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 regarding donor and patient safety, and product manufacturing. The committee includes liaisons from AABB, the Advanced Medical Technology Association, America's Blood Centers, the American Red Cross, the Armed Services Blood Program and the College of American Pathologists.
Peter Marks, MD, PhD expressed appreciation for the opportunity to discuss issues facing the blood community. FDA discussed the impact that the pending Congressional budgetary issues for FY2014 would have on the agency. In the event a federal operating budget is not established for FY2014, FDA would remain open, but only for essential staff for public health safety issues. If a budget is established, it is expected that FDA would operate under a similar FY13 budget (i.e., a sequestered budget).
The Food and Drug Administration Safety and Innovation Act (FDASIA), enacted in 2012, renewed several existing user fee programs and established new user fees for generic drugs and biosimilar products. FDASIA provided FDA additional authority over the drug supply chain and drug supply shortages, and enabled FDA to implement a management review process to create a more structured review process, which will be funded by user fees. Other notable aspects of FDASIA are mandates for more patient-focused workshops including additional patient representatives in such workshops. FDASIA also brought about a new expedited review process based on surrogate clinical data for life-saving products, which is called a Breakthrough Therapy Designation. CBER has not determined how widely the process will be used.
In effort to harmonize national and field office inspections, program alignment is being considered to facilitate such an effort and ensure inspections are performed in a more consistent manner. Additionally, CBER is keeping an eye on pharmaceutical compounding legislation as it is being developed by Congress to ensure such legislation does not adversely affect the blood supply. For example, splitting components to address the medical needs for pediatric patients might be considered compounding under a broad interpretation of some proposed legislation.
In April 2014, there will be a major relocation of the Office of Blood Research and Review to the new White Oak campus in Silver Spring, Md. This move will bring the regulatory and research functions together in one location. It was noted that staff involved with the influenza functions of CBER will relocate to the White Oak campus after the end of the flu season.
As a follow-up to earlier committee discussions, Dr. Marks emphasized continued efforts to improve inter-center communication with the Center for Drug Evaluation and Research (CDER) when a contraindication for blood donation is included in newly approved package labeling for drugs regulated by CDER. The FDA participants also noted that the recently finalized Unique Device Identification (UDI) final rule does not apply to blood and blood components themselves; however, the UDI does apply to medical devices that are related to blood collection, processing and storage.
Susan Stramer, PhD, AABB president, provided an overview of recent association activities and topics relevant to recipient and donor safety. The evolution of AABB policy with respect to transfusion-related acute lung injury (TRALI) was summarized. Updated standards for TRALI risk reduction were approved by the AABB Board of Directors for the 29th edition of Standards for Blood Banks and Transfusion Services that will take effect on April 1, 2014. The development of the standards included a 60-day public comment period, followed by a public workshop, "Current Perspectives on TRALI Risk Reduction," held in July 2013 as an opportunity for feedback to be considered before the final recommendation of standards was provided to the AABB Board of Directors. An update on other AABB standards setting activities was given. The sixth edition of Standards for Cellular Therapy Product Services took effect on July 1, 2013. The second edition of the Standards for Molecular Testing for Red Cell, Platelet, and Neutrophil Antigens became effective on October 1, 2013. In addition, the eighth edition of Standards for Immunohematology Reference Laboratories became effective on October 1, 2013. A new set of standards for patient blood management is being formed and expected to be ready for public comment in October 2013.
The work of the Quarantine Release Errors (QRE) Task Force, which was created following a FDA/United States Department of Health and Human Services-sponsored and industry co-sponsored workshop in September 2011, also was highlighted. The task force developed a white paper that was published in August 2013. The white paper contains common terminology, including a consensus definition of QREs and processes to stratify risks of QREs. It also explores work environments and human factors that might contribute to QREs and provides references, suggested reading lists and appendices.
Updated materials related to emerging infectious disease tracking and recommendations were summarized. Association Bulletin #13-02, "West Nile Virus Nucleic Acid Testing – Revised Recommendations," was published in June 2013. The recommendations in this bulletin update previous criteria used to convert to individual-donation nucleic acid testing (NAT) from mini-pool-NAT, (MP-NAT), and reversion to MP-NAT following cessation of West Nile virus activity. Association Bulletin #13-03, "Updated Criteria for Donor Deferral and Blood Component Retrieval in Known or Suspected Common Source Outbreaks of Hepatitis A Virus Infection," was published in July 2013. It contains recommendations regarding hepatitis A common source outbreaks or situations where an infected food handler has been identified and postexposure prophylaxis has been recommended for persons exposed to potentially contaminated food. Lastly, several new and updated fact sheets by the Emerging Infectious Diseases subgroup of the Transfusion Transmitted Diseases (TTD) committee were summarized. In July 2013, a new fact sheet for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was created and fact sheets titled Anaplasma phagocytophilum, Babesia Species, Ehrlichia Species, and Hepatitis A Virus were updated. Pathogen reduction tables were also updated to include Octaplas, a solvent/detergent-treated plasma product.
