As we begin to lift our heads and think about what post-pandemic life might look like, many of us now have a different appreciation for the role clinical trials can play in our medical care. One of the most frightening things, early on in the COVID-19 pandemic, was how little was known about how to treat the illness—but a key component of an academic medical center’s mission is to identify and develop treatments for difficult diseases. So at Yale, doctors treating COVID-19 patients were able to give them access to new treatments via clinical trials even early on in the pandemic.
“Since nobody knew the best way to treat COVID-19, most of the people who came into the hospital with the virus—and even those whose disease severity allowed them to stay at home—were offered a clinical trial if we thought there was a reasonable one that might help them and lead to better understanding of the disease,” says Brian Smith, MD, co-director of the Yale Center for Clinical Investigation (YCCI) and deputy dean for clinical and translational science at Yale School of Medicine. This approach was consistent across the Yale New Haven Health System at its multiple sites along the Connecticut coastline, from Greenwich to Westerly, Rhode Island.
But this was challenging to pull off.
In March 2020, life changed at Yale School of Medicine, just as it did everywhere else. Researchers running clinical trials for everything from diabetes to heart disease had to put hundreds of those studies on pause (exceptions included active therapeutic trials where patients needed to continue treatment to manage their disease).
As severe cases and deaths related to COVID-19 began to multiply, and the realization set in that their expertise was needed to address COVID-19, many researchers pivoted their investigative work to address the pandemic.
Doctors and researchers shared ideas and insights, launching collaborations among colleagues, not only at Yale but worldwide. Nancy J. Brown, MD, Dean of Yale School of Medicine, convened the COVID-19 Response Coordination Team (CoReCT) as a university-wide collaboration to bring the broadest possible expertise together to address the pandemic. “We knew that we needed to be agile and work across boundaries,” Dean Brown says.
Members of a new institutional review panel held virtual meetings seven days a week to review new research proposals. Within a month, the board had approved more than 180 COVID-related trials, a number that would mushroom in the ensuing months. By March 2021, the YCCI was immersed in no less than 59 pediatric studies and 657 adult studies, approaching COVID-19 from a multitude of angles. A year after the pandemic began, as many as 4,500 people had participated in a COVID-19-related clinical trial at Yale.
“We’ve been able to do extraordinary work in unprecedented times,” says Tesheia Johnson, MBA, MHS, deputy director and chief operating officer of YCCI. “We had studies that literally went from early-stage concept review to activation in four or five days, and that just wasn’t heard of before COVID.”
Different kinds of COVID-19 clinical trials
Just like everyone else, Yale researchers have had their own pandemic stressors to deal with, including juggling work with childcare, feelings of isolation, fear of exposure, and worries that loved ones could get infected. All of that was both difficult and motivating as they joined colleagues across the country in studying COVID-19. “To be honest, I don’t do this type of research a lot,” says Charles Dela Cruz, MD, PhD, a pulmonary specialist who also runs a laboratory that studies pathophysiology and cell-based studies, among other things. “But the pandemic showed up on our doorstep.” Dr. Dela Cruz often treats patients in the intensive care unit. “I just felt like I needed to contribute to figuring out how to treat COVID-19.”
At first, most of the trials focused on hospitalized patients with severe illness; later, investigators tackled vaccines and treatments to help people fighting the disease at home avoid hospitalization. “Registries, therapeutic, non-therapeutic—the trials have been across the board,” Johnson says. “We’ve done COVID-19 research in every category.”
Vaccines: Some of the most exciting trials focused on potential vaccines, partly because progress was, by necessity, rapid and productive. Last summer, Yale New Haven Health was one of 150 testing centers around the world to host Pfizer-BioNTech’s Phase 3 vaccine clinical trials, which contributed to the establishment of Pfizer vaccine’s 95% efficacy rate against the original virus. Onyema Ogbuagu, MBBcH, an infectious diseases specialist, was Yale’s principal investigator for—and one of the earliest recipients of—the Pfizer vaccine, the first one to be administered in the U.S. in December 2020 when it was granted emergency use authorization (EUA) from the Food and Drug Administration (FDA). “It’s exciting to not only study a drug and see how well it works, but also receive it yourself and the benefit firsthand,” Dr. Ogbuagu says. He also is directing Phase 2 trials for another vaccine—an adjuvanted recombinant protein-based vaccine (similar to influenza vaccines) from a company called Sanofi.
Treatments: Dr. Ogbuagu also conducted clinical trials at Yale for remdesivir, the only COVID-19 treatment so far to receive full FDA approval. Yale has also been the site for studies of other treatments, including convalescent plasma, led by Mahalia S. Desruisseaux, MD, which has been described as potentially promising if given to a patient within a few days of diagnosis.
In collaboration with neurosurgeon Murat Gunel, MD, Dr. Dela Cruz served as principal investigator for a multi-institutional Phase 2 trial that (the two doctors hope) may eventually lead to a drug that could be given soon after infection to prevent people from getting seriously ill. Dr. Dela Cruz says that the drug being studied—LAM-002A (apilimod)—is one of the most promising treatments for newly infected patients. Already in use for some autoimmune diseases, it has a proven safety record and has been shown to block cellular entry and trafficking of the SARS-CoV-2 virus.
