FDA grants emergency use authorisation for convalescent plasma even in the absence of evidence from randomised, controlled trial. Mr. Trump, FDA Commissioner and Secretary of Health and Human Services made a false claim that convalescent plasma reduces mortality by 35%., while the preprint does not make any such claim.First it was with hydroxychloroquine, and now the U.S. Food and Drug Administration appears to have been pressured or bullied into granting Emergency Use Authorisation for investigational convalescent plasma for treating COVID-19 patients who have been hospitalised even before scientific evidence from randomised, controlled studies could be collected.
The FDA on August 23 granted an emergency use authorisation for convalescent plasma, and called the EUA for convalescent plasma as “another achievement in administration’s fight against [the] pandemic”, which Dr Eric Topol, Scripps Research Director & Founder, Scripps Research Translational Institute says is unusual of the FDA. “I have never seen such a statement with any FDA approval,” he tweeted.
The FDA has gone ahead and granted EUA despite reservations expressed a week back by top federal health officials including Dr Francis S. Collins, Director of NIH and Dr Anthony S. Fauci, Director of National Institute of Allergy and Infectious Diseases. The experts had cautioned the FDA saying that the “emerging data on the treatment was too weak”, The New York Times reported on August 19.
At a White House press briefing on August 23, U.S. President Donald Trump said: “Today, I’m pleased to make a truly historic announcement in our battle against the China virus that will save countless lives. The FDA has issued an emergency use authorization — and that’s such a powerful term: emergency use authorization — for a treatment known as convalescent plasma… It’s had an incredible rate of success.” Mr. Trump said that the efficacy of convalescent plasma has been tested on “over 100,000 COVID-19 patients and it has proven to reduce mortality by 35%”.
Alex Azar, Secretary of Health and Human Services, who followed Mr. Trump at the briefing, too echoed the same message. “We dream in drug development of something like a 35% mortality reduction,” he said. “This is a major advance in the treatment of patients.”
The FDA Commissioner Dr Stephen M. Hahn also repeated the same message in relation to emergency use authorization issued for the convalescent plasma saying a “35% improvement in survival is a pretty substantial clinical benefit”.
Health experts disagree
But top health experts across the world have reacted sharply at the false claim of 35% reduction in mortality. “I hope that convalescent plasma turns out to be beneficial in randomised trials. The benefit is however likely to be marginal, if at all, and not the 35% improved survival homerun that is being claimed. Yes, a pandemic is still not reason enough to abandon good science,” Dr C.S. Pramesh, Director of Tata Memorial Hospital tweeted. “The miraculous 35% risk reduction [that FDA Commissioner Dr Hahn] spoke about is actually only a 4.8% absolute risk reduction.”
“The 35% risk reduction was not plasma versus no plasma, it wasn’t even early vs late plasma, but a select subgroup of high IgG antibody plasma transfusion with low IgG plasma. Clearly a misleading statement from the U.S. FDA Commissioner,” Dr Pramesh tweeted. “U.S. FDA Commissioner Dr Hahn announced that 35 out of 100 patients treated with convalescent plasma will benefit from it. This demonstrates either a lack of understanding of basic statistics (relative risk vs absolute risk) or external pressures.”
The EUA for convalescent plasma is not based on any randomised, placebo-controlled study but from data obtained from the ongoing National Expanded Access Treatment Protocol (EAP) sponsored by the Mayo Clinic. In a preprint posted on August 12 at medRxiv server, researchers from Mayo Clinic and other institutions conducted an observational study of 35,322 patients who were transfused with convalescent plasma. “Being an observational study, it is subject to very high levels of systematic bias,” Dr Pramesh says.
Dr Craig Spencer, of New York-Presbyterian/Columbia University Medical Center says: “I had Ebola and was treated with convalescent plasma. It was before we had good data on it. And it actually made me worse. Convalescent plasma has an incredible history and works for many diseases. But it didn’t for Ebola. And might not for COVID-19. Only good science can tell us.”
“Convalescent plasma has no randomized trials. It contains many antibodies that have no neutralizing effect. If it has efficacy, it will be relatively modest, at best,” Dr Topol says. About the FDA statement, Dr Topol says: “Not only blatantly wrong; an egregious public statement.”
What the study found
They found that the seven-day mortality rate was 8.7% in patients transfused within three days of COVID-19 diagnosis but mortality increased to 11.9% in those who received the transfusion four or more days after diagnosis. Similar findings were observed in 30-day mortality — 21.6% mortality if convalescent plasma was transfused within three days of diagnosis versus 26.7% mortality if convalescent plasma was transfused four or more days after diagnosis. The observational study was not a comparison of how patients fared when transfused with convalescent plasma compared with a control arm that did not receive convalescent plasma transfusion. It was only designed to compare how early versus late transfusion of convalescent plasma impacted the survival rate of hospitalised COVID-19 patients.
The researchers also studied how there was a graded reduction in mortality depending on the levels of IgG antibodies in the transfused plasma. In those who received plasma with high levels of IgG antibodies, the seven-day mortality was 8.9%, compared with 11.6% mortality in those who received plasma with medium levels of IgG antibodies. The mortality was 13.7% in those who got plasma with low levels of IgG antibodies. Similar, dose-response relationship with IgG was also observed in thirty-day mortality, they write.
“The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma,” the researchers write.
Why conducting RCT trails will become difficult
Citing the reasons why a randomised, controlled trial (RCT) was not undertaken, the authors write: “The very nature of RCT requires subject willingness to be randomised to active treatment or placebo or a comparator agent. There was no consensus in April nor is there a global consensus now regarding what would be an appropriate placebo-control to use. Also, many COVID-19 patients would likely have been distrustful of being randomized to a placebo based upon historical precedent.”
If the researchers found it difficult to conduct a randomised controlled trial, the false, misleading claim of 35% improved survival with plasma therapy will only make it more difficult to conduct such a trial in the future.
“With a public proclamation of a 35% improved survival (which is false), you have effectively killed the possibility of a well-powered randomized trial, which is what is really needed to show whether convalescent plasma is actually useful in COVID-19,” says Dr Pramesh. “Physicians and patients who are not aware of the ambiguity and serious biases inherent in an observational study and the far more modest benefit (if any) than the touted 35% will henceforth be reluctant to participate in a randomised trial.”