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April 1-2, 2009: Blood Products Advisory Committee Meeting Summary Minutes

Food and Drug Administration
Center for Biologics Evaluation and Review

QUICK MINUTES SUMMARY FOR THE
BLOOD PRODUCTS ADVISORY COMMITTEE

April 1-2, 2009
Hilton Hotel Washington DC North/Gaithersburg, Gaithersburg, MD

Committee Members
Dr. Frederick P. Siegal ## 
Dr. Mark Ballow
Dr. Henry M. Cryer, III
Dr. Adrian M. Di Bisceglie +
Dr. Willarda V. Edwards #
Dr. Maureen A. Finnegan
Dr. Simone A. Glynn
Dr. F. Blaine Hollinger
Dr. Roshni Kulkarni
Dr. Katherine A. McComas
Dr. Francisco Rentas
Dr. Andrea Troxel #
Dr. Donald Trunkey
Dr. Ann B. Zimrin
Dr. Richard A. Colvin *
Dr. Celso Bianco **

Temporary Voting Members
Dr.Harvey J. Alter +
Dr. William C. Blackwelder +
Dr. William Bower
Dr. Jay H. Hoofnagles +
Dr. Lori P. Knowles ++
Dr. James H. Maguire +
Dr. Kenrad E. Nelson

Temporary Non-Voting Member

Speakers
Richard Henry+
Dr. Susan L. Stramer +
Dr. Susan P. Montgomery +
Dr. Michael P. Busch +

FDA Participants
Dr. Jay Epstein
Dr. Sanjai Kumar +
Dr. Robin Biswas +
Dr. Richard Forshee +
Dr. Melissa A. Greenwald +
Dr. Robert Duncan +
Dr. Alan Williams ++
Dr. Mark Weinstein ++
Dr. Carolyn Wilson ++
Dr. C.D. Atreya ++    
Dr. Hira Nakhasi ++
Dr. Indira Hewlett ++

Designated Federal Official
William Freas, Ph.D.

Committee Management Specialist
Pearline Muckelvene

*Consumer Representative
** Industry Representative
# Did not attend
## Chair
+ Attended April 1 only
++ Attended April 2 only


The Chair, Dr. Frederick P. Siegal, called the meeting of the Blood Products Advisory Committee to order at 8:00 a.m. EST on April 1, 2009.  In open session, the Committee listened to update presentations from two speakers.  In open session, the Committee then discussed Topic IA, Blood Donor Screening for Hepatitis B Virus (HBV) Infection by Nucleic Acid Testing (NAT) and Topic I.B, Testing donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps) for hepatitis B virus infection by nucleic acid testing

An Open Public Hearing was announced.  There were six oral presentations from the public

In the afternoon, in open session, the Committee discussed Topic II: Potential Testing Strategies for T. cruzi Infection in Blood Donors. FDA sought the Committee's assessment of the data to support selective testing of prospective repeat blood donors for evidence of T. cruzi infection.

An Open Public Hearing was announced.  There were five presentations from the public.

At 8:00 am on April 2, 2009 the meeting reconvened.  During Topic III, the FDA sought the advice of the Committee on appropriate manufacturing standards for plasma products collected from Whole Blood donors to make injectable products. 

An Open Public Hearing was announced.  There were three oral presentations from the public.

In the afternoon during Topic IV, the Committee reviewed the research programs in the  Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, OBRR, CBER.   

Following is a summary of the discussion.  Additional information and specific details may be obtained from the transcript of the meeting.  The transcript may be viewed on the World Wide Web at the April 1-2, 2009: Blood Products Advisory Committee Meeting Transcripts main page

Committee Updates
On Wednesday, April 1, Richard Henry presented a summary of the December 17-18, 2008 meeting of the HHS Advisory Committee on Blood Safety and Availability. Dr. Sanjai Kumar then presented a summary of the September 12, 2008 FDA workshop on approaches to minimize the risk of transfusion-transmitted babesiosis in the United States.

Topic IA: Blood Donor Screening for Hepatitis B Virus (HBV) Infection by Nucleic Acid Testing (NAT)

FDA sought the advice of the Committee on issues related to blood donor screening for hepatitis B virus (HBV) DNA by nucleic acid testing (NAT) to prevent transfusion transmission of HBV. Dr.  Robin Biswas introduced the topic of HBV NAT screening and provided an overview of currently required screening for HBV in blood donors. Dr. Michael Busch of Blood Systems Research Institute presented on HBV viral dynamics, infectivity and incidence window-period modeling. Next, Dr. Susan Stramer of the American Red Cross provided data on the estimates of yield of HBV NAT and on observable yield data. Finally, Dr. Richard Forshee provided FDA's perspective on modeling and yield data. 

