PFDA, Community Meets to Discuss Priorities Article

PFDA, Blood Community Representatives Meet to Discuss Priorities

Reviews issues discussed during a recent meeting of FDA and blood community representatives where the two groups presented and reviewed issues important to their operations.

On Oct 04, 2007, Food and Drug Administration (FDA) staff met with AABB’s FDA Liaison Committee in Bethesda, MD, to discuss topics of mutual concern in the areas of donor and patient safety. The committee includes liaisons from AABB, the American Red Cross (ARC), America’s Blood Centers (ABC), Advanced Medical Technology Association (AdvaMed), the College of American Pathologists (CAP) and the U.S. Department of Defense (DoD).

FDA Outlines Current Initiatives and Priorities

A number of rules and guidance documents released in recent months by FDA address critical issues, including the classification of in vitro human immunodeficiency virus (HIV) drug resistance genotype assays, minimum sensitivity standards for hepatitis B surface antigen (HBsAg) assays, informed consent for plasma donors participating in plasmapheresis and immunization programs, revisions to some requirements for blood and blood components, final requirements and recommendations for hepatitis C virus (HCV) Lookback and draft recommendations for computer crossmatches.  FDA also provided an update on pending documents of particular importance to the transfusion medicine community.  The many comments received on the March 2003 proposed rule on safety reporting requirements, in particular to the proposed definition for serious adverse reactions, are being considered within the context of FDA’s efforts to improve the safety of a broad range of human drugs and biological products, including blood and blood components.  The agency continues to work on final issues related to the July 2003 proposed rule on revisions to labeling and storage requirements for blood and blood components, including source plasma. 

FDA acknowledged the importance to the blood community of two draft guidance documents addressing 1) platelets collected by automated methods (September 2003) and 2) pre-storage leukocyte reduction of whole blood and blood components (January 2001), emphasizing that the documents have been the subject of public meeting discussions.  The agency has invested effort into developing a statistical framework for quality control that will provide statistically meaningful data while not being overly burdensome to the reporting facility.  This quality control framework is important to both documents. Regarding the draft guidance for nucleic acid testing (NAT) for HIV-1 and HCV testing, product disposition and donor deferral and reentry (June 2000), FDA noted the complexity of the issues being addressed. Careful evaluation of comments received to the docket has guided development of a comprehensive set of recommendations.  The agency also noted that it is actively working on recommendations for deferrals relating to malaria.  A draft guidance document for malaria was issued June 2000 and a workshop was held July 2006.  Finalizing recommendations for variant Creutzfeldt-Jakob disease (vCJD) risks associated with transfusion in France (August 2006) is also receiving priority attention from the agency.

Other priority considerations for FDA include: donor screening for Chagas’disease, West Nile virus NAT testing, TRALI, the abbreviated donor history questionnaire (DHQ), management of donors with risks for HIV group O, validation of blood establishment computer software (BECS) and deferral issues relevant to recipients of a xenotransplant. An update was provided on the activities of CBER’s Blood Safety Team.  Primary goals of the cross Office team are to improve CBER’s response to blood safety issues, improve the value of safety information  and broaden public and regulated industry access to the information, improve the processing of blood safety information, and enhance external outreach, evaluation and risk communication. Current activities include development of the first annual donor fatality report, as well as assessing the relative significance of blood product deviation events as they are currently reported.  The team is also looking at ways to obtain ‘denominator’ data to extract value from currently collected data and is assessing the value of developing a post donation information workshop.

Biovigilance activities are coordinated within a larger Health and Human Services initiative focused on blood, tissues and organs.  A gap analysis has been completed to identify strengths, weaknesses, opportunities, and threats within the following areas: donor events and outcomes, recipient events and outcomes, product deviations, emerging infectious disease (EID) monitoring, and ability to track denominator data.  Opportunities identified include development of policies to improve donor and patient safety, exploring options to collect denominator data for products and units transfused, developing statistical modeling for blood usage, evaluating the usefulness of some reporting categories currently used, and increasing the use of technologies such as barcoding and radio frequency identification.

