DEPARTMENT OF HEALTH AND
HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS
EVALUATION AND RESEARCH
BLOOD PRODUCTS ADVISORY
COMMITTEE
MEETING
THURSDAY, MAY 1, 2008
The meeting came to order at 8:30 a.m. in
the Plaza Meeting rooms of the Hilton Washington DC Rockville, 1750 Rockville
Pike,
PRESENT:
FREDERICK
P. SIEGAL, MD CHAIRMAN
MARK
BALLOW, MD MEMBER
HENRY
M. CRYER III, MD, PHD MEMBER
ADRIAN M. DI BISCEGLIE, MD MEMBER
WILLARDA
V. EDWARDS, MD, MB MEMBER
MAUREEN
A. FINNEGAN, MD MEMBER
SIMONE
A. GLYNN, MD, MSC, MPH MEMBER
MATTHEW J. KUEHNERT, MD MEMBER
ROSHNI KULKARNI, MD MEMBER
CATHERINE
S. MANNO, MD MEMBER
KATHERINE
A. MCCOMAS, PHD MEMBER
FRANCISCO
J. RENTAS, PHD MEMBER
ANDREA
B. TROXEL, SCD MEMBER
ANN B.
ZIMRIN, MD MEMBER
JUDITH
R. BAKER, MHSA CONSUMER REPRESENTATIVE
LOUIS
M. KATZ, MD INDUSTRY REPRESENTATIVE
THOMAS
R. FLEMING, PHD TEMPORARY VOTING MEMBER
B.
GAIL MACIK, MD TEMPORARY VOTING MEMBER
IRMA
O. SZYMANSKI, MD TEMPORARY VOTING MEMBER
DONALD
W. JEHN, MS EXECUTIVE SECRETARY
This
transcript has not been edited or corrected, but appears as received from the
commercial transcribing service. Accordingly, the Food and Drug Administration
makes no representation as to its accuracy.
I-N-D-E-X
PAGE
WELCOME
Frederick P. Siegal, M.D., 4
Chairman
CONFLICT
OF INTEREST STATEMENT
Donald W.
UPDATES
Jerry A. Holmberg, Ph.D. 14
Maria Rios,
Ph.D. 30
Melissa A.
Greenwald, M.D. 45
Robert Duncan,
Ph.D. 50
Melissa A.
Greenwald, M.D. 61
Dorothy Scott, M.D. 66
Larry J. Dumont, MBA, Ph.D. 82
Louis M. Katz,
M.D. 100
Salim A.
Haddad, M.D. 121
REPORT
ON CBER SAFETY TEAMS
Jonathan Goldsmith, M.D. 131
Ruth Solomon, M.D. 126
Open
Public Hearing 179
BEST
COMMITTEE REPORT
Ping He, M.D. 207
Richard Davey, M.D. 258
Mark Stafford-Smith, M.D. 297
Larry Dumont, MBA, Ph.D. 325
Jessica Kim, Ph.D. 363
Open
Public Hearing 401
Open
Committee Discussion 402
Adjourn
P-R-O-C-E-E-D-I-N-G-S
8:35 a.m.
CHAIR SIEGAL: Good morning and welcome to BPAC. We have a number of new members to
welcome. Over the last two days some of
us had the opportunity to revisit the issue of hemoglobin-based oxygen carriers
at a fascinating meeting that was co-sponsored by CBER and NHLBI, and I
personally look forward to a slightly less contentious meeting today, but,
anyway, welcome.
I'd
like to welcome the new members, Dr. Katherine McComas from Cornell; Dr. Rentas
from Walter Reed; Dr. Troxel from the University of Pennsylvania; Dr. Ann
Zimrin also from the University of Maryland; and Don Trunkey, who won't be
here, from Oregon Health and Science University.
In addition, we have several
temporary voting members. I'd like to
welcome back Dr. Irma Szymanski and Tom Fleming, who've been here many times
before. And Tom Atkinson of the University
of Alabama at Birmingham; Dr. Andrea Apter, University of Pennsylvania; Larry
Borish, University of Virginia; and Gail Macik, also from the University of
Virginia who are temporary voting members.
I hope I haven't left anybody
out. We'll go around the room and
introduce ourselves. I'm Fred
Siegal. I'm, obviously, the chair. I'm a clinical immunologist with a background
in immunodeficiency diseases in AIDS, and I'm particularly interested in
mechanisms of immune deficiency, particularly cellular.
To my right, Don, want to introduce
yourself?
MR. JEHN: Yes.
I'm Don Jehn, the designated federal official for the Blood Products
Advisory Committee.
