Food and Drug Administration (FDA) staff from the Center for Biologics Evaluation and Research (CBER) met with representatives from the AABB’s FDA Liaison Committee (the Liaison Committee) to discuss topics of mutual concern regarding donor and patient safety. The meeting, held at AABB’s Bethesda, Maryland office, included representatives from AABB, American Red Cross (ARC), America’s Blood Centers (ABC), Armed Services Blood Program, AdvaMed and the American Society for Apheresis (ASFA).
FDA Initiatives and Priorities
CBER’s Director, Peter Marks, MD, PhD, expressed appreciation on behalf of the FDA for the opportunity to exchange information and discuss topics of mutual interest. FDA’s current priorities include:
- Comprehensive regenerative medicine policy framework in
November 2017 to spur innovation, efficient access to potentially transformative products, while ensuring safety & efficacy
- Influenza vaccine improvement initiatives, including actions to assist manufacturers in moving forward.
- Human resources initiatives
Directly Related to the work of AABB:
- Evaluation of Zika virus (ZIKV) testing policy
- Recovered Plasma
- Device reclassifications
- Bacterial Contamination of Platelets - additional public discussion might be considered by CBER
- FDA and Department of Defense program to expedite availability of medical products for the emergency care of military personnel in
- Pathogen Reduction Technology- future steps expected to be a quantum leap to the next level
AABB Initiatives and Priorities
AABB President, Mary Beth Bassett, presented an overview of AABB’s Initiatives and Priorities since the January 2017 Liaison Committee Meeting. Ms. Bassett’s presentation announced AABB’s new CEO, Debra BenAvram, FASAE, CAE, who will join the association in June 2018 and welcomed Nicole Verdun, MD, as the Acting Director of the Office of Blood Research and Review. Ms. Bassett provided updates on the following:
- Donor Health and Safety Committee:
- Recommendations of the March 2017 Association Bulletin #17-02, “Updated Strategies to Limit or Prevent Iron Deficiency in Blood Donors,” to blood collection establishments to take action(s) with all donors or selected subpopulations at risk for iron deficiency
- The AABB Ad Hoc Working Group on Iron Management Among Blood Donors
- The 2017 report to the Board of Directors following an analysis of young donor data from large studies conducted after the 2008 Association Bulletin was issued
- Regulatory Activities:
- Comments to the Docket:
- Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion, submitted 04/17
- Labeling of Red Blood Cell Units with Historical Antigen Typing Results, submitted March 2017
- Use of Serological tests to Reduce the Risk of Transmission of
Trypanosoma cruzi Infection in Whole Blood and Blood Components Intended for Transfusion, submitted February 2017
- Blood Products Advisory Committee (BPAC) Statements and Presentations:
- Joint Statement Before BPAC on August 2016 Zika Guidance Document, December 2017
- Statement on Iron Management in Blood Donors, May 2017
- Statement Before BPAC on “Blood Donor Deferral Policy for Reducing the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Products”, April 2017
- BPAC presentation during the Open Hearing “2017 Platelet Bacterial Risk Control Survey” November 2017
- Circular of Information - recognized as an acceptable extension of container labeling, October 2017
Discussion of Specific Topics
Implementation of Individual Risk Assessment
As expressed in the April 2017 Statement Before BPAC on “Blood Donor Deferral Policy for Reducing the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Products”, the December 2016
Joint Statement on FDA MSM Deferral Policy and the November 2016
Joint Comments to the FDA on "Blood Donor Deferral Policy for Reducing the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Products", our organizations continue to support FDA’s commitment to reevaluate and update blood donor deferral policies as new scientific information becomes available. The AABB’s Donor History Task Force has performed an extensive review of the feasibility of individual risk assessment in anticipation of changes to FDA’s policy.
The Liaison Committee asked what additional information would be useful as FDA considers moving from the existing time-based deferrals for risk behaviors to alternate deferral options, such as the use of individual risk assessments.
The agency continues to review available options to safely update the current deferral policies (see Docket
FDA-2016-N-1502, for comments as solicited by FDA in the
July 2016 Federal Register notice. FDA is actively engaging advocacy groups. FDA noted that policy decisions will be based on the evaluation of data, risk, and experiences specific to the United State, rather than rely upon data from other countries.
Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion, recommendations in the
March 2016 draft guidance.
