CURRENT FDA INITIATIVES AND PRIORITIES
Food and Drug Administration Initiatives and Priorities presented by Jay Epstein, MD, director, Office of Blood Research and Review, Center for Biologics Evaluation and Research, and Leslie Kux, deputy director, Office of Compliance and Biologics Quality, included information on the FDA Transparency Initiative initiated in January 2009, guidance documents issued in 2009 and those that OBRR is giving high priority to in 2010, blood supply monitoring during the H1N1 influenza pandemic, current concerns and initiatives in addressing emerging infectious agents, an update on the OBRR Quality Program, and an introduction to new staff working in OBRR and the Division of Blood Applications. In addition, Kux provided information on FDA’s agencywide initiatives related to compliance and enforcement. Of particular interest is the requirement that an establishment respond to a 483 within 15 days if the response is to be evaluated prior to any additional action by the agency.
CURRENT AABB INITIATIVES AND PRIORITIES
Jacquelyn Fredrick, president of AABB, introduced the discussion of AABB Initiatives and Priorities and reviewed the association’s Statement of Intent in support of the strategic plan that is focused on patient and donor safety through the practice of transfusion medicine and cellular therapies. Five critical focus areas for achieving the goal of improved patient and donor health include member engagement, excellence in medicine, knowledge translation, regulatory advocacy, and standards and accreditation.
SPECIFIC TOPICS OF DISCUSSION WITH FDA
Interpretation of Recommendations Contained in Guidance Documents
Guidance documents are published with a statement that the contents are nonbinding and that alternative approaches can be used if they satisfy the regulations and statutes. Generally, the alternative approaches require validation to show they are equally effective. Blood establishments have had different experiences at the time of inspection when they have implemented a validated alternative approach, and some examples were discussed. FDA was asked to clarify its policy on review and acceptance of validated data to support implementation of an alternate approach to nonbinding recommendations contained in a guidance document.
In general, properly validated alternatives that meet the published recommendations should be acceptable. However, the alternatives should not be a deviation from manufacturer’s instructions, and in the case of equipment, it is important to ensure the equipment is working properly. A discussion with the consumer safety officer, or CSO, before implementing the alternative procedure may be helpful, and Richard Davey, MD (301-827-2763), and Leslie Holness, MD (301-827-6115), made their phone numbers available to establishments that would like to call them.
Statistical Sampling Plans for Product Quality Control
The Code of Federal Regulations written specifically for blood components (21 CFR 600 series) requires that modest numbers of blood components be tested on a monthly basis to satisfy quality control, or QC, requirements. However, current good manufacturing practices, or cGMP, that have broad applications for blood components (21 CFR 200 series) require the use of statistically significant sampling plans. In recent years, the blood community and FDA have discussed several approaches. When the December 2007 guidance for collection of Apheresis Platelets was published, a binomial sampling plan was recommended. (Prior to that, the potential use of scan statistics had been introduced but at that time was untested in the blood center environment and was essentially abandoned.) Many blood establishments continue to struggle with issues related to correct use of a statistically significant sampling plan, particularly when the institution does not collect enough platelets to use the binomial sampling plan.
Several sampling plans were reviewed, including hypergeometric distribution statistics, which are more adaptable to facilities that collect and process smaller numbers of units. The hypergeometric plan supports sample sizes of n<60 for QC purposes. However, it is not applicable to undefined population sizes and therefore is not valid for process validation. (Tables based upon hypergeometric distribution have been prepared by the Office of Biostatistics and Epidemiology, CBER, and are expected to be made publicly available in the future.) Clusters of failures at the endpoints of the sample size may be masked when using binomial or hypergeometric approaches, but such clusters could be identified through use of scan statistics. Scan statistics is conceptually and computationally complex but software now exists to manage the use of this method. References for the various statistical approaches were provided on the final slide. When asked how an establishment would get FDA acceptance of a statistical process that has not been recommended by FDA, the committee was reminded that any sound and “known” process should be acceptable. Novel approaches might also be acceptable and a pre-implementation conversation with the CSO could answer all questions.
The Blood Products Advisory Committee recently advised the FDA to place certain boundaries around a phase III clinical trial for pathogen inactivation of human platelets, effectively requiring a three-fold increase in the size of the trial and perhaps rendering it financially infeasible. The committee believes it is important that the inactivation processes not only be effective against disease agents but that they also result in a safe product for patient transfusion. However, there is concern following discussions at the November 2009 BPAC meeting that approval of any pathogen inactivation process or product is moving further into the future. FDA was asked about current considerations of this issue, particularly in the context of the July 2008 request from the
assistant secretary for health to further the progress of pathogen reduction in the U.S.
