At the end of August, the Food and Drug Administration (FDA) issued an emergency use authorization for convalescent plasma, allowing hospitals to administer the plasma without participating in any kind of experimental trial. Although studies of the treatment are ongoing, the agency wrote in its decision that it believed “the known and potential benefits of COVID-19 convalescent plasma … outweigh the known and potential risks of such protocols.”
Since early in the pandemic, New Orleans healthcare providers have been on the forefront of plasma therapy — administering blood plasma from recovered COVID-19 patients to someone who is infected, a process that in theory might speed recovery.
“We started collecting convalescent plasma back in April. We were one of the first in Louisiana, maybe throughout the country, collecting convalescent plasma,” said Tim Peterson, the medical director for two large Louisiana blood banks, the Blood Center and Lifeshare Clinic, and who holds an appointment at Tulane School of Medicine.
He doesn’t know exactly how many units of plasma the clinics have distributed, but estimated that “it’s in the thousands,” distributed to at least 30 hospitals across Louisiana and Mississippi. He cautioned that he isn’t a clinician, but that he’s optimistic about the treatment, based on what he’s heard about rapid recoveries.
But the expanded use of plasma comes in the middle of national controversy over the FDA’s approval process, and unanswered questions about the efficacy of convalescent plasma. The way that local healthcare providers have responded to the decision may be a preview of future emergency use authorizations, including for a vaccine.
The gold standard for establishing the effectiveness of any treatment, whether vaccine or plasma, is a randomized control trial, in which some patients receive the treatment, and others receive a placebo, like salt water or a sugar pill. Neither group is told what substance it received. By comparing outcomes between the two groups, researchers can sort out the effects of a specific treatment from the placebo effect or individual variation. But the emergency use authorization has created an ethical dilemma for some researchers. Should they use a still-unproven treatment on their patients? And can they justify administering a placebo to some patients for the sake of science, now that they have the FDA’s permission to use plasma to treat patients?
“There’s not even close to perfect evidence,” said Nakhle Saba, a professor of clinical medicine at Tulane University’s School of Medicine who was the principal investigator of Tulane’s convalescent plasma trial. “What we can say is that there is an efficacy signal, and we know it is safe.”
But now that the FDA has given its preliminary stamp of approval to the treatment, he has misgivings about participating in control trials, instead saying he would administer it to any patient who asked.
“Although my heart is with science and I want to get the definitive answer, I just take it on myself: If I catch it, and I’m in a bad situation, I would get the plasma. And I would use it on my patients.”
Concerns over the FDA’s approval process
Convalescent plasma therapy involves taking plasma from a recovered COVID-19 patient and injecting it into someone who’s currently ill. The plasma carries antibodies from the recovered patient, which could help the sick fight off an infection.
“We know from the old days of influenza and measles and SARS that plasma theoretically works,” Saba said. But that doesn’t necessarily mean that it’s effective for all diseases.
Until late last month, the plasma could only be administered as part of a clinical trial that the FDA could use to test if the treatment is effective. Now, with the emergency use authorization, the treatment can be given at any time.
In the days following the authorization, the National Institutes of Health issued a stark dissent: “There are currently no data from well-controlled, adequately powered randomized clinical trials that demonstrate the efficacy and safety of convalescent plasma for the treatment of COVID-19.”
Some national observers believe that the authorization was premature, and influenced by political considerations. Eric Topol, an expert on clinical trial methodology at Scripps Research in California, told Science Magazine that the decision represented a “loss of independent FDA assessment of evidence and data overridden by political pressure” to roll out treatments for Covid-19.
A group of former FDA officials wrote in July that access to plasma should be expanded, but only so that better data could be gathered.
“Let’s get the trials done, and if the results are life saving, let’s make it the standard of care” wrote Robert Califf, a former FDA commissioner, on Twitter. “If not we can avoid the huge expense & effort & keep looking for best treatments.”
Convalescent plasma is different from a vaccine or a treatment like hydrochloroquine, said Saba. He said he doesn’t think the hasty plasma authorization means that a vaccine will be treated the same way.
