When the US Food and Drug Administration (FDA) approved convalescent plasma for emergency use for Covid-19, FDA Commissioner Steven Hahn made a statement that shocked and confused medical experts. He said, “35 out of 100 Covid-19 patients would have been saved because of the administration of plasma.” In reality, only 3 out of 100 patients in a recent trial may have benefited from plasma (the trial did not have a control arm so the real benefit is still unknown).
How could the FDA Commissioner get this so wrong? And why was convalescent plasma approved for emergency use just four days after the approval was put on hold due to data concerns? We’re taking a look at the roller coaster of events behind this emergency approval, and what it means for the FDA and approvals going forward.
What is convalescent plasma?
On August 19, The New York Times reported that the FDA’s Emergency Use Authorization (EUA) approval for convalescent plasma was on hold, due to concerns from leading federal health officials about the lack of data showing efficacy. But then four days later, the FDA changed course, giving its approval for emergency use for the treatment. What happened?
Convalescent plasma, or CP, refers to the infusion of blood plasma from people who have recovered from Covid-19. The plasma is assessed for safety, purified, and given to another patient suffering from Covid-19, so the antibodies in the plasma can help them fight the virus.
Many Covid-19 patients have already received CP through the FDA’s “compassionate use” program. CP for Covid-19 appears to be safe, with less than 1% of 20,000 patients having a serious reaction one week after transfusion, according to a Mayo Clinic trial.
However, the treatment has not yet shown to be effective for Covid-19. The most recent data on CP is from a Mayo Clinic trial of 35,000 patients with Covid-19 comparing the death rates of those who were treated with plasma within three days of diagnosis with those treated later. The researchers found that the death rate after seven days was 8.7% in patients treated with CP early and 11.9% in those treated later. Death rates after one month were also lower in patients who received plasma rich in antibodies compared to patients who received plasma with fewer antibodies. But the trial had no control group and was not randomized, which means that the lower death rate in the patients who got CP early or high-antibody plasma could be due to other factors having nothing to do with the treatment.
It was these concerns about the lack of sufficient data that compelled National Institutes of Health (NIH) leaders Francis Collins, Anthony Fauci, and H. Clifford Lane to try to put the brakes on the Emergency Use Operation until better evidence emerges.
FDA under pressure
In the days following the NIH intervention, President Trump put Hahn’s feet to the fire by lashing out at the FDA on Twitter and in the media, and accusing the agency of collaborating with “the deep state” to delay the approval. By August 23, the FDA had changed course and approved CP for emergency use.
But Hahn did more than just approve CP, he praised its effectiveness. At the news conference about the EUA, both Trump and Hahn said that convalescent plasma reduced deaths by 35%. Where did this number come from? Apparently, this was the relative reduction in deaths among a small subset of patients in the Mayo Clinic study who were under 80 years old, not on ventilators, and received plasma with high levels of antibodies early in their diagnosis. Investigators of the Mayo Clinic trial were confused, as this subset analysis was not part of the study they conducted, nor was this statistic in the FDA’s authorization letter.
Even worse, Hahn seemed to forget the difference between relative and absolute risk when he spoke at the news conference when he claimed that “35 out of 100 Covid-19 patients would have been saved because of the administration of plasma.” Scientists quickly denounced the statement as “blatantly wrong” and called for a public correction (so far, Hahn has made a correction on Twitter but not an official statement).
Other experts have pointed out that the problem is not just Hahn mistaking relative vs absolute risk, but also his failure to explain that there was no randomization or control group in the trial to begin with. Because of these features of the trial, we don’t know if there is any real survival benefit to CP yet.
🤦🤦 that was just PART of the error; the entire comparison is flawed.
— Vinay Prasad (@VPrasadMDMPH) August 25, 2020
It is not a suitable control.
The data don't show anything useful
And that is precisely a regulatory failure https://t.co/5v3bU5knOi
What this means for future treatments
This isn’t the first time the FDA has gone against scientific consensus in what appears to be an effort to appease demands from the White House. The FDA’s emergency approval of CP mirrors their original approval of hydroxychloroquine, which later had to be walked back because it was found to harm patients more than help them. Although CP appears safer than hydroxychloroquine, there is still no high-quality evidence to support its use for Covid-19.
“The rush to offer unproven treatments outside of well-designed clinical studies undermines high-quality science and condemns us to repeat age-old errors.”
Shannon Brownlee and Jeanne Lenzer, in Issues in Science and Technology
The irony is that we could have conducted randomized controlled trials for CP months ago but did not, what StatNews reporter Matthew Herper calls a “big failure on the part of the government response.” Unfortunately, the emergency approval threatens future randomized trials, because once a treatment is deemed successful in some way, people will be unlikely to agree to be randomly assigned to standard treatment. The New York Times reported that in the case of CP, “scientists have struggled to recruit patients for randomized trials, as many patients and their doctors — knowing they could get the treatment under the Mayo program — have been unwilling to risk receiving a placebo.”
The circumstances of the approval has also raises concerns about whether the FDA is adequately maintaining its independence from the White House. The more that politics affects or appears to affect FDA decisions, the less the public can trust that the treatments approved by the FDA are scientifically proven to work.
This does not bode well for the rollout of a Covid-19 vaccine–a case in which establishing treatment safety and efficacy is paramount and securing public trust is vital. With already dangerous levels of vaccine hesitancy in the US, the possibility that politics rather than evidence is driving vaccine approval decisions could delay the eradication of Covid-19.
If an EUA for #COVID19 vaccine is managed like today’s convalescent plasma announcement, we are in trouble. We need to know the process for evaluating safety/efficacy is based on science not politics. Today’s announcement did not provide that assurance. We must do better. 1/x
— Vivek Murthy (@vivek_murthy) August 23, 2020