CURRENT FDA INITIATIVES AND PRIORITIES
Jay Epstein, MD, director, Office of Blood Research and Review, Center for Blood Evaluation and Research, reviewed the following programs:
- The new CBER-wide Laboratory of Emerging Pathogens, which was established to proactively address emerging and re-emerging pathogens, including dengue virus, chikungunya virus, West Nile virus, malaria, Babesia, Leishmania, Chagas', HIV drug resistant and recombinant variants, hepatitis B virus mutants, bioterrorism agents, xenotropic murine leukemia virus-related virus.
- The Rare Disease Review Group, established as a part of the initiative on rare diseases, which is considering how FDA currently evaluates drugs, biologics and medical devices for treating rare diseases and how that process can be optimized. The Neglected Tropical Disease Review Group is reviewing present FDA guidance and different local and international programs that encourage development of medical products for these diseases and identifying opportunities to enhance agency efforts.
In addition, Epstein mentioned that the agency is seeking continued dialogue with blood establishments, test kit manufacturers, government partners and other stakeholders to address barriers to the development of new assays, recognizing the role of multiple parties in finding solutions.
Lore Fields, MT(ASCP)SBB, Consumer Safety Officer, OBRR, described the eSubmitter pilot evaluation program
http://edocket.access.gpo.gov/2010/pdf/2010-22167.pdf for Whole Blood and Blood Components that is scheduled to begin Dec. 6 with nine establishments that have enrolled. In addition to all products that can be submitted for licensure, annual reports can be filed and requests for alternative procedures can be made. The pilot is likely to run for at least six months and will be extended if needed to enable a variety of templates to be used.
Mikhail Menis, PharmD, MS, Office of Biostatistics and Epidemiology, CBER, provided a presentation on the use of CMS data to assess occurrence and risk factors of transfusion-related adverse reactions. The current blood safety focus with CMS includes evaluating the occurrence of serious transfusion-related adverse events (e.g., TRALI, HTRs) and risk factors among elderly Medicare beneficiaries in various service settings (inpatient, outpatient) and changes over time; evaluating the uptake of newly introduced ICD-9-CM blood safety codes (e.g., TACO, PTP, FNHTR); assessing occurrence of potentially transfusion-transmittable emerging infectious diseases (e.g., Babesiosis) among the elderly in the U.S.; and planning to conduct near real-time surveillance of transfusion-related adverse events (e.g., TRALI).
Elizabeth Lybarger, LT, Division of Human Tissues, Office of Cells, Tissue and Gene Therapy, CBER, provided an update on the division's concern with the lack of emerging infectious disease data that is specific to tissue products. Subsequent to the May EID workshop sponsored by CBER, the division is working to develop a research agenda to inform health policy decisions regarding screening and testing requirements for detection of EIDs in donors of human organs, cells, and tissues for transplantation. Earlier discussions specific to tracking tissues are still ongoing. Progress has been made by the American Association of Tissue Banks on a donor history questionnaire for tissue donors. It was noted that the questionnaire would likely publish for public comment in the near future.
CURRENT AABB INITIATIVES AND PRIORITIES
James P. AuBuchon, MD, president, AABB, introduced the discussion of AABB initiatives and priorities in support of the association's strategic plan that is focused on patient and donor safety through the practice of transfusion medicine and cellular therapies. Five critical focus areas for achieving the goal of improved patient and donor health include member engagement, excellence in medicine, knowledge translation, regulatory advocacy, and standards and accreditation. In the coming year AABB will concentrate its programs on measurable improvements in cellular therapies; biovigilance, including progress toward clinically applicable interventions resulting from the analyses of data from the Hemovigilance Module of the Centers for Disease Control and Prevention's National Healthcare Safety Network, and further development of a robust donor system; and patient safety in the hospital practice of transfusion medicine, specifically through efficient blood utilization and management. AABB will continue to advocate for FDA's use of evidence-based decision-making in areas that pose the greatest risk to patients and donors. AABB's specific regulatory initiatives for the year include addressing any proposed regulations affecting donor eligibility and donation suitability; plasma regulations; cellular therapies; donor history questionnaires; Circular of Information for Blood Components; donor screening and re-entry; and disaster preparedness.
SPECIFIC TOPICS OF DISCUSSION WITH FDA
July 2010 BPAC Meeting
July 26-27 Blood Product Advisory Committee meeting, the panel discussed XMRV; issues related to the risk of Babesia infection by blood transfusions and the status of laboratory tests; and blood donor hemoglobin/hematocrit qualification standards, iron status and interdonation interval. Participants at the liaison committee meeting discussed some of the outcomes of the BPAC meeting.
