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BPAC Meeting Summary – 11/17-11/18/16

The 114th meeting of the Blood Products Advisory Committee (BPAC) to the Food and Drug Administration (FDA) was convened in Silver Spring, Md., on November 17-18, 2016 to advise the FDA on strategies to manage iron deficiency associated with blood donation. The committee also discussed proposed procedures for assuring donor safety for collections of blood from female donors with hemoglobin values of 12.0-12.4g/dL or a hematocrit value between 36% and 38%. In the afternoon, the committee met in open session to discuss adverse reactions related to blood donation in teenage (16 to 18 years) donors and the effectiveness of several mitigation measures.

On November 18, the committee met in an open session to hear an informational session on Zika virus (ZIKV) infection and blood safety in the United States. Following the informational session, the committee heard presentations on the following topics: (1) The Transfusion Transmissible Infections Monitoring System (TTIMS); and (2) a summary of the FDA workshop on preclinical evaluation of red blood cells for transfusion.

Topic IA - Considerations for iron management in blood donors

Background

FDA solicited advice from the committee on acceptable procedures for iron management in blood donors because iron deficiency is an undesired result of blood donation despite hemoglobin testing and deferral practices to protect the health of blood donor. Iron deficiency, seen in both genders, is most notable in premenopausal females. Donation frequency is a major risk factors for iron deficiency in blood donors. Data were presented from National Heart, Lung and Blood Institute Retrovirus Epidemiology Donor Studies (REDS-II) and Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) studies.

Wendy Paul, MD, Division of Blood Components and Devices (DBCD)/Office of Blood Research and Review (OBRR)/Center for Biologics Evaluation Review (CBER)/FDA, provided a historical perspective, current FDA requirements, and considerations for iron management. In September 2008, the BPAC discussed iron deficiency in blood donors and agreed that iron depletion is a concern and that accurate, convenient, and rapid tests for iron stores were not available. The committee discussed the risks and benefits of alternative strategies to mitigate iron depletion in donors with no consensus on recommendations for implementation of these strategies. Hemoglobin and hematocrit standards in male and female allogeneic donors and the appropriate interdonation interval were discussed at the July 2010 BPAC meeting. The committee heard the preliminary results of the REDS-II Donor Iron Status Evaluation (RISE) study that examined predictors of iron deficiency and low hemoglobin among blood donors and recommended further analysis of the results of the REDS II RISE study before adjusting the interdonation interval. FDA’s November 2011 public workshop concluded donor education, ferritin testing, interdonation interval, iron supplementation and mitigation efforts needed additional consideration. In 2012, AABB published “Association Bulletin #12-03 - Strategies to Monitor, Limit, or Prevent Iron Deficiency in Blood Donors.” The bulletin recommends actions to reduce the risk of iron deficiency in blood donors, including ferritin testing, iron supplementation and/or extending the interdonation interval. Dr. Paul concluded with an introduction of the relevant studies, and posed questions to frame the committee discussions.

Ritchard G. Cable, MD, Scientific Director, American Red Cross (ARC) Blood Services, reviewed various REDS and other key studies, tracing the data back to 1977, when iron deficiency was first described in blood donors, through the finding of REDS-III RBC Omics of 2015. The REDS-II Donor Iron Status Evaluation (RISE) improved understanding of the course of iron deficiency in blood donors. Investigators developed models to predict the absent iron stores (AIS) and iron-deficient erythropoiesis (IDE). Frequent donation was the variable most closely associated with AIS and IDE. The likelihood of having AIS and/or IDE was increased in donors with lower body weight who were female, younger, and/or menstruating. Thirty-nine percent of RISE donors reported taking iron supplementation, which appeared to have a small protective effect for AIS, but not IDE. The prevalence of iron deficiency in blood donors may be influenced by geography, underlying donor requirements, and donor recruitment and collection practices.

