect to remote working in general," Rueter said. "You could argue that maybe this is the time to think about how to set up something like that for clinical trial participation."

Precision Oncology News is closely tracking how the COVID-19 pandemic is impacting the development of and access to molecularly-informed cancer treatments. We want to hear from oncologists, cancer drugmakers, molecular diagnostics firms, and patients. If you want to share your experience please contact [email protected].