Food and Drug Administration staff from the Center for Biologics Evaluation and Research (CBER) met with AABB's FDA Liaison committee to discuss topics of mutual concern regarding donor and patient safety and product manufacturing. The committee includes liaisons from AABB, the Advanced Medical Technology Association (AdvaMed), America's Blood Centers (ABC), the American Red Cross, the Armed Services Blood Program and the College of American Pathologists.
CURRENT FDA INITIATIVES AND PRIORITIES
FDA participants provided a review of the current status of blood screening being performed under investigational new drug (IND) for dengue (DENV) and described development of the first DENV RNA International Standards (one for each Serotype, DENV 1-4). A CBER lot release panel has been produced containing three members per serotype. Likewise, following a review of blood donor screening for
Babesia being performed under IND studies, a report was provided of the
Babesia Antibody Panel established by CBER. This panel is based on a plasma sample from a patient during the acute phase of
B. microti infection and is available for testing and validation by interested laboratories. The FDA plans to expand the panel with additional serum/plasma samples from
B. microti-infected individuals from endemic regions of the United States.
An FDA workshop to be held April 10-11, 2013, will focus on advances in nucleic acid and protein-based detection methods and their application in multiplex detection of transfusion-transmissible agents in blood donors and red blood cell antigen phenotyping. The major objectives of the workshop are 1) to review the status of multiplex platforms and the technological advances in molecular and protein-based pathogen detection methods; and 2) to discuss the scientific pathways to support the development of multiplex assays to screen donors for blood-borne pathogens and blood group antigen typing.
CURRENT AABB INITIATIVES AND PRIORITIES
Over the next year, AABB will continue to provide members with education and tools enabling the highest level of quality care for donors and patients while focusing on cellular therapies, patient blood management and the U.S. Biovigilance Network. Overall strategic goals include: engagement to ensure a viable membership in transfusion medicine and cellular therapies and to return/provide valued services to the membership; excellence in medicine to promote science, research, and data collection and analysis to advance evidence-based practice in transfusion medicine and cellular therapies; knowledge translation effectively acquiring, translating and delivering new and existing knowledge to professionals in transfusion medicine and cellular therapies; international technical assistance providing advice, guidance, mentoring and formal training in all aspects of blood banking to enhance supply and safety through the U.S President’s Emergency Plan for AIDS Relief (PEPFAR) task orders and cooperative agreements (2004-2017); regulatory advocacy for the development of rational regulation that optimizes patient and donor care and safety; and standards and accreditation in which AABB is the global leader in standards setting and accreditation for existing and new therapies for transfusion medicine and cellular therapies.
SPECIFIC TOPICS FOR DISCUSSION WITH FDA
Eligibility of Donors Based on Legal Gender
In May 2009, the AABB FDA Liaison committee asked the agency if it is permissible to determine a donor’s eligibility based on his or her legal gender. The FDA responded that risk must be the basis for the assessment of donor eligibility. The response from the agency was that based on existing data, a transgendered female donor (born male) would be deferred based on a history of MSM. The FDA has no data from which to assess risk of a transgendered male (born female). Although only a small proportion of the population is transgender, this situation continues to pose a dilemma for blood collectors.
The FDA was asked how blood centers could approach the scenarios listed below when developing standard operating procedures (SOPs) for their center.
- A male has completed a sex-change process that includes surgical creation of female genitalia and then has sex with a man. Is this considered male-male sex?
- If the person described in #1 had sex with a man before undergoing gender transition, would acknowledgement of this prior activity preclude blood donation now?
- A person who was born a male may have completed the hormonal change to female but not yet the surgical creation of female genitalia. Psychologically, this person may well consider themself to be female, look female and respond to donor qualification questions as a female. The person may have had sex with a man but not respond to the question about men having sex with men. How would a blood establishment deal with this scenario if brought to the center’s attention?
FDA participants reiterated that donor eligibility assessments must be made based on risk exposure. The second and third scenarios represent examples of MSM. Regarding the first scenario — an assessment of the presenting donor’s history must include the time prior to surgery before a determination of eligibility can be made. FDA participants noted that SOPs describing the process for such an assessment can be submitted to the agency for review.
The MSM policy in Canada was briefly reviewed. Currently the donor in #1 would be eligible and the donors in #2 and #3 would be deferred. Canadian Blood Services and Hema-Quebec will submit a proposal to the Canadian authority — Health Canada — that the past five years is the appropriate period to review for MSM risk.
