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 (ARC); the Armed Services Blood Program and the College of American Pathologists.
Current FDA Initiatives and Priorities
Peter Marks, MD, expressed appreciation on behalf of the FDA for the opportunity afforded by the meeting to exchange information and views between the agency and members of the blood community.
Hira Nakhasi, PhD, provided a summary of the FDA workshop titled "Application of Advances in Nucleic Acid and Protein-Based Detection Methods for Multiplex Detection of Transfusion-Transmissible Agents and Blood Cell Antigens in Blood Donations," held on the National Institutes of Health campus April 10-11, 2013 — the workshop
transcript is available on the FDA's website. An important objective of the workshop was to discuss the scientific pathways to support the development of multiplex assays to screen blood donors for bloodborne pathogens and to perform blood group antigen and HLA typing. Recent advances in gene- and protein-based pathogen and blood cell antigen detection methods on multiplex platforms and the current state of multiplex platform technology were reviewed. Following the workshop, next steps were determined to include extended outreach to encourage dialogue with stakeholders, discussion of logistics of implementation of multiplex assays in blood establishments, as well as a need to clarify priorities and encourage funding opportunities. In another forum, a discussion of considerations for appropriate pathogens for multiplex assays should be held.
Alan Williams, PhD, provided an update on several activities related to the decision to look at potential changes to the current policy of deferral from blood donation for males who have sex with other males (MSM), even once since 1977. Several studies have been underway since a
2010 meeting when the Advisory Committee for Blood Safety and Availability recommended a review of the current suboptimal policy. A challenge to revising the current policy is posed by the changing epidemiology in the U.S. as evidenced by an increase in reported HIV in younger MSM.
Paul Mintz, MD, summarized recent product approvals. Apheresis PF24 (Plasma Frozen Within 24 Hours After Phlebotomy) and PF24RT24 (Plasma Frozen within 24 Hours After Phlebotomy Held at Room Temperature Up To 24 Hours After Phlebotomy) clearances were obtained by three companies following the Blood Products Advisory Committee (BPAC) meeting in May 2012. Manufacture of these products provides logistical advantages to eight-hour Fresh Frozen Plasma. Octaplas, a solvent/detergent treated plasma product, was approved in early 2013 with indications for 1) replacement of multiple coagulation factors in patients with acquired deficiencies due to liver disease and in patients undergoing cardiac surgery or liver transplantation and 2) transfusion or plasma exchange in patients with thrombotic thrombocytopenic purpura. SOLX System was approved in April 2013 with the first new additive solution (AS-7) approved for Red Blood Cell storage in the U.S. since 1988. The products are leukocyte-reduced red cells and plasma. Kcentra (4-Factor Prothrombin Complex Concentrate, Human) was approved for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (e.g., warfarin) therapy in adult patients with acute major bleeding.
Current AABB Initiatives and Priorities
Susan Stramer, PhD, president of AABB, provided an overview of some of the factors affecting the transfusion medicine landscape such as the Affordable Healthcare Act, the commoditization of blood, the development of new technologies and the increasing implementation of patient blood management (PBM) programs. Updates on the association's commitment to PBM, the development of standards for reducing the risk of transfusion-related acute lung injury (TRALI), and activities of the Quarantine Release Errors Task Force also were discussed.
The strengths of AABB's PBM program were highlighted by the association's standards setting activities, educational programs and tools, guidelines, research funding via the
National Blood Foundation and consensus building. An overview of AABB's educational modules for PBM also was presented. It was noted that the success of AABB's PBM initiative incorporates collaborations with other organizations such as the Society for Advancement of Blood Management (SABM), Joint Commission and Network for Advancement of Transfusion Alternatives (NATA). In the future, PBM-related activities will focus on the development of business plans, use of novel educational tools, clinical practice guidelines, and the development of standards and accreditation programs.
