Members of the Blood Products Advisory Committee to the Food and Drug Administration convened for their 101st meeting in Gaithersburg, MD on August 2-3 to advise the FDA on two issues related to whole blood donors – Trypanosoma cruzi testing, and Whole Blood interdonation intervals during a severe emergency.
The Food and Drug Administration sought the committee's assessment of data from the "Trypanosoma cruzi Incidence Study in Blood Donors" and its implications for one-time testing of blood donors for evidence of T. cruzi infection. Robert Duncan, PhD, Center for Biologics Evaluation and Research, FDA, presented an overview of the evolution of the FDA policy governing the testing of donors for T. cruzi.
In December 2006, the FDA licensed the Ortho T. cruzi ELISA Test System for the detection of antibodies to T. cruzi in individual human donors, including donors of whole blood, blood components, and source plasma and other living donors. A second serological test for detection of antibodies to T. cruzi, the ABBOTT PRISM Chagas, was licensed in April 2010. Both tests exhibited high sensitivity and specificity in the clinical trials that were performed in support of licensure. As assays became licensed by FDA, blood establishments began voluntarily testing every donation — a universal testing scheme — and a large portion of the U.S. blood supply was being tested beginning in 2007, prior to the FDA guidance being issued.
At the April 2009 BPAC meeting, the FDA sought advice from the committee regarding selective testing strategies for T. cruzi infection in repeat blood donors. Data presented at this meeting, which included look back studies of recipients of blood products from donors who later tested confirmed-positive by the Radio Immune Precipitation Assay (RIPA) for T. cruzi, revealed two transmissions (both from the same infected donor) out of 253 total recipients. This represented a transmission rate much lower than the expected rate. After discussing possible testing strategies, BPAC voted in favor of a selective testing strategy in which one negative test would qualify a donor for all future donations without further testing or the need to be asked questions regarding risk of a newly acquired infection. The committee's recommendation was contingent upon the continuation of studies to determine the incidence of new infections in previously screened negative donors. In the latter part of 2009, most blood centers began shifting to one-time selective testing for T. cruzi.
In December 2010, the FDA issued a final guidance titled, "Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components Intended for Transfusion." This guidance recommended one-time testing of each blood donor using a licensed test for antibodies to T. cruzi. Donors who test nonreactive would be qualified to return to donate without further testing of subsequent donations for antibodies to T. cruzi. The guidance also stated that "FDA intends to reevaluate the recommendation for one-time testing after reviewing the outcome of ongoing studies of the risk of newly acquired cases of T. cruzi infection together with other relevant information."
In June 2009, the American Red Cross (ARC) and Blood Systems, Inc. (BSI) presented a plan to the FDA for the T. cruzi incidence study to attempt to determine the rate of newly acquired T. cruzi infections among blood donors who had previously tested negative for T. cruzi in the areas of the U.S. where there is indigenous risk or risk from travel to endemic areas.
The T. cruzi incidence study proposed to continue universal screening in the highest yield regions to expand data on incidence of T. cruzi infection and establish risk factors associated with incident infections. The study sites were specifically selected to capture two main sources of risk of incident T. cruzi infections: 1) donors who are exposed to T. cruzi because of travel to endemic area(s) in Mexico and Central and South America, and 2) donors who are exposed to indigenous infection with T. cruzi (in U.S. endemic areas, which encompasses all states coast to coast south of Ohio). Participating ARC centers that continued universal testing included facilities in the following locations: Southern California, Southwest (Oklahoma/Texas), and the Greater Ozarks (Arkansas). One external site that also continued universal testing was the Community Blood Centers of Florida, although donor observation period data were not collected from this site and therefore was not included in the analysis. BSI similarly continued universal testing in one of its California centers (United Blood Service, UBS, Central Coast). UBS blood centers had previously enacted a series of questions to capture a history of travel to Latin America. During the study, UBS blood centers (all BSI centers excluding Blood Centers of the Pacific and UBS Central Coast) would continue to question prospective donors about travel to Latin America, and to test in real time those donations from donors acknowledging recent travel (since their last donation) to T. cruzi-endemic countries, as a means to further separate the risk of travel-associated T. cruzi infection from indigenous T. cruzi infection.