Joseph E. Kiss, MD, Medical Director, Hemapheresis and Blood Services, the Institute for Transfusion Medicine, presented the key findings from the Hemoglobin and Iron Recovery Study (HEIRS). The objective of HEIRS was to determine the effect of oral iron supplementation on time to recovery of 80% of hemoglobin (HB) removed and recovery of iron stores (ferritin results) to baseline. Data showed that donors receiving iron supplementation experienced accelerated hemoglobin recovery postdonation, with nearly 90% of the net gain in the first 8 weeks following donation. The data showed donors on a standard diet without iron supplementation who were required over 24 weeks to replace the iron lost during donation, making increased interdonation interval a less effective option for management of iron deficiency.

Bryan Spencer, MPH, ARC, presented on overview of the Strategies to Reduce Iron Deficiency (STRIDE) study which pointed to the need for increased awareness of the high prevalence of iron deficiency in blood donors that is not prevented by current donor screening practices and that iron status in donors is currently not evaluated. STRIDE data showed that providing iron supplements or iron status information (ferritin results) are operationally effective means to mitigate iron deficiency in blood donors based on these key findings: (1) taking 19 mg iron or 38 mg iron pills administered once daily over 60 days were both effective mitigation strategies, (2) iron supplementation improved the hemoglobin status and ferritin levels of frequent blood donors with infrequent adverse event unrelated to iron content, (3) donors took the initiative to prevent or treat iron deficiency when provided education and specific information about their iron status, and (4) continued donation in frequent donors without mitigation of iron losses results in progressive worsening of iron deficiency.

Mindy Goldman, MD, Medical Director, Donor and Clinical Services, Canadian Blood Services (CBS), presented data on iron deficiency and ferritin testing from a large national study. In addition to demonstrating a positive impact on donors, the study showed iron deficiency to be common in donors, with the greatest impact on female donors. In 2017, CBS plans to implement an increase in the minimum interdonation interval to 84 days (limited to 4 donations/year), and selective ferritin testing followed by donor education to support a change in donation pattern and iron supplementation.

Jed Gorlin, MD, MBA, Innovative Blood Resources/Memorial Blood Centers, reviewed donation frequency and severity of iron depletion, and presented data on donor ferritin screening and iron replacement from a study conducted with Mississippi Valley Regional Blood Center. Few donor centers in the United States have taken steps to mitigate low iron stores but other countries have gender specific criteria for hemoglobin, and interdonation intervals, with a maximum annually. Donors deferred for 112 days for low ferritin levels were less likely to be deferred at the next donation. This study demonstrated that it is possible to perform ferritin testing after donation, distribute iron, as needed, and achieve donor compliance with a supplementation regimen that significantly improves ferritins levels. However, alternative methods to providing iron should be considered because mailing iron supplements to donors can be cumbersome and expensive.

Open Public Hearing

Steve Kleinman, MD, Senior Medical Advisor, presented AABB’s statement on Management of Iron Deficiency with Blood Donation. AABB expressed support of strategies to mitigate iron loss as necessary to protect the health and safety of altruistic volunteer donors, while ensuring a blood supply that is adequate to meet the needs of patients. AABB’s Donor Health and Safety Committee has been actively examining these issues and stands ready to facilitate discussions to develop evidence-based recommendations for mitigation strategies. Furthermore, AABB’s structure and organization positions the association to develop impactful standards, promote donor awareness, and provide supportive educational materials.

Questions for the Committee

  1. Does the available scientific evidence support the need for routine monitoring of iron stores in:
    1. All blood donors
      Vote: Yes = 9, No = 5, Abstain = 1
    2. Frequent donors (male and female)
      Vote: Yes = 14, No = 1, Abstain = 0
    3. Premenopausal female donors
      Vote: Yes = 14, No = 0, Abstain = 1
  2. Does the available scientific evidence support the need for routine monitoring of iron stores with effective iron supplementation:
    1. All blood donors
      Vote: Yes = 4, No = 10, Abstain = 1
    2. Frequent donors (male and female)
      Vote: Yes = 11, No = 4, Abstain = 0
    3. Premenopausal female donors
      Vote: Yes = 10, No = 4, Abstain = 1
  3. Does the available scientific evidence confirm that iron supplementation in blood donors:
    • Mitigates iron deficiency? Vote: Yes = 14, No = 1, Abstain = 0
    • Improves hemoglobin recovery? Vote: Yes = 12, No = 2, Abstain = 1
  4. Please comment on the feasibility of iron supplementation in consideration of:
    1. Potential adverse effects
    2. Adherence
  5. Please comment on whether available scientific data support the following methods for iron supplementation in blood donors:
    1. Educational material provided to the donor
    2. Iron supplements provided to the donor by the blood center
      1. If yes, what minimum effective dose would the committee recommend?
      2. Should iron supplements be offered to all blood donors or to select high risk donors?
  6. Please comment on whether there are adequate data at this time in support of a strategy of increasing the minimum inter-donation intervals for men and women, absent monitoring of iron stores.

