National Convalescent Plasma EUA Results: Not Sufficient Evidence for Claim that Convalescent Plasma Reduces COVID-19 Death Rate
TrialSite initially covered the National Convalescent Plasma Study, led by Mayo Clinic, with great enthusiasm. In fact, many dozens of physicians reached directly out to TrialSite to request a connection to the sponsor—which the TrialSite accommodated. At the pandemic onset, an urgency drove all to seek answers quickly. Now that data is available from over 35,000 COVID-19 patients, the findings are on the one hand somewhat positive with some association of benefit, but on the other hand, due to a confluence of factors, the study results don’t lead to powerful evidence confidently advancing practice.
Although Mayo Clinic and several other investigators who led the initiative suspect that convalescent plasma from recovered COVID-19 patients can help others recover, there is a lack of definitive evidence for any U.S. Food and Drug Administration (FDA)-based claims. With over 64,000 patients in the U.S. administered convalescent plasma, the use of a century-old method to stop infectious disease prior to vaccines hasn’t led to clear evidence to transform practice.
This study was a formal “Expanded Access Program” or EAP for the treatment of COVID-19 patients with human convalescent plasma. The multicenter EAP includes 2,807 acute care facilities in the U.S. and territories. Enrolled adult participants transfused under the purview of the U.S. Convalescent Plasma EAP program between April 4 and July 2020. These patients were hospitalized with (or at risk) with severe or life-threatening (critical) COVID-19 respiratory syndrome.
During the study, the investigators offered a transfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. The study was able to secure sufficient volumes of donated convalescent plasma from qualified donors (again, they must have been recovered COVID-19 patients). The antibodies in the units collected were unknown at the time of collection and transfusion.
The researchers recently posted in the results to the preprint server medRxiv and reported the main outcomes and measures. For example, the investigators report seven and thirty-day mortality metrics: “35,322 transfused patients had heterogeneous demographic and clinical characteristics.” 52.3% of the patients were in the intensive care unit (ICU) and 27.5% in a more dire situation needing mechanical ventilation when the plasma transfusion was administered.
The team reported that the seven-day mortality rate equaled 8.7% [95% CI 8.3%-9.2%] for patients that received a transfusion within three days of COVID-19 diagnoses but 11.9%[11.4%-12.2%] in patients transfused four or more days after diagnosis (p<0.001). For 30-day mortality found similar metrics (21.6% vs. 26.7%, p<0.0001). The study authors observed a “gradient of mortality” in relation to IgG antibody levels in the transfused plasma. For example, those patients that actually were the recipient of high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); while those receiving medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6 ( 10.3%, 13.1%) and for those recipients of low IgG plasma ( <4.62 S/Co) with mortality equaling 13.7% ( 11.1%, 16.8%) (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for seven days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units.
The study authors report that these relationships between lower mortality or death rate and both earlier time to transfusion and higher antibody levels lead to what they call “signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients.” However, the conclusion isn’t strong when the authors declare, “the information included in the report could be “informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma.”
First, the EUA wasn’t a formal, randomized clinical trial. For example, different patients were treated in various ways, depending on which hospital they were located. This was acceptable as at pandemic onset, there was a real concern that many people would die if there wasn’t immediate access to the EUA. So the EUA offers a program to monitor and track patient status and outcomes, but the results cannot be declared evidence because it isn’t clear if high survival rates, for example, are the result of the convalescent plasma or another part of the care protocol at the particular hospital.
As reported by the Baltimore Sun’s Lauran Neergaard, Dr. Mila Ortigoza of New York University recently stated on this topic, “For 102 years (since the 1918 flu pandemic) we’ve been debating whether or not convalescent plasma works” and followed now “we really need indisputable evidence.”
Moreover, in addition to the basic question as to if convalescent plasma is proven to help reduce death rate (which again it isn’t proven), a myriad of other critical questions pursue from when convalescent plasma should be used (early on, later, etc.), what doses to what antibody types work best?
Ongoing Clinical Trials
The good news is that there are clinical trials ongoing designed to generate stronger evidence for the case of convalescent plasma. However, the challenge is that as the virus speeds up and then slows down and then surfaces in another part of the country, it’s difficult to complete any study. Moreover, some patients (or their families) capitalize on the EUA and request convalescent plasma over participation in a randomized controlled trial.
Principal Investigator POV
TrialSite reported the enormous interest of receiving quests from many dozens of doctors to participate, as well as hundreds of patients to volunteer, donate, or report they had a sick relative in need of the treatment. TrialSite referred the doctors to the website referred to us by Dr. Joyner. The patients were referred to various qualified blood collection centers in their home states. Mayo’s Michael Joyner reminded that the original intent of the National Convalescent Plasma study was to track whether this approach was safe, targeting initially 5,000 participants. Joyner was quoted, “There’s probably reasonable, actionable evidence from our findings to really reaffirm” historical lessons of plasma therapy, that the earlier to use the better as reported in the Washington Post.
Michael Joyner, MD