On August 23, 2020, the US-FDA issued an Emergency Use Authorization (“EUA”) allowing the off-label use of convalescent plasma to treat COVID-19, having concluded that the totality of evidence supported this use. An EUA allows for use of an unapproved therapeutic product by clinicians when needed during public health emergencies. The FDA granted the EUA based on convalescent plasma safety and effectiveness data submitted by the Mayo Clinic under an Expanded Access Program (“EAP”). The EAP, also known as “compassionate use”, allows for treatment outside of clinical trials for patients with serious or life-threatening disease, when there is no comparable or satisfactory alternative treatment. Under an EAP, the Mayo Clinic enrolled about 90,000 COVID-19 patients (as of August 13) and provided safety data for 20,000 patients to the FDA. In deciding to grant the EUA, the FDA reviewed the following information about treating COVID-19 patients with convalescent plasma: (1) patient data supplied by the Mayo Clinic; (2) unpublished clinical trial data; and (3) reports of trials published in peer-reviewed clinical journals during the first 8 months of 2019.
The first published reports of use of convalescent plasma for treating COVID-19 describe many small clinical trials, both controlled and uncontrolled, and one randomized, placebo-controlled trial. Theoretically, convalescent plasma should be effective for treating COVID-19 because the plasma contains antibodies to the SARS-CoV-2 virus. As convalescent plasma transfusion was successfully used in China to treat SARS, clinicians began using this therapy for treating COVID-19 infections. Prior to the initiation of FDA’s EAP for convalescent plasma, most information available about its safety and effectiveness was from small case study trials and observational trials of COVID-19 patients, all of which are published in peer-reviewed clinical journals. Results from one large, randomized, placebo-controlled trial of convalescent plasma-treated patients in China are also published. Findings from all trials published to date suggest that convalescent plasma is effective for treating severe COVID-19 infections.
The small trials of convalescent plasma safety and effectiveness used a variety of study designs and conditions. Trials were conducted in China, Korea, and the US from Jan. – Apr. 2020 and used from 2 to 25 patients. Two matched control trials compared effects in convalescent plasma-treated patients with effects in control patients matched for demographics, co-morbidities, and disease severity. Patients were hospitalized males and females, ranging in age from 28 to 75 years. The most frequent co-morbidities were cardiovascular disease, high blood pressure, and diabetes. Patients were diagnosed with severe infections if they had pneumonia and signs of respiratory failure. Patients were diagnosed with critical infections if they required invasive mechanical ventilation, and experienced either shock or multiple organ failure requiring treatment in an ICU. Convalescent plasma was obtained from recovered patients who had been infected with COVID-19 and were 7-21 days from recovery. The volumes of plasma transfused to the hospitalized patients ranged from 200 to 300 mL per treatment. Some transfused patients in these trials received several transfusions given at least 2 days apart. Viral loads before and after transfusions were tested in swabs from patients’ throats, nasopharyngeal areas, sputum, or serum. Patients were receiving many different therapies, including hydroxychloroquine; antiviral drugs; antibiotic drugs; steroids; gamma globulin, and/or the immunomodulator interferon α-2b. In several Chinese trials, patients also received Chinese traditional medicines. Most of the hospitalized patients received either supplemental oxygen or ventilator treatment, either non-invasive or invasive, depending on disease severity.
In small, observational trials, many of the COVID-19 patients who received convalescent plasma had dramatic reductions in SARS-CoV-2 viral loads. Rapid and dramatic reductions in SARS-CoV-2 viral loads occurred in the patients who received convalescent plasma. The SARS-CoV-2 viral loads were negative in 100% of the patients who received convalescent plasma by several days after transfusion. By comparison, only 30-40% of control patients in the matched control trials had negative SARS-CoV-2 test results, often not until the end of the study observation period.
In the observational trials, clinical improvement occurred in patients receiving convalescent plasma, with improvement more pronounced in severe disease than in critical disease. In severely-infected hospitalized patients, clinical improvement rates and study discharge rates were relatively high during the study observation periods, which ranged from 14 to 28 days. In patients with severe infections treated with convalescent plasma, 70% to 100% of patients showed clinical improvement and 30 to 100% were discharged from the hospital. Mortality was 0% in patients with severe COVID-19 in all trials, but 30% in controls in the matched control trial. Clinical improvement was generally not as pronounced in patients with critical COVID-19 infections who received convalescent plasma. Among convalescent plasma-treated critically ill patients, 75% to 100% showed clinical improvement and 60 to 75% were discharged from the hospital. In the one matched control trial of patients with critical infections, clinical improvement occurred in 16% of the patients who received convalescent plasma and in 7% of the matched controls. All other patients in both the convalescent plasma-treated and control groups died. This was despite the fact that 100% of patients who received convalescent plasma had negative viral loads within days after the transfusions. The investigators observed that all patients in the convalescent plasma-treated group who died did not receive their transfusions until more than 20 days after hospital admission; thus the late initiation of treatment may have contributed to the high mortality rate.
