Food and Drug Administration

††††††††††††††††††††††††††††††††††† Center for Biologics Evaluation and Research

††††††††††††††††††††††††††††††††††††††††††††††† ††† SUMMARY MINUTES

††††††††††††††††††††††† †††††††† BLOOD PRODUCTS ADVISORY COMMITTEE

††††††††††††††††††††††††††††††††††††††††††††††† 90th Meeting:August 16, 2007

††††††††††††††††††††††† †† Doubletree Hotel & Executive Meeting Center, Bethesda, MD



Committee Members†††††††††††††††††††††††††††††††††††††††††††††††††† FDA Participants

Dr. Frederick Siegal, Chair†††††††††††††††††††††††††††††††††††††††† Ms. Jennifer Scharpf, M.P.H.

Dr. Mark Ballow†††††††††††††††††††††††††††††††††††††††††††††††††††††††† Ms. Lore Fields

Dr. Henry Cryer††††††††††††††††††††††††††††††††††††††††††††††††††††††††† Dr. Paul Mied

Dr. Adrian Di Bisceglie††††††††††††††††††††††††††††††††††††††††††††† Dr. Mei-ying Yu

Dr. Willarda Edwards†††††††††††††††††††††††††††††††††††††††††††††††† Ms. Sheryl Kochman

Dr. Maureen Finnegan††††††††††††††††††††††††††††††††††††††††††††††† Dr. Kathryn Carbone

Dr. Simone Glynn†††††††††††††††††††††††††††††††††††††††††††††††††††††† Dr. C.D. Atreya

Dr. Keith Quirolo††††††††††††††††††††††††††††††††††††††††††††††††††††††† Dr. Basil Golding

Dr. George Schreiber†††††††††††††††††††††††††††††††††††††††††††††††††

Dr. Irma Szymanski

Dr. Donna Whittaker††††††††††††††††††††††††††††††††††††††††††††††††† Guest Speakers

Ms. Judith Baker, M.H.S.A.†† *††††††††††††††††††††††††††††††††† Dr. Jerry Holmberg

Dr. Louis Katz††††††††††††††††††††††† **††††††††††††††††††††††††††††††††††††††††††† Ms. Jane Seward, M.B.B.S., M.P.H.

††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††† Dr. William Moss

Committee Members Absent††††††††††††††††††††††††††††††††††††† Dr. Toby Simon

Dr. Matthew Kuehnert†††††††††††††††††††††††††††††††††††††††††††††† Dr. Don Baker

Dr. Roshni Kulkarni††††††††††††††††††††††††††††††††††††††††††††††††††† Dr. Othmar Zenker

Dr. Catherine Manno†††††††††††††††††††††††††††††††††††††††††††††††††

Dr. Thomas Quinn††††††††††††††††††††††††††††††††††††††††††††††††††††† Non-Voting Temporary Member

††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††† Dr. James Allen†† ***

Temporary Voting Members††††††††††††††††††††††††††††††††††††††

Dr. Melvin Berger†††††† ****††††††††††††††††††††††††††††††††††††††† Committee Management Specialist

Dr. Richard Colvin†††††††††††††††††††††††††††††††††††††††††††††††††††† Pearline Muckelvene


††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††† * Consumer Representative

Executive Secretary††††††††††††††††††††††††††††††††††††††††††††††††††† ** Industry Representative

Donald Jehn, M.S.††††††††††††††††††††††††††††††††††††††††††††††††††††† *** Topic I only

††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††††† **** Topic II only





These summary minutes for the August 16, 2007 Meeting of the Blood Products Advisory Committee were approved on ______September 14, 2007_____


I certify that I participated in the August 16, 2007 Meeting of the Blood Products Advisory Committee and that these minutes accurately reflect what transpired.



// Original Signed // ††††††††††††††††††††††††††††††††††††††† // Original Signed //

_________________________††††††††††††††††††††† ___________________________

Donald W. Jehn††††††††††††††††††††††††††††††††††††††††††††† Frederick Siegal, M.D.

Executive Secretary††††††††††††††††††††††††††††††††††††††† Chair




































††††††††††††††††††††††††††††††††††† †††††††† Food and Drug Administration


††††††††††††††††††††††††††††††††††††††††††††††††††††††††††† MINUTES


††††††††††††††††††††††††††††††††††††††††††††††††††††††††††† ††† for the


††††††††††††††††††††††† †††† BLOOD PRODUCTS ADVISORY COMMITTEE


††††††††††††††††††††††††††††††††††††††††††††††† 90th Meeting, August 16, 2007



Committee Updates


Dr. Jerry Holmberg presented to the Committee a summary of the May 10-11, 2007 meeting of the DHHS Advisory Committee on Blood Safety and Availability.The next update presented to the committee was by Ms. Jennifer Scharpf on the April 26-27, 2007 FDA workshop on Immune Globulins for Primary Immune Deficiency Diseases:Antibody Specificity, Potency and Testing.Finally, Ms. Lore Fields presented a summary of the August 15, 2007 FDA workshop on Licensure of Apheresis Blood Products.