Pandemic planning activities are focused on regulatory considerations in the face of pandemics, including potential interventions, triggers and pathways for implementation, and how to maintain flexibility while preserving public safety.  FDA staff and the AABB Interorganizational Task Force on Pandemic Influenza and the Blood Supply met in June to discuss such issues.  One possible intervention under discussion is decreasing the 56-day donation interval, in combination with routine hemoglobin level checks of donors.  The task force agreed that this intervention could have a substantial and positive impact on the blood supply.  (FDA indicated willingness to consider how decreased intervals between donations might also extend to double-red cell collections and suggested that the AABB TF should develop a proposal for consideration by the agency.)  Temporary modifications related to other deferrals, including travel, have been estimated to have only a modest impact on the available inventory. FDA cited the importance of defining trigger mechanisms for turning the intervention(s) on and off.  FDA noted that advance planning and having guidance in place prior to the actual need is the ideal, although pathways utilized in prior emergency situations have included issuance of emergency guidances and use of enforcement discretion.  FDA internal planning includes a CBER level continuity of operations (COOP) plan.  Mathematical modeling of blood supply impact by a pandemic and geographical information systems to identify blood establishments affected during an emergency are being explored and FDA plans to test some of these models with blood establishments in the near future.

The FDA Amendments Act (FDAAA), was signed into law on September 27th.  The Act will be important in setting FDA priorities, including regulations and guidance.  FDAAA reauthorized the Prescription Drug User Fee Act and Medical Device User Fee and Modernization Act, and included a strong focus on pediatrics (including biologics).  Other provisions include the creation of a foundation (Reagan-Udall) through which additional funds could be obtained to modernize product development, accelerate innovation, and enhance product safety:  expansion of the clinical trial registries that reside on the National Institutes of Health web site; provisions intended to enhance drug safety; and food safety.

On an international level FDA interacts with various standards setting organizations.  Among these is the World Health Organization, and as a WHO Collaborating Center for Biological Standardization.  FDA assists in the development of international standards and/or reference materials for areas such as in vitro diagnostic tests including NAT, plasma proteins, and blood group reagents.  FDA is also a member of the newly formed WHO Blood Regulators Network.  Members of the BRN each have comprehensive regulatory schemes with international influence.  Goals of the network include enhanced communication, rapid regulatory response, and a convergence of regulatory thinking, although harmonization per se is not within the scope of Network goals. OBRR participates with the Council of Europe and is involved with updates to the Guide for Preparation, Use and Quality Assurance of Blood Components.  

AABB Current Initiatives and Priorities

AABB continues to be focused on a myriad of issues related to donor and patient safety. Activities related to TRALI, biovigilance, availability of tests for donor screening, implementation of ISBT 128, and bacterial contamination of platelet components were highlighted at the meeting.

AABB Association Bulletin #06-07 Transfusion-Related Acute Lung Injury contains recommendations to further reduce the risk of TRALI in blood and blood component recipients. The association bulletin recommends that blood centers minimize the preparation of high plasma-volume components from certain donors; implementation of appropriate evidence-based hemotherapy practices; and the need for monitoring of the incidence of reported TRALI and TRALI-related mortality. Follow-up to the bulletin includes distribution of a member survey requesting information on progress and barriers to efforts to mitigate the risk of TRALI. 

Active biovigilance programs include the Chagas’ and West Nile virus surveillance systems on the AABB web site.  In addition, the Emerging Infectious Diseases (EID) subgroup of AABB’s Transfusion Transmitted Diseases committee is nearing the completion of a project to compile fact sheets on approximately 65 EID agents – evaluating each for potential transfusion transmission.  AABB has created two biovigilance working groups – the Recipient Biovigilance WG is working with CDC to develop a national hemovigilance system using the model of the National Health Surveillance Network, and the Donor Biovigilance WG will develop definitions for events to be captured in a surveillance system.

