ASH Comment on Emergency Use Authorization for Convalescent Plasma
August 28, 2020
Input from ASH President Stephanie J. Lee, MD, MPH
On 8/23/2020, the FDA granted emergency use authorization (EUA) and published a fact sheet for COVID-19 convalescent plasma (CCP) to treat hospitalized patients diagnosed with COVID-19. With this EUA, the expanded access program (EAP) will close as of 8/28/20, potentially disrupting access to CCP until blood collection centers and hospitals can meet the new requirements for administration under the EUA. For information on how an EUA differs from an EAP, see the ASH convalescent plasma FAQs). The EAP has provided CCP to over 70,000 patients and collected basic safety and some efficacy information; its discontinuation was based on the assessment that it was unlikely to provide further scientific information. The scientific community is divided over whether the currently available evidence meets the 4-part criteria required for an EUA: potentially effective intervention for a serious or life-threatening disease where benefits outweigh risks and when there are no adequate, approved, and available alternatives. An FDA executive summary of its decision is available. The switch to the EUA may result in more patients having access to CCP because of decreased regulatory and Institutional Review Board oversight requirements, barriers that proved challenging for many hospitals during intense pandemic pressure.
Issuance of the EUA is anticipated to have several additional downstream consequences. Enrollment of hospitalized patients into definitive randomized trials to better understand the risks and benefits of CCP, already slow under current conditions due to the EAP, may slow down further or stop altogether. This reflects the reality of patients’ and physicians’ preferences to use “open-label” CCP, rather than enroll in a clinical trial where they may be randomized to a control group that does not get CCP. There will no longer be national collection of safety and outcomes data, although the limitations of the current EAP data set illustrate that some questions cannot be answered through observational research, no matter how large the sample size. There is also the potential of adverse or confounding effects of widespread CCP utilization on early phase drug and antibody clinical trials. Paradoxically, discontinuation of CCP use through the EAP may now allow CCP to be considered an acceptable concurrent treatment rather than an exclusion criterion for other trials, although interpretation of these trials may become more challenging. Finally, the supply of CCP may be insufficient if demand increases, particularly as a higher fraction of recovered COVID-19 patients will be barred from donating CCP for 3 months due to receiving CCP themselves during their acute illness and antibody titers wane with time (plasma donation within 3 month of receiving a blood product is not allowed per current FDA guidance on donors).
Slow enrollment on clinical trials impedes our ability to answer critical questions and make evidence-based recommendations. We also risk allowing a treatment to become standard of care without rigorous analysis of benefits versus risks. We have been wrong many times before in medicine when we thought the answer was intuitive and obvious from observational studies. Despite the EUA, which is a temporary designation, randomized trials are still needed to establish whether CCP should be fully approved or the EUA withdrawn. Although current observational data in CCP suggest that higher immunoglobulin titers and treatment within 3 days of diagnosis resulted in better survival, there were clearly both known and unknown confounders. Only large randomized trials will deliver a clearer answer. We still do not know the best specific dosing parameters: e.g. timing, dose and antibody titers and types. We do not know the effectiveness in special populations such as people with immunocompromised immune systems or in specific contexts such as prophylaxis after known exposure or in pre-hospitalized patients. We also do not know if convalescent plasma is more or less effective with dexamethasone or remdesivir. Carefully designed RCTs should be carried out to answer these questions, and may be easier to complete without a placebo arm, but instead compare doses or timing.
Thus, the American Society of Hematology makes the following recommendations:
- Encourage enrollment in well-designed clinical trials studying the efficacy and optimal regimens for CCP
- Urge recovered COVID-19 patients to donate CCP
- Consider changes to existing interventional trials regarding concurrent use of CCP and renew the focus on questions that can be answered in the context of widespread EUA availability of CCP
For additional information, see:
- ASH Convalescent plasma FAQs
- FDA announcement of EUA
- FDA Fact Sheet on EUA
- FDA Executive Summary of the EUA decision
- FDA: Three options to administer convalescent plasma given the Emergency Use Authorization, and a 90-day period of enforcement discretion to use up already-collected plasma that would not otherwise meet EUA