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, America's Blood Centers, the American Red Cross, the American Society for Apheresis, the Armed Services Blood Program and the College of American Pathologists.
FDA Initiatives and Priorities
Peter Marks, MD, PhD, expressed appreciation on behalf of the FDA for the opportunity to exchange information and discuss issues facing the blood community. Jay Epstein, MD, discussed the CBER move to the FDA’s White Oak Facility and the ensuing Office of Blood Research and Review (OBRR) reorganization. Other priorities include hiring staff – some of whom will be for positions that were not filled during sequestration – and sustaining research funding including accessing foundations such as the Bill and Melinda Gates Foundation.
Reorganization changes include restructuring the Division of Hematology into the Division of Hematology Research and Review (DHRR) – which will oversee the Laboratories of Plasma Derivatives, Cellular Hematology, Biochemistry and Vascular Biology, and Hemostasis – and the Division of Hematology Clinical Review (DHCR), which will oversee the Clinical Pharmacology Group, the Pharmacology/Toxicology Group, the Clinical Review Branch, and the Hematology Product Review Branch. DHRR will be headed by Basil Golding, MD, and DHCR by Paul Mintz, MD. The Division of Blood Applications has been renamed the Division of Blood Components and Devices (DBCD) to more appropriately reflect the work of the division. Richard Davey, MD, will continue to direct the division. The Regulatory Project Management (RPM) Branch, formerly under the Division of Blood Applications, will report to the RPM Staff in OBRR. In addition, the move to the White Oak facility allows OBRR to centralize formerly geographically diverse administrative staff and functions under the Supervisory Program Manager.
Blood safety initiatives reviewed by FDA included donor deferral policies, emerging infection diseases (EID), products and technologies on the market, and new technologies. The ongoing studies related to MSM (men who have sex with men) blood donor deferral policy are on target and are expected to complete by the end of the year; at which point the FDA plans to address the policy in a timely manner. The FDA noted the complexities involved in developing policy for emerging infection diseases (Dengue and Chikungunya viruses,
Babesia, and Middle Eastern Respiratory Syndrome – Coronavirus) due to seasonality and varying severity of disease outbreaks; nonetheless these remain priority issues. Guidance on the use of cleared/approved tests to detect bacterial contamination of platelets was acknowledged as a priority. The FDA drew attention to the January 2014 workshop, “Strategies to Address Hemolytic Complications of Immune Globulin Infusions,” where state of the science and cutting edge technology were leveraged to address a pertinent transfusion medicine issue. Studies assessing the safety of older, stored red blood cells have raised concerns. Meeting participants agreed the effects of the results of such studies on inventory management and blood banking in general is not fully understood; prospective studies of stored blood would be informative. Under the review of new technologies, it was noted that novel clotting factors have increased half-life; multiplex assays with the potential to test for hundreds or thousands or analytes/agents are generating interesting discussions around development of clinical trials; and pathogen reduction technologies remain a priority.
The FDA addressed guidance topics that they plan to address in 2014, with the caveat that the lists, as published, may be updated as topics shift in urgency. CBER’s current
guidance agenda includes bacterial detection, syphilis and regulatory applications.
CBER Regulatory Submissions Address:
Food and Drug Administration
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OBRR Main Phone Line: +1.240.402.8360
AABB Initiatives and Priorities
Lynne Uhl, MD, AABB President-Elect, provided an overview of association initiatives and strategic goals, published in the
AABB 2013 Annual Report. She updated the meeting attendees on activities to mitigate transfusion-related acute lung injury (TRALI). The requirement for TRALI risk reduction in plasma components became effective April 1, 2014, as Standard 184.108.40.206 in the 29th edition of Standards for Blood Banks and Transfusion Services. Additionally, Association Bulletin #14-02 “TRALI Risk Mitigation for Plasma and Whole Blood for Allogeneic Transfusion” provides recommendations on methods to meet the standard. AABB also has worked with the Centers for Medicare & Medicaid Services (CMS) to address the classification of human leukocyte antigen (HLA) testing. CMS determined that HLA antibody screening for the purpose of TRALI risk mitigation performed in order to qualify blood donors can be classified as either histocompatibility or general immunology.
