COVID‐19 convalescent plasma donor recruitment: beware the Faustian bargains

As novel coronavirus infections (COVID‐19) spread across the United States in March 2020, the Food and Drug Administration (FDA) announced a patient‐specific emergency Investigational New Drug (eIND) pathway for convalescent plasma (CP) as well as an expanded access program. ¹ , ² With no clearly effective alternative therapy and high mortality rates for patients requiring mechanical ventilation, there is obvious interest in the immediate use of CP. ³ This presents a number of ethical issues, since randomized trials have not proven that CP is effective or safe. ⁴

Given an exponential growth of cases and deferral period after illness (currently 14 days) there certainly will be less CP available than potential recipients over the coming weeks to months. As a result, less CP will be available for the randomized, placebo‐controlled trials and for making commercial hyperimmune globulin, both of which are needed to determine if, how much, and when during the illness passive antibody therapy is beneficial. As we prepare a centuries‐old therapy, let us not forget the battlefield advice to “hold your fire until the enemy is within range” or the lesson of Faust: avoid trading the appearance of short‐term power for inevitable suffering.

Second, it is unclear how serology (antibody) tests relate to in vivo potency. Likely, the in vitro assay that best mirrors in vivo conditions—viral neutralization titer—is not readily available. Furthermore, it has not been proven that neutralization titer relates to in vivo potency. These issues of uncertain and variable potency may cripple our ability to learn from initial experiences.

Third, most blood is collected in the US by blood centers that are not affiliated with hospitals or patient testing laboratories, however physicians and hospitals are more readily able to identify and recruit potential CP donors. One proposed “work around” system would involve hospitals sending donors to blood centers for collection, with units returned to the hospital which sent the donor. If this mechanism is used for COVID‐19 CP, large hospitals in areas with prevalent disease and wide‐spread testing will be in the best position to identify and recruit potential CP donors, and have the best access to CP. This may produce a geographic inequality in the availability of CP.

Alternatively, using a traditional directed donor pathway, donors may designate their CP donation to a friend or family member. Suddenly, the question is not one of ethical medical triage, but whether a patient has someone to donate CP for them. This may create an incentive for donors to misrepresent during donor screening, in order to avoid being deferred. It raises another question: can donors donate for someone who is not yet eligible to receive CP? Should transfusion services “hold” the unit(s) in case or until the intended recipient becomes eligible, even while others in need die? If blood banks refuse to hold units for future directed use, then donors may be incentivized to not donate for the general good, due to the fear that they will be unable to donate when a loved one is in need. Would an ethical option for hospitals be to hold donor‐directed units during the deferral period, then release them to general inventory if the donor does not present to donate again? But what if the donation fails due to vein infiltration or phlebotomist error?

Interestingly, hospital‐based blood centers may have an early advantage in donor recruitment and collections, disrupting the recent advantage national blood centers have enjoyed over smaller, local collection centers. Hospitals that begin collecting CP effectively may provide alternative supply routes to other hospitals (especially without crossing state lines for unlicensed collection centers). These hospitals may face a different ethical problem: if the supply of CP is locally robust, should it be the patient, the attending physician, or the healthcare organization policymakers who decide whether to use the plasma on a compassionate use basis, despite the safety and efficacy unknowns? Similarly, who decides whether a patient could or should get a second dose of CP?

Although the rapid development of multicenter randomized control trials for CP is promising, these trials will only be enrolling at select sites and available to a small percentage of patients nationally. ³ Should we push forward with these trials and also collect as much CP as possible for compassionate use, in other words “not allowing perfect to become the enemy of a potential good”? However, how do we ethically offer both compassionate use (guaranteed CP) and randomized trial enrollment (potential placebo) to the same patients? Do we restrict compassionate use at some institutions but not others?

An alternative would be true nationalization of recruitment, collection, and treatment employing the nationʼs contract research organizations for nation‐wide, prospective placebo‐controlled trials combined with allocation to the rapid development of hyperimmune globulin. ⁴ , ⁵

CONFLICT OF INTEREST

TJG is the principal investigator of the COVID‐19 Convalescent Plasma Collection Study at NorthShore University HealthSystem.