The Food and Drug Administration convened a meeting of the Blood Products Advisory Committee July 26-27 in Gaithersburg, Md. The main agenda items for the meeting were the risk of babesia infection by blood transfusion and the status of laboratory tests; donor hemoglobin/hematocrit standards and frequency of donation; and an informational presentation on xenotropic murine leukemia virus-related virus, or XMRV. Updates also were provided to the committee regarding the June 10-11 meeting of the Advisory Committee on Blood Safety and Availability, with a report on the FDA’s current policy addressing blood donation by men who have had sex with men; the Dec. 14-15 FDA workshop titled “Emerging Arboviruses: Evaluating the Threat to Transfusion and Transplantation Safety”; the May 11-12 FDA workshop titled “Emerging Infectious Diseases: Evaluation to Implementation for Transfusion and Transplantation Safety”; and the Q Fever epidemic in the Netherlands.
This summary provides an overview of the presentations given on the main agenda items addressed by the committee, along with votes taken by the panel to provide guidance to the FDA Office of Blood Research and Review that could help shape future regulatory policy decisions.
Risk of Babesia Infection and Status of Laboratory Tests
BPAC was asked to address the risk of transfusion-transmitted Babesia, or TTB, infection and the status of laboratory tests. TTB was first reported in the U.S. in 1979, and since then more than 100 cases and 11 deaths have been reported to public health agencies. Sanjai Kumar, PhD, of the Division of Emerging and Transfusion-Transmitted Diseases within FDA’s Office of Blood Research and Review and Barbara Herwaldt, MD, MPH, of the Parasitic Diseases Branch of the Centers for Disease Control and Prevention each presented background information on Babesia infection. They described babesiosis as a tick-borne zoonosis caused by infections of humans with intra-erythrocytic protozoa of the genus Babesia and noted that several species of Babesia are present in the United States, with the majority of U.S. cases of babesiosis caused by infections with Babesia microti, the species that is prevalent in the endemic areas of the Northeast (New Jersey, New York, Connecticut, Rhode Island and Massachusetts) and upper Midwest (Wisconsin and Minnesota). A few other Babesia species such as B. duncani (formerly called WA1-type Babesia) and related organisms (CA1-type Babesia) are implicated in transmission of Babesia in several western U.S. states, while the other “B. divergens-like” agents such as MO1 have been reported in multiple U.S. states. Tick “season” generally is recognized to run May through September. Currently reportable to public health agencies in several states, babesiosis will become a nationally notifiable disease in the U.S in 2011.
Babesiosis is characterized by a wide spectrum of clinical manifestations that range from asymptomatic to severe acute or even fatal illness in some individuals. Otherwise healthy individuals may have persistent parasitemia for periods ranging from months to more than two years without overt clinical illness, and these individuals may appear to meet all requirements for healthy blood donors. Seropositive and/or parasitemic donors have been found year-round. Eight of nine fatal TTB cases were transfused between August and December, and a case in April was presumed due to a donation from an asymptomatic chronically infected person. Risk factors for severe babesiosis include asplenia, advanced age, and various causes of immune deficiency; neonates, immunocompromised and asplenic individuals, and the elderly are at the highest risk of severe disease.
Routine intervention strategies in the U.S. are minimal. Using a standardized, FDA-recognized donor history questionnaire, donors are asked if they have ever had babesiosis and are indefinitely deferred if they respond affirmatively. However, given the persistent asymptomatic stage where most infected donors would be, the question is presumed to be largely ineffective. Although some commercial laboratories offer serologic and molecular testing, there are no FDA-approved test kits for screening donors for Babesia infections. The laboratory developed tests used in some highly endemic areas have limitations for use in routine donor screening.