AABB's hemovigilance activities were summarized. AABB's patient safety organization (PSO), the AABB Center for Patient Safety, confidentially analyzes data on adverse reactions and incidents associated with transfusions for PSO members through the Centers for Disease Control and Prevention National Healthcare Safety Network. Services offered to PSO members include benchmarking, data review and quality control, member training for properly classifying reports, and analysis. In addition, AABB and its Donor Hemovigilance Working Group expect to release the first annual Donor Hemovigilance Report for 2012 participants entering data into the Donor HART (Hemovigilance Analysis & Reporting Tool) software.
AABB-proposed TRALI standards will require the use of plasma for transfusion from donors with low risk of having alloreactive antibodies. Blood centers are currently unable to meet the need for low-risk group AB plasma for transfusion. Diminishing demand for and collections of whole blood, coincident with declining red blood cell transfusions, further threatens the plasma supply of this and other blood types. Plasma collected concurrently with plateletpheresis is a potential source to meet this demand. Availability of platelet additive solutions (PAS) can provide additional plasma for transfusion by apheresis. Routine collection of apheresis plasma concurrently with platelets would help fill the need for TRALI low-risk plasma, with excess plasma being sent to fractionation to offset the cost of PAS and maintain maximal flexibility to avoid waste of the resource. However, blood centers are inhibited by current rules preventing the routine conversion of apheresis plasma to fractionation, requiring complex collection algorithms to collect and freeze plasma from selected donors, or routine wastage of excess apheresis plasma.
AABB's Interorganizational Plasma Task Force and Liaison committee continue to encourage FDA to rapidly facilitate a simple pathway that allows apheresis plasma collected concurrently with platelepheresis to be used for transfusion or fractionation, as clinical needs for transfusion vary.
In addition to hearing a response to the issue described above, the Liaison committee asked for an update of the agency's current considerations for apheresis PF24 (Plasma Frozen Within 24 Hours After Phlebotomy) and PF24RT24 (Plasma Frozen within 24 Hours After Phlebotomy Held at Room Temperature Up To 24 Hours After Phlebotomy) and how these products will fit into the regulatory scheme currently under development for plasma for fractionation.
The FDA representatives restated their commitment to providing a flexible pathway that allows plasma collected by manual and automated methods with a cellular product (concurrent plasma) to be used for further manufacture. They reviewed the process of rulemaking that is necessary and noted that other existing regulations have to be taken into consideration (e.g., source plasma, fresh frozen plasma and short supply agreements), as well as devising standards* for the new product. The April 2009 Blood Products Advisory Committee (BPAC) discussion regarding informed consent is an important consideration for the agency. FDA still intends to publish its current thinking in a draft guidance document. When responding to a question about the range of transfusable products that would be covered in the draft guidance, the FDA participants indicated it is their intent that the newly licensed PF24 and PF24RT24 would also fit within the regulatory scheme.
*Note: The AABB Interorganizational Plasma Task Force proposed "open-ended" labeling with regard to freezer temperature and time the product was place in the freezer to allow the final product manufacturer to determine the appropriate specifications. FDA is considering different labeling standards for different "collected" products as an alternative to the task force proposal.
AABB's Transfusion Transmitted Diseases committee monitors information on MERS-CoV as it becomes available and the Emerging Infectious Diseases subgroup of TTD has created a MERS-CoV Fact Sheet.
Liaison committee members reported on daily surveillance performed by members of the TTD Committee to follow the epidemic curve of MERS-CoV. What remains an unanswered question is whether the agent is viremic. The FDA participants reported the same surveillance activity by various Public Health Service (PHS) agencies as well as ongoing studies looking for evidence of viremia. The World Health Organization is sponsoring international reference preparations with a focus on serology reagents for epidemiology studies, and previously released special travel alerts for pilgrims traveling to Saudi Arabia.
