As of Aug. 13, more than 90,000 patients hospitalized in the U.S. with COVID-19 already had been given access to convalescent plasma through a national expanded use protocol (EAP) sponsored by the Mayo Clinic. The FDA’s decision Sunday to grant emergency use authorization (EUA) for the potential therapy will further expand access to convalescent plasma for hospitalized patients throughout the country at a time when fully approved COVID-19 treatments are nonexistent and even EUAs are few and far between.

The announcement came just three days after Anand Shah, deputy commissioner for medical and scientific affairs at the FDA, addressed media reports last week that suggested politics were at play in trying to speed an EUA for plasma. The decision, when it came, would be made on the “totality of the data,” not politics, Shah said, noting that convalescent plasma has been used for more than a century to treat a variety of diseases. That use included the 1918 influenza, 2003 SARS and 2009 influenza H1N1 pandemics.

The COVID-19 plasma EUA was granted in response to a request from Robert Kadlec, Health and Human Services’ assistant secretary for preparedness and response. The FDA decision was based on data obtained from the ongoing Mayo EAP, results from small clinical trials conducted earlier in the pandemic, preclinical evidence and historical evidence of the use of convalescent plasma in prior outbreaks of respiratory viruses, FDA Commissioner Stephen Hahn told Kadlec in a letter Sunday.

Regardless of the grounds for granting it, the EUA came under fire before it was even granted. Aside from all the political posturing in the heat of an election year, the biggest complaint is that the anti-SARS-CoV-2 antibody-rich plasma has yet to be proven in a robust randomized, controlled trial (RCT), although it is being tested in trials in many countries around the world, including Australia, Canada, China and the U.K.

An RCT conducted in China earlier this year using well-characterized plasma units with a high titer of antibodies appeared to signal a more favorable outcome for patients treated with plasma, but the trial was terminated early when the pandemic ebbed in China, making it difficult to fully enroll the study. Consequently, the study was underpowered with 52 severely ill patients randomized to the treatment arm and 51 to the control arm. Thus, many of the comparisons were not considered statistically significant, according to an article in the June 3, 2020, issue of JAMA.

However, the primary outcome of time to clinical improvement within 28 days was 2.15 days shorter in the intervention group compared with the control group, and clinical improvement at 28 days occurred in 27 patients, nearly 52%, in the intervention group versus 22 patients, about 43%, in the control group. The study did not look at plasma in earlier stages of COVID-19.

Future of clinical trials

With the pandemic still raging in the U.S., patients are being recruited for dozens of trials testing plasma in various stages of the infection. Hahn doesn’t want the EUA to interfere with those trials. Noting the need for “adequate and well-controlled randomized trials” to definitively demonstrate the efficacy of plasma and to determine its optimal attributes and the appropriate patient populations, Hahn told Kadlec, “ongoing clinical trials of COVID-19 convalescent plasma should not be amended based on the issuance of this EUA; providers are encouraged to enroll patients in those trials.”

As of Monday, 52 plasma trials, including the Mayo EAP and other expanded access programs, were listed in Clinicaltrials.gov. Of those, 39 were listed as recruiting, and six were shown as “available.” Three were not yet recruiting, and a few others were listed as active but not recruiting.

If convalescent plasma becomes standard of care now that the EUA has been granted, sponsors may find it challenging to recruit for RCTs in which patients could be denied access to it. Although the EUA, according to Hahn, is not intended to make convalescent plasma the new standard of care for treating patients with COVID-19, there are few other options available.

To date, the FDA has granted 268 EUAs for COVID-19 diagnostics, lab tests, medical devices and personal protection equipment, but it has authorized the emergency use of only six therapies – one of which, for hydroxychloroquine, has been revoked.

Of the five current therapeutic EUAs for COVID-19, only convalescent plasma and Gilead Sciences Inc.’s remdesivir are authorized for use as a treatment for the infection itself; the other three are authorized to maintain sedation in patients on ventilators or as part of continuous renal replacement therapy.

With remdesivir in limited supply until Foster City, Calif.-based Gilead can fully ramp up manufacturing of the antiviral to meet the global demand, convalescent plasma could become the default treatment. “Convalescent plasma is one of few interventions that can be made available rapidly following the emergence of a new epidemic,” according to Laurence Corash, chief scientific officer at Cerus Corp., of Concord, Calif., which is teaming up with several collaborators in its home state to optimize convalescent plasma therapy for COVID-19 patients.

News of Sunday’s EUA created a bit of a wave for some companies developing plasma products. Adma Biologics Inc. (NASDAQ:ADMA), of Ramsey, N.J., gained 14%, closing at $2.87. Kamada Ltd. (NASDAQ:KMDA), of Rehovot, Israel, closed at $11.73, up 17%. Xbiotech Inc. (NASDAQ:XBIT), of Austin, Texas, closed at $19.57, a gain of 6.6%.