David Leiby, PhD, of the Transmissible Disease Department at the American Red Cross and Department of Microbiology and Tropical Medicine at The George Washington University presented ARC’s findings from B. microti seroprevalence studies, a 2009 NAT pilot study, a longitudinal natural history study and the results of a lookback study. The seroprevalence study conducted from 1999 to the present was primarily focused in Connecticut but recently expanded to included donors in Massachusetts, New Hampshire and Maine. Studies initially targeted only highly endemic foci but were subsequently expanded to be statewide. The study demonstrated that there is a seroprevalence among Connecticut blood donors of 1 percent per year; a portion of donors are parasitemic; and infections have a focal endemicity but are found across the entire state. The NAT pilot study included approximately 1,000 blood donations in Connecticut collected from August to October 2009 from Middlesex and New London counties. Twenty-five donors (2.5 percent) tested positive by IFA. Three donors (0.3 percent) tested positive by PCR, two of which were IFA-positive and one of which was IFA-negative. One apparent window period infection was detected. All NAT cases were found by the first week of September, indicating a potential role for NAT during tick season; however, technological hurdles with the NAT test remain. The Babesia natural history study is a long-term, ongoing program that enrolls Connecticut and Massachusetts donors from the seroprevalence study. The donors will have samples collected for testing every 30 to 60 days and are administered risk-factor questionnaires. The goal of the study is to investigate infection/resolution patterns over time. Though chronically infected carriers pose significant TTB risk, the majority of infected donors resolved their infection and should be considered for re-entry. Lookback reviews have been conducted in Connecticut from 1999 to 2005, and the results verify transmission risk.
Mark Walderhaug, PhD, of the Office of Biostatistics and Epidemiology presented the FDA risk assessment of TTB based on data sets from CMS (cases of babesiosis) and CDC (observed cases of TTB) and a probabilistic model to predict cases of babesiosis and TTB in each state. The risk assessment model is intended to overcome TTB reporting limitations: 1) babesiosis is reportable in only a few states; 2) CMS data relies on passive reporting; 3) misdiagnosis and non-diagnosis, especially in non-endemic areas, is assumed to be high; and 4) mild, asymptomatic cases are undiagnosed. The model assumed that: 1) asymptomatic carriers are responsible for TTB cases; 2) asymptomatic prevalence is a fixed ratio to symptomatic incidence; 3) reported cases of babesiosis are a measure of a state’s potential for asymptomatic carriers; 4) risk is uniform throughout a state; and 5) the ratio of infected units to asymptomatic donors is 1:1. Therefore, the results presented from this FDA analysis could be improved through the availability of more observational data, better understanding of infectivity and more accurate knowledge of the asymptomatic to symptomatic ratio. The FDA model indicated 20 states and the District of Columbia would be appropriate areas for testing, rather than the seven states that are generally thought of as endemic. Several states listed had isolated cases that were presumably related to travel to endemic areas or imported blood.
Questions for the Committee:
Do the FDA risk analysis and the available CMS and CDC data sets together support the concept of regional testing of blood donors for Babesia infections?
Yes-12, No-0, Abstain-0. The nonvoting industry representative indicated agreement with the “yes” vote.
Several committee members indicated their understanding of ‘“regional” to be “focal.” Some committee members expressed concerns about the model because it included non-endemic states based on isolated cases that were likely travel related or due to imported blood. Several members pointed to the results of studies that were presented and noted that those data seemed more relevant to a decision of the need to screen donors. The discussion of this question reflected a consensus that more data is needed to determine precisely which regions of which states should be tested and acknowledgment that a suitable test has not been made available for donor screening.
Given the current sensitivity limitation of NAT for Babesia, please comment whether the public health benefits of NAT testing warrant consideration of broad-based regional testing of donors by NAT.
The committee indicated that it was not presented with the data to allow for discussion on the topic although it seemed from the presentations that NAT was not yet an ideal test for Babesia in a routine donor screening environment.
Considering the current technologies, please comment on the suitability of antibody testing for Babesia infections in blood donors.
The committee again indicated that it had not been presented with the data to allow for discussion on the topic. The committee did receive some clarification that current IFA technology is an objective “ELISA-like” test.
