Food and Drug Administration

Center for Biologics Evaluation and Research



92nd Meeting:  September 10-11, 2008

Hilton Hotel, 1750 Rockville Pike, Rockville, MD



Committee Members                                       FDA Participants

Frederick Siegal, M.D., Chair                         Robin Biswas, M.D.

Mark Ballow, M.D.                                         Paul Buehler, Ph.D.

Henry Cryer, M.D., Ph.D.                              Elizabeth Callaghan, M.S.

Adrian Di Bisceglie, M.D.                              Salim Haddad, M.D.

Willarda Edwards, M.D., MBA*****           Leslie Holness, M.D.

Maureen Finnegan, M.D.                                Sheryl Kochman

Simone Glynn, M.D., MSc, M.P.H.               Sanjai Kumar, Ph.D.

Matthew Kuehnert, M.D.                               Toby Silverman, M.D.

Roshni Kulkarni, M.D.                                   Jaro Vostal, M.D.

Katherine McComas, Ph.D.                            Mark Walderhaug, Ph.D.

Francisco Rentas, Ph.D.                                  Hong Yang, Ph.D.

Ann Zimrin, M.D.                                          

Judith Baker, M.H.S.A.*                                Guest Speakers

Louis Katz, M.D. **                                       Paul Arguin, M.D.

                                                                        Celso Bianco, M.D.

Committee Members Absent                          Mark Brecher, M.D.

Catherine Manno, M.D.                                  Gary Brittenham, M.D.

Thomas Quinn, M.D.                                      Barbara Bryant, M.D.

Donald Trunkey, M.D.                                   Ritchard Cable, M.D.

                                                                        Sarah Cusick, Ph.D.

Temporary Voting Members                           Jerry Holmberg, Ph.D.

Arthur Bracey, M.D.                                       David Leiby, Ph.D.

Thomas Fleming, Ph.D.                                  Karin Magnussen, M.D.

Harvey Klein, M.D.                                        Thomas Montag-Lessing, M.D.

Thomas McCutchan, Ph.D.*****                   Bryan Spencer, M.P.H.

Barry Skikne, M.D.****                                 Dan Waxman, M.D.


Temporary Non-Voting Members                   Designated Federal Officer

John Barnwell, Ph.D., M.P.H.*****              Donald Jehn, M.S.

Fernanda Lessa, M.D., M.P.H.***

                                                                        Committee Management Specialist

* Consumer Representative                            Pearline Muckelvene

** Industry Representative

*** Topic I only

**** Topic II only

***** Topic III only



These summary minutes for the September 10-11, 2008 Meeting of the Blood Products Advisory Committee were approved on October 17, 2008.


I certify that I participated in the September 10-11, 2008 Meeting of the Blood Products Advisory Committee and that these minutes accurately reflect what transpired.




 /// Original Signed ///                          /// Original Signed ///

______________________________            _________________________________

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

Designated Federal Officer                            Chair



































for the



92nd Meeting – September 10-11, 2008


Committee Updates


On Wednesday, September 10, Dr. Jerry Holmberg presented to the Committee a summary of the May 29-30, 2008 meeting of the DHHS Advisory Committee on Blood Safety and Availability.  On Thursday, September 11, Dr. Paul Buehler and Dr. Toby Silverman summarized the April 29-30, 2008 workshop titled, “Hemoglobin Based Oxygen Carriers:  Current Status and Future Direction.”  Next, Ms. Sheryl Kochman presented an update to the Committee on the July 10-11, 2008 Blood Establishment Computer Software Conference.  Ms. Elizabeth Callaghan then presented on the development of an automated blood application system.  The final update was presented by Dr. Robin Biswas on FDA’s draft guidance for industry, “Requalification Method for Reentry of Blood Donors Deferred Because of Reactive Test Results for Antibody to Hepatitis B Core Antigen (Anti-HBc).”


During the Open Public Hearing on September 11, Dr. L. Bruce Pierce from Biopure Corporation commented on hemoglobin based oxygen carrier safety; Mr. Jim MacPherson from America’s Blood Centers presented a summary of the 2008 Blood Establishment Computer Software Conference; Dr. Louis Katz, representing America’s Blood Centers, provided a summary of the 24 hour hold workshop held on September 9, 2008; and, Mr. David Cavanaugh, on behalf of the Committee of Ten Thousand, provided testimony on FDA’s draft guidance on a requalification method for reentry of blood donors deferred because of reactive test results for anti-HBc.   


