Food and Drug Administration (FDA) 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. The Liaison Committee includes representatives from AABB, the Advanced Medical Technology Association, the American Red Cross, the American Society for Apheresis, America's Blood Centers, the Armed Services Blood Program and the College of American Pathologists.
Peter Marks, MD, PhD, noted the value of the dialogue between the FDA and the transfusion medicine community, and expressed appreciation on behalf of the FDA for the opportunity provided by the AABB Liaison Committee. Celia Witten PhD, MD spoke briefly on the 21st Century Cures Act, noting related CBER activities on regenerative advanced therapies and a forthcoming report on vaccines. Dr. Marks mentioned the federal hiring freeze and executive orders issued by the new Administration. With respect to the impact on Rules and Guidances issued by CBER, Dr. Marks stated that they have requested an interpretation, to assist with understanding of what will affect Rules vs Guidances, and will communicate information publicly as it is available.
Jay Epstein, MD, announced new FDA appointments within the Office of Blood Research and Review (OBRR): Nicole Verdun, MD, Deputy Director, Orieji Illoh, MD, Director, Division of Blood Components and Devices (DBCD), Wendy Paul, MD, Deputy Director, DBCD, Anne Eder, MD, PhD, Associate Deputy Director, Division of Emerging and Transfusion-Transmitted Diseases, and others who are new Consumer Safety Officers.
Dr. Epstein discussed the realignment of some staff to Office of Tissues and Advanced Therapies intended to permit OBRR to more clearly focus on transfusion with a programmatic approach. Specifically mentioned was the fact that the plasma derivatives program relocated while transfusable plasma products, plasma expanders and hemoglobin-based oxygen carriers remained with OBRR. OBRR remains focused on other priorities as well, which include:
AABB President, Zbigniew M. Szczepiorkowski, MD, PhD, presented an overview of updates to AABB’s Mission, Vision and Core Values. Dr. Szczepiorkowski’s presentation also provided updates on the priority initiatives of AABB’s Donor Health and Safety Committee (DHSC) to protect donors. Dr. Szczepiorkowski’s presentation focused attention on the critical role of risk-based decision making (RBDM). In addition, he spoke of AABB’s commitment to utilizing RBDM to pursue a new paradigm intended to optimize the safety of the blood supply, allocate resources based on the magnitude of the risk, and consider social, economic, and ethical factors in an evidence based decision making process involving all stakeholders.
Management of iron deficiency in all blood donors and adverse reactions and injuries following donation from teenage donors as discussed at the
November 2016 BPAC meeting
The Liaison Committee referenced the findings presented at the BPAC meeting which identified iron deficiency as a potential concern for all donors, most notably in frequent donors, premenopausal female donors, and teenage donors. Scientific evidence was presented in support of ferritin testing as a safety measure to monitor iron stores. Similarly, data supported the role of iron supplementation and donor education as mitigation strategies.
Other presentations focused specifically on the growing number of teenage donors, and the disproportionate rate of adverse reactions, as well as iron deficiency in this population of donors. Analysis of the new data from the CHILL study (Comparison of the History of Donation and Iron LeveLs in Teen Blood Donors) is ongoing but preliminary data show 1) the greater prevalence of iron deficiency and lower average ferritin level in first-time teen donors as compared to adults, 2) modeling to assess the impact of blood donation in teen donors differs from that used to study adults, and 3) mitigation measures should be implemented and further studies are needed to evaluate the impact of blood donation on teens. The BPAC agreed that 1) teenage donors are susceptible to developing iron deficiency, 2) adverse reactions and injuries in teenage blood donors is a notable enough concern to require intervention, and 3) education material and parental consent are important issues, but did not support a move toward interventions that restrict the donor pool to individuals aged 18 years and over.
The Liaison Committee briefly reviewed development of AABB recommendations and Standards on these issues as well as the positions shared by others in industry at the recent BPAC meeting.
