Resources for Clinicians
NOTE: The framework for administration of CCP is rapidly evolving and this information is provided by AABB with the intent of helping hospitals understand options and considerations for ensuring that the use of CCP is compliant with current federal directives. It is important to check relevant resources, including those linked on this page, to make sure you are following the most recent developments, options and requirements.
Administration of CCP must take place under one of the two FDA-approved pathways. It is regulated as an investigation product because it is not an FDA-approved blood product. The first regulatory pathway authorizes the administration of investigational CCP under an FDA-approved investigational new drug application (IND).For use of unlicensed CCP outside of the IND framework, FDA has established a second pathway by issuing an Emergency Use Authorization (EUA) which only authorizes treatment of hospitalized patients using CCP that is tested and labeled as high-titer CCP.
Most CCP transfusions in the US will likely take place under FDA’s EUA for high-titer CCP. This EUA was last revised February 23, 2021; a summary of these revisions is available from AABB.
As mentioned, CCP can also be transfused as part of an FDA-approved clinical trial, or under a single patient IND for emergency use.
There are currently several different IND pathways, designed to meet the needs of different patient populations and different hospitals, at different times. This framework is intended to provide wide flexibility to hospitals. General information is available from FDA.
Current FDA Guidance provides for an IND application for expanded access as an alternative for use of investigational convalescent plasma for patients with serious or immediately life-threatening COVID-19 disease who are not eligible or who are unable to participate in randomized clinical trials
During the COVID-19 pandemic, INDs for expanded access, that are not single patient INDs, may be submitted via email to CBERDCC_eMailSub@fda.hhs.gov
During this public health emergency, FDA continued to facilitate access to investigational convalescent plasma through the process of a physician requesting a single patient IND for an individual patient with serious or life-threatening COVID-19. This process allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization, if certain regulatory criteria are met. A licensed physician seeking to administer investigational convalescent plasma to an individual patient must request the IND. Refer to Section III.A. in FDA’s current guidance for more information on obtaining a single patient emergency IND.
An Overview of Current and Ongoing Research Examining COVID-19 Convalescent Plasma
A synopsis of major research*:
Two randomized controlled trials comparing patients treated with CCP to those in a control group who received standard care have closed early:
- The trial by Li et al. in China terminated early due to a lack of enrollment. When all results from the trial were considered, no significant difference was found between those who received CCP versus the control group. However, in a subgroup analysis, patients with severe COVID-19 infection showed a significant benefit when compared to the control cohort based on clinical improvement at 28 days [21 patients (91.3%) in the intervention group vs 15 patients (68.2%) in the control group (hazard ratio, 2.15 [95% CI, 1.07-4.32]; P = .03)]. No significant improvement was found with the subgroup analysis of patients with life-threatening disease [rates of clinical improvement at 28 days: 6 patients (20.7%) in the CCP group vs 7 patients (24.1%) in the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83)].
- Patients with milder disease might benefit from CCP transfusions.
- The trial by Gharbharan et al. from The Netherlands closed early when an interim analysis found that most of the patients enrolled in the trial had neutralizing antibody titers that were comparable to the titers within the CCP used for treatment. Patients had been symptomatic for approximately 10 days when their antibody levels were tested. These observations caused concerns about the potential benefit of CCP in the study population. No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) was observed between plasma treated patients and patients on standard of care. These results were reported in a pre-print; a peer-reviewed version has not yet been released.
- It remains unknown whether patients treated earlier in their disease course – before they develop high titer antibodies – might derive benefit from CCP transfusion.
Two case-controlled studies matched COVID-19 patients treated with CCP with untreated controls. Neither study has been peer-reviewed.
- Liu et al. from Mt. Sinai hospital in New York City reported the outcomes of 39 patients with severe to life-threatening COVID-19 who received CCP. These patients were compared to a cohort of retrospectively matched controls who did not receive CCP. The authors report that CCP improved survival for non-intubated patients (hazard ratio 0.19 (95% CI: 0.05 ~0.72); p=0.015), but no survival advantage was identified for intubated patients (1.24 (0.33~4.67); p=0.752). These results were reported in a pre-print; a peer-reviewed version has not yet been released.
- Abolghasemi et al. from Tehran, Iran reported the outcomes from 115 patients with COVID-19 who were treated with CCP and who were matched to 74 untreated control patients. All patients were early in disease (<= 7 days since illness onset) and were excluded if on mechanical ventilation. Comparison of outcomes included all-cause mortality, total hospitalization days (LOS) and patients’ need for intubation. A total of 98 (98.2%) patients who received CCP were discharged from the hospital versus 56 (78.7%) patients in the control group. The LOS was significantly lower (9.54 days) in the CCP cohort compared with the control group (12.88 days). Only 8 patients (7%) in the CCP cohort required intubation compared to 20% in the control group. These results were reported in a pre-print; a peer-reviewed version has not yet been released.
- Joyner et al. released a pre-print of a meta-analysis that aggregated outcome data from RCT, cases-controlled studies and cases series that included 804 adult patients. The patient populations varied widely, but all included patients who with severe or life-threatening COVID-19. The study reported “Among RCTs, patients transfused with convalescent plasma exhibited a reduced mortality rate (13%) compared to non-transfuse COVID-19 patients (26%; OR: 0.46, P = 0.03). Among matched control studies, patients transfused with convalescent plasma exhibited a reduced mortality rate (12%) compared to non-transfused COVID-19 patients (25%; OR: 0.41, P = 0.001).” When patient outcomes from controlled studies were aggregated, patients transfused with convalescent plasma exhibited a reduced mortality rate (13%) compared to non-transfused COVID-19 patients (25%; OR: 0.43, P< 0.001). These results were reported in a pre-print; a peer-reviewed version has not yet been released.
- Joyner et al. published an analysis of key safety metrics after transfusion of ABO-compatible human CCP in 5,000 hospitalized adults with severe or life-threatening COVID-19. The incidence of all serious adverse events (SAEs) in the first four hours after transfusion was <1%. Of the 36 reported SAEs, only 2 (of 36) were judged as definitely related to the CCP transfusion by the treating physician. The 25 reported incidences of related SAEs included mortality (n = 4), transfusion-associated circulatory overload (TACO; n = 7), transfusion-related acute lung injury (TRALI; n = 11), and severe allergic transfusion reactions (n = 3).
*AABB is reviewing additional research and will add relevant information as soon as possible.
For Academic Hospitals Conducting Additional Clinical Trials
There are three additional protocols under evaluation by the FDA. These are research protocols for specific patient populations. The protocols involve extensive reporting requirements and should only be used by academic hospitals with trained research staff.
- The PEP protocol is designed to test CCP as a prophylactic therapy for adults who are exposed to COVID-19 (e.g., health care workers). This protocol was written by researchers at Johns Hopkins School of Medicine.
- A protocol designed to treat patients with COVID-19 with mild to moderate disease was written by researchers at the Mayo Clinic in collaboration with Johns Hopkins University, Washington University in St. Louis and other parties.
- A protocol for severely ill patients with COVID-19, sponsored by Johns Hopkins University.
A protocol has been proposed for CCP administration in pediatric patients. (Updates soon)
Support CCP Donor Recruitment
Blood collectors need clinicians’ help to educate patients on the need for CCP donations, identify prospective donors and refer individuals to local blood collectors for evaluation. Please share with your colleagues the letter that AABB sent to hospitals encouraging them to collaborate with blood suppliers to identify and refer individuals who have recovered from COVID-19 for donation of CCP.