Table 1.

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