Topic I:  Strategies to Enhance Bacterial Safety of 7 Day Platelets for Transfusion


FDA sought the advice of the Committee on the development of new testing paradigms that will reduce the rates of bacterial contamination and septic transfusion associated with apheresis platelet products.  Dr. Jaro Vostal introduced the topic of bacterial contamination of platelets to the Committee and provided an overview of currently available bacterial detection devices.  Dr. Mark Brecher, of the University of North Carolina, then presented to the Committee a historical perspective on the issues related to detection of bacterial contamination of platelets by reviewing scientific literature, a chronology of device development and utilization, and septic reaction case reports.  Next, Dr. Thomas Montag-Lessing, of the Paul Ehrlich Institute (PEI) in Germany, provided the Committee an overview of the PEI Blood Bacteria Standards for use as a tool for the validation and assessment of methods for screening and pathogen reduction in blood components.  He also discussed options for rapid methods for bacteria detection in platelets, including use of flow cytometry, the Pan Genera Detection system, real time universal bacteria (fungi) PCR/NAT, and continuous pH monitoring.


Dr. Louis Katz, M.D., of the Mississippi Valley Regional Blood Center and on behalf of AABB Task Force, then discussed the proposed redesign of the PASSPORT study, a post-marketing surveillance of bacterial contamination rates of 7 day platelets. Dr. Katz discussed the main criteria of the redesigned study including: 1) use of a standardized skin preparation, 2) use of a diversion pouch on inlet line of apheresis kits, 3) strategies to enhance sensitivity of release test, and 4) clinical surveillance.  Finally, Dr. Salim Haddad presented FDA’s perspective on the redesign of the PASSPORT study including a comparison between the FDA and industry proposals to re-introduce 7 day platelets.  Dr. Haddad then outlined FDA’s proposal comprised of active reporting of septic transfusion reactions;  establishment of an independent committee to evaluate septic transfusion reactions and to define stopping rules; taking aerobic and anaerobic cultures at day 5; and, surveillance cultures at outdate, after day 7.            


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


  • The Committee asked what is known about the threshold for septic reaction with colony forming units and if there was any evidence from interdicted units about bacterial levels and clinical outcomes. 
  • The Committee discussed the feasibility of FDA’s proposed study in the hospital setting.  Financial and human resource constraints, limited access to the BactT Alert test system, and lack of expertise in sterile sampling techniques were cited as major obstacles to culturing platelets at day 5 and day 7.  Additionally it was stated that some hospitals may not be interested in 7-day platelets if the supply of 5-day platelets was adequate.
  • Several members commented that a control group is needed to truly assess the proposed study endpoints.     
  • The Committee discussed the functional viability of 7 day platelets.  
  • Committee members commented on the appropriate length of time for clinical surveillance of patients for septic transfusion reactions.  It was discussed that observing patients 10-14 days post transfusion would ensure late reactions are captured; however, it was also noted that most reactions occur soon after transfusion and the longer patients are observed, the higher the likelihood sepsis could be acquired from another source.
  • A Committee member remarked that day 5 testing would provide concrete information on the bacterial status of the product whereas Industry’s proposal may not be rigorous enough.
  • The distinctions between an active and passive surveillance system were highlighted by FDA and industry.  The limitations and merits of clinical surveillance were also discussed, as well as the process by which physicians would be informed of and required to participate in the study. 
  • The Committee discussed specific limitations of industry’s proposal to utilize only clinical surveillance to identify septic transfusion reactions, including underreporting of transfusion reactions, immune status of the recipient population,  and the large study sample size needed.