Donor Written Statement of Understanding
At the September 2011 meeting, AABB’s FDA Liaison committee discussed the importance of the donor education process being developed by industry. The FDA was updated on the progress of ABC’s working group to produce model education, informed consent and parent/guardian permission materials comprehensible to donors recruited to give blood in community blood centers. At that time, the working group's focus was on materials intended to educate donors about the donation process. The working group stated an intent to obtain stakeholder input, ensure language appropriate to the intended audience, and perform pilot studies before presenting the finished materials to stakeholders and the FDA.
At the current meeting, an update was provided on outstanding issues of the project that include: revising the (longer) resource document, addressing donor consent, ascertaining conformance with AABB Standards, discussing potential documents that may be superseded, obtaining FDA input particularly related to
BPAC recommendations and funding for validation studies. When completed, the materials will be piloted by blood establishments. FDA participants noted that they would be happy to review and comment on the materials if requested to do so.
Current Required Donor Testing for Hepatitis
In November 2011, the FDA published the “Draft Guidance for Industry: Use of Nucleic Acid Tests on Pooled and Individual Samples from Donors of Whole Blood and Blood Components, including Source Plasma, to Reduce the Risk of Transmission of Hepatitis B Virus.” (The guidance was published Nov. 15, 2012 with
final recommendations). The FDA has recommended the use of an FDA-licensed HBV NAT to be necessary to adequately and appropriately reduce the risk of HBV transmission. The guidance states that an “FDA-licensed HBV NAT can detect evidence of infection at an earlier stage than is possible using previously approved hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc) tests.” The HBsAg and anti-HBc tests still must be performed.
There are other redundancies in screening markers such as HCV and HIV. For syphilis, another marker, there has not been a case of transfusion transmission since the 1960s; the spirochete has not been shown to survive during component storage and viable spirochetes are not present in antibody confirmed-positive blood donors. While eliminating a single test on an automated
multiplex platform — such as HBsAg on the PRISM — will not have the desired outcome of improved efficiency or reduced cost, AABB’s FDA Liaison committee asked the agency to enter into a dialogue on criteria and/or studies that would be required to generate the data to support the elimination of some screening tests.
With regard to hepatitis B assays the FDA referenced specific data that was presented at a previous BPAC meeting on breakthrough infections (following hepatitis B vaccination) and said that the agency would probably look to a review of additional data at a future BPAC meeting to evaluate further the issue of breakthrough infections. Breakthrough infections are discussed in “Rationale for Donor Screening Using HBV NAT” on Page 6 of the final guidance document.
Donor Deferral for History of Hepatitis After Age 11
21 CFR 640.3(c) (1) states that “No individual shall be used as a source of Whole Blood if he has a history of viral hepatitis after the 11th birthday.” This basic deferral policy, which originated prior to the introduction of any form of donor testing for hepatitis infectivity, was later modified in recognition of the fact that clinically apparent viral hepatitis occurring before age 11 is invariably due to hepatitis A virus, which does not have a chronic carrier state. In the past, the FDA has been asked to consider changing the requirement from a permanent deferral to a time-limited deferral of one year or six months from the end of the hepatitis occurrence. Such a change was not considered appropriate in the context of the continuing occurrence of non-A, non-B hepatitis and/or the possible occurrence of other putative, but unidentified viral hepatitides. That rationale seems no longer relevant for the following reasons:
- Three tests are used to identify current or prior HBV infection among donors
- Two tests are used to identify current or prior HCV infection among donors
- As a result of NAT, the infectious window period for HBV and HCV has been reduced to a period of weeks to days
- The last newly identified agents putatively associated with transfusion-associated hepatitis, HGV/GBV-C and TTV/SENV have all been cleared as agents responsible for any cases of human hepatitis
- There has been no reported case of transfusion-transmitted hepatitis E virus, HEV, in the U.S.
The FDA was asked to discuss the rationale for continuing to permanently defer donors with a history of hepatitis after age 11 and a procedure for reinstatement of these donors using available testing such as hepatitis A virus, cytomegalovirus and Epstein-Barr virus testing.
