FDA Liaison Meeting - 10/29/08

Food and Drug Administration staff met with AABB’s FDA Liaison Committee Oct. 29  to discuss topics of mutual concern in the areas of donor and patient safety — donor eligibility, availability of suitable assays and pathogen reduction. The committee includes liaisons from AABB, the American Red Cross, America’s Blood Centers, Advanced Medical Technology Association, the College of American Pathologists and the Armed Services Blood Program.

CURRENT FDA PRIORITIES AND INITIATIVES

Jay Epstein, MD, director of the Office of Blood Research and Review, summarized a number of priorities and initiatives the agency is engaged in.

Implementation of the FDA Amendments Act of 2007 (FDAAA) continues to be a priority. FDAAA imposes approximately 138 new requirements, with the most pressing requirement related to the pediatric population. Title III — Pediatric Medical Device Safety and Improvement Act — and Title IV — Pediatric Research Equity Act — now require pediatric studies when submitting an application or supplement for review or an explanation of why studies in pediatric populations are not relevant. Title IX of FDAAA — Enhanced Authorities Regarding Post-market Safety of Drugs and Biologics — provides FDA with new authorities to require post-market epidemiologic studies and clinical trials. Labeling provisions of FDAAA overlap with Structured Product Labeling requirements, the focus of a Nov. 17 FDA workshop. Key to the success of the agency’s electronic initiatives are changes in the labeling provisions, especially reformatting package inserts and implementation of structured product labeling.

In previous years, FDA was downsizing due to budget constraints, but appropriations in fiscal year 2008 allowed the agency to begin hiring a large number of new staff. The hiring surge — expected to carryover into FY09 — will bolster surveillance activities and support implementation of the requirements of FDAAA.

The blood community’s drive toward biovigilance is echoing at FDA. The early stages of the public-private partnership (utilizing blinded data) should be able to assist in defining baselines, monitoring for trends and determining if any gaps exist in the system. The agency has implemented safety teams for blood, tissue and vaccines that will provide added internal coordination to manage unexpected events. Part of the biovigilance effort is disaster preparedness and, specifically, pandemic planning. A pandemic would significantly impact the availability of blood donors and the materials required to collect and process blood components. FDA’s goal is to draft candidate guidance documents and have them ready for publication in the event of a disaster such as a flu pandemic. The Centers for Disease Control and Prevention and FDA also are discussing the potential use of convalescent plasma because there is historical evidence of its use during the pandemic of 1918. The option of convalescent plasma use could be important if the stockpile of vaccines is inadequate or if the stockpiled vaccine is ineffective against the outbreak strain.      

The Critical Path Initiative also was identified as a main concern for FDA. The Office of Blood Research and Review uses research to address scientific issues that are directly related to the mission of the FDA. Priority research areas include:

·          Rapid detection of pathogens, including genetic variants, emerging infectious diseases and bioterrorism agents. This initiative is not funded and is currently in the proposal stage.

·          Development and evaluation of proteomics- and genomics-based biomarkers for efficacy, quality, toxicity and consistency of blood components as well as blood derived products and their analogues, including blood substitutes.

·          Maintaining lines of communication with industry. Participation on AABB task forces in a liaison role was cited as very helpful to the FDA.

The agency will be deploying the direct recall classification system Dec. 17, and this system will be used in conjunction with the current electronic blood product deviation report system. At the time of deployment, only blood and plasma recalls will be subject to the new electronic system and only if the original BPDR was filed electronically. The DCR system will import 90 percent of the required information from the previously filed BPDR, thus reducing the amount of time a facility would have to devote to data input related to a recall. Additionally, the agency is in the development stages of a Turbo Biologics License Application system and is considering a follow-on licensing workshop.

AABB INITIATIVES AND CURRENT PRIORITIES

AABB President Jay Menitove presented initiatives and priorities of the organization for the upcoming year. The U.S. Biovigilance Network is an important tool to advance patient safety and remains a top priority for AABB. Communicating the importance of biovigilance is critical to the success of the program, which is dependent on active engagement of the entire transfusion community to provide the data that will fuel the network, provide capital, and advocate for the network’s development and sustained operation.