The statement submitted by the AABB Babesia Work Group supported mplementation of a regional testing strategy limited to areas that are highly endemic for Babesia but was not in agreement with the broad 20-state strategy proposed by FDA, which included states that have reported isolated incidence of TTB. AABB’s statement also affirmed that data are currently insufficient to inform whether NAT or antibody testing are preferable technologies for donor screening.
Hemoglobin/Hematocrit Standards and Frequency of Donation
Orieji Illoh, MD, of the Division of Blood Application in FDA’s OBRR outlined the issues surrounding the agency’s request for comments and supporting data on hemoglobin (Hgb) and hematocrit (Hct) acceptance standards and the interdonation interval for allogeneic blood donors. Current standards were set in 1999 when FDA finalized a rule (Revisions to the Requirements Applicable to Blood, Blood Components, and Source Plasma, Federal Register, Aug. 19, 1999) establishing a minimum hemoglobin requirement of 12.5g/dL or hematocrit of 38 percent for both male and female allogeneic donors - 21 CFR 640.3(b)(3). This rule also established an interdonation interval of eight weeks - 21 CFR 640.3(b).
Illoh provided an overview of blood Hgb as a simple point of care test that has been used in the blood center setting as an indirect measurement of iron status when determining the donor’s eligibility to donate blood. However, studies have shown that Hgb levels are not a good indicator of iron status. A wide variety of testing methodologies for the measurement of hemoglobin or hematocrit have been approved in the U.S., with highly variable performance characteristics. In addition, the interdonation interval, defined as the minimum period of time that must elapse between blood donations by the same individual, also has been demonstrated to affect blood iron stores.
The definitions for normal population Hgb ranges used at the BPAC discussion were derived from the National Health and Nutrition Examination Survey III, or NHANES III, which found that 95 percent of Caucasian men over 18 years of age had hemoglobin concentrations greater than 13.5 g/dL, while 95 percent of Caucasian women over 18 had hemoglobin concentrations greater than 12.0 g/dL. Definitions for normal hemoglobin ranges have been demonstrated to be lower for African-American males and females. Using the NHANES normals and the FDA minimal acceptance criteria for blood donors (12.5 g/dL for males and females), male donors can meet the minimum standard for blood donation while falling into the anemic range on the NHANES scale, and females who are in the normal NHANES range are excluded from blood donation.
In a proposed rule published in November 2007 (Requirements for Human Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use, docket number FDA-2007-0573) FDA proposed to continue requiring the existing minimal Hgb and Hct acceptance standards but specifically solicited comments and supporting data on the following:
- Changing the acceptable hemoglobin or hematocrit levels to 12.0g/dL or hematocrit of 36%, respectively, as acceptable minimal values for female allogeneic donors.
- The possibility of adverse effects if a minimum of 12.0 g/dL or hematocrit of 36 percent is used for females.
- The possibility of adverse effects if a minimum of 12.5 g/dL or hematocrit of 38 percent is used for males.
- Establishing a more stringent interdonation interval.
FDA considered some of the issues at a September 2008 BPAC meeting, including partial results of the ongoing REDS-II Donor Iron Status Evaluation, or RISE, study that were further reported at this meeting. In addition, in preparation for the current committee meeting, FDA asked one blood organization — the American Red Cross — to perform an impact analysis on the current blood supply of several possible changes to the current acceptance standards and interdonation intervals for male and females.
Barbara Bryant, MD, of the University of Texas Medical Branch, Galveston, presented data from a study performed at NIH on the role of iron replacement in routine management of blood donors — I.R.O.N Protocol — Iron Replacement Or Not. Focused medical history screening was used to identify causes of low Hgb values and depleted or deficient iron stores with the result that some donors were referred to primary care physicians. Ferritin levels were performed on 1,355 low fingerstick Hgb donors and 410 control subjects. The 39-month study followed 1,180 female donors and 175 male donors (mean of 11.8 g/dL for females, 11.9 g/dL for males) and a control group of 147 females (mean Hgb 13.7 g/dL) and 263 males (mean Hgb 14.9 g/dL). In general, donors who were enrolled in the study with low Hgb and were administered iron supplements experienced a rise of Hgb levels to within normal ranges, at which point Hgb levels remained relatively consistent. An important observation noted during this study was the discordancy between venous hemoglobin measurements and fingerstick hemoglobin measurements and the further complexity this introduces when comparing to normal ranges — such as the NHANES values — that are venous samples. Bryant also determined that mean corpuscular volume, or MCV, is a useful screening tool to detect iron deficiency in a healthy blood donor population. Based on her study, Bryant suggests administration of a two-month supply of oral iron tablets to all donors with an Hgb of less than 12.5 and referral of those donors whose levels do not respond to iron supplement therapy to their primary care physicians.
