In March, as grim headlines grew of Chinese and Italian hospitals overwhelmed by patients sickened by the novel coronavirus, physician-scientists Albert Ko, MD, and Carrie Redlich, MD, MPH, worried about how to keep Yale New Haven Hospital (YNHH) health care workers safe. YNHH admitted its first COVID-19 patient on March 14. Just over two weeks later, Ko and Redlich began enrolling participants in the medical school’s first two COVID-19 clinical trials. “The response was overwhelming,” Redlich says. “We recruited 1,500 health workers in record time and still receive emails from people who want to join.”
Ko, chair and professor of epidemiology (microbial diseases) at Yale School of Public Health, and professor of medicine (infectious diseases) in the medical school, and his team started a trial to detect which health care workers and patients at YNHH and its affiliated hospitals and clinics had active viral infections. His team collects participants’ nasal swab samples and stores them in a biorepository for current and future research.
Redlich, professor of medicine (occupational medicine) and of environmental health sciences, and her colleagues collect blood samples of health care workers who may have been infected, relying on serology tests.
“Even if we didn’t fully understand the biology of the virus yet, we could put measures in place to prevent our health care workers from getting infected,” Redlich explains.
How did both physician-researchers start their observational trials so quickly? A significant part of the answer comes from a reorganized and streamlined Yale Center for Clinical Investigation (YCCI).
Without a centralized infrastructure in place, “investigators like Ko and Redlich would not have been able to start their trials so soon,” says Eric Velazquez, MD, Robert W. Berliner Professor of Medicine (Cardiology).
‘It’s kind of amazing’
In early March, the U.S. was flying blind into a national public health emergency the likes of which had not been seen since the Spanish flu of 1918. COVID-19 put the country’s unprepared federal, state, and local health agencies in a vise grip, making swift, coordinated action difficult.
However, YCCI was poised to be agile. Its leadership had—albeit unwittingly—been preparing to handle a pandemic.
In April 2019, Velazquez was appointed YCCI’s deputy director for clinical trials innovation. Velazquez had led several landmark cardiology clinical trials before arriving to Yale a year earlier. In the spring of 2019, YCCI’s leadership began to address two challenges. First, the center needed to begin working on a 3,997-page grant renewal application for the Clinical and Translational Award (CTSA), a five-year grant from the National Institutes of Health. Since 2006, the CTSA has provided the lion’s share of YCCI’s funding, in addition to support from the medical school, Yale Medicine, and YNHH.
As part of that submission, Velazquez and his team wanted to reorganize the center so that it could function with even greater efficiency.
“The goals were to develop a central authority to evaluate and review the conduct of clinical trials, and put in place mechanisms to be responsive to the regulatory needs of our investigators,” Velazquez says.
By January, as COVID-19 began its global spread mostly under the radar, YCCI had a centralized command center with a single study intake process for research initiated across the university, a streamlined participant consent process, and a knowledge hub that accounted for every single ongoing investigational new drug (IND) application to the Food and Drug Administration (FDA).
When the pandemic arrived in New Haven, YCCI leadership knew that the vast majority of its hundreds of ongoing trials needed to be paused for the safety of their participants, who could no longer go into hospitals and clinics due to a risk of exposure to the virus.
“In a systematic way, we paused almost all non-COVID clinical participatory research,” Velazquez says. “This happened in one week. It’s kind of amazing.”
YCCI, under the leadership and round-the-clock guidance of co-directors John Krystal, MD, chair of psychiatry and Robert L. McNeil, Jr. Professor of Translational Research and professor of psychiatry and of neuroscience and Brian Smith, MD, chair and professor of laboratory medicine, of biomedical engineering, of medicine (hematology) and of pediatrics, could not have acted so swiftly without an enormous team effort from departments and offices across the university.
“Faculty and leaders within Yale’s clinical research programs recognized this as an extraordinary time and came together to face the challenge,” says Smith, who is also Deputy Dean for Clinical and Translational Research. “So many people need to be recognized for their hard work.”
Tom Balcezak, MD, MPH, chief clinical officer of Yale New Haven Health, worked with the system’s hospitals, from Bridgeport to Greenwich, to arrange for a single institutional review board (IRB) facilitating both the safe pause of existing trials and the enrolling in newly activated COVID-19 trials. YNHH funds one-third of YCCI’s budget, Smith says.
