Keeping Blood for Transfusions Safe: Are Current FDA Regulations and Surveillance for Donated

KEEPING BLOOD FOR TRANSFUSION SAFE

NORTHEASTERN UNIVERSITY

Keeping blood for transfusions safe: Are current FDA regulations and surveillance for donated blood sufficient?.docx

Girish Appannaprasad

Urshula Nokham

Jennifer O’Mahony

Meng Meng Xu

Page | 1 Introduction

“Every two seconds, someone in the U.S. needs blood.”1 “More than 44,000 blood donations are needed every day”2 “A single car accident victim can require as many as 100 pints of blood”.3

The statistics are staggering. In present day society, many of us take for granted the availability of donated blood when tragedies occur and assume that the FDA is ensuring that the blood we receive is safe. The FDA was not around back in 1818 when the first successful transfusion of human blood to a patient occurred4; however, as new diseases began emerging, the FDA stepped in in 1972 to regulate U.S. blood and plasma centers.5 Today, there exist extensive regulations around donated blood products as detailed in 21 CFR 606 (Current GMPs for Blood and Blood

Components)6, 607 (Establishment Registration and Product Listing for Manufacturers of Human

Blood and Blood Products)7, 610 (General Biological Product Standards)8, 630 (General

Requirements for Blood, Blood Components, and Blood Derivative)9, and 640 (Additional

1 American Red Cross “Blood Facts and Statistics” http://www.redcrossblood.org/learn-about-blood/blood-facts- and-statistics#blood-supply [accessed 6/19/2013].

2 Ibid 1.

3 Ibid 2.

4 American Red Cross “History of Blood Transfusion” http://www.redcrossblood.org/learn-about-blood/history- blood-transfusion.[accessed 6/19/2013]

5 Ibid 4.

6 FDA “21 CFR 606: Current Good Manufacturing Practice for Blood and Blood Component” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=606 . [accessed 6/19/2013].

7 FDA “21 CFR 607: Establishment Registration and Product Listing for Manufacturers of Human Blood and Blood Products” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=607 [accessed 6/19/2013].

8 FDA “21 CFR 610: General Biological Products Standards” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=610 [accessed 6/19/2013].

9 FDA “21 CFR 630” General Requirements for Blood, Blood Components, and Blood Derivatives” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=630&showFR=1 [accessed 6/19/2013]. KEEPING BLOOD FOR TRANSFUSION SAFE

Standards for Human Blood and Blood Products).10 Clearly, the FDA has recognized the importance of ensuring a safe blood supply.

As new transmissible diseases appear on the scene, the importance of regulations and continued surveillance by the FDA are considered essential to protect the public from exposure.

The overall success rate for the FDA is encouraging as the risk of acquiring a virus from a blood transfusion is low – 1 in 2 million for HIV, 1 in 200,000 for Hepatitis B, 1 in 1 million for

Hepatitis C.11 While tests are available to screen for many life-threatening viruses and bacteria we do know about, new, as yet unknown viruses and bacteria may adversely affect the blood supply. How prepared is the FDA to deal with these new challenges at both a regulations level and at the surveillance level? How well does the FDA currently communicate their findings and actions to the public?

The scope of this paper will be broken down into three parts 1) an introduction to and overview of the FDA regulations for blood products for donation; 2) an examination of the current landscape around scientific testing with a focus on novel approaches the FDA is considering to de-risk the blood supply from unknown or less common viruses and bacteria and

3) an analysis of FDA surveillance activities including an assessment of how well the FDA is doing to prevent outbreaks and communicate with the public. In conclusion, the team will provide a summary of key findings, an overall assessment of the current regulations, and recommendations for improvements.

10 FDA “21 CFR 640: Additional Standards for Human Blood and Blood Products” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=640 [accessed 6/19/2013].

11 National Heart, Lung, and Blood Institute “What are the risks of a blood transfusion” http://www.nhlbi.nih.gov/health/health-topics/topics/bt/risks.html [accessed 6/19/2013].

