Bioethicists, pharmaceutical companies and contract research organizations (CROs) are going to study the COVID-19 vaccine trials and distribution for decades to come. The scale with which trials were launched and the speed at which they were completed was incredibly impressive. But industry leaders have already pointed out missteps and lessons for future improvement.
Clinical trial experts are following those conversations closely. In particular, they want to know how CROs and medical professionals can attract such a high level of interest in future clinical trials, and how they can make those trials more effective.
Clinical trial professionals across the country were pleased with the willingness of Americans to participate in COVID-19 vaccine trials. Many leaders who have spent years trying to improve recruitment strategies suddenly found hopeful candidates showing up.
Paul Evans, president and CEO of Velocity Clinical Research in North Carolina, said in August 2020 that his company planned to recruit 10,000 volunteers to participate in the COVID-19 vaccine trials. He said he was surprised at how eager people were to participate.
“I’ve been working in this business for 30 years,” Evans. said “Outside of a COVID study, you might have to reach out to four or five, up to 10 people to find [one person] who is suitable.”
One big reason for this was the media coverage surrounding the COVID-19 vaccine and its clinical trials. The nation looked on eagerly as the first trials started. This interest turned into advertising dollars and marketing campaigns.
In Rochester, New York, local entrepreneur Todd Butler launched a campaign called "Bring Roc Back" to encourage people to sign up for COVID-19 vaccine trials. The campaign featured photos of community members before the pandemic, enjoying activities like family birthday parties, concerts and conferences.
"Not only do we have a message that's intended to draw upon the emotional connection that people have to things that they can't do anymore," Butler said. “We're also trying to live this in a way that allows people to feel that this is a trustworthy thing to do.”
While future clinical trials might not have the same level of awareness or number of eager patients, residual collective memories of this pandemic could encourage more people to sign up for future trials.
Having distributed trial locations across the country certainly made it easier for Americans from all walks of life to participate in the vaccine trials.
“A great deal of attention and research has been paid to the reasons why patients don’t participate in trials,” says Dr. Joseph Unger, associate professor at the Fred Hutchinson Cancer Research Center in Seattle. “It leaves the impression that patients themselves are the main barrier to trial participation, when, in fact, many structural and clinical barriers get in the way long before patients are offered the option of a trial.”
For example, the Applied Research Center of Arkansas is the only site in the state that has been approved to conduct phase III trials of the AstraZeneca COVID-19 vaccine. Donna Wright, a nurse practitioner and owner of the center, had 100 participants in November willing to take part in the trial. Her goal was to test 1,000 to 1,500 people. The discrepancy was due in part to the fact that participation for those outside of Little Rock was difficult. Participation for those patients means time, money and transportation costs.
Even eager participants might not realize how involved a clinical trial is until they start learning about the terms and conditions. In an article for Healthline, Dr. Richard Novak, chief of the division of infectious diseases at the University of Illinois at Chicago College of Medicine, explains how trial participants will need to commit to the Moderna trial for two years.
Over that time, they will have attended about 10 on-site visits, have had their blood taken, and have any symptoms or changes in health recorded in a digital diary. That commitment could be too steep for many potential participants.
It’s entirely possible that the COVID-19 vaccine will impact future studies, particularly how researchers treat placebo patients.
Currently, doctors and trial leaders are grappling with whether they should tell placebo patients that they didn’t get the active, which could compromise data from blind or double-blind experiments. Does the need for strong data outweigh a single person’s need for protection during a pandemic?
“In the face of the surge that we are in now, I personally would have a very hard time continuing people on placebo knowing that you’re going to see more cases of COVID and potentially deaths,” says Dr. Susan Little, professor of medicine at University of California San Diego.
When people signed up for the COVID-19 vaccine trial, they knew there was a chance they would get the placebo. Many took the risk in hopes of getting a live vaccine that worked. The vaccine manufacturers have since begun calling participants to let them know whether they received the live vaccine or placebo.
While most patients opt to receive the live vaccine after they are told they are on a placebo, a few have opted to keep on the trial as a placebo candidate and will avoid getting the vaccine for the rest of their two-year agreement. Dr. Carlos Fierro, principal investigator at Johnson County Clinical Trials in Kansas, supports letting trial candidates know their status so they can take action to protect themselves.
"It's a loss from a scientific standpoint, but given the circumstances, I think it's the right thing to do," he says.
Some researchers are already looking at ways to conduct clinical trials in the future that can protect placebo recipients.
Steven Goodman, an epidemiologist from Stanford University, recently proposed using a blinded crossover process, in which trial participants receive another round of shots. In the second round, the placebo group gets the active vaccine and vice versa. The only difference is the arm in which they are injected. Goodman believes this option can reduce bias while allowing for better data collection.
Another interesting lesson to come from the COVID-19 vaccine’s development is how some patients were willing to consider human challenge trials. With this process, patients are intentionally exposed to the virus in a controlled setting to learn more about the disease and test different treatments.
“Deliberately infecting volunteers with a known human pathogen is never undertaken lightly,” says Peter Openshaw, an immunologist at Imperial College London. “However, such studies are enormously informative about a disease.” Openshaw believes that these studies can “de-risk” the development of drug treatments and vaccines.
Human challenge trials differ from the phase III COVID-19 vaccine trials, where patients either receive a placebo or live vaccine and doctors test which group has more infections. “Challenge trials have a lot of promise and potential,” says Seema Shah, a bioethicist at Northwestern University. “But we have to be sure that they're going to realize that potential and that we can manage the risks appropriately.”
Studies like these are crucial in answering questions that go beyond the scope of this immediate pandemic. In the U.K., a CRO called Open Orphan is running a challenge trial that tests patients from 18 to 30 years old.
“Data from this study will immediately facilitate the challenge model to be used for vaccine efficacy testing as well as to answer a wide range of fundamental scientific questions that are not feasible with traditional field trials, such as exactly what type of immunological response is required to confer protection from re-infection," says Dr. Andrew Catchpole, the company’s chief scientific officer.
Historically, human challenge trials have been used for diseases like malaria or typhoid, which are treatable and have a cure. This is not the case for COVID-19 human challenge trials.
Looking ahead, future COVID-19 human challenge trials could be valuable for better understanding the disease and for better vaccine development, but they would require a larger sample size of the population. That would conflict with the current efforts to get people vaccinated today.
“Denying the most promising existing protection (the proven vaccine) to thousands of participants not only raises questions about their fair treatment, it also complicates their recruitment,” Nir Eyal, Arthur Caplan and Stanley Plotkin write in The BMJ.
There are plenty of takeaways for CROs evaluating phase III of the COVID-19 vaccine trials. Researchers can better understand patient behavior, what motivates people to sign up and what pushes candidates away. There is also a very human aspect to these trials, and how CROs and researchers answer those questions today will reverberate throughout future research.