CHAIR SIEGAL: Dr. Macik?
DR. MACIK: Good morning.
I'm Gail Macik, or Mah-chik is the correct pronunciation actually from
the
DR. SZYMANSKI: Hi.
I'm Dr. Irma Szymanski, currently at
DR. FLEMING: Thomas Fleming, Department of Biostatistics,
DR. KULKARNI: Roshni Kulkarni, pediatric hematologist from
DR. McCOMAS: Katherine McComas from the Department of
Communication at
DR. RENTAS: Frank Rentas, the Chief of Blood Services at
DR. TROXEL: Andrea Troxel from the Department of
Biostatistics at the
DR. ZIMRIN: Ann Zimrin, hematology/oncology,
MS. BAKER: Judith Baker,
DR. KATZ: Louis Katz,
DR. KUEHNERT: Matt Kuehnert, I'm the Director of the Office
of Blood, Organ and Other Tissue Safety at CDC.
DR. GLYNN: Simone
Glynn, NHLBI.
DR.
FINNEGAN: Maureen Finnegan, orthopaedic
surgeon, U.T. Southwestern in Parkland.
DR.
BISCEGLIE: Adrian Bisceglie, I'm a
hematologist at St. Louis University.
DR.
CRYER: Gill Cryer, Department of
Surgery, UCLA in
DR. BALLOW: I'm Mark Ballow, allergy immunology, SUNY,
CHAIR SIEGAL: Thank you, everybody. Mr. Jehn, do you have some announcements?
MR. JEHN: Yes. I
wanted to welcome everybody again, and this is the 91st meeting of
the Blood Products Advisory Committee. I
have the conflict of interest statement to read today. It's rather lengthy, so bear with me.
The Food and Drug Administration is
convening the May 1-2, 2008, meeting of the Blood Products Advisory Committee
under the authority of the Federal Advisory Committee Act, FACA, of 1972. With the exception of the industry
representative, all participants of the committee are special government employees
or regular federal employees from other agencies and are subject to the federal
conflict of interest laws and regulations.
The following information on the
status of this advisory committee's compliance with federal ethics and conflict
of interest laws including, but not limited to, 18 U.S. Code, Section 208 and
712 of the Federal Food and Drug Cosmetic Act are being provided to
participants at this meeting and to the public.
FDA has determined that all members of the advisory committee are in compliance
with federal ethics and conflicts of interest laws.
Under 18 U.S. Code 208, Congress has
authorized FDA to grant waivers to special government employees and regular
government employees who have financial conflicts when it is determined that
the agency's need for a particular individual's service outweighs his or her
potential conflict of interest.
Under 712 of the Food and Drug and
Cosmetic Act, Congress has authorized FDA to grant waivers to special
government employees and regular government employees with potential financial
conflicts when necessary to afford the committee their essential expertise.
Related to the discussions at this
meeting, members and consultants of this committee have been screened for
potential financial conflicts of interest of their own, as well as those
imputed to them, including those of their spouses and minor children, and for
the purposes of 18 U.S. Code 208, their employers. These interests may include investments,
consulting, expert witness testimony, contract and grants, CRADAs, teaching,
speaking, writing, patents and royalties, and primary employment.
The committee will discuss the
Biomedical Excellence for Safer Transfusion, BEST, committee report on blood
cell recovery. This is a particular
matter of general applicability, Topic 1.
For Topic 2, the committee will discuss, review and make recommendations
on Lev Pharmaceuticals, Incorporated clinical trial for the use of plasma drive
C1S trace inhibitors, Cinryze, for the prophylaxis of hereditary angioedema
attacks. This is a particular matter
involving specific parties' product discussion.
For Topic 3, the committee will hear
an overview of the research programs in the laboratory of hepatitis and related
emerging agents, division of emerging and transfusion transmitted
diseases. There is no conflict of
interest involved with this overview.
In addition, the committee will hear
updates and informational presentations on several topics. There is no conflict of interest involved
with these informational updates.
Based on the agenda and all
financial interest reported by members and consultants, conflict of interest
waivers have been issued to Dr. Ballow in accordance with 18 U.S. Code 208,
Section 3 and 712 of the Food and Drug and Cosmetic Act. Dr. Ballow's waivers include a consulting
arrangement with the firm that could be affected by the committee's discussion
of Topic 2. The waivers allow Dr. Ballow
to participate fully and vote on the committee discussion.
FDA's reason for issuing waivers are
described in the waivers documents, which are posted on FDA's website at www.fda.gov OHRMS dockets default at HTM. Copies of the written waivers may obtain by
submitting a written request to the agency's Freedom of Information Office,
Room 6-30 of the
With regard to FDA's
guest speakers, the agency has determined that the information being provided
is essential. The following information
is being made public to allow the audience to objectively evaluate any presentation
and/or comments.
