COVID-19 a ‘real wake-up call’ in how cancer clinical trials are conducted

The COVID-19 outbreak and subsequent disruptions to daily life, working conditions and the economy have had a profound impact on how clinical trials for cancer are conducted, with potentially lasting implications.

The FDA released guidelines in March on how researchers and clinicians should proceed in completing or streamlining clinical trials already underway amid the pandemic. Recommendations included allowing patients to be treated at a community clinic by local physicians instead of at the trial center, mailing prescriptions and conducting consultations via telemedicine.

Although these ideas were prompted by COVID-19, experts said the recommendations could improve the overall trial process and serve as a silver lining to the pandemic if they are implemented long-term.

“This came as a real wake-up call for the clinical trial structure,” Gwen Nichols, MD, chief medical officer of the Leukemia & Lymphoma Society, told HemOnc Today. “Because the process for safety in the past has been highly regulated, both investigators and regulators erred on the side of caution, doing everything at the clinical trial site. This minimized the number of laboratories and any kind of variability in how the trial is undertaken. That is now changing under these new guidelines, and I am hopeful they will stick even after we get through this pandemic.”

HemOnc Today spoke with experts on the long-term outlook of cancer clinical trials; how telemedicine has assisted the industry in salvaging trials; and whether disruptions in the economy could affect funding, patient accrual and drug development over the next few years.

Guideline changes

The FDA has had very strict rules on oncology clinical trials because of how toxic treatments can be. Experimental drugs may cause adverse events that local oncologists outside of the trial team may not recognize.

Due to these safety concerns, the FDA has mandated that patients in clinical trials be treated only by physicians and nurses on the specific study team and at the specific study site. That sometimes requires patients to travel long distances several times a month for something as routine as a blood count or a CT scan, which can limit the potential pool of patients to those who can afford frequent trips to the site and hotel stays.

Amid the COVID-19 outbreak, however, the FDA acknowledged that clinical trials across diseases might be impacted by quarantines, medical and drug supply disruptions, site closures and travel limitations. The agency’s guidance contains 13 considerations on whether to salvage or cancel clinical trials.

The common theme was safety, which the guidance described as “paramount.” Each trial sponsor, clinical investigators and institutional review boards should decide whether the patients’ “safety, welfare and rights [are] best served by continuing ... in the trial as per the protocol or by discontinuing the administration or use of the investigational product or even participation in the trial,” the agency wrote.

Other considerations include the use of virtual visits, delaying recruitment, implementing COVID-19 screening procedures, expediting changes in trial protocol and exploring alternative drug administration methods.

The NCI also has released guidance specific to cancer clinical trials, including recommendations on the overnight shipping of medication to trial participants.

These FDA and NCI guidelines present a unique opportunity to prove the feasibility of receiving some treatment and consultations at local clinics from local teams rather than traveling to large cancer centers, Nichols said.

“This change points out a big problem of patients trying to find clinical trials,” she said. “Previously, if you didn’t have a site near you providing a clinical trial, then getting on one and getting to every appointment was a major undertaking.”

However, because the guidelines are nonbinding and most hospital staff were scrambling to handle the COVID-19 crisis, every organization quickly developed its own priorities, Randall Oyer, MD, medical director of the Ann B. Barshinger Cancer Institute of Penn Medicine’s Lancaster General Health and president of Association of Community Cancer Centers, told HemOnc Today.

“We view being on a clinical trial as a top recommendation for treatment, and we want to maintain that for a number of reasons,” Oyer said. “For one, clinical trials are no longer looked at as a last-ditch effort; they are now the best chance of [a patient] getting cured because they have specific enrollment criteria that match a patient’s specific type of cancer [with treatment] that has been designed for that defect or malignancy. So, when someone’s best option is a clinical trial and you are actively treating cancer, you want to do your best to make sure that continues as long as it’s safe and feasible.”

Oyer added that it is unknown exactly how the virus will affect outcomes of those enrolled on trials for other conditions.

“That’s part of what we hope to accomplish in our reporting process as these trials continue,” he said. “There are standard methods of reporting when a person develops an infection while on trial. Those have been updated to specify suspected or confirmed COVID-19. The investigators look at that and try to develop answers to questions everyone has.”