The T. cruzi incidence study protocol included the following criteria for an incident case. "For the purposes of this protocol, an incident case/seroconverter was defined as an ELISA-repeatedly reactive and RIPA-positive donor who had a prior ELISA nonreactive donation (S/CO < 0.5) and who has serologic progression on follow up by ELISA (S/CO > 2.0) while remaining RIPA positive. The donor may have positivity in PCR or Hemoculture in follow-up testing and/or may have identified risk factors." [Sic]
Brian Custer, PhD, MPH, BSI and Susan Stramer, PhD, ARC, presented the results of the studies that concluded in January 2011 and the implications for selective testing. To address the travel-associated and indigenous sources of T. cruzi infection risk, data were presented showing the total number of donors and mean observation periods from sites where risk of travel-associated infection is most likely, sites where risk of indigenous infection is most likely, and overall nationwide risk.
The following data were collected over a total of four years at three sites, and 54 months at the Southern California site, which had initiated testing earlier under an investigational new drug application:
Twenty-two donors were identified who had inconsistent EIA and/or RIPA results and although none of the donors ever met the study definition for an incident case, there was a thorough review of the available data related to the donors and discussion by the committee of potential implications of the assumption that such donors were seroconverters. According to the FDA analysis, the maximum potential risk of a positive donation in the blood supply, based on a worst case interpretation that all potential seroconverters were infected donors, would be 1/976,007 for universal testing and 1/353,601 for universal testing in the high prevalence areas of the U.S. The number of positive donations that would be estimated to occur in the blood supply per year would range from zero to 18 nationwide and from zero to two in the high prevalence areas.
AABB presented a statement on behalf of AABB, America's Blood Centers, and the American Red Cross that articulated the joint position of these organizations that the T. cruzi incidence study data demonstrate that one-time testing is sufficient to qualify allogeneic donors for repeat donation, and that a requirement to retest test-negative donors following a defined period of time such as two or five years would add no value relative to the low risk of transfusion transmission. The organizations also suggested withdrawal of the current requirement that blood collectors ask donors if they have ever had Chagas' disease, as this question provides no reduction in the risk of transfusion transmission of T. cruzi.
Committee Discussion and Vote — The question originally posed by FDA to BPAC was, "Are the scientific data on the risk of incident infections among blood donors sufficient to conclude that a one-time negative test for antibodies to T. cruzi can qualify the donor for all future donations without further testing?" However, following the thorough discussion of the 22 cases — with inconsistent EIA and/or RIPA results, yet never defined as incident cases — the question was changed so that the committee's vote was inclusive of "newly detected infections." BPAC ultimately voted nine yes, two no, with one abstention, that the scientific data on the risk of "newly detected infections" among blood donors are sufficient to conclude that a one-time negative test for antibodies to T. cruzi can qualify the donor for all future donations without further testing.
During the committee discussion period, the concern was raised by the FDA regarding how accurately the current data can be applied to changes to the risk of transfusion transmitted T. cruzi that may result from demographic changes, climate change, or changes in travel patterns. The industry representative to the BPAC, Celso Bianco, MD, as well as Dr. Custer both indicated that studies being conducted outside the U.S., specifically in Brazil may inform the answer to such questions. In addition, Dr. Bianco noted that the ongoing testing of first-time donors will provide an indication as to when the blood community should readdress this question in the future.
On August 3, the committee heard several presentations regarding the ability of the public and private sectors to meet the demands of disruptions in the supply or sudden extraordinary demand for blood products, and the possible ramifications that such events may have for patients. Alan Williams, PhD, Associate Director for Regulatory Affairs, Office of Blood Research and Review, Center for Biologics Evaluation and Research, provided an overview of emergency preparedness systems in the U.S., and the currently existing FDA emergency measures, regulations and guidance that were also outlined in appendix A of the Issue Summary. The FDA proposals to be discussed by the committee were developed to assist blood establishments in their emergency preparedness planning, and Williams reviewed public health emergencies or scenarios where it might be advisable that donors "shelter in place" but select donors could be recalled to the blood center to donate. Dr. Williams then presented additional data and background information that would be useful in informing two specific options that FDA asked the committee to consider for implementation during emergency situations. Specifically, he outlined the safety concerns and potential benefit of a one-time annual reduced interdonation interval of four weeks (without physician review) and 48 hours (with physician review) for Whole Blood donation, by manual collection, in emergencies for repeat donors who meet a specific double red blood cell apheresis nomogram and all other donation requirements.