Patient Blood Management (PBM) continues to be a strategic initiative to optimize the care of patients who may require a transfusion. AABB has new and diverse offerings in their standards, education, advocacy, publications and consulting departments. Uhl described AABB’s new partnerships with the American Hospital Association, the American Board of Internal Medicine and other professional societies. Such collaboration helps with the association’s mission to align transfusion medicine with broader changes in health care.
Highlights of AABB international activities include work in Latin America. A 2011 agreement between AABB and the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH) developed a joint accreditation program for blood banks and transfusion services, and cellular therapy services. The accreditation program is now active; both public and private facilities are candidates for accreditation. Additionally, the Grupo Cooperativo De Medicina Transfusional (GCIAMT) is working with AABB to identify collaborative efforts such as accreditation programs and educational sessions at the AABB annual meeting.
Collaborations with other health care associations remain a major priority of the association. Current examples include partnership with the American Hospital Association to support the initiative on Appropriate Use of Medical Resources and support of phase two development associated with the Alliance for Blood Operator’s Risk-Based Decision Making Project. In addition, AABB appointed delegates to participate in each of the four working groups for the National Heart, Lung, and Blood Institute’s State of the Science effort to establish a research agenda.
An update on hemovigilance priorities included expanding the AABB Center for Patient Safety (CPS). The center has more than 60 hospital participants to date and is growing. Increasing the quality of data gathered and enhancing offerings to participants, such as reports utilization, remain a focus of the center. Discussion surrounding this topic clarified the difference between the “one way” input of data into the Center for Disease Control and Prevention’s National Healthcare Safety Network (NHSN) and the availability of a “two way” communication that is enabled when participants elect to also participate in the AABB CPS. CPS member hospital hemovigilance data is reported to the NHSN and shared with the CPS. AABB CPS subsequently downloads member hospital data into the CPS database. If information is lacking, CPS can work with their reporting member hospital to complete and enhance the reported data. The ultimate goal of the CPS is to improve patient safety through patient safety activities. In order to accomplish this, the CPS must ensure quality data flows into the NHSN for analysis downstream. AABB hopes to continue its role with the National Blood Collection and Utilization Survey when HHS releases the survey contract. The survey is administered on a biennial basis – but there is a concern that today’s mature markets should be assessed more frequently.
Managing plasma for further manufacture remains a priority for AABB. Donations from whole blood donors are collected utilizing manual techniques and/or automated collection technology. The dual use of collection protocols responds to a shrinking donor population that is not always available at the venue, or on a schedule, that is convenient for the blood establishment. Blood collectors maximize the collection of each eligible donor. Donors expect it and collectors need flexibility in managing their inventory especially while looking at options for mitigating TRALI risks. The lack of a regulatory pathway to allow plasma — collected infrequently by apheresis from whole blood donors — to be labeled for further manufacture at any time during storage is impeding movement toward maximizing inventory. The requirement to wait for the frozen product collected by apheresis technology to expire before sending it for further manufacture is not practical. Fractionators do not want the product and management of the sample for hepatitis A virus and human parvovirus B19 testing is too complicated.
Update from AABB Transfusion Transmitted Diseases Committee on Chikungunya virus
A review of recent data/knowledge of Chikungunya virus (CHIKV) was provided as background to the current activities of the Transfusion Transmitted Diseases (TTD) committee. CHIKV is an alphavirus — not a flavivirus such as West Nile virus (WNV) and dengue virus (DENV). The
Aedes aegypti mosquito is the vector for the Asian strain of CHIKV and also for DENV in the Caribbean region. A.
aegypti is present across the southeastern United States. Approximately 20% of CHIKV cases are asymptomatic compared to 50-80% for DENV and greater than 80% with WNV.
Until December 2013, CHIKV was confined to Asia, Africa and Europe with explosive outbreaks occurring 2005-2007.
A. albopictus was the vector for the East/Central/South/Africa (ECSA) strain involved in these earlier outbreaks. More than 300,000 cases occurred in Reunion and islands of the Indian Ocean with greater than 40% of the population infected; approximately 250 cases occurred in northern Italy. The countries involved implemented available interventions:
- Suspended blood collection in areas with “risk” above a certain threshold (e.g., greater than that of hepatitis B virus transfusion risk)
- Implemented platelet pathogen inactivation
- CHIKV nucleic acid testing
- Donor deferral if lived in or traveled to an epidemic area
There was no transfusion transmission of CHIKV documented.