FDA participants responded that patient safety and efficacy of the transfused product remain of paramount concern for them, and they remain very interested in the prospects for pathogen inactivation processes coming to the U.S. market. Agency representatives continue to engage the trial sponsor in conversations about possible trial designs. The Laboratory of Cellular Hematology in the Division of Hematology is conducting research on the action of UV light on platelets and red cells. Committee members reiterated concerns that pathogen inactivation appeared unlikely to be a potential tool for use with emerging infectious disease agents in the U.S. in the event that infectious disease tests become increasingly difficult to obtain or become unavailable.
Infectious Disease Testing
The lack of availability of tests is not restricted to those that are thought to be useful only in selective testing situations (dengue, Babesia). Universal testing volumes — such as for human T-cell lymphotropic virus I and II — alone also do not create a market incentive, and the confirmatory test market will always be small. The committee’s discussions with FDA included:
How to obtain testing (low level or universal) against a lack of market incentive — transfusion medicine infectious disease tests are a very low percentage of the in vitro diagnostic market.
HTLV-I/II testing is required by regulations, and there is concern that in 2010, the one licensed test distributed in the U.S. may at some point in time not be universally available because of lot issues relating to manufacturing.
Re-entry of some donors, especially those deferred in high numbers for markers that have low prevalence in the U.S. population, is very desirable, yet there are no licensed tests available. Are there other options for re-entry?
FDA participants stated they share the same concerns and said they have interacted with several AABB task forces and manufacturers in an effort to support products coming to market.
Committee members and FDA agreed there are shared responsibilities and opportunities to resolve some of the issues. The problems have been described multiple times, and the time appears ripe for a roundtable summit.
Disasters and Pandemic Preparedness
The transfusion medicine community acting through the Interorganizational Task Force on Domestic Disasters and Acts of Terrorism and other working groups has met repeatedly over the past few years and engaged with government liaisons and participants in an effort to establish robust preparedness plans for unplanned events. The goal of such planning is to ensure an adequate and safe supply of blood (and tissues) for the patient community in the event of a disaster or pandemic. A final unresolved issue for blood establishments is that of pre-determining which processes and procedures may be necessary to vary from during the manufacturing process. One area of focus is relaxation of certain donor requirements in order to ameliorate catastrophic shortages. Preparation of a robust preparedness plan is hampered by a facility’s inability to write the necessary standard operating procedures and train staff under acceptable
cGMP conditions during an emergency.
The agenda submitted in advance to FDA asked for a discussion of options available to blood establishments including, but not limited to, alternative procedures/variances, as well as areas where enforcement discretion might be more appropriate in the event of an unexpected, sudden expansion of a pandemic. Clarification of existing regulations with regard to emergency situations would be helpful. The goal is to find concrete steps that would enable establishments to have a fully robust preparedness plan that could be initiated rapidly in the event of need.
FDA participants acknowledged their understanding of the need to preplan and have attempted to provide some additional guidance in the form of the draft guidance issued in November 2009: “Recommendations for the Assessment of Blood Donor Suitability, Blood Product Safety, and Preservation of the Blood Supply in Response to Pandemic (H1N1) 2009 Virus.”
Blood Pressure and Pulse Measurements in the Allogeneic Blood Donor Population
At the November BPAC meeting the committee considered evidence of currently available data for blood pressure and pulse measurements as predictors of risk for adverse reactions to blood donation and whether data support specific ranges for these measurements as predictors of adverse reactions. BPAC advised that while blood pressure measurements are not predictors of adverse reactions, pulse appears to have relevance. Committee discussion further suggested that measurement of blood pressure and pulse may be of value even if FDA does not retain them as donor eligibility determinations.
Following the BPAC discussion, FDA participants were asked about their current considerations for the use of blood pressure and pulse measurements in the allogeneic blood donor setting. Several items were noted:
· BPAC’s concern with the paucity of data on donors with blood pressures >180.
· Knowledge gaps creating an opportunity for surveillance.
· Establishing limits in regulations may not be ideal.
· Having no requirements may not be ideal.
Abbreviated Donor History Questionnaire
BPAC advised that the use of the abbreviated donor history questionnaire (DHQ) is desirable and suggested that a post-implementation study/data collection would be appropriate. The AABB Donor History Task Force developed a study (with the advice of FDA liaisons to the task force) and submitted it to FDA in April 2008. The task force has been told on several occasions that the plan submitted satisfactorily addressed all outstanding issues.
FDA was asked to explain the pathway for advancing the abbreviated donor history questionnaire and responded that the necessary guidance document is in an editing stage. The post-implementation plan will likely be referenced in the guidance. This draft guidance is on OBRR’s priority list for 2010, but the time frame is not definitely known.