Page | 3 FDA Regulations of the blood supply

The Center for Biologics Evaluation and Research is the FDA organization responsible for regulating the US blood supply.12 They “approve licenses for blood products, approve devices used for blood collection and infectious disease testing, develop and enforce quality standards, inspect all blood facilities at least every two years, inspect “problem” facilities more often, monitor reports of errors and adverse events, and take regulatory or legal actions if problems are found”.13

Despite the plethora of potential risks associated with blood products, the United States has one of the safest blood supplies in the world.14 In order to achieve this status, the FDA has established a “five layer system of overlapping safeguards”, which starts at the blood collection center and extends to manufacturers and distributors of blood products. The five layers are as follows.15

 Potential donor screening (21 CFR 640.3 Suitability of Donor16). Prior to donation, a

donor questionnaire17 is filled out in order to ensure that the donor’s blood would not

12 FDA “Regulation of the Blood Supply” http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/RegulationoftheBloodSupply/ [accessed 6/19/2013].

13 FDA “Have you given blood lately?” http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm048368.htm#FDAOversight [accessed 6/19/2013].

14 FDA “Keeping Blood Transfusions Safe: FDA’s Multi-Layered Protections for Donated Blood” http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/BloodSafety/ucm095522.htm [accessed 6/19/2013].

15 Ibid 14.

16 FDA “21 CFR 640.3 Suitability of donor” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=640.3 [accessed 6/19/2013].

17 FDA “Abbreviated Donor History Questionnaire” http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/QuestionsaboutBlood/UCM272981.p df [accessed 6/19/2013]. KEEPING BLOOD FOR TRANSFUSION SAFE

pose a potential health hazard to the recipient. To note, some exclusion criteria (i.e.

having same sex sexual intercourse or living in a high risk country for a period of time)

has proven controversial18,19 and the FDA has drawn criticism for these exclusion criteria

contributing to shortages in blood supplies.20

 Testing of blood for blood-borne agents (21 CFR 610.40 Test Requirements21) including

HIV-1, HIV-2, HBV, HCV, HTLV-1, Syphilis, and CMV.

 Maintenance of blood establishment“Blood establishments should keep a current list of

individuals who have been deferred as donors and check all potential donors against this

current list” as per (21 CFR 610.41). 22

 Quarantine blood products until they are thoroughly tested and the donation records have

been verified (21 CFR 610.46 HIV “lookback” requirement23; 610.47 HCV “lookback”

requirement24). The “lookback” requirement is used to identify “prior donations from

donors with positive screening tests and inform the patients who received these products

18 Trotter, Shay (2013) “Some protest FDA ban on blood donations from gay men” in The Lantern http://www.thelantern.com/campus/some-protest-fda-ban-on-blood-donations-from-gay-men-1.3019055[accessed 6/19/2013].

19 Kohn, David (2003) “Donor exclusion, testing of blood supply overdone, causing shortages critics say” in SunSentinel http://articles.sun-sentinel.com/2003-12-01/news/0312010094_1_mad-cow-disease-blood-supply-drug- administration-s-blood [accessed 6/19/2013].

20 Ibid 19.

21 FDA “21 CFR 610.40 – Test Requirements” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=610.40[accessed 6/19/2013].

22 FDA “21 CFR 610.41– Donor Deferral” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=610.41 [accessed 6/19/2013]

23 FDA “21 CFR 610.46 – Human immunodeficiency virus (HIV) “lookback” requirements http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=610.46

24 FDA “21 CFR 610.47 – Hepatitis C virus (HCV) “lookback” requirements” General Biological Products Standards http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=610.47[accessed 6/19/2013].

Page | 5 (recipients). When a blood donor tests repeatedly reactive in screening for an infectious

disease, the possibility exists that the donor may have had an undetectable infection at the

time of a previous donation. This is due to the window period or time between donor

infection and the appearance of detectable markers of disease.”25

 Blood centers “must report to FDA any manufacturing problems or breaches of

safeguards and correct system deficiencies that are found through FDA inspections” as

per 21 CFR 606.170 Adverse Reaction File and 21 CFR 606.171 Reporting of product

deviations by licensed manufacturers, unlicensed registered blood establishments, and

transfusion services.26,27,28

The FDA, in alliance with the Centers for Disease Control and Prevention (CDC) and the

National Institutes of Health (NIH), frequently reviews all of its efforts to ensure blood is safe.

When required, the FDA also consults the Blood Products Advisory Committee (BPAC) to review and evaluate available data concerning the safety, effectiveness, and appropriate use of blood, products derived from blood and serum or biotechnology. Perhaps most importantly,

CBER requires that owners or operators of establishments that manufacture blood products register with the FDA, pursuant to section 510 of the Federal Food, Drug, and Cosmetic Act29

25 United Blood Services for Hospitals and Physicians “Regulatory Requirements” http://hospitals.unitedbloodservices.org/regulatory-requirements.html [accessed 6/19/2013].

