Why we don’t know if convalescent plasma works to treat Covid-19

When the US Food and Drug Administration (FDA) authorized the emergency use of convalescent plasma for the treatment of Covid-19, the decision was met with mixed reviews. On the one hand, it would allow more hospitalized patients to access a potentially life-saving treatment for an illness with no surefire drugs.

On the other, there’s still no clear evidence that convalescent plasma improves patients’ outcomes. And the reason isn’t necessarily that plasma is ineffective: It’s that few are willing to fund the research to find out for sure.

“There’s no money to be made in plasma,” says Jeffery Henderson, a physician and infectious disease researcher at Washington University St. Louis. Because it’s a biological product, it can’t patented or sold for a profit. As a result, no single research group or company has funded a large, randomized controlled trial of plasma, the highest standard of clinical evidence.

The trouble comes down to the way that pharmaceutical companies bring new therapies to market. In 1962, the US government passed a law that said all new treatments, including drugs and biological products like plasma, had to be backed by substantial evidence of safety and efficacy. For nearly six decades, the burden of conducting this research has mostly fallen on big pharma.

It isn’t cheap: Between 2012 and 2018, the median cost of bringing a drug to market was $985 million, about $19 million of which goes to clinical research. Typically, drug companies are happy to invest. Once their product is approved, they can sell it at a price that makes up for the loss (and then some).

Covid-19 convalescent plasma, though, isn’t profitable. In fact, it’s donation-based: All of the nearly 100,000 people who have received convalescent plasma as part of their treatment have gotten it from individuals who had the disease, recovered, and donated units of the antibody-containing liquid part of their blood.

This lack of profitability is why plasma has never taken off as a therapy, even though it’s a century-old idea. Small studies dating back to the 1918 flu pandemic show that convalescent plasma was effective in treating new cases of influenza; more recently, convalescent plasma has been shown to help fight SARS, MERS, and even Ebola infections. But there’s never been the kind of massive trial regulators would want to see before rubber-stamping plasma as a suitable treatment.

Ironically, these decades of minor research may have even made it harder for Covid-19 convalescent plasma studies to get funding. Compared to the flashy new innovations most research grants go on to fund, “convalescent plasma sounds like horse and buggy,” says Henderson.

What research that does exist on convalescent plasma has been run by academic institutions that rely mostly on federal funding. Henderson is one of the thousands of physicians involved in convalescent plasma’s expanded access program (EAP), a network spearheaded by researchers at the Mayo Clinic in Rochester, Minnesota, and the FDA. Initial research from 35,000 of its patients showed a benefit from earlier access: If patients received plasma within three days of diagnosis in the hospital, 8.7% died within a week, compared to 11.9% if they received plasma four days or later after diagnosis.

Even that program almost didn’t get off the ground. Henderson says it struggled to get funding from groups like the US National Institutes of Health and the Department of Defense. Eventually, the EAP program got some funding from the US Biomedical Advanced Research and Development Authority, as well as smaller private donors, including Google’s former CEO Eric Schmidt and his wife Wendy Schmidt.

And it wasn’t able to conduct the critical randomized trials that plasma needs. The researchers could retroactively note which patients received what kinds of plasma — a sort of pseudo-randomization, R. Scott Wright, director of the Human Research Protection Program at Mayo, told Wired. But they can’t go back in time and compare plasma to a placebo treatment. Ideally, both doctors and patients would be masked as to whether or not they received the proper treatment, to avoid any bias in the outcomes.

Some institutions are still carrying out small randomized controlled trials to answer some of the basic questions surrounding convalescent plasma, like how to determine dosing and when to give it to patients. One of these trials, spearheaded by Liise-anne Pirofski, an infectious disease specialist at Albert Einstein College of Medicine in New York, finally received funding from the US National Institutes of Health on Aug. 18.

“It’s important for Covid-19, but what it’s really important for is the future,” says Pirofski. “We had SARS, MERS, now we have Covid-19,” she says. “We have every reason to believe that we’re going to have something else.” Pirofski believes that further studies of convalescent plasma could show conclusively whether it’s a valuable therapy — for everything from novel ailments to the annual flu to drug-resistant bacterial infections. It will all depend on the organizations willing to fund that research.

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