Eight months into the COVID-19 pandemic in the U.S., it remains unclear whether two of the most promising treatments actually work.
With a vaccine not expected until 2021, there's an urgent need for effective therapeutics for COVID-19. Thousands of Americans are currently hospitalized, and the Centers for Disease Control and Prevention reported projections of up to 205,000 deaths in the U.S. by mid-September.
But the clinical trials necessary to provide that evidence for convalescent plasma and monoclonal antibodies have been fraught with delays and have had problems recruiting volunteers. Many trials are only beginning now, months into the pandemic, because researchers focused their early efforts on therapies, such as hydroxychloroquine, that didn't pan out.
Randomized, placebo-controlled clinical trials, considered the gold standard, evaluate whether a treatment works by comparing it to a placebo. At the outset, neither the researchers nor the participants know who is getting the real thing and who is getting the placebo.
That's created challenges for researchers running the trials.
"There are people who say, 'I don't want to be a guinea pig. If you think this stuff works, why not give me the real stuff?'" as opposed to a placebo, said Dr. Shmuel Shoham, an associate professor of medicine in Johns Hopkins University School of Medicine's infectious diseases division.
The idea behind both convalescent plasma and monoclonal antibodies is to provide the immune system with a boost to fight off the virus. Convalescent plasma refers to the antibody-rich blood product taken from patients who've already recuperated, and monoclonal antibodies are a synthetic version of those antibodies that could be mass-produced in a lab.
But tens of thousands of COVID-19 patients who may have been eligible for clinical trials evaluating these therapies have already received convalescent plasma through the expanded access program run by the Mayo Clinic, taking them out of the running to be a trial participant.
"Some of us jumped on that bandwagon quickly," Dr. Ashok Balasubramanyam, vice president for academic integration and senior associate dean for academic affairs at Baylor College of Medicine, said, citing early evidence from China that suggested a therapeutic benefit to convalescent plasma.
"The program was very liberal," Balasubramanyam said. "Anybody could sign on to it and get rapid FDA approval."
That's not necessarily a bad thing during a pandemic in which millions of Americans have been infected. Convalescent plasma has a long history of use for other illnesses and is considered safe overall.
If it's unlikely to hurt, and indeed might help, many patients opt to get the plasma.
Shoham and his colleagues at Johns Hopkins are leading a nationwide clinical trial effort to learn whether convalescent plasma can either prevent the illness or keep infected people well enough to stay out of the hospital.
But fewer than 100 participants out of a planned 1,000 have signed on so far.
One study site in Florida had to close, Shoham said, because clinical research coordinators there became too overwhelmed caring for COVID-19 patients. Others have had difficulty finding an appropriate space certified by a blood bank to do the infusions.
"We got walloped with this virus," Shoham said. "It's taken us a while to get back on our feet."
Plasma for hospitalized patients
The National Institutes of Health has given $34 million to Vanderbilt University Medical Center in Nashville to run a large-scale, randomized, controlled trial to determine whether convalescent plasma can help very sick patients hospitalized with COVID-19.
"We were told to get this answer as fast as we possibly can," said Dr. Todd Rice, an associate professor of medicine at Vanderbilt. Up to 1,000 patients will be recruited at 50 sites nationwide. Rice will lead the monumental effort.
"Convalescent plasma is not the easiest thing to to procure. It's a blood product, and ideally it has to go through testing to make sure the patient has the correct antibodies that will actually neutralize the virus," Rice said. "It's not quite like just saying, 'Here's a drug. Take it.'"
Federal investigators are watching the clinical trials closely. The U.S. Food and Drug Administration is reportedly considering whether to issue an emergency use authorization for convalescent plasma, a move that would expand doctors' ability to access the product.
"Per policy, we are not able to comment on whether or not we will take any action regarding emergency use authorization for convalescent plasma and will render a decision at the appropriate time," Dr. Anand Shah, FDA's deputy commissioner for medical and scientific affairs, said in an email.
"The science is really important, because we've taken some wrong turns in recent months," Balasubramanyam said. The FDA had to rescind an emergency use authorization for hydroxychloroquine in June, after evidence showed the medication carried too many risks and did not work to treat COVID-19.
With convalescent plasma, Balasubramanyam said, "we've got a hint that it works. Now it's incredibly important that we're sure it works."
Results will depend, in part, on people's willingness to volunteer for randomized clinical trials. Doing so means a patient may be assigned to receive a placebo, rather than the real, antibody-rich plasma.
Kellie Guyton, 34, of Winfield, Alabama, knew she would need specialized care when she was hospitalized with COVID-19 in July. Previous heart surgeries and a kidney transplant put her at higher risk for complications from the coronavirus.
But Guyton opted to participate in the trial at Vanderbilt.
"I thought that if it doesn't affect me negatively, I'm all for it," Guyton said. "It's a chance to help the next person down the line. It could be your grandmother or your neighbor or your best friend."
The convalescent plasma supply relies on enough people who have recovered from the virus to take the time to donate and is therefore a limited resource.
That's where monoclonal antibodies could be of use. Scientists collect convalescent plasma, zero in on the strongest and most specific antibodies to the coronavirus, then reproduce them in a lab in large quantities.
Several drugmakers are developing monoclonal antibodies, including Regeneron and Eli Lilly. Both companies began clinical trials in early June. But results from two such trials, run by the National Institutes of Health, won't come until later this year.
Duke University's Human Vaccine Institute Pandemic Prevention Program recently announced it, too, will develop and study a monoclonal antibody to prevent infection from SARS-CoV-2, the virus that causes COVID-19.
It's unclear how long such protection would last. The goal would be to give it to people in high-risk groups, such as those in long-term care facilities, doctors, nurses, even National Guard troops, if they're needed to help in areas with widespread infection.
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It's a long way from clinical use. Researchers hope to start enrolling patients by next spring.
"We have to go through the preclinical safety and efficacy studies," said Gregory Sempowski, who is leading the trial. "It just takes time. We're doing it on a much more accelerated schedule than we're used to."
All of these research projects require a careful balance of both respect for the scientific process that can be time-consuming as well as the understanding among investigators that they need to move more quickly than the coronavirus, which has sickened nearly 6 million people in the U.S. and killed more than 175,000 Americans.
"It's important for the public to understand that scientific approach to treatment," Balasubramanyam said. "It's also important for the scientists understand the need for speed."
Despite early delays, Shoham remains hopeful the convalescent plasma trials will soon gain steam.
"I think within a couple of strong weeks, we'll be much further along," he said. "Then hopefully we'll have an answer for doctors, for patients, for families, for the FDA."