How the FDA’s EUA for Convalescent Plasma Will Impact Healthcare Providers and Researchers

August 25, 2020
Firm Publication

On Sunday, August 23, the Food & Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for investigational COVID-19 convalescent plasma (CCP) for the treatment of COVID-19 in hospitalized patients. This EUA has important implications for healthcare providers, licensed blood establishments, and researchers conducting clinical studies of CCP.

Background on COVID-19 Convalescent Plasma

On March 27, 2020, the Secretary of Health and Human Services (HHS) activated the FDA commissioner’s authority, pursuant to Section 564 of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 360bbb-3), to issue EUAs allowing unapproved medical products or unapproved uses of approved medical products for the diagnosis, treatment, or prevention of COVID-19. The FDA has subsequently issued many EUAs for diagnostics, personal protective equipment, and drugs like hydroxychloroquine (for which the EUA was subsequently revoked), to combat COVID-19.

CCP is antibody-rich plasma donated by those who have recovered from COVID-19. Scientists hope that administering CCP to COVID-19 patients could help them recover faster. Convalescent plasma has been used during other outbreaks, including the 1918 influenza pandemic and the more recent Ebola outbreaks, but without data sufficient to demonstrate its effectiveness. To see whether it helps with COVID-19, a number of randomized, controlled trials began.

The FDA also worked with the Mayo Clinic to establish a national expanded access program for convalescent plasma. Expanded access programs provide patients who cannot access clinical trials with investigational products with less rigorous data collection than would be available through a clinical trial.

The Mayo Clinic’s expanded access program was not a randomized, controlled trial, so some public health officials (including Drs. Francis Collins and Anthony Fauci) and former FDA commissioners have questioned whether the Mayo Clinic’s data – some of which is not yet peer-reviewed – was strong enough to support the issuance of an EUA. Nevertheless, the statutory criteria for approval of an EUA, which include that the product “may be effective” in its proposed use, are significantly less stringent than the criteria for FDA approval of a new treatment, which require that the product actually be effective.

The decision memorandum backing the FDA’s actions states that the data “support the conclusion that CCP to treat hospitalized patients with COVID-19 meets the ‘may be effective’ criteria for issuance of an EUA. Adequate and well-controlled randomized trials remain nonetheless necessary for a definitive demonstration of … efficacy and to determine the optimal product attributes and the appropriate patient populations for its use.”

What the EUA Means for Healthcare Providers

Until Sunday’s EUA, the three main ways providers could legally offer CCP to patients were the following:

  • A clinical trial approved by the FDA under 21 CFR Part 312.
  • The Mayo Clinic’s expanded access program.
  • A single patient emergency use approved by the FDA according to 21 CFR § 312.310.

Once the Mayo Clinic’s expanded access program was established, the majority of patients receiving CCP did so through this program.

While CCP clinical trials will likely remain active (although likely underpowered) following the August 23rd EUA, there will be no reason to obtain single-patient emergency use approvals and little incentive to continue the Mayo Clinic program, which is, therefore, discontinuing new physician and new patient enrollments on August 28. The Mayo Clinic has notified providers that have already obtained patient consent for enrollment in its program to complete the patient enrollment form as soon as possible.

Any CCP administered as part of the Mayo Clinic program should be done consistent with the Mayo Clinic program protocol and informed consent requirements.

Going forward, for CCP obtained according to the EUA (i.e., outside the Mayo Clinic program), the FDA’s Fact Sheet for Health Care Providers explains how providers are required to communicate with patients about CCP (which includes giving them the required Fact Sheet for Patients and Parents/Caregivers) and gives guidance about dosage, administration, storage, interactions, and use of CCP in specific populations (e.g., pediatrics, pregnant or nursing mothers, etc.). It also explains how adverse events must be tracked and reported and cautions providers against using any printed material or advertising describing CCP as safe or effective.

What the EUA Means for Blood Establishments

The CCP covered by the EUA must be collected by FDA-registered blood establishments from individuals whose plasma contains anti-SARS-CoV-2 antibodies and who meet all donor eligibility requirements. Those eligibility requirements include specific SARS-CoV-2 neutralizing antibody titers, “if available.” However, the FDA has not authorized any antibody tests that quantitatively measure SARS-CoV-2 antibodies; blood establishments should be sure to implement such testing if it becomes authorized and watch for guidance on previously-collected units.

For purposes of the EUA, units tested by the Ortho VITROS SARS-CoV-2 IgG test and found to have a signal-to-cutoff value of 12 or greater qualify as high titer CCP. Units containing anti-SARS-CoV-2 antibodies but not qualified as high titer by that test are considered low titer units and must be labeled accordingly. If a blood establishment is considering using an alternative test to qualify high titer CCP, it must contact the FDA Center for Biologics Evaluation and Research to determine acceptability of the proposed test, which if accepted, would require an amendment to the EUA.

Both the EUA and the accompanying Fact Sheet for Health Care Providers contain important additional information about unit labeling and recordkeeping that blood establishments should carefully review.

Additional Considerations for Research Institutions 

This EUA does not affect the regulatory status of ongoing or planned CCP clinical trials, which will still require an investigational new drug application approval from the FDA. But even before the EUA, clinical trials of CCP were struggling to enroll participants because of the popularity of the Mayo Clinic expanded access program. The EUA, many researchers are concerned, will “open the floodgates” for the limited supply of CCP to be used in treating patients who can afford the therapy instead of the clinical trials needed to determine whether CCP is effective. Indeed, the FDA mentioned this concern in its June vaccine guidance, stating that “issuance of an EUA for a COVID-19 vaccine prior to the completion of large randomized clinical efficacy trials could reduce the ability to demonstrate effectiveness of the investigational vaccine….”

U.S. institutions may need to await the results of foreign clinical trials, including two large trials across the U.K. – the RECOVERY trial and the REMAP-CAP trial – to have more definitive data on whether and when CCP works. Those trials will test CCP in thousands of hospitalized and intensive care patients, respectively, and compare its effectiveness to other experimental treatments such as antivirals, anti-inflammatory drugs, and hydroxychloroquine.

Notably, the Fact Sheet for Health Care Providers states that because of the absence of prospective, randomized trials, “convalescent plasma should not be considered a new standard of care for the treatment of patients with COVID-19.” This statement is not found in other COVID-19 therapeutic EUAs, such as the EUA for remdesivir or the (now revoked) EUA for hydroxychloroquine. Institutions with the expertise to make their own determinations about whether to use CCP for their hospitalized COVID-19 patients should, therefore, do so using published papers, the Mayo Clinic preprint, and the FDA decision memorandum referenced above.

If you have any questions about the FDA’s EUA for CCP, please contact the authors.