An overview of TRALI-related AABB Association Bulletins was provided. AABB's Blood Bank/Transfusion Services Standards Program Unit (BB/TS SPU) and AABB's TRALI Task Force developed and proposed standards to reduce the risk of TRALI. A
public workshop will be held on July 8, 2013, to discuss the scientific and operational issues, including any potential product shortages, associated with proposed standards.
The work of the Quarantine Release Errors Task Force, which was created following an FDA/U.S. Department of Health and Human Services-sponsored and industry co-sponsored workshop in Sept. 2011, also was highlighted. The task force is charged with establishing definitions of common quarantine release errors (QREs), developing a method to capture critical data and developing a risk-based method to stratify QREs. The task force has drafted a white paper containing appendices that include helpful tools for assessing events, deviations, hazards and risks; determining factors that influence human behavior/errors; and considerations for process design to minimize QREs.
Specific Topics for Discussion with FDA
Options to Further Reduce the Risk of Bacterial Contamination in Platelets
AABB standards (22.214.171.124 and 126.96.36.199.1) and Association Bulletin (AB #12-04) recommendations continue to set the pace for requirements to reduce the risk of bacterial contamination in platelets. In 2012, AABB sponsored a public workshop on this topic and FDA raised the topic with the BPAC. On several occasions in 2012, FDA representatives indicated the agency would consider drafting guidance on this subject, yet it did not appear on the list of guidance documents CBER is planning to publish during 2013.
FDA representatives were asked to discuss the agency's current considerations on the subject of options to further reduce the risk of bacterial contamination in platelets and responded that guidance would be drafted to address the multiple complex issues. Inputs from the AABB workshop, the BPAC meeting and comments submitted to related dockets would all be considered. In response to an inquiry, it was noted that FDA remains open to consideration of extended shelf-life platelets based on suitable protocols that include testing for bacterial contamination to support the extended labeling period.
Labeling Blood Components With "Historically Negative" RBC Antigen Results
Following discussions at the spring 2012 Liaison committee meeting, AABB formed an interorganizational work group, which included FDA liaisons, to look at the variety of protocols in use by blood centers to provide antigen results — other than ABO and RhD — to hospital customers for a unit of red cells when the current donation was not tested. Subsequent to formation of the work group, FDA asked the BPAC for recommendations on the subject and members of the BPAC made recommendations consistent with the thinking of the AABB work group. The AABB work group forwarded recommendations to the BB/TS SPU and the recommendations have been incorporated into the 29th edition of Standards for Blood Banks and Transfusion Services that was released for public comment at the end of April.
FDA representatives were asked to discuss any concerns they may have with the recommendations the AABB work group made to the BB/TS SPU. The discussion primarily revolved around the various methods used by blood centers to provide current results versus historical results to their customers: For example, does the center take full advantage of the options provided by ISBT labeling? Is the information provided on a tie tag? Is a combination of options used? Committee members responded that due to lack of guidance, the current methods would vary depending on the center and the desire of its customer.
CDER/CBER Dialogue Relevant to Warnings Against Blood Donation in FDA-Approved Medication Package Inserts
This topic was discussed at the September 2011 and April 2012
FDA Liaison meetings. In the last update to the AABB Liaison committee, FDA participants stated that notification to industry in a timely manner is the focus of the discussions with Center for Drug Evaluation and Research (CDER). Several challenges were noted: establishing a line of communication with the appropriate office at CDER, understanding the rationale behind the actual warning and determining the appropriate mechanism for communicating with industry. Currently CBER is concentrating its efforts with the Office of New Drugs at CDER. Communications have been elevated to the director level within the centers.
The AABB Donor History Task Force (DHTF) maintains a current listing of medications —
Medication Deferral List — that is intended for use in screening blood donors. Medications appear on the list if the drug adversely affects the potency of the product or if a single exposure to the level of residual drug that may be present in a blood component poses risk to recipients, especially during pregnancy. In February, the DHTF became aware of a new isotretinoin drug (Pregnancy Category X) – Absorica. The package insert carries the following statement: "No Blood Donation — Patients must be informed not to donate blood during isotretinoin therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to isotretinoin."