Dr. Williams explained the rationale for consideration of reduced interdonation intervals for Whole Blood collection in severe emergencies. Double red cell collections by apheresis are a rapidly growing portion of the blood supply and the procedures are safe and well tolerated by donors. In emergencies, staff trained to use the apheresis equipment and procedures may not be available. The devices may not be easily relocated within a damaged facility. The available number of portable units may be limited, or electrical outages may impede the usefulness of the automated devices during a prolonged emergency. Use of the conservative nomogram that is approved for use with the double apheresis collections supports safe collection of a second unit of Whole Blood, with a shortened interdonation interval, and may assist with maintaining an adequate blood supply.
John Hess MD, MPH, FACP, FAAS, Professor of Pathology and Medicine, Associate Medical Director, Blood Bank Medical Director, Stem Cell Lab, University of Maryland School of Medicine, Baltimore, and Chair, Conventional Components Committee, Biomedical Excellence for Safer Transfusion Collaborative, presented a history of blood utilization and availability in emergency situations. His presentation provided examples of several natural disasters and terrorist attacks that have occurred worldwide and how such events influenced disruptions in the supply of blood products and/or increased demand for these products. His presentation also included suggested interventions that could facilitate maintaining an adequate blood supply during an emergency. These measures included adjustments in how demands for blood are triaged and rationed; providing blood products that would, under normal circumstances, be considered "outdated" but may still be badly needed during a disaster; and reductions in blood testing that involves use of short dated red cell reagents (e.g., not retesting for alloantibodies every three days). Dr. Hess also emphasized that during an emergency event, many blood establishments and transfusion center systems could fail to meet certain stringent regulatory requirements due to unavoidable obstacles such as loss of supervisory personnel or workers with needed technical expertise; abnormal or loss of computer system function; or shortage of needed materials for laboratory operation or patient and donor care (e.g. testing reagents or medical gloves).
Jerry Holmberg, PhD, Senior Advisor for Blood Policy, U.S. Department of Health and Human Services (HHS), and Executive Secretary of the Advisory Committee on Blood Safety and Availability, presented the HHS responsibilities for disaster preparedness and the blood supply under the Emergency Support Function #8 (ESF#8). Under ESF#8 of the U.S. Department of Homeland Security's National Response Framework (Public Health and Medical Services Annex) HHS and its governmental and non-governmental partners are responsible for efforts to help ensure blood and blood product safety and availability during an emergency. ESF#8 defines the roles and responsibilities of HHS and defines a liaison relationship between HHS and the AABB Interorganizational Task Force on Domestic Disasters and Acts of Terrorism (Disaster Task Force) to assist in blood supply logistics and the coordination of national public messages on the need to donate blood. However, it is important to recognize that although tabletop exercises have been conducted, the adequacy of the U.S. blood system has not to date been tested by a severe domestic emergency, such as a large earthquake in a major city, a multisite nuclear or terrorist event, or a severe pandemic, where a significant number of blood donors, blood establishment staff, and vendors of blood-related supplies may be affected.
