NEW YORK – From March to June, many cancer drug trials had to stop enrollment because of the COVID-19 pandemic, but emergency amendments enabling virtual evaluations, local monitoring, and at-home treatment enabled some research to continue despite lockdowns and safety measures limiting in-person care.
Cancer researchers who used such strategies to "bring the trial to the patient" during the pandemic are more motivated than ever to make such decentralization a more permanent feature of the US research enterprise. Studies are already underway to see if technology-enabled remote monitoring can expand access to clinical trials, and in particular, ease enrollment challenges for precision oncology drug trials reliant on patients with rare tumor markers.
"The pandemic didn't invent decentralized or virtual studies, or [this idea of] bringing the trial to the patient. But the pandemic certainly accelerated it," said Gateway for Cancer Research CEO Michael Burton. "And I don't think we're going back."
For nearly 30 years, Gateway has been funding Phase I and Phase II studies, and in recent years, these studies have increasingly focused on precision oncology. To date, the organization has supported over 180 studies, and currently has more than 50 active trials. Burton estimated that upwards of 70 percent of Gateway-supported studies were impacted by the pandemic. There were some immunotherapy trials where patients were on their last line of treatment that kept going because of the disease severity, but enrollment within many drug trials slowed and some had to be entirely suspended.
In addition to drug studies, the organization also funds research to find ways of improving cancer patients quality of life, and "right off the bat, one of the first institutions that pulled back in that area was MD Anderson Cancer Center," Burton recalled. Other cancer centers followed, shifting lab testing space and other resources to COVID-19 related care and research, and implementing safety measures to limit SARS-CoV-2 transmission that kept patients from accessing trials.
A survey of 34 academic and community cancer research programs conducted in late March by the American Society of Clinical Oncology provides a broader view of the decisions made by cancer centers because of COVID-19. Approximately 60 percent of the respondents' research programs halted screening and enrollment for certain clinical trials, while more than 50 percent said their institutions also prioritized enrollment for some trials based on patients' needs, safety, and disease severity; the burden enrollment would have on patients and the trial site; and availability of resources.
These data point to the difficult decisions cancer centers had to make quickly to balance access to critical care with safety: Cancer patients are among the most vulnerable to the ravages of coronavirus, with a 16 percent mortality rate, three times higher than in the general population. Although cancer patients are used to accepting a high level of risk in their care, the added fear of a potentially deadly viral infection likely made patients more cautious. "Patients weren't eager to get into planes, trains, and automobiles to get access to their studies," said Burton.
The US Food and Drug Administration recognized early on that patients wouldn't be able to travel to clinical trial sites due to lockdown rules, and in March issued guidance allowing protocol adjustments that would allow trials to decentralize. The agency told sponsors to consider conducting drug safety evaluations via phone or use labs and imaging centers closer to patients for response monitoring. For drugs that must be administered in a healthcare setting, the agency was open to nurses or trained non-medical personnel administering them to patients at home.
The Centers for Medicare & Medicaid Services also expanded reimbursement for telehealth services and said states could waive in-state licensure requirements for physicians seeing Medicare patients remotely and across state lines, via telemedicine.
These emergency guidelines allowed cancer researchers to quickly pivot to telemedicine and remote monitoring strategies for some trials. According to the ASCO survey, more than 90 percent of respondents said they reviewed patients' symptoms using remote strategies and nearly 88 percent said they engaged with patients via telemedicine whenever possible.
Gateway similarly reached out to its grantees to help them adapt trials in the time of COVID-19, but also wanted to explore how these technology-enabled decentralization strategies could become a more permanent fixture in the research community and expand clinical trial access over the long term. The organization put out a call for proposals in May on how telemedicine, wearables, remote monitoring, and mobile nurse management might be used to bring clinical trials to patients.
"The impact of this pandemic on clinical studies and the patients who depend on them has dramatically underscored the vulnerabilities of a clinical trial model that centralizes the delivery of investigational protocols and requires patients to 'go to the trial,'" Gateway said in announcing the grant opportunity in May. "The pandemic's deleterious effect on the field's ability to conduct trials makes it clear that the status quo is no longer an option."
In the span of about a week, Gateway received around 60 inquiries. "It was very clear the field is very interested in this," Burton said.
The trouble with centralization
In 2010, an Institute of Medicine report included the sobering figure that only 3 percent of adult cancer patients participate in clinical trials. The 3 percent figure is commonly cited, though according to a 2018 report from the American Cancer Society's Cancer Action Network, a more accurate estimate is that 8 percent of cancer patients participate in clinical trials.
Either way, clinical trial participation has been historically low among cancer patients due to a variety of factors. Patients often don't meet narrow eligibility criteria for studies. The opportunities for participation are concentrated at leading, well-resourced cancer centers and not at community care centers where most patients are treated. And importantly, many patients simply can't afford to travel to these far away study sites.
A big reason for the centralized nature of clinical trials is regulation. When drugmakers gather evidence to support regulatory approval of investigational treatments, those studies have to be tightly controlled according to protocols that are standardized across trial sites. It's easier to control all the moving parts of a clinical trial — consenting patients, screening them for trial eligibility, genomic testing, administering treatments, and outcomes monitoring — if these activities are taking place at a limited number of designated sites that are following the study protocol.
