CURRENT FDA INITIATIVES AND PRIORITIES
Karen Midthun, MD, director, Center for Biologics Evaluation and Research, Food and Drug Administration, recognized AABB's role as a partner in safety initiatives and the AABB voluntary standards as complementary to regulations and informative to the agency's decision making. She further noted the important work of the association's task forces and committees. Other initiatives, priorities and updates included the following:
- CBER is staying attuned to current Center for Device and Radiological Health interest in fostering medical device innovation and making the 510(k) program a blueprint for smarter medical device oversight.
- Executive order that requires the agency to submit a plan with the goal of making the regulatory system less burdensome.
- FDA has several public workshops planned for 2011 - procoagulant activity in immune globulin products, toxicities related to hetastarch, donor deferral hemoglobin standards, and quarantine and release errors. The workshops will be announced on the FDA
- FDA is using population-based administrative databases to assess occurrence and risk factors of transfusion-related adverse reactions such as thrombotic adverse events related to immune globulins, developing methods to conduct near real-time surveillance of transfusion-related adverse events and evaluating occurrence of serious transfusion-related adverse events and risk factors among elderly and non-elderly in the U.S. Validation of data being used may occur in the medical records department prior to entry.
eSubmitter pilot evaluation program for Whole Blood and Blood Components has received 11 submissions from the nine establishments enrolled. It is a pilot program, and a few changes have been made to the program as it has been used.
FDA Basics for Industry was launched in January and provides a range of Web-based basic services.
CURRENT AABB INITIATIVES AND PRIORITIES
Jim AuBuchon, president, AABB, noted that the Interorganizational Task Force on Domestic Disasters and Acts of Terrorism and, in particular, several of its subcommittees were actively monitoring supply chain issues related to the earthquake and tsunami disaster in Japan. Supplies to date have not suffered interruptions or contamination, and FDA was asked for an update of their considerations on the situation. Jay Epstein, director, Office of Blood Research and Review, responded that the agency had allotted considerable resources to monitoring the situation and preparing scientifically and operationally sound plans to address donor evaluation for radiation exposure, should the need arise. Several scenarios have to be considered — marrow suppression can be delayed for approximately 60 days following an initial feeling of sickness, exposure that was internal (e.g., due to ingestion of vegetables), and external exposure due to materials that were possibly contaminated and left Japan. The recommendations under consideration could be released as draft or for immediate implementation.
Epstein also responded to a question about potential federal agency shutdowns due to budget negotiations and said that essential FDA services would continue.
SPECIFIC TOPICS OF DISCUSSION WITH FDA
History of Chagas' Disease
The December 2010
guidance document published by FDA recommends that every allogeneic blood donor be tested at least one time for antibodies to T. cruzi and asked at every donation for a history of Chagas' disease. However, the guidance document did not provide a reference for evidence that asking this question will improve safety beyond what is achieved by performing the test. Test results are not captured from donors who respond yes, and questions that are not enhancing safety increase the complexity of the history and divert the attention of the donor from other more important issues. FDA participants were asked about the utility of questioning donors concerning a history of Chagas' disease and responded that the recommendation contained in the guidance encompasses the principles of multiple layers of safety. Generally, prior to introduction of a test, questions are used as a primary screening tool and assume a secondary role following introduction of a test.
Further discussion emphasized AABB's goal to review and remove from the donor history questionnaire any question that is of little to no value, in support of increasing the donor's focus on questions that will provide a greater return on increasing safety. FDA participants indicated a willingness to review a proposal/data regarding this concern.
Donor Safety Deviations
On occasion, blood establishments discover that a product has been collected without appropriate documentation of information that is strictly for the well being of the donor, e.g. pulse and blood pressure, and an otherwise acceptable product is manufactured. Eligibility criteria that would be considered an indicator of risk to the recipient were appropriately assessed prior to donation. FDA was asked the following: if the facility is capturing incidents of this nature — deviations related to donor safety — in the establishment's deviation investigation protocol and investigating them for purposes of process improvement, is this sufficient in order for the medical director to be able to release these products to inventory without having to call FDA first.
With explanation that safety, potency and purity of the product must be assured and that donor safety standards cannot be ignored, the answer was yes. FDA participants further explained that policies must be in place to maintain control of processes.
The November 2010 FDA Liaison Meeting included a brief discussion related to a review and potential relaxation of criteria for variant Creutzfeldt-Jakob disease, or vCJD, deferrals. The specific question for discussion at the 2010 meeting was whether FDA would consider the performance of a formal risk assessment of the potential for transmission of vCJD by transfusion from 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. At that time, FDA participants noted that they were developing a new model and would welcome data on deferred allogeneic whole blood donors.
