1. CBER Hemoglobin/Hematocrit Acceptance Standards and Interdonation Interval in Blood Donors Introduction Blood Products Advisory Committee July 27, 2010 Orieji Illoh, MD Office of Blood Research and Review Center for Biologics Evaluation and Research Food and Drug Administration

2. CBER 1 Outline Introduction Hemoglobin standards – Regulatory history – Relationship to population norms – Relationship to iron status of donor – International standards – Estimated effect of changes on the blood supply Interdonation interval – Current US and international requirements – Relationship to iron status of the donor – Effect of changes on the blood supply Questions for the committee

3. CBER 2 Introduction Consideration of the balance between donor safety and blood supply Donor safety issues Hemoglobin standards Interdonation interval Blood supply issues Impact of any changes in hemoglobin standards or interdonation interval on blood supply

4. CBER 3 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

5. CBER 4 Why adjust interdonation interval? Improve donor safety Allow adequate time for iron recovery Decrease the incidence of iron deficiency among blood donors

6. CBER 5 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 collection of a potent product – Ensure donor safety

7. CBER 6 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

8. CBER 7 Chronology of FDA requirements for hemoglobin standards There have been discussions about changing hemoglobin standards and interdonation interval in the past The threshold of 12.5g/dL was established in 1958 and has not changed The interdonation interval of 8 weeks was established in 1999 and has not changed

9. CBER 8 Previous public discussions Workshop: “Maintaining Iron Balance in Women Blood Donors of Child Bearing Age.” June 8, 2001 Discussed Iron deficiency in female premenopausal blood donors – Medical issues related to iron replacement – Iron replacement and possible protocols Recommended implementation of a research program on iron replacement

10. CBER 9 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 Increasing the interdonation interval

11. CBER 10 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

12. CBER 11 BPAC: September 10, 2008 Topic: Iron Status in Blood Donors Committee members agreed that iron depletion in blood donors is a concern Discussed testing for iron status in the donor setting Discussed alternative strategies to mitigate iron depletion – Iron supplementation, dietary recommendations – Changing Hb/hct acceptance standards – Modification of interdonation interval

13. CBER 12 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.

14. CBER 13 Considerations for Changing Hemoglobin Acceptance Standards

15. CBER Definitions of anemia NHANES III and Scripts –Kaiser databases Blood. 2006 Mar 1;107(5):1747-50 Group 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 20-49 11.5

16. CBER 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.

17. CBER 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.

18. CBER 17 Adverse effects Are there adverse effects of maintaining a minimum hemoglobin of 12.5g/dL (hct 38%) for males? – Underlying medical conditions may not be addressed – Promotes iron deficiency? Are there adverse effects of lowering hemoglobin to 12.0g/dL (hct 36%) for females? – Promotes iron deficiency?

19. CBER Australian blood donors: Iron storage status of donors with different predonation thresholds 1535 males 1487 females Dev Biol (Basel). 2007;127:137-46. Total donor population iron deficient (%) ARCBS Hb threshold from 1/1/04 Males ≥ 12.6g/dL6.2 Females ≥ 11.8g/dL22.0 ARCBS Hb threshold from 1/1/05 Males ≥ 13.0g/dL6.0 Females ≥ 12.0g/dL20.6

20. CBER Association of hemoglobin levels with iron status in male blood donors Fe deficient: ferritin < 18 mcg/L Fe depleted: ferritin 18-29 mcg/L Fe replete: ferritin ≥ 30 mcg/L From BPAC presentation by Dr Barbara Bryant Sept, 2008 Hemoglobin levels Iron status<12.0 (n=57 ) 12.0- 12.4 (n=69) 12.5-12.9 (n=9) 13.0 – 13.4 (n= 20) >13.5 (n= 230) % Fe deficient 6346562519 % Fe depleted712222518 % Fe replete3042225063

21. CBER 20 Association of hemoglobin levels with iron status in female blood donors Hemoglobin levels (g/dL) Iron status 11.5 (n= 173) 11.5-11.9 (n= 215) 12.0-12.4 (n=379) ≥ 12.5 (n=145) % Fe deficient 40231410 % Fe depleted 27293530 % Fe replete 33485160 Fe deficient: ferritin < 9 mcg/L Fe depleted: ferritin 9-19mcg/L Fe replete: ferritin ≥ 20 mcg/L From BPAC presentation by Dr Barbara Bryant Sept, 2008

22. CBER International donor Hb levels (g/dL) Hb-maleHb-female Council of Europe 13.512.5 Australia13.012.0 UK13.512.5 Health Canada12.5 Both Sexes FDA12.5 Both sexes

23. CBER 22 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 phenotypes RBCs required for sickle cell patients May impact availability of male plasma

24. CBER 23 Effect on blood availability - Males If standard is changed to 13.5g/dL there may be a loss of about 3% Caucasian donors and as many as 21% African American donors (Transfusion; 2006 Oct;46(10):1667-81 ) Assuming a 4% loss of about 4,000,000 male whole blood donors with an average donation rate of 1.5, there would be an approximate loss of about 240,000 units/year

25. CBER Effect on blood availability - Females If the standard is dropped to 12.0g/dL, there may be gain of about 9% Caucasian female donors. (Transfusion; 2006 Oct;46(10):1667-81) Assuming 4,000,000 female donors with an average donation rate of 1.5/yr, there would be an approximate gain of 540,000 units/yr.

