The 112th meeting of the Blood Products Advisory Committee (BPAC) to the Food and Drug Administration (FDA) was convened in Silver Spring, Md., on May 13, 2015 to advise the FDA on strategies for implementation of serological and nucleic acid testing for Babesia microti in blood donations. In the afternoon the Committee heard updates on considerations for hemoglobin S testing in blood donors, and revised blood donor deferral policy for men who have sex with men (MSM). FDA staff also provided a review of the research programs in the Laboratory of Cellular Hematology, Division of Hematology, Office of Blood Research and Review.
The Center for Biologics Evaluation and Research convened the Blood Products Advisory Committee (BPAC) to discuss strategies for implementation of antibody and nucleic acid-based testing for Babesia microti in blood donations. B. microti is among the most frequently transfusion-transmitted infections reported to the FDA with associated fatalities — for which no donor testing is available. However, recent investigational testing of blood donations for B microti infections has provided data to the FDA on the potential utility of testing. The INDs have been sponsored by Imugen Pharmaceuticals, Inc., and Immunetics, Inc.
Note: The August 2009 issue of TRANSFUSION included a Supplement on emerging infectious disease (EID) agents and their potential threat to transfusion safety. Members of AABB’s Transfusion Transmitted Diseases (TTD) Committee identified 68 infectious agents and described them in detail. Babesia species was categorized priority red (highest priority) along with dengue and variant Creutzfeld-Jakob disease. Read the updated Babesia Species Fact Sheet.
The FDA reviewed several available data sources to assess babesiosis risk in the United States, and proposed to the BPAC that the risk of acquiring Babesia infection by blood transfusion is nationwide. Resources used by the FDA included the National Babesiosis Surveillance program (CDC 2011-13), Transfusion-Transmitted Babesiosis Cases (CDC 1979-2009), and Center for Medicare & Medicaid Services (CMS) health records for beneficiary claims for diagnosis of babesiosis in persons 65 and older (2006-2013). In part, the risk is assessed to be nationwide due to
- donors from non-endemic areas that travel to endemic areas and acquire the infection;
- donors who normally reside in endemic areas and may donate elsewhere; and
- blood products that may be shipped between widely separated regions of the U.S.
Although tick-borne transmission may be seasonal, it appears TTB cases continue year round due to chronic asymptomatic infections.
The FDA presented risk models based on the CMS data. (The risk models, and summations of data provided to the FDA by Imugen and Immunetics are explained in the Issue Summary, which FDA made available prior to the meeting.) Use of the CMS database was summarized: “Therefore, we believe that babesiosis occurrence rates among the U.S. elderly Medicare beneficiaries, based on CMS data, provide the best available population-based estimate of babesiosis occurrence in the U.S. blood donors/general population, and as such was further used to assess number of TTB units prevented and false positive units diverted, overall and by state, for different blood donor screening strategies.” The FDA listed the limitations of using the database:
- Difficulty in identifying incident vs. prevalent cases as diagnosis codes do not necessarily represent incident events, and tests are not well recorded;
- Possible misdiagnosis or misrecording of babesiosis diagnosis;
- Lack of clinical detail for diagnosis code verification and for TTB case identification;
- Lack of clinical information to ascertain Babesia species;
- Test results are generally not available in claims data;
- State-level results are based on the beneficiary’s state of residence, which may not be the state in which the individual was initially infected; and
- In the future, medical record review is needed to assess positive predictive value of the ICD-9-CM diagnosis code for babesiosis.
Attendees at the meeting heard presentations from the IND sponsors regarding tests for detection of B. microti. Imugen presented information about an AIFA (arrayed fluorescence immunoassay) test for detection of antibody and a PCR (polymerase chain reaction) test for detection of DNA. Immunetics presented information about an EIA (enzyme immunoassay) test for detection of antibody.
Imugen Study Summary
A prospective study by the American Red Cross in four endemic states (selective counties in MN, WI, MA, CT on certain days) from June 2012 – Sept. 2014:
Immunetics Study Summary
- 89,141 screened donations;
- 339 (0.38%) reactive donations;
- Nine window-period (WP) units — 100-fold greater WP yield than HIV and hepatitis B virus (HBV), and 20-fold greater yield than hepatitis C virus (HCV);
- Four of every 1,000 donations were positive for B. microti — based on antibody- or PCR-testing or both;
- Additional donors were followed in a linked prospective study that continued through March 2015 with a total of 383 reactive donations — 381 confirmed positive. Positive predictive value (PPV) is calculated overall at 99.98%.