CHIKV (Asian strain,
A. aegypti vector) emerged in St. Martin (two autochthonous cases identified on Dec. 2, 2013) and rapidly spread to the islands of the Caribbean (to date it is not reported in the U.S. Virgin Islands or Puerto Rico) and northern South America. Data published in ProMed as of May 9 include more than 45,000 suspected cases of which 4161 are lab confirmed. Autochthonous transmission has not been reported in North America.
The TTD Committee monitors DENV and CHIKV. Fact sheets have been created and updated for both agents and are publicly available on the
AABB web site. Other recent activities related to CHIKV include:
- Monthly calls with FDA representatives and a subgroup of the committee to keep abreast of concerns and activity.
- Committee subgroup is developing an enhanced postdonation information sheet designed to elicit call-backs from donors who traveled prior to donation and develop symptoms after their donation.
- Need to understand donor travel and temporal donation patterns following travel, allowing an opportunity to model impacts of short-term deferral for travel to affected areas; design of a survey is under discussion.
- Engage vendors in developing nucleic acid assays (prototypes as a minimum) to detect CHIKV using available test platforms.
Discussion of Specific Topics
Managing components collected during therapeutic phlebotomy from men using testosterone
Hematocrit is monitored in patients receiving testosterone treatment due to the known side effect of increased red blood cell count. A hematocrit of greater than 50 percent prompts either a reduction of the dose administered or cessation of treatment. There does not appear to be guidelines for the use of therapeutic phlebotomy, however prescriptions are written for the procedure.
A variance was recently listed under Exceptions and Alternative Procedures Approved Under 21 CFR 640.120 to “Allow individuals on prescription testosterone to donate blood and blood components more frequently than every eight weeks without examination or certification of health by physician at time of donation, provided the donor is referred with a prescription by a physician containing instructions regarding frequency of phlebotomy and hematocrit/hemoglobin limits and to be exempt from placing special labeling about the donor’s disorder on the blood components. This approval is granted under the condition that only the Red Blood Cells collected from these individuals may be distributed; the plasma and platelet components from these individuals should not be distributed for transfusion.”
Following publication of the variance, the RBCs from a donor who undergoes a therapeutic phlebotomy can be distributed if all other allogeneic criteria are met, but the plasma from these male donors must be discarded and platelets cannot be made. During the discussion it was pointed out that other male donors using the prescribed medications present to donate without the prescription and it may or may not be known to the blood collector that the medication is being used. In this case, all blood components are made and used. If the donor responds yes to the donor history questionnaire (DHQ) concerning vaccines or other shots within eight weeks, the use of testosterone is not a reason to exclude the donor from donating blood. Donors using testosterone gels or patches would not respond yes to any questions on the DHQ. Allogeneic donors using prescribed testosterone could have levels comparable to those presenting for therapeutic phlebotomy. Treatment guidelines recommend testosterone levels in the mid-normal range with dose adjustments as necessary to prevent risk of thrombotic complications.
Participants at the meeting engaged in a discussion to understand 1) the evidence relied upon by the agency to exclude accepting Plasma/Platelets from donors taking prescribed testosterone who present with a request for therapeutic phlebotomy and 2) if studies were performed, what level of plasma testosterone would be considered acceptable to release plasma collected during therapeutic phlebotomy.
The FDA representatives indicated that a paucity of data on plasma testosterone levels in donors who develop polycythemia plus the minimal information known about the injectable product led to the approach taken in the published variance. With one approved injectable formulation, transient spikes in testosterone levels above the upper limit of the reference range occurred in some (7%) men. FDA representatives said they would welcome any proposed study and suggested that proposals of a modest size and complexity could provide the necessary information regarding the levels of testosterone from these therapeutic donors. Dilution factors that occur at transfusion allay safety concerns, but neonates remain a population that may be at risk, especially with the practice of using dedicated RBC units for multiple transfusions.