For Topic 1, Dr. Larry
Dumont was formerly employed by Gambro BCT, Incorporated, where he was the
project leader for 7-day platelets and the PASSPORT study. In addition, he is the co-leader of the
clinical studies team and a member of the executive committee for the BEST
collaborative. He is also a consultant
for and receives research support from several firms that could be affected by
the committee discussions.
Dr. Louis Katz is
serving at the industry representative, acting on behalf of all related
industry, and is employed by the
This conflict of
interest statement will be available for review at the registration table. We would like to remind members, consultants,
and participants that if discussions involve any other products or firms not
already on the agenda for which an FDA participant has a personal or imputed
financial interest, the participant's need to exclude themselves from such
involvement and their exclusion will be noted for the record.
FDA encourages all
other participants to advise the committee of any financial relationships that
you have with a sponsor, its product, and, if known, its direct
competitors. Thank you.
I now turn over to the
Chair.
CHAIR SIEGAL: Thank you, Mr. Jehn.
We have a number of
updates today and Don's already mentioned all of them in passing, so we might
as well get started directly. I've been
asked to point out that committee members are encouraged to ask questions
between and after each presentation.
So we'll start with
Jerry Holmberg, Ph.D., Executive Secretary of the Advisory Committee on Blood
Safety and Availability, who's going to talk about the August '07 and January
'08 meetings of the DHHS Advisory Committee on Blood Safety and
Availability. Dr. Holmberg.
DR. HOLMBERG: Good morning.
Welcome to those people returning to the BPAC and also welcome to the
new members of the Blood Products Advisory Committee.
What I would like to
do is to give a quick overview of some of the last two recommendations, meeting
recommendations, for the Advisory Committee for some of you that are new to the
BPAC. The Advisory Committee on Blood
Safety and Availability is an advisory committee at the secretarial level. It has the responsibility to look at various
issues, including safety and availability, but also transfusion and
transplantation safety.
Since our last meeting
we've had some changes in the administration in the Office of the Secretary,
and especially the Assistant Secretary for Health. Dr. Garcia joined us in February/March. He was confirmed by the Senate. He is an admiral in the United States Public
Health Service, four-star admiral, and was just commissioned last week.
We also have a
non-political appointee, Dr. Don Wright, who came to us from the Bureau of
Labor, or I should say OSHA, Health Safety, and he is the principal Deputy
Assistant Secretary for Health. And then
we also have Dr. Parekh, who is the Deputy Assistant Secretary for Health for
Science and Medicine.
Some of the
recommendations over the period of 2000 to 2008 I want to quickly give you an
update on some of those, not specific, but an overview. Our recommendations are posted on the
website, hhs.gov/blood safety. I think
this is very remarkable. Most recently
my office went through and looked at the various recommendations since 2000,
year 2000. There were 42 recommendation
topic groups, in other words, a subject where there were several recommendations
under one topic, and I have to say that over 100 actions by the department and
the operating divisions have been noted on those 42 recommendation topic
groups.
Now, when I say about
operating divisions within the Office of the Secretary and the HHS, we do have
the public health services that represent or have something to do with tissues
or transplantation safety, CDC, CMS, FDA, HRSA, and NIH, and specifically not
only with various institutes within NIH, but also NHLBI.
At the August meeting
of the Advisory Committee on Blood Safety and Availability, the main topic that
was discussed during this period was to look at the flexibility or the
elasticity of the blood supply when it's faced with various challenges. And the first challenge that we were asked to
comment about was primarily the impact of erythropoiesis stimulating agents.
In the summer of last
year, CMS came forward with a proposed national coverage determination that
would lower the trigger for use of the ESAs down to 10 grams of hemoglobin and
also over a period of eight weeks. This
caused a lot of concern and our committee was asked to take a look at the
availability of blood products if this national coverage determination was
reduced down to 10 grams of hemoglobin.
The committee actually
came forward and said that, first of all, that there needs to be a review of
the perspective data collection data and that we need to do some data
collection. The specific recommendation
was that the committee believes that there is inadequate information to
accurately assess the impact of CMS's national coverage determination for ESAs
on the management of anemia in the general patient population and in cancer
patients.
Since this
recommendation has come out, the Secretary has communicated to CMS officially
with the findings of the committee, and also within the department. We've had
various meetings with CMS and also with FDA.