In addition to the
2017 Platelet Bacterial Risk Control Survey presented at the
November 2017 BPAC meeting, AABB has submitted comments to the docket in
May 2016 and
April 2017, based upon FDA’s stated interest in receiving new information as it becomes available.
The Liaison Committee referenced the opinions offered by
November 2017 BPAC on bacterial risk control strategies using culture methods,
agreeing that data supports the following:
- Five-day storage of apheresis platelets without secondary testing, if platelets are cultured no sooner than 24-36 hours post collection using a test sample volume of at least 3.8% of the collection volume;
- a) Culture of apheresis platelets sampled no sooner than 36-48 hours after collection using a test sample volume of at least 16mL per split without secondary testing to extended dating to day 7 post collection;
b) Repeat culture on Day 4 using a test sample volume of 16 mL per component divided into an aerobic and anaerobic culture tube to extend dating to day 7; and
- Primary testing of platelets using large sample volumes for culture in both anaerobic and aerobic systems.
When asked what additional information would be useful as FDA moves toward finalizing recommendations, the agency noted that this is a remarkably complex topic which will likely require additional public comment. FDA found the presentation of the AABB’s 2017 Platelet Bacterial Risk Survey to be valuable and encouraged AABB to continue to use surveys to engage members and obtain current information and data as necessary.
Strategies to Reduce the Risk of Transfusion-Transmitted Zika Virus
December 2017 Joint Statement Before BPAC on the
August 2016 Zika Guidance Document, our organizations provided an update on the blood community’s experience with ZIKV testing. A review of the
November 2017 BPAC opinions on current strategies to reduce the risk of ZIKV transmission by blood and blood components, showed that the BPAC agreed that:
- At this time, the available scientific data on the course of the ZIKV epidemic does not justify the elimination of all blood safeguards for ZIKV, pending another significant outbreak in the United States or its territories;
- The available scientific data on the course of the ZIKV epidemic does not identify a risk to the blood supply that justifies continuing universal Individual Donor (ID)-Nucleic Acid Testing (NAT);
- a) The available scientific data on the risk of transfusion-transmitted ZIKV does not support the regional use of ID-NAT in at-risk states and territories combined with the use of Mini-Pool (MP)-NAT in all other states;
b) The available scientific data on the risk of transfusion-transmitted ZIKV does support the use of MP-NAT in all states and territories with a trigger for ID-NAT to be defined;
c) There was no BPAC consensus opinion on this question - 3c) Does the available scientific data on the risk of transfusion-transmitted ZIKV support discontinuation of all testing in some states and territories?
- The vote would be deferred for the following agenda item:
Please comment on the following criteria to switch from MP-NAT to ID-NAT within a defined geographic area or a state:
- A defined number of presumptive viremic donors in a 7-day rolling period based on results of MP-NAT in a defined geographic collection area.
- A defined number of cases based on 1) presumptive viremic donors in a 7-day rolling period and 2) a defined threshold of symptomatic clinical cases reported by national surveillance in a defined geographic collection area.
- Selective ID-NAT performed based on the donors’ responses to questions about travel to ZIKV endemic or epidemic countries, sexual contact with partners diagnosed with ZIKV, and/or sexual contact with partners having travel risk for ZIKV would not provide an adequate and appropriate safeguard against transfusion transmission of ZIKV; and
- The option to provide ID-NAT negative blood to selected patients based on clinical indications (e.g., pregnant women, intrauterine transfusions, neonates) and ZIKV-untested blood components for all other transfusion recipients would not provide an adequate and appropriate safeguard against transmission of ZIKV.
The Liaison Committee noted that the next version of Zika Guidance listed on the
2018 CBER Guidance Agenda is labeled as “Draft”; thus, it is anticipated that the cycle needed to issue a draft for comment and to finalize the guidance will require industry to continue with Zika ID-NAT for quite a time.
The Liaison Committee discussed the on-going efforts of the TTD Arbovirus Subgroup, including AABB, the Centers for Disease Control and Prevention, and FDA representatives, to develop a document to define trigger and de-trigger criteria for use with a new MP testing policy in the US. The Liaison Committee discussed the urgent need for recommendations in a final FDA guidance to facilitate a more rapid transition to MP testing. FDA indicated that, at this time, it has no additional concerns to be addressed and appreciates the opportunity to participate on the Arbovirus Subgroup calls. There is currently no timeline for finalizing a ZIKV testing guidance.