Ritchard Cable, MD, a REDS-II investigator, presented preliminary results from the RISE study. RISE is a longitudinal study, involving the six REDS-II centers, that is designed to evaluate the effects of blood donation intensity on iron and hemoglobin status. Two cohorts of blood donors were enrolled in RISE: 1) a first-time and reactivated donor cohort with no whole blood or red cell donation in the previous two years; and 2) a frequent donor cohort with greater than two donations within the previous year for females or greater than three donations within the previous year for males. Donors enrolled in the study agreed to donate frequently for the 15- to 24-month study period. Iron status and related variables were evaluated at baseline and at the end of the study. In addition, donation outcomes were recorded for all visits, and additional iron measures were performed at interim visits for 1) first-time and reactivated donors; 2) donors with Hgb deferrals; and 3) selected female repeat donors. In this study, donor iron status was described in terms of absent iron stores, or AIS, correlating in other studies with absent bone marrow iron stores, and iron-deficient erythropoiesis, or IDE. Cable explained enrollment variables associated with AIS and IDE such as red cell donation frequency, age, gender, weight, smoking, self-prescribed iron supplement, menopausal or “ever” pregnant status, and participating center.
The “effect of previous 12-month RBC donation frequency” on plasma ferritin and hemoglobin at time of enrollment was studied, and with respect to plasma ferritin levels after two to three donations, the male and female populations looked very similar — the mean levels for the male donors dropped toward the female levels. Decreases in Hgb levels were not as clearly observed in male donors.
The RISE study data collection phase concluded in January 2010. Analysis of enrollment data is complete and was “in press” at the time of the BPAC presentation. During the course of the study, 12,695 visits were logged and 11,381 donations were made. Although analysis of the longitudinal data is ongoing, a preliminary analysis of these data was presented at the meeting. In general, the percentage of Hgb-based deferrals for all cohorts decreased as the donation interval increased. It was not unexpected to find that the percentage of deferrals for males and females from the first-time donor cohort was much higher than that of frequent donors. Of the 9,901 return donations studied, 9.5 percent were Hgb deferrals. The following variables were found to be significant in predicting Hgb/Hct deferral at any return visit once the donor was enrolled in the study: days since last donation, race/ethnicity, gender, age in women, and the blood center. Donor weight and number of red blood cell units donated in the previous 24 months as well as previous white blood cell or double red cell donation were not found to be significant factors. Cable summarized the following conclusions from the enrollment data:
- Frequent whole blood and red cell donors have a high prevalence of iron deficiency.
- Ferritin levels decrease with increasing donation frequency and this decrease is more remarkable in men.
- Donation intensity, gender, weight, and age are important independent predictors of AIS/IDE.
- Reducing the allowable frequency of blood donation is likely to reduce the prevalence of iron deficiency among frequent blood donors.
- Implementing routine iron supplementation may also positively affect the donor’s iron status.
The future RISE analyses are expected to inform: 1) development of additional models for predicting hemoglobin deferrals and measures of iron stores, including models that would focus on the information that would be routinely known to the center at the time of donor presentation (e.g., gender and age) to predict a donor’s iron status, and expanded models for Hgb deferral and iron stores; and 2) identification of optimal laboratory measures that predict iron depletion and Hgb deferral at subsequent visits. Cable noted that information from the ongoing analysis should ultimately be used to project the impact of various blood donation guidelines on iron status of blood donors, potential for Hgb deferral, and the adequacy of the blood supply.