Informational Presentations on WHO Biological Standards


Following the updates, the Committee was provided informational presentations on WHO biological standards.Dr. Paul Mied presented a summary of the†† January 29-30, 2007 WHO Meeting with WHO Collaborating Centres for Biological Standards and Standardization to support the development of WHO biological reference preparations for blood safety-related in vitro diagnostic tests. Dr. Mied outlined the priority projects identified by the WHO Collaborating Centers, including the replacement of existing reference preparations, development of new reference preparations and proposed reference preparations for further discussion. Dr. Mied explained that a five year, In Vitro Diagnostics strategic plan will be presented to the WHO Expert Committee on Biological Standardization (ECBS) for endorsement in October 2007.††††††††


Dr. Mei-ying Yu then provided the Committee an overview of potency and safety standards for plasma derivatives.Dr. Yu summarized CBERís role in developing and establishing global potency standards for plasma derivatives through close collaboration with the WHO Collaborating Centers.She then reviewed potency standards for clotting factors, immune globulins and albumin, as well as safety standards for in-process control methods for testing for Parvovirus B19 and Hepatitis A in plasma for further manufacturing.Finally, Dr. Yu reviewed standards currently under development.






Next, Ms. Sheryl Kochman reviewed the joint WHO/FDA minimum potency standards for blood grouping reagents.She discussed the importance of new standards development to ensure relevance to current blood grouping regents derived from monoclonal antibodies, as well as adequate supplies.Ms. Kochman summarized the collaborative process for the development of three new international standards: anti-D standard 99/836, anti-A standard 03/188 and anti-B standards 03/164.She stated that all three standards are now available through CBER.††

Topic I:†† Response to the Office of Blood Research and Review Office Level Site Visit for Research, July 22, 2005


Dr. Kathryn Carbone provided an introduction to the Committee on research programs conducted at the Center for Biologics Evaluation and Research (CBER).Dr. Carbone summarized CBERís research management initiative and identified CBERís 2007 research priorities.She also explained CBERís research evaluation program for investigators, comprised of annual internal reviews and four year cycle reviews by both external and internal committees.Finally, Dr. Carbone outlined the process for Office level review of research programs and summarized the findings of the Advisory Committees in response to the 2005-2006 Office level site visits.†††††


Dr. CD Atreya then provided the Office of Blood Research and Review (OBRR) response to the July 22, 2005 site visit.Dr. Atreya discussed the four key issues identified by the BPAC in their report: 1) sufficient time and qualified personnel to perform mission related research; 2) support for mission critical research; 3) research prioritization and; 4) visibility of OBRR research. He then explained how OBRR has addressed each of the issues.Dr. Atreya summarized the key scientific needs identified by OBRR and the process for determining the Officeís six priority research areas.He stressed that major program changes have been implemented to ensure a more structured and transparent managed research program within the OBRR.


No public comments were presented during the Open Public Hearing.


During the discussion period, the Committee responded favorably to the OBRRís response to their report.The Chair of the Site Visit Committee thanked the OBRR staff for their thoughtful response to the report and said he was also pleased to see a response by CBER management.The Chair said he was encouraged by the progress and noted a clear improvement in the quality and focus of OBRRís research since 1998 when the first report was published.†† In agreement with other Committee members, the Chair expressed concern over appropriate resources to sustain the research programs. Further, the members commented on the increased use of the CBER website to showcase CBER research.Members also asked for clarification on how dedicated time for research is evaluated and protected.One member asked if OBRR has experienced any change in recruitment or retention of investigators since the 2005 site visit.Members also questioned how the FDA consolidation at White Oak may affect dedicated laboratory space and collaborative efforts with the National Institutes of Health.Finally, Committee members commented on the development of reference standards as part of the managed research program and asked specific questions related to OBRRís efforts on biovigilence and clinical guidelines for transfusion medicine.


