There is no blood donor screening test for malaria licensed for use in the U.S. The risk posed to the blood supply from transfusion-transmitted malaria, or TTM, is abated by deferral of allogeneic blood donors with a history of malaria or possible exposure to malaria via travel to or prior residency in endemic areas. Based on surveillance studies conducted by the Centers for Disease Control and Prevention, the rate of TTM has held steady since 1974 at approximately 0.25 cases per million blood units collected; however, from 2000 to 2008, the TTM rate fell to 0.027 cases per million blood units collected. Though the TTM rate has improved, data presented suggest that current donor deferral polices relative to travelers to endemic areas have led to deferrals of between 1 and 3 percent of all presenting blood donors. These data do not include donors who “self-deferred” by not attempting to donate blood due to their knowledge of current policies.
Current deferral criteria for allogeneic blood donors are described in the 1994 memorandum Recommendations for Deferral of Donors for Malaria Risk:
Following several presentations to BPAC, FDA’s risk-benefit assessment and the rationale for proposing a change with regard to travel to Quintana Roo, Mexico, was summarized by Sanjai Kumar, PhD.
Approximately 150,000 donors are deferred annually because of a history of malaria or travel to or prior residence in endemic areas. Of these donors, approximately 61,000 (nearly 41 percent) are deferred because they traveled to malaria-endemic areas of Mexico. During the last three years (2006-2008), malaria transmission in Mexico has been of low intensity and relatively stable (average of 2,300 malaria cases annually). There is great disparity in the number of malaria cases reported from different Mexican states, and the contribution of different Mexican states to the number of donor deferrals for malaria exposure among U.S. travelers is highly uneven. According to a 2006 REDS II — Retrovirus Epidemiology Donor Study II — survey in blood centers located in four northern states, approximately 85 percent of donors were deferred for malaria exposure because they had traveled to Quintana Roo, a state with very low malaria transmission. In another survey conducted by Blood Systems Research Institute, or BSRI, in blood centers located in three southern states bordering Mexico, approximately 37.6 percent were deferred because they had traveled to Quintana Roo.
FDA’s probabilistic risk model suggested a point estimate of 0.088 malaria-infected blood collections per year resulting from visits to endemic areas in Mexico. The point estimate for risk due to visits to Quintana Roo based on the REDS II survey was 0.028 infected blood collections per year, and based on the BSRI survey was 0.005 infected blood collections per year. The point estimate for risk based on both surveys combined was 0.016 infected blood collections per year. If prospective blood donors who visited Quintana Roo are allowed to donate blood without any deferral, the overall calculated risk of collecting infected blood units, for both surveys combined, is increased from 1.50 to 1.52 infected blood collections per year or one additional case in 61 years.
In the future, FDA might consider extending the exemption for travel to other low-malaria-risk Mexican states, if data show convincingly that substantial donor losses result from travel to states that remain at very low malaria risk. Conversely, FDA would reverse exemption from deferral of donors for travel to malaria-endemic states of Mexico, if FDA becomes aware of a change in malaria transmission in Mexico that might increase the malaria risk for U.S. travelers.
Question to the committee:
Does the committee agree that, based of FDA’s current risk-benefit assessment, it is acceptable to allow blood collection, without deferral, from U.S. residents who have visited Quintana Roo?
BPAC recommended by a 17-1 vote to allow blood collection, without deferral, from U.S. residents who have visited Quintana Roo, Mexico. AABB supported the proposal made by the FDA.
Blood Pressure and Pulse Measurements in Allogeneic Blood Donors
FDA asked the committee’s advice on donor assessments for blood pressure and pulse as they relate to the donation process itself and as predictors of donation-related adverse reactions.
According to the National Blood Collection and Utilization Survey (2007), conducted by AABB and published by the Department of Health and Human Services, there were 9.53 million allogeneic blood donors in the U.S. during 2006, with 28.5 percent being first time donors. In the U.S., measurement of blood pressure has been a part of the assessment of donor health prior to blood donation for many decades. In 1987, AABB set upper limits for donor systolic and diastolic blood pressure at 180 mmHg and 100 mmHg respectively. More recently, AABB dropped the requirement for measuring blood pressure and pulse from its Standards for Blood Banks and Transfusion Services.
As a measure to ensure the donor is in good health and to ensure the safety of the donation process to the donor, FDA’s current regulations for Whole Blood (21 CFR 640.3)(b) and Source Plasma 640.63(2) donation require a “demonstration that systolic and diastolic blood pressure are within normal limits, unless the examining physician is satisfied that an individual with blood pressures outside these limits is an otherwise qualified donor under the provisions of the section.” These regulations do not explicitly define what should be regarded as a normal systolic or diastolic blood pressure range for the purposes of Whole Blood or Source Plasma donation. The current Source Plasma regulations further require that the donor have a “normal pulse rate.” These measures are intended to ensure that the donor is in good health and that the donation process will be safe for the donor.
On Nov. 8, 2007, FDA published the proposed rule, “Requirements for Human Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use.” In this document, FDA proposed to specify parameters for systolic and diastolic blood pressure for Whole Blood and Source Plasma donors (systolic not to exceed 180 mmHg or fall below 90 mmHg, diastolic blood pressure not to exceed 100 mmHg or fall below 50 mmHg). For Whole Blood donors, FDA also proposed to require that a donor’s pulse be regular and in the range of 50-100 bpm.