26 FDA “Keeping blood transfusions safe: FDA’s multi-layered protections for donated blood” http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/BloodSafety/ucm095522.htm [accessed 6/19/2013].

27 FDA “21 CFR 606.170 – Adverse reaction file” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=606.170 [accessed 6/19/2013].

28 FDA “21 CFR 606.171 – Reporting of product deviations by licensed manufacturers, unlicensed registered blood establishments, and transfusion services” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=606.171 [accessed 6/19/2013].

29 “Federal Food, Drug, and Cosmetic Act – Section 510” http://www.gpo.gov/fdsys/pkg/USCODE-2010- title21/pdf/USCODE-2010-title21-chap9-subchapV-partA-sec360.pdf [accessed 6/19/2013]. KEEPING BLOOD FOR TRANSFUSION SAFE and 21 CFR 60730, unless exempt under 21 CFR 607.65.31 This exemption includes pharmacies, persons who manufacture in vitro diagnostic blood products, carriers of blood products, and persons who manufacture products for non-human use.32 A list of every blood product manufactured, prepared, or processed for commercial distribution must also be submitted to the

FDA each June and December or if a change occurs as per 21 CFR 607.30.33 Patient safety is further enhanced by establishment registration and product listing. The ability to track the blood products provides several benefits such as ensuring security and safety of blood and getting the blood quickly to the right patients when it is needed.34

In conclusion, it is interesting to note that only 62% of countries have legislation covering blood transfusions.35 Furthermore, “unnecessary transfusions and unsafe transfusion practices can expose patients to the risk of serious adverse transfusion reactions and transfusion transmissible infections (TTIs).”36 “Only 109 countries have national guidelines on the appropriate clinical use of blood.”37 Of these, “86% high-income countries have a national

30 FDA “21 CFR 607 – Establishment registration and product listing for manufacturers of human blood and blood products” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=607 [accessed 6/19/2013].

31 FDA “21 CFR 607.65: Exemptions for blood product establishments” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=607.65 [accessed 6/19/2013].

32 Ibid 31.

33 FDA “21 CFR 607.30 – Updating blood product listing information” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=607.30 [accessed 6/19/2013].

34 “BloodTrack® Remote blood inventory and bedside transfusion management system” http://www.haemonetics.com/en/Solutions/Blood%20Management %20Solutions/~/media/Files/Brochures_US/BloodTrack_AD.pdf [accessed 6/19/2013].

35 World Health Organization (2013) “Blood safety and availability” http://www.who.int/mediacentre/factsheets/fs279/en/ [accessed 6/19/2013].

36 Ibid 35.

37 Ibid 36.

Page | 7 haemovigilance system, compared to only 34% of low- and middle-income countries.”38 The

World Health Organization recommends that all activities related to blood collection should be regulated at the national level and that there should be uniformity in the standards in order to ensure consistency in quality of blood products.39 In the opinion of this team, the current FDA regulations provide a sufficiently thorough (albeit sometimes controversial) set of regulations to enable safety in the blood supply and should be regarded as a model for other countries.

Detection of Transfusion Transmissible Infections

The World Health Organization (WHO) recommends that all blood donations be screened for infection prior to use.40 The WHO notes that “Screening should be mandatory for HIV, hepatitis

B, hepatitis C and syphilis”41. Their statistics show that “25 countries are not able to screen all donated blood for one or more of the above infections”.42 “Irregular supply of test kits is one of the most commonly reported barriers to screening.”43 “24% of blood donations in low-income countries are not screened following basic quality procedures which include documented standard operating procedures and participation in an external quality assurance scheme.”44 “The prevalence of TTIs in blood donations in high-income countries is considerably lower than in

38 Ibid 37.

39 Ibid 38.

40 World Health Organization (2013) “Blood safety and availability” http://www.who.int/mediacentre/factsheets/fs279/en/ [accessed 6/19/2013].

41 Ibid 40.

42 Ibid 41.

43 Ibid 42.

44 Ibid 43. KEEPING BLOOD FOR TRANSFUSION SAFE low- and middle-income countries.”45 “The prevalence of HIV in blood donations in high-income countries is 0.003% (median), in comparison with 0.1% and 0.6% in middle- and low-income countries respectively”.46 It is apparent that the FDA regulation of the U.S. blood supply is as

“good as it can get” given current technology but can improvements be made? To answer this question, we will look at what the FDA requires for detection of infectious agents, what are the remaining challenges, and what is on the horizon in terms of novel technologies.