One of the most recent meetings that FDA held was the Oncological Drug
Advisory Committee, and I believe that was back on April 13th or
March 13th. I can't remember
the day. They seem to all blur
together. But it was in the last couple
of months that the ODAC met and some of the recommendations that came out of
that were basically to come in line with the 10 grams of hemoglobin for the
trigger and also to recommend that the labeling be changed to discourage the
use of ESAs in breast and head and neck cancers, especially metastatic cancers.
Also the committee was
asked to look at the elasticity of the blood supply, especially in light of
different scenarios that may take place as far as being prepared in response to
the natural disaster or manmade disaster that may present itself, and that the
committee felt that the blood supply is a critical part of the nation's health
care infrastructure. The advisory
committee believes that the knowledge of the realtime national blood and blood
product inventory and its dynamics is essential for emergency preparedness and
response.
The committee finds
that the blood center data are extensive but not comprehensively aggregated nor
available to HHS. Hospital data
reporting is essential but limited.
Although the blood supply is elastistic, it is unclear whether it is
sufficient elastic to address potential disasters and the committee recommended
that there be established sufficient hospital and blood donor center
participation, and the inventory reporting develop comprehensive models and
also to define shortage scenarios that would require implementations of
alternative strategies, support operational research to characterize and to
recruit potential donors who do not now routinely donate.
Since August we have
moved quite rapidly on this. There were
some things that were already in the works, such as the Blood Availability
Safety Information System, which is a nationwide system to collect data on
blood centers and also hospitals to look at the supply and demand.
We've worked a little
bit more, and I'll show you a graph, we've worked with the blood community, the
blood centers, and I have to say that starting after the first of the year this
year we are now getting an aggregate report from the American Red Cross, the
Americas Blood Centers, and the Blood Centers of America through the AABB as an
aggregated report.
We're also working
with the Biomedical Advance Research and Development Authority, which is within
HHS, to work on various scenarios and also to work on modeling that would be
required to be able to predict how much blood we would need in a scenario.
I'll show you the next
slide. This may be a little bit
difficult to read. But this data
actually is representative of what was presented yesterday to me. This is an aggregated report from all three
blood organizations through the AABB.
And the second one, the lowest column there, is actually the group O-s,
and you can see we're at about 2.1 day supply of O-s in this
country.
Now, this is really
only an estimate of what is available in the blood centers, and down below is
actually an attempt to give us an estimate of what is available within the
blood centers and what might be available within the hospitals, and this is
based on an assumption that the hospitals have about an eight day blood supply.
Even though the 2.1
day supply of group O- looks serious, and it is serious, the blood
supply is able to respond and we believe, that between the two-day supply
within the blood center and the eight-day supply which might be in the
hospital, is sufficient. Also what we're
seeing at the present time, and at one point last month, this was actually down
to less than two days. It was down to
about 1.9 days of group O- blood available. And what we're seeing right now is that there
is a response, a seasonal response, in donations.
We're also trying to
work on getting more data for the hospitals and we've been in contact and
discussions with various states to try to get more hospital participation so we
can have a better reflection of what is happening.
Now, let me turn to
January 2008's meeting. At that meeting
we looked quite a bit at the infectious diseases and the emerging infectious
diseases, and what new technologies and what were the barriers to advancing
technology to reduce the risk of infectious disease and safety issues to the
blood supply.
This may be a little
bit hard to read, but let me just read it to you. The Advisory Committee on Blood Safety and
Availability finds that accumulating evidence for the efficacy and safety of
pathogen reduction warrants a commitment and concerted effort to add this
technology as a broadly applicable safeguard, which additionally would provide
a reasonable protection against potential emerging infectious diseases.
This would result in a
proactive, preeminent strategy that would broadly render most known agents
noninfectious and preventing emerging agents from becoming transfusion
risk. To achieve this goal, government,
industry, blood organizations, and public stakeholders need to work in concert
to commit the required financial and technical resources.
The committee went on
to recommend to the Secretary that the Secretary adopt as a high priority the
urgent development of safe and effective pathogen reduction technologies for
all blood transfusion products and implementation as they become available;
provide resources to overcome current barriers to development and validation of
pathogen reduction technologies; to ensure adequate safety monitoring of
pathogen reduced blood products, post marketing using an active national
hemovigilant system and to ensure that other efforts to improve blood safety
and availability are not compromised by those efforts.
I'd like to say that
since the January meeting we've made great progress on this, but I have to be
honest with you and say that the department is still working on these recommendations. We're having discussions internally on what
this means and how we can put our hands around this, but it is out there in the
public domain as a recommendation to the Secretary.