Topic II:Measles Antibody Levels in U.S. Immune Globulin Products


In the afternoon, Dr. Basil Golding introduced the topic of measles antibody levels in U.S. Immune Globulin products.He presented the issue that measles antibody levels are dropping in Immune Globulins to the point that products may fail lot release specification tests and this may lead to product shortages.Dr. Jane Seward from the Centers for Disease Control and Prevention provided an overview of current measles epidemiology in the United States and indicated that most cases are imported and outbreaks are small (66 cases since 2001).Following Dr. Sewardsís presentation, Dr. William Moss from Johns Hopkins Bloomberg School of Public Health discussed measles in immunocompetent and immunodeficient hosts, indicating that antibodies and T cell play important roles in host defense.Dr. Toby Simon then presented CSL Behringís data on measles antibody titers in plasma donors showing that titers were decreasing mainly because the proportion of older donors with higher titers and that were naturally infected are decreasing.Dr. Don Baker, representing Baxter Healthcare Corporation, presented data from a longitudinal study of measles antibody titers in IGIV and Dr. Othmar Zenker, representing CSL Behring, presented data on measles antibody titers in primary immune deficient patients receiving Immune Globulin products.According to Dr. Zenkerís data the lot release specification could be decreased to 0.30 x CBER standard and still result in protective trough levels.


During the Open Public Hearing, Ms. Mary Gustafson presented the Plasma Protein Therapeutics Association statement of measles antibody levels in US Immune Globulins and supported CBERís proposal to lower the minimum specification for lot release. Ms. Marcia Boyle, president of the Immune Deficiency Foundation, then commented on FDAís proposal to lower the minimum titer for measles antibodies in US Immune Globulins and expressed her concern that FDA should act to ensure product is available.†††††††


The following issues were discussed before the Committee formally addressed the questions posed by FDA:


  • Several Committee members stated that the presentations demonstrated that patients would not be at risk if the measles antibody level specification was lowered.However, Committee members asked for clarification why 0.48 of the potency in the CBER standard was selected as the appropriate level.††††††


  • One Committee member asked about the feasibility of collecting plasma from donors outside of the U.S. who have had natural measles infection.FDA responded that only plasma from U.S. licensed blood centers is currently accepted, citing concerns regarding infectious diseases and licensure requirements.




o       Committee members expressed concern that if anti-measles titers continue to decline, FDA will be facing this same issue in the near future.The Committee stressed the importance of collecting data now to determine the minimum protective level.One Committee member asked if measles titer is needed as a measure of potency at all.

o       One Committee member who supported lowering the measles antibody specification level indicated the issue would not need to be reexamined unless: 1) antibody levels in immune globulins are demonstrated to decline further; 2) measles occurs in patients with primary immune deficiency diseases (PIDD), or 3) epidemiological data show measles resurgence in the U.S.

o       The Committee discussed the precautions taken currently for PIDD patients who travel to measles endemic areas.††††††

The Committee then addressed the following questions:


1.Do Committee members concur with the FDA proposal to lower the minimum measles antibody specification for IGIV and IGSC from 0.60 x †††††† CBER standard, to 0.48 x CBER standard?


The committee concurred with the FDA proposal (13 yes votes, 1 no vote).No further comments were discussed by the committee.††††

2.CBER is considering requesting additional studies to confirm that PIDD patients will achieve trough levels of measles antibodies above 120 mIU/mL if treated with IGIV and IGSC products that meet the proposed revised potency standard of 0.48 x CBER standard.Do the Committee members agree that this information is needed?

The committee agreed that additional studies are needed (13 yes votes, 1 no vote).

The Committee discussed that additional studies are needed to ensure patients are achieving protective trough levels.One member commented that while 120 mIU/mL correlates with protection, it does not define immunity.It was also discussed that patients with T-cell deficiencies are at the greatest risk and should be treated with higher doses to achieve titers that achieve "sterilizing immunity."

3.Please comment on the need for and feasibility of any alternative strategies that CBER should consider to reduce the likelihood of failed lots of IGIV and IGSC based on potency testing for measles antibodies in order to ensure availability of product for PIDD patients.

The Committee discussed the variability of measles titers and titers for other pathogens (e.g. S. pneumoniae, H. influenza and varicella zoster) in immune globulin products.The Committee agreed that it would be helpful for clinicians concerned about a particular pathogen if information about antibody titer levels was included on the product label. One Committee member cautioned, however, that while information on the label may lead to the use of a particular product, it does not always predict clinical outcome.

One Committee member asked if Hepatitis A antibodies are also declining in IGIM, which is indicated for post-exposure prophylaxis to Hepatitis A.FDA responded that anti-HAV titers have declined and noted that titers in recovered plasma are lower than Source Plasma.††

Finally, the Committee commented that physician and patient education may be needed so that adjustments in therapy can be made to assure that protective titers are achieved for PIDD patients going on travel or in times of measles outbreak.