FDA participants reviewed some of the history behind the regulation — first established in the 1950s and last modified in
1993. It was further noted that while assays are available for HAV, CMV and EBV, there are none for
HEV. HEVantibody prevalence has been demonstrated in some donor samples — although confirmatory assays are not available for further testing. Studies will be undertaken shortly to determine HEV incident cases in blood donors and if further actions are needed to protect the safety of the U.S. blood supply. The FDA made some proposals regarding hepatitis deferral in the 2007 proposed rule “Requirements for Human Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use.” (AABB comments to the proposed rule recommended removal of the current requirement to permanently defer donors with a history of hepatitis after age 11.)
BLA Submissions That Appear to Be on Hold Until Publication of a Final Guidance Document
Blood centers have reported that when they contacted their consumer safety officer regarding the status of their BLA submissions, they were informed that the submissions are being held awaiting the publication of a final guidance, specifically the leukoreduction guidance.
AABB’s FDA Liaison committee and the FDA discussed the procedure (formal or informal) for CSO review of BLA submissions during the period after a draft guidance is published but before a final guidance is published.
FDA participants noted that firms could submit applications/supplements at any time and they will be reviewed on their own merit; this includes submissions during the time after issuance of a draft guidance but before the issuance of a final guidance. New policy issues may be identified during the course of the reviews that need to be resolved and this may influence review and approval of the submissions. However, submissions are not reviewed against recommendations published in a draft guidance and a supplement should not be “held” waiting for a different guidance. There is no policy at the FDA to do this, and consumer safety officers engaged in the review process are clear on the process.
September 2012 BPAC Meeting
Sept. 20-21 Blood Products Advisory Committee meeting included topics of interest to AABB’s FDA Liaison Committee: hepatitis E virus (HEV) and blood transfusion safety, and strategies to further reduce the risk of bacterial contamination in platelets.
The incidence of HEV in the general U.S. population is unclear and likely underestimated due to the lack of well-validated assays, asymptomatic infections and the fact that HEV is not a reportable disease. BPAC was asked to discuss the potential risk of HEV to transfusion safety.
FDA participants provided an overview of their interest in HEV: it has been recognized since 2004 as a transfusion-transmissible infectious agent and recent epidemiological data suggest that it may pose a safety threat to the U.S. blood supply. Although there have been no cases of transfusion-transmitted infection reported in the U.S., there are documented cases from Japan, the United Kingdom, Saudi Arabia and France. Documented cases of HEV infection are uncommon in the U.S., but some studies have detected a high prevalence of antibodies to HEV in blood donors, suggesting the possibility of transmission by blood transfusion. The agency is interested in developing pedigreed panels from HEV-infected individuals that can be used to characterize serological assays and also to have further screening of blood donor samples by PCR. The American Red Cross has committed to performing PCR testing on approximately 20,000 samples.
As the major viral threats to blood safety have been mitigated by testing, the risk of bacterial contamination of platelets stands out as a leading infectious risk of blood transfusion. The options presented to the BPAC focused on some strategies to mitigate the residual risk of bacterial contamination of platelets.
Discussions at the
July public workshop sponsored by AABB and the BPAC meeting focused on assessing the need for actions to decrease the current risk of transfusion of bacterially contaminated platelet products. BPAC advised that rapid testing techniques, in addition to culture, could be of value. FDA participants noted that guidance is under consideration.
Follow up to Oct. 19, 2012 Public Workshop on Statistical Process Control
Blood establishments manufacture products in accordance with specific standards established by FDA regulations and guidance, as well as in accordance with specifications developed by device manufacturers and industry standards. To ensure that product standards are met, blood establishments validate manufacturing processes at implementation and then monitor these processes on a regular basis using quality control methods. Statistical sampling plans that are capable of identifying when the manufacturing process varies or has a high frequency of nonconformance are a regulatory requirement (21 CFR 211.160(b)) and are recommended in guidance (“Draft Guidance for Industry: Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion”).
The goal of the FDA workshop, co-sponsored by AABB and ABC, was to educate blood establishments on statistical process control theory and options for the implementation of scientifically sound sampling plans in blood establishments.
The FDA was asked to provide an update of the process FDA investigators will use to review the sampling plans in blood establishments and their application to product manufacturing and quality control as well as the training investigators will have in statistical process control.
Training for investigators includes use of established compliance programs. There is no specific training on statistical plans; investigators will continue to look for assurance that processes are in control and performed according to the firm’s SOPs.
transcript of the September workshop is available.)