FDA Liaison Committee members remain interested in this issue and asked what data could be provided on deferred allogeneic donors (vCJD-associated risks) that would inform the new model. However, the model is not fully developed, and it seems there is concern that travel deferral data may not be useful, as the period of time that donors are being asked to recall is lengthy and it is not certain how reliable their recall would be.
Leukoreduction of Blood Components
Draft Guidance for Industry "Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion," published January 2011, provides recommendations for statistical sampling approaches based on the binomial statistics, scan statistics and hypergeometric distribution. Experience with these approaches to quality control of leukoreduced cellular products has not been piloted by the FDA statisticians or published in the literature. There is concern that the recommendation for using one specific statistical approach versus another is based on theory, without actual validation in the manufacturing environment of blood centers. This may create problems, should the current filters not behave as predicted. How will this impact production? What will be the clinical benefit? Members of the committee suggested the possibility of assisting FDA with conducting studies in collaboration with licensed establishments for validation of these and maybe other statistical approaches to quality control for leukoreduction of whole blood and blood components.
FDA participants noted their reason for recommending only a binomial method for purposes of validation is that, in their opinion, it offered the appropriate confidence level for the 5 x 106 specification. The clinical reasons for which the leukoreduced products are being transfused implied the need for a statistical-based approach to validation and monitoring. FDA participants did not respond to the suggestion for collaborative studies to validate the suggested approaches.
Bacterial Contamination of Platelets
The private sector has recognized that bacterial contamination of platelets represents the largest risk of pathogen transmission currently extant in the blood supply. In order to reduce that risk, several accrediting organizations have required implementation of steps to reduce the likelihood of contamination reaching the unit and/or application of a testing method to detect bacteria that reach the unit. Under current requirements of AABB and CAP, it is believed that all platelet units being transfused in the U.S. have been tested using an FDA-cleared test or one of equivalent sensitivity.
The FDA has recognized many other pathogen risks in the blood supply and has taken steps to ensure that effective tests are being applied to reduce these risks (or required use of health screening questions when tests were not available). FDA participants were asked about current considerations regarding formal recognition by FDA of this risk and a recommendation for application of an effective testing method to detect bacterial contamination in platelet products. In addition, they were asked to explain what would be required of a test to be designated a release test.
In response, it was noted that requirements related to a release test for bacterial contamination in platelet products was discussed at the
March 2006 BPAC meeting. Regarding application of effective testing methods to detect bacterial contamination in platelet products, FDA encourages the use of both technologies currently in use (culture and point of issue), as they both contribute to safety of the transfused product.
24-Hour Room Temperature Hold of Whole Blood
Members of the blood community and manufacturing industry are very interested in having the option of making components from whole blood that has been held at 20-24 C for up to 24 hours. The January 2011 Transfusion Supplement provided a review of the subject. FDA was asked to provide its current considerations regarding the requirements of a clinical trial that could lead to licensure of components generated from a unit of whole blood kept at room temperature for longer than eight hours, and up to 24 hours. It was noted that data generated by Canadian Blood Services, as submitted to Health Canada, was available to document the safety and efficacy of the components. FDA participants noted that they have been in conversation with some U.S. sponsors about requirements. The AdvaMed representative present at the meeting agreed that manufacturers are working through the BEST collaborative to get at some issues that must be addressed.
REMS (Risk Evaluation and Mitigation Strategies) Applied to BLAs
The September 2009 Draft Guidance for Industry "Format and Content of Proposed REMS, REMS Assessments, and Proposed REMS Modifications" indicates that products regulated by both CDER and CBER are covered by REMS. CDER has used REMS for more than160 new medications as of February 2011. FDA participants were asked if REMS could be used to move a new pathogen-reduced blood component product to market more quickly, including U.S.-based postmarket surveillance, by limiting its use to adults requiring only a specified number of doses.
In response, FDA explained that a sponsor must first establish the safety and effectiveness of a product before REMS can be applied. Once safety and efficacy are established, REMS may be required to ensure that the drug's benefits outweigh its risks. However, to date, we have not identified a safe subset of patients in whom the pathogen-reduction technology can be used. FDA participants also noted that post-marketing strategies and commitments are commonly used tools.
FDA was asked to address the request for contact information in the following scenarios:
Discrepant information/responses between consumer safety officers and field representatives.
When this occurs during an inspection, it is best to tell the lead inspector that there is a discrepancy and ask the lead to call CBER. If this is not during the inspection, then the establishment could call the consumer safety officer.
An ongoing FDA inspection and the inspector is confrontational.
The advice given was to call the district office and speak with the supervisor. If by chance the blood establishment does not have a relationship with the office, the contact information can be obtained from the Form 482 that the inspector presented at the beginning of the inspection.