The FDA requires donor screening and testing for 7 specific diseases—Hepatitis B and C,

Human Immunodeficiency Virus (HIV) types 1 and 2, Human T-Lymphotropic Virus I and II, and syphilis.47 In addition to the aforementioned diseases, the FDA highly advocates supplementary analysis for West Nile Virus and Chagas.48 These diseases were chosen because they are obviously transmissible via blood and there is no effective intervention for complete eradication.

Hepatitis B and C (HBV/HCV) are viruses that cause inflammation of the liver. While

HBV vaccines have been approved to prevent transmission49, only HCV therapeutics (no vaccines) have been approved.50,51 Enzyme-linked immunosorbent assay (ELISA) is first used

45 Ibid 44

46 Ibid 45.

47 FDA, "Keeping Blood Transfusions Safe: FDA"s Multi-layered Protections for Donated Blood." http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/BloodSafety/ucm095522.htm. [accessed 6/19/2013].

48 Ibid 47.

49 FDA “Hepatitis B Vaccine (Recombinant)” http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm094041.htm [accessed 6/19/2013].

50 FDA “FDA approves Incivek for hepatitis C” http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm256299.htm. [accessed 6/19/2013].

51 FDA “FDA approves Victrelis for Hepatitis C” http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm255390.htm [accessed 6/19/2013].

Page | 9 for blood donor screening to detect HCV antibodies in human serum or plasma.52 HCV recombinant immunoblot assay (RIBA) is then applied to verify anti-HCV tests that have already identified antibodies to HCV.53 The FDA has also approved nucleic acid amplification testing

(NAT) to test for HCV.54 NAT amplifies the virus’ nucleic acid “more than a million-fold”—this allows for the verification of small traces of the virus’ RNA.55

The most common method for detecting HBV involves analyzing donor blood for HBV surface antigens (HBsAg) and HBV surface antibodies (HBsAb).56 The prevalence of HBsAg is indicative of HBV infection. Conversely, the presence of HBsAb is indicative of the donor’s ability to recover from an “acute infection”—to clarify, it serves as an indication of a successful vaccination.57 Additionally, the FDA has also approved the use of NAT to detect HBV.

Enzyme Immunoassay (EI) is used to detect antibodies to both HIV-1 and HIV-2 in a test that uses serum or plasma. Confirmation of a positive test is done by HIV-1 immunofluorescence assay and HIV-2 enzyme immunoassay.58 The FDA began obligatory HIV testing (for the antibodies anti-HIV-1 and anti-HIV-2) in 1985, when the risk of HIV

52 American Red Cross “Blood Testing” http://www.redcrossblood.org/learn-about-blood/what-happens-donated- blood/blood-testing [accessed 6/19/2013].

53 Lab Tests Online, "Hepatitis C Testing." http://labtestsonline.org/understanding/analytes/hepatitis-c/tab/test.

54 FDA “Guidance for Industry: Use of Nucleic Acid Tests of Pooled and Individual Samples from Donors of Whole Blood and Blood Components (including Source Plasma and Source Leukocytes) to Adequately and Appropriately reduce the Risk of Transmission of HIV-1 and HCV” http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm07 4934.htm [accessed 6/19/2013].

55 Ibid 54.

56 Ibid 55.

57 Hepatitis B Foundation, "Blood Tests." http://www.hepb.org/patients/your_blood_tests.htm [accessed 6/19/2013].

58 American Red Cross “Blood Testing” http://www.redcrossblood.org/learn-about-blood/what-happens-donated- blood/blood-testing [accessed 6/19/2013]. KEEPING BLOOD FOR TRANSFUSION SAFE transmission from donated blood exceeded that of any other risk exposure.59 NAT tests are also be utilized to detect HIV and “closes the window period between infection and the detection of the antibody by about 4-7 days."60

Human T-Cell Lymphotropic Virus (HTLV) types I and II, are both retroviruses that affect humans. In the US, the combined acquisition of HTLV-I and II is very low—1 in

2,000,000 in donated blood.61 HTLV-1 has been linked to adult T-cell leukemia or lymphoma

(ATL) and a “chronic degenerative neurologic disease,” HTLV-1-associated myelopathy

