COVID-19 forced researchers to try new ways of running clinical trials. Now they want to make some of those changes permanent.
Courtesy of Patrick Boyle, Association of American Medical Colleges (AAMC)
When COVID-19 forced Penn Medicine Abramson Cancer Center to scale back its clinical trials last year, investigators there worried about how pandemic restrictions might impede research into the fight against cancer. How could they run trials if patients couldn’t come to the Philadelphia center for treatments, tests, and evaluations? In addition, nearly 90% of its clinical trials temporarily suspended enrollment when the pandemic restrictions began.
Then investigators started working with trial participants in ways that seem simple but had not previously been allowed by government regulators or companies that sponsor trials: They shipped research medications to patients, let them get some tests done at their local doctor’s offices rather than at the cancer center, and enrolled some participants remotely rather than by meeting them in person.
A little more than a year after the COVID-19 restrictions began, the center’s clinical trials are approaching full capacity, says Center Director Robert Vonderheide, MD, DPhil.
Across the country, countless trials that were severely cut back or paused because of the pandemic managed to keep going by changing long-standing practices — and some of those changes could become permanent.
“We’ve learned that certain demands that we assumed to be the way a clinical trial has to work are challengeable,” Vonderheide says. “We’re rethinking doing clinical research in ways that the pandemic showed us were possible, safe, and effective — and probably more cost-effective.”
Even before COVID-19, momentum was building among researchers, regulators, and sponsors to rethink the rules and practices that have built up over the years around clinical trials. The pandemic provided opportunities to test some of the ideas.
“Major changes in clinical trials practice have been embraced nationwide,” a group of researchers wrote in the Journal of the National Cancer Institute last fall. “There is a growing consensus that the regulatory and clinical research process alterations that have been adopted in response to the pandemic … should be implemented long term.”
Alan Bryce, MD, chair of the Division of Hematology and Medical Oncology at Mayo Clinic in Arizona, says most of the ideas share one objective: “We can make trials more friendly to both patients and staff.”
Below are some of the main ideas for how to do that.
Participating in a clinical trial is such a big decision that researchers almost always sit down with potential participants in person to walk them through the process and answer all questions: about the science behind the therapy that’s being tested (including how an experimental drug works in the body), about procedure details (such as how often the person will have to visit the clinic where the trial is being conducted), about potential benefits (such as slowing degradation from a disease), and about risks (including side effects).
The pandemic forced many researchers to conduct those conversations online and get written consent through electronic documents. That allowed people to join trials that they otherwise might not have. For example, Massachusetts General Hospital (MGH) and Boston Medical Center used a mix of in-person and remote meetings to enroll dozens of women in a study of breast cancer survivors, says Erica Warner, ScD, MPH, project director of the Harvard/MGH Center on Genomics, Vulnerable Populations, and Health Disparities.
But while remote consent “sounds good in theory, many patients and research teams might not prefer it,” says Daniel Ford, MD, MPH, director of the Johns Hopkins Institute for Clinical and Translational Research (ICTR) in Baltimore.
At the ICTR, people didn’t sign up for trials any more frequently after remote consultations than they did through in-person meetings before the pandemic, Ford says. Other trials reported mixed results. Researchers believe the remote process can impede their ability to personally connect with some potential participants and instill confidence in the trial.
Still, they hope that remote screening and consent will remain an option. “We’re not saying replace” in-person consent, Vonderheide says. “We’re saying permit this tool to be deployed” in the right circumstances.
One common impediment for participating in a clinical trial is traveling to the trial site for various procedures and consultations anywhere from every couple of months to several times a week. The burden is particularly heavy for people who must travel long distances or have limited access to transportation, such as those who need to use public transit or rely on someone to drive them to their appointments.
“When a patient has to come to Center City Philadelphia once a week, and they live an hour away, that’s discouraging” for those who are thinking of joining a trial, Vonderheide notes.
During the pandemic, researchers rethought what procedures needed to be done in person.
“Suddenly, you could do video visits” and accomplish many of the same objectives, explains Bryce at Mayo. Some trials at Mayo, he explains, expanded the period between required visits to the site by several weeks.
But as anyone who has joined a Zoom meeting knows, video gatherings can be clunky. Some patients are not adept at using computers and phones to participate in meetings. Others feel that in-person meetings give them more personal and focused attention, which can be especially important to people who are in a clinical trial to treat a severe disease, notes a journal article by researchers at Tufts University.
