Examples of differences in clinical studies of convalescent plasma for COVID-19, and their potential impact
| Element variable . | Types of differences and potential impact . |
|---|---|
| Study design and infrastructure | |
| Type of study | • Access/emergency use program without randomization or control group: |
| • May be faster to establish initially; cannot determine efficacy but useful for safety data | |
| • May “compete” with concurrent RCTs for participant recruitment and/or product availability | |
| • Adaptive design may permit faster testing of new therapies, with fewer patients, and more rapid allocation to promising therapies as results become available | |
| • Platform study: may be faster and more efficient to add new therapeutic domains (eg, CP) to established trial platform or clinical registry | |
| Study logistics | • Informed consent: practical issues of obtaining written consent from patients in physical isolation; deferred consent may reduce barriers to study entry |
| • Ethical issues: eg, equity of access to product/study vs “right to try” | |
| • Issues of blinding vs open label, for example: | |
| • If using a placebo control, product appearances and difficulty ensuring adequate concealment | |
| • If using a plasma control: challenges in product labeling, checking, and storage and documentation requirements to preserve blinding | |
| • If CP compared with non-CP plasma, ensuring that control plasma does not contain antibody to SARS-CoV-2 | |
| • Wider national/international collaboration and use of standardized protocols may enable continuation and prevent studies closing prematurely | |
| Outcomes, monitoring, and follow-up | Can be difficult to compare results between studies due to many different outcomes and duration of follow-up: eg, |
| • Mortality | |
| • Clinical improvement (variably defined, eg, use of COVID-19/other scales) | |
| • Requirement for intensive care unit/mechanical ventilation | |
| • Length of hospital/intensive care unit stay | |
| • Viral clearance | |
| • Data for health economics analyses generally lacking so far | |
| Adverse event reporting | • Different SAEs recorded, both transfusion-related and other, at different times, eg, within 4 h, 24 h, 7 d, longer |
| • Variation in use of local or international definitions for categorization, severity, imputability, etc | |
| Blood donor eligibility and characteristics | |
| Blood donor sex | • Many countries do not routinely collect plasma for clinical use from female (especially multiparous) blood donors to minimize the risk of TRALI |
| • If plasma from females not used as clinical plasma for CP, may be used for fractionation for hyperimmune-immunoglobulin product | |
| Infection type, severity, recovery | Wide range internationally of clinical severity of prior COVID-19 illness and minimum recovery period prior to donation, eg, minimum 14 vs 28 d recovery; viral mutation/strain may influence immune profile and duration of antibody response ? clinical impact |
| Donor adverse events | Variably defined/captured/reported by blood establishments internationally |
| Potential impact on donor health and well-being | |
| Intervention | |
| Convalescent plasma product (see also “Study logistics” above) | • Inherent biological variability: nonstandardized product |
| • Collection method (whole blood vs apheresis) and interval: influence volume of CP available and whether multiple doses are from same or different donors | |
| • Dose (volume, NAb content, other specification) administered | |
| • Antibody and other characteristics (minimum NAb and other content) | |
| • Testing performed | |
| • What is measured: eg, IgM, IgG, total, neutralizing activity, other | |
| • How measured: type of test (known variation between tests, both commercial and in-house), test sensitivity, specificity (mostly lacking so far) | |
| • Use of pathogen reduction technologies | |
| • Timing of doses (how soon after symptoms develop, interval between doses if >1) | |
| Standard of care, any other interventions | • Standard/usual care may vary between sites • Other interventions, if any |
| Participants | |
| Demographics, baseline characteristics, and study eligibility criteria | • Clinical status, eg, exposed but asymptomatic, mild illness, hospitalized, critically ill, ventilated (note that all trials reported to date have been in hospitalized patients) |
| • Infection type, eg, viral mutation/strain | |
| • Immune profile, eg, endogenous NAb detectable at baseline, presence of circulating viral nucleic acid, HLA type, impairment of immune function, either underlying condition, therapy, etc, effects currently unknown | |
| • Comorbidities: patients with impaired cardiorespiratory and/or renal function may be more at risk of TACO | |
| • Few data currently available for children | |
| • ABO blood group: preliminary data suggest certain ABO blood types may be associated with susceptibility to and/or severity of infection with SARS-CoV-2 |