XMRV is a scheduled topic for discussion at the December BPAC meeting. Blood industry participants indicated that blood collectors continue for the most part to use educational materials to actively discourage donation by patients who have been diagnosed with chronic fatigue syndrome.
Babesia – The discussion focused on the understanding of regional versus focal testing. AABB participants reiterated AABB's
position presented at the BPAC meeting. Participants were updated on the work of the AABB Babesia Task Force in its efforts to assist facilities in reporting transfusion-associated babesiosis.
Blood donor hemoglobin/hematocrit standards – One outcome of the BPAC meeting was a realization that there are additional data that were not available for review at the BPAC meeting. AABB provided an update on a new interorganizational task force that has been assembled to evaluate issues such as hemoglobin/hematocrit levels and interdonation intervals and make recommendations as appropriate. FDA participants announced that a workshop is planned for the fourth quarter of 2011 on hemoglobin and iron stores in blood donors.
June 2010 ACBSA Meeting on MSM and Blood Donation
The Advisory Committee on Blood Safety and Availability at its June meeting generated a comprehensive set of recommendations to the secretary for health arising from the discussion of donor deferral policies and MSM. Although the
recommendations are to the secretary and are not immediately directed to FDA, the areas of interest are a direct overlap with those of OBRR, and several of the suggested areas of research were noted – validation of modifications to the donor questionnaire that would better differentiate low versus high risk MSM and heterosexuals, including studies to investigate transfusion transmitted infectious disease and sexually transmitted disease markers in potential donor subsets; establishing the ability to characterize risk in different donor subgroups (e.g., younger age donors); determining the feasibility of donor pre-testing to limit risk while characterizing donors who might be recruited under modified eligibility criteria.
FDA participants provided an update on activities of the Public Health Service Working Group that was created to make recommendations for a better policy for determining donor eligibility within an improved or equivalent blood safety environment following the ACBSA discussion. The scope of the initiative is not settled. Communication has been established with the National Center for Health Statistics in the event validation of interview questions is required. Emerging infectious diseases have not been discussed in depth, but concern about this topic exists. At this point in time budgets have not been established to pursue any studies. AABB participants noted that the Transfusion Transmitted Diseases Committee is available to offer input on infectious disease studies under consideration and the Donor History Questionnaire Task Force is available to offer input on the development of donor screening questions.
July 2010 Workshop on Oversight of Laboratory Developed Tests
The FDA workshop on oversight of laboratory-developed tests (July 19-20) reviewed issues that have the potential to impact several areas relevant to laboratories (transfusion services, reference laboratories) when they must perform testing in the absence of FDA-approved or -cleared kits, or when the test is outsourced. According to the
Federal Register notice published for the public meeting, FDA is considering a risk-based application of oversight to LDTs as the appropriate approach. Until now FDA has generally exercised enforcement discretion with respect to laboratory-developed tests developed, validated and offered within a single laboratory, and the components were generally regulated individually as analyte-specific reagents or other specific or general reagents. The tests were developed and offered in laboratories certified by CLIA to perform high-complexity-level testing.
The Center for Devices and Radiologic Health has not published additional public material since the workshop. However, a guidance document to establish the framework for change will be published, and CBER is engaged in the development of the guidance.
Pathogen reduction/inactivation continues to be a topic of great interest to the AABB FDA Liaison Committee, as it is to FDA. The recent ACBSA recommendations to the secretary, related to risk associated with MSM, again call for the implementation of pathogen reduction technologies for all transfusible blood components. A recent
BPAC meeting yielded recommendations that may or may not move the process forward. Members of the blood community are still concerned that that the BPAC recommendation for a blinded, phase IV study will not only be unacceptable to the company whose product was under discussion but to future manufacturers as well. Liaison meeting participants understand that the FDA is not required to act on the BPAC recommendations and continues to urge consideration of well-designed smaller studies. FDA participants noted their full support of the ACBSA recommendation that pathogen-reduction technologies be adopted for all transfusible blood components and provided a review of their perspective on some current issues.
The technologies have been shown to be effective against many organisms including some emerging pathogens and may prevent GVHD and other white blood cell-related adverse events. However, they may not be effective against all organisms or 100 percent effective against sensitive pathogens. Current technologies are not applicable to all types of transfusion products and may 1) have toxicity due to residual compounds; 2) damage the transfusion product; 3) lead to alloimmunization by neoantigens; and 4) cause unexpected adverse events.