Development of the next generation of leaders in transfusion medicine is a business imperative with so many current leaders projected to retire in the next decade. AABB is fully committed to mentoring and providing professional development to up-and-coming industry professionals who will serve as the backbone of transfusion and cellular therapies in years to come.

Another priority is to help the community navigate through a changing corporate investment environment in transfusion medicine and cellular therapies. There is a growing concern that fewer companies see financial return on investments in transfusion medicine and cellular therapies and are diverting resources to other more lucrative alternatives. Ongoing technological advancements are critical to ensure continuous improvements in care and safety for donors and patients. It is the responsibility of AABB and the leaders in the community to work with the public and private sectors to overcome barriers and identify potential solutions to issues that threaten advancements and the ability to deliver the highest standard of care possible.

DISCUSION OF AGENDA ITEMS

Proposed Rule on Donor Eligibility/Donor Screening – Requirements for Human Blood and Blood Components Intended for Transfusion or for further Manufacturing, November 8, 2007

Proposed Changes Conflicting with Existing Guidance Documents

There are numerous proposed changes that appear to be in conflict with current guidance documents, and the committee requested clarification on how the apparent disagreements between the proposed rule on donor eligibility/donor screening will affect published guidance documents. For example:

·          The proposed rule requires that additional questions be added to the donor history questionnaire, including recent dental procedure and major surgical procedure in past 12 months; unexplained weight loss (>10 percent in past six months); and if a health care practitioner has ever advised the donor not to donate. However, during the development of the DHQ these topics were discussed with FDA, and the DHQ has been deemed acceptable by FDA for use without the requirement to evaluate donors for these issues.

·          The published “Guidance for Industry and FDA Review Staff: Collection of Platelets by Automated Methods,” issued in December 2007, permits donors who have ingested drugs that adversely affect platelet function to be collected as long as they are not the sole source of platelets. The guidance also acknowledges that platelet counts are not always known prior to collection. In contrast, the proposed rule states a donor must not serve as a source of platelets for transfusion if the donor has recently ingested drugs that adversely affect platelet function and requires a platelet count prior to each donation.

While responding to these concerns, FDA reminded the committee that due to the extent of the rule revisions and the amount of time involved in rulemaking, some of the revisions may have been drafted before related guidance documents were published. Thus, the proposed rule may be out of sync with recommendations contained in later guidance documents. Internal working groups at FDA are evaluating the merits of the many comments to the proposed rule that were received to the docket on these and other issues. However, in the event that a final rule is contrary to a guidance document, the final rule takes precedence, and the guidance document would have to be revised.  

Eligibility Determination on the Day of Collection

At a previous FDA Liaison Committee meeting in April 2007, the use of a 24-hour period instead of calendar day to define “day of collection” for determining donor suitability was discussed. According to the published meeting notes, “FDA recognizes changes in industry practices whereby collection of blood and components may take place at varying times in a 24-hour day. FDA also appreciates that there are instances in which there is missing donor information and a need to recontact a donor to establish donor suitability on the day of collection. FDA believes that collection of additional donor information within 24-hours of the donor session could be consistent with the requirements of 21 CFR 640.3 on determination of donor suitability that, ‘… such determination shall be made on the day of collection,’ but that such an interpretation would need to be established through publication of a guidance document under FDA’s Good Guidance Practice regulations. Pending publication of any such guidance, FDA is willing to review SOPs for re-contacting donors within a 24 hour period of the donor session. FDA believes that any such SOP, including SOPs for re-contacting a donor on the same calendar day, should be part of a product deviation investigation, and that candidate SOPs should be submitted as prior approval supplements. In urgent situations where a firm needs to recontact a donor, but lacks an approved procedure in place, the establishment may contact a consumer safety office in the Division of Blood Applications to request verbal approval of a variance, followed by submission of a written request.”