| Element variable . | Types of differences and potential impact . |
|---|---|
| Study design and infrastructure | |
| Type of study | • Access/emergency use program without randomization or control group: |
| • May be faster to establish initially; cannot determine efficacy but useful for safety data | |
| • May “compete” with concurrent RCTs for participant recruitment and/or product availability | |
| • Adaptive design may permit faster testing of new therapies, with fewer patients, and more rapid allocation to promising therapies as results become available | |
| • Platform study: may be faster and more efficient to add new therapeutic domains (eg, CP) to established trial platform or clinical registry | |
| Study logistics | • Informed consent: practical issues of obtaining written consent from patients in physical isolation; deferred consent may reduce barriers to study entry |
| • Ethical issues: eg, equity of access to product/study vs “right to try” | |
| • Issues of blinding vs open label, for example: | |
| • If using a placebo control, product appearances and difficulty ensuring adequate concealment | |
| • If using a plasma control: challenges in product labeling, checking, and storage and documentation requirements to preserve blinding | |
| • If CP compared with non-CP plasma, ensuring that control plasma does not contain antibody to SARS-CoV-2 | |
| • Wider national/international collaboration and use of standardized protocols may enable continuation and prevent studies closing prematurely | |
| Outcomes, monitoring, and follow-up | Can be difficult to compare results between studies due to many different outcomes and duration of follow-up: eg, |
| • Mortality | |
| • Clinical improvement (variably defined, eg, use of COVID-19/other scales) | |
| • Requirement for intensive care unit/mechanical ventilation | |
| • Length of hospital/intensive care unit stay | |
| • Viral clearance | |
| • Data for health economics analyses generally lacking so far | |
| Adverse event reporting | • Different SAEs recorded, both transfusion-related and other, at different times, eg, within 4 h, 24 h, 7 d, longer |
| • Variation in use of local or international definitions for categorization, severity, imputability, etc | |
| Blood donor eligibility and characteristics | |
| Blood donor sex | • Many countries do not routinely collect plasma for clinical use from female (especially multiparous) blood donors to minimize the risk of TRALI |
| • If plasma from females not used as clinical plasma for CP, may be used for fractionation for hyperimmune-immunoglobulin product | |
| Infection type, severity, recovery | Wide range internationally of clinical severity of prior COVID-19 illness and minimum recovery period prior to donation, eg, minimum 14 vs 28 d recovery; viral mutation/strain may influence immune profile and duration of antibody response ? clinical impact |
| Donor adverse events | Variably defined/captured/reported by blood establishments internationally |
| Potential impact on donor health and well-being | |
| Intervention | |
| Convalescent plasma product (see also “Study logistics” above) | • Inherent biological variability: nonstandardized product |
| • Collection method (whole blood vs apheresis) and interval: influence volume of CP available and whether multiple doses are from same or different donors | |
| • Dose (volume, NAb content, other specification) administered | |
| • Antibody and other characteristics (minimum NAb and other content) | |
| • Testing performed | |
| • What is measured: eg, IgM, IgG, total, neutralizing activity, other | |
| • How measured: type of test (known variation between tests, both commercial and in-house), test sensitivity, specificity (mostly lacking so far) | |
| • Use of pathogen reduction technologies | |
| • Timing of doses (how soon after symptoms develop, interval between doses if >1) | |
| Standard of care, any other interventions | • Standard/usual care may vary between sites • Other interventions, if any |
| Participants | |
| Demographics, baseline characteristics, and study eligibility criteria | • Clinical status, eg, exposed but asymptomatic, mild illness, hospitalized, critically ill, ventilated (note that all trials reported to date have been in hospitalized patients) |
| • Infection type, eg, viral mutation/strain | |
| • Immune profile, eg, endogenous NAb detectable at baseline, presence of circulating viral nucleic acid, HLA type, impairment of immune function, either underlying condition, therapy, etc, effects currently unknown | |
| • Comorbidities: patients with impaired cardiorespiratory and/or renal function may be more at risk of TACO | |
| • Few data currently available for children | |
| • ABO blood group: preliminary data suggest certain ABO blood types may be associated with susceptibility to and/or severity of infection with SARS-CoV-2 |