“We’ll find the balance” on when to use remote and in-person visits, Ford says.
Traditionally, clinical trial medications are administered at the trial site, where staff can assess patients to determine if doses should be changed, correctly administer the drugs, and (in some cases) monitor the effects. During the pandemic, many patients were reluctant or unable to come in to receive their medications.
Some trials started sending research medicines to their patients — particularly those that people could easily and safely take at home, such as certain pills and liquids.
Several factors must be taken into account, explains Ruben Mesa, MD, executive director of the Mays Cancer Center, home to UT Health San Antonio MD Anderson. The center’s questions included: Does the medication require special skills or supplies (such as injections)? Does it need to be shipped or stored in a specific way (such as at certain temperatures)? Can the researchers monitor the patient remotely to adjust the doses if necessary?
Adopting this as a routine procedure would make it easier for people to join and remain in trials — especially those who travel long distances to get to the trial site.
You’ve got to drop everything and hang out at the medical center that’s providing the medicine,” Mesa says of the requirement. “If a patient is self-administering a medicine, it certainly makes the trial much easier to participate in.”
Mesa suggests that in the future, even medications that need to be administered by trained medical personnel — such as through an IV — could be sent to a medical facility near a patient’s home. He wonders, “What if you have a local doctor on the other side who is willing to accept the medicine and administer it to the patient?”
Participants in clinical trials often undergo a dizzying array of tests and biological data collection that they don’t understand the need for — and sometimes the researchers don’t, either. Many of the procedures are required by government oversight agencies and trial sponsors (which provide funding, oversight, and data analysis), in part based on the theory that the more information that’s gathered, the better.
“Many of these tests are unnecessary for the purposes of the trial,” Vonderheide notes.
The requirements have grown over the years along with the development of more ways to measure and assess elements in the human body, like the makeup of tumors, says James Doroshow, MD, director of the Division of Cancer Treatment and Diagnosis at the National Cancer Institute. He notes that requirements have gradually expanded to a point “that is difficult to sustain”.
“Someone has to get it [the sample] from the patient,” he explains. “Someone records that in the health record. It gets put into another database. It involves data managers, doctors, nurses, pharmacists. It becomes very expensive” and time-consuming.
When COVID-19 hit, trial investigators worked with regulators and sponsors to implement several changes already under consideration to make testing less burdensome for patients. They reduced the number of tests required, lengthened the time between tests, and arranged for samples to be collected at sites closer to patients’ homes, such as at local hospitals.
“We learned that not every blood test for every time point for every trial has to happen at our clinic,” Vonderheide explains. Collecting those samples at facilities near participants’ homes “was really convenient for patients. There was no degradation of data integrity and there was no danger to patient safety.”
Oversee from a distance
Staff from organizations that sponsor clinical trials typically spend a significant amount of time at the sites before and during the trials. They examine each site to ensure that it meets the sponsor’s requirements, train investigators on procedures such as data input, monitor the trial for quality control, and interview investigators and patients.
“Clinical trials normally have a fairly intense face-to-face monitoring process,” Mesa says.
Much of that work was done remotely during the pandemic. Monitors received data and reports electronically, conducted interviews by phone and videoconference, and had their questions answered by email. Many investigators and monitors think a lot of those practices should continue.
The in-person visits “impose tremendous travel requirements on sponsor employees,” require significant coordination between trial and sponsor staff, and consume precious time and space at the site during the visits, nine University of Pennsylvania researchers wrote in a paper published online last month in the journal Cancer. They urged that sponsors conduct “nearly all” of their activities remotely.
“The pandemic has demonstrated that most sponsor activities can be performed virtually without compromising quality,” they wrote.
In a presentation last December about remote monitoring and auditing of trials during the pandemic, administrators at Memorial Sloan Kettering Cancer Center presented data about the impact of that practice since it began there in 2011. The center, based in New York, reported that remote monitoring resulted in shorter visits between research associates and monitors, faster turnaround time for answering monitors’ questions, and significant cost reductions for each monitor.
Researchers are optimistic that regulators and sponsors will provide continuing flexibility to implement these and other changes. Some changes are already underway: The Food and Drug Administration, which had started to explore clinical trial changes before the pandemic, published updated guidelines last November.
More revised guidelines appear likely, as everyone rethinks many of the trial requirements that have accumulated over the years.
“A lot of questions [about requirements] are evolving,” Mesa says. “Which of them really were necessary versus which were just business as usual? What’s effective? What isn’t?