In DepthCOVID-19

In plasma OK, critics see politics, not science

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Science  28 Aug 2020:
Vol. 369, Issue 6507, pp. 1038-1039
DOI: 10.1126/science.369.6507.1038

Science's COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation


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After echoing Trump's claims about convalescent plasma, the Food and Drug Administration's Stephen Hahn (left) backtracked.

PHOTO: PETE MAROVICH/GETTY IMAGES

It was, U.S. President Donald Trump said, “a very historic breakthrough” in the fight against COVID-19 that “would save countless lives.” To critics, the emergency use authorization (EUA) that the U.S. Food and Drug Administration (FDA) issued last Sunday for the use of convalescent plasma to treat people with severe COVID-19 looked more like a breakdown, with the evidence overstated and potentially worrisome consequences for the evaluation of other experimental medicines.

Flanked at a Sunday evening press conference by FDA Commissioner Stephen Hahn, Trump claimed the antibody-rich plasma, which comes from people who have recovered from the disease, was “safe and very effective,” and had been “proven to reduce mortality by 35%”—what he called “a tremendous number.” But that number has received a tremendous amount of scrutiny. It surprised even the researchers who conducted the study on which Trump apparently based the declaration. “I don't know where the 35% number comes from,” says Arturo Casadevall of Johns Hopkins University's Bloomberg School of Public Health, an author of the study, which has been posted as a preprint but has yet to be peer reviewed. Researchers' best guess was that it reflected cherry picking of data from a small subset of the study—and that the EUA, issued on the eve of the Republican National Convention, represented as much political theater as science.

Randomized, controlled trials (RCTs), the gold standard for assessing experimental treatments, haven't yet shown that COVID-19 patients benefit from convalescent plasma. One such study, which includes thousands of patients, is underway as part of the Recovery trial in the United Kingdom. The EUA rests heavily on data from the COVID-19 Plasma Consortium, funded by the Department of Health and Human Services to provide access to the treatment and assess its safety. The group has treated more than 90,000 patients at nearly 3000 sites. That study has no untreated control group, however, so it cannot determine whether convalescent plasma has any risks that outweigh benefits.

The treatment was allowed under FDA's Expanded Access program, which makes experimental treatments available to patients. Casadevall says this program requires burdensome, time-consuming paperwork that the EUA will do away with. That will be helpful for understaffed hospitals that treat “underserved populations,” he says. “I think the FDA made the right call. The political noise is unfortunate.”

Others say the political noise is drowning out the science.

Hahn claimed at the press conference that Trump's 35% figure translates to 35 lives saved per 100 sick people. Casadevall and others suspect that number is based on a small part of the study. One possibility is an analysis involving about 3000 patients that assesses the impact of different COVID-19 antibody levels in the plasma. In this group, 8.9% of those who received plasma containing high antibody levels died within 7 days, versus 13.7% of those who received plasma with low levels. Although that is a 35% relative difference, the absolute difference, 4.8%, amounts to 4.8 lives saved per 100 sick people—not 35. And after 30 days, the relative difference had dropped to 25%. At that point, the mortality rates were 22.3% and 29.6%, respectively, among recipients of plasma with high and low levels of antibodies—hardly a historic breakthrough.

The White House claim is “statistical acrobatics,” says Luciana Borio, a former chief scientist at FDA who also worked on the Trump White House's National Security Council. On Monday evening, Hahn acknowledged he had made a mistake, tweeting that the criticism was “entirely justified. What I should have said better is that the data show a relative risk reduction not an absolute risk reduction.”

Nicole Bouvier, a virologist and infectious disease clinician at the Icahn School of Medicine at Mount Sinai—a participant in the Mayo Clinic–led consortium—says the data gathered so far do suggest convalescent plasma helps some COVID-19 patients. “There is probably a benefit to it, but it's probably not a major breakthrough,” Bouvier says. She wishes the U.S. government had organized large-scale RCTs for the intervention. “We're trying to build a wall of evidence and we're putting in pebbles,” she says.

Borio and others worry the EUA may make it harder to gather that kind of evidence for other treatments. Convalescent plasma contains a mixture of different antibodies, only some of which hinder the virus, and Borio and many others have high hopes for a more targeted and standardized intervention: “monoclonal” preparations that contain high levels of the most potent antibodies only. But now that the EUA has put convalescent plasma within reach of more patients, it may become harder to enroll people in RCTs for monoclonal antibodies, Borio says.

Myron Cohen of the University of North Carolina, Chapel Hill, who oversees large-scale RCTs of monoclonals now taking place under the aegis of the U.S. National Institutes of Health, agrees. “If potential study participants for a COVID-19 treatment … believe there is a beneficial and safe agent they can receive without randomization to a placebo, they may logically and often choose that path,” Cohen says.

Given that tens of thousands of Americans have already received convalescent plasma through FDA's Expanded Access program, it's unclear how many more people the EUA will actually benefit. Bouvier says her hospital may not even be able to use the EUA, because it requires that convalescent plasma be first characterized with a specific antibody test that it does not have.

Eric Topol, a cardiologist who directs the Scripps Research Translational Institute, says the EUA “again represents the FDA caving directly to Trump pressure,” as he believes it did when it issued an EUA (later rescinded) for hydroxychloroquine treatment for COVID-19. “It sadly and unacceptably exemplifies loss of independent FDA assessment of evidence and data overridden by political pressure,” Topol says.

Many scientists worry the same could happen in future decisions about EUAs for COVID-19 vaccines—with far greater potential consequences because vaccines presumably will be given to hundreds of millions of healthy people.

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