Comments on 4-6

The committee reached consensus based on the data presented as follows:

  • iron supplementation is operationally feasible,
  • iron supplementation can be expected to have minimal potential adverse effects,
  • variable compliance in donors can be expected,
  • donor education will enhance compliance, understand and the benefit to the donor.

Topic 1B: Considerations for blood collections from female donors with hemoglobin levels between 12.0 -12.5 g/dL or hematocrit values between 36-38%

Background

FDA presented issues for consideration by the committee on acceptable procedures for the collection of blood and blood components from female donors with hemoglobin levels between 12.0-12.5g/dL or hematocrit values between 36-38%.

Orieji Illoh, MD, Division of Blood Complements and Devices, Office of Blood Research and Review/CBER/FDA, presented new regulations in FDA’s May 2015 final rule, “The Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use” (donor eligibility rule). The donor eligibility rule raised the minimum requirement for hemoglobin to 13.0 g/dL in male donors and left the minimum for female donors unchanged at 12.5 g/dL. The new regulations permit collection of a sub-group of female donors with a hemoglobin level between 12.0 -12.5 g/dL, recognizing that this subgroup of female donors has HB levels that are within normal limits for females. FDA requires blood establishments to submit a Post Approval Supplement (PAS) to demonstrate that they have “taken additional steps to assure that this alternative standard is adequate to ensure that the health of the donor will not be adversely affected due to the donation, in accordance with a procedure that has been found acceptable for this purpose by FDA.” FDA’s new regulations did not define the additional steps or acceptable procedures but suggested procedures or steps to enroll such donors could include a pre-donation measure of iron stores by means of a ferritin test, or iron replacement therapy and monitoring of iron stores.

Sharon Carayiannis, Deputy Director, AABB Regulatory Affairs, presented “Management of Risk for Iron Deficiency in Female Blood Donors with HB Levels of 12.0 - <12.5.” The two evidence-based approaches, developed by the AABB Donor Health & Safety Committee’s Working Group on Management of Female Hemoglobin Levels, are intended to serve as templates for a blood establishment electing to develop SOP’s for submission to FDA as a PAS. Both templates are designed to be used with female donors 18 years of age and older, who have hemoglobin levels in the 12.0-<12.5g/dL range. With the first approach, “Management of risk for iron deficiency in female blood donors using extended deferral”, an eligible donor is permitted to donate, iron supplementation is encouraged, and an extended deferral period of six months is assigned to provide time to replenish iron stores. The second approach, “Management of risk for iron deficiency in female blood donors using ferritin testing”, permits an eligible donor to donate, iron supplementation is encouraged, and ferritin testing is performed postdonation using a predonation sample. The ferritin test result from the predonation sample serves as a basis for donor follow up and determines the interdonation interval. Female donors with a low ferritin level, less than 26 ng/mL, receive a letter to communicate the test result and an extended deferral of 16 weeks, and to encourage iron use. The template has a tiered approach that also provides safety measures for donors with higher ferritin levels who are eligible to donate following a routine deferral period.

Questions for the Committee:

  1. Given that close to half of women with hemoglobin values between 12.0-12.5 g/dL will be iron deficient or iron depleted, please comment on the proposed procedures for collection of blood from female donors with hemoglobin values between 12.0-12.5 g/dL:
    1. Collection of blood, ferritin testing, followed by iron supplementation and 16 week deferral if ferritin level is low.
      1. Collection of blood prior to obtaining results of ferritin test result
      2. Proposed deferral period for females with low ferritin
      3. Iron supplementation options
    2. Collection of blood, 6 month deferral, and iron supplements for 60 days. No ferritin testing.
      1. Collection of blood without prior knowledge of ferritin levels
      2. Proposed deferral period
      3. Iron supplementation options
  2. Please discuss any alternative procedures that FDA should consider to permit collection of blood from female donors with hemoglobin values of 12.0-12.5 g/dL.