Pathogen reduction of labile blood products could improve blood product safety, especially for platelets, but should not add greater risks.
- Clinical trials with pathogen reduced red cells have demonstrated antibody generation.
- Clinical trials with pathogen-reduced platelets have demonstrated decreased efficacy and associated adverse events, including acute lung injury in the SPRINT trial
Further clinical trials of current technologies are needed to resolve FDA's concerns over decreased efficacy and increased adverse events seen with pathogen-reduced platelets.
FDA Updates and Current Considerations for the Topics: Evaluation of Blood Donors for Blood Pressure and Pulse and Plasma for Further Manufacture
Requirements for Human Blood and Blood Components Intended for Transfusion for Further Manufacturing Use, Proposed Rule, was issued in November 2007. FDA provided an expanded comment period to accommodate the many proposals for changes to the regulations that were contained in this regulatory document and received many comments from blood and plasma establishments and interested parties. At previous meetings with this committee, FDA participants have noted that it is likely the rule will not be reissued as a draft. However, it is also likely that all proposals may not be issued as final at the same time. The BPAC has been asked to make recommendations on some topics, and the Liaison Committee has also engaged in discussion on some of the topics.
Evaluation of blood donors for blood pressure and pulse – The
BPAC has been asked to make recommendations, the
issue has been discussed previously in this forum, and substantial comments were submitted to the docket. In response to a request for an update on FDA's current considerations of these two donor eligibility criteria, FDA participants noted that the agency remains concerned with the idea of accepting donors outside the previously accepted ranges ("zone of experience") that were/are being used.
Plasma for further manufacture – The proposed rule offers an opportunity to update the regulations relevant to automated collection of plasma from donors qualified under whole blood donor regulations. A proposal from the AABB Plasma Task Force was submitted to the docket. FDA subsequently made a
proposal to the BPAC that was a way forward and would lay the groundwork for a draft guidance to describe the framework for a change to the regulations (and interim variance structure), but more than one year later there has been no draft guidance issued. The AABB Plasma Task Force remains in contact with blood establishments and FDA on this important issue. FDA participants acknowledged the level of interest and noted their work with the Plasma Task force on matters related to concurrent plasma. At this time FDA has completed consideration of the regulations that will be affected and is moving forward, utilizing good guidance practice policies to publicize current thinking in a draft guidance document.
Travel-Related Deferral for Malaria Risk
At the November 2009 BPAC
meeting the committee agreed with the FDA, CDC and industry presentations that travel to some low-risk areas of Mexico did not present increased risk to the U.S. blood supply, and BPAC recommended by a 17-1 vote to allow blood collection, without deferral, from U.S. residents who have visited Quintana Roo, Mexico.
When asked how/when they would move forward to make this consensus known to blood establishments so that blood donors can be accepted for donation even though they may have visited Quintana Roo, Mexico, within the recent 12 months, FDA participants responded that dengue, also present in this area of Mexico, was a confounding issue. FDA is taking into consideration the fact that blood donors who have been deferred for possible exposure for malaria are by default also being excluding for risk of dengue. Several liaison committee participants strongly urged FDA not to use malaria deferrals as a surrogate deferral for dengue and to address the need for a dengue policy separately.
At the April 2009 BPAC
meeting FDA posed several questions to the committee concerning antibody testing for Trypanosoma cruzi. A majority of the committee voted in favor of a selective strategy to test blood donors and agreed that one negative test should allow future donations without further testing or risk-based questions to assess the potential for newly acquired infections, but it also determined that studies should continue to define the incidence of new infections in donors who previously screened negative. A majority of the committee also agreed with FDA's position that scientific data on the effectiveness of risk questions do not support a selective testing strategy in which donors who previously tested negative for T. cruzi antibodies are tested again only if their answers to these questions indicate the potential for new infection.
Since FDA licensed the first test system for antibodies to T. cruzi in 2006, blood establishments have been testing donors on a voluntary basis, initially utilizing a universal strategy and more recently moving to selective testing strategies. FDA participants were asked for an update on considerations for determining eligibility of donors with regard to T. cruzi and progress on publication of a guidance document containing final recommendations. FDA participants responded that the considerations have not changed beyond what was presented at the April BPAC meeting, and they expected the guidance document to publish in the near future.
Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components Intended for Transfusion published Dec. 6, 2010.