In finishing up, I
just want to let you know that our next meeting is going to be on May 29th
and 30th of this month. We
will have updates on safety in transfusion and transplantation.
We're also going to
have an update on the HBOC meeting and the rule making associated with the
vascularized composite allographs, and we're also going to have discussion on
the transfusions associated with older red cells. And some of us that were at the meeting
yesterday for the HBOC, a lot of that was a good preliminary to the discussion
at the end of May.
I also would like to
make known to the committee, and also to the audience, is that we are seeking
nominations to the Advisory Committee on Blood Safety and Availability. The notice went in the April 15th
Federal Registry and the nominations are due June 30th. And thank you very much.
CHAIR SIEGAL: Thank you, Dr. Holmberg. Next we'll hear from Maria Rios of FDA on the
I should say, are
there any questions for Dr. Holmberg? I
apologize for forgetting that. DR.
RIOS: Okay.
DR. FLEMING: Just one clarification. You were talking the erythropoietin
stimulating agents, ESAs, and the ODAC recommendation that came through
recently about head, neck and breast cancer.
I think you said particularly in the advanced disease setting. My understanding is that was true, but there
principal focus was on low risk, the surgical adjuvant disease settings given
the venothrombotic events at six to seven percent increase in a five to 20
percent potential increase in mortality that they had actually first
discouraged the use in the lower risk adjuvant setting and then also added the
breast cancer and head and neck advanced disease setting. Isn't that correct?
DR. HOLMBERG: Yes, it is.
Thank you.
CHAIR SIEGAL: Any other questions?
DR. FINNEGAN: As far as the supply of O- is
concerned, has anyone looked at user usage and can that be altered so that
perhaps the supply is not as low as it is?
DR. HOLMBERG: Well, the committee has grappled with that
many times as far as utilization guidelines and it really comes down to an
issue of the Secretary making recommendations to the practicing physicians, is
that really appropriate. And so we're
really looking to a scientific body, the peer review process, to hopefully
implement some of those utilization guidelines.
But, yes, there are attempts at the present time to look at the various
guidelines issues and that's all I can say at the present time.
DR. FINNEGAN: Because there are multiple medical
associations that the Secretary could deal with that would be happy to --
hematology,
DR. HOLMBERG: Yes. And we have worked with some of those groups
and we continue to work with them.
CHAIR SIEGAL: Okay.
Anyone else? Dr. Szymanski?
DR. SZYMANSKI: I'd like to ask, is there any understanding
why ESAs are harmful in those conditions described?
CHAIR SIEGAL: Dr. Holmberg?
DR. HOLMBERG: I thought I was finished. I didn't hear that question.
DR. SZYMANSKI: Is there any understanding why ESAs are
harmful in those conditions you stated?
DR. HOLMBERG: Well, without getting into a lot of the specifics,
at least with some of the high risk such as the breast, the metastatic breast,
and also the head and neck, it's my understanding as far as the erythropoiesis
or the EPO receptors that may be on some of those cancers and the risk of
spreading the metastasis of that, but also I have to say that there is also the
risk of, especially higher than the 12 grams, the increased thrombosis that was
presented by Dr. Fleming, clarified by Dr. Fleming.
CHAIR SIEGAL: If there are no others, Dr. Rios.
DR. RIOS: Okay.
I will present an update to you on West Nile season and then I will
present to you the guidance on blood donor screening for infection with
In an update in 2007,
it's the ninth consecutive year of West Nile outbreak in the
Please remember that
about 80 percent of the infections by
So in the ninth year
of consecutive outbreaks,
This shows the number
of human cases from 1999 to 2007. You
can see that it peaked in 2002 and 2003, which the largest number of neuroinvasive
cases and cases in general, and close to 3,000 cases of neuroinvasive
disease. And that dropped in 2004 to
lower than 1,200 cases of neuroinvasive disease, but sustained above the 1,000
number throughout these six years.
And one can calculate
the number of cases that occur of infection based on neuroinvasive cases if CDC
considers 1:150 neuroinvasive case, 1:150 is a neuroinvasive case. More recent data show that these number is
actually low estimation and it's more accurate 1:353 cases.
Taking that into account, there has been between 1.7 and 3.9
million infections in the
So West Nile is
important in the
This year
Blood screening for
West Nile using MP-NAT has been implemented as you well know from 2003 and now
and has been extremely successful and it's a joint collaborative effort between
test kit manufactures, the public health department's blood centers and it's
incredible cooperation to get to this.