The proposed rule, once finalized, would have made FDA’s regulations on donor blood pressure and pulse consistent with previous industry standards. Comments on the proposed rule have questioned both the need and the scientific rationale for the proposed measurement of pulse rate and blood pressure and the proposed ranges or limits for pulse, blood pressure and temperature.
The committee heard presentations from the American Red Cross (Anne Eder, MD, PhD) and Blood Systems Inc. (Peter Tomasulo, MD) regarding various studies and data reviews they have performed and interventions they have undertaken in order to lower the incidence of donor reactions, particularly vasovagal/syncope reactions. Pulse does not appear to be a measure of donor health and has a weak correlation with donor reactions. Also, other donor groups are at much greater risk of reactions. Blood pressure did not show a correlation with reactions. ARC and BSI have targeted their interventions to issues that have the greatest impact on the reactions: young donors, donors with lower blood volumes, first time donors. Interventions include pre-donation education, distraction strategies, attention to fluid consumption, modified requirements related to age and blood volume, and muscle tensing. It has been suggested that vasovagal reactions occur less frequently among apheresis donors than among whole blood donors, perhaps mitigated by the ongoing fluid replacement and the slower donation process. For this reason, the organizations are also looking at whether the donors should be recruited for the automated red cell collections.
Wouter Wieling, MD, Academic Medical Center, Amsterdam, gave insight into the epidemiology and pathophysiology of faints and provided suggestions for physical maneuvers to prevent faints. His primary point was that a fall in central blood volume and cardiac output are key factors in faints, and effective interventions have to be geared to these factors. Christopher France, PhD, Department of Psychology, Ohio University, informed the committee about studies he has completed on mitigating adverse reactions in blood donors. He looked at psychological predictors of reactions, interventions to reduce reactions, and pre-donation education. Using a subjective assessment process — Blood Donor Reactions Inventory — he also determined that distraction strategies, pre-donation fluid consumption and muscle tensing procedures are successful interventions to reduce donor reactions.
Questions for the committee:
Additional discussion by the committee was summarized by Jay Epstein, MD, director, Office of Blood Research and Review: “We have heard the concern of the committee that the current data really don't speak to donors who have pulses and blood pressures outside of the previously accepted range. I think we have heard that there would be utility in monitoring blood pressure, pulse and serious adverse reactions if we cease to make the current ranges part of the eligibility determination. I think that what we have not clarified is whether in the end, if we thought that there was no predictive value of blood pressure and pulse for donor adverse reactions, would we want to retain it anyway as a public health measure. But I would suggest that that is a question that was explored with the Secretary's Advisory Committee for Blood Safety Availability, that it is part of a much broader question of the public health role of the donor room, and we are not really asking the committee to opine on that issue.”
The Cerus SPRINT study of pathogen inactivated, or S59, platelets identified potential safety and efficacy concerns. Following discussions between FDA and Cerus on the design of future studies aimed at addressing these issues, FDA asked the committee’s advice regarding the design of a new phase III study and the adequacy of the proposed product development program, which includes a phase IV study and staged rollout of the product.
A summary of FDA concerns presented for the BPAC discussion
Issue Summary — The FDA has concerns about efficacy (bleeding events) and safety (imbalance of adverse events). Even though the previous study (SPRINT) met the primary endpoint, secondary endpoints did not support the study conclusion that the pathogen reduction platelets were non-inferior to untreated platelets. More platelets and more frequent transfusions were needed. Mean days of grade 2 bleeding were higher in the treatment arm (p = 0.023). Additionally, hemostatic adverse events were more frequently observed in the test arm. The data did not establish whether the reduced hemostatic efficacy was attributable to lower platelet numbers or impaired platelet function.
The major differences in grades 3 and 4 clinical adverse events were of concern to the FDA. The increased acute respiratory distress syndrome, or ARDS, in the treatment arm compared to the control is particularly noteworthy, since ARDS is a clinical condition with a relatively high mortality (40 percent). If this result is true, relatively minor improvements in transfusion-transmitted disease safety (reduction in 1/118,000 incidence of sepsis) would be potentially offset by a 1.6 percent (5/318 versus 0/327) or 2.2 percent (12/318 versus 5/327) increase in incidence of serious pulmonary events compared to reference platelets.
The expert pulmonary panel that re-analyzed patient charts identified additional cases of acute lung injury, or ALI, and ARDS. According to this analysis, the differences between the treatment and control arms for ALI and ARDS were not statistically significant, but the number of cases of ARDS found in the test arm was more than two-fold higher than in the control arm (12 versus five). FDA regards this difference as a safety concern even though the post-hoc analysis did not achieve statistical significance. A larger study and/or a study with more careful pulmonary monitoring may have yielded a more definitive statistical outcome.
FDA Perspective presented by Jaro Vostal, MD, PhD:
Cerus representatives/spokespersons (Carol Moore; Laurence Corash, MD; Claire Sherman, PhD; Georges Andreu, MD; Gordon Rubenfeld, MD) reviewed the study design of the proposed trials (phase III and phase IV) and information obtained from prior clinical trials that were used to guide the design of the proposed studies as well as the French experience using Intercept platelet concentrates. Intercept was first used in France in 2005, and in 2006 it was a vital tool in the response to the chikungunya epidemic in La Reunion. To date, Intercept has been used in 60 centers in 20 countries, with 350,000 doses transfused, and has been used as a replacement for bacteria detection, gamma irradiation and cytomegalovirus, or CMV, serology.
The committee engaged in a lengthy discussion of the trial design and ultimately supported continuation of a phase III study with very tight modifications and a staged rollout of a future product that would require participation in a post-market study that is a randomized controlled trial.
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