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 make sure 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 COVID-19 convalescent plasma, or CCP, must take place under one of the FDA-approved pathways for this investigational new drug, or IND. While the protocols described below include patient eligibility criteria, clinicians should also review additional guidance on the indications for use of CCP, such as these recommendations from New York Blood Center.
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.
The first two pathways described are for general clinicians and do not involve extensive clinical data reporting requirements. In addition, there are other protocols under evaluation by the FDA. These are research protocols for specific patient populations. Protocols 3-6 involve extensive reporting requirements and should only be used by academic hospitals with trained research staff.
Obtaining CCP Under National Expanded Access Treatment Protocol or For Immediate Emergency Use
National Expanded Access Treatment Protocol IND:
This protocol is offered by Mayo Clinic. Hospitals registered with this protocol may transfuse CCP for any patient with, or at risk of, severe or life-threatening COVID-19 disease. This protocol is far less cumbersome than the eIND pathway since it will cover all clinicians in a hospital and does not require qualifying patients individually with the FDA.
What physicians need to do:
The national program website has more information about the Expanded Access Program for the Treatment of Patients with COVID-19.
Emergency IND (eIND):
Approval to administer CCP under this eIND is patient-specific and limited to those who have severe or immediately life-threatening COVID-19. To determine whether a patient qualifies, FDA encourages use of the criteria in the National Expanded Access Treatment Protocol (discussed in more detail under #1 above) although pediatric patients qualify to receive CCP under this eIND pathway.
The application is simple and relatively easy to fill out, and is appropriate for situations where approval is needed within 4-8 hours.
Hospitals have reported that approval via this mechanism has typically been provided in under 4 hours. Once the form is completed it should be submitted by email.
The completed form should include:
- a brief clinical history of the patient, including:
- current therapy
- rationale for requesting the proposed investigational treatment.
- information regarding where the COVID-19 convalescent plasma will be obtained (which blood center)
- a brief clinical history of the patient, including:
Providers should complete the form to the extent possible, and FDA will work with the provider if additional information is required.
Upon approval, FDA will send the requesting physician a confirmatory email that includes the emergency IND number. IRB approval is not required ahead of time and it is recommended that hospitals notify their IRBs after the fact.
However, if approval is required in less than 4 hours, you should contact FDA’s Office of Emergency Operations by phone at 1-866-300-4374. After obtaining verbal authorization, you will still need to submit the electronic form within 15 working days of the authorization.
An Overview of Current and Ongoing Research Examining COVID-19 Convalescent Plasma
As of July 29, 2020, the pre-published1-4 (non peer-reviewed) and peer-reviewed5 evidence to support the efficacy of COVID-19 convalescent plasma (CCP) remains limited. There have been two randomized controlled trials, two matched case-control studies, multiple case series and a meta-analysis. In interpretations of the data, the common thread is that CCP appears to be effective for patients early in disease or with less severe disease; however, the quality of evidence to date is low, and firm conclusions regarding the efficacy of CCP cannot yet be drawn.
To date, more than 48,000 units of CCP have been transfused to adult patients with severe or life-threatening COVID-19 through the Mayo Clinic’s Expanded Access protocol. An analysis performed after 5,000 units were transfused demonstrated that CCP is safe to transfuse in adults.6
A synopsis of the major trials and studies*:
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.5 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.1 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.2 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.3 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.4 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.6 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 COVID-19 patients 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 COVID-19 patients, 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.
- Gharbharan A, Jordans CCE, GeurtsvanKessel C, Hollander JGd, Karim F, Mollema FPN, Stalenhoef JE, Dofferhoff A, Ludwig I, Koster A, Hassing R-J, Bos JC, Pottelberge GRv, Vlasveld IN, Ammerlaan HSM, Segarceanu E, Miedema J, Eerden Mvd, Papageorgiou G, Broekhorst Pt, Swaneveld FH, Katsikis PD, Mueller Y, Okba NMA, Koopmans MPG, Haagmans BL, Rokx C, Rijnders B. Convalescent Plasma for COVID-19. A randomized clinical trial, 2020.
- Liu STH, Lin H-M, Baine I, Wajnberg A, Gumprecht JP, Rahman F, Rodriguez D, Tandon P, Bassily-Marcus A, Bander J, Sanky C, Dupper A, Zheng A, Altman DR, Chen BK, Krammer F, Mendu DR, Firpo-Betancourt A, Levin MA, Bagiella E, Casadevall A, Cordon-Cardo C, Jhang JS, Arinsburg SA, Reich DL, Aberg JA, Bouvier VOPNM. Convalescent plasma treatment of severe COVID-19: A matched control study: Mount Sinai, 2020.
- Abolghasemi H, Eshghi P, Cheraghali AM, Fooladi AAI, Moghaddam FB, Imanizadeh S, Maleki MM, Ranjkesh M, Rezapour M, Bahramifar A, Einollahi B, Hosseini MJ, Jafari NJ, Nikpouraghdam M, Sadri N, Tazik M, Sali S, Okati S, Askari E, Tabarsi P, Aslani J, Sharifipour E, Jarahzadeh MH, Khodakarim N, Salesi M, Jafari R, Shahverdi S. Clinical efficacy of convalescent plasma for treatment of COVID-19 infections: Results of a multicenter clinical study 2020.
- Joyner MJ, Klassen SA, Senefeld JW, Johnson PW, Carter RE, Wiggins CC, Shoham S, Grossman BJ, Henderson JP, Musser JM, Salazar E, Hartman WR, Bouvier NM, Liu STH, Pirofski L-a, Baker SE, Helmond Nv, Wright RS, Fairweather D, Bruno KA, S.Paneth N, Casadevall A. Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy 2020.
- Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, Hu C, Tao C, Yang R, Wang J, Yu Y, Guo Y, Wu X, Xu Z, Zeng L, Xiong N, Chen L, Man N, Liu Y, Xu H, Deng E, Zhang X, Li C, Wang C, Su S, Zhang L, Wu Y, Liu Z. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA 2020.
- Joyner MJ, Wright RS, Fairweather D, Senefeld JW, Bruno KA, Klassen SA, Carter RE, Klompas AM, Wiggins CC, Shepherd JR, Rea RF, Whelan ER, Clayburn AJ, Spiegel MR, Johnson PW, Lesser ER, Baker SE, Larson KF, Ripoll JG, Andersen KJ, Hodge DO, Kunze KL, Buras MR, Vogt MN, Herasevich V, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, van Buskirk CM, Winters JL, Stubbs JR, Paneth NS, Verdun NC, Marks P, Casadevall A. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients. J Clin Invest 2020.