This centralized clinical trial model is particularly problematic in the era of precision oncology, however. "One of the main reasons someone doesn't receive a matching therapy is not because there isn't a clinical trial," said Sameek Roychowdhury, a medical oncologist at Ohio State University's Comprehensive Cancer Center, who is involved in a number of precision oncology drug studies. "It's because the existing clinical trial [sites] where they could match to a therapy are too far away, and they can't travel or it's too costly to travel across the country every one or two weeks."
On the other hand, patients may be more motivated to travel to participate in a study if the investigational drug is targeting a specific biomarker, according to Ross Camidge, director of the Thoracic Oncology Clinical and Clinical Research Programs at the University of Colorado School of Medicine. If patients have the biomarker of interest, there is a much higher likelihood that they will see their tumors shrink.
The US Food and Drug Administration's recent approval of selpercatinib (Eli Lilly's Retevmo), for example, was based on response rates of 73 percent in previously untreated medullary thyroid cancer patients with RET mutations and 84 percent in treatment-naïve non-small cell lung cancer patients with RET fusions. For patients hoping to match to a biomarker-targeted drug study like this, "suddenly, the cost of that airline ticket and the inconvenience becomes much more reasonable," said Camidge.
But another consequence of these biomarker-driven trials is that because these tumor markers tend to be rare in the population, study sponsors have to look for participants all over the world, which increases the likelihood that patients with the biomarker of interest will be located far away from the physical study site.
The University of Colorado enrolled patients for studies that supported FDA approval of crizotinib (Pfizer's Xalkori) for ALK-positive NSCLC in 2011. Patients traveled to Colorado from 15 US states, and one patient flew in from South Africa. These patients didn't just travel to Colorado once to enroll in the study but had to make frequent trips, every few weeks, for other routine assessments.
"You'd ask, 'Why can't we just use a local lab?'" Camidge said, acknowledging that drugmakers tend to avoid such protocol adjustments because of regulatory requirements. "It was all sort of ridiculous." In a 2012 paper, Camidge and Swedish Cancer Institute's Howard West described the willingness of motivated cancer patients to travel to partake in biomarker-informed drug trials but recognized even then that the increasing availability of such therapies underscored the need to decentralize certain aspects of the clinical trial model.
For example, FDA's requirement that responders or non-responders to a drug must be identified using a companion diagnostic with premarket approval led drugmakers to stipulate centralized molecular testing within precision medicine studies. In the initial crizotinib studies, for example, patients had to travel to study sites just to sign a pre-screening consent form so their tumor samples could be sent for centralized biomarker evaluation.
"There is no reason to follow this precedent," Camidge and West wrote in the Journal of Thoracic Oncology. They noted that if patients could provide consent over the phone and sponsors covered the cost of shipping the sample for screening, it would save patients from having to travel to the study site unnecessarily, before they even knew if they had the biomarker that would allow them to partake in the trial.
Additionally, they proposed that locally available tests could be used to capture patients' biomarker status for enrollment, and confirmation can occur via retrospective centralized testing. Today, clinical trials are making more use of molecular testing available at local cancer centers and via commercial labs as tumor profiling becomes part of the standard of care for many tumor types. With the wider commercial availability of next-generation sequencing panels that assess hundreds of genes for cancer-linked alterations, patients often know the molecular features of their disease and search for trial opportunities based on that information.
For example, one of the biggest players in cancer genomic profiling, Foundation Medicine, is providing genomic profiling to patients enrolled in the Target Rare Cancer Knowledge study. The aim of the study is to expand molecular testing and personalized medicine access to more patients with rare cancers. The trial's main sites are MD Anderson and the University of California, San Diego, but patients are not required to physically travel to these locations. They can consent remotely and continue to receive care locally with their treating physician.
Although the evolution toward biomarker-guided drugs has forced the traditional clinical trial model to evolve in some ways, the distance separating patients from studies remains "one of the greatest hurdles in precision oncology," in Roychowdhury's view.
The FDA is approving more and more precision oncology drugs, but the biomarkers these drugs target are getting rarer; some of these therapies target molecular alterations that show up in less than 1 percent of tumors. To complete a trial for a drug targeting such a rare biomarker can require hundreds of clinical trials sites around the world, an expensive prospect for drugmakers.
For example, the STARTRK-2 basket trial — data from which supported the 2019 FDA approval of entrectinib (Genentech's Rozlytrek) in NTRK fusion-positive solid tumors and ROS1 fusion-positive NSCLC — involved several hundred patients enrolled across 145 study locations.
"What if we had a telemedicine strategy where we could enroll and treat patients remotely working with their local oncologist?" posited Roychowdhury. "What if this is a new way for us to identify patients with really rare cancer targets?"
Roychowdhury recently received a $333,000 grant from the Gateway for Cancer Research to explore this very question within a precision oncology study. He and his colleagues are using telemedicine and other decentralization strategies to enroll patients around the country with solid tumors (other than lung cancer) with ALK and ROS rearrangements and investigate their outcomes on brigatinib (Alunbrig). Takeda, which markets brigatinib, is also supporting Roychowdhury's research.