Regarding development of AABB recommendations/standards on management of iron deficiency:
- Association Bulletin #12-03 was issued in 2012 with several recommendations for action to monitor, limit, or prevent iron deficiency in blood donors and included a donor education sheet designed to assist with movement to iron supplementation.
- Standards evolved with a requirement that “Donors are given educational materials regarding the risks of post donation iron deficiency.”
- The DHSC has submitted its draft of updated recommendations on the subject and will recommend that Blood Banks and Transfusion Services Standards Program Committee consider the recommendations contained in the bulletin.
Industry speakers at the November 2016 BPAC noted:
- Understanding of the issues continues to unfold as data from recent studies yields additional information.
- Growing support for strategies incorporating a combination of ferritin testing, extended donation intervals or annual maximum donations, iron supplementation and donor education material to protect donor health and safety as part of an industry-driven initiative.
- Managing the risk for iron deficiency associated with blood donation is most effectively addressed by an industry-driven approach that evolves as new data becomes available rather than through additional regulations.
FDA referenced Association Bulletin #12-03 and expressed concern regarding the slow progress of blood centers in implementing interventions recommended by AABB. FDA participants emphasized the role of the BPAC, the importance of its advice to adopt additional measures to mitigate iron deficiency using:
- Routine monitoring of ferritin levels,
- Iron supplementation, and
- Effective donor education and counseling to enhance the benefit to the donor.
FDA has determined that there is a role for policymaking on this issue.
AABB underscored its commitment to leading an industry-driven initiative, following RBDM, when possible, for optimal action, and reiterated plans to release updated recommendations on the subject.
The discussion turned to the issue of adverse events in teenage donors and the Liaison Committee’s request for discussion of additional measures considered adequate to address the concerns associated with the elevated risk for adverse reactions and injuries, and iron deficiency in young donors. Data presented at the November 2016 BPAC meeting estimated 10% of the U.S. blood supply is collected from young donors. FDA participants reviewed the outcome of the BPAC discussion to address the risk for adverse reactions and injuries in the young donor population: 1) Rather than limit collections to donors 18 years and older, limit blood donation to 15% of the estimated blood volume (EBV) was an effective measure; 2) Ensure increased fluid intake prior to donation; 3) Use muscle tensing techniques during donation; 4) Enhance information provided in donor education and parental consent. FDA also noted that a policymaking role exists for the agency on this topic.
AABB again expressed their commitment to leading an industry-driven initiative, as evidenced by the Board of Directors’ decision to task the DHSC with an additional charge to “perform analysis of the young donor data and prepare recommendations for consideration for policy position development and/or standards changes.” The DHSC will review current Association Bulletin #08-04, data used at the BPAC, as well as any other brought to their attention.
August 2016 Zika Guidance
Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components; Guidance for Industry required individual donation testing for Zika virus under IND. The testing requirement was implemented in two tiers at 4 weeks and 12 weeks from the date of publication. Blood collectors in Zika-affected areas (Puerto Rico and Florida) were already testing. The Liaison Committee believes that improvement in the regulatory process for evaluating risks and benefits is necessary to strengthen the response to emerging threats at the regional and national levels and is interested in a decision making process that permits discussion between regulators and industry experts to develop a robust understanding of issues before implementing a plan. An adequate assessment should consider the risks and resources available, minimum requirements likely to achieve the intended outcome, and options for an effective industry-driven response. FDA’s ability and willingness to work with industry experts to reach a timely and effective outcome is vital to ensuring a safe and adequate blood supply and the Liaison Committee inquired about options within FDA’s authority to engage industry when addressing emerging risks to the safety and availability of the blood supply.
FDA participants stated that the agency values collaboration, public input, and a transparent process for guidance development. FDA utilizes open public hearings and workshops and will consider proposed guidance submitted to the agency. FDA reviewed the “Good Guidance Practices” at 21 CFR 10.115, specifically prohibiting certain FDA activities. The agency can listen to public input but does not selectively consider advice that may be considered to benefit one group. FDA stated that, while not the norm, the agency will exercise its authority to issue a Level I guidance for immediate implementation to protect the public health, such as was seen with the August 2016 Zika guidance. FDA believes the August 2016 guidance was necessary to address unique and quickly emerging risks associated with Zika virus. Sexual transmission of Zika virus provides a potential for a self-sustaining transfusion-transmission problem that the agency is concerned about.