(HAM).62 Similar to HTLV-I, HTLV-II has been linked to leukemia and neurodegenerative conditions, specifically hairy-cell leukemia.63 The FDA recommends enzyme immunoassays but also suggest assays to identify the antibodies associated with HTLV—anti-HTLV-I and anti-

HTLV-II.64

Treponema pallidum (syphilis) is a species of bacteria most commonly transmitted via sexual contact. 1,200 cases of syphilis were detected in US donors between 1995 and 2000.65

Infected individuals may be asymptomatic for years only to experience irreparable damage,

59 Donegan, Elizabeth. University of California San Francisco, "Transmission of HIV by Blood, Blood Products, Tissue Transplantation, and Artificial Insemination." http://hivinsite.ucsf.edu/InSite?page=kb-07-02-09 [accessed 6/19/2013].

60 Ibid 58.

61 Ibid 59.

62 Mayo Clinic, "Human T-Cell Lymphotropic Virus Types I and II (HTLV-I/-II) AntibodyScreen with Confirmation, Serum.". http://www.mayomedicallaboratories.com/test-catalog/Clinical and Interpretive/9539 [accessed 6/19/2013].

63 Ibid 62.

64 U.S. Food and Drug Administration, "Human T-Lymphotropic Virus Types I and II." http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProducts BLAs/BloodDonorScreening/InfectiousDisease/ucm090941.pdf [accessed 6/19/2013].

65 Transfusion medicine “Transfusion-transmitted disease Syphilis” http://www.pathologyoutlines.com/topic/transfusionmedsyphilis.html [accessed 6/19/2013].

Page | 11 including paralysis, neurological damage, blindness, and heart and liver damage.66 Blood banks began testing for syphilis in the 1940s, with the last reported transfusion of syphilis in 1966.67

The FDA recommends two serological screening tests to detect syphilis—nontreponemal and treponemal assays.68 Nontreponemal assays detect active syphilis.69 Treponemal assays ascertain the specific antibodies associated with the treponeme organism. This method differs from nontreponemal assays in that anyone who has ever been infected will test positive for the antibodies.70

West Nile Virus (WNV) is a flavivirus transmitted via mosquito bites and is common in

Africa, West Asia and the Middle East.71 It became epidemic in the US circa 2002. Individuals who are symptomatic experience fever, headache, body pain, vomiting and rash.72 Severe progression will only occur in 1% of infected populations and is characterized by the neurological conditions encephalitis and meningitis.73 Analysis for WNV is first done via

66 Centers for Disease Control and Prevention, "Syphilis - CDC Fact Sheet.", 2013. http://www.cdc.gov/std/syphilis/stdfact-syphilis.htm [accessed 6/19/2013].

67 Ibid 65.

68 U.S. Food and Drug Administration, "Guidance for Industry: Recommendations for Screening, Testing, and Management of Blood Donors and Blood and Blood Components Based on Screening Tests for Syphilis." http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/U CM340993.pdf [accessed 6/19/2013].

69 Ibid 68.

70 Ibid 69.

71 Centers for Disease Control and Prevention, "West Nile Virus.", 2013. http://www.cdc.gov/westnile/symptoms/ [accessed 6/19/2013].

72 Ibid 71.

73 Centers for Disease Control and Prevention, "West Nile Virus.", 2013. http://www.cdc.gov/westnile/symptoms/ [accessed 6/19/2013]. KEEPING BLOOD FOR TRANSFUSION SAFE minipool (MP)-NAT (pooled plasma from 6-16 individuals) and confirmed by ID-NAT (testing of specific individuals from a positive MP test).74 There is no treatment available for WNV.

The Trypanosoma cruzi organism is a parasite that causes Chagas disease.75 The organism is endemic to Latin America, but in non-endemic areas, blood transfusion is the

“predominant route of human infection.”76 Alter et. al. state that acute progression of the disease is “mild and treatable” with use of experimental drugs available through the CDC.77

Unfortunately, chronic illness occurs in most infected individuals, for which there is no intervention.78

While it appears the FDA has a handle on testing for diseases, how well are they doing combatting diseases that are less common or as yet, unknown? An example of the former is

Hepatitis E for which the FDA currently does not require testing since there are no FDA approved diagnostic or blood screening tests for the virus.79 At the 104th Blood Products

Advisory Committee Meeting in 2012, the FDA acknowledged the potential risk of HEV to the

74 U.S. Food and Drug Administration, "Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Donors of Whole Blood Components Intended for Transfusion." http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Bl ood/UCM189464.pdf [accessed 6/19/2013].