Jamie Blietz, MBA, CAE, Director, AABB National Blood Exchange, and Staff Liaison to the AABB Interorganizational Task Force on Domestic Disasters and Acts of Terrorism (Disaster Task Force), presented to the committee the coordination role that the Disaster Task Force has during an emergency event. The Disaster Task Force ensures coordination of blood supply logistics during an emergency or disaster, and fosters collaboration and partnership between government agencies, nonprofit organizations and the private sector. The Disaster Task Force includes representatives from major blood collection organizations; government entities such as HHS, FDA, the Centers for Disease Control and Prevention, and the Armed Services Blood Program Office; nonprofit stakeholders such as the Advanced Medical Technology Association, America's Blood Centers, the American Red Cross, American Hospital Association, College of American Pathologists and the Plasma Protein Therapeutics Association. The Task Force is intended to bring these interested stakeholders together on an ongoing basis to address emergency preparedness concerns such as communication, transportation and storage of blood and blood products and address issues such as media relations, staffing shortages, and power, fuel, or water supply shortages. Immediately following emergencies and disasters which may affect the blood supply, the Task Force meets to assess the circumstances and to coordinate members' response activities. When a particular region or locality is affected, representatives from blood establishments in any affected area are invited to participate in the Task Force's activities. The ability of the Task Force to convene the needed personnel to respond to an emergency has been tested, and Mr. Blietz noted the remarkable success with which the Task Force has been able to coordinate responses. The Task Force makes recommendations to blood establishments for meeting community needs during emergencies and helps to coordinate delivery of blood and blood components and necessary supplies to affected communities. The U.S. has a large network of blood centers and a generally robust blood supply. To date, the U.S. has not experienced critical shortages of blood or blood products as a result of an emergency or disaster, and it is widely believed that blood already on hospital shelves would be adequate to meet all but the direst emergency needs. However, currently, the disaster planning initiatives of the Task Force are exclusively funded by the non-government entities participating, and sustained funding of the Task Force's activities is a serious concern.
Louis Katz, MD, Medical Director, Mississippi Valley Regional Blood Center, presented practical considerations of emergency response from the perspective of a blood establishment medical director. He cited useful resources that, in planning for disruption in the blood supply during a disaster, blood centers can utilize, such as those available from AABB and the May 2008 edition of CHEST, and also described the ABC/BCA emergency operations systems. He provided data from ABC that indicated the vast majority of blood centers have their own disaster planning procedures and collaborate in their planning with local hospitals that also have disaster planning procedures. His presentation emphasized that responding to localized blood shortages during an emergency event would require implementation of measures that fall outside of the status quo not only for blood centers, in their need to increase the blood supply, but also for hospitals, out of the need to reduce the demand for blood. The "supply side" emergency measures include increased collection by established groups and general appeal, increase O positive and negative inventory, use of frozen blood reserve if available, increasing autologous transfusions, and adjustments in donor eligibility. The eligibility requirements that Dr. Katz proposed to adjust included the interdonation interval, travel deferral for malaria, transmissible spongiform encephalopathies deferral, donor hemoglobin level deferral, and double red cell collections. Though he acknowledged widespread adoption of disaster planning, these plans have not been adequately tested. To decrease the demand for blood during an emergency disruption in the blood supply, hospitals would possibly need to take measures that would include peri- and post-operative salvage, autologous predeposit, erythropoiesis-stimulating agents for appropriate chronic anemia, limiting of O negatives to fertile females, enforcement of conservative transfusion triggers, decreasing the elective blood use in the intensive care unit, and rationing based on survival prognosis. Dr. Katz showed data from the TRICC (Transfusion Requirements in Critical Care) study of transfusion triggers and indicated the expected publication of FOCUS (Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair) will further inform measures that clinicians could implement to reduce the demand for blood. John R. Feiner, MD, Department of Anesthesia and Perioperative Care, University of California, provided information on the physiology of acute anemia and the results of a study he conducted, over a 10 year period, of volunteers with acute isovolemic hemodilution to a hemoglobin level of less than 7 g/dL. The purpose of the study was to understand compensation for and tolerance of acute anemia — Feiner's interest at the time was in transfusion thresholds — however, the experience is relevant to the donation of 450 mL of Whole Blood. His analysis of study data could find measurable effects at very low hemoglobin levels, only, and showed that acute anemia is well tolerated by healthy individuals.
