A decision by the Food and Drug Administration to grant an emergency use authorization for antibody-rich plasma taken from recovered Covid-19 patients for treating those hospitalized with the disease has come under criticism from some experts.
Despite the lack of data from large, randomized controlled trials of convalescent plasma, the EUA that the FDA granted Sunday was not seen as unmerited based on the available data. Nevertheless, some experts expressed concern that it could make it harder to enroll patients into RCTs and that political pressure could be behind the decision, or at least that there was a risk of the appearance of such pressure being at play. The headline’s inclusion of the phrase “another achievement in administration’s fight against pandemic” didn’t help dispel the latter perception, either.
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Unlike the now rescinded EUA issued in March for the malaria and autoimmune disease drugs hydroxychloroquine and chloroquine, the one for convalescent plasma does not specify that it is for patients for whom clinical trials are unavailable.
“They could have done that – they didn’t,” said Alison Bateman-House, an assistant professor in the Department of Population Health at New York University’s School of Medicine, in a phone interview, emphasizing that what was problematic about the EUA was the way it was handled and the potential to hinder trial enrollment, not that it was scientifically unwarranted. “So they really needed to justify on what grounds these decisions were being made – and they didn’t.”
The issuance of the EUA closely followed a report last week that the FDA had initially decided against authorizing convalescent plasma, after federal health officials intervened because the data were deemed insufficiently strong. But the authorization announced Sunday was not apparently based on any new data or a close reevaluation of existing data.
“I believe there are several problems with the EUA that was granted,” Dr. Katharine Bar, an assistant professor of medicine at the University of Pennsylvania, wrote in an email. “First, the decision was made on preliminary or suggestive evidence, rather than the high-quality RCT data traditionally used. Second, the EUA will make it more challenging to complete the RCTs needed to eventually get more conclusive data one way or the other.”
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The EUA was based on data from small clinical trials as well as a Mayo Clinic-sponsored expanded access protocol, or EAP. Despite having tens of thousands of patients and data indicating that early infusion with convalescent plasma containing high concentrations of antibodies can reduce mortality, the EAP is not a randomized trial, thereby making it difficult to draw firm conclusions, even if the results appear promising. On the other hand, some of the purported benefit appears overstated, such as a 35% benefit in survival erroneously cited by FDA Commissioner Stephen Hahn, Department of Health and Human Services Secretary Alex Azar and President Donald Trump at a press conference Sunday and later reiterated on Twitter by the FDA.
ClinicalTrials.gov lists more than a dozen RCTs of convalescent plasma taking place around the U.S., enrolling anywhere from a few dozen to more than 1,000 patients. In a press conference Monday, World Health Organization chief scientist Dr. Soumya Swaminathan said emergency use listing was the purview of individual countries, but said the WHO prefers that convalescent plasma be subjected to testing in RCTs.
“We recommend that convalescent plasma is still an experimental therapy,” she said. “It should be continued to be evaluated in well-designed randomized clinical trials.”
However, others contend that the EUA may not pose such a problem, given that there many patients available, but not all of them are able to enter a clinical trial designed to determine who does and does not respond to convalescent plasma treatment.
“I don’t think there will be a paucity of eligible patients to be able to address those questions with well-designed trials,” said Dr. Gailen Marshall, an associate professor of medicine at the University of Mississippi who is running a single-arm trial of convalescent plasma in Covid-19 patients. Marshall added that none of the physicians he had spoken to at his hospital, the University of Mississippi Medical Center in Jackson, or at the two nearby hospitals planned to use the EUA, but even if they did, it would not likely challenge clinical trial enrollment.
Others, like Dr. Anne Brown, a pulmonary disease specialist at Inova Fairfax Hospital in Virginia, and Dr. Joakim Dillner, a professor of infectious disease epidemiology at the Karolinska Institute in Stockholm, were also supportive of the decision. “I think it was a bold move, and I must say it was the correct move,” Dillner said in a phone interview.
Still, the timing and circumstances of the decision have led to worries that it may have been at least in part due to political pressure. It came a day after Trump baselessly accused the FDA of slow-walking Covid-19 vaccines and treatments and the day before the start of the Republican National Convention – charges against which Hahn was seen as insufficiently willing to defend career FDA staffers, Bateman-House said, adding she had been “besieged” with messages from people who had formerly worked with the agency and were bewildered by what they saw as the commissioner’s unwillingness to defend his colleagues. Given that and the lack of apparent new data going into the EUA that was granted, Bateman-House said the agency should have been more transparent, as the perception that partisan politics could play a role in its decision making could be very damaging to an agency whose strength lies in the faith that its policies are guided by science and data.
“I guess the way to rectify that damage would be to release any information that led to this decision,” she said. “That’s the best they could do, but I don’t know that they have any other data to share.”
While emphasizing his view that the science was supportive of the EUA, Marshall acknowledged the trepidation some members of the public might have about using convalescent plasma due to the perception that the decision was politicized, especially due to the rapid reversal from what was reported last week.
“I understand: ‘First they say no and then they say yes – is this political and is it dangerous for me to participate,” he said. “I would try my best to lay out information for them to change their mind about that anxiety.”
Photo: kuarmungadd, Getty Images
