Current standards, donor safety, and blood supply Workshop: Hemoglobin standards and maintaining adequate iron stores in blood donors November 8, 2011 Orieji Illoh, MD Office of Blood Research and Review Center for Biologics Evaluation and Research Food and Drug Administration

Outline Introduction. Hemoglobin standards. Workshop objectives. Regulatory history Considerations to adjusting hemoglobin standards Previous Public discussions Workshop objectives.

Introduction Consideration of the balance between donor safety and blood supply Donor safety issues. Hemoglobin standards Blood supply issues. Impact of any changes in hemoglobin standards on blood supply

Why adjust hemoglobin standards? Establish ranges within physiologic norms. Avoid donations from male donors in “anemic” range. Allow more donations from female donors in “normal” range. ~95% of hemoglobin donor deferrals occur in women. Hemoglobin deferrals have a negative impact on future blood donations.

Hemoglobin measurement Test characteristics. Simple, point of care test. Testing methods differ and are affected by physiologic and operator variables. Quantitative methods reliably measure hemoglobin within 0.2g/dL to 0.5g/dL. Relationship to donor health. Used as an indirect measurement of iron status. Studies show that hemoglobin is not a good indicator of iron stores.

Hemoglobin measurement Current requirement: 21CFR 640.3(b)(3) Blood hemoglobin level no less than 12.5g/dL or hematocrit no less than 38% in both male and female allogeneic donors. Purpose Ensure donor safety. Ensure collection of a potent product.

Chronology of FDA requirements for hemoglobin standards The threshold of 12.5g/dL was established in 1958 and has not changed. Gender specific hemoglobin standards were proposed in the past but never finalized. There have been discussions about changing hemoglobin standards in the past. 7

Considerations for Changing Hemoglobin Acceptance Standards

Definitions of anemia Group White men 20 -59 13.7 Black men 20-59 12.9 Hemoglobin levels below which 5% of the normal subjects in the population will be found (g/dL) White men 20 -59 13.7 Black men 20-59 12.9 White women 20-49 12.2 Black women 11.5 NHANES III and Scripts –Kaiser databases Blood. 2006 Mar 1;107(5):1747-50

Hemoglobin distribution in men NHANES II data: Hb concentrations in men 18 to 44 years of age. (◆) Caucasian men; (░) African American men. Transfusion. 2006 Oct;46(10):1667-81.

Hemoglobin distribution in women NHANES II data: Hb concentrations in women 18 to 44 years of age. (◆) Caucasian women; (░) African American women. Transfusion. 2006 Oct;46(10):1667-81.

Adverse effects At a minimum hemoglobin of 12.5g/dL (hct 38%) for males Underlying medical conditions may not be addressed Worsening of existing iron deficiency? At a minimum hemoglobin of 12.0g/dL (hct 36%) for females Iron deficiency?

Australian blood donors: Iron storage status of donors with different predonation thresholds Total donor population iron deficient (%) ARCBS Hb threshold from 1/1/04 Males ≥ 12.6g/dL 6.2 Females ≥ 11.8g/dL 22.0 ARCBS Hb threshold from 1/1/05 Males ≥ 13.0g/dL 6.0 Females ≥ 12.0g/dL 20.6 1535 males 1487 females Dev Biol (Basel). 2007;127:137-46.

International hemoglobin standards Single hemoglobin standard: 12.5g/dL Country Hb-male g/dL Hb-female g/dL United States 12.5 Canada Switzerland

International hemoglobin standards Gender specific: Males 13.0g/dL, Females 12.0g/dL Country Hb-male (g/dL) Hb-female France 13.0 12.0 Australia Israel

International hemoglobin standards Gender specific: Males 13.5g/dL, Females 12.5g/dL Country Hb-male g/dL Hb-female g/dL Europe: Council of Europe 13.5 12.5 United Kingdom Scotland Germany Sweden

International hemoglobin standards Gender specific: Males 13.0g/dL, Females 12.5g/dL or 11.5g/dL Country Hb-male g/dL Hb-female g/dL Brazil 13.0 12.5 Hong Kong 11.5

Effect on blood availability - Males There will be a loss of male blood donors if the hemoglobin threshold is raised. Loss of male African American donors. Special phenotype RBCs required for sickle cell patients. May impact availability of plasma from male donors.

Effect on blood availability - Females If the standard is dropped to 12.0g/dL, there may be gain of female donors.

Previous public discussions

FDA Proposed Rule (November 2007) FDA asked for comments and supporting data on: Changing the hemoglobin or hematocrit levels to 12.0g/dL or 36%, as acceptable minimal values for female allogeneic donors The possibility of adverse effects if a minimum of 12.0g/dL or hematocrit of 36% is used for females The possibility of adverse effects if a minimum of 12.5g/dL or hematocrit of 38% is maintained for males

Representative comments to the Proposed rule Wait for results of REDS II study on iron status in blood donors. Agree with proposal to lower hemoglobin standard in women to 12.0g/dL. Hemoglobin down to 12.0 g/dL is normal for females. Enormous potential to improve the blood supply. Disagree with proposal to lower hemoglobin standard in women to 12.0 g/dL. Does not have any positive benefit to the donor. May make women susceptible to iron deficiency or anemia.

Blood Products Advisory Committee: September, 2008 Topic: Iron Status in Blood Donors. Discussed alternative strategies to mitigate iron depletion. Changing Hemoglobin/hematocrit acceptance standards. Iron supplementation, dietary recommendations. Modification of interdonation interval.

Advisory Committee on Blood Safety and Availability - December 2008 Recommendations FDA should reconsider donor hemoglobin acceptance values. Adopt different, gender-appropriate acceptance values The current single value (12.5 g/dL) permits acceptance of a significant number of "anemic" males while excluding many normal females.

BPAC meeting, July 27, 2010 Committee votes Committee recommendations 10-0 to increase hemoglobin requirement for male donors. 9-0 (one abstention) against a decrease in hemoglobin requirement for female donors. Committee recommendations Await final analysis of study on blood donors before considering any changes to the interdonation interval.

Key points Donor safety issues. Blood availability issues. Blood collection from anemic males with current hemoglobin standard. Blood availability issues. Potential gain of female blood donors. Potential loss of male blood donors. http://www.anemia.org

Workshop objectives- today Obtain current information on the relationship between donor hemoglobin standards and donor safety. Discuss the effect of hemoglobin standards on blood availability. Discuss hemoglobin measurement methods in blood donors.