Several members of the Liaison Committee described a difference between successful implementation of the requirements of the guidance, and the ability to be able to do the same in the near future with another emerging infectious agent. The daily requirements of the INDs are many and are ongoing. They described the system as lacking any excess capacity. The Liaison Committee reiterated support for the use of RBDM in such a scenario and identified the FDA’s reassessment of the current recommendations for Zika testing as a top priority. FDA participants noted their awareness of the many issues the industry is balancing and said they are committed to monitoring through the year to enable a reassessment of the August 2016 ID-NAT testing recommendation. They clarified the role of the Office of Biostatistics and Epidemiology (OBE) in decision making with respect to the risks posed by Zika. OBE will continue to participate to address future risks, such as Babesia.
FDA participants heard the Liaison Committee’s concerns regarding for the high rate of ineligible cord blood donors due to a lack of pathway to use the Zika test under IND for donors who travel and indicated they are waiting for additional data prior to making recommendations.
Laboratory Developed Tests (LDTs)
FDA declined pursuing regulatory actions for LDTs at the time of the 60-day deadline for FDA to inform Congress but did not post a public notice of that decision when the November deadline passed. The Liaison Committee is interested in FDA’s plans and timeline for reevaluating future actions related to LDTs.
FDA participants referred the Liaison Committee to the posting of “Discussion Paper on Laboratory Developed Tests (LDTs)” dated January 13, 2017, on the FDA’s LDT webpage. The discussion paper provides information relevant to FDA regulatory activities.
Inadvertent Collections from a Donor Found Ineligible Due to a Donor Safety Issue (e.g., prior to the eligibility date) and Discard of Product as Unsuitable
The May 2015 Final Rule, Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use, (the final rule) describes requirements for donor eligibility and product suitability. Currently, §630.10(a) states that a donor is not eligible if any factors are identified that may adversely affect the health of the donor, and §630.30 states that such a donation would be considered unsuitable and must not be released for transfusion or further manufacturing use. The broad application of this approach captures donations that are collected in error, such as prior to the 56-day interval, from a donor who otherwise meets all criteria and would be eligible to donate within days. The preamble of the final rule explains:
“The requirements in §§606.160(e) [records of deferred donors] and 630.10(d)(1) will help assure that blood and blood components that are not suitable for use are not collected or distributed. These provisions protect donors from making donations that should not be collected, protect recipients from the release and use of unsuitable donations, and help establishments to conserve resources used in collecting, testing, and manufacturing blood and blood components. Moreover, since §630.10(d)(1) helps to prevent the collection of unsuitable units, we believe that it will be feasible for establishments to comply with these requirements while at the same time maintaining adequate supplies of suitable blood and blood components.”
The Liaison Committee requested clarification on this issue, emphasizing that a very low rate of error will exist despite a strong focus on error prevention, and discard of such products that are safe, pure and potent, and have met all other criteria, does not help establishments to conserve resources.
FDA stated the new regulations at §630.30 are consistent with FDA’s intent to prevent such collections, which should be prevented or minimized by a strong quality system. FDA indicated that a blood collection facility would be expected to comply unless the donation was a rare product, or selected/directed donation. FDA would be interested in data regarding the frequency of such errors, the effectiveness of corrective actions. FDA would consider an alternative procedure that included a submission of SOPs providing an approach to document errors, monitoring, investigations, and decision making algorithms. AABB agreed to ask its Regulatory Affairs Committee to identify a model or template to assist blood establishments in preparing an SOP for FDA approval.