“Think about it as equivalent to a blood transfusion. Thousands of patients across the country have received plasma under different circumstances, which helps demonstrate that the treatment is, if not necessarily effective, then likely safe.”
A rushed vaccine, on the other hand, could cause health problems among recipients. In some cases, that’s taken the form of unexpected allergic reactions. In one notable case, an under-tested vaccine administered to children in the Philippines actually increased sensitivity to the target virus in many cases.
Even before the emergency use authorization, “It [wasn’t] that difficult to get approved for usage anyway,” Peterson said. Hospitals needed to provide it according to the protocols of a national study, run by the Mayo Clinic, or receive approval from the FDA for an independent study. Doctors could also petition the FDA for case-by-case approvals.
In fact, even before the authorization, his blood banks had been looking for more plasma donors.
Ochsner had been treating patients under the Mayo Clinic protocols since April 1, and administered convalescent plasma to about 125 patients, according to Sandra Kemmerly, the system medical director of hospital quality for Ochsner. The system anticipates that its demand will increase because of the authorization. LCMC Health, which runs five major hospitals in the New Orleans area, did not respond to several requests for comment about their use of convalescent plasma.
Tulane Medical Center, meanwhile, received approval to administer plasma under an independent study that would treat less critically ill patients.
“When Tulane reviewed the Mayo protocol,” said Peterson, who is an investigator on the Tulane study, “we said it’s good, but we would like to have the option to give [plasma] to patients earlier, maybe for a patient who wasn’t ventilated, but whose oxygen levels had dropped so far that they were in imminent danger.”
Saba said that the Tulane study ended up providing plasma to 16 or 17 patients, and said that the results were encouraging, and that he’s in the process of getting them published. “We treated a small number relative to the national [studies], but we’ve seen a similar trend. The earlier you give it, the better the results. It was striking, in some patients, how fast they responded.”
In the case of one immunocompromised woman, he said, “She came to the hospital, she had really bad pneumonia. We were able to treat her right away, within two days.”
She was given one dose of plasma, and “within 12 to 24 hours, her oxygen requirement went down dramatically, and they gave her a second unit because she was so immunocompromised, and she got off oxygen in a day or so, and then she was discharged home.”
It was harder to tell how patients who had been on oxygen for long periods of time were affected, though. “We still saw some improvement, but we don’t know if it was from the plasma, because they were on remdesivir, on dexamethasone, on other clinical trials, so you don’t know which is which.”
But neither that study, nor any of the other studies that have given New Orleans residents access to plasma, were randomized control trials, in which some patients receive a placebo, and some receive treatment.
Changing research decisions
Saba said that his team nearly joined a randomized control trial with Vanderbilt University, but decided against it in large part because of the emergency use authorization.
“We told Vanderbilt that we are a go, and we can contribute a lot of patients,” he said. “Then after the FDA issued the EUA, we actually pushed the brakes. The physicians and sub-investigators on my trial determined whether we should go or not. Some of them would say, ‘We should do it, we need that answer.’ And some will be like, ‘What are you going to tell the patient? Can you hold off from giving them plasma?’ The FDA says it probably works, given the available data.’ ”
Todd Rice, a principal investigator with the Vanderbilt trial, said that other treatment centers have decided not to participate in the control trial for similar reasons. “It hasn’t been very many, to be honest with you. … There’s a lot of places out there that think that data isn’t that strong.”
He explained that in the end, a trial is worse off if not all study sites are on the same page about the ethics of treatment.
“If a patient starts to get worse, will they give them plasma? If that happens with patients in the control arm, that’s not good for the study,” he said.
At the same time, he said, the Vanderbilt trial will have safeguards built in–the data will be evaluated at intermediate steps along the way, and if it becomes obvious that convalescent plasma is helping, the trial could end early and all patients would receive the treatment.
Even knowing those safeguards, Saba said that he couldn’t justify giving a placebo to patients.
“I’ve been trying so hard for the past several days to take sides. Should I be with the FDA, saying that it probably works, or should I take sides with the NIH where I trained? Should I side with the real science or the real answer. It’s so hard. For my patients, I just want to give them plasma.”