75 Centers for Disease Control and Prevention, "Parasites - American Trypanosomiasis (also known as Chagas Disease)." http://www.cdc.gov/parasites/chagas/disease.html [accessed 6/19/2013].

76 Ibid 75.

77 Alter, Harvey J., and Susan L. Stramer et al. "Emerging Infectious Diseases that Threaten the Blood Supply." Seminars in Hematology. no. 1 (2007): 32-41. http://www.seminhematol.org/article/S0037-1963(06)00238- 1/abstract [accessed 6/19/2013].

78 Ibid 77.

79 “FDA Panel votes to specify risk for hepatitis E in blood transfusions” (2012) Infectious Disease News http://www.healio.com/infectious-disease/gastrointestinal-infections/news/print/infectious-disease-news/ %7Bfbb549f8-85bb-4fcf-9b0c-d3b2d4930063%7D/fda-panel-votes-to-specify-risk-for-hepatitis-e-in-blood- transfusions [accessed 6/19/2013].

Page | 13 US blood supply and noted that the exact incidence level is unknown.80 Similarly, there does not yet exist a test for Creutzfeldt-Jakob disease (mad cow) despite it being a potential risk to the blood supply.81

Detection of low viral loads, less common viruses, and as yet unknown infectious agents continue to pose a challenge to ensuring that the blood supply is safe. On a more positive note, new technologies such as Cerus’ INTERCEPT may bring provide some relief.82,83 “The

INTERCEPT system is designed to reduce the risk of transfusion-transmitted diseases by inactivating a broad range of pathogens such as viruses, bacteria and parasites that may be present in donated blood. The nucleic acid targeting mechanism of action enables INTERCEPT treatment to inactivate established transfusion threats, such as hepatitis B and C, HIV, West Nile virus and bacteria, and is designed to inactivate emerging pathogens such as influenza, malaria and dengue. Cerus currently markets and sells the INTERCEPT Blood System for both platelets and plasma in Europe, the Commonwealth of Independent States, the Middle East and selected countries in other regions around the world. In the United States, Cerus is seeking regulatory approval of the INTERCEPT Blood System for platelets and for plasma.”84 It will be interesting to see how the FDA views the technology and welcomes its implementation. Thus far the FDA has agreed to allow Cerus to proceed with a Pre-Market Application (PMA) based on existing

80 “104th Blood Products Advisory Committee Meeting” September 20, 2012 Rockville, MD. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics/bl oodproductsadvisorycommittee/ucm325681.pdf [accessed 6/19/2013].

81 FDA “FDA’s role in regulating and protecting the nation’s blood supply” http://www.fda.gov/newsevents/testimony/ucm114940.htm [accessed 6/19/2013].

82 http://www.cerus.com/ [accessed 6/19/2013].

83 http://www.cerus.com/Investors/Press-Releases/Press-Release-Details/2013/Cerus-Announces-FDA-Agreement- on-Modular-Premarket-Approval-PMA-Application-Submission-Process-for-INTERCEPT-Platelets/default.aspx

84 Ibid 83. KEEPING BLOOD FOR TRANSFUSION SAFE clinical data.85 The PMA includes a post-marketing study commitment but will not require an additional Phase III clinical study.86

Surveillance

Both the CDC and the FDA are responsible for monitoring the blood supply for infectious agents that can potentially threaten our health and safety. The FDA does this by setting standards and regulating blood collection and distribution, monitoring accidents and adverse events, and by continually strengthening the overlapping safeguards that protect patients from unsuitable blood and blood products.87 Furthermore, they work to better understand the impact of storage containers and conditions, ensure that blood transfusions are minimized, evaluate new technologies, and assess artificial oxygen carriers.88 Complimentary to the efforts of the FDA, the CDC assists the state and the local health departments and hospitals by investigating reports of potential infectious diseases transmission and contamination of the blood supply.89 Moreover, CDC is responsible for monitoring the safety of the blood supply by collecting adverse reactions reports and errors or incident reports associated with blood transfusion in the U.S.90

85 “Cerus Announces FDA Agreement on Modular Premarket Approval (PMA) Application Submission Process for INTERCEPT Platelets” April 2013. http://www.cerus.com/Investors/Press-Releases/Press-Release- Details/2013/Cerus-Announces-FDA-Agreement-on-Modular-Premarket-Approval-PMA-Application-Submission- Process-for-INTERCEPT-Platelets/default.aspx. [accessed 6/19/2013].