  • One Committee member commented that an adjudication committee comprised of experts should assess cases of septic transfusion reactions.  Further, it was discussed that cases of septic transfusion reactions in the first PASSPORT study may not have represented true failures since the endpoints were poorly defined.             
  • The Committee members discussed whether the proposed PASSPORT study should be a consented trial for patients receiving day 6 and 7 platelets.  FDA clarified that PASSPORT is a post marketed study of licensed products and not a clinical trial.
  • A Committee member questioned the benefit of 7-day platelets except in periods of platelet shortage.
  • The Committee discussed the safety of 7 day platelets in the context of whole blood derived platelets, which are not cultured prior to use at day 5.   
  • Several Committee members asked industry to clarify the demand for 7 day platelets and data on shortage in the system.  The economic impact of outdated platelets and the patient safety issue of unfilled orders were discussed.  Members of industry commented that delays in implementing TRALI mitigations strategies and an increased use of whole blood-derived platelets have been observed since 7 day platelets have been unavailable.  Whole blood derived platelets are generally tested by surrogate markers rather than by culture, which raises potential safety concerns. Industry commented that even with increased supply, there is still an unmet demand for platelets.
  • FDA inquired about the weak market penetration of the FDA cleared pre-storage pooling system for whole blood derived platelets. Industry replied that the pre-storage pooling system was operationally difficult to use.
  • One Committee member commented that the study would have a higher likelihood of success statistically if cultures were done at day 5.
  • The Committee and FDA discussed the utility of the 12 hour hold following the culture on day 5. The hold period may be irrelevant since day 5 testing applies to platelets to be transfused on days 6 and 7.
  • The Committee asked FDA if the rapid, point of release test was being considered as an option for culturing platelets at day 5.  FDA responded that the sensitivity of the rapid test at day 4 and 5 is not sufficient for independent use of the test and citing the high miss rate observed in the Irish study.
  • FDA was asked whether the day 5 testing would be maintained after the conclusion of the study. FDA indicated that the decision would be data-driven.



The Committee then addressed the following question:


1. Does the Committee agree with FDA that reporting of sepsis should be active and not passive?


The Committee agreed with FDA that reporting of sepsis should be active. (13 yes votes, 1 no vote, 1 abstain).



2.      In addition to reporting of sepsis does the Committee agree with FDA that:


  1. Additional aerobic and anaerobic cultures should be performed on day 5 both to increase the safety of platelet on day 6 and 7 and as a baseline measure? 


The Committee voted affirmatively that additional aerobic and anaerobic cultures should be performed on day 5 both to increase the safety of platelet on day 6 and 7 and as a baseline measure? (11 yes votes, 2 no votes, 2 abstain).


  1. Surveillance cultures should be performed at outdate (after day 7) to provide a bacteriological endpoint for the study?


The Committee agreed that surveillance cultures should be performed at outdate (after day 7) to provide a bacteriological endpoint for the study? (12 yes votes, 2 no votes).



Topic II:  Iron Status in Blood Donors


FDA sought the advice of the Committtee on the impact of blood donation on donor iron stores and donor health and possible strategies to mitigate iron depletion in the donor setting.  Dr. Leslie Holness introduced the topic to the Committee and provided an overview of FDA’s current requirements for hemoglobin, hemoglobin requirements in several other countries, available hemoglobin screening tests and biochemical measurements of iron status. 


Next, Dr. Gary Brittenham, of Columbia University, provided the committee an overview of iron metabolism and iron deficiency in blood donors and highlighted the clincial consequences and manifestations of iron deficiency.  He discussed the outcomes of a study using carbonyl iron replacement in the blood donor setting for women of childbearing age.  Dr. Sarah Cusick, fom the Centers for Disease Control and Prevention, discussed the epidemiology and assessment of iron status in U.S. adults, reviewing data on iron deficiency from the National Health and Nutrition Examination Surveys (NHANES) and data on iron indicators from the National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population.  She also presented CDC’s recommendations for primary and secondary prevention of iron deficiency.  Dr. Karin Magnussen, of Copenhagen University Hospital, then discussed the European Unions regulation regarding hemoglobin donation intervals in different Europena countries and a a Danish study on iron replacement in blood donors with low hemoglobin.






Next, Dr. Barbara Bryant, of the University of Texas, Medical Branch, Galveston, presented an overview of a study done while she was at the National Institutes of Health. She studied the long-term health effects of blood donation on donor’s hemoglobin levels and iron stores and evaluated the safety, practicality and efficacy of oral iron replacement in blood donors.  Dr. Dan Waxman then discussed the Indiana Blood Center’s experience with an iron replacement program for women blood donors aged 18-50 years.  Finally, Dr. Ritchard Cable, of the American Red Cross, presented a progress report on RISE (REDS Donor Iron Status Evaluation), part of the REDS II cohort study.