The language in the proposed rule — “You must determine donor eligibility on the day of donation, and before collection” — is not consistent with the discussions at the April 2007 FDA  Liaison meeting. The committee’s overall position is that there should be an option under which already donated blood can be held in quarantine when it takes longer than “end of day” or more than 24 hours to resolve a question of the donor’s eligibility. This is especially true when the criterion at issue is one of donor safety or issues that may affect recipient safety, but are historical in nature and for which the passage of an additional day or two will not affect the response. During the discussion it was noted that there is no scientific reason why a unit of blood or blood component could not be held in quarantine while resolving any donor eligibility criteria issue. Blood and blood components already are quarantined for various reasons after collection, and inventory management systems are able to manage these complications.

FDA reiterated that all comments to the proposed rule are currently under consideration, and at this point there is no clarification beyond what was provided in 2007.

Component Plasma Licensure Pathway

Component plasma has been a frequent topic of discussion at FDA Liaison Committee meetings and is the focus of the AABB Interorganizational Plasma Task Force, which has submitted to FDA a proposal for licensure of component plasma for further manufacture.  The goal of the proposal is to license a product that can be collected manually or by apheresis, thereby allowing for the same flexibility in inventory management that is currently available for Recovered Plasma collected by manual processes. Licensure would obviate the need for a short supply agreement and would allow labeling based on product specifications contained in the agreement with the manufacturer.

FDA explained that component plasma licensure is an area of active work within the agency, and there is the potential to review the strategy at a future Blood Products Advisory Committee meeting, although nothing has been planned. However, under existing regulations, plasma collected by apheresis that will be sent for further manufacture is considered to be Source Plasma. FDA currently is developing a framework for rulemaking; however, given the timeline inherent in regulatory change, the committee stressed that a viable interim option is needed. The committee’s concerns were acknowledged, but it was stressed that a variance is not the appropriate option for changing a routine process unless the FDA has a framework for new regulation. It is expected that a draft guidance document will be informative concerning the direction of future rulemaking and will allow a process for granting a variance to current regulations. This pathway has been successfully used for dealing with collection of blood from donors with diagnosed hemochromatosis.  With regard to the timeline for issuance of draft guidance, FDA noted that it gets much closer all the time.

Several blood centers have obtained supplements to collect and label Source Plasma but do not appear to be using the option. FDA requested clarification concerning the problem of using a Source Plasma supplement; the agency has previously indicated that a supplement submission in this situation would not trigger a full-blown inspection such as would occur should a Source Plasma center request a supplement. Blood centers that are collecting concurrent plasma from whole blood donors on an infrequent basis and that already have licensed their apheresis FFP should expect a simplified supplement approval process. Committee members explained that the impediment to fully utilizing the infrequent Source Plasma option is the requirement to immediately freeze the plasma, which is not logistically feasible in many blood establishments because of the number of donations collected on mobiles or at fixed locations distant from the manufacturing site.

Pathogen Reduction  

At the January 2008 Advisory Committee for Blood Safety and Availability meeting, the committee recommended that the secretary: 1) adopt as a high priority the urgent development of safe and effective pathogen-reduction technologies for all blood transfusion products and implementation as they become available; 2) provide resources to overcome current barriers to development and validation of pathogen reduction technologies; 3) ensure adequate safety monitoring of pathogen reduced blood products post-marketing using an active national hemovigilance system; and 4) ensure that other efforts to improve blood safety and availability are not compromised by these efforts. These recommendations were endorsed by the assistant secretary of health. At the most recent FDA Liaison Committee meeting in March 2008,FDA stated that the agency’s emergent infectious disease focus was on the development of new screening tests rather than pathogen reduction. This direction/decision was driven by the scientific expertise in the agency during the past decade and the funding of bioterrorism initiatives, e.g., nanotechnology and multiplex assays.