86 Ibid 85.

87 Centers for Disease Control and Prevention “Monitoring Blood Safety” http://www.cdc.gov/bloodsafety/monitoring/blood-safety.html [accessed 6/19/2013].

88 Davey, Richard J. “The Safety of the Blood Supply” http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM245738.pdf [accessed 6/19/2013].

Page | 15 Critical surveillance methods implemented by both organizations ensure the safety of the blood supply. Methods include up front donor screening of medical history and physical examination.91 The FDA database reveals that, “this ‘up-front’ screening eliminates approximately 90% of unsuitable donors.”92 Screening donated blood for viruses that cause infectious diseases is the second surveillance method. Finally, blood centers make use of the donor deferral list. The National Donor Deferral Registry (NDDR) is a database of deferred plasma donors in the U.S.93 It permanently excludes those who “test reactive” to Hepatitis B

Surface Antigen, HCV, or HIV1/2. Temporary deferral is determined based on the donor’s screening results. The donor can donate blood once the problem clears or when certain time period has passed.94 The FDA requires that every blood establishment keep current a list of deferred donors and it is the responsibility of each blood establishment to ensure blood is not collected from a donor who is on the deferral list as per 610.41.95 Lastly, the FDA conducts inspections of licensed and unlicensed blood banks, brokers, reference laboratories and contractors as per 7342.001.96 Perhaps the most critical component (and what could potentially be a weak link if neglected) is not only for the agency to conduct these routine inspections, but

91 Elizabeth Streeter, About the Screening Test for Blood Donation, eHow, http://www.ehow.com/facts_5775315_screening-test-blood-donation.html [accessed 6/19/2013].

92 Blood & Blood Products, U.S. Department of Health & Human Services, http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/default.htm [accessed 6/19/2013].

93 “National Donor Defferal Registry” http://www.pptaglobal.org/program/deferral.aspx [accessed 6/19/2013].

94 Elizabeth Streeter, About the Screening Test for Blood Donation, eHow, http://www.ehow.com/facts_5775315_screening-test-blood-donation.html [accessed 6/19/2013].

95 FDA “21CFR 610.14 Donor deferral” http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr=610.41 [accessed 6/19/2013].

96 FDA “ Compliance Program Guidance Manual: Chapter 42 Blood and Blood Products” http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceA ctivities/Enforcement/CompliancePrograms/UCM337001.pdf [accessed 6/19/2013]. KEEPING BLOOD FOR TRANSFUSION SAFE when necessary, take legal action against organizations that repeatedly violate FDA regulations as has occurred in the past with the American Red Cross.97

Discussion/Conclusion

After conducting research on the safety of the U.S. blood supply, this team agrees that the

FDA (in conjunction with the CDC and NIH) is currently doing all it can from a regulatory and surveillance perspective to keep the U.S. blood supply as safe as possible. Most commendably, in the past few years, the FDA has self- identified several areas for improvement including eliminating industry influence to the Blood Products Advisory Committee by electing new members (“the BPAC provides technical advice to the FDA on scientific issues relating to safe and effective blood products and related devices”98, issuing new guidances to ensure that the most up to date processes are utilized, and approving novel diagnostic tests such as the HIV-1 p24 antigen detection method in order to close the window between infection and detection,99 In addition to these changes, the FDA, in a step to better engage the public, “provided enhanced public access to recalls and withdrawals of blood and blood products and has increased public input in the discussion regarding policy development on withdrawal and notification of plasma products. “100

97 ABC News “FDA: Red Cross Blood Processing Flawed” http://abcnews.go.com/US/story?id=94821&page=2 [accessed 6/13/2013].

98 FDA “FDA’s role in regulating and protecting the nation’s blood supply” http://www.fda.gov/newsevents/testimony/ucm114940.htm [accessed 6/19/2013].

99 Ibid 96.

100 Ibid 97.

Page | 17 One suggestion for improvement would be for the FDA to focus energies on developing faster, more consolidated testing methods for detection of viruses and bacteria (i.e. protein or

RNA chip technology?). That being said, trying to improve upon 1 in 250,000 to 1 in 2,000,000 chances of contracting a disease are pretty difficult statistics to try to improve upon.