Another growing concern is the lack of availability of donor screening test kits and reagents.

  • HTLV - Ortho Clinical Diagnostics is departing from the HTLV screening assay market by mid-2008.  Similarly, Abbott has stated that its bead-based assays for HTLV have a limited remaining life-span.  With the unknown timeline for licensure of PRISM’s platform for HTLV, the blood community is extremely concerned. In addition, there is no licensed supplemental test for HTLV, with no indication that any manufacturer is developing a candidate test. Absence of the OCD screening test leaves uncertainty in the availability of a second licensed screening test for the management of donors with repeatedly reactive HTLV screening results.
  • HBsAg - Abbott has a licensed PRISM core reagent, but the HBsAg and core bead assays have a limited lifespan.  The high degree of non-specificity of licensed anti-HBc assays in use since the late 1980s combined with the lack of an FDA approved supplemental anti-HBc assay has made the lack of an FDA approved re-entry program for anti-HBc a significant issue.
  • HIV - Western Blot tests required to confirm a repeatedly reactive antibody test for HIV are woefully outdated when compared to the sensitivity and specificity of the screening test.
  • Clinical trials for new assays are troubling - manufacturers have developed protocols that fall short of meeting the needs of the community, and the requirement for separate informed consent impedes enrollment in studies that might provide data to support use of better tests.  In an effort to bridge this gap, AABB’s Transfusion Transmitted Diseases committee has met with one trial sponsor to ask them to broaden the scope of their trial and the Bacterial Standards Contamination Task Force is working with another manufacturer to set up additional clinical trials for a recently cleared device.
  • Current issues with Anti-D and the Olympus platform are an example of how a wide variety of tests and reagents used in transfusion medicine can fall prey to availability issues. 

AABB facilities are working towards implementation of ISBT 128 in May, 2008, with several blood systems having already implemented.

The proposed 25th edition of Standards for Blood Bank and Transfusion Services contains a requirement for diversion pouches, in addition to other steps that facilities have undertaken to limit and detect bacterial contamination in blood products.

Discussion of Agenda Items

Blood establishments are making changes in their plasma inventories in an effort to mitigate the risk of TRALI in transfusion recipients.  At present, inventory management is the only viable option for pursuing this strategy, yet regulatory licensing constraints do not currently provide the flexibility that blood establishments believe they need for the successful implementation of these strategies, given the increasing trend toward automated blood collections.  With increased dependence on automated collection platforms to meet the ever-present demand for blood products, blood centers seek the same flexibility in managing plasma inventories for transfusion and manufacturing that they have with manual collections.  At the recent FDA workshop on licensure for apheresis products, FDA indicated that 40% of the applications submitted for review are for apheresis products.  However, FDA regulations still do not allow ‘plasma for transfusion’ products collected by apheresis technology to be converted to ‘plasma for manufacture’ (prior to expiration) if not needed for transfusion; nor do they allow a product equivalent to ‘recovered plasma’ when donors are collected by apheresis technology.  The AABB Interorganizational Plasma Task Force has submitted a proposal to FDA for licensure of plasma for further manufacture (collected via manual or automated methods) and requested that changes to the regulations be initiated to make this a reality.

FDA explained the process the agency is considering to respond to this need for a regulatory pathway for the one-way conversion of apheresis FFP (prior to expiration) to a licensed concurrently collected plasma product for further manufacture.  FDA is considering the standards for the new plasma product and is working on a framework for the necessary regulatory revisions.  While the new regulations are under development, FDA could consider the use of variances to existing regulations, providing an interim regulatory pathway for conversion of apheresis FFP to concurrent plasma for further manufacture.  Any such pathway would be made publicly available through issuance of a guidance document.  Another option, currently available to all facilities, is to obtain a source plasma license (infrequent plasmapheresis program).