Anne Eder, MD, PhD, executive medical officer at ARC, presented an impact analysis of changes to the current FDA policy for whole blood donors — regarding minimum Hgb requirements and the interdonation interval — on the current donor base. The analysis was prepared based on questions submitted to the ARC by FDA.
- What would be the impact of changing the minimum pre-donation Hgb from 12.5 g/dL to 13.0 g/dL for males?
- What would be the impact of changing the minimum pre-donation Hgb to 13.5 g/dL for males?
- What would be the impact of changing the minimum pre-donation Hgb to 12.0 g/dL for females?
- Interdonation Interval:
- What would be the impact of changing the interdonation interval from eight weeks (about six to seven times per year) to 12 weeks (about four to five times per year) for males?
- What would be the impact of changing the interdonation interval from eight weeks (about six to seven times per year) to 16 weeks (about three to four times per year) for females?
The analysis showed that the loss to the blood supply that would result from changing the minimum Hgb requirement for men to 13.0 would essentially be balanced by a corresponding decrease of the minimum Hgb requirement to 12.0 for females. However, if the minimum Hgb requirement for males were raised to 13.5, this would have a detrimental effect on the blood supply. According to the analysis, changing the interdonation interval is predicted to have a significant detrimental effect on collections.
In response to questions from the committee, primarily arising from the discussion on donation intervals, Richard Benjamin, chief medical officer at ARC, noted that although iron status is thought to have adverse effects on donors, adverse outcomes resulting from low iron levels has not been widely observed in the donor population. Blood centers defer donors with hemoglobin levels below the minimum acceptable standard, and there are probably adverse consequences to the blood center; however, FDA should not be prescriptive in the complement of interventions that a blood center can use to maximize the robustness and antigenic diversity of the blood supply while protecting the health of the donor. Blood centers should have the flexibility to use the optimal complement of various measures, considering blood center operational capabilities, blood availability and donor health for each blood center.
Questions to the Committee:
Does the available scientific evidence support changing the donor hemoglobin acceptance standard for males?
The committee vote was Yes-10, No-0, Abstain-0. The nonvoting industry representative indicated agreement with the “yes” vote.
If yes, what hemoglobin acceptance standards does the committee recommend?
The committee made no specific recommendation to raise the minimum standard for males to 13.0 g/dL but noted that FDA should look at the impact on availability, including rare phenotype inventories and TRALI mitigation strategies. Some members commented that no studies had been presented to show adverse consequences with use of the 12.5 g/dL acceptance standard for males. Other concerns that should be evaluated included how changing the acceptance standard for whole blood donors might affect availability of other components such as apheresis platelets.
Does available scientific evidence support changing the donor hemoglobin acceptance standard for females?
The committee vote was No-9, Yes-0, Abstain-1. The nonvoting industry representative indicated agreement with the “no” vote.
Committee members noted that despite the apparent loss to the blood supply that results from deferring females who are within the normal NHANES ranges, the available scientific evidence does not support changing (lowering) the acceptance standard.
Committee discussions of the remaining questions (potential use of gender specific interdonation intervals) indicated that the current data do not sufficiently inform decisions regarding interdonation intervals. AABB — in a statement presented at the meeting — and various other speakers urged FDA to wait for the final analysis of the REDS-II RISE data so that all available scientific evidence is evaluated and incorporated into its decision-making process. With regard to mitigations to lessen possible adverse effects on the blood supply if FDA does mandate changes, the committee cautioned that availability issues should be looked at carefully. Several members indicated that iron supplements for repeat/frequent female donors is likely to be an appropriate thing to do. It also was noted that application of some of the published hemoglobin ranges (population studies) are not directly applicable to blood donors since iron-deficient females were excluded from the published data, and such females are presumably in the donor population.
FDA provided an informational presentation to BPAC on collaborative efforts of public health agencies, academia and blood establishments to evaluate whether XMRV poses a safety concern for the blood supply.
