Food and Drug Administration
Center for Biologics Evaluation and Research
BLOOD PRODUCTS ADVISORY COMMITTEE
92nd Meeting: September
Hilton Hotel, 1750 Rockville Pike, Rockville, MD
Committee Members FDA
Frederick Siegal, M.D., Chair Robin Biswas, M.D.
Mark Ballow, M.D. Paul
M.D., Ph.D. Elizabeth
Bisceglie, M.D. Salim
Willarda Edwards, M.D., MBA***** Leslie
Maureen Finnegan, M.D. Sheryl
Simone Glynn, M.D., MSc, M.P.H. Sanjai
Matthew Kuehnert, M.D. Toby Silverman, M.D.
M.D. Jaro Vostal, M.D.
McComas, Ph.D. Mark
Ann Zimrin, M.D.
Louis Katz, 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
Donald Trunkey, M.D. Ritchard Cable, M.D.
Temporary Voting Members Jerry Holmberg, Ph.D.
Arthur Bracey, M.D. David
Thomas Fleming, Ph.D. Karin
Harvey Klein, M.D. Thomas
Thomas McCutchan, Ph.D.***** Bryan
Barry Skikne, M.D.**** Dan
Temporary Non-Voting Members Designated Federal Officer
John Barnwell, Ph.D., M.P.H.***** Donald Jehn,
* 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
Donald W. Jehn,
Federal Officer Chair
BLOOD PRODUCTS ADVISORY COMMITTEE
92nd Meeting – September 10-11, 2008
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 Robin Biswas on FDA’s draft guidance for industry,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).”
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.
Strategies to Enhance Bacterial Safety of 7 Day Platelets for
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
Louis Katz, M.D., of the Mississippi Valley
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:
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.
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.
members commented that a control group is needed to truly assess the
proposed study endpoints.
Committee discussed the functional viability of 7 day platelets.
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.
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.
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.
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
and the large study sample size needed.
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.
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.
Committee member questioned the benefit of 7-day platelets except in
periods of platelet shortage.
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
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.
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.
Committee member commented that the study would have a higher likelihood
of success statistically if cultures were done at day 5.
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.
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.
was asked whether the day 5 testing would be maintained after the
conclusion of the study. FDA indicated that the decision would be
The Committee then addressed the following question:
1. Does the Committee agree with FDA
that reporting of sepsis should be active and not passive?
Committee agreed with FDA that reporting of sepsis should be active. (13 yes
votes, 1 no vote, 1 abstain).
addition to reporting of sepsis does the Committee agree with FDA 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?
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).
- 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).
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
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:
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.
Committee member asked if there was any concern that donor iron
supplementation could worsen undiagnosed hereditary hemochromotosis.
racial differences in iron deficiency and donor response to iron
supplementation were discussed by the Committee.
considerations of administering carbonyl iron and iron in blister packs in
homes with young children were discussed.
Committee member expressed concern with iron supplementation in male
donors, as it could mask underlying disease, especially gastrointestinal
Committee discussed the challenges and costs associated with referring
iron deficient donors to primary care physicians for further follow
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.
impact of iron depletion in donors on blood availability was discussed.
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:
depletion in blood donors a concern?
The Committee unanimously agreed that iron depletion in
blood donors is a concern.
If so, are
there tests for iron status that would be practical and appropriate in the
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.
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
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
The potential negative impact on the blood supply of
increased inter-donation intervals was also discussed.
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.
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
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.
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.
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:
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.
Committee member asked if the U.S. pattern of donor deferral
for travel to malaria endemic areas is similar in Mexican blood
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
number of Biological Product Deviation reports submitted by industry to
FDA related to deferrals for travel to malaria endemic areas was
Committee commented that the highest risk is among donors who were born
and resided in Africa.
Committee member commented on the additional cost of testing for blood
commented that FDA’s risk assessment model and the model presented by
American Red Cross vary because the assumptions in the models are
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.
Committee member commented that a four month deferral with antibody
testing is a very safe donor reentry method for travelers to Mexico.
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.
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?
the specific questions were not addressed since the Committee requested to see
data from model scenarios not presented at the meeting.
agreed to consider and provide the Committee alternative strategies at a future