Suggestions regarding a study on safety of plasma and platelet transfusions include:
- Sample size is negotiable, but including three hundred donors on testosterone who present for therapeutic phlebotomy and an appropriate control group (e.g., random donors and donors who use the gels and patches) could allow appropriate confidence limits.
- History from the therapeutic donor is important; which product is used, when was last dose.
The agency does not know what the acceptable end result is, but would like to discuss the results of a study such as the one outlined above.
Optional measures employing additional bacterial detection testing that may allow extension of platelet shelf life to 7 days
In recent years there has been much activity in the area of recognition of the importance of bacterial contamination of platelet components, measures to limit and detect the contamination, and review of data to gauge the effectiveness of such measures. Members of the transfusion medicine community and the FDA have engaged in many discussions at workshops, Blood Products Advisory Committee Meetings (BPAC), and previous FDA Liaison Committee meetings in an effort to move toward safer components. Previous attempts to add testing steps later in the life of the component have not progressed due to tremendous operational and logistical issues within the confines of current regulations and/or cleared products. FDA representatives have publicly stated the agency is drafting a guidance document related to bacterial contamination of platelet products; the timeline for issuance of a draft is unknown and publication of the final guidance is further into the future.
During this interim, blood establishments continue to look for a path forward and the AABB Bacterial Contamination Work Group (BCWG) is monitoring recent activity related to additional bacterial testing of stored platelets and extension of platelet shelf life to a 7 day storage interval. Dartmouth-Hitchcock Medical Center has shared information related to testing of platelets later in the storage period by rapid immunoassay and associated extension of platelet storage to 7 days. Blood Systems, Inc. has discussed the utility of proportionate sampling volume as well as a delayed sampling algorithm to achieve 7-day shelf life. The BCWG sees this as an opportunity to improve the safety of platelet transfusion by allowing use of bacterial detection methods beyond the standard early release culture. This responds to a call for action on storage days 4 and 5 to address bacterial contamination safety concerns as recommended in the September 2012 FDA BPAC meeting. There also is a broader impact of 7 day storage resulting in decreased outdating that will improve product availability that is of vital importance to AABB.
FDA representatives also expressed their concern for the need to have adequate inventories of matched products over the weekend and to decrease outdates when inventories do not match the need for product. The issue of extension of shelf life to 7 days is currently under consideration.
The ensuing discussion highlighted the need for blood establishments to have flexibility to employ additional bacterial detection testing that may allow extension of platelet shelf life to 7 days. Transfusion services and blood collectors interact in a myriad of ways to obtain and provide components for transfusion; it is not feasible for a single solution to be administered across all establishments. The need for a regulatory pathway to allow individualized solutions is important. Additional consideration also is required regarding devices related to the potential production of platelets with a 7 day shelf life. It may include how to use all of the currently available cleared assays with the collections sets that were originally cleared for 7 day storage along with the PASSPORT study. FDA participants stated that the draft guidance continues to be high priority for them and they continue to focus on the concerns noted.
Licensure of Apheresis Cryoprecipitated AHF
The elements listed below have been shared with the Liaison Committee by a facility amending its biologics license application (BLA) for the purpose of obtaining a license for Apheresis Cryoprecipitated Antihemophilic Factor. The facility reports that the process has gone well and they attribute it to early and frequent communication with their FDA Consumer Safety Officer. FDA participants at the Liaison Committee commented that the manufacturing variables should be close to what is used in the establishment’s manually collected processes; the automated collection should be in a “closed system.” The elements are provided here to assist other establishments that may be interested in the licensure process.
APHERESIS CRYOPRECIPITATED AHF
Prior Approval Supplement
- Source component – FFP collected by closed system apheresis
- Final product volumes as similar as possible to Cryoprecipitated AHF
- ACDA anticoagulant
- Submit only SOPs that would be different from current Cryo procedures; otherwise reference prior submission tracking number (STN) for Cryoprecipitated AHF licensure
- Cover letter – indicate that donor eligibility criteria does not differ from donors for Cryoprecipitated AHF
- Use existing variance for infrequent Plasma Pheresis
- Approved validation plan, data, and executive summary
- QC (2 consecutive months) – 4 single products or one pool of at least 4 products
- Failed QC is a failure in either Factor VIII or Fibrinogen (both must pass)
Proposed Rules – a discussion of the process for ensuring content is current, and the final regulation is published with its intended impact when significant time elapses after the comment periods close.
