Food and Drug Administration staff from the Center for Biologics Evaluation and Research (CBER) met with AABB's FDA Liaison Committee to discuss topics of mutual concern in the areas of donor and patient safety and product manufacturing. The committee includes liaisons from AABB, the Advanced Medical Technology Association (AdvaMed), America's Blood Centers (ABC), the American Red Cross, the Armed Services Blood Program, and the College of American Pathologists.
Several FDA spokespersons provided highlights of the agency's current initiatives. Peter Marks, MD, PhD, who recently joined CBER as Deputy Center Director, remarked on FDA involvement with donor hemovigilance work, specifically Donor HARTTM, the expanding ability of the Office of Biostatistics and Epidemiology (OBE) to mine large databases such as the insurance database available through the Centers for Medicare and Medicaid Services, and research on high throughput microarray test systems.
Diane Maloney, JD, Associate Director for Policy, CBER provided an overview of the three draft guidance documents issued on biosimilars and the website that FDA maintains to track related information. A biosimilar is a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency. Comments to the draft documents are due by April 16.
Kate Cook, JD, Regulatory Counsel, CBER reviewed the process for reauthorization of the Prescription Drug User Fee Act. The current 5-year reauthorization deadline is September 30. The fees are used to fully fund the CBER device program. Derivative product applications are accompanied by fees; biologics license applications, and amendments, for blood products are not.
Teresita C. Mercado, MS, MT(ASCP), Chief, Devices Review Branch (DRB), Office of Blood Research and Review (OBRR), reported on work of the Laboratory of Immunohematology and Molecular Testing. The lab is involved with development of reference panels for HLA antigen and antibody determination in collaboration with international organizations involved in histocompatibility, immunogenetics and transplantation, as well as reference materials for molecular testing for red blood cell antigens. The lab also collaborates with international organizations and transplantation communities to standardize HLA antigen and antibody assays and the molecular testing for red blood cell antigens. Development of accurate and sensitive methods based on cutting-edge technologies, including sequenced-based assays, is recognized to be critical to industry.
Lore Fields, MT(ASCP)SBB, DBA, Blood and Plasma Branch (BPB), OBRR announced that FDA would be holding a public workshop on statistical process controls for blood establishments in the fall. The workshop will be sponsored by FDA, the U.S. Department of Health and Human Services Office of the Secretary, AABB and America's Blood Centers. The goal of the workshop is to discuss statistical process control theory and options on how to implement statistical sampling plans during validation and quality control of manufacturing processes for whole blood and blood components. A planning committee has been established and details of the workshop will be announced in the Federal Register.
Mark Walderhaug, PhD, Associate Director for Risk Assessment, Office of Biostatistics and Epidemiology, presented information about a potential workshop on the development of computer simulation models of the U.S. blood supply and their application in planning for national emergencies. FDA has been working on a stock and flow model of the U.S. blood supply and presented some results at an ABC annual meeting in 2009. Since then, the model has been enhanced and OBE is looking for input to make the model more valuable to planners and the blood community. The workshop will likely be held in the summer. Walderhaug also reviewed the November 2011 workshop "Data and Data Needs to Advance Risk Assessment for Emerging Infectious Diseases for Blood and Blood Products".
Hira L. Nakhasi, Ph.D., Director, Division of Emerging and Transfusion Transmitted Diseases (DETTD), OBRR briefed participants on plans for a potential workshop in early 2013 on technologies for the detection of emerging and transfusion-transmitted disease agents – multiplexed/multiarrayed blood donor screening. AABB, AdvaMed, America's Blood Centers, and HHS have committed to sponsor the workshop.
Darrell Triulzi, MD, president, AABB, discussed several AABB initiatives including Patient Blood Management (PMB), Cellular Therapies, Biovigilance, an AABB task force review of donor hemoglobin and iron levels, and a task force convened to review quarantine release errors (QREs). AABB has developed educational and support services for PBM programs – evidence-based approaches to optimize the care of patients who might need a transfusion. AABB supports the hospital focus on patient-centric outcomes and multidisciplinary approaches to the appropriate use of blood and strategies to avoid unnecessary blood transfusion through the following: recently released red blood cell transfusion clinical practice guidelines; the primer Getting Started in Patient Blood Management intended to assist clinicians; and collaboration with the Society for Advancement of Blood Management (SABM) on a series of eight webinars.