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


  • The Committee members discussed iron deficiency in blood donors in terms of a public health issue and questioned if blood establishments could and should play an active role in mitigating the problem through diagnosis and referral of iron deficient donors.
  • One Committee member asked if there was any concern that donor iron supplementation could worsen undiagnosed hereditary hemochromotosis.
  • The racial differences in iron deficiency and donor response to iron supplementation were discussed by the Committee.
  • Safety considerations of administering carbonyl iron and iron in blister packs in homes with young children were discussed.  
  • One Committee member expressed concern with iron supplementation in male donors, as it could mask underlying disease, especially gastrointestinal cancers. 
  • The Committee discussed the challenges and costs associated with referring iron deficient donors to primary care physicians for further follow up.    
  • The Committee discussed the potential cardiovascular benefits of iron depletion through blood donation.  One Committee member cautioned that discussing this potential benefit could incentivize donors inappropriately.  
  • The impact of iron depletion in donors on blood availability was discussed.
  • One Committee member commented that tissue iron status is of greatest concern, as depleted tissue iron stores result in the loss of tissue, muscle function and the ability to make hemoglobin.














The Committee then addressed the following questions:


1.      Is iron depletion in blood donors a concern?


The Committee unanimously agreed that iron depletion in blood donors is a concern.


2.      If so, are there tests for iron status that would be practical and appropriate in the donor setting?


The Committee commented that currently there are no convenient, rapid tests available that will give an accurate prediction of donor iron stores.  It was discussed that serum ferritin and the logarithm of the ratio of soluble serum transferrin receptor/ferritin (TfR) ration are the best indirect measures of iron status.  However, the Committee members noted that these tests are relatively expensive, not commercially available, and results are not available rapidly.  


An industry representative on the Committee commented that implementing tests for iron status as an upfront donor screen would not be practical.  Rather, it would only be feasible to assess those donors that are not eligible to donate based on current hemoglobin standards. 


FDA reminded that Committee that the proposed donor eligibility rule, which published in November 2007, asked for comments on the appropriateness of lowering the minimum hemoglobin standard for women to 12.0 g/dL and of the copper sulfate based screening method for testing for hemoglobin levels in blood donors.


3.  Please discuss the risks and benefits of alternative strategies to mitigate iron depletion in donors including:


a) iron supplementation;


Committee members commented that a randomized control trial in blood donors is needed to assess whether iron supplementation improves iron stores and to study the affect of iron supplementation on biomarkers.  Off target effects, such as cardiovascular risks, masking GI cancers in men and iron overdose, need to be monitored.  


The Committee discussed issues related to blood centers treating blood donors for iron deficiency.  While some Committee members expressed concern about blood centers  treating donors as patients, others commented on the benefits of iron supplementation programs and noted that the active involvement of physicians at blood centers has led to successful iron supplementation programs.






b) dietary recommendations;


Committee members commented that educational brochures should be distributed at the time of blood donation that discusses iron depletion and dietary recommendations.  However, other Committee members questioned the effectiveness of this strategy, noting limited donor compliance with suggested dietary changes.


            c) modification of the inter-donation interval;


One Committee member commented that since compliance with iron supplementation and dietary recommendations is low, modification of the inter-donation interval may be the only feasible option.  Another Committee member noted that a randomized controlled trial would establish data to determine the appropriate inter-donation interval.


The potential negative impact on the blood supply of increased inter-donation intervals was also discussed.    


d) changing the acceptance standard for donor hemoglobin/hematocrit.


The Committee discussed that, in general, changing the hemoglobin acceptance standards will not alleviate the eventual iron depletion in repeat blood donors.  One Committee commented that the acceptance standards for men and women blood donors should be revisited.  However, it was noted that establishing different standards for men and women donors introduces complexity in the screening process at blood establishments and may increase the likelihood of errors.   



Topic III:  Options for Blood Donor Screening and Reentry for Malaria


FDA sought the advice of the Committee on options for blood donor screening for the presence of malarial antibodies as evidence for malaria exposure and on a possible mechanism to allow more rapid reentry of donors who traveled to Mexico.  Dr. Sanjai Kumar introduced the topic to the Committee, summarized malaria biology and pathogenesis, risk of transfusion transmitted malaria in the U.S., FDA’s current recommendations for donor deferral for malaria, and currently available technology to detect malarial infections.