PF24 and PF24RT24
The AABB Interorganizational Plasma Task Force submitted a protocol to the FDA for licensure of a product(s) that would be labeled for further manufacture; the product is currently shipped under short supply agreement as recovered plasma. FDA has indicated that the regulatory pathway for the new product(s) will be publicly available in a draft guidance document. One concept of the protocol submitted by the task force is that the regulatory pathway developed by the FDA should accommodate new products that are licensed and may need to be relabeled for further manufacture. Subsequent to the May 2012 BPAC meeting, apheresis device manufacturers have begun resubmitting their BLAs for PF24 and PF24RT24.
The FDA was asked to discuss the agency’s current considerations for PF24 and PF24RT24 and how it will fit into the regulatory scheme currently under development.
2011 BPAC discussion and recommendations received from the committee, the FDA currently is focused on developing the scheme for plasma collected concurrently with cellular products. There may be further discussion before plasma collected from whole blood donors as a single component proceeds further down the same path.
Labeling of Units With Historical RBC Antigen Testing Results
At the April 2012 meeting, AABB’s FDA Liaison committee discussed that blood centers perform RBC antigen testing — both serological and genetic — and it is the practice of many blood centers to provide this information to their customers either on the shipping document or a tie tag attached to the unit. However, the committee understands that the practice of using tie tags has been questioned and that FDA interprets 21 CFR 606.121(j) to disallow the use of tie tags for this purpose. Since the April meeting, AABB has established a working group — which includes FDA representation ¬— that has been reviewing RBC antigen testing and labeling processes currently in use, and is working on a protocol that would provide an acceptable mechanism for multiple establishments to use.
Participants discussed the progress of the AABB working group and the data or information the agency needs from hospitals regarding their use of historical RBC antigen testing results.
The FDA noted that they are interested in a discussion concerning the benefits and risks of labeling RBC units with historical antigen typing test results. Concerns include: 1) assurance of the quality of the antigen typing results based on the reagents or the tests that have been used, 2) accurate linkage of the donor’s historical antigen test results to the current donation through positive identification of the donor, and 3) feasibility of confirming the historical antigen test results on the current donation, either by the blood collector or the transfusion service. The FDA would be interested to know more about 1) current practices for obtaining antigen-negative units, 2) potential benefits and risks of labeling RBC units with historical antigen typing test results, 3) processes used for labeling RBC units with historical antigen typing test results, and 4) processes in place to assure adequate linkage of historic results with current donation. Other areas of interest are the use of serologic versus molecular (gene-based) testing, policies for confirmatory testing, and experience on the use of historical typing results to label units. FDA participants indicated the subject would likely be discussed at an upcoming BPAC meeting.
Hepatitis C virus (HCV) Recombinant Immunoblot Assay (RIBA) Shortage
In March 2012, Ortho Clinical Diagnostics sent their customers an important notification regarding an inventory shortage of CHIRON® RIBA® HCV 3.0 SIA. In July 2012, Ortho notified their customers that further production planning is underway, and they expect to have availability of the product in the U.S. during this summer. Later communications indicate that production may not be back online prior to the end of October when distributed lots of RIBA would expire.
The RIBA assay is used to further test blood donations that are HCV antibody (anti-HCV) repeatedly reactive (RR); the test also is used as a diagnostic for the same purpose. HCV RIBA is the only licensed antibody supplemental test available in the U.S. to confirm RR results. The primary concern is the FDA required actions that are needed to manage donors and their prior donations in the absence of an antibody-based supplemental test. These activities include appropriate messaging for donor deferrals, notification and counseling, and activities related to appropriate consignee notification and recipient tracing (lookback). In the absence of a licensed supplemental antibody test, all donors who test anti-HCV RR and are HCV RNA-negative by NAT will be notified only of their anti-HCV RR. Consequently, such donors will be confused, anxious and will seek counseling from their primary care physician who will have only limited tools for appropriate testing. FDA liaisons to AABB’s Transfusion Transmitted Diseases committee have been helpful in providing guidance to establishments seeking alternative procedures as allowed under 21 CFR 640.120. The American Red Cross has received approval for an alternative procedure and is sharing it widely through AABB and ABC communication channels to assist other establishments. Additional information can be found on the AABB website.
Issues like this continue to plague the transfusion medicine community and the item was placed on the agenda to de-brief and discuss unforeseen issues that may emerge. In addition the committee continues to believe that lack of manufacturers who are active in providing licensed donor screening assays and supplemental/confirmatory tests is a crucial issue and looks forward to discussions with the agency in the hopes that a plan for action from the transfusion medicine community will emerge.