Presentations in the Open Public Hearing were made by the following: Dr. Jeff Linnen, Gen-Probe Incorporated; Dr. John Saldanha, Roche Molecular Systems; Dr. Steven Kleinman on behalf of AABB; Dr. Susan Rossmann on behalf of America's Blood Centers; Mr. Glenn Mones, representing the National Hemophilia Foundation; and, Mr. Cory Dubin, representing the Committee of Ten Thousand.

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

  • The Committee members discussed the limitations of the chimeric mouse model to assess infectious potential of units from HBV vaccinated donors with breakthrough infections. Some members commented that the model would poorly predict human disease, while others commented that the mouse model could be useful to predict HBV infectivity.
  • The Committee asked if individuals with vaccine breakthrough HBV infections developed HBV chronicity and if breakthrough infections were related to the number of vaccinations received by the individual.
  • One Committee member commented that the HBV breakthrough infections could potentially be vaccine failures, an important distinction when considering infectious potential.
  • The Committee asked what factors have changed over the past ten years since the utility of HBV NAT was last examined by the HHS Advisory Committee for Blood Safety and Availability. The following distinctions were highlighted by FDA and industry: 1) the feasibility of implementing HBV NAT has increased since FDA has approved two multiplex NAT tests; 2) automation has led to the use of smaller minipools and individual unit NAT; 3) there is a younger cohort of vaccinated blood donors; and, 4) increased awareness of breakthrough HBV infections.
  • Committee members commented on the decreasing rate of HBV in the US and the relatively low risk for recipients of blood transfusions. FDA and Committee members responded that HBV transmission can lead to morbidity and mortality, particularly in immuno-compromised individuals or neonates.
  • Committee members commented that in the absence of evidence, it should be assumed that transmission could occur theoretically from vaccine breakthrough HBV infections. Some Committee members discussed the precautionary principal, noting that if it is feasible, HBV NAT testing should be implemented.
  • The Committee discussed the benefit of using a test with the sensitivity of 100 IU/mL for individual samples. One member commented that moving from minipools of 16 to 8 doubled the workload without an observed benefit.

The Committee then addressed the following questions:

  1. Does the Committee agree with FDA that units from donors with apparent vaccine breakthrough HBV infections (HBV NAT positive and anti-HBs positive) should be presumed infectious pending further studies?

The Committee agreed with FDA (14 yes, 2 no, 2 abstain) that units from donors with breakthrough infections should be presumed infectious.

  1. Please comment on the value and design of candidate studies using animal models to assess the infectious potential of units from hepatitis B vaccinated donors with "breakthrough" hepatitis B infections.

The Committee members expressed diverse opinions on the value of animal studies. While some Committee members expressed that chimeric mice studies would predict infectivity, others disagreed and noted that studying genotype, how frequently infections would appear, and clinical outcomes in humans are not feasible in murine studies. The Committee also commented on the overall challenges and expense of conducting murine studies and the increasing difficulties in conducting non-human primate studies.

One Committee member suggested that look back studies could be conducted on transfusion recipients who have received blood from donors with HBV vaccine breakthrough infections. These studies could be conducted in regions where HBV is much more prevalent, such as in China or Thailand.

  1. Considering the estimated yield of HBV infected window period donations, and the answer to question 1, please comment on the benefit of routine screening of blood donors by HBV NAT if testing were performed using available licensed tests on minipools, assuming a sensitivity of at least 100 IU/mL for individual samples.

Overall, the Committee supported routine HBV NAT testing and establishment of a minimum sensitivity. However, the Committee commented that the scientific data do not support that using a minipool of 16 samples is better than a minipool of eight samples.

Topic I.B.:  Testing donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps) for hepatitis B virus infection by nucleic acid testing

FDA sought the advice of the Committee on issues related to testing donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps) for HBV DNA by NAT. Dr. Melissa Greenwald introduced the topic of testing donors of HCT/Ps for HBV by NAT and discussed the lack of yield data for HBV NAT in living and cadaveric donors. Dr. Susan Stramer, of the American Red Cross, then presented data on HIV, HCV and HBV risk in living and cadaveric donor’s tissue HCT/P donors.

Following the presentations, the Committee asked questions related to what data is known about infectious disease and HBV transmission rates to recipients of HCT/Ps in the United States. The committee later asked Dr. Stramer to comment about what has been learned from Japanese and German experiences in implementing individual NAT for HBV in tissue donors, including if a decrease in incidence of HBV transmission has been observed.

The Committee then addressed the following questions:

  1. Please comment on the potential benefit of HBV NAT testing in the ID NAT format and in the small minipool format for living donors of hematopoietic stem/progenitor cells (HPCs) and DLI.

One committee member commented that the HBV testing requirements should be the same as it is in blood donors, with other committee members indicating agreement (no vote was taken). 