The association is expanding its role in cellular therapies by developing clinical requirements to add to existing AABB laboratory standards. Collaboration with the International Cellular Medicine Society (ICMS) will establish for that organization a global accreditation program for clinics and facilities providing autologous cell-based therapies.
An update was provided on the following components of the U.S. Biovigilance Network: AABB's Patient and Donor Safety Center (PDSC) and its relation to the CDC's Hemovigilance Module of National Healthcare Safety Network (NHSN); and the Donor Hemovigilance Reporting Tool (Donor HART). AABB's PDSC has 34 participating hospitals and the training is targeted at respiratory reaction classification. CDC reports that the most active participants in the NHSN are from the PDSC. In the Donor HART program, the pilot program was expanded to include additional blood centers. Data Use Agreements are in review with HHS, and FDA's input is being sought for National Aggregate Report development.
An AABB Interorganizational Task Force on Hemoglobin Deferral has been convened to provide expertise on issues of donor hemoglobin and iron levels, interdonation intervals, measurements of serum iron and iron supplementation, and the potential impact of changes to current qualifying criteria on collection and availability of the blood supply. The task force has submitted a report to the AABB Board of Directors that may be public in the near future. The Interorganizational Task Force on Quarantine Release Errors is a new task force convened to develop a process to stratify risks of different QREs as a follow-up to the September 2011 FDA workshop on the same topic.
It was noted that the 2011 National Blood Collection and Utilization Survey was released February 2012 to blood centers, cord banks, and hospitals and the resulting report is expected to be available in late 2012.
January 6, 2012, Morbidity and Mortality Weekly Report – "Guidelines for Safe Work Practices in Human and Animal Medical Diagnostic Laboratories, Recommendations of a CDC-convened, Biosafety Blue Ribbon Panel" contained the following recommendations (pages 72-73):
"Wipe outer surfaces of blood bags and components with a towel moistened with appropriate disinfectant before release for infusion, ensuring that the disinfectant will not compromise the plastic bag."
This particular set of recommendations was developed without interaction with staff from the Office of Blood, Organ, and Other Tissue Safety at CDC. Manufacturers of blood bags have no stated recommendations for what is an appropriate procedure. At least one unofficial, small study has been performed, and it would appear that at least for some component bags the recommendation to use alcohol would be "okay." Following interaction with individuals from the blood banking community as well as the offices of blood at CDC and FDA an erratum was published by CDC on March 30, 2012. The sixth bullet of paragraph 11.4.1, page 72, should read:
Gloves should be worn when spiking or otherwise entering blood bags. The blood banks should have written procedures to decontaminate or discard blood or component containers visibly soiled with potentially infectious materials (i.e., wiping with an alcohol pad or swab) (Buchta C, Blacky A, Leitner GC, et al. Surface disinfection of packed red blood cells with 70% ethanol. Int J Surg 2006;4:118–21).
Members of the Liaison Committee were aware of the proactive engagement of OBRR in discussions with CDC, industry and bag manufacturers, and asked if there was a way to have a review of similar recommendations in the future to avoid publication of recommendations that were counter to good manufacturing practices. Participants discussed the roles of the different agencies involved and agreed that in the majority of cases appropriate reviews are requested and provided.
The AABB Donor History Task Force maintains a Medication Deferral List that is intended for use in screening blood donors. Medications appear on the list if the drug adversely affects the potency of the product, or if a single exposure to the level of residual drug that may be present in a blood component poses risk to recipients (especially in pregnancy). Recently the DHTF discussed another example where the package insert for the drug Erivedge advised patients not to donate blood or blood products while receiving the drug and for at least 7 months after the last dose. The Task Force has decided not to include this on the Medication Deferral List as donors receiving treatment for cancer (in this case advanced, metastatic basal cell cancer) would be deferred from blood donation.
The Liaison Committee is aware that Center for Drug Evaluation and Research (CDER) reviews and approves medications and associated labeling/package inserts and that there is no direct mechanism in place for CBER to be alerted when a newly approved medication contains a warning against blood donation. Recognizing that decisions on whether blood donation should be avoided while taking a medication are complex, the Committee asked for an update on discussions with CDER and whether OBRR will be involved with CDER in the reviews.
FDA participants stated that notification to industry in a timely manner is the focus of the discussions with CDER. Several challenges were noted: establishing a line of communication with the appropriate office at CDER; understanding the rationale behind the actual warning; and determining the appropriate mechanism for communicating with industry. Currently CBER is concentrating its efforts with the Office of New Drugs at CDER. Communications have been elevated to the director level within the centers.