Immunetics information included linked and unlinked donor studies with Blood Systems Research Institute, Creative Testing Solutions, New York Blood Center, and Memorial Blood Centers. Screening was performed with enzyme immunoassay screening (EIA), and followup testing was performed using PCR, blood smears IFA, and immunoblots. The study is ongoing with results to date summarized as:
- EIA is effective in detecting the vast majority of PCR-positive samples based on performance on clinical babesiosis samples;
- EIA yields a false positive rate of less than 0.1% overall among blood donors;
- PPV of EIA is approximately 60% in endemic areas;
- The yield of PCR-positive/EIA positive is approximately 20% in endemic areas;
During the open public hearing a third presentation was made concerning a Grifols Procleix assay under development by Hologics to be used for pooled testing (lysed red cells). The assay will screen for B. microti, B. duncani, B. divergens, and B. venatorum.
Also in the open public hearing, presentations were made by AABB and ABC in support of regional testing. Both organizations raised strong objections to the use of unvalidated CMS data as the basis for the FDA’s policy-making for blood donor testing, especially when relevant data is available from screening blood donors. (See above for the list of limitations noted by the FDA) The AABB presentation also provided a brief restatement of AABB actions since the late 1980s to mitigate TTB.
As early as 1989 AABB initiated a recommendation for indefinite deferral of blood donors who provided a history of babesiosis and followed that in 1991 with a standard in the 14th edition of the Standards for Blood Banks and Transfusion Services that remains in effect today. The current AABB Donor History Questionnaire contains the related question, (Have you ever had babesiosis?) but limited data available to date indicate this question is only marginally effective at preventing cases of transfusion-transmitted Babesia (TTB). [Tonnetti et al., Transfusion-transmitted Babesia microti identified through hemovigilance. Transfusion 2009;49:2557-63.] In 2008 the AABB Board of Directors established the TTD Babesia Work Group to provide leadership with the goal of analyzing risks to the U.S. blood supply for TTB and developing scenarios to mitigate the risk.
Questions for the Committee
Do the available scientific data and FDA analysis support the concept of nation-wide, year round testing of blood donors for Babesia risk by an antibody-based test?
If not, please comment on alternative options that FDA should consider, including limitation of antibody testing to specific states.
VOTE: Yes – 11; No – 3, plus the nonvoting industry representative
Does the Committee agree that NAT-based testing should be performed in blood donations in certain high-risk states?
VOTE: Yes – 14, plus the nonvoting industry representative
If so, please advise whether year round NAT testing should be considered in the following:
5 states (highest endemic): CT, MA, RI, NY and NJ
9 states (all known endemic): CT, MA, RI, NY, NJ, NH, ME, MN and WI
VOTE: 8, nonvoting industry representative indicated this preference
15 states plus DC (largest risk capture with smallest number of states): CT, MA, RI, NY, NJ, MD, NH, ME, DC, VA, MN, VT, PA, DE, WI and FL
Please comment on alternative options that FDA should consider for blood donation testing by NAT.
Committee comments: included the idea that data from antibody testing could be used to indicate inclusion of states for NAT testing.
Please comment whether it would be appropriate to apply a time-based deferral for those donors who have B. microti-positive test result(s)?
- If so, please advise on a suitable deferral period for donors who had B. microti-positive test result(s)?
Committee comments: several members noted that presented data indicated that many donors would likely have detectable antibody well beyond a year and suggested that 2 years was a reasonable place to begin.
Hemoglobin S Testing of Blood Donors
The BPAC was updated about the considerations given to this topic by the Advisory Committee for Blood and Tissue Safety and Availability (ACBTSA) when they met in November 2014. Currently, there are no FDA recomendations or regulations for hemoglobin S (Hb-S) testing at the time of donation, even though the trait could result in product loss due to the glycerolization process that occurs when red cell products are frozen, or due to filtration of blood for leukocyte reduction. There are currently two types of tests for Hb-S that are used by blood manufacturers: sickle solubility tests or molecular methods. The ACBTSA was asked to include ethical and logistic issues when considering donor consent and notification considerations.The Committee was also reminded that the FDA has no regulatory oversight for donor consent related to Hb-S testing or notification of positive results. The ACBTSA was informed that current practice varies, with some establishments providing notifications. It was noted that hospital transfusion services may not inform blood collectors of Hb-S results. The ACBTSA found: the overall benefits of notification outweigh the risks; donors should be informed beforehand that testing may occur; donor notification is the responsibility of the blood collector (transfusion services should pass along relevant information); test-positive donors should be advised if there are other donations programs in which they are eligible to participate. The FDA intends to issue a draft guidance in consideration of the ACBTSA recommendations.
Considerations for a Revised Blood Donor Deferral Policy for Men Who Have Sex with Men
The FDA published a draft guidance “Revised Recommendations for Reducing the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Proucts” on May 12, 2015. When finalized the guidance will implement FDA’s recommendations for MSM blood donation policy and supersede earlier recommendations from 1992. An immediate impact of the guidance, when finalized, will be a change in the deferral period for blood donations from men who have sex with men; it will become a 12-month deferral rather than the current indefinite deferral.