  1. Please comment on the potential benefit of HBV NAT testing in the ID NAT format for:
    1. other living donors; and
    2. cadaveric donors

The committee discussed how it would be impossible to pool cadaveric donor specimens because of the variable quality of the specimens. There were no comments indicating that HBV NAT testing should not be recommended for HCTIP donors. HBV NAT testing was thought reasonable given the large number of tissue products that can be made from a single donor.

Topic II: Potential Testing Strategies for T. cruzi Infection in Blood Donors

FDA sought the Committee's assessment of the data to support selective testing of prospective repeat blood donors for evidence of T. cruzi infection. Dr. Robert Duncan introduced the topic for the Committee, providing background on T. cruzi, the causative agent of Chagas disease, and discussed the current status of testing blood donors for T. cruzi in the United States. He then presented several potential testing strategies for T. cruzi infection in blood donors. Next, Dr. Susan Montgomery, from the Centers for Disease Control and Prevention, discussed the epidemiology of Chagas disease in the United States. Dr. Susan Stramer then presented the American Red Cross' experience with blood donor testing for T. cruzi. She was followed by Dr. Michael Busch who discussed Blood System's experience asking Chagas risk questions and testing donors for T. cruzi. Finally, Dr. Richard Forshee presented FDA's risk analysis for selective testing strategies.

The Committee heard presentations from the following individuals in the Open Public Hearing: Dr. Michael Busch, presenting a joint statement of Blood Systems Research Institute and the American Red Cross.; Dr. Steve Kleinman, representing AABB; Mr. Glenn Mones, representing the National Hemophilia Foundation; Dr. Merlyn Sayers, from the University of Texas, Southwest and North Texas; and, Dr. Susan Rossmann representing America's Blood Centers.

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

  • Committee members commented that immunosuppression, particularly following transplantation, affects the rate of development of Chagas disease.
  • The Committee discussed the sensitivity of the licensed assay and its cross reactivity with other parasitic infections, such as Leishmania.
  • The Committee asked if prevalence data is known for individuals who have spent considerable time in an endemic area, such as Peace Corps volunteers. One committee member indicated that the highest risk exposure is long time residence in a house that has been colonized by the insect and that infection generally occurs in childhood.
  • It was discussed that donors with newly acquired, acute Chagas disease are more likely to transmit the disease than individuals with chronic disease.
  • The feasibility of selective testing strategies in blood centers was discussed. Representatives from blood establishments commented that one time donor testing is currently feasible. However, additional selective testing strategies would require modifications to their computer systems, which are cleared by the FDA.
    Further, industry representatives commented that implementation of more complicated testing strategies increases the likelihood of error.
  • The Committee asked why blood donors failed to answer risk questions accurately. One member recommended a follow up should be conducted to examine the issue.
  • The Committee discussed the positive impact of vector control programs in many parts of South America, as well as how environmental changes can increase the prevalence of the vector (e.g. following Hurricane Katrina in the Gulf Coast).
  • The Committee asked if the true prevalence of Chagas disease in the donor population is known. It was discussed that the current estimate is one per 29,000 nationally; however, it is known that certain areas, such as Los Angeles, may be as high as one in 3,000.
  • Borderline reactive donations were discussed and whether the cut off of the assay should be lowered. Industry representatives commented that the apparent seroconversions observed in donors actually were reflective of borderline reactive donations and no cases with evidence of a new infection were identified since
    the implementation of the test two years ago.
  • The Committee discussed the differential transmission of T. cruzi by type of blood component, noting that Platelets stored at room temperature had the highest transmission rat¢, in contrast to refrigerated Red Blood Cells or frozen Plasma. It was postulated that the use of fresh whole blood for transfusion in South America
    may account for the higher rate of transmission of T. cruzi than that observed in the Unites States.
  • The Committee members commented that there are no data on incident cases in the U.S. and the twenty-two months of data presented since the implementation of the test is not sufficient to assume that newly acquired infection in the U.S. is not a problem.
  • The Committee noted that two-time testing will not identify incident cases and a long term study is needed to understand incidence of Chagas disease in the U.S. Representatives from the American Red Cross and Blood
    Systems Inc. committed to conducting a follow up study.

The Committee then addressed the following questions:

  1. Does the Committee agree with FDA that the scientific data on effectiveness of risk questions in general do not support a selective testing strategy in which donors who previously tested negative for antibodies to T. cruzi are tested again only if their answers to risk questions indicate they have risk of a newly acquired infection?
    The Committee agreed with FDA (16 yes votes, 1 no vote).
  2. Do the combined scientific data on risk of transfusion transmission of T. cruzi support a selective testing strategy in which:
    1. One negative test would qualify a donor for all future donations without further testing or questions regarding risk of a newly acquired infection, subject to continuation of studies to define the incidence of new infections in previously screened negative donors?
      The Committee voted affirmatively (12 yes votes, 5 no votes).
    2. If the answer to 2A is "no", would negative tests on two independent donations qualify a donor for all future donations without further testing or questions regarding risk of a newly acquired infection, subject to continuation of studies to define the incidence of new infections in previously screened negative donors?
      The Committee did not vote on question 2B.
  3. Please provide any additional comments on considerations for selective testing for antibodies to T. cruzi in repeat donors.
    One Committee member recommended testing repeat donors every few years to identify incident infections and another member recommended prospective studies in high risk regions of the country.