HIV Pre-Exposure Prophylaxis (PrEP) in Donors
The Liaison Committee discussed the increasing use of PrEP and its potential impact on testing. Discussions focused on deferral criteria for use of the PrEP medications,
Truvada, and the option to add Truvada to the Medication Deferral List (MDL) if indicated based on interference with testing. FDA was aware of the use of Truvada as prophylaxis and did not have any additional information related to donor eligibility. FDA noted that the current indications for use by individuals at increased risk would result in a donor deferral for those behaviors. FDA did not advocate nor oppose the addition of Truvada to the MDL.
The Liaison Committee reviewed concerns regarding use of this medication in certain populations of donors, and its potential impact on the donor programs. New data is anticipated and will be shared with the FDA and the Transfusion Transmitted Disease Committee when it becomes available.
Citizen Petition to Remove from the Market Hydroxyethyl Starch (HES)
The Liaison Committee reviewed the Citizen Petitioners,
Docket No. 2017-P-0867, requesting the immediate removal from the market of HES based on its risk and the availability of safer alternatives. The
February 2018 joint letter from ABC, ARC, AABB, and ASFA expressed support of the agency’s continuing review and opposed a blanket rescission of the FDA approvals for HES preparations. The comments support the agency’s evaluation of the data and the “niche” indications for use in therapeutic and donor apheresis, umbilical cord blood, bone marrow and peripheral hematopoietic stem cell processing storage and transplantation.
FDA expressed appreciation for the joint letter, indicating that the agency understands and will consider the applications in therapeutic procedures in their decision-making processes.
AABB’s Request for Regulatory Reform
October 2017 letter to the Commissioner, AABB requested FDA consider reevaluating certain regulations and recommendations that are considered outdated, duplicative, overly burdensome and unnecessary to protect the public health. AABB noted that the
2018 CBER Guidance Agenda indicates FDA’s plans to issue draft and final recommendations related to requests in this letter. The Liaison Committee expressed an interest in providing additional information that would be useful as the agency plans to respond to requests for re-evaluation of numerous recommendations and regulations in need of reform.
The Liaison Committee requested FDA consider this and other reasonable examples of unnecessary limitations that result in product loss without enhancing the safety of the blood supply. What options exist to expedite this change?
What additional information would be useful as FDA responds to our request for re-evaluation of numerous recommendations and regulations in need of reform?
FDA described on-going efforts to review outdated, duplicative, and overly burdensome regulations. The agency provided two examples of requests for data necessary to update policy:
- Syphilis Testing:
While FDA recognizes the limitations of serological testing for syphilis, current scientific data remains insufficient to warrant discontinuation of donor screening for antibodies to syphilis. The agency also reported that countries which do not test donors for syphilis have recently reported transfusion-transmitted syphilis from refrigerated blood components.
FDA has sought public comments on the continued need for syphilis testing on several occasions, including in the proposed rule entitled “Requirements for Human Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use,” November 8, 2007, (72 FR 63416)
To date, FDA has not received data that would support eliminating testing, such as the prevalence of syphilis among blood donors, the infectivity of components from seropositive donors and spirochete survival studies in blood components under current manufacturing and storage conditions, including room temperature storage of platelets and granulocytes.
- Statistical Sampling Plans:
The agency is interested in data regarding alternative proposals and options that will represent a least burdensome approach to monthly quality control processes that would still comply within the framework of FDA’s current thinking regarding statistically valid, scientifically sound sampling plans.
Additionally, based on a request from ABC, the Liaison Committee reviewed an additional example of adverse impact of outdated regulations. ABC described the burden of the restrictions on the distribution of products in interstate commerce during the validation period. ABC noted that use of products should be permitted
prior to licensure because unlicensed products undergo 100% quality control testing during the licensure process and would meet all FDA product specifications before distribution.
FDA representatives responded that the agency does not have the authority to permit the distribution of an unlicensed product, including those that undergo validation testing. FDA is bound by Federal Statute which does not permit the distribution of unlicensed products in interstate commerce.