To date there has been 2,600 interdicted units due to reactivity to NAT
to
There is a task force
of West Nile that AABB believes that discuss this date is an update what's to
be done. This is the summary of
transfusion transmission cases that where 23 cases -- a total of 32 cases
confirmed to be transmitted by transfusion to date, plus 56 cases that were
inconclusive because they couldn't be resolved for several reasons.
You can see that the
drop from 23 cases in 2002 to six cases after implementation of NAT shows the
efficacy of the assay to prevent blood transmission by
-- West Nile transmission by transfusion. There was another case in 2004, none in 2005
that has been documented. We don't know
if there are any that has not been, and two cases in 2002 and I'll address this
a little bit later.
The current test
algorithm means that the assays is performed around using MP-NAT six of 16
specimens, the test kit manufacturer, and if the pool is negative and the unit
is suitable for transfusion, then the unit is released. If the MP is reactive, then the units are
tested independently to identify the positive.
We will just go
quickly because I will address these later to show that further testing,
repeating the same NAT plus antibody has a positive predictive value of 98
percent and sensitivity of 98 percent, and these data was provided to or
generated by the blood establishments and discussed thoroughly in the West Nile
Virus Task Force and has been provided to us.
So the further
testing, the repeat NAT and antibody testing as well leads to the definition of
what the donor has to be told. And if
it's ID-NAT reactive unit repeating in the repeat NAT, then it's positive
regardless of antibody. If it's antibody
positive and not repeat NAT, then it's considered positive regardless of the
NAT.
There is a portion,
however, that does not repeat ID-NAT and it's subset for
We mentioned some
issues, we had some issues. I have been
told that the time is short so I will skip a lot of these slides now. But in any case, MP-NAT would lose a lot of
reactive units, 25 percent of reactive units.
Last year we presented
that in the blood establishment have been testing for ID-NAT in the situation
where the peak, the
I'm sorry. I have to skip a lot here. I have been told to speed up.
Based on the lack of
sensitivity of or perfect sensitivity of MP-NATs, ID-NAT has been used, as I
said, to detect additional units. A
uniform criteria is desirable. There is
automated system and last year there was a paucity of data to recommend uniform
criteria.
So AABB issued
bulletins in 2007 and again in 2008, which is available and I have to just say
briefly to you that the West Nile Virus Task Force discussed the issue and they
actually took the lead the investigate the appropriateness of the criteria used
to ID-NATs, to implement ID-NAT.
And the ARC study was
presented the task force and Dr. Stramer kindly provided her data for us to
present here. The ID-NAT was required to
detect 27 percent of the cases in 2002 and 2003 and these were retrospective
assays tests; 29 in 2005; 36 in 2006, and in some cases here ID-NAT was
implement with 2 PVD only and without the ratio; and 44 percent in 2007 when
the criteria was evaluated.
I'm going to put just
these here that the evaluated criteria was 1 PVD. That it's presumptive viremic donor and the
PVD is defined by signal to cut off higher than 17 and all repeat reactivity if
not is the signal to cut off is below 17.
So 42 were identified
with 1 PVD; 31 with 2 PVD; and five, 2 PVD plus 1:1000. So if you go from 2 PVDs in 1:1000 to 1 PVD
there is 8.4-fold increase in the detection.
And 2 PVD in 1:100 to 2 PVD, it's 6.2-fold increase.
There is also
consideration that if the unit is positive for IgG but not IgM donation, those
IgG, not IgM are being considered false positive. So if you retrieve the so-called false positive,
there is still an increase of 6.4 from 2 PVD in 1:1000 to 1 PVD, or an increase
of 4-folds from 2 PVD in 1:1000 to 1 PVD.
What I will present to
you now is what we have in the West Nile NAT guidance to the industry, and
please note that this is a draft guide and it's for comment purposes only, not
for implementation. The draft guidance
was published for comments on April 28 and the 90-day comment period closes in
July 27, '08. Please submit any comments
that you may have and they will be considered.
Please also submit any additional data that may support your comments
for proper evaluation and consideration.
The recommendations on
tests is that the screen for West Nile should be performed year-round using
licensed NAT on donor samples of whole blood and blood components intended for
transfusion. It's to be performed either
by MP- or ID-NAT, and the ID-NAT should replace MP-NAT during the activity in
your region. That has to be previously
defined.
I'm just going to go
quickly through this screening. The
algorithmics, the same thing, you test ID-NAT.
It's either six or 16. If the
units are nonreactive and suitable for transfusion, they're released. If MP-NAT is reactive, it goes the same path
as when screening ID-NAT. If the sample
is reactive, further tests need to be done, and
MP-NAT is resolved to identify single unit that caused the reactivity in
the pool. The ID-NAT nonreactive units,
if suitable, are released for transfusion.