Chagas ’ disease
When asked to comment on current considerations for universal vs selective testing for Chagas’disease, FDA reiterated its position that, prior to considering selective testing, several years of universal testing is necessary in order to determine prevalence of the disease in the donor population. The effectiveness of any selective testing strategies would need to be validated against universal testing. With regard to a question about confirmatory testing, it was noted that there is no approved supplemental test for use in donor screening and that submissions for a candidate test would be welcomed. Currently, research or diagnostic testing is used for follow-up of repeatedly reactive test results for purposes of donor counseling.  FDA expressed its appreciation for the Chagas’ surveillance information that is available on the AABB web site.

FDA stated that its current considerations relating to recommendations for WNV testing of blood donors are consistent with its views presented at the April Blood Products Advisory Committee meeting, including donor testing and counseling and triggers to be used to switch from mini-pool testing to individual donation testing and back again.  FDA considers development of the guidance a priority.  Participants at the meeting noted that implementation of the AABB Association Bulletin #07-02, West Nile Virus – Recommendations for Triggering Individual Donation Nucleic Acid Testing and Developing a Communication Plan,appears to have been successful.

Circular of Information
The proposed Circular of Information for the Use of Human Blood and Blood Components was submitted to FDA in August 2007 for review and approval.  This revision would replace the one approved in 2002 and is currently in use.  FDA was asked to provide an update on the review.  Subject-matter experts within the agency are currently reviewing relevant sections.  Initial review remarks should be available in the very near future.  Licensure of a second WNV test occurred after the Circular was submitted for review; appropriate WNV language will now be included in the document.

Donor History Questionnaire, full-length
Version 1.1 of the full-length Donor History Questionnaire materials has been officially recognized by FDA. Version 1.2, to include deferral for transfusion in France, was submitted, April 2007, to the docket for the Draft Guidance for Industry: Amendment (Donor Deferral for Transfusion in France Since 1980) to "Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products" – August 2006.  (The guidance document has not been made final.) The latest version of the DHQ (v 1.3) containing additional minor changes to the Medication List, Flowcharts and Donor Education Materials was submitted to FDA in July 2007 for review.  FDA was asked to provide an update on the status of the review and recognition of v 1.3 via guidance document. FDA stated that the review has been completed and comments were shared with the AABB Donor History Task Force on Oct 3.  Recognition of v1.3 is tied to the revised guidance on vCJD that will add the deferral for transfusion in France. It is anticipated once v1.3 is recognized establishments that implement v1.3 without modification will be able report the change to FDA in their annual report (similar to implementation of v1.1).  Implementation of the newer version before that time will require a licensed facility to file a submission with FDA.  Committee members asked if there is a possibility for other pathways for implementation, particularly when a newer version does not introduce additional risk to the donor qualification process, or when there is a delay in issuance of the relevant guidance document. FDA indicated its willingness to explore additional options.

Donor History Questionnaire, abbreviated
Version 1.3 of the abbreviated DHQ was submitted to FDA for review in July 2007.  This version of the aDHQ contained minor changes to the Medication List, Flowcharts and Donor Education Materials.  The aDHQ materials also contained a proposed implementation plan.  FDA stated that it had completed the review of all materials including the implementation plan.  FDA provided final review comments on the questionnaire materials to the task force on Oct 3.  Some scientific and feasibility concerns with the post-implementation plan exist and will be discussed with the task force.  FDA stated that they will officially recognize the aDHQ in a guidance document. 

BECS WorkshopThe Alliance of Blood Operators (ABO), representing members in North America and Europe, has asked FDA to consider different regulatory strategies to BECS.  In Europe blood establishment computer software is not regulated and vendors with products currently used throughout the European Union do not want the burden of submitting a 510(k) in the US.  Within the US there are few new vendors entering the market, and existing vendors are slow to update their software. ABC has offered to host the workshop. FDA is considering the workshop and noted that reviews of software submitted via the 510(k) process often identify problems with the software that are then corrected prior to clearance. This concern is applicable to BECS submissions from small and large vendors. FDA has requested that ABO undertake several initiatives and address several issues prior to the workshop.