Plasma Obtained From Whole Blood Donors for Further Manufacturing Use
A regulatory framework for plasma obtained by apheresis that could be used for further manufacture was proposed for BPAC’s
discussion last April.
FDA was asked for an update on current considerations for these blood components and responded that staff within OBRR continue to look at the issues raised by the BPAC discussion and remain in contact with the AABB task force. There was nothing definite to report.
Requirements for Human Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use, Proposed Rule, November 2007
The committee was interested to hear an update on progress regarding reconciling comments received to the proposed rule and to know if it is likely to be reissued as a proposal or to be published as a final rule.
FDA continues to look at the many proposals put forth in the document and has engaged BPAC in discussions on some of the subjects (i.e., hemoglobin and blood pressure/pulse). It took more than 10 years to draft the document, and it likely will not be reissued as a draft. However, it is also likely that all proposals may not be issued as final at the same time.
Publication of Documents
The FDA Liaison Committee remains concerned with the significant delay in publishing documents that are of critical importance to blood establishments. Updates to several documents provided by discussions at the meeting are included in the list below. FDA participants stated that although they have assigned the documents priority for 2010, they are not in control of the overall process and timelines involved.
o Guidance document that would recognize the abbreviated DHQ – A draft is on the 2010 priority list for OBRR.
o Guidance document that would recognize v1.3 of the DHQ – A guidance with final recommendations is on the 2010 priority list for OBRR. The AABB Donor History Task Force has decided to proceed with posting v1.3 on the AABB Web site along with instructions for submitting the materials to FDA as a Prior Approval Supplement to the establishment’s Biologics License Application before implementation.
o Nucleic Acid Testing (NAT) for Human Immunodeficiency Virus Type 1 (HIV-1) and Hepatitis C Virus (HCV): Testing, Product Disposition, and Donor Deferral and Reentry (draft guidance, July 2005) – A guidance with final recommendations is on the 2010 priority list for OBRR.
o Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion (draft guidance, January 2001) – Reissuance as a draft guidance is a priority for OBRR in 2010.
o Revisions to Labeling and Storage Requirements for Blood and Blood Components, Including Source Plasma (proposed rule, July 2003) – No update was provided.
o Safety Reporting Requirements for Human Drug and Biological Products (proposed rule, March 2003) – No update was provided.
Diane Maloney, JD, Associate Director for Policy, Center for Biologics Evaluation and Research (CBER)
Jay Epstein, MD, Director, Office of Blood Research and Review (OBRR), CBER
Ginette Michaud, MD, Deputy Director for Science and Medicine, OBRR
Alan Williams, PhD, Associate Director for Regulatory Affairs, OBRR
Jennifer Scharpf, MPH, Associate Director for Policy and Communications and Chief, Policy and Publications Staff, OBRR
Basil Golding, MD, Associate Director for Medical Affairs, 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
Jaro Vostal, MD, Chief, Laboratory of Cellular Hematology, Division of Hematology (DH), OBRR
Richard Davey, MD, Director, Division of Blood Applications (DBA), OBRR
Orieji Illoh, MD, Medical Officer, DBA
Leslie Holness, MD, Chief, Blood and Plasma Branch (BPB), DBA
Judy Ciaraldi, BS, MT(ASCP)SBB, CQA(ASQ), Consumer Safety Officer, BPB
Leslie Kux, JD, Deputy Director, Office of Compliance and Biologics Quality, CBER
Melissa Greenwald, MD, Human Tissue and Reproduction Branch, Division of Human Tissues, Office of Cellular Tissue and Gene Therapy, CBER
Leslie Wheelock, RN, MS, Director, Division of Manufacturers Assistance and Training, (DMAT), Office of Communications, Outreach and Development, CBER
Faye Vigue, MT (ASCP), Consumer Safety Officer, DMAT, Manufacturers Assistance and Technical Training Branch
Jackie Fredrick, MBA, MT(ASCP), President, AABB
Karen Shoos Lipton, JD, Chief Executive Officer, AABB
James AuBuchon, MD, President-Elect, AABB
M. Allene Carr-Greer MT(ASCP)SBB, Director, Regulatory Affairs, AABB
Patricia Pisciotto, MD, AABB
Col. Stephen Beardsley, MS, MT(ASCP)SBB, DOD
Richard Benjamin, MD, ARC
Celso Bianco, MD, ABC
Khatereh Calleja, JD, AdvaMed
Katharine Downes, MD, CAP
Mary O’Neill, MD, ARC
Tom Schallert, ABC
Aaron Lyss, AABB