The two documents listed below were cited as examples of proposed regulations about which blood establishments are concerned and wonder how the final regulation could take into account the changes in industry that have occurred in the years that have elapsed since the comment period closed. With regard to the safety rule, the comment period closed more than 10 years ago and the postmarket part of the rule still has not been published. The 2007 proposal was so extensive a six-month extension was granted for comments to be gathered and the period for comment submission closed six years ago.
Safety Reporting Requirements for Human Drug and Biological Products proposed rule published in 2003; comments from industry were submitted in late 2003.
Requirements for Human Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use published in 2007; comments from industry were submitted in mid-2008 following an extension of the original comment period.
Members of the committee commented on the possibility of rules being republished as proposed regulations — when a significant amount of time has passed — to give the public an opportunity to comment on the contents. FDA noted that as a general matter the regulations are published as a final rule as soon as possible after the comment period closes. However, on occasion complex proposals, coupled with significant comments, can require the agency to seek additional information. During the interim when comments are being evaluated and additional information is needed, FDA staff have multiple ways to remain current on the topic: public discussions, liaison roles, literature searches and actively seeking public input. All of these inputs are tracked in the public record as rulemaking progresses from a proposal to the final product. It also was noted that the agency is required to publish a final rule that is relevant to the proposed intent; changes that appear in a final rule should be logical outgrowths of what has occurred in the interim. Concurrent guidance documents clarify regulations and can be especially helpful when the rule is published under the oversight of multiple centers (Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research).
Food and Drug Administration
Peter Marks, MD, PhD, Deputy Director, Office of the Center Director (OD), Center for Biologics Evaluation and Research (CBER)
Diane Maloney, JD, Associate Director for Policy, OD
Johnathan McKnight, JD, Regulations and Policy Staff, OD
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Ginette Y. Michaud, MD, Deputy Director, OBRR
Martin Ruta, PhD, JD, Regulatory Counsel, OBRR
Hira L. Nakhasi, PhD, Director, Division of Emerging and Transfusion Transmitted Diseases, OBRR
Paul D. Mintz, MD, Director, Division of Hematology Clinical Review, OBRR
Salim Haddad, MD, Senior Medical Officer, Division of Hematology Research and Review, OBRR
Richard Davey, Director, Division of Blood Components and Devices (DBCD), OBRR
Orieji Illoh, MD, Deputy Director, DBCD
Barbara Peoples, Consumer Safety Officer (CSO), OBRR
Hoi May Chan, CSO, OBRR
Gilliam Conley, Director, Division of Inspections and Surveillance (DIS), Office of Compliance and Biologics Quality (OCBQ), CBER
Pauline Cottrell, CSO, Manufacturers Assistance and Technical Training Branch (MATTB), Office of Communications, Outreach and Development, CBER
Lynne Uhl, MD, President-Elect, AABB
Susan Stramer, PhD, Immediate Past-President, AABB
Miriam A. Markowitz, CEO, AABB
M. Allene Carr-Greer, MT(ASCP)SBB, Director, Regulatory Affairs, AABB
Anne F. Eder, MD, PhD, College of American Pathologists
Richard Benjamin, MD, American Red Cross
Kathryn Waldman, BA, American Red Cross
Ruth Sylvester, MT(ASCP)SBB, America’s Blood Centers
Cdr. Roland Fahie, MS, MT(ASCP)SBB, Armed Services Blood Program
Ruey Dempsey, Advanced Medical Technology Association
Walter Linz, MD, American Society for Apheresis
Eva Quinley, MT(ASCP)SBB, MS, CQA(ASQ), Accreditation Program Committee, AABB
Susan D. Roseff, MD, Standards Program Committee, AABB
Elizabeth Barrows, MS, PMP, RAC, Deputy Director, Regulatory Affairs, AABB
Jean Otter, MT(ASCP)SBB, Division Director of Programs, AABB
Eduardo Nunes, MPP, Senior Director of Policy, Standards, and Global Development, AABB
Jacqlyn Riposo, Policy Specialist, AABB