  • Ensure representation of the views of smaller facilities through a representative survey of smaller centers and transfusion services regarding capabilities and access to information technology updates.
  • Provide an opportunity for an FDA review of the history of the regulation of blood establishment computer software, to include software design problems encountered during FDA reviews.

Participants AABBD.
Michael Strong, PhD, MT(ASCP), BCLD(ABB),  President, AABB
Christopher D. Hillyer, MD, Past President, AABB
J. Daniel Connor, MM, President-electKaren
Shoos Lipton, JD, Chief Executive Officer, AABB
Thomas Angle, MT(ASCP)SBB, Vice President, Colonial Division, ARC Blood ServicesCol.
Steven Beardsley, MS, MT(ASCP)SBB, DoD
Roger Dodd, PhD, AABB Transfusion-Transmitted Diseases Committee
Harvey Klein, MD, AABB Standards Program UnitMary O’Neill, MD, American Red Cross
Ruth Sylvester, MS, MT(ASCP)SBB, Director, Regulatory Services, ABC
Allene Carr-Greer, MT(ASCP)SBB, Director, Regulatory Affairs, AABB
Joseph L. Giglio, MS, MT(ASCP)SBB, CSQE(ASQ), CQA, Deputy Director, Regulatory Affairs, AABB
Barbee Whitaker, PhD, Director, Special Projects, AABB
Caryl Auslander, BA, Public Policy Specialist, AABB
Ashley Smith, BS, Science Writer, AABB

Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Jonathan Goldsmith, MD, Deputy Director, OBRR, CBER
Martin Ruta, JD, Regulatory Counsel, OBRR, CBER
Alan Williams, PhD, Associate Director for Regulatory Affairs, OBRR, CBER
Elizabeth Callaghan, MS, SBB(ASCP), Acting Director, Division of Blood Applications (DBA), OBRR, CBER
Jennifer Scharpf, MPH, Associate Director for Policy and Communications and Chief, Policy and Publications Staff, OBRR, CBER
Hira Nakhasi, PhD, Director, Division of Emerging and Transfusion-Transmitted Diseases (DETTD), OBRR, CBER
Paul Mied, Ph.D. Deputy Director, DETTD,OBRR, CBER  
Indira Hewlett, PhD, Laboratory of Molecular Virology, DETTD,OBRR, CBER
Mark Weinstein, PhD, Associate Deputy Director, OBRR, CBER
Robert Duncan, PhD, Laboratory of Bacterial, Parasitic, and Unconventional Agents,  DETTD, OBRR, CBER
Judy Ciaraldi, BS, MT(ASCP)SBB, CQA(ASQ), Consumer Safety Officer, DBA, OBRR, CBER
Gilliam Conley, MS, Director, Division of Inspections and Surveillance, Office of Compliance and Biologics Quality, CBER
Leslie Holness, MD, Blood and Plasma Branch,  OBRR, CBER
Joan Blair, Senior Advisor for International Affairs, Immediate Office of the Director (IOD), CBER
Jean Hu-Primmer, MS, Senior Scientist for Emerging and Pandemic Threat Preparedness, IOD, CBERLCDR
George Gentile, Emergency Operations Manager, CBER
Seamus O’Boyle, Public Affairs Specialist, Office of Communication, Training and Manufacturers Assistance (OCTMA)
Lanessa Hill, Public Affairs Specialist, Division of Communication and Consumer Affairs, OCTMA, CBER

Scott Brubaker, CTBS, Chief Policy Officer, AATB

Reprinted with permission of AABB, Bethesda, Md., Copyright (year) AABB. All rights reserved. To receive your own copy of AABB News each month and read articles similar to this one, visit and click on “Join AABB.”


FDA Link

  • Guidance for Industry: Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion

Additional Article

  • ?Potential Risk of Variant Creutzfeldt-Jakob Disease (vCJD) From Plasma-Derived Products?
    Full Article