The DHTF and its FDA liaisons have established a mechanism to update donor history questionnaire materials when they become aware that these drugs have come on the market, but the Liaison committee continues to be concerned about the lack of a communication alert when the drugs are approved. FDA representatives present at the Liaison committee meeting reported that recent progress has been made and a method has been established whereby CBER staff will be notified by CDER when such a drug is approved for market.
Transmissible Spongiform Encephalopathies Advisory Committee Meeting Held March 14, 2013
The Transmissible Spongiform Encephalopathies Advisory Committee met to discuss FDA's
draft risk assessment model for potential exposure to the variant Creutzfeldt-Jakob disease (vCJD) agent in red blood cells for transfusion in the U.S.
When travel deferrals related to vCJD risk were originally enacted, the FDA committed to an ongoing review of the appropriateness of the deferrals. Furthermore, not only does the new risk assessment model provide a point from which to review the deferrals, but it is noted that France now has a defined time for return to food safety. Liaison committee members and FDA participants discussed several facets of the model and potential implications. AABB will refer the matter to its Transfusion Transmitted Diseases Committee.
Currently blood donors are assessed for vCJD risk in Europe/France using the following questions:
- In the past three years have you
- Been outside the United States or Canada?
- From 1980 through 1996
- Did you spend time that adds up to three (3) months or more in the United Kingdom? (Review list of countries in the U.K.)
- Were you a member of the U.S. military, a civilian military employee, or a dependent of a member of the U.S. military?
- From 1980 to the present, did you
- Spend time that adds up to five (5) years or more in Europe? (Review list of countries in Europe.)
- Receive a blood transfusion in the United Kingdom or France? (Review list of countries in the U.K.)
Secondary Polycythemia Due to Prescribed Testosterone
Some blood establishments have reported various scenarios that occur in the evaluation of male donors who receive treatment for low testosterone and develop secondary polycythemia. FDA participants provided responses to the following scenarios.
If the collection of blood is requested as a therapeutic phlebotomy solely for secondary polycythemia due to testosterone administration from an otherwise qualified individual, can this blood be used for allogeneic transfusion without special labeling or a variance?
Response: No, special labeling is required by 21 CFR 640.3(d) – Therapeutic bleedings. FDA would review an alternative procedure submitted under 21 CFR 640.120.
If a potential donor presents for regular donation (without a physician's order for therapeutic phlebotomy), but volunteers that he has been advised by his physician that "donating blood regularly would be a good idea" to keep his hematocrit under control, can the donor be regarded as a regular, qualified allogeneic donor?
Response: When the donor provides information that he is undergoing testosterone therapy, FDA believes the response provided to question #1 is appropriate.
MDDS vs. BECS and Relevant Regulatory Requirements
A program titled "Regulation of Blood Establishment Software as a Medical Device" was presented by FDA at a Pharma Conference on Jan. 29, 2013. Subsequent to the presentation, concerns have been raised related to the determination of what is a Medical Device Data System (MDDS) vs. Blood Establishment Computer Software (BECS), especially given the scope of MDDS regulations for a business entity.
The discussion was not fully informative on the topic of MDDS issues as there was no one present at the Liaison committee meeting to represent the Center for Devices and Radiological Health (CDRH). However, it was clarified that if software is connected to, or interacts with the BECS, then CBER will regulate it to the level of a BECS.
A preliminary announcement was made by ABC representatives that they are planning a public workshop later in the year and CDRH as well as CBER will be invited to participate.
"Guidance Agenda: Guidance Documents CBER Is Planning to Publish During CY 2013," Published by FDA in Early 2013.
