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Montefiore in the News

August 21, 2020

A treatment made from the blood of recovered Covid-19 patients seemed promising in March. Today … well, it’s still just promising.

"There were elements within this pragmatic design that allowed for something similar to randomization," says one researcher. "I call it pseudo-randomization.”Photograph: Guillermo Legaria/Getty Images

As of Monday, August 17, a nationwide program to treat Covid-19 patients with a fluid made from the blood of people who’d recovered from the disease—so-called convalescent plasma—had reached 97,319 patients.

That’s a huge number of people, considering that nobody really knows whether convalescent plasma actually works against Covid-19.

A spontaneously generated, self-assembling group of clinicians and cross-disciplinary researchers that built the nationwide program to ensure “expanded access” to convalescent plasma also created protocols for randomized, controlled trials, the gold standard for evidence in science. They hoped to test plasma’s ability to prevent disease after exposure, its capacity to treat Covid-19—and what Michael Joyner, an exercise physiologist at the Mayo Clinic who was instrumental in setting up the expanded-access network, called a “Hail Mary” protocol to try to help people who are severely ill, on ventilators.

The distribution system got approved and built; the trial protocols did not. They never began.

There are plenty of reasons to think plasma might help fight Covid-19. Physicians have used it for more than a century; it’s made by taking blood from people who’ve recovered from a disease and spinning it in a centrifuge down to a frothy, yellow liquid that contains the sum total of the donor’s immune response—molecules that attack all invading germs, and some that specifically target all the individual pathogens the donor has ever encountered. But actual rigorous trials of the stuff are rare. Dozens of randomized, controlled clinical trials are underway—tests that systematically compare the same kinds of people at similar stages of the disease who get convalescent plasma to those who don’t.

Even without that rigor, this year tens of thousands of people received plasma for Covid-19. It played out as a one-on-one decision between physicians and patients, not a population-scale experiment designed to elicit knowledge about its efficacy. A preprint from the expanded-access group, not yet peer-reviewed, recounts the outcomes of more than 35,000 of these recipients at hundreds of hospitals. It retroactively splits that population into groups based on when in their illness they got plasma, or how laden the plasma was with the antibodies that actually do the disease-fighting.

But, as the researchers and outside experts both acknowledge, that’s not as good as a clinical trial in which people get randomly assigned to a group that gets a drug (or procedure or surgery or whatever) versus a group that doesn’t, and then someone compares the results. And that’s a palpable loss.

“Fifty thousand people have been given a treatment, and we cannot know whether it worked or not,” says Martin Landray, one of the leaders of the Randomised Evaluation of Covid-19 Therapies (or Recovery) Trial in England, a large-scale, multi-center, multi-drug randomized controlled trial that showed that the corticosteroid dexamethasone saved the lives of Covid-19 patients and the autoimmune drug hydroxychloroquine did not. (That 50,000 number was from a few weeks back, just after the plasma preprint came out.) “You wouldn’t need to randomize 50,000 patients. You wouldn’t need to randomize 5,000 patients to get the answer,” he says. “But that one difference is the difference between the effort being worthwhile or not.”

Here’s another perspective, using the more up-to-date number: “In my mind, treating 98,000 people with plasma and not having conclusive data if it worked is problematic, and we should have a more robust data set before we give 98,000 people a product,” says John Beigel, associate director for clinical research at the National Institute of Allergy and Infectious Diseases’ Division of Microbiology and Infectious Diseases. Beigel was the lead author on the study of the drug remdesivir that led to its incorporation into the US standard of care for Covid-19.