Recent discussions of the Liaison committee with the FDA indicated that the agency will communicate in the near future on the subject of detection of bacterial contamination in platelet components and the communications will likely touch on point-of-issue (POI) testing. As of mid-August there are two manufacturers with POI quality control products cleared for use with apheresis platelets and whole-blood-derived platelets.
The Liaison committee would like to have a clear understanding of how CBER and the Office of Blood Research and Review see its authority to require POI testing for platelet bacterial contamination in hospital transfusion services – is there a path via guidance or does this require rulemaking, or both?
The FDA participants noted a draft guidance remains a high priority and the agency is actively working on the guidance. FDA is considering the data and stakeholder input received at the AABB public workshop and the September 2012 BPAC discussions and recommendations, as well as the various methodologies available to detect bacterial contamination in blood products. FDA noted that its regulations apply to hospital laboratories under the oversight of the Centers for Medicare and Medicaid Services.
Blood centers have established limits/acceptance criteria for vital signs in standard operating procedures (SOPs) as a requirement of the Code of Federal Regulations (CFR) although there are robust data demonstrating that pulse and blood pressure, or BP, do not predict reactions. FDA investigators have reviewed these SOPs and inconsistently cited blood establishments with observations about the acceptability of the established limits. There is no guidance document or regulation that defines the specified limits.
The Liaison committee asked for a discussion to better understand the position of the FDA on the observations being cited by the investigators.
Liaison committee members provided the rationale behind AABB's decision to drop the requirement in Standards for Blood Bank and Transfusion Services to measure BP and pulse due to a lack of predictive value; sex, age, and volume of blood loss all had higher value. Also included was information on the recent study performed by Héma-Québec for Health Canada prior to the decision by Health Canada that pulse no longer be a required element of blood donor evaluation.
The FDA participants reviewed current regulations and reminded the committee that an important regulation is that an establishment must comply with the requirements of its SOPs. Other regulations include "within normal limits" for BP, and the need to establish limits for measurements that are taken. Pulse is not required by current regulations; it is included in a 2007 proposed rule, "Requirements for Human Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use," as are the upper and lower limits for BP and pulse that FDA judged to be industry practice at the time. The BPAC met in November 2009 to discuss relevant parts of the proposed rule in light of the fact that AABB had dropped its requirement for BP and pulse. The BPAC concluded that pulse is not a strong indicator for donor reactions and there is a lack of data on reactions for donors with BP greater than 180 mmHg. The BPAC had no clear recommendations for the agency.
Regarding the FDA investigator observations, the FDA participants noted that there has not been a reference to a firm having established inappropriate limits for BP and/or pulse in a regulatory letter as there is no regulation that can be referenced. It is not easy to search FDA Form 483s to see if or how often investigators may have listed such an observation on the form. As a helpful hint, the following reminders were offered:
- During an inspection it is best, and most efficient, for the firm to speak directly with the investigator who is on site.
- If a firm believes an investigator needs clarification on a subject, the firm can suggest the investigator call CBER.
- If/when a firm believes an investigator is inappropriate, the contact information for the district office, located at the top of FDA Form 482, should be used.
The Liaison committee would like to have an update from any of the studies/reports the agency is following that will have bearing on considerations for revision of the current policy for deferral of men who have sex with men (MSM) from blood donation.
A PHS working group was charged to develop and carry out scientific studies to validate candidate revised eligibility criteria for MSM as blood donors: one operational and three research projects were approved.
Operational assessment – There should be action to investigate and reduce the risk of quarantine release errors — accidental release of blood not suitable for use. QREs potentially become more of a safety issue if a large influx of individuals with prevalent infection were to appear for blood donation. FDA sponsored a public workshop in September 2011 to discuss the extent and characteristics of blood establishment QREs and the levels of control offered by blood establishment computer software (BECS) management of blood inventory. Following the workshop, AABB formed an interorganizational task force to develop common terminology and further explore several factors involved in QREs. The task force published a white paper in August.
Research studies
- The Centers for Disease Control and Prevention's National Center for Health Statistics has completed a cognitive evaluation of the AABB Donor History Questionnaire (DHQ). The goal of the study is to understand if potential blood donors correctly understand and properly interpret the current standard questionnaire used to obtain donor history. Data collection is finalized and the analysis is in progress.
- REDS II (Retrovirus Epidemiology Donor Study) sites were identified for a study of transfusion-transmitted viral rates and risk factors, in an effort to determine the current epidemiology of infectious disease markers in U.S. blood donors, and how incidence and prevalence of these markers relate to the risk of blood-transmissible diseases and risk factors in current donors. Data collection has been completed and analysis is underway.