Draft Guidance on Blood Safety Recommendations in Response to the 2009 H1N1 Influenza Pandemic
FDA issued Recommendations for the Assessment of Blood Donor Suitability, Blood Product Safety, and Preservation of the Blood Supply in response to Pandemic (HINI) 2009 Virus, draft guidance in November 2009. The draft guidance, among other things, provided several helpful updates and clarifications to establishment regulatory reporting requirements to FDA.
- Use of a different outside test lab, provided the test lab is registered with FDA and has been performing donor testing now CBE (not CBE 30).
- Activation of an establishment's alternate or back-up contractor, in the event of a pandemic or for other reason, remains in the annual report category.
- Implementation of self-administered donor history questionnaires, provided [that facilities followed] the critical control points described in FDA's "Guidance for Industry: Streamlining the Donor Interview Process: Recommendations for Self- Administered Questionnaires" (July 2003), and the submission contains the content recommended for all self-administered procedures and computer assisted interactive procedures outlined in the same guidance.
This draft guidance also provided an opportunity for FDA to define the term "day of collection" as found in 21 CFR 640.3(a) and 640.63(a) as "within 24 hours of the collection."
FDA participants were asked for progress on finalizing the recommendations contained in the guidance and replied that due to the expiration, in June 2010, of the public health emergency declared by the Department of Health and Human Services in response to the H1N1 influenza, the draft guidance would not become final. However, because the recommendations have general applicability and utility in times other than response to severe pandemics, they would be finalized in a different guidance.
Guidance for Industry: Recommendations for Blood Establishments: Training of Back-Up Personnel, Assessment of Blood Donor Suitability and Reporting Certain Changes to an Approved Application published Dec. 3, 2010.
Abbreviated Donor History Questionnaire
The BPAC has advised that the use of the abbreviated donor history questionnaire, previously submitted to FDA for review and acceptance, is desirable and suggested that a post-implementation study/data collection would be appropriate. The AABB DHTF developed a study (with the advice of FDA liaisons to the task force) and submitted it to FDA in April 2008. The task force has been told on several occasions that the plan submitted satisfactorily addressed all outstanding issues. FDA participants at previous liaison meetings explained that the necessary guidance document is in an editing stage, the post-implementation plan will likely be referenced in the guidance, and the draft guidance is on OBRR's priority list for 2010.
FDA responded to a request for an update on progress with issuing the guidance document by stating that it believes the document will be published in the very near future and there are no problems or questions that they are currently addressing. Liaison committee participants expressed concern that the process appears to be stalled at this particular step. The DHTF is especially concerned that it will become necessary to revise the full-length version (especially given the interest expressed by the ACBSA) before the abbreviated version is recognized. FDA participants reiterated their belief that there are no problems with the guidance document that need to be addressed and it should publish soon.
Publication of Documents
AABB remains concerned with the continued significant delay in publishing documents that are of critical importance to its members. A review of transcripts from the listening sessions held by the FDA Transparency Task Force revealed this to be a concern echoed by various industry sectors, and comments were submitted to the docket providing several examples of delayed documents and the impact that delay has on blood establishments.
Updates were requested for the following:
- Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion – draft guidance, January 2001.
- Revisions to Labeling and Storage Requirements for Blood and Blood Components, Including Source Plasma – proposed rule, July 2003.
- Safety Reporting Requirements for Human Drug and Biological Products – proposed rule, March 2003. (FDA noted that progress on this proposed rule is driven by the Center for Drug Evaluation and Research.)
FDA participants explained that CBER tries very hard to track progress on the documents and respond to requests within the agency for information and clarifications but that other centers may have overlapping and competing priorities that must be addressed.
TSEAC Meeting (Oct. 28-29)
At the recent meeting of the Transmissible Spongiform Encephalopathies Advisory Committee, FDA presented the results of a quite sophisticated risk assessment of plasma-derived therapies indicating that, because of a number of factors including the removal of prions during fractionation, these products were quite safe. At the same meeting FDA compared eligibility criteria for HCT/P donors, including risk associated with travel to specific geographical areas and the receipt of blood transfusions received in these areas with those for blood donors. FDA did not ask the committee to consider any factors that could warrant changes in the current additive deferral policies.
Could the risk assessment approach be applied to blood donors in order to establish some acceptable risk different from zero when relaxation of some of the requirements could take place? Such risk assessment would take into account factors such as the declining incidence of vCJD, the prevalence of food controls, the reduction in the estimates of prevalence of abnormal prions in the general population, the lower estimates for a potential "second wave" of disease among individuals who are heterozygous (methionine/valine) or homozygous for valine at codon 129, among other issues. Would FDA consider the performance of a formal risk assessment of the potential for transmission of vCJD by transfusion of individuals who have spent time in the U.K. and Europe in order to define at what point, as the epidemic subsides, the current criteria could be modified or relaxed? Is there any way the blood banking community could assist FDA in this endeavor?