Blood collection establishments maintain a high level of interest in a regulatory pathway that will provide flexible options for plasma to be sent for further manufacture. During the “Ask the FDA & CMS/CLIA” session at the AABB Annual Meeting in October of 2016, FDA representatives noted that plasma collected by plasmapheresis does not meet the existing definition of Source Plasma under 21 CFR 640.60. This issue is impeding the development of draft guidance by the agency. For blood collectors, the lack of flexible options permitting the conversion of apheresis plasma to plasma for further manufacture prior to expiration is necessary to improve inventory management and prevent wastage.
The Liaison Committee asked FDA participants to continue to pursue the resolution of this priority issue, and inquired about additional information from industry that might assist FDA. FDA representatives acknowledged the concerns, indicating rulemaking to establish a new plasma product is necessary. Industry representatives have previously provided proposals and alternatives and, at this time, specific additional information is not being requested.
Source Plasma Freezers
The Liaison Committee continues to be interested in a change to FDA’s interpretation of the regulation at §640.69(b) resulting in a requirement that Source Plasma must be placed in freezers within 30 minutes.
“Storage. Immediately after filling, plasma intended for manufacturing into injectable products shall be stored at a temperature not warmer than -20 deg. C, except for plasma collected as provided in 640.74.”
FDA participants noted that establishment SOPs have been approved that allowed for placement into freezers for up to two hours after filling/collection. Liaison Committee participants requested that FDA consider the merits of the request for a change to a greater period of time, based on worldwide practices, appropriate handling by fractionators via contracts with collectors. Twenty-four hours, or as permitted in contracts with fractionators to ensure proper manufacturing, was suggested.
Reporting Requirements for Implementing Non-invasive Hemoglobin Testing in Blood Donors
The regulations of §601.12, “Changes to an approved application”, identify the requirements for minor changes submitted in an Annual Report (§601.12(d)) and major changes submitted in a Prior Approval Supplement (PAS) (§601.12(b)).
OBRR staff updated the Liaison Committee of the decision to ask licensed blood establishments, who plan to implement non-invasive hemoglobin testing for blood donor eligibility determinations, to report the change in a PAS rather than an Annual Report. The Office determined this to be a major change due to the technology involved, lack of published literature for review, and knowledge that some countries had adopted, then dropped the technology due to poor correlation with female donors. FDA participants asked if any Liaison Committee members had data/insight on the performance and accuracy of non-invasive hemoglobin devices in a blood donor setting. The observations and data from one member were shared. From a limited sampling of donors, it appeared there was good correlation with male donors and less correlation with female donors.
Guidance Document Anticipated by Industry
The 2017 CBER Guidance Agenda for Industry did not include plans for a Babesia guidance.
FDA explained that Babesia is no longer on the list because a test has not been licensed. When a licensed test becomes available the topic will be reintroduced.
Guidance Documents Published as Final in 2016
Recommendations for Assessment of Blood Donor Eligibility, Donor Deferral and Blood Product Management in Response to Ebola Virus- Guidance for Industry
The safety measures recommended by FDA will be triggered by widespread transmission of Ebola virus. The guidance also refers to areas with former widespread transmission and travel to or residence in an area endemic for Ebola.
AABB requested a clarification on the use of the term “endemic” and noted the CDC website referenced by the guidance does not provide information on areas endemic for Ebola virus. FDA agreed to provide a clarification on the terms used.
Guidance Documents Published as Draft in 2016
Labeling of Red Blood Cell Units with Historical Antigen Typing Results-Draft Guidance for Industry
The Liaison Committee shared that industry has an optimistic view of the draft guidance, and requested FDA clearly identify any limitations on the type of facility that can implement the recommendations. Industry will be submitting comments to the docket.
Guidance Documents Expected to publish in 2017
Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion-Final Guidance for Industry
Implementation of Pathogen-Reduction Measures to Reduce the Risks of Transfusion-Transmissible Infections in Transfused Platelets and Plasma; Draft Guidance for Industry (not yet issued)
The Liaison Committee inquired whether the pathogen-reduction methodology information would be removed from the Bacterial Risk Control Guidance. FDA indicated there would be no conflict between the two documents and that the Pathogen-Reduction document is intended to assist facilities with submissions for licensure of these products.
