While the emergency use authorization (EUA) the FDA granted Aug. 23 for convalescent plasma remains a political talking point, the agency moved ahead Sept. 2, issuing an updated, immediately effective guidance on the use of convalescent plasma to treat COVID-19 patients in ongoing clinical trials, on an expanded access basis or under the EUA.

Just a day earlier, the NIH’s COVID-19 Treatment Guidelines Panel issued a statement saying there is insufficient data to recommend either for or against the use of convalescent plasma and stressing that it should not be considered standard of care for treating coronavirus infections.

The concern about it becoming standard of care echoed what FDA Commissioner Stephen Hahn said when he announced the EUA, which was requested by Robert Kadlec, Health and Human Services’ assistant secretary for preparedness and response.

At that time, Hahn said the EUA was not intended to make convalescent plasma the new standard of care for treating patients with COVID-19, and he called for robust clinical trials to continue testing its safety and efficacy and to determine its optimal use.

The updated guidance repeats the call for clinical trials, but it makes no reference or recommendation about not using convalescent plasma as standard of care. However, it does point out that, even with the EUA, convalescent plasma is still considered an investigational product.

The guidance explains the different pathways available for using and testing convalescent plasma and addresses the collection of the plasma, recordkeeping requirements, and the FDA’s compliance and enforcement policy regarding the investigational new drug (IND) use of the product.

Labeling extension

Responding to concerns about the new labeling requirements being imposed on convalescent plasma now that there’s an EUA, the FDA said it would give blood establishments 90 days to develop the necessary procedure to manufacture COVID-19 convalescent plasma under the EUA conditions, which include testing plasma donations for anti-SARS-CoV-2 antibodies using the Ortho Vitros SARS-CoV-2 IgG to determine suitability before release and then qualifying units as high titer or low titer based on that testing.

After the grace period, establishments that are unable to develop the EUA procedures will be limited to administering investigational convalescent plasma under an IND, according to the updated guidance.

In the meantime, plasma units that don’t meet the new labeling requirements can be used so long as:

  • they’re intended to treat hospitalized patients with COVID-19;
  • the provider obtains adequate informed consent, including a statement identifying the use as investigational and a discussion of potential risks and benefits;
  • the plasma is collected by registered blood establishments from qualified donors;
  • the container label contains the statement, “Caution – Limited by federal (or United States) law to investigational use.”

The 90-day extension will allow for the use of plasma collected before the EUA, with its new labeling requirements, was granted. Michbio was one of many groups that expressed concern about immediately meeting those requirements. “Hundreds, if not thousands, of in-date, ready to transfuse [plasma] units across the country have been rendered unusable by the specifics of the EUA,” the group said when it urged the FDA to rethink those requirements.

“This labeling issue, if not rapidly corrected, will lead to significant delays in transfusion of patients across the country for the foreseeable future or put transfusion services licenses at risk for willfully violating FDA requirements,” Michbio said last week after the EUA was granted.

Trials still needed

In updating its guidance, the FDA reiterated that “the EUA is not intended to replace clinical trials that are critically important for the definitive demonstration of safety and efficacy of investigational convalescent plasma.” The agency encouraged doctors to enroll patients in ongoing trials, as that’s the only way to fully answer the questions about the effectiveness of convalescent plasma in treating COVID-19.

The lack of a completed, robust trial is what has fueled accusations that politics, not science, drove the EUA. While recognizing the need for randomized, controlled trials, the FDA based its emergency use decision on past use of convalescent plasma, including during the 1918 influenza, 2003 SARS and 2009 influenza H1N1 pandemics.

It also cited data from a national expanded access protocol (EAP), sponsored by the Mayo Clinic, that had enrolled more than 90,000 patients hospitalized in the U.S. with COVID-19. That protocol ended after the EUA was granted.

The NIH panel didn’t find the EAP data convincing. Among hospitalized patients in the Mayo protocol who were not intubated, 11% of those receiving high antibody titers died within seven days of transfusion compared with 14% of those who received low antibody titers. Among those who were intubated, there was no difference in seven-day survival.

“Although these data suggest that convalescent plasma with high antibody titers may be beneficial in nonintubated patients, uncertainty remains about the efficacy and safety of convalescent plasma due to the lack of a randomized control group and possible confounding in the Mayo Clinic’s EAP,” according to the NIH guidelines panel.

Another concern the panel has with the use of convalescent plasma is that the antibody levels in currently available plasma are highly variable, while the assays to determine the effective antibody titers are limited.

Meanwhile, Democrats on the Senate Health, Education, Labor and Pensions (HELP) Committee are calling for an immediate committee hearing on “the undue political influence of the White House” on the FDA and the CDC. The letter requesting the hearing, with Hahn as a witness, cited the convalescent plasma EUA as an example of that influence.

Although a recent study of 20,000 COVID-19 patients had found convalescent plasma a safe treatment, the letter said, “the FDA initially chose to hold off on issuing an EUA for blood plasma after top government scientists – including [the NIH’s] Dr. Anthony Fauci and Dr. Francis Collins – publicly urged the FDA to wait before reviewing more convincing effectiveness data.” But then politics kicked in, the letter claimed, and the EUA was granted.