Committee comments on 1 and 2:
The committee strongly preferred the approach using ferritin testing, and preferred the testing to be performed prior to donation. Some members indicated that a ferritin test prior to collection for first time donors would better protect donor safety. The committee was less inclined to accept an extended deferral in the absence of ferritin testing, as used in the “No Ferritin Testing” approach, as an an adequate mitigation strategy. No alternative procedures for collections from this subgroup of female donors was offer by the committee.

Topic II: Blood Collection and Adverse Events in Teenage (16-18 years) Blood Donors

Background

FDA asked BPAC to consider 1) issues related to adequate mechanisms to prevent adverse reactions and injuries following blood donation from teenage donors, and 2) that teenage blood donors are more susceptible to developing iron deficiency and the resulting short or long term effects.

Emily Storch, MD, DBCD/OBRR/CBER/FDA, presented background for teenage blood donors (16-18 years o), who comprise a disproportionate number of blood collections with increasing recruitment of teenage blood donors through high school blood drives. In addition to concerns regarding known higher risks for acute donation-related adverse reactions and injuries, unanswered questions exist, such as short and long term effects of iron deficiency. Given that evidence shows significant and lasting iron depletion in adult donors, the effect likely extends to teenage blood donors but long term studies of iron deficiency related to blood donation in teenagers have not been performed.

Anne Eder, MD, PhD, Associate Deputy Director, Division of Emerging and Transfusion-Transmitted Diseases/ OBRR/CBER/FDA, presented data on teen blood donation and adverse reactions based largely on her previous work while employed with the ARC. Where state policies exist, they vary widely regarding the minimum age and parental consent for teenage donors. The AABB “Association Bulletin #08-04”, recommended mitigation measures as noted earlier in this summary. The review of trends showed an increase in teenage donors after 2002 and a higher rate of adverse reactions, including a 14.5 higher rate for a serious injury for a 16-17 year old as compared to the rate for a 20 year old. Donor selection criteria to address lower total blood volume of teenage donors and blood loss is likely to decrease symptomatic reactions but does not have an effect on rates of syncope or related injury. There was limited success with interventions to decrease immediate reaction.

Hany Kamel, MD, Vice President, Corporate Medical Affairs, Blood Systems, Inc. presented interventions to reduce vasovagal reactions in whole blood donors. The new interventions, using physiological mechanisms, include applied muscle tension, dietary salt supplement and water for blood volume restoration, and distraction, were shown to positively impact the donor experience.

Christopher France, PhD, Ohio University, presented data on predicting and preventing faint and pre-faint reactions among blood donors. In addition to addressing blood volume loss and fluid replacement, psychological factors, such as fear, in young blood donors can be addressed by 1) using donor education and preparation, 2) identifying high risk donors and using distractions, 3) use of experienced phlebotomists, and 4) use of coping options that include virtual reality technology. These measures can increase donor confidence and future donations.

Bryan Spencer, MPH, ARC, presented the findings of a new study, Comparison of the History of Donation and Iron Levels in Teen Blood Donors (CHILL). Based on the prevalence of low iron stores in teen donors, ages 16-18, the study focused on the prevalence of AIS and the impact of donation on the iron status of teen donors. Data analysis of the CHILL study is ongoing; preliminary data show:
1) the average ferritin levels of first-time (FT) teen donors to be equivalent to population norms,
2) the greater prevalence of iron deficiency and lower average ferritin level in FT teen donors as compared to adults,
3) modeling to assess the impact of blood donation in teen donors differs from that used to study adults,
4) indicates mitigation measures should be implemented and further studies are needed to evaluate the impact of blood donation on teens.