Earlier this year, the FDA approved brigatinib for ALK-positive, metastatic NSCLC. The drug is also an inhibitor of ROS1 and has shown preliminary activity in lung cancer patients with ROS1 fusions. Between 3 percent and 5 percent of NSCLC patients harbor ALK fusions and around 1 percent have ROS1 fusions.
These gene rearrangements show up in other kinds of tumors, though even more infrequently. For example, ALK fusions have been reported in 0.2 percent of tumors outside of lung cancer. Although Roychowdhury and his colleagues have been trying to study how ALK- and ROS1-positive solid tumor patients would fare on brigatinib for about a year, they haven't been able to enroll any patients in their trial, though not all study locations were recruiting during this time.
Opening many physical study sites is difficult for rare biomarker-targeted drugs, not only because of the expense, but because some cancer centers will not participate in studies with a low probability of enrolling patients. "There is an incentive to only doing studies that you can enroll to," said Roychowdhury. "That makes sense, but it also means that studies for ultra-rare targets have an uphill climb."
With the Gateway grant, his group is interested to see if National Cancer Institute-designated comprehensive cancer centers and oncologists in the NCI's Community Oncology Research Program will be more willing to enroll and follow cancer patients in such studies virtually via telemedicine. In order to be screened for the study, patients can be tested on any CLIA-certified test to learn their ALK or ROS1 status, though they will have to submit tissue for retrospective central biomarker confirmation at OSUCCC. "One of the reasons you hear for why a patient didn't get a matching therapy in precision oncology trials is that it took too long to get the therapy," noted Roychowdhury. "We won't delay therapy for central confirmation."
His group will be advertising the opportunity to enroll patients in the brigatinib study widely within the cancer clinical trial community, to diagnostics firms doing molecular testing for cancer patients, and to patient groups. "We're going to carefully adapt the study so it's clear how we acquire data and collaborate locally," said Roychowdhury, who is eager to test out this approach in other studies. He has submitted a proposal to use a telemedicine approach in a second rare biomarker-defined drug study and is in discussions with a drug firm about exploring a decentralized strategy for a third program.
Pandemic changes here to stay?
From March to May, Roychowdhury was using telemedicine to check in with almost all his cancer patients. In September, he is using telemedicine to see between 5 percent and 15 percent of patients because quarantine and safety restrictions are still in place in some cases. Importantly, during the critical months of the pandemic, he was able to keep up with all his patients enrolled in an active study via telemedicine thanks to emergency amendments and cooperation from the drug industry.
Flexibility from regulators and payors also helped. "The pandemic happened and literally overnight [CMS] said it will reimburse telemedicine visits, which clearly proves that the infrastructure was all there," said Camidge. "There had to be some motivation to actually do it."
Now, that the pandemic has proven telemedicine is feasible, "there's a lot of interest in what telemedicine is going to look like, whether it's for standard care or for clinical trials activities going forward," Roychowdhury said. ASCO's survey of academic and community cancer research programs in March revealed that 90 percent of the respondents felt that allowing telehealth visits for study participants would improve clinical trials and 77 percent indicated similar support for remote review of patients' symptoms.
While oncologists, drugmakers, researchers, and patients may be willing to make more use of telemedicine and remote strategies, other decision makers in the community haven't yet committed to such changes long term. "There is concern about the FDA's position on this once the pandemic is in the rearview mirror, and the position of the payors because they have been flexible with reimbursement for telemedicine," said Gateway's Burton.
Based on guidance from CMS, states have also been allowed to waive physician state-licensing requirements during the pandemic so they can provide telemedicine to patients residing in other states. This is particularly important in the cancer clinical trial setting, because inter-state travel is so common. As of September, 46 states have waived state licensing requirements for doctors providing telemedicine, though some of these waivers are slated to expire soon and commercial insurers' coverage requirements vary. As such, hospitals may approach telemedicine with more caution from a liability or revenue standpoint.
When the pandemic hit, Camidge, like Roychowdhury and most other doctors concerned about the welfare of their patients, used telemedicine to provide care in and outside of research settings. "I had a duty of care to my patients, so I would phone them and put a note into the electronic medical record," he said. While Camidge did this without giving much thought to whether that interaction was going to be billed and reimbursed, the hospital might feel differently.
"The physicians mostly just want to look after their patients, and if patients are choosing to stay in another state when they're doing that, the physicians probably don't care," he said. "But the health system and the medical legal experts may care. And that's what we have to figure out."
Ultimately, regulators and payors will want to see data on how telemedicine-enabled protocol adjustments during the pandemic impacted study enrollment, retainment, and data collection. As an organization funding cancer research, Gateway will be closely tracking these parameters as well, though to Burton it feels like the pandemic has fundamentally shifted people's thinking on how cancer trials should be conducted in this country. "It's my sense that it will be hard to put this genie back in the bottle because [telemedicine] will ultimately prove [to be] beneficial to the field at large, but more importantly, to the patients," he said.