Next, Mr. Bryan Spencer, of the American Red Cross, presented data from the REDS-II study on the risk for malaria infection in U.S. donors deferred for travel to malaria-endemic areas.  Dr. Celso Bianco, from America’s Blood Centers (ABC) then presented data from a survey of ABC members on donor deferrals due to travel to malaria areas.  Captain Paul Arguin, M.D., from the Centers fro Disease Control and Prevention, presented the risk of malaria infection among U.S. travelers to Mexico by reviewing data from several U.S. travel surveys, the National Malaria Surveillance System and Mexican surveillance data.  Dr. David Leiby, of the American Red Cross, then discussed the impact of malaria deferrals on donor availability and the results of a study that conducted serologic testing of donors deferred for malaria risk. 


Finally, Dr. Hong Yang and Dr. Mark Walderhaug presented FDA’s risk analysis for malaria exposure in blood donors.  The risk assessment model presented three scenerios for antibody testing: testing all donors (universal testing); reentry testing of all malaria-at-risk donors; and reentry testing of travelers who visited malaria endemic areas in Mexico.  All scenerios assumed testing would be conducted using a two species test (for P. falciparum and P. vivax) after a four month deferral period after donors left a malaria-endemic area.


During the Open Public Hearing, Mr. Colin Knox from Lab 21 Healthcare, Dr. George Dawson from Abbott Laboratories and Dr. Patrick Jacquier from Bio-Rad DiaMed presented their respective data on testing for malarial antibodies.  Dr. Steven Kleinman, on behalf of AABB, then commented on alterative approaches to mitigating the risk of transfusion transmitted malaria and recommended eliminating the deferral period for travel to malaria endemic areas of Mexico.      


The following issues were discussed by the Committee:  


  • The FDA and Committee members asked what is known about the undiagnosed acquisition of malaria infection and if there is potential underreporting of cases of malaria in the United States.
  • One Committee member asked if the U.S. pattern of donor deferral for travel to malaria endemic areas is similar in Mexican blood establishments.  
  • One Committee member asked if there is any concern that removing the questions and geographic deferrals related to HIV Group-O risk in certain parts of Africa would increase the number of malaria at-risk donors.  
  • The number of Biological Product Deviation reports submitted by industry to FDA related to deferrals for travel to malaria endemic areas was discussed.
  • The Committee commented that the highest risk is among donors who were born and resided in Africa.
  • One Committee member commented on the additional cost of testing for blood establishments.
  • FDA commented that FDA’s risk assessment model and the model presented by American Red Cross vary because the assumptions in the models are different.
  • Committee members commented that it could take a very long time to assess the effectiveness of donor antibody testing since malaria infectivity does not necessarily correlate with the known sensitivity of the assay and the presence of antibody in the donor. 
  • One Committee member commented that a four month deferral with antibody testing is a very safe donor reentry method for travelers to Mexico.  
  • One Committee member highlighted the instability of malaria in certain regions of the Caribbean and FDA commented that data shows resurgences of malaria in certain regions of Mexico.  
  • One Committee member asked about a possible 5th species of malaria present in monkeys.
  • The Committee asked if a four month deferral following travel to a malaria endemic area would provide adequate time to identify acute infection.  It was discussed that the deferral in the U.K. is six months.
  • The Committee asked how FDA would regulate a malaria antibody test.  FDA responded that the regulatory pathway depends on whether the test would be a donor screening test or test for re-entry.
  • One Committee member expressed concern that testing a population at low risk for malaria would lead to numerous false positives.  Another Committee member commented that donor counseling would be necessary.
  • Members of industry commented on the complexity of serological testing for reentry and that donors deferred for travel to malaria endemic areas do not necessarily return to donate.          
  • The Committee requested to see a fifth model scenario in which travelers to Mexico would be reentered as donors without antibody testing.
  • The biostatistician on the Committee commented that by removing the deferral for travel to Mexico, the rate of infected units would increase to 1 infected unit per million from 1 infected unit per 10 million.                 


The Committee was asked to address the following questions:  


1. Given the historic risk of TTM from Plasmodium malariae and Plasmodium ovale, is testing for antibodies only to Plasmodium falciparum and Plasmodium vivax after a four-month deferral, practical and appropriate for use to screen and reenter donors deferred for any risk of malaria? 


2. Can selective testing for antibodies to Plasmodium falciparum and Plasmodium vivax four months after possible exposure be used as a criterion to screen and reenter donors deferred for travel to Mexico?  


However, the specific questions were not addressed since the Committee requested to see data from model scenarios not presented at the meeting. 


FDA agreed to consider and provide the Committee alternative strategies at a future meeting.