How Coronavirus Is Fast-Tracking Medical Research
The first Covid-19 cases arrived at Stanford’s hospital about two weeks ago, during the second week of March, mostly from the local community. “It’s a condition that has no known definitive treatment,” says Neera Ahuja, medical professor, hospitalist, and medical director of the general medicine inpatient wards at Stanford University. The trends from China suggested to Ahuja that within two weeks, the number of reported cases in Santa Clara County, where Stanford is located, could jump to 700. Like other doctors around the world, Ahuja and her team gave people with Covid-19 who were not showing signs of improving hydroxychloroquine, a malaria drug that had shown some benefit, through compassionate use, which allows people to take commercially available medications for critical situations where it may help.
But concrete evidence was entirely lacking. Like other doctors around the world, Ahuja found herself confronting an irony: No treatment options and an impending onslaught of patients were the ideal combination for experimental research. Starting a clinical trial at Stanford to study treatment options made sense; it was the only thing that did.
But there was a problem: Clinical trials are not known for their speed. The average new drug takes at least 10 years to move from lab to market, with up to seven of those years spent on human testing. Even studying an already existing drug for a new disease can take years. Ethics, logistics, regulations, departments, committees, paperwork, funding, approval by federal agencies — they all turn the wheels square.
Yet alongside the tragic stories that Covid-19 is writing — the deaths, the illnesses, the isolation, the economic disaster — the virus’ willful human hosts are forging their own tales of humanity, dedication, kindness, and generosity. Inside the world of medical research, melting barriers are giving treatment discovery a chance before it’s too late. The response by a world so tightly bound by regulations is joining the ranks of so many other aspects of this pandemic in earning the title “unprecedented.”
The average new drug takes 10 years to move from lab to market, with up to seven of those years spent on human testing.
At Stanford, Ahuja connected with Kari Nadeau, who treats and studies food allergies. Food allergy research is supervised by the National Institute for Allergy and Infectious Diseases (NIAID), the same federal agency overseeing Covid-19 research, so Nadeau knew who to call. The NIAID responded within 24 hours. On Monday, February 24, the World Health Organization had recognized remdesivir, an antiviral drug developed years ago that once carried the hope of treating Ebola infections (other drugs proved more effective), as a lead candidate for treating Covid-19.
The NIAID was sponsoring a large clinical trial of the drug taking place at up to 50 sites across the United States and internationally and wanted Stanford to join. The study randomly assigns newly diagnosed patients to treatment with either remdesivir or a placebo. If one of these options shows a benefit in the coming weeks, then it will become the new control arm against another treatment.
Ahuja and Nadeau immediately contacted the university’s institutional review board (IRB), a committee that every research institution has for reviewing and approving experimental studies. The IRB granted approval a few days later, a process that normally takes months. The doctors rushed to contact other local hospitals about working with Stanford on the study, knowing California was likely heading toward a shelter-in-place order that could slow their progress. On one occasion, Nadeau had the head of contracts, the head of legal, and the head of risk management on the phone with an hour’s notice.
Regulatory reviews by the U.S. Food and Drug Administration (FDA) that usually require several months were done in two weeks. When I spoke with Ahuja on March 17, the Stanford trial site was about to start enrolling patients. What was absent, Ahuja says, was time to reflect. “We didn’t have time to be fully relaxed and academic,” she says. “We didn’t have that luxury.”
The research is vital. Earlier in March, Ahuja received a copy of the Chinese Ministry’s official government manual for Covid-19 care, which includes several antiviral medications among the possible treatment approaches. Preliminary data from China hinted that remdesivir, which blocks the virus’ ability to replicate its genetic material, might work, but the findings weren’t reliable, because they were based on anecdotal reports acquired patient by patient, rather than testing a systematic, predefined protocol for treatment.
Only a clinical trial can provide the rigorous data required for the FDA to approve a drug, for insurers to cover it, and for patients to be assured that the treatment a doctor is offering is based on the best knowledge available. “We’re not playing with lives here,” Nadeau says.
While Ahuja was scrambling to initiate the study, Caleb Skipper, who researches infectious disease at the University of Minnesota, was redirecting his energy. Skipper is usually focused on conducting trials in Africa to treat fungal infections stemming from HIV/AIDS, but the pandemic had brought that work to a hard stop. Turning their focus to the coronavirus was the obvious move. He and his mentor, David Bowlaire, scanned the ongoing Covid-19 research and found a gap. Researchers were looking at treatments to eradicate the virus, but no one was looking at how to stop the disease from progressing.