- A REDS III study – Blood Drops – will undertake to define what motivates a male with MSM behavioral history to donate, and would MSM be likely to comply with modified deferral criteria. The study started in May; data are expected to be available not earlier than April 2014.
Study data will be used to improve understanding of current epidemiology and knowledge, attitudes and behaviors about donation. A better understanding of non-compliance may inform potential safety improvements and/or interventions. Analysis of the AABB DHQ may identify flaws in question design and/or lead to development of new questions (including non-MSM) and improve donor attention to the screening process.
"Draft Guidance for Industry on Contract Manufacturing Arrangements for Drugs: Quality Agreements"
In the
draft guidance, FDA recommended use of written Quality Agreements to delineate responsibilities and assure the quality, safety and effectiveness of drug products. AABB provided brief comments in support of written Quality Agreements and encouraged FDA to recognize the variability in Quality Agreements that different facilities will use to describe contract manufacturing arrangements, noting that "there is no one template that works for all facilities, even for those facilities that are contracting out the same operation." Additional member remarks include brief discussions about whether blood establishments would identify the applicability of this guidance document for their operations and would identify all the areas to which it might apply (e.g., testing, irradiation, equipment management, product quality control and/or facility management).
The Liaison committee asked the FDA representatives to explain the level of interest the agency has in applying these recommendations to blood establishments.
The FDA participants acknowledged that the comments submitted by AABB were received and provided a brief overview of the draft guidance, such as the quality agreement is directed to current Good Manufacturing Practices activities within an establishment. FDA brought attention to a 2008 guidance titled, "Cooperative Manufacturing Arrangements for Licensed Biologics," a reference footnoted in the quality agreement draft guidance, as it provides additional information regarding the responsibilities of licensed biological product manufacturers and those of contract manufacturers.
"Electronic Distribution of Prescribing Information for Human Prescription Drugs Including Biological Products" is included in the 2013 HHS Unified Agenda – spring listing – with the notice of a proposed rule perhaps being released in October. The abstract included for item 0910-AG18 noted the "rule would require electronic package inserts for human drug and biological prescription products with limited exceptions, in lieu of paper, which is currently used. These inserts contain prescribing information intended for healthcare practitioners. This would ensure that the information accompanying the product is the most up-to-date information regarding important safety and efficacy issues about these products."
CFR citations listed with the abstract are: 21 CFR 201.100; 21 CFR 201.306; 21 CFR 201.310; 21 CFR 606.121; 21 CFR 606.122; 21 CFR 610.60; and 21 CFR 610.61. The citations include the Circular of Information for Human Blood and Blood Components and for 351 cellular therapy products (cord blood). 21 CFR 606.122 currently states "A circular of information must be available for distribution if the product is intended for transfusion."
The Liaison committee on behalf of the Circular of Information Task Force asked what the implications of this particular item on the Unified Agenda will be for the Circular of Information for Human Blood and Blood Components.
As this proposed rule is currently under development, the FDA participants were unable to provide any specific information. However, it was noted that the rule would apply to blood and blood components, and stakeholders were encouraged to review the proposals, when published, and submit comments. The Food and Drug Administration Amendments Act (FDAAA) of 2007 set up key provisions for the submission of electronic information to the FDA and established standards for labeling, which is the primary mechanism for developing this proposed rule. The FDA participants also noted that about 20 licensed blood establishments are now using the eSubmitter program to submit various kinds of information electronically to the FDA.
FDA guidance, "Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products," published in 2010, contains a donor reentry algorithm for risk of familial CJD.
"IV. Recommendations for Donor Deferral
C. Donor Reentry after Donor Deferral for Risk of Familial CJDIf you defer a donor because of family history of CJD, you may reenter that donor if:
1) The diagnosis of CJD in the family member(s) is confidently excluded, or CJD in the family member(s) is iatrogenic, or the family member(s) is (are) not a blood relative(s), or
2) Laboratory testing (gene sequencing) shows that the donor does not have a mutation associated with familial CJD."
Relatives presenting to donate have not understood why, if testing done at autopsy shows their family member died of sporadic and not familial CJD, they are still deferred from donating blood. The current (2010) donor reentry algorithm addresses risk of familial CJD. In conversation with the FDA, it appears the intent is that if families provide evidence (i.e., sequencing) that the deceased family member had sporadic CJD the donor would be reentered for blood donation.