The BPAC meeting originally scheduled for February 29 to discuss "new plasma products manufactured following storage at room temperature for up to 24 hours, namely, plasma for transfusion prepared from whole blood held at room temperature for up to 24 hours prior to separation and freezing, or from apheresis plasma held at room temperature for up to 24 hours before freezing" was cancelled in lieu of discussion at a public workshop. The Committee placed this topic on the agenda in hopes of discussing with FDA the objectives for the workshop and potential addition of cellular components (red cells and platelets) be included on the workshop agenda. However, one week prior to the Liaison meeting, FDA again called for a meeting of the BPAC to discuss the topic.
Agency participants noted that they have data that could be used to characterize PF24RT24 – plasma collected by apheresis and maintained at room temperature for up to 24 hours before being placed in the freezer. These data can be compared to data from fresh frozen plasma studies. FDA noted that the need for a workshop would be reassessed after the BPAC meeting and also that they have no data from any manufacturers on red cells or platelets prepared after being held at room temperature. Liaison Committee participants stressed that the appropriate focus for the BPAC discussion should be "What level of decrement is clinically relevant?" rather than strict comparison of the coagulation factor level for each protein that can be compared. It was noted that the Indications for use for PF24 in Circular of Information states, "see FFP," and the Contraindications are the same with a limited difference being, "In addition, this product is not indicated for treatment of deficiencies of labile coagulation factors including Factors VIII and V."
Blood centers perform RBC antigen testing, both serological and genetic and it is the practice of many blood centers to provide this information to their customers either on the shipping document or a tie-tag attached to the unit. However, the Committee understands that the practice of using tie-tags has been questioned and that FDA interprets 21 CFR 606.121(j) to disallow the use of tie-tags for this purpose.
"(j) A tie-tag attached to the container may be used for providing the information required by paragraph (e) (1)(iii), (2)(ii), and (4),(h), or (i)(1), (2), and (3) of this section."
However, the language in section (j) appears to state that some information — required by other CFR sections — can be made available by way of a tie-tag instead of being on the blood bag label, rather than a direction that it must appear on a tie-tag. This same information could apparently be placed on the blood bag label if a blood center chose that option. Liaison Committee participants noted that the language does not appear to preclude the use of tie-tags for other information that is not required by the CFR to be on the blood bag label.
21 CFR 640.5 "All laboratory tests shall be made on a specimen of blood taken from the donor at the time of collecting the unit of blood, and these tests shall include the following…" was pointed out by FDA staff as another important CFR reference. The agency interprets this reference to include "all testing" and furthermore all options for providing information to the consignee are considered "labeling," whether it is the Circular, the unit label, or an attached tie-tag. To FDA the issue does not hinge on an interpretation of 606.121(j), but on the fact that if the agency is going to sanction the practice it must review the process and define the standards under which it will accept the practice, including quality of the phenotype results/reagents used, linkage of the historical typing to the donor, etc. There was a brief discussion of whether the regulations need to be updated to be applicable to molecular testing and use of microarrays. A licensed establishment can submit a request as a prior approval supplement (PAS), and the agency will review its processes which will include the procedures for the confirmation testing. Following more discussion of the issues involved and the likelihood that the agency will receive many PAS requests, it was determined that a working group could be established to review the process and present a protocol that would provide an acceptable mechanism for multiple establishments to use. AABB agreed to organize a work group.
When discussing bacterial screening of platelets at the September 2011 AABB FDA Liaison meeting, FDA remarked that the agency encourages the use of both screening technologies currently available (culture and point of issue) — as they both contribute to safety of the transfused product — and indicated that FDA might consider a guidance that discussed the various methods. FDA participants also remarked that while they are aware of the results of the recent Verax PGD study (published in Transfusion, December 2011), they noted that the false positive rate is considerable.
In response to the Committee's request for an update of FDA's current considerations of this topic, FDA staff said that the agency is keeping abreast of available information and is aware that there are a variety of experiences and considerations from different establishments with respect to the one point of issue product that is currently available. Noting that it is a complex issue, the agency is considering that discussion in a public forum may be appropriate prior to issuing guidance or other regulatory action.The Advisory Committee on Blood Safety and Availability in June 2010 generated a comprehensive set of recommendations to the HHS arising from the discussion of donor deferral policies related to MSM. HHS agencies have been planning studies and projects to address the ACBSA recommendations that arose from these discussions of donor deferral policies related to MSM.