Indira Hewlett, PhD, chief of the Laboratory of Molecular Virology in the Division of Emerging and Transfusion-Transmitted Diseases within the Office of Blood Research and Review at FDA, presented historical background related to identification of XMRV and various studies looking for possible disease associations of XMRV. Potential associations with prostate cancer and or chronic fatigue syndrome, or CFS, were the diseases most frequently discussed, as was the fact that current study results are not in agreement. She indicated that additional studies are needed to evaluate the role of XMRV in disease using well-standardized assays.
Although there is no evidence of XMRV transmission by transfusion, it is theoretically possible since XMRV has been detected in blood cells and there is evidence of cell free virus. As there currently is no evidence of transmission by transfusion or association with a TTD, FDA has not established donor policy specific to XMRV. Current regulations require that a donor be in good health and medical directors at blood collection centers should exercise judgment in determining whether CFS patients are in good health at the time of donation. FDA does not have any policy that further addresses XMRV or CFS specifically, but AABB Association Bulletin #10-03 recommends that blood collectors use donor education materials on CFS and indefinitely defer donors who voluntarily disclose their CFS diagnosis. Donor deferral has been introduced in parts of Canada, Australia, New Zealand and the U.K. for donors who voluntarily disclose their CFS diagnosis.
FDA intends to periodically update BPAC on progress in the agency’s understanding of XMRV and transfusion safety, and as additional data are obtained on prevalence in blood donors and transfusion risk, BPAC may be asked to advise FDA on appropriate measures for maintaining the safety of the blood supply.
Peter Ganz, BSc, PhD, director of the Centre for Blood and Tissues Evaluation with Health Canada, presented the Health Canada perspective on the possible association of XMRV with a transfusion-transmissible disease. According to Ganz, voluntary disclosure of a diagnosis of CFS results in an indefinite deferral from blood donation. Prostate cancer patients are permanently deferred, and prior donations are retrieved and destroyed. Health Canada issued a Directive on Universal Leukoreduction in 1998, and there is an expectation of some protective effect if the virus is mostly associated with WBCs. The agency supports further studies to demonstrate transmission via transfusion and the effectiveness of leukoreduction in preventing XMRV transmission through transfusion.
Robert Silverman, PhD, of the Cleveland Clinic provided a review of studies that led to the identification of XMRV and updates of relevant research. Silverman offered that the discordant findings of various XMRV studies associating XMRV with prostate cancer and CFS could be caused by laboratory contamination, geographic distribution, sequence variants, clinical criteria for patient selection, a lack of standardized methods, or a lack of widely available positive control human specimens.
Michael Hendry, DSc, chief of the Laboratory Branch of the Division of HIV/AIDS Prevention at the Centers for Disease Control and Prevention, reviewed the findings of various studies that provided data on the XMRV prevalence in persons with CFS, and presented the methods and results of the CDC’s recently published study in the journal Retrovirology looking into the possible association of XMRV with CFS. The study reported negative results using polymerase chain reaction, or PCR, and serology. Hendry also offered several possible explanations for discordant results between studies: differences in patient population; complexities of CFS; and lab methods used. Hendry concluded that more research is needed to determine the prevalence of XMRV in the general populations, to investigate its transmissibility, and to standardize testing across labs.
Graham Simmons, PhD, provided an update on the activities of the National Heart, Lung and Blood Institute, or NHLBI, Blood XMRV Scientific Research Working Group. The study was established to standardize and validate assays to evaluate transfusion risk in future studies through the Retrovirus Epidemiology Study Group, or REDS. Currently there are no FDA-approved assays for XMRV detection, and assays used in cohort studies have not been standardized. Simmons outlined the four phases of the analytical and clinical panel development: 1) analytical panel production; 2) pilot studies to look at factors such as sample types and timing of processing; 3) clinical sensitivity and specificity; and 4) clinical panels for donor prevalence.
Stuart Le Grice, PhD, of the National Cancer Institute presented information related to the specific XMRV assay under development at the Center for Cancer Research.