He and Bowlaire proposed a study comparing hydroxychloroquine with placebo to prevent Covid-19 from becoming symptomatic after exposure. Hydroxychloroquine is the anti-malaria drug hailed by President Trump as the savior of the pandemic, and the evidence supporting its powers against the virus is thin at best. But Skipper wasn’t after a cure. The study isn’t seeking to drain the bathtub, only find a more effective stopper.
The Minnesota team encountered the same warp-speed phenomenon that Ahuja had. Skipper has conducted numerous Phase 3 trials — the final step before the FDA will approve a treatment — and knew how long regulatory approval could take. “In this case, the thing that usually takes a year took one week,” he says. The university’s IRB reviewed the protocol in a day, as did the FDA, Skipper says. “The whole medical research system rallied to make sure this happened quickly,” he says.
I asked Skipper what he thought was missing from the process. “Multitasking,” he says. With nothing legitimate competing for attention, everyone could focus on the singular mission. He also noted the willingness among colleagues to share data, a practice far outside the comfort zone of a world where career advancement depends on publishing new findings. The threat posed by Covid-19 had evaporated that worry completely. “I hope that continues,” Skipper says.
Inside the world of medical research, melting barriers are giving treatment discovery a chance before it’s too late.
Not everyone has found the regulatory gates magically swinging open. Tom Pitts, a neurologist in private practice in New York City, had the idea that targeting the immune system might work better than targeting the virus, because it’s the immune reaction against the unknown viral invader that causes all the respiratory trouble. “The virus isn’t really killing anybody,” Pitts says. “It’s provoking the immune system to kill you.” He had the idea of treating Covid-19 with eculizumab, a monoclonal antibody that targets an immune system protein called C5 and is approved for two diseases—one affecting the kidneys and another affecting red blood cells. Testing his idea, though, would require finding someone who was treating patients, which Pitts was not. The fastest way to obtain that information was through the CDC, but no one there would talk to him. “I couldn’t get past the call center,” Pitts says. “The CDC gets a big thumbs down from me.” The FDA quickly authorized Pitts to use eculizumab on people with Covid-19, but assisting with clinical trial arrangements isn’t in that agency’s purview.
Eventually, Pitts opened a compassionate use study in which patients are given permission to take the antibody. It’s not the formal clinical trial he wanted and won’t generate the hard data needed to test his hypothesis. He says an industry-sponsored study of another immunomodulatory drug in which he’ll participate will open soon, though he could not disclose the name of the antibody or the company. But the experience stung. “In this country, if you are not the director at Harvard or something and have a direct line, you really can’t get your voice heard by anybody,” Pitts says.
In the weeks since his compassionate use trial was added to the Covid-19 trials list at ClinicalTrials.gov, Pitts says he has heard from physicians at Ohio State University, the University of North Carolina at Chapel Hill, and a hospital in Milan, Italy, among others, wanting to include their patients.
The transformation extends beyond the search for treatments. Bioengineer Stephen Quake, co-president of the Chan Zuckerberg Initiative’s Biohub, which supports research collaboration among UC Berkeley, UC San Francisco, and Stanford, is working with scientists to model the trajectory of the virus so authorities can make informed decisions about when or whether to reopen schools or lift other restrictions. Groups in Italy, Chile, the Czech Republic, and Spain are investigating whether 3D printers can be used to make desperately needed ventilators. And at the University of Pittsburgh, Junmei Wang is using molecular modeling to find existing drugs that will bind to the protein on which the virus lands, thereby blocking it from settling into the body, work that could vastly accelerate the search for viable treatment candidates. As Quake puts it, “nothing in my lifetime” compares to the speed with which efforts to combat Covid-19 are moving.
For Ahuja, though, it’s not just the speed that has been so remarkable; it’s also the compassion. She tells the story of a doctor whose beard, which he had for a long time, didn’t fit under the surgical mask. His colleagues encouraged him to wear a more intensive mask that was larger but in short supply. “No problem,” he told the team. “I’ll be right back.” “He went to the bathroom and shaved his beard,” says Ahuja through tears. “And then three other staff members did the same thing.”
When we spoke, Ahuja said that no one admitted to the intensive care unit had been able to leave yet. She knows there will not be enough hospital beds to serve all the patients, and she knows the reality she is facing every time she dons her protective gear and walks into a patient’s room. “The depth of how big of a threat this is to the entire globe flashes before your eyes,” Ahuja says. But the response to that threat — the speed of it, the humanity of it — keeps her going. “I’m worried,” she says, “but I’m optimistic.”