FDA participants acknowledged that this particular issue had become complicated and that any establishment in need of an alternative procedure, because they are dealing with a donor that has a repeatedly reactive antibody result AND a negative NAT result, should contact the agency. Alternative procedures can be granted verbally, with the written application as follow-up. Testing and donor notification regulations that are involved include 21CFR 610.40(e), 610.47(a)(3), and 610.47(b)(3).
Guidance Documents and Rules
- the importance of these draft documents to AABB’s FDA Liaison committee was highlighted for FDA participants.
“Draft Guidance for Industry: Implementation of Acceptable Abbreviated Donor History Questionnaire and Accompanying Materials for Use in Screening Frequent Donors of Blood and Blood Components”
“Draft Guidance for Industry Recommendations for Donor Questioning, Deferral, Reentry and Product Management to Reduce the Risk of Transfusion-Transmitted Malaria”
Peter Marks, MD, PhD, Deputy Center Director, Center for Biologics Evaluation and Research
Jay S. Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Ginette Y. Michaud, MD, Deputy Director for Medical and Scientific Affairs, OBRR
Martin Ruta, PhD, JD, Regulatory Counsel, OBRR
Robin Biswas, MD, Deputy Director for Medical Issues, Division of Emerging and Transfusion Transmitted Diseases (DETTD), OBRR
Paul Mied, PhD, Deputy Director, DETTD
Jennifer Scharpf, MPH, Associate Director for Policy and Communications, OBRR
Salim Haddad, MD, Senior Medical Officer, Division of Hematology (DH), OBRR
Paul D. Mintz MD, Deputy Director, DH
Jaroslav Vostal, MD, Chief, Laboratory of Cellular Hematology, DH
Richard Davey, MD, Director, Division of Blood Application (DBA), OBRR
Orieji Illoh, MD, Deputy Director, DBA
Leslie Holness, MD, Chief, Blood and Plasma Branch (BPB), DBA
Judy Ciaraldi, Consumer Safety Officer (CSO), BPB
Lore Fields, MT(ASCP)SBB, CSO, BPB
Gilliam Conley, Director, Division of Inspections and Surveillance (DIS), Office of Compliance and Biologics Quality (OCBQ), CBER
Ellen Lazarus, MD, Director, Division of Human Tissues, Office of Cellular, Tissue, and Gene Therapies (OCTGT), CBER
Karoll Cortez, MD, MHS, Medical Officer, OCTGT
Faye Vigue, Branch Chief, Manufacturers Assistance and Technical Training Branch (MATTB), Division of Manufacturers Assistance and Training, (DMAT), Office of Communications, Outreach and Development (OCOD), CBER
Pauline Cottrell, CSO, DMAT, MATTB, OCOD
Estelle Russek-Cohen, PhD, Acting Director, Division Biostatistics, Office of Biostatistics and Epidemiology (OBE), CBER
John Scott, PhD, Acting Deputy Director, Division of Biostatistics, OBE
Susan Stramer, Ph.D., President, AABB
Graham Sher, MD, Ph.D., President-Elect, AABB
Darrell Triulzi, MD, Immediate Past President, AABB
M. Allene Carr-Greer, MT(ASCP)SBB, Director, Regulatory Affairs, AABB
Kathleen Houston, BS, MT(ASCP)SBB, Accreditation Program Committee, AABB
S. Gerald Sandler, MD, CAP
Richard Benjamin, MD, ARC
Ruth Sylvester, MT(ASCP)SBB, ABC
William Turcan, MT(ASCP)SBB, DoD
Khatereh Calleja, JD, AdvaMed
Dan Waxman, MD, ABC
Louis M. Katz, MD, TTD Committee, AABB (by telephone)
Patricia Pisciotto, MD, Standards Program Committee, AABB (by telephone)
Becky See, MS, MLS (ASCP)cm, CQA(ASQ), Deputy Director, Regulatory Affairs, AABB (by telephone)
Jean Otter, MT(ASCP) SBB, Division Director, Programs, AABB
Philip Schiff, JD, Division Director, Administration and Business Development, AABB
Eduardo Nunes, MPP, Senior Director of Policy, Standards, and Global Development
Rafael Cassata, MS, RAC, Deputy Director, Cellular Therapy, Regulatory Affairs, AABB
Jacqlyn Riposo, Policy Specialist, AABB