The Liaison committee requested that the guidance document be amended so the reentry offered via Recommendation IV. C. is not restricted to "risk of familial CJD," and that the qualifiers for donor reentry include demonstration that the absence of familial mutations in the CJD patient be evidence for permitting the relative to donate or to be re-entered.
The FDA participants provided this response to assist with donor reentry: The current (2010) FDA Guidance on "Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant of Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products," recommends, at IV.C.2, "Donor Reentry after Donor Deferral for Risk of Familial CJD" — that "If you defer a donor because of family history of CJD, you may reenter that donor if: … 2) laboratory testing (gene sequencing) shows that the donor does not have a mutation associated with familial CJD." FDA noted that the language of the guidance at IV.C.2 does not specify whose genes should be sequenced to establish that the donor is not at risk of familial CJD. So long as the sequencing of the CJD-affected blood relative's PRNP genes was conducted by a qualified laboratory using a strategy designed to sequence both copies of the gene, both sequences were normal, and results of the sequencing were adequately documented and are available in accessible medical records, there is no scientific reason to sequence the actual donor. Similarly, should the CJD-affected family member have been a second-degree relative (e.g., grandparent, uncle or aunt) and both PRNP genes of the donor's appropriate parent were sequenced and found to be normal, there is no scientific reason to sequence the actual donor. FDA will consider clarifying the language on this point in some subsequent revision of the guidance.
Peter Marks, MD, PhD, Deputy Center Director, Center for Biologics Evaluation and Research (CBER)
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Ginette Y. Michaud, MD, Deputy Director for Medical and Scientific Affairs, OBRR
Martin Ruta, PhD, JD, Regulatory Counsel, OBRR
Alan Williams, PhD, Deputy Director for Operations and Regulatory Affairs, OBRR
Jennifer Scharpf, MPH, Associate Director for Policy and Communications, OBRR
Joseph L. Giglio, MS, MT(ASCP)SBB, CSQE(ASQ), CQA, Associate Deputy Director for Quality Assurance, OBRR
Hira L. Nakhasi, PhD, Director, Division of Emerging and Transfusion Transmitted Diseases (DETTD), OBRR
David Asher, MD, Chief, Laboratory of Bacterial, Parasitic & Unconventional Agents, DETTD
Salim Haddad, MD, Senior Medical Officer, Division of Hematology (DH), OBRR
Paul Mintz, MD, Deputy Director, DH
Orieji Illoh, Deputy Director, Division of Blood Applications (DBA), OBRR
Judy Ciaraldi, BS, MT(ASCP)SBB, CQA(ASQ), Consumer Safety Officer, Blood and Plasma Branch, DBA
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
Melissa Greenwald, MD, Chief, Human Tissue and Reproduction Branch, Division of Human Tissues, Office of Cellular Tissue and Gene Therapy, CBER
Faye Vigue, Consumer Safety Officer, Chief, Division of Manufacturers Assistance and Training (DMAT), Manufacturers Assistance and Technical Training Branch (MATTB), Office of Communications, Outreach and Development (OCOD), CBER
Debra Vause, Consumer Safety Officer, MATTB, OCOD
Susan Stramer, PhD, President, AABB
Darrell Triulzi, MD, Immediate Past President, AABB
M. Allene Carr-Greer, MT(ASCP)SBB, Director, Regulatory Affairs, AABB
Anne Eder, MD, PhD, American Red Cross and College of American Pathologists
Ruth Sylvester, MT(ASCP)SBB, America's Blood Centers
Cdr. Roland Fahie, MS, MT(ASCP)SBB, Armed Services Blood Program
Ruey Dempsey, JD, Advanced Medical Technology Association
Kathleen Houston, BS, MT(ASCP)SBB, Accreditation Program Committee, AABB
Louis Katz, MD, Transfusion Transmitted Diseases Committee, AABB
Patricia Pisciotto, MD, Standards Program Committee, AABB
Rafael Cassata, MS, RAC, Deputy Director, Cellular Therapy, Regulatory Affairs, AABB
Barbee Whitaker, PhD, Director, Research & Data Analytics, AABB
Eduardo Nunes, MPP, Senior Director of Policy, Standards, and Global Development, AABB
Jacqlyn Riposo, Policy Specialist, AABB
4550 Montgomery Avenue
Suite 700, North Tower
Bethesda, MD 20814
301.907.6977