Topic III: Current Considerations on Plasma Obtained from Whole Blood Donors for Further Manufacturing Use

FDA sought the advice of the Committee on appropriate manufacturing standards for plasma products collected from Whole Blood donors to make injectable products. Dr. Alan Williams introduced the topic and provided FDA's regulatory perspective on plasma for further manufacturing use. Dr. Williams discussed FDA's proposal to define two new plasma products that could potentially replace recovered plasma as source materials to make injectable products. Dr. Mark Weinstein then presented FDA's considerations for manufacturing standards and categories for labeling for the proposed products.

Presentations were made by the following individuals during the Open Public Hearing: Dr. Susan Wilkinson, representing AABB; Ms. Mary Gustafson, representing the Plasma Protein Therapeutics Association; and Mr. Cory Dubin, representing the Committee of Ten Thousand.

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

  • The Committee discussed the distinctions between FDA's considerations for labeling and the current European labeling requirements for plasma for further manufacturing, and the potential impact of different labeling requirements.
  • Committee members asked if whole blood donors are currently aware that their donations may be used as source material for further manufacture, rather than for transfusion.
  • The Committee, as well as patient advocates, commented that communication with the donors about the use of their donations is necessary to maintain donor trust. One Committee member stressed the importance of communicating to the donors the distinction between 1) local versus global use and 2) altruistic versus
    commercial use to avoid perception of commercial exploitation.
  • The Committee discussed the value and limitations of the informed consent process, as well as the importance of accurate recruitment messages.
  • The Committee asked if stability data supported FDA's proposal for a 10 year dating period for the new plasma products, noting that unlike Source Plasma, the products are not frozen immediately.
  • Committee members asked FDA to clarify how conditions for storage and freezing of the plasma used for manufacturing affect the quality of the final injectable product.
  • Committee members expressed support for the two distinct products, but favored simplified labeling categories if feasible.

The Committee then addressed the following questions:

  1. Does the Committee agree with the framework for the standards proposed by FDA for collection, freezing, storage and labeling for Concurrent Plasma and. Component Plasma are reasonable and appropriate to ensure the quality necessary for manufacture into injectable plasma products?

The Committee agreed unanimously (15 yes votes, 0 no votes) with the framework for the standards for Concurrent and Component Plasma as proposed by FDA.

  1. Please comment on the impact that the proposed new products would have on maintaining the voluntary donor pool that is critical to community-based voluntary blood donation.

Committee members stressed that the impact of the proposed products and the informed consent process on the voluntary donor pool needs to be studied further. The Committee also discussed the value of informed consent and clear, upfront community recruitment messages. One member recommended FDA should develop a model informed consent form for industry use. Another member suggested on-line registration prior to arrival at the collection center could provide the potential donor with more information. One member commented that donors should receive the positive message that their donations will be utilized to the fullest extent possible. 

One member suggested donors could provide consent for the particular use of their donation. Other Committee members commented that the effect of consenting for choice needs to be studied further before implementation.

Topic IV: Review of the Research Programs in the Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, OBRR, CBER (Site Visit, October 22, 2008)

Dr. Carolyn Wilson provided the Committee with an introduction to CBER research programs. She explained that research is a critical element in CBER's approach to regulation and provided an overview of CBER's research priorities a well as the process for internal and external evaluation of individual research programs. Next, Dr. C.D. Atreya presented an overview of the Managed Research Initiative in the Office of Blood Research and Review (OBRR) and OBRR's current research priority areas. Dr. Hira Nakahai subsequently provided the Committee with an introduction to the mission and organization of the Division of Emerging and Transfusion Transmitted Diseases (DETTD). He discussed the impact of DETTD's research as it relates to FDA's regulatory mission and then reviewed the regulatory and scientific challenges related to blood safety and availability. Next Dr. Indira Hewlett summarized the purpose of the site visit of October 22, 2008 and further discussed the research programs of the Laboratory of Molecular Virology (LMV) by providing a brief overview of each of the research programs evaluated by the site visit team, including:

  • The Hewlett laboratory focused on virus evolution pathogenesis and diagnosis; detection methodologies; and pandemic, Smallpox and blood safety
  • The Rios laboratory focused on West Nile Virus infection and pathogenesis; and
  • The Dayton laboratory focused on HIV pathogenesis and biomarker development.

Before discussing the Site Visit Report in closed session, the Committee asked a few clarifying questions related to the research programs discussed.