Because potential candidates for the drug need to be identified soon after infection, it was difficult to get the 142 participants needed for the LAM-002A trial, says Dr. Dela Cruz, noting that this grew easier as testing became quicker. Because the trial participants were infectious, the study presented logistical challenges, too. (A newly created clinical trial unit was rapidly brought up at Yale’s West Campus, equipped with the necessary negative pressure units and was also spacious enough to meet physical distancing requirements.) The study took seven months to complete. Data is currently being analyzed, with additional phases to be based on the results.
One of the lessons [of the pandemic] is that you really can achieve a lot when everyone’s attention is on one thing. Charles Dela Cruz, MD, PhD, a pulmonary specialist who also runs a laboratory that studies pathophysiology and cell-based studies
Some clinical trials have been pursued with astonishing speed; others are moving slowly—some could take years to yield results, which is exactly how things happen in the world of medical research. “Not all of these trials are going to have some fabulous cure at the end, and some will have negative results,” says Dr. Smith. “But, negative trials are just as important as the positive ones, because they can tell you what not to do. Sometimes, that can steer you into determining what you should be doing.”
A structure was in place
Though the pandemic presented many opportunities to conduct impactful scientific research, there were also obstacles. “I don’t think any of us would deny that this has been challenging in ways you might not think about,” says Dr. Smith. For example, in normal times researchers often work closely together—maybe sharing a microscope in a laboratory so that more than one person can look at something. “The need for physical distancing was challenging,” Dr. Smith says. And researchers needed personal protective gear, such as N95 respirators, which at times were very hard to get.
Another issue was communicating about clinical trials with family members of people who were being treated in the hospital. “We couldn’t connect with families by the bedside—it had to be by phone or Zoom,” says Dr. Dela Cruz. “It’s a random person calling on the phone saying your loved one is not doing so well and there are clinical trials available. But many of our families were willing to participate to make their loved ones better.”
Up-to-date technology was invaluable. The electronic medical record provided real-time data (with privacy safeguards in place) that allowed researchers to monitor the COVID-19 situation as it evolved, providing quick views of how many patients were in the hospital or on ventilators at a given point. “That data was also being shared across the country,” Dr. Smith says.
Zoom and telehealth platforms helped, too, and may bring permanent changes to the world of medical research. “I think what we’re seeing is this real trend—people love the fact that they can participate in a clinical trial with fewer visits to Yale,” Johnson says. “They say, ‘This is great, I would participate in more studies if I could do it from my living room.’ So, these are the things we need to keep doing.”
COVID-19 intensified the challenges of convincing people of diverse backgrounds to join a clinical trial. The virus hit people of color especially hard—American Indians, Black Americans, and Latinos are all about three to four times more likely to be hospitalized from the disease than white Americans.
But, at Yale, more than 40% of the participants in YCCI’s Phase 3 Pfizer vaccine trials were people of color, and that’s partly thanks to another organization that was already in place: the 10-year-old YCCI Cultural Ambassadors program, a partnership between YCCI, the African Methodist Episcopal (AME) Zion Church, and Junta for Progressive Action, that aims to increase diversity so that research will benefit people of all backgrounds. The Ambassadors distributed masks and shared important information in their communities about the need to help find cures and test vaccines.
One of those ambassadors was Rev. Leroy O. Perry, paster of St. Stephen’s AME Zion Church, who shifted his efforts as an Ambassador to the pandemic. “There is social, psychological, and historical resistance when it comes to minority involvement in medicine in America,” Rev. Perry says. “Much of our work over the past 10 years has been dedicated to addressing the concerns that have caused this resistance.” He now meets weekly with health professionals and community leaders making sure people in the community have accurate information about the vaccines as well as access.
“I personally took part in the Pfizer study to demonstrate the need for minority participation and to hopefully arrest any fears as to the safety of the vaccine,” Rev. Perry says. He encouraged family members, friends, and parishioners in his church to do the same.
How could COVID-19 steer future clinical trials?
In 2021, the pandemic continues to be unique in the world of clinical trials, says Dr. Dela Cruz. “Nobody could have imagined this,” he says. “It’s almost like a big experiment, where you have one virus infecting a large population. One of the lessons is that you really can achieve a lot when everyone’s attention is on one thing—and that’s everybody, not just clinicians and researchers, but also companies, government agencies, funders, and policymakers.”
Still, researchers hope COVID-19 clinical trials at Yale and across the country will motivate more people to participate in trials for all kinds of diseases, even in normal times. “I share the success of my congregation in Branford. Ninety-seven percent of them have taken the vaccine, and five participated in the Pfizer study,” says Rev. Perry, who hopes this will set an example for the future.
Dr. Smith hopes people will look at effective COVID-19 vaccines that are already being administered and the treatments that could help prevent severe illness in the future and realize the role clinical trials play in medical care. “This is how we make advances in the ways we care for patients, families, and the greater community,” he says. “It’s good for me. It’s good for you. And it’s good for all of us together.”