FDA participants responded that new modeling is under way, and they would welcome data on deferred donors.
Update from AdvaMed Forum on Development of Assays for Use With Blood Donors
Attendees at the meeting held in early November and sponsored by AdvaMed, represented assay manufacturers, blood establishments, and the Food and Drug Administration.
FDA participants presented their perspective of issues discussed at the meeting:
- Cooperative strategies are needed.
- Manufacturers discussed the need to address the following:
- Lower the costs of bringing assays to market
- Reduce regulatory uncertainties (scope of studies, lack of mandate for use of assay)
- Have greater regulatory flexibility (scale requirements for the market size)
- Earlier release of FDA guidance documents that contain the following information could be helpful:
- Technical specifications for development of the assay, perhaps even to the level that donor screening and diagnostic assays could be developed for the same platform
- FDA current thinking on recommendations for donor testing.
- Public funding (opportunities are needed).
- Potential application of orphan drug or device regulations.
Liaison committee participants who also were present noted that it is important to take these steps:
- Blood industry/assay manufacturer community input should be sought prior to the development of guidance.
- All parties should think about funding as much as regulatory barriers and that representatives from the U.S. Department of Health and Human Services should be involved in the discussions.
Diane Maloney, JD, Associate Director for Policy, Center for Biologics Evaluation and Research (CBER)
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR)
Ginette Michaud, MD, Deputy Director for Science and Medicine, OBRR
Alan Williams, PhD, Associate Director for Regulatory Affairs, OBRR
Basil Golding, MD, Associate Director for Medical Affairs, OBRR
Martin Ruta, PhD, JD, Regulatory Counsel, OBRR
Joseph L. Giglio, MS, MT(ASCP)SBB, CSQE(ASQ), CQA, Associate Deputy Director for Quality Assurance, OBRR
Hira Nakhasi, PhD, Director, Division of Emerging and Transfusion-Transmitted Diseases (DETTD), OBRR
Paul Mied, PhD, Deputy Director, DETTD
Indira Hewlett, Ph.D., Chief, Laboratory of Molecular Virology, DETTD
Pradip Akolkar, PhD, Senior Regulatory Scientist, Product Release Branch (PRB), DETTD
Sanjai Kumar, PhD, Supervisory Research Biologist, Laboratory of Hepatitis and Related Emerging Agents (LHREA), DETTD
Jaro Vostal, MD, Chief, Laboratory of Cellular Hematology, Division of Hematology, OBRR
Richard Davey, MD, Director, Division of Blood Applications (DBA), OBRR
Orieji Illoh, MD, Medical Officer, DBA
Leslie Holness, MD, Chief, Blood and Plasma Branch (BPB), DBA
Judy Ciaraldi, BS, MT(ASCP)SBB, CQA(ASQ), Consumer Safety Officer, BPB
Lore Fields, MT(ASCP)SBB, Consumer Safety Officer, BPB
Lt. Elizabeth Lybarger, MFS, MS, Senior Regulatory Review Officer, Human Tissue and Reproduction Branch, Division of Human Tissues, Office of Cellular Tissue and Gene Therapy
Steven Anderson, Deputy Director, Office of Biostatistics and Epidemiology (OBE)
Mikhail Menis, PharmD, MS, Epidemiologist, Analytic Epidemiology Branch, Division of Epidemiology, OBE
Faye Vigue, MT (ASCP), Consumer Safety Officer, DMAT, Manufacturers Assistance and Technical Training Branch
James P. AuBuchon, MD, President, AABB
Karen Shoos Lipton, JD, Chief Executive Officer, AABB
Darrell J. Triulzi, MD, President-Elect, AABB
M. Allene Carr-Greer MT(ASCP)SBB, Director, Regulatory Affairs, AABB
Louis Katz, MD, AABB
Kathleen Houston, BS, MT(ASCP)SBB, CQA, AABB
Patricia Pisciotto, MD, AABB
Richard Benjamin, MD, ARC
Col. Stephen Beardsley, MS, MT(ASCP)SBB, DOD
Celso Bianco, MD, ABC
Khatereh Calleja, JD, AdvaMed
Cdr. Roland Fahie, MS, MT(ASCP)SBB, DOD
Gerald Sandler, MD, CAP
Aaron Lyss, AABB