Linda Coleman, director of Yale’s Human Research Protection Program (HRPP), put in long hours to quickly restructure Yale IRBs, developing a new COVID-19 IRB review panel that met seven days per week to support the research community to modify existing clinical trial protocols and help new ones get approved. The HRPP provides administrative and regulatory support to the university’s six IRBs, among its many other roles. YCCI staff members, clinical leaders, and YCCI’s Deputy Director Tesheia Johnson, MBA, MHS, met weekly to answer questions from investigators and to prepare for COVID trials.
With this shift in focus, YCCI was able to handle “a tsunami of phenomenal ideas from our investigative community,” Velazquez says. For any trial that included testing a treatment or drug, YCCI provided support for investigators to submit new drug applications (NDAs) because COVID-19 was a brand-new disease. NDAs are demanding due to their regulatory-intensive nature, Velazquez says. “We had a process to get those studies evaluated, refined, and enhanced to link investigators to resources they would need” for the applications, he adds.
The time from idea to starting a clinical trial, together with feedback and FDA approval, dropped dramatically, from a six-month or more process, to about 10 to 20 days. This time frame includes submission, approval, and first patient enrollment, Velazquez says.
Lisa Mosley, executive director of Yale’s Office of Sponsored Projects and Jeff Allen, director of Clinical Agreements in the university’s Office of Sponsored Projects, helped trials get contracted in two or three days, which is “an incredible timeline,” Smith says.
Yale Medicine’s CEO Paul Taheri, MD, together with Marna Borgstrom, CEO of YNHH and Yale New Haven Health, and other clinical leaders arranged for certain clinical trials to stay up and running, while also leading preparations to provide care for COVID patients admitted to the hospital.
“We have Alzheimer’s disease, cardiology, and cancer trials—just to name some—that provide patients with clinical care and we couldn’t shut those down,” Smith explains.
While YCCI tested its streamlined process on COVID-19-related trials, two multi-disciplinary teams joined forces to sort through the quickly changing field of COVID-19 and identify promising research ideas.
Early on, Nancy J. Brown, MD, Jean and David W. Wallace Dean of Medicine and C.N.H. Long Professor of Internal Medicine, invited researchers from across the university to join the COVID-19 Response Coordination Team (CoReCT) with the goal of facilitating collaboration among scientists and physicians around the world to combat COVID-19 . CoReCT formed a number of subcommittees, including one focused only on clinical trials led by Murat Gunel, MD, chair and Nixdorff-German Professor of Neurosurgery and professor of genetics and of neuroscience.
Among the estimated ongoing 35 therapeutic clinical trials, all aspects of COVID-19 are being addressed. “I think it’s important to point out that this is not a single disease,” Gunel says. Some preclinical studies are addressing prophylactic approaches, with vaccines as the primary focus. Other basic science research is addressing different pathways of the virus’ ability to enter a cell and break open the protein capsule that eventually releases the virus’ RNA. Another area of clinical investigation is preventing the progression of the disease, Gunel explains. “We know COVID-19 can progress through respiratory symptoms, but it also affects gastrointestinal, cardiovascular and neurology systems,” he says.
Yale is one of few sites investigating interleukin-6 (IL-6) receptor antagonist drugs as potential treatments. The FDA’s response to approve the trial was immediate. “The rapid rate of return of studies has been mind-boggling,” Gunel says.
Another team formed to respond to COVID-19 clinical research is the Advanced Therapy Group (ATG), co-chaired by Naftali Kaminski, MD, Boehringer Ingelheim Pharmaceuticals, Inc. Endowed Professor of Medicine (Pulmonary). This group, which now includes just over 40 members, works to identify new targets, therapies, clinical approaches, and diagnostics of the novel coronavirus. Initially its members focused on finding quality medical literature amid the flurry of studies rushed to publication. But the focus quickly shifted to finding ways to guide clinical management of COVID-19 based on available evidence and evaluating as many clinical trials as possible that are highly like to work, Kaminski explains.
“We wanted to ensure that a lot of researchers had the opportunity to become principal investigators on studies,” Kaminski says.
For about six weeks, ATG members and support staff were constantly mobilized to work, logging hours 24/7. More recently, Kaminski asked everyone to take breaks to avoid burn-out.
As the university slowly reopens to researchers who can resume non-COVID-19 work, Kaminski urges those scientists to embrace that work. “We don’t want to run the risk of diverting all intellectual and temporal resources to COVID and miss basic research that will be required to find a cure for this epidemic,” Kaminski says. “I tell researchers that if they are a good immunologist, critical care scientist, geriatrician, or whatever they may be—keep doing your research because it’s going to help us.”