It's been a few months since the world was focused on convalescent plasma – the idea that the antibody-rich plasma extracted from the blood from recovered Covid-19 patients could help treat the sick. Now, the hype for these trials is back, along with a limited version of approval from the U.S. Food and Drug Administration (FDA).
On Sunday, the FDA granted convalescent plasma therapy an Emergency Use Authorization (EUA). It is now approved for use in hospitalized patients for whom there are no adequate or approved alternatives. EUAs can be granted if a treatment shows signs that it "may be effective" and doesn't carry great risks for patients.
Does convalescent plasma therapy work?
There are early signs that the convalescent plasma can effectively treat hospitalized patients: In a research letter published on March 27, researchers based in China showed that three of five critically ill patients were discharged after receiving it.
Some data also suggests it is safe: The Mayo Clinic is leading an expanded access program for convalescent plasma and reported in June than less than one percent of 20,000 patients experienced "transfusion events," or blood clots. Nearly 70,000 patients throughout the US sick with the novel coronavirus have received convalescent plasma already.
However, the evidence is far from perfect. So far, there have only been two published randomized controlled clinical trials – the only type of study that can prove that treatments are effective. Both were terminated early, and one was only published as a pre-print (a non-peer-reviewed study).
Michael Joyner is the leader of the Mayo Clinic's convalescent plasma expanded access program. He's also the first author of a pre-print paper. This paper was in the process of being reviewed by the FDA as recently as last Wednesday, as the agency debated whether or not to issue a EUA.
His paper showed that 8.7 percent of severely ill patients in that expanded access program died after they received plasma three days after diagnosis. By contrast 11.9 percent of those who received plasma four days or later died.
Joyner and his colleagues argue this was a "signal of efficacy" for convalescent plasma treatment because more of those who got it earlier lived. However, the study not include a control group, so it can't prove that convalescent plasma works.
Enter the FDA — Joyner tells Inverse that, in his view, the FDA's designation is appropriate given the evidence. The authorization will expand access to the treatment, and reduce the clerical issues associated with prescribing it, he explains.
"There is a chance that if you get convalescent plasma, early in the course of the disease, there's a pretty good chance it may shorten the course of their disease and reduce chances of dying — with the world 'may' underlined," Joyner says.
Despite the fact that the treatment has been touted as a "breakthrough" by President Trump, the recent approval does not clarify the two most pressing questions:
- Does the treatment actually work?
- Who will benefit the most from getting it?
We're still lacking treatments for people with moderate to mild illness who may become very ill. When convalescent plasma was first floated as a treatment for Covid-19 in March, scientists theorized it could benefit all patients, regardless of their illness severity.
Joyner agrees that use on mild patients is a focus.
"Historically that would be a kind of a sweet spot for it," he says. "The EUA is for hospitalized, reasonably sick, very sick, or super sick patients."
The FDA's approval doesn't open up access to patients in that sweet spot, nor does it apply to the use of convalescent plasma for those who may become sick, but aren't yet.
Clinical trials will have to prove whether or not that "sweet spot" is available. While patients with mild symptoms have been central to the conversation and promise of plasma since the treatment was first floated, it has not been a focus of the FDA's decision.
Why is the FDA interested in this therapy now?– The emergency use of convalescent plasma has been quietly simmering away all summer. The Trump administration, as well as organizations like the Red Cross, has been calling for people to donate convalescent plasma. That plasma is needed for clinical trials to happen.
Joyner says that there was considerable interest in convalescent plasma therapy when he began looking for funders for his research in March and April. But there was "limited interest" in randomized controlled clinical trials, he says. Instead, the focus was on more refined versions of convalescent plasma.
"There was a lot of focus on hyperimmune globulin products or monoclonal antibodies in a number of the big funders," he says. "That's what they were focused on."
"The FDA will tell you they're moving in this direction, but they'll never give you a hard date."
The government has also been investing in plasma-based treatments. In June, the White House held a roundtable discussing the use of convalescent plasma therapies as part of Operation Warp Speed, the program aimed at rapidly delivered Covid-19 treatments and therapies. At the briefing, Secretary of Health and Human Services Alex Azar said that the biotech company Regeneron had received $450 million to produce their monoclonal antibody cocktail (monoclonal antibodies are a highly purified version of convalescent plasma).
"What makes OWS [Operation Warp Speed] so bold is that we’ve now paid to begin making doses of this Regeneron product before it receives FDA authorization or approval," Azar said.
Joyner says he's unsure of why the approval went through now, rather than earlier this summer or even later in the fall.
"The FDA will tell you they're moving in this direction, but they'll never give you a hard date," he says. "We thought it might be 10 days ago – I don't know why."
What does this mean for the rest of us? – Joyner says, so far, the evidence regarding convalescent plasma makes for an "emerging positive picture." There are signs it may work, but only early ones.
Either way, the picture is incomplete. Though the signs of efficacy may be there, it's not enough to prove that this treatment works – though it's possible it may, emphasizes Joyner.
But keep in mind, that may is underlined.