A biologics license application submission for which they cannot obtain a response or other feedback in a timely manner.
The CSO is the first point of contact. When that does not result in a response, then ask for the chief of the Blood and Plasma Branch (Dr. Leslie Holness).
Guidance Documents /Rules
Several items continue to be of concern, and FDA was asked for any new information that can be provided.
A guidance document that will allow use of the abbreviated donor history questionnaire submitted by the AABB Donor History Task Force.
The guidance document continues to have high priority in the Office of Blood, and whenever it is returned to have a question addressed, the appropriate priority is assigned. Participants at the meeting were not able to say when it will be issued, only that it would be a draft guidance. The goal of acceptance through guidance is that licensed establishments would be able to report implementation in the establishment's Annual Report.
A guidance document that would allow blood collection, without deferral for malarial risk, from U.S. residents who have visited Quintana Roo, Mexico.
The guidance is in progress and will include the considerations of the
November 2009 BPAC meeting and a definition of residency.
A guidance document that would provide a process for plasma collected by automated methods, from donors qualified under the whole blood donor regulations, to be used in further manufacturing.
This subject will be discussed at the
April 2011 BPAC meeting.
Publication of "Revisions to Labeling and Storage Requirements for Blood and Blood Components, Including Source Plasma" (proposed rule, July 2003) as a final rule so that, among other things, thawed FFP (fresh frozen plasma) and PF24 (plasma frozen within 24 hour of collection) no longer require a variance in order to be kept 24 hours after thaw.
FDA had no update.
Blood donors and products are tested and managed according to the
1991 memorandum released by FDA. A
draft guidance issued for comment in 2003 has not been finalized. In response to a question asking what data drive the requirement to screen donors for syphilis, FDA participants noted that as recent as 2010, American Red Cross data from serological testing revealed a reactive rate of approximately 1:26,000. The testing was performed with an automated specific antibody test — available automated methodology is treponemal based — and it is not known if this represents current active infections. Culture data would be required to help resolve the question of current usefulness of the screening process, and the study has not been performed. In the interim, FDA believes that universal screening for syphilis is a valid safety measure.
Karen Midthun, MD, Director, Center for Biologics Evaluation and Research (CBER)
Diane Maloney, JD, Associate Director for Policy, CBER
Barbara Buch, MD, Associate Director for Medicine, CBER
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Ginette Michaud, MD, Deputy Director, OBRR
Alan Williams, PhD, Associate Director for Regulatory Affairs, OBRR
Jennifer Scharpf, MPH, Associate Director for Policy and Communications, OBRR
Martin Ruta, PhD, JD, Regulatory Counsel, OBRR
Hira Nakhasi, PhD, Director, Division of Emerging and Transfusion-Transmitted Diseases (DETTD), OBRR
Paul Mied, PhD, Deputy Director, DETTD
Robin Biswas, MD, Senior Regulatory Scientist, DETTD
David Asher, MD, Laboratory of Bacterial, Parasitic, & Unconventional Agents, DETTD
Sanjai Kumar, PhD, Supervisory Research Biologist, Laboratory of Hepatitis and Related Emerging Agents (LHREA), DETTD
Robert Duncan, PhD, Staff Scientist, Laboratory of Emerging Pathogens, DETTD
Jaroslav Vostal, MD, Chief, Laboratory of Cellular Hematology, Division of Hematology (DH), OBRR
Nisha Jain, MD, Chief, Clinical Review Branch, DH
Richard Davey, MD, Director, Division of Blood Applications (DBA), OBRR
Sheryl Kochman, MT(ASCP), Deputy Director, DBA
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
Mark Walderhaug, PhD, Associate Director for Risk Assessment, Office of Biostatistics and Epidemiology (OBE), CBER
Hong Yang, PhD, Biologist, OBE
Gilliam Conley, MT(ASCP)SBB , Director, Division of Inspections and Surveillance, Office of Compliance and Biologics Quality (OCBQ), CBER
Lore Fields, MT(ASCP)SBB, Consumer Safety Officer, BPB
Faye Vigue, MT (ASCP), Consumer Safety Officer, DMAT, MATTB, OCOD, CBER
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
Celso Bianco, MD, ABC
Ruth Sylvester, MT(ASCP)SBB, ABC
Richard Benjamin, MD, ARC
Mary O'Neill, MD, ARC
Khatereh Calleja, JD, AdvaMed
William Turcan, MT(ASCP)SBB, ASBP
Gerald Sandler, MD, CAP
Phil Schiff, JD, Division Director, AABB
Becky See, MLS, Deputy Director, Regulatory Affairs, AABB
Aaron Lyss, BA, AABB