In a randomized placebo-controlled trial conducted in China, treatment with convalescent plasma produced clinical improvement in patients with severe COVID-19 disease but not with critical COVID-19 disease; however, the trial was halted early due to lack of availability of patients. This trial investigated 103 patients, of whom 43 were diagnosed with severe COVID-19 disease and 50 with critical COVID-19 disease. Patients were males and females, with an average age of 50 years. All patients were receiving supportive therapies in addition to convalescent plasma. Outcomes were good in the patients with severe disease who received convalescent plasma. Within the 28-day observation period, clinical improvement occurred in 91% of severely-infected patients who received convalescent plasma treatment, compared to 68% of severely-infected control patients. In addition, no convalescent plasma-treated patients with severe infections died, compared to 9% of control patients. Finally, severely-infected patients receiving convalescent plasma were discharged from the hospital sooner than severely-infected control patients – at a median of 13 days versus 19 days. By contrast, in the patients with critical disease, there was no difference between the convalescent plasma-treated group and the control group with respect to clinical improvement or mortality – 29% of the treated group patients died compared to 36% of the control group patients. Viral loads were negative in most trial patients, regardless of infection severity, by 72 hours after convalescent plasma transfusions. Two patients in this trial – one with severe infection and one with critical infection – suffered mild allergic-type reactions following convalescent plasma transfusions and these adverse reactions were quickly resolved following corticosteroid therapy.
Data supplied by the Mayo clinic to the FDA provided strong evidence of convalescent plasma effectiveness for treating patients with severe COVID-19 infections. In addition, the Mayo clinic studies compared effects of convalescent plasma with high antibody titers to effects of convalescent plasma with low antibody titers. Antibody titers were assayed in convalescent plasma by determining ability to neutralize native SARS-CoV-2 virus and ability to neutralize the SARS-CoV-2 virus spike protein. FDA scientists performed the data analyses. FDA scientists found that there was a 21% reduction in 7-day mortality (from 14% to 11%) in patients transfused with high versus low titer convalescent plasma. FDA concluded that the dose-response between antibody level and reduction of mortality provided evidence that anti-SARS-CoV-2 antibody is the active agent in convalescent plasma for treating COVID-19.
Convalescent plasma treatment showed a good safety profile in clinical trials and in the Mayo clinic data. In only one of the published trials, did two transfused patients show a possible allergic response, which resolved in a few days with corticosteroid treatment. No safety signals attributable to the transfusions were observed in any of the other published trials. In the Mayo clinic safety data from 20,000 patients, the incidence of allergic transfusion reactions was < 1%, the incidence of blood clotting reactions was < 1%, and the incidence of cardiac events was 3%. The FDA and Mayo clinic both concluded that the majority of blood clotting and cardiac adverse events seen in the 20,000 patients were not related to the convalescent plasma treatment.
The FDA concluded that the benefits of treating COVID-19 patients with convalescent plasma outweigh the risks. In addition, although most studies show greater effectiveness in patients with severe disease, the FDA concluded that convalescent plasma treatment can potentially provide benefit to COVID-19 patients with either severe or critical disease. On its website, the FDA asks recovered COVID-19 patients to consider donating plasma to help treat others with COVID-19 disease. The FDA also issued a Guidance for Industry on administration, study, and quality control of convalescent plasma for treating COVID-19.
In conclusion, results of the clinical trials published to date and FDA’s benefit-risk analysis suggest that convalescent plasma treatment is safe and effective for treating COVID-19. Convalescent plasma transfusion appears to be most effective for treating patients with severe COVID-19 infections. Notably, in most trials, 100% of the transfused patients had negative SARS-CoV-2 viral loads within days following the transfusions. Available evidence to date suggests that it is reasonable to consider including convalescent plasma as a component of COVID-19 treatment regimens. The FDA also came to this conclusion in granting an EUA for use of convalescent plasma in treating COVID-19. In its EUA documentation, the FDA recommends starting such convalescent plasma treatment as early as possible during the course of COVID-19 disease. Finally, the FDA stresses that randomized controlled clinical trials are needed to provide definitive safety/effectiveness evidence.