The committee inquired about FDA activity within its labs that might enhance the agency’s knowledge, assist in solving problems encountered by industry and lead to review of a pathogen-reduced product submission. FDA indicated that the pathogen-reduction processes and technology are included in the Critical Path Initiative and are a priority for the agency. It was noted that the science of pathogen reduction is currently being applied in Europe and will soon be applied in Japan. FDA has a research program that is designed to train scientists in pathogen-reduction technology, discover how pathogen-reduction processes might affect blood products, develop biomarkers to measure any product damage, develop animal models, and study adverse events. Because the technology has been implemented in Europe, there are large amounts of data that FDA could utilize, provided the data are sufficiently robust to meet U.S. regulatory requirements. It was noted that the CE mark used in Europe is not equivalent to FDA approval and that many EU countries impose additional requirements — similar to what FDA would require — before the product can be marketed in a specific country.

FDA also noted that European studies are funded by the governments, which are responsible for the delivery of health services. In the U.S., the government and user community are not always the same, and funds from the user community could serve to expedite the research. In response to a question from the committee regarding AABB and blood community support for this initiative, FDA indicated that advocacy for research funding on matters of priority is always welcomed.

Increasingly Limited Number of Blood Screening Assay Manufacturers and Assays

The number of manufacturers in the market place for blood donor screening assays has been shrinking. This trend can lead to deterioration of the performance characteristics of the remaining assays and/or delay improvements of test performance. Due to the extensive commitment of resources, including funding to develop, validate and bring a product to market followed by limited return on investment, there is concern that there will be no further improvements to existing assays; no new assays brought forward for existing markers, including confirmatory assays; and no new marker tests available as needed in the event of an emerging agent. Test kit manufacturers see a shrinking market and increases in costs that cannot be recovered, and they have shifted their investments for research and development to other markets with a greater return on revenues.

FDA recognizes the seriousness of this issue and believes that the agency, manufacturers and the blood community have a shared responsibility to enhance communication, particularly in the areas of emerging agents and improvement of current assays. Discussions at public meetings have revealed that concerns focus on clinical trial requirements, the product review and approval process, and cost issues associated with bringing a product to market.

The discussion included alternatives to full-scale U.S. trials, such as: 1) use of panels (although given the difficulty of obtaining a representative panel for some markers, this might not be helpful); 2) use of data from outside the U.S. when it is sufficiently robust to meet FDA requirements; 3) use of small preclinical trials. Other issues discussed included alternative regulatory pathways to licensure, public funding to defray the costs and establishment of centralized testing laboratories for re-entry testing if consideration could be given to use of assays not currently licensed as confirmatory/supplemental in the U.S. 

The suggested path forward is to bring organizations — public and private — together to identify and discuss the barriers and to emphasize that the diminishing number of manufacturers in the blood industry is a public health issue. It was noted that many of these same issues were faced by the vaccine industry but were turned around when government funding became available, stimulating economic growth in this area.

September 2008 Blood Product Advisory Committee Topics

Bacterial Testing of Platelets

FDA engaged the BPAC in a discussion of seven-day apheresis platelets and asked the committee to evaluate the merits of a new PASSPORT study that uses an additional test late in the storage period versus an approach that would use enhanced techniques during collection and culture set-up, with a focus on clinical outcome of the transfusion instead of microbiological outcome (results of culture). FDA and study sponsors are in agreement that baseline data on age of platelets at time of transfusion and active surveillance of transfusion reactions are needed. BPAC agreed with FDA’s approach for performance of a second culture on day five in order to store apheresis platelets for seven days.