26. CBER 25 Interdonation interval

27. CBER 26 Interdonation interval An appropriate interdonation interval should ensure donor safety by allowing time for adequate red blood cell recovery. 21CFR 640.3(b) – A person may not serve as a source of Whole Blood more than once every 8 weeks ~ 6 donations/year

28. CBER 27 Iron loss following blood donation Iron loss following blood donation ~ 200mg Premenopausal women have lower iron stores than men Frequent blood donations deplete iron stores Replacement of lost iron is dependent on exogenous sources

29. CBER 28 Effects of iron deficiency Adverse effects include anemia, fatigue, restless leg syndrome, possible cognitive impairment, depression, and anxiety. There are reports suggesting a beneficial effect of low iron stores in males undergoing repeated phlebotomy – Favorable lipoprotein profile compared to non blood donors – Lower risk of cardiovascular disease – Possible reduction of iron-induced oxidative stress van Jaarsveld et al. Atherosclerosis. 2002 Apr;161(2):395-402. Salonen et al. Am. J. Epidemiol. 148 (1998):445–451.

30. CBER 29 Studies of iron stores and donation frequency High prevalence of iron deficiency in frequent blood donors – REDS II donor iron study Repeat donations lead to decreased serum ferritin in male and female donors – Røsvik AS, et al. Transfus Apher Sci. 2009 Dec;41(3):165-9 Clear correlation of iron deficiency with frequency of donation – Page EA et al. Transfus Med. 2010 Feb;20(1):22-9 Depletion of iron stores occurs gradually with increased frequency of blood donation – Simon TL et al. JAMA. 1981 May 22-29;245(20):2038-43.

31. CBER Effect of donation frequency on hemoglobin and iron status Transfus Apher Sci. 2009 Dec;41(3):165-9 Serum ferritin (μg/L) for both genders at four donations without iron supplement (red = women, blue = men). Hb (g/dL) for both genders at four donations without iron supplement (red = women, blue = men).

32. CBER International standards CountryMinimum hemoglobin Interdonation interval or frequency per year United States12.556 days Canada12.556 days United Kingdom12.5 for women 13.5 for men 112 days Australia12.0 for women 13.0 for men 84 days Netherlands12.5 for women 13.5 for men Women: 18 weeks, 3x/year Men:10 – 11 weeks, 5x/year Hong Kong11.5 for women 13.0 for men Women: 3x/year Men: 4x/year

33. CBER 32 Increasing the interdonation interval May decrease the risk of iron deficiency May allow more time for iron recovery. May decrease future donor deferral for low hemoglobin Will adversely affect the blood supply

34. CBER 33 Effect on blood availability Increasing the interdonation interval may negatively affect the supply of the following: Red blood cells especially O negative RBCs and other rare phenotypes Collections obtained by apheresis – Other blood components – Double red blood cells Blood components other than red blood cells Availability of donors for reagent manufacturers.

35. CBER 34 Key points Donor safety issues – Blood collection from anemic males with current hemoglobin standard – Iron deficiency due to frequent donations Blood availability issues – Potential gain of female blood donors – Potential loss of male blood donors

36. CBER 35 Questions for the Committee 1.Does available scientific evidence support changing the donor hemoglobin acceptance standard for males? a)If yes, what hemoglobin acceptance standards does the committee recommend? 2.Does available scientific evidence support changing the donor hemoglobin acceptance standard for females? a)If yes, what hemoglobin acceptance standards does the committee recommend?

37. CBER 36 Questions for the Committee 3.Please comment on the risks and benefits of extending interdonation intervals as a strategy to prevent iron deficiency in male donors. 4.Please comment on the risks and benefits of extending interdonation intervals as a strategy to prevent iron deficiency in female donors. 5.If any changes to the hemoglobin standard or interdonation interval were to be made, what mitigations can be considered to lessen possible adverse effects on the blood supply?

38. CBER 3738 Speakers Ritchard Cable, MD – American Red Cross, Framingham, CT – REDS II donor iron study Barbara Bryant, MD – University of Texas Medical Branch, Galveston, TX – NIH study on Iron stores in blood donors Anne Eder, MD - American Red Cross, Washington, DC – Impact of changes in hemoglobin standards or interdonation interval on blood availability