Long-term changes

With the rules surrounding clinical trials being changed so quickly and easily amid the pandemic, some researchers have suggested that an update may have been long overdue.

They also hope that this could lead to changes in how trials are conducted in the future.

The new flexibility of allowing patients to be treated at local clinics while maintaining virtual appointments with the clinical trial site are among the most impactful changes, experts said.

“I don’t know why we have the narcissistic view in medicine where we think we are the only ones who can see a patient and make an assessment,” Edward S. Kim, MD, FACP, chair of solid tumor oncology and investigational therapeutics and medical director of the clinical trials office at Levine Cancer Institute at Atrium Health, as well as a HemOnc Today Editorial Board Member, told HemOnc Today. “We have medical colleagues and easy access to information. We are proving that we can do remote communication quite effectively.”

The goal is to accomplish as much as possible without forcing a patient to travel to the central trial site.

However, it is unlikely that participation can occur exclusively from a remote or virtual location. That is especially true if the drug under investigation has not been tested in humans and its potential adverse events are unknown.

The feasibility of remote trial participation depends on the likely adverse events of the treatment, as well as the level of testing and documentation required, according to Nichols.

“There are a lot of issues around documentation of taking medicine and disposing of it,” Nichols said. “This is especially true in the oncology field because many of these medications can be toxic to other family members or the person administering it.

“Not every treatment is a pill that can be popped into your mouth, so not everything can be done in a busy local clinic,” she added. “But, even doing 20% more at home or at the local clinic than we are doing now will be a huge help to these patients now and in the future for all clinical trials.”

Even this small shift of conducting more routine treatments at local clinics or through telehealth will change the makeup of most clinical trials across the country.

“A trial that involves taking medicine and then 2 weeks later determining if the patient’s blood count or breathing is better are the kinds of things that can be done at local clinics,” Nichols said. “Medication administration and documentation are going to still be very carefully monitored, but there will be opportunities to send medication to the patient directly or allow them to get medication from the pharmacy and bring it home with them.”

Permanent adoption of these policies could exponentially expand the pool of potential trial participants, thereby improving on the lack of diversity in clinical trials.

This lack of trial diversity is a well-known problem. For instance, a database study by Loree and colleagues — published in 2019 in JAMA Oncology — of all reported landmark trials supporting FDA oncology drug approvals between July 2008 and June 2018 showed that Black (22% of expected) and Hispanic (44% of expected) patients were consistently underrepresented compared with their burden of cancer incidence, whereas white (98% of expected) and Asian (438% of expected) patients were not.

“Increasing remote participation will help more patients get into clinical trials because they won’t have to travel long distances, and it will incentivize local doctors to put patients onto clinical trials because they won’t be losing their patients,” Nichols said.

This process will require that the local treating team be trained, motivated and compensated for participation, Nichols said.

“The local doctors can be trained online, but you have to document that the whole team has read all the trial material,” she said. “We are learning that digital health may help with this because it is not as time-consuming.”

Telehealth

The use of telehealth has been slowly increasing across the country for the past several years.

Now, the world of telehealth is expanding from routine patient visits to clinical trials.

“Previously, if you were not physically present for a meeting for a clinical trial, you were considered absent, even if you were there through a conference or video call,” Kim said. “In the medical community in today’s society, being on the phone or on a video is now part of the norm.”

Experts hope the increased use of telehealth during the COVID-19 outbreak will continue after the pandemic is over.

“Telehealth has been used immensely,” Charles Blanke, MD, professor of medicine at Oregon Health & Science University and chair of SWOG Cancer Research Network, and a HemOnc Today Editorial Board Member, said in an interview. “Without telehealth, everything we have been doing and discussing would have gone out the window and it would have been the end of clinical research until this whole thing is over.

“I am hopeful that clinical trials can now be easier for people who live in rural areas or for those who don’t live anywhere near a cancer center to participate,” he added. “If we can make telehealth a standard of clinical research in the future ... it would be a fantastic positive to come out of this whole COVID situation. I believe it will happen.”

ASCO survey data collected early during the pandemic showed a quick transition to telehealth. Waterhouse and colleagues surveyed 14 academic and 18 community-based clinical trial programs in late March. At that time, more than half of respondents reported remote site initiation visits (65.5%) and remote monitoring by sponsors or contract research organizations (71.9%). A majority of the respondents also reported that their institutions had already implemented remote review of patient symptoms (90.6%) and telehealth visits (87.5%).