Blood centers that are interested in a new PASSPORT protocol have pointed out that the product at day five would, in most cases, not be within the control of the blood centers but would be in a hospital transfusion service, which would make compliance very difficult. For example, while hospital laboratories are capable of performing blood cultures, they do not necessarily have the culture systems that are approved for use in the PASSPORT protocol, and their inventory management processes are not supportive of product culturing and relabeling. In discussions with members of the FDA Liaison Committee, FDA representatives recognized the public health benefit of having seven-day platelets available if safety concerns can be alleviated and noted that a new study should include an intervention to increase safety and provide a method to obtain baseline contamination rates that can be compared to contamination rates at day seven. When asked to clarify viable alternatives, agency representatives mentioned the possibility of a two-tiered study whereby participation by facilities that perform blood collection and function as a transfusion service might contribute sufficient data from secondary cultures, while other participants might only provide surveillance culture data. A role for adjunct QC testing might also be defined. Conversations to explore these and other alternatives are ongoing with study sponsors. 

Many facilities currently use surrogate tests, such as pH or glucose, to detect bacterial contamination of whole blood-derived platelets rather than a culture-based test. When asked to comment on current considerations for a stand-alone, point-of-issue test to be used for leukoreduced and nonleukoreduced whole blood-derived platelets, or pools, FDA acknowledged the importance of such a test to increase the safety of platelets that are currently tested using surrogate methods rather than a culture test. The committee was informed that spiking studies to show analytical sensitivity of candidate tests have been allowed; this method would not be limited to leukoreduced products unless the manufacturer determines that leukocytes have an inhibitory effect.

Blood Donor Screening and Deferral/Re-entry Due to Malaria Exposure

Current recommendations from FDA on blood donor screening for risks related to malaria are found in a 1994 guidance document. A revised guidance document was published in draft form in June 2000, but the recommendations never became final. In the intervening years, the topic has continued to be discussed in public venues. FDA and HHS sponsored a workshop in July 2006, and at the September 2008 BPAC meeting, FDA engaged the committee in a discussion of options for blood donor screening and re-entry for malaria.

Data presented at BPAC indicated that the malarial risk for travelers to Mexico is minimal, yet such travel accounts for the majority of the malarial deferrals of U.S. donors. The elimination of a deferral period for travel to Mexico — supported by the blood community — would increase the risk of transmission by a very small amount, which could be mitigated by strengthening deferral policies that are applied to those donors who are the source of almost all transfusion-transmitted malaria.

On the recommendation of BPAC, FDA is considering alternative approaches to blood donor screening and the associated risks. FDA will participate in the AABB task force looking at various ways to analyze transfusion-transmitted malaria that reflect its current epidemiology and transfusion-transmission risk in the U.S.     

Iron Status of Blood Donors

The BPAC was asked by FDA to discuss several issues related to iron status in blood donors, including whether iron depletion in donors is a concern. The committee unanimously voted that iron depletion in frequent blood donors is a concern but was unable to provide clear recommendations regarding donor testing or mitigation strategies.

FDA representatives acknowledged this concern and indicated that this issue is a high priority for the agency. It was placed on the BPAC agenda due to recently published articles and discussions concerning a shrinking blood donor base and because the recently released proposed rule on donor eligibility and donation suitability raised the question of different qualifying values for male donors versus female donors.

The FDA Liaison Committee discussions touched on many of the same issues and questions that were discussed at the September BPAC meeting:

·          Some donor populations might warrant a work-up prior to beginning an iron supplement, while others would not.

·          The potential that iron supplementation would mask an undiagnosed disease.

·          The appropriate form of iron that would be recommended or provided.

·          The potential liability a blood center assumes if the relationship with the donor is actually that of doctor and patient.

·          A neutral approach, and one that is practiced by some blood centers, is to provide iron supplements to equal the amount of iron that is routinely lost via a blood donation.

The U.S. is not the only country exploring this topic, and there was general agreement that a discussion would be timely.

Workshops

Babesiosis

The FDA-sponsored workshop held Sept. 12 to consider approaches to reduce the risk of transfusion-transmitted babesiosis in the U.S. provided a significant amount of information. FDA was asked to explain its current considerations with regard to blood and HCT/P donor screening.