In the ID-NAT positive
units go down to further testing for donor counseling, the unit should be
discarded, defer the donor for 120 days, retrieving date product prior to the
collection during the period back to 120 days and initiate
ID-NAT for that region.
ID-NAT, we're waiting
for ID-NAT implementation. MP reactive
test specimens, if in the pool, if you get one ID-NAT reactive unit, you should
initiate ID-NAT within 24 hours of the collection. If more than 24 hours, it's taken to initiate
ID-NAT retrospective test of the units between the date of collection and the
date of results are encouraged should the study unit defer the donor and
retrieve in-date products.
If blood establishment
used as an assay that does not discriminate between
Additional tests are
waiting for donor counseling purposes. I
have mentioned to you before that perform additional tests is recommended,
repeat NAT using the same assay or equal sensitivity assay, and perform
antibody using a cleared antibody assay.
If ID-NAT reactive, MP
antibody to positive O, ID-NAT reactive with
If ID-NAT nonreactive
in West Nile antibody negative, then the donor should be notified of deferred
and should be counseled as inconclusive because I showed you that two percent
of these population here may, in fact, have a true infection, and we encourage
the donor to return for follow up and be tested in 30 days after the initial
testing.
Also, one has to keep
in mind that the virus has cross reactivity with JE serocomplex
The recommendation
regarding label, is that the container label and instruction circular should be
changed to reflect the
Thank you.
CHAIR SIEGAL: Thank you, Dr. Rios. Let's hold the questions under after Melissa
Greenwald speaks. As of now, you have
-2.5 minutes to talk. That's a joke.
COMMANDER
GREENWALD: Good morning, everyone. Maria had the hard part and I think I have a
much easier part to talk about
So as a little bit of
background to remind you of what's been going on with us that, along with
office of blood, CBER has also been considering cell and tissue donors ever
since the first workshop back in November 2002.
And we didn't have our 1271 regulations in place at that time, so,
obviously,
But
And this is just a
reminder of the relevant communicable disease agents or diseases for all cell
and tissue donors and these are the ones that are defined by the regulations
themselves. So they're specifically
listed in the regulations.
And then we also had a
provision in the definition of a relevant communicable disease that gives us
criteria to use to define new relevant communicable diseases as we have new
emerging infectious diseases. And these,
including
We had originally also
proposed SARS as a relevant communicable disease, but since, unlike
So through the
guidance where we made
So one of them is
reviewing other medical records for risk factors, as well as a donor medical
history interview. And these are the
criteria that we require regarding the medical history interview and review of
medical records for
Then we also look for
clinical evidence of
So we gave the
description as basically information and then the medical directors, or the
person making donor eligibility determination, may take that information in
light of other information obtained about the donor. So we described the mild symptoms and then
possible severe symptoms of
And we did sort of try
to give clues in our guidance. Of
course, we reconsider testing recommendations in the future. At that time we weren't prepared to make
testing recommendations.
But we have published
draft guidance with the office of blood, and so we've made, for the first time,
a guidance for both of our offices at the same time so that everyone can be on
the same page and not wonder if we're going to do something different.
So in the draft
guidance for cell and tissue donors we recommend year-round testing by
individual donor NAT for all HCT/P donors.
And, just like for blood, according to good guidance practices, you know
we publish draft guidance to allow public comment and we will take those into
consideration before we make final recommendations.
Thank you.
CHAIR SIEGAL: Thank you, Commander Greenwald. Time is very late. Are there any essential questions before we
move on to T. cruzi? All
right. We'll be hearing from Commander
Greenwald again.
So now we're going to
hear from Robert Duncan of FDA, and eventually, again, Dr. Greenwald on
screening for T. cruzi. Dr.
Duncan?
DR. DUNCAN: Good morning.
In the interest of time I'm going to go fairly quickly over my
slides. Some of them have been presented
to BPAC in the past, beginning with not reading the title to my talk.
But I want to just
show the background of the disease to make the point that our current
considerations on use of testing for Chagas Disease in the blood donor
population is based on an understanding of the disease, the likely nature of an
infected donor based on studies that have been going on for many years,
primarily in Central and South America.
Our current
considerations are also based on an assessment of the risk of transfusion
transmission of Trypanosoma cruzi and based on the best knowledge from
studies of
But more to the point,
our current considerations are based on the fact that the FDA approved a blood
donor screening assay, the Ortho T. cruzi ELISA test system for testing
blood donors for infection with T. cruzi. Up to now there is no supplemental test for T.
cruzi antibodies, which means there's no possibility of a re-entry
algorithm without the availability of a supplemental test.