FDA Proposed Rule
Postmarketing Safety Reporting Requirements for Human Drugs and Biological Products, Final Rule: As published on the December 23, 2016, in the HHS Semiannual Regulatory Agenda, this rule (listed as item 273) has a publication date projected for August of 2017 and is expected to have significant impact on industry.
Liaison Committee participants noted their continued interest in how the requirements may have changed from the proposals of the 2003 document. However, no additional information is available.
Peter Marks, MD, PhD, Director, Office of the Center Director (OD), Center for Biologics Evaluation and Research (CBER)
Celia M. Witten, PhD, MD, Deputy Director, OD,
Diane Maloney, JD, Associate Director for Policy, OD
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Martin Ruta, PhD, JD, Regulatory Counsel, OBRR
Alan Williams, PhD, Associate Director for Regulatory Affairs, OBRR
Jennifer Scharpf, MPH, Associate Director for Policy and Communications, OBRR
Hira Nakhasi, PhD, Director, Division of Emerging and Transfusion Transmitted Diseases, OBRR
Anne Eder, MD, PhD, Associate Deputy Director, Division of Emerging and Transfusion-Transmitted Diseases
Orieji Illoh, MD, Director, Division of Blood Components and Devices (DBCD), OBRR
Wendy Paul, MD, Deputy Director, DBCD
Richard McBride, MS, MT(ASCP)SBB, Chief, Blood and Plasma Branch (BPB), DBCD
Judy Ciaraldi, BS, MT(ASCP)SBB, CQA(ASQ), Consumer Safety Officer (CSO), BPB
Emily Storch, MD, Medical Officer, BPB
Hong Yang, PhD, Biologist, Office of Biostatistics and Epidemiology, CBER
Wilson Bryan, MD, Director, Office of Tissues and Advanced Therapies, CBER
Sharon O’Callaghan, CSO, Division of Inspections and Surveillance, Office of Compliance and Biologics Quality, CBER
Faye Vigue, CSO, Chief, Division of Manufacturers Assistance and Training (DMAT), Office of Communication, Outreach and Development (OCOD), CBER
Cynthia Whitmarsh, CSO, DMAT
Zbigniew M. Szczepiorkowski, MD, PhD, President, AABB
Donna Regan, MT(ASCP)SBB, Immediate Past President, AABB
Mary Beth Bassett, BS, MT(ASCP), President-Elect, AABB
Thomas Hopkins, Interim CEO, AABB
Jean Otter, Vice President, Regulatory, AABB
M. Allene Carr-Greer, MT(ASCP)SBB, Director, Regulatory Affairs
Eva Quinley, MT(ASCP)SBB, MS, CQA(ASQ), Accreditation Program Committee, AABB
Betsy Jett, Regulatory Affairs Committee, AABB
Susan L. Stramer, PhD, Transfusion Transmitted Diseases Committee, AABB
Roger Dodd, PhD, Transfusion Transmitted Diseases Committee, AABB
Ruey Dempsey, Advanced Medical Technology Association
Dayand Borge, MD, PhD, American Red Cross
Kay Crull, MS, MT(ASCP), American Red Cross
Walter Linz, MD, American Society for Apheresis
Christine Zambricki, DNAP, CRNA, America's Blood Centers
Louis M. Katz, MD, America's Blood Centers
Capt. Roland Fahie, MS, MT(ASCP)SBB, Armed Services Blood Program
Karen King, MD, College of American Pathologists
Sharon Carayiannis, Deputy Director, Regulatory Affairs, AABB
Karen Palmer, CQA(ASQ), MT(ASCP), Deputy Director, Regulatory Affairs, AABB
Arnold McKinnon, Volunteer Coordinator and Advocacy Specialist, Regulatory Affairs, AABB