In January the AABB DHTF submitted the new draft of the Full-Length Donor History Questionnaire and accompanying materials to CDC's National Center for Health Statistics to be included in an MSM study. More recently, the National Institutes of Health announced a proposed data collection project titled "Opinions and Perspectives about the Current Blood Donation Policy for Men Who Have Sex with Men." The NIH study has three objectives: (1) assess opinions and themes within the MSM blood donor population; (2) assess compliance and non-compliance in the MSM population with the current blood donation policy; and (3) assess motivations for donating in the group of self-identified MSM who are active blood donors in the U.S.
In as much as the FDA is involved in these HHS projects and teams, the Liaison Committee asked for an update of the MSM studies and projects.
A study on the epidemiology of transfusion-transmissible infections in U.S. blood donors, supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) is being conducted as part of the second Retrovirus Epidemiology Donor Study (REDS–II). This study includes the American Red Cross, Blood Systems, Inc., and the New York Blood Center. The study that includes an analysis of data on the prevalence and incidence of certain major transfusion-transmissible infections (e.g. HIV, HBV, HCV) obtained from routine donation testing of blood donors, was initiated in 2011 and is expected to provide baseline estimates of the current risks of transfusion-transmitted viral infections in the U.S. blood supply.
An evaluation of the Blood Donation History Questionnaire (DHQ) is underway by the National Center for Health Statistics of the Centers for Disease Control and Prevention (NCHS, CDC). Several factors, including culture, social conditions, and language fluency, contribute to different interpretations of the questions that comprise the current blood donation screening questionnaire. A study to assess donor understanding and interpretation of the DHQ screening questions (i.e., cognitive evaluation) was conducted approximately ten years ago by NCHS. Because techniques for questionnaire evaluation have advanced considerably over the past decade, the HHS Office of the Assistant Secretary for Health funded NCHS to re-evaluate the DHQ, with particular emphasis on donor understanding of the behavioral risk questions intended to prevent transmissible infections. This study will help determine whether the existing MSM deferral questions are understood and properly interpreted by donors. It may also determine more effective ways to communicate with at-risk populations through donor questions. Forty interviews have been conducted in the Washington, D.C. area, and evaluation will occur in a second geographic location. FDA noted that it is important that the results of the evaluation be transmitted to the AABB DHTF.
A study funded by the FDA and carried out by the NHLBI REDS–III program will assess attitudes and behaviors of MSM toward current and possible future blood donation policies. The study is specifically designed to examine whether MSM comply with the current deferral criteria and whether MSM would be likely to comply with potential different deferral criteria. The study will likely be completed by second quarter of 2013.
The goal of these studies is to determine if among presenting donors a subset of MSM can be identified that are at no higher risk than other donors. There will have to be a level of assurance that compliance with deferral criteria is achievable.
The final rule published January 2012, titled "Revisions to Labeling Requirements for Blood and Blood Components, Including Source Plasma" (effective date July 2, 2012) includes updates to several regulations that will eliminate the need to use variances related to ISBT labels and expiration time of thawed FFP. As with any rule or guidance document, new requirements or recommendations must be implemented by the effective date and may be implemented prior to that time.
In response to the question of whether existing recommendations or requirements, including related variances, could be discontinued once the rule has been published in the Federal Register, FDA participants responded "no." The current regulations remain a requirement until the effective date of the new rule and there is no way to discontinue them prior to that time – except through use of Alternative Procedures (21 CFR 640.120).
Recently the agency has responded to several inquiries concerning the required time for returning cryoprecipitate (individual and pooled products) to the freezer once the manufacturing process has begun. The time spent discussing this issue is appreciated as this is an area that has evolved without regulations to cite, and from time to time interpretations of what must occur by the end of a particular period of time differ. Having the response confirmed at the Liaison Committee meeting provides a record of the response that can be widely disseminated to blood centers/blood banks.
The response supplied is that single or pooled products should be placed in the freezer within one hour, and that the one hour period begins when the thawed product is removed from the refrigerated centrifuge. Furthermore, if a licensed facility wants to extend the manufacturing time for producing pooled cryoprecipitate (the period of time between removal of the first unit from the refrigerated centrifuge and returning the pool to the freezer),a request for approval of the SOP for an extended period of time must be submitted as a prior approval supplement. The request for the extended period would need to be accompanied by data such as Factor VIII and fibrinogen levels.
