How the Food and Drug Administration saved thousands of lives
As the COVID-19 calamity has droned on, we have become accustomed to criticisms in our nation’s response. However, some things were done right. Two years ago, in the darkest days of the early pandemic, the Food and Drug Administration (FDA) made the unprecedented decision to make convalescent plasma (CP) available to American citizens before complete evidence of efficacy and safety had emerged. This was done by creating a Mayo Clinic registry in April 2020, that allowed physicians to administer CP while collecting clinical information on the patients and on their course of disease.
Convalescent plasma is a form of antibody therapy. People infected with a microbe make antibodies that aid recovery and protect from repeat infection. Convalescing patients have these antibodies in their plasma, which can be used to protect others from the same infection. Antibody therapies were first developed in the 1890s and an enormous body of medical knowledge shows that they are effective when used early in the course of disease. The FDA action relied on solid historical evidence as well as reports from China that CP was safe and likely effective.
The Mayo Clinic registry rapidly produced evidence that CP was safe, dispelling any concerns that antibody administration would worsen infection through a mechanism known as antibody-dependent enhancement (ADE). This finding also reassured the then-nascent vaccine efforts because prior coronavirus vaccines had been plagued by concerns about ADE. One can only imagine the detrimental effect on vaccine development in the event the registry had found evidence of harm from antibody administration. At the very least, vaccines rollouts would have been delayed as more safety data would have been needed. The CP effort made a quiet, unsung, yet critically important contribution to the development of COVID-19 vaccines.
The Mayo Clinic registry also found strong evidence of CP efficacy. In early summer 2020, Mayo scientists found a dose-response relationship of antibody levels in plasma to mortality— the more antibody given, the lower the death rate, which is a powerful indicator of efficacy. The analysis showed that patients needed to be treated early during hospitalization and that the mortality benefit was limited to those not receiving mechanical ventilation. But these findings were ignored by many randomized trials then ongoing, which often treated late in disease and without confirming antibody levels in administered CP. Not surprisingly these trials produced negative results. However, four better designed and more appropriately targeted randomized clinical trials in the U.S. — from Columbia, Einstein, Pennsylvania and Johns Hopkins universities — produced results that in aggregate confirmed the registry finding of CP effectiveness.
Based on the Mayo Clinic safety and efficacy results the FDA issued an Emergency Use Authorization (EUA) for CP use on Aug. 23, 2020. Unfortunately, the announcement was marred by exaggerated claims during a presidential news conference, sowing distrust in the medical community. The FDA decision was criticized by many physicians on the grounds that it was inappropriate to authorize a therapy without thorough evidence of efficacy. Making CP available for treatment, it was argued, might prevent the launching of rigorous clinical trials to establish its safety and effectiveness. Now, with the experience of the past the past two years, it is evident that none of these criticisms were accurate or relevant. Today, CP is recommended by the Infectious Society of America and Association for the Advancement of Blood and Biotherapies.
With the EUA, CP began to be widely used for hospitalized patients with COVID-19 in the United States. By the fall 2020, about 40 percent of all inpatients were being treated with plasma, and by March 2021, approximately 500,000 patients had been treated with CP. The use of CP correlated with significantly reduced mortality — we estimate that the deployment of CP in the U.S. saved around 100,000 lives.
We can now begin to assess things done well and things done poorly in response to the pandemic. The FDA decision to authorize CP use six months into the pandemic was correct and courageous. The U.S. was the only nation to take this approach for CP, providing a much-needed therapy for the American public early in the pandemic when other effective treatments were absent.
The United States went from using zero units of CP in March 2020 to more than 20,000 units per week by the fall. That was possible because the blood industry mobilized along with thousands of altruistic donors stepping forward. Citizen organizations like Survivor Corps worked to promote it and a dedicated core of physicians used it.
Today, we know that early use of CP is effective against COVID-19 and, as the variants have defeated most monoclonal therapies, CP has emerged as an important antibody therapy, especially for immunosuppressed patients. In a pandemic response punctuated by many foibles, the FDA actions on CP shine brightly and provides a roadmap for future actions during infectious disease outbreaks.
Arturo Casadevall, MD, Ph.D., is a Bloomberg distinguished professor and Chair of the Department of Molecular Microbiology and Immunology at Johns Hopkins School of Public Health.
Nigel Paneth, MD, is professor emeritus of epidemiology, biostatistics and pediatrics at Michigan State University.
Casadevall and Paneth are members of the leadership group of the National COVID-19 Convalescent Plasma Project and have been co-authors with FDA and Mayo Clinic scientists in publications about plasma