Review of the Proposals for Committee Discussion — Dr. Williams reviewed the nomogram and proposals for the committee and responded to questions during the discussion. Nomograms for double RBC collection by apheresis (based upon FDA-cleared manufacturer's instructions for use) have been in place for several years and have an established record of safety and donor acceptance. The concept of the nomogram in association with a 16 week period of deferral, is to assure that donors are not placed at risk for undue loss of iron. Additionally, use of the nomogram prevents removal of a fluid volume in excess of that which would not be tolerated by the donor. FDA chose the most conservative FDA-cleared donor eligibility nomogram currently in use (with apheresis devices) and clarified during the committee discussions that the hemoglobin criteria is applicable at the first donation only. Hemoglobin criteria at the second donation — during the period of the emergency — would be 12.5 g/dL.
| Weight (pounds) | Height (feet/inches) | Hematocrit (%) | Hemglobin (g/dL) | |
|---|---|---|---|---|
| Males | 150 | 5'1" | 42 | 14.0 |
| Females | 175 | 5'5" | 42 | 14.0 |
Proposal 1:
FDA believes a benefit of this proposal in preparedness planning will be the ability of blood establishments to review and tag records of eligible and willing donors during normal operations to be recalled during an emergency. A part of FDA's rationale behind the proposal is to assist emergency preparedness planning for an event in which eligible donors may "shelter in place" but respond to a phone call to donate.
Proposal 2:
FDA considered that this proposal would enable blood establishments to prepare standard operating procedures for use during an emergency for eligible and willing donors who could be called back — or who might respond to an appeal — if severe shortages exist.
The major concern expressed by FDA on the first proposal related to donor iron loss. Donors are deferred from all donations for 16 weeks following a double RBC apheresis procedure to provide time for replacement of iron and recovery of the donor's normal hemoglobin/hematocrit. The most conservative FDA-cleared donor eligibility nomogram currently in use for two unit RBC apheresis allows for safe removal of up to 420 ml of RBC per collection. As the red cell loss from two 500 mL Whole Blood collections may approximate 420 mL, the use of this specific algorithm helps to provide assurance that the donor would not be placed at risk for excessive RBC or fluid loss.
The major concern expressed by FDA regarding the second proposal is whether the donor would still be in a fluid deficit following donation of the first unit, potentially only 48 hours previously. The devices commonly used for double RBC apheresis infuse 250-500 ml of saline following RBC collection. Dr. Williams noted the experience with safety of plasmapheresis under current donation standards (two times per week with an interval of not less than 48 hours) as well as other data and experiences that support the safety of fluid volume replenishment within a 48-hour period. FDA believes the minimum four week and 48-hour interdonation intervals under consideration for Whole Blood unit collection are viewed as sufficient for complete replacement of the intravascular fluid volume.
Committee Discussion and Vote — The committee was asked if the available data supported the safety of collecting blood during a severe emergency under the proposals offered by FDA.
Proposal 1 — Yes (unanimous)
Proposal 2 – The bulk of committee discussion concerned any potential benefit to physician involvement as recommended in proposal 2. FDA participants explained that it was an added step due to the fact that Whole Blood donors ordinarily would not be allowed to donate until the eight week interdonation interval had passed. The interdonation interval was being greatly lessened; therefore, it may be advisable for a physician review to be included in the process. The committee discussion favored accepting the proposal except for concern about having to use a physician for review during an emergency. It was noted that the current guidelines for collection of two units at one time by apheresis do not require a physician review, and the normal intravascular refilling rate in a normally hydrated individual is such that a donor could likely donate safely again within 48 hours. The committee asked to split the second proposal into two votes.
The committee's vote that a physician review is not necessary removes the logistical and operational difference between the two proposals and was noted by FDA participants.
Currently, FDA is considering issuance of an "emergency measures" guidance as a way to publicize the existence of a new variance. Most important, this would serve as a basis for blood establishment planning, but which would only activate in an emergency. The emergency measures guidance would be congruent with a proposed modification to 21 CFR 640.120(b) that FDA put forth in a 2007 Proposed Rule. (NOTE: The proposals made in 2007 have not been finalized as of this writing.) The modification to 21 CFR 640.120(b) — that permits the Director of the Center for Biologics Evaluation and Research to issue an exception or alternative to the regulations in the event of a public health emergency — could extend applicability of the exception or alternative to multiple blood establishments in specified locations. This variance would be initiated only when necessary to assure the availability of blood, blood components, and blood products. FDA was not able to articulate when the variance could be activated, only that it would be in response to a declared emergency.
The joint statement presented by AABB, on behalf of AABB, the American Red Cross and America's Blood Centers, encourages the FDA to move the results of the committee's discussion into the guidance process as quickly as possible, thereby enabling blood establishments to update their preparedness plans.
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