And much of this
information was presented one year ago at a BPAC, so I'm just updating things
that have changed. And the biggest thing
that has changed is we have been watching the progress of blood donor
screening. These data are available to
us, very thankfully, to the AABB, which has made a tremendous effort to post
the information. I updated this as of
yesterday with April 25th data.
So up to that time, more than 11.8 million donors have been
screened. And in that actual clinical
experience the characteristics of the test that were identified in the clinical
trials have pretty much held up. We're
very happy about that.
One thousand four
hundred ninety-two (1,492) repeatedly reactive donors represents about 0.01
percent of the donor pool. That's pretty
close to the estimate of what would happen and that repeat reactive rate is low
enough that even without re-entry there has not been a significant effect on
blood availability as a result of this testing.
These donors are also
retested on a more specific, but unlicensed T. cruzi radioimmune
precipitation assay, and by looking at that data we can make some other
estimates about the performance of the test.
Nine hundred eighty (980) of those 1,400 are nonreactive or false
positives. Three were
indeterminate. Four hundred and
fifty-two (452), however, were positive with the RIPA assay or 31 percent of
the repeated reactives, which is a pretty good positive predictive value for a
screening test.
The other thing about
those 452, those are the true positives that have been detected to date, which
calculates approximately to 0.0038 percent prevalence among blood donors, and
that's a little lower than some of the estimates that I showed in the earlier
slide for previous data. But it still
represents a substantial number of potentially true positive cases that have
been interdicted and are making the blood supply safer.
This map shows a
little bit about how those 452 cases are distributed across the country, and
though there are some clusters in California and Florida, the major message for
us is that it is spread widely throughout the country making any kind of
strategy for a geographically focused screening unlikely, both with the
mobility of the population as well as the mobility of blood and the wide
distribution of the RIPA reactive cases.
The prevalence is widespread throughout the country.
There's two other
points that I'd like to make that comes from my scrutiny of data that's made
available to us from the American Red Cross, and on two points:
1) Is there evidence
for vector borne transmission in the
And I highlight this
point because it will really make a difference in how we view implementation of
testing. A situation where all the
reactive cases are long term, chronic, asymptomatic individuals that acquire
their infection earlier in life in the endemic area dictates one sort of
situation. If there are newly acquired
cases, potentially window period cases, potentially early infection, the test
that we're using, the Ortho T. cruzi ELISA test system, has not
particularly been validated with a newly acquired infection, so there are some
-- those are questions that will arise if there's substantial evidence for
endemic transmission in the United States.
To date there are
about 15 cases that I've been able to glean out of the study that had no
history of immigration or travel to or parents who immigrated from an endemic
area. Some of those have been followed
up quite extensively and some risk factors have been identified, a time in the
forest, a time in areas of the country where it is known that there are insect
vectors that are infected, where there are animals in the wild that are
infected. So the possibility is there
that there is a very low level of the long term is autochthonous transmission.
2) Is there new
evidence of transfusion transmission?
This, of course, will
be something we're watching as the testing continues to unfold. And this is the information develops from a
lookback of repeat reactive or confirmed positive donors who have had prior
donations. From that study 65 recipients
of blood products from 37 seropositive donors have been tested. The recipients have been tested. Among them, 57 of the recipients tested
negative on all tests, indicating no transfusion transmission.
One of the recipients
is seropositive, but his birthplace in
So at this point the
results would be that there's no clear case of transfusion transmission from
lookback on the confirmed positive donors out of the 452 tested. And this would suggest a lower rate of
transfusion transmission than has been documented in Central and
There could be a lot
of reasons for that. We are looking at
long term, chronic blood donors as opposed to in an endemic area where there
would be a mixed population of donors with different stages of the disease.
This whole lookback
procedure also selects for the healthy recipient because of the transfused
products that were identified from seropositive donors, about not quite half of
them were transfused into recipients who are now deceased. The only ones that were followed up were the
ones who are living. So there's a
selection for the healthier recipient in the first place.
So there's a lot of
factors not to conclude that this indicates there is no transfusion
transmission. That has been
documented. We will need to continue to
look at this data as time goes on, but it's just one of the points to draw out
of the testing that's been done.
So our current
considerations for donor management would be that we're considering whether all
donations should be tested for antibodies of T. cruzi, and we currently
consider that for any kind of selective testing plan, that an appropriate
methodology needs to be validated during a period of universal screening. Any repeat reactive we consider the
possibility they should be deferred indefinitely and the re-entry will depend
on a supplemental test.
However, for
counseling purposes, the additional information can be used to communicate to
the donor the medical significance of infection and referral