Draft Guidance for Industry: "Recommendations for Screening, Testing, and Management of Blood Donors and Blood and Blood Components Based on Screening Tests for Syphilis" was made available on Feb. 26, 2013, with comments to the docket due May 28, 2013. AABB, ARC and ABC representatives noted that they would review the draft recommendations that updated the 1991 FDA Memorandum and would submit joint comments to the FDA. (Subsequent to the liaison committee meeting, the
comments were submitted.)
Guidance for Industry:
"Recommendations for Donor Questioning, Deferral, Reentry and Product Management to Reduce the Risk of Transfusion-Transmitted Malaria" – the docket for comments to the draft guidance closed in 2012. A few highlights of the
comments submitted jointly by AABB, ABC and ARC were reviewed to reiterate concerns regarding the complexities that many of the recommendations will introduce to donor history rooms.
Guidance for Industry: "Blood Establishment Computer System Validation in the User's Facility" was published in April. (Subsequent to the Liaison committee meeting AABB's analysis of the guidance was posted on the AABB website.)
Guidance for Industry: "Implementation of Acceptable Abbreviated Donor History Questionnaire and Accompanying Materials for Use in Screening Frequent Donors of Blood and Blood Components," This guidance was published by FDA on May 8. Remarks at the Liaison meeting were brief, in anticipation of the document being published, and focused on the efforts of the DHTF to prepare for the post implementation study of the abbreviated questionnaire.
Draft Guidance for Industry: "Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture" — During the Liaison committee meeting there was no information exchanged on FDA current considerations for this draft guidance. The document subsequently published on May 31.
Peter Marks, MD, PhD, Deputy Center Director, Center for Biologics Evaluation and Research (CBER)
Diane Maloney, JD, Associate Director for Policy, CBER
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
Alan Williams, PhD, Deputy Director for Operations and Regulatory Affairs, OBRR
Jennifer Scharpf, MPH, Associate Director for Policy and Communications, OBRR
Joseph L. Giglio, MS, MT(ASCP)SBB, CSQE(ASQ), CQA, Associate Deputy Director for Quality Assurance, OBRR
Hira L. Nakhasi, PhD, Director, Division of Emerging and Transfusion Transmitted Diseases, OBRR
Salim Haddad, MD, Senior Medical Officer, Division of Hematology (DH), OBRR
Paul 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
Nadine Brock, MT (ASCP), Consumer Safety Officer, DBA
Darcel Bigelow, Consumer Safety Officer, Devices Review Branch, DBA
Jennifer Jones, MBA, Consumer Safety Officer, Blood and Plasma Branch, DBA
Gilliam Conley, Director, Division of Inspections and Surveillance (DIS), Office of Compliance and Biologics Quality (OCBQ), CBER
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
Steve Anderson, PhD, MPP, Deputy Director, Office of Biostatistics and Epidemiology, CBER
Safa Karandish, MT(ASCP), Consumer Safety Officer (CSO), Human Tissue and Reproductive Branch, Division of Human Tissue, OCTGT
Debbie Vause, Consumer Safety Officer, Division of Manufacturers Assistance and Training, Manufacturers Assistance and Technical Training Branch, Office of Communications, Outreach, and Development, CBER
James Berger, Senior Advisory for Blood Policy, Health and Human Services, Office of the Assistant Secretary for Health, Office of HIV/AIDS and Infectious Disease Policy
Susan Stramer, PhD, President, AABB
Miriam Markowitz, MS, incoming Chief Executive Officer, AABB
Graham Sher, MD, PhD, President-Elect, 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
Kathryn Waldman, ARC
Ruth Sylvester, MT(ASCP)SBB, ABC
Ruey Dempsey, AdvaMed
Roger Dodd, PhD, TTD Committee, AABB
Patricia Pisciotto, MD, Standards Program Committee, AABB
Rafael Cassata, MS, RAC, Deputy Director, Cellular Therapy, Regulatory Affairs, AABB
Jacqlyn Riposo, Policy Specialist, AABB