The Liaison Committee would like the agency to discuss how the Regulatory Site Visit Program (RSVP) has helped FDA with the following: (1) staying abreast of changes in industry; and (2) realizing the applicability of guidance recommendations and regulatory requirements to manufacturing processes.
FDA staff noted the importance of the RSVP to the CBER training and development programs for regulatory review, compliance and other staff. Site selection criteria are always listed in the Federal Register Notice, and one important criterion is that the host site must have a successful compliance record with FDA – this means that the site must have been previously inspected at least once. Host site applications have been made from vaccine, plasma, cell, tissue and gene therapy, medical device and blood establishments. In 2011 there were no applications. Staff that attend the site visits report that they do find the visits to be educational and informative and value the "successful compliance history" criterion that is used in selecting the sites.
The December 2011 agenda announced the draft Guidance Documents that FDA will work on during 2012. FDA was unable to comment on the specific documents as they are in the process of being written/released. The Liaison Committee noted the relevance of the documents.
Peter Marks, MD, PhD, Deputy Center Director, Center for Biologics Evaluation and Research (CBER)
Kate Cook, JD, Regulatory Counsel, Office of the Director, CBER
Diane Maloney, JD, Associate Director for Policy, CBER
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Ginette Y. Michaud, MD, Deputy Director, OBRR
Martin Ruta, Ph.D., J.D., Regulatory Counsel, OBRR
Alan Williams, PhD, Deputy Director for Operations and Regulatory Affairs, OBRR
Jennifer Scharpf, MPH, Associate Director for Policy and Communications, OBRR
Hira L. Nakhasi, Ph.D., Director, Division of Emerging and Transfusion Transmitted Diseases, OBRR
Salim Haddad, MD, Senior Medical Officer, Division of Hematology (DH), OBRR
Paul D. Mintz MD, Deputy Director, DH
Jaroslav Vostal, MD, Chief, Laboratory of Cellular Hematology, DH
Richard Davey, Director, Division of Blood Application (DBA), OBRR
Orieji Illoh, MD, Deputy Director, DBA
Teresita C. Mercado, MS, MT(ASCP), Chief, Devices Review Branch, DBA
Zhugong Liu, MD, PhD, Senior Scientist, Laboratory of Immunohematology and Molecular Testing, DBA
Leslie Holness, MD, Chief, Blood and Plasma Branch (BPB), DBA
Judy Ciaraldi, BS, MT(ASCP)SBB, CQA(ASQ), Consumer Safety Officer(CSO), BPB
Lore Fields, MT(ASCP)SBB, CSO, BPB
Hoi-May Chan, MT(ASCP)SBB, CSO, BPB
Mark Walderhaug, PhD, Associate Director for Risk Assessment, Office of Biostatistics and Epidemiology, CBER
Gilliam Conley, Director, Division of Inspections and Surveillance, Office of Compliance and Biologics Quality, CBER
Karoll Cortez, MD, MHS, Medical Officer, Office of Cellular, Tissue and Gene Therapies, CBER
Faye Vigue, CSO, Division of Manufacturers Assistance and Training (DMAT), Chief, Manufacturers Assistance and Technical Training Branch (MATTB), Office of Communications, Outreach and Development (OCOD), CBER
Pauline Cottrell, CSO, DMAT, MATTB, OCOD
Darrell J. Triulzi, MD, President, AABB
Karen L. Shoos, JD, CEO, AABB
Susan Stramer, Ph.D., President-Elect, AABB
James P. AuBuchon, MD, FCAP, FRCP(Edin) Immediate Past President, AABB
M. Allene Carr-Greer, MT(ASCP)SBB, Director, Regulatory Affairs, AABB
Louis M. Katz, MD, TTD Committee, AABB
Patricia Pisciotto, MD, Standards Program Committee, AABB
Kathleen Houston, BS, MT(ASCP)SBB, Accreditation Program Committee, AABB
S. Gerald Sandler, MD, CAP
Richard Benjamin, MD, ARC
Celso Bianco, MD, ABC
Ruth Sylvester, MT(ASCP)SBB, ABC
Cdr. Roland Fahie, MS, MT(ASCP)SBB, DOD
Khatereh Calleja, JD, AdvaMed
Jean Otter, MT(ASCP) SBB, Division Director, Programs, AABB
Becky See, MS, MLS (ASCP)cm, CQA(ASQ), Deputy Director, Regulatory Affairs, AABB
Jacqlyn Riposo, Policy Specialist, AABB
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