Why FDA’s emergency use authorization for plasma could have limited implications

Erin McCallister Senior Manager, Health Research Institute, PwC US August 27, 2020

The FDA’s Aug. 23 decision to grant an Emergency Use Authorization (EUA) for convalescent plasma to treat COVID-19 has prompted many headlines, but the availability of the treatment and existing widespread use could mute the EUA’s effects.

Convalescent plasma is collected from individuals who have recovered from infection with SARS-CoV-2, the virus that causes COVID-19, and have developed antibodies to the virus that are believed to help fend off the infection in ill patients. Convalescent plasma can be collected from individuals two weeks after they’ve recovered from the virus.

According to the authorization memorandum, the FDA was unable to assess the benefit of convalescent plasma in randomized controlled trials because many have either not yet completed or were stopped early because of poor enrollment. The agency did assess data from multiple studies, including two randomized trials that did not complete enrollment, three nonrandomized studies and several retrospective matched cohort studies. The trials either showed a trend toward survival but were not statistically significant or showed no difference compared with the control.

The FDA also assessed the results from 20,000 patients enrolled in the expanded access program (EAP), where it found low rates of adverse events and various post hoc subgroup analyses showed statistically significant benefits on survival in those treated more quickly after diagnosis who were more than 80 years old. An EAP is, in the words of the FDA, “a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.”

HRI impact analysis

There is concern among some researchers that the EUA could make it difficult to enroll patients in clinical trials for the plasma therapy because they may not want the risk of being randomized to a placebo. However, the EUA may have only an incremental effect beyond that already exerted by the EAP.

The FDA has facilitated early access to convalescent plasma since April through the coordination of a national EAP with academic medical centers and the American Red Cross. Since then, the EAP has grown to include more than 90,000 people. The program was discontinued with the granting of the EUA, but as of Aug. 25, the program was available at 2,787 sites. According to USCovidPlasma.org (accessed on Aug. 26), patients were eligible for the EAP if they had a positive test for SARS-CoV-2, were admitted to an acute care facility and were considered to have severe or life-threatening disease.

The population indicated for treatment with convalescent plasma in the EUA mirrors these criteria.

According to ClinicalTrials.Gov (accessed on Aug. 26), since April 3 when the EAP was started, 40 interventional trials of convalescent plasma have been launched in the US; two (here and here) have reached their enrollment goals and three are enrolling by invitation only. Thirty-five are either still recruiting patients or haven’t yet started recruitment.

The two studies that have completed enrollment began after the EAP, including one that started after May 1, when enrollment in the EAP began to increase. The two studies have small trial sizes of 10 and 29, respectively, and both are single-arm trials, making it difficult to discern the effect of convalescent plasma on patients.

With the EUA seemingly an extension of the EAP, it does put the ability to discern a benefit in jeopardy if doctors choose to treat patients via the EUA rather than enroll them into a trial.

The availability of plasma could also be a limiting factor in both the reach of the EUA and the ability to complete trials. On the same day the EUA was granted, the American Red Cross issued a press release citing “an emergency shortage” of convalescent plasma. The organization has obtained plasma from more than 14,000 donors since April.

As cases wane in the US, it could further complicate the donation levels for plasma. According to the Johns Hopkins University of Medicine COVID-19 tracker, the seven-day rolling average of cases in the US declined to approximately 38,000 as of Aug. 25 from nearly 70,000 during much of July. Fewer sick individuals will mean fewer recovered plasma donors.

The Department of Defense is trying to improve the processing of donated plasma. On Aug. 17, the department awarded a grant of $750,000 to help a company scale up a plasma separation process that could result in higher yields of immunoglobulins for COVID-19 patients.

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Trine K. Tsouderos

HRI Regulatory Center Leader, PwC US

Tel: +1 (312) 241 3824

Ingrid Stiver

Senior Manager, Health Research Institute, PwC US

Erin McCallister

Senior Manager, Health Research Institute, PwC US

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