Questions for the Committee:

  1. Does the available scientific evidence confirm that adverse reactions and injuries after blood donation in teenage donors is a concern? Vote: yes = 15, unanimous
  2. Considering possible mechanisms to reduce the risk of adverse reactions and injuries in teenage blood donors:
    1. Does the available evidence support applying donor-specific selection criteria (e.g. EBV >3500 ml) as a means to mitigate donor reactions?
      Vote: yes = 15, unanimous
    2. Do the available data indicate that specific measures (e.g. applied muscle tension) to mitigate reactions are effective?
      Vote: Yes = 10, No = 4, Abstain= 1
      The committee offered comments supporting mitigation measures such as supportive fluids given 5-30 minutes before donation.
  3. Please comment on the need to ensure parental consent material contains adequate information on the increased risk of adverse reactions and injuries in teenage donors?

    Discussions indicated the committee was in favor of parental consent that includes adequate information to inform parents of the increased risk.

  4. Considering the available scientific evidence related to iron deficiency in teenage blood donors:
    1. Does the available scientific evidence suggest teenage donors are susceptible to developing iron deficiency?
      Vote: Yes = 15, Unanimous
    2. If so, please comment on possible interventions including:
      1. Further studies evaluating the effect of iron deficiency in teenage blood donors. The committee agreed that further studies are needed, including studies to address iron deficiency in the absence of anemia which improve the safety of donors of all ages.
      2. Donor education
        The committee agreed that donor education should be adequate to inform the donor and assists with donor safety.
      3. Iron management by ferritin testing, iron supplementation or limiting donation frequency.

    The committee discussions indicated that some members do support these mitigation measures, citing the CHILL data and the decision by some centers to begin ferritin testing of teen donors who are 16-18 years old.

  5. Please discuss whether there is enough associated risk in teenage donors to warrant restriction of the donor pool to individuals aged 18 years and over.

    The committee’s comments indicated general agreement that improved donor safety should be the focus rather than losing donations from 16 and 17 year olds.

Topic III: Informational Session: Zika Virus and Blood Safety in the United States

Background

The second day of the BPAC meeting began with an overview to update the committee on the ZIKV. Ingrid Rabe, MBChB, MMed, CDC, provided an overview of transmission of ZIKV in the general population, the status of ZIKV in the Americas, with an update on geographic and seasonal trends, as well as transmission in the United States. Many questions remain regarding ZIKV and the level of risk during pregnancy as well as the full range of potential health problems. Preventive measures continue to include insect repellent, protective clothing, window screens, postponing travel and limited exposure to others during the first week of infection to prevent further transmission.

Hira Nakhasi, PhD, OBRR/CBER/FDA, summarized the agency’s efforts to ensure blood safety and reviewed the potential for transfusion-transmitted ZIKV infection, including 2 probable cases in Brazil. The data from ZIKV testing under approved Investigational New Drug (IND) showed a peak in early July 2016 at 1.80% for the weekly detection rate in blood donors tested in Puerto Rico. FDA noted that ID-NAT testing under IND has prevented potential cases of transfusion-transmitted ZIKV by identifying and interdicting over 300 likely positive blood donations in Puerto Rico and a small number in several other areas of the United States. As of Nov. 9, 2016, ZIKV cases in the US totaled 139 locally acquired, 4,035 associated with travel, as compared to ZIKV cases in US territories which totaled 31,093 locally acquired and 105 associated with travel. FDA’s recommendations mandated in the August 2016 Zika Guidance provided a tiered 4 to 12 week implementation period based on proximity to areas of locally acquired cases and other epidemiological linkages.

Representatives from Hologic and Roche each provided an overview of testing under their IND protocols, updates on experiences with ZIKV testing under IND, including test characteristics and performance.

In the open public hearing, Susan Stramer, Chair, AABB Transfusion Transmitted Diseases Committee, presented a Joint Statement regarding the FDA’s August 2016 Guidance on ZIKV from AABB, America’s Blood Centers, and the ARC. The Statement expressed support for efforts to minimize or prevent transfusion-transmitted ZIKV infection, as well as concerns about the FDA’s process for finding a balance between the costs and overall value of the measures mandated by FDA guidance. FDA presented a statement emphasizing FDA’s role in responding to the risks associated with transmission of the ZIKV infection and expressing their intent to periodically reexamine the agency’s recommendations and approach.

The session closed with updates from FDA on the TTIMS and the FDA Workshop on Pre-Clinical Evaluation of Red Cells for Transfusion.