Additional studies on the risk of transfusion transmission of Babesia by asymptomatic donors and the appropriate testing method to be used (antibody vs. DNA, or a combination of both) need to be performed. Liaisons from FDA will participate in the AABB task force looking at Babesia and other tick-borne diseases with the goal of analyzing risks to the U.S. blood supply and developing scenarios to mitigate the risk.

Blood Establishment Computer Software

FDA provided an update on the July 2008 BECS Workshop sponsored by the Alliance of Blood Organizations and some of the next steps it is considering. The workshop was well attended and included representatives of blood organizations — technical and managerial staff as well as CEOs — manufacturers of BECS and FDA.

The “next steps” that were taken away from the workshop by the FDA were:

·          There needs to be greater communication at all levels, specifically among quality assurance, information technology and operational personnel, CEOs, FDA, and the manufacturers.

·          FDA should review the 510(k) process to see if it could be modularized.

·          FDA should consider providing a guidance document for validation and submission of a 510(k). There is some guidance available, but one document focused on BECS could be helpful.

·          A follow-up workshop, perhaps in 2009, is being considered.

Publication of Documents

The significant delay in publication of guidance and regulations was a final topic of discussion, with committee members emphasizing the importance of some of the documents. For example, updated versions of the AABB Donor History Questionnaire can be implemented only through the prior approval supplement process until such time as the draft guidance related to vCJD risk in France — originally published in August 2006 — is issued in final form. Follow-up testing and donor notification based on use of nucleic acid testing results, without performing HIV western blot or HCV RIBA, is currently being exercised through a variance process until the July 2005 guidance on NAT testing is issued with final recommendations. While it is understood that the actual content of documents awaiting publication cannot be discussed, the committee members noted that current agency procedures do not even keep blood establishments informed as to progress toward publication of the documents. FDA representatives, while not able to state when a particular document in question would be published, acknowledged that transparency of the process is a concern and is being discussed. 

Participants:

AABB

Jay Menitove, MD, AABB President

J. Daniel Connor, MM, AABB Past President

Karen Shoos Lipton, JD, Chief Executive Officer, AABB

Col. Steven Beardsley, MS, MT(ASCP)SBB, DoD

Celso Bianco, MD, ABC

Khatereh Calleja, JD, AdvaMed

Gerald Sandler, MD, CAP

Mary O’Neill, MD, ARC

Harvey G. Klein, MD, AABB Standards Program Committee

M. Allene Carr-Greer, MT(ASCP)SBB, AABB

Joseph L. Giglio, MS, MT(ASCP)SBB, CSQE(ASQ), CQA, AABB

Aaron Lyss, BA, AABB

FDA:

Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), Center for Biologics Evaluation and Research (CBER)

Martin Ruta, JD, Regulatory Counsel, OBRR

Hira Nakhasi, PhD, Director, Division of Emerging and Transfusion-Transmitted Diseases (DETTD), OBRR

Paul Mied, Ph.D, Deputy Director, DETTD, OBRR

Sheryl Kochman, BS, MT(ASCP), Acting Director, Division of Blood Applications, OBRR

Leslie Holness, MD, Chief, Blood and Plasma Branch, OBRR

Jaroslav Vostal, MD, PhD, Chief, Laboratory of Cellular Hematology, Division of Hematology (DH), OBRR

Salim Haddad, MD, Medical Officer, DH, OBRR

Judy Ciaraldi, BS, MT(ASCP)SBB, CQA(ASQ), Consumer Safety Officer, DBA, OBRR

Seamus O’Boyle, Public Affairs Specialist, Office of Communications, Training and Manufacturers Assistance, CBER

David Asher, MD, Supervisory Medical Officer, DETTD, OBRR

C.D. Atreya, PhD, Associate Director for Research, OBRR

Jennifer Scharpf, MPH, Associate Director for Policy, OBRR

Linda M. Alms, Microbiologist, OBRR

Laura D. Hieronymus, Consumer Safety Officer, OCBQ, CBER

Diane Maloney, JD, Associate Director for Policy, Office of the Director, CBER