FDA shared recent activities related to Regulatory Reform:
As part of the implementation of
Executive Order 13771 entitled, “Reducing Regulation and Controlling Regulatory Costs,” and
Executive Order 13777 entitled, “Enforcing the Regulatory Reform Agenda,” the FDA sought comments and information from interested parties to help FDA identify existing regulations and related paperwork requirements that could be modified, repealed, or replaced, consistent with the law, to achieve meaningful burden reduction while allowing us to achieve our public health mission and fulfill statutory obligations. CBER received a number of responses to the request for comments including comments from the AABB, ABC, Blood Centers of America, APlus Coalition, a device manufacturer, drug manufacturers, other trade organizations and individuals. Some of the comments urged caution to not reduce protection of the public health. The comments of the blood organizations were to some extent overlapping. In addition to reviewing the comments we have received, FDA is reviewing existing regulations to determine whether any regulations could be modified, repealed or replaced to reduce burden and allow FDA to achieve its public health mission. This is an ongoing effort.
Biologics Effectiveness and Safety (BEST) Sentinel Initiative Industry Day
The agency presented an overview of the
BEST Initiative and the agency’s plans to focus on hemovigilance. The program would expand CBER’s volume of available electronic health records (EHR), as well as post-market surveillance. The agency is looking for innovative methods to enhance EHR evaluation and to automate adverse event reporting. To date, two Requests for Information have been issued and FDA is interested in acquiring future sources.
Peter Marks, MD, PhD, Director, Officer of the Director (OD), Center for Biologics Evaluation and Research (CBER)
Diane Maloney, JD, Associate Director for Policy, OD
Nicole Verdun, MD, Acting Director, Office of Blood Research and Review (OBRR), CBER
Martin Ruta, PhD, JD, Regulatory Counsel, OBRR
Jennifer Scharpf, MPH, Associate Director for Policy and Communications, OBRR
Anne Eder, MD, PhD, Associate Deputy Director for Medical Issues and Policy Development, OBRR
Hira Nakhasi, PhD, Director, Division of Emerging & Transfusion Transmitted Diseases (DETTD), OBRR
Orieji Illoh, MD, Director, Division of Blood Components and Devices (DBCD), OBRR
Salim Haddad, MD, Branch Chief, Clinical Review Staff, DBCD
Emily Storch, MD, Clinical Review Staff, DBCD
Judy Ciaraldi, Consumer Safety Officer (CSO), Blood and Plasma Branch, DBCD
Alan Williams, PhD, Associate Director for Regulatory Affairs, Office of Biostatistics and Epidemiology, CBER
Scott Brubaker, Director, Division of Human Tissues, Office of Tissues and Advanced Therapies, CBER
Stacey Rivette, CSO, Division of Manufacturers Assistance and Training, Office of Communication, Outreach and Development, CBER
FDA Liaison Committee
Mary Beth Bassett, BS, MT(ASCP), President, AABB
Thomas Hopkins, Interim CEO, AABB
Michael Murphy, MD, FRCP, FRCPath, FFPath, President-Elect, AABB
Zbigniew M. Szczepiorkowski, MD, PhD, FCAP, Immediate Past President, AABB
Susan L. Stramer, PhD, Transfusion Transmitted Diseases Committee, AABB
Dave McKenna, MD, Standards Program Committee, AABB
Betsy Jett, Chair, Regulatory Affairs Committee, AABB
Darrell Triulzi, MD, Chair, Accreditation Program Committee, AABB
Louis Katz, MD, America’s Blood Centers
Ruth Sylvester, MT(ASCP)SBB, America’s Blood Centers
Ruey Dempsey, AdvaMed
P. Dayand Borge, MD, PhD, American Red Cross
Kay Crull, MS, MT(ASCP), American Red Cross
Walter Linz, MD, American Society for Apheresis
Capt. Roland Fahie, MS, MT(ASCP)SBB, Armed Services Blood Program
Eduard Nunes, Vice President, Quality Systems, Standards & Accreditation
Steve Kleinman, MD, Senior Medical Advisor
Sharon Carayiannis, MT (ASCP)HP, Director of Regulatory Affairs
Karen Palmer, MT(ASCP), CQA(ASQ), Deputy Director of Regulatory Affairs
Arnold McKinnon, BA, Regulatory Specialist
Christine Bales, BS, MT(ASCP), I, CQA(ASQ), Vice President, Consulting and Global Services, AABB Division of Global Services
Leah Mendelsohn Stone, JD, Director, Public Policy and Advocacy, AABB