However, telehealth may not be a catch-all solution for conducting clinical trials during the pandemic, as not all adverse events can be captured via remote monitoring, Chaya S. Moskowitz, PhD, and Katherine S. Panageas, DrPH, wrote in a viewpoint published in JAMA Oncology.

“As telemedicine options are being implemented at lightning speed, adverse events such as assessment of pruritus can adequately be evaluated using remote video consultation,” they wrote.

“However, adverse events that require testing for organ function or laboratory abnormalities will be affected, complicating interpretation of safety data from these trials,” they added. “The window in which dose-limiting toxic effects are assessed should not be changed to accommodate these challenges.”

Further, obtaining insurance coverage has long been a hurdle in implementing telehealth visits.

As a result of the pandemic, CMS expanded its coverage to cover 100% of the costs of telehealth appointments. However, there is no set standard for private insurers.

“The insurance companies need to allow patients to see their doctors via telehealth,” Kim said. “If there is an agreement that this is safe, effective and satisfactory for patient care, then the insurance companies need to buy in, and we will see it expand exponentially. This is especially true when talking about contagious infectious diseases.”

Moreover, the administration of health insurance in the U.S. may need to change moving forward to better expand access to clinical trials.

For instance, in some states, people with Medicaid cannot participate in clinical trials, Kim said.

“That’s wrong,” he said. “There is a bill in Congress to try to rectify that. We should not discriminate access to clinical trials based on whether someone is able to access the health care system. When patients are on clinical trials, they get the drugs and the tests for free, so sometimes it could be less expensive for them.”

Expanding access to health care will be especially important in the months to come due to the widespread job loss, and resulting loss of health insurance, associated with the economic downturn related to the pandemic.

“We have been advocating for the loosening of some restrictions in the insurance industry,” Nichols said. “A patient’s insurance may only cover inpatient infusions at a specific clinic in New York City, and now the only place they can safely get it is at their local clinic or by a nurse coming to their house. Their insurance may not cover that. This is a terrifying time even for people getting regular therapy outside of clinical trials.”

Impact on drug development

Although the pandemic stands to have a profound impact on how clinical trials are performed in the future, it will undoubtedly affect which current clinical trials can continue, potentially stunting drug development in the coming years.

“Many of the big centers where these trials are happening can’t afford to deal with adverse events related to cancer trials because of COVID-19,” Nichols said. “So now, we are asking which trials are critical to continue and which ones should be put on hold or canceled.”

Further, because the standard for initiating a trial has been raised, there may be fewer studies published over the next year.

“We raised the bar for activation of new studies at our institution,” Blanke said. “In general, we are still looking at trials that offer treatments with a potentially immediate and real benefit to the individual patient. In other words, we are not doing trials that have placebos, where half the group doesn’t even get the therapy, or population-based studies for prevention.”

Blanke added that accrual fell about 50% immediately after the COVID-19 outbreak and consequent shutdown.

Such changes may affect the pipeline of drugs that are approved in the coming years, experts said.

As of July 1, the launch of five drugs had been delayed due to COVID-19, according to reporting from Reuters. This included one oncology drug, isatuximab-irfc (Sarclisa, Sanofi Genzyme), which was launched in March for the treatment of multiple myeloma but the full commercialization for which was subsequently delayed until the pandemic subsides.

Many more drugs further down the pipeline also may be impacted.

“The global effort to find a treatment or vaccine for COVID-19 is taking up a lot of oxygen in the clinical trial space,” Kenneth I. Kaitin, PhD, professor and director of the Tufts Center for the Study of Drug Development, told HemOnc Today. “There are trials being delayed or canceled all around the world, not just in the United States. The result of this will be a slower introduction of new medicines reaching the market.”

The slowdown could be substantial in the oncology field because, before the pandemic, it was the preeminent field for research and development, Kaitin said.

Between 2010 and 2018, the number of cancer drugs approved was double the next therapeutic area, according to a review of drug approvals conducted by Kaitin and colleagues at Tufts University.

Breakthroughs in immunotherapy have contributed to that explosion in development, Kaitin said, but there may be a lag before this development can take off again.

“A lot of companies that were doing these clinical trials are going to be downsizing if they are not focusing on COVID-19,” he added. “They’re having trouble conducting the trials, they have overhead to pay, funding is decreasing and, at least in the short term, some stock prices have fallen. Even when this all gets under control, there will need to be a ramp-up period where companies rehire and get their sites up and running at full capacity again.”

The economic downturn may also affect companies’ ability to obtain a reasonable return on investment after their drugs reach the market.

“Patents are generally awarded during an early stage of preclinical development before the drug is approved, a stage referred to as lead identification and optimization,” Kaitin said. “If it takes you an extra year to get your drug on the market, due to delays in the development phase, then you’ve lost a year of effective patent life.

“Of course, because nearly all companies are in the same boat, this might not put any one company at a competitive disadvantage,” he added. “Yet, in an area like cancer drug development, where drugs tend to receive relatively rapid regulatory review and approval, there is likely to be a mad rush to the finish line for most competitors. I think nearly all companies are aware of this and already take it into consideration in their development planning.”

Potential limitations of telehealth also may affect drug development.

According to the viewpoint by Moskowitz and Panageas, endpoint analyses of ongoing trials might be impacted by modifications or delays in assessment of patient monitoring, which could skew the determined efficacy of agents under review and prematurely halt their investigation.

“In single-arm early-phase studies, delaying or skipping early scans may result in missing responses for therapies with a short duration of response, affecting estimation of both the objective and best overall response rates,” they wrote. “Failure to capture these responses will result in underestimation of the response rate and may lead to overlooking potentially promising therapies. Trials using a two-stage design may be stopped erroneously.”

However, accrual issues shouldn’t impact trial results, Oyer said.

“Individual cases that are missing significant data points cannot be included in final published results of clinical trials,” he said. “But, the flexibility of the NCI and FDA has now given us the responsibility to document everything that happened with the trial and why a patient on trial may not be able to travel into a distant medical center and instead will need follow-up with a local oncologist who will pinch-hit for the clinical trialist. No one is going to take irresponsible risks with these patients.”

Trials after COVID-19

Despite the impact of the economic downturn and pandemic on cancer clinical trials, researchers are confident a silver lining will emerge in the form of a permanent, positive change in the way trials are conducted.

If some of changes are adopted as a standard — such as those that expand trial access to patients in remote locations — the industry could benefit in the long term and come out better on the other side.

“Any time there is a tragedy, you try to take positives out of it,” Kim said. “Sept. 11 was a horrible day for the world, but it exposed the lack of communication between various agencies and first responders in terms of what radios or frequencies they were on. It started a conversation on how they could all connect and have a coordinated effort.

“In this case, COVID-19 is forcing us to set aside our own biases and, for the safety of our patients, do telehealth and let these trials continue at a different area,” he added. “And wow, we have realized we can practice a lot of medicine this way.”

References:

FDA. FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency. Available at: www.fda.gov/media/136238/download. Accessed July 6, 2020.

Kaitin KI (ed). Cancer drug approvals grew from 4% of U.S. total in the 1980s to 27% in 2010-18. Tufts CSDD Impact Report. Tufts Center for the Study of Drug Development. September/October 2019;21(5).

Loree JM, et al. JAMA Oncol. 2019;doi:10.1001/jamaoncol.2019.1870.

Moskowitz CS and Panageas KS. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2020.2370.

NIH. Coronavirus guidance. Available at: https://ctep.cancer.gov/investigatorResources/corona_virus_guidance.htm. Accessed July 6, 2020.

O’Donnell C and Mishra M. New drug launches stalled by COVID-19 pandemic. Reuters. July 1, 2020.

Waterhouse DM, et al. JCO Oncol Pract. 2020;doi:10.1200/OP.20.00275.

For more information:

Charles Blanke, MD, can be reached at blankec@ohsu.edu.

Kenneth I. Kaitin, PhD, can be reached at kenneth.kaitin@tufts.edu.

Edward S. Kim, MD, FACP, can be reached at edward_kim@kenan-flagler.unc.edu.

Randall Oyer, MD, can be reached at randall.oyer@pennmedicine.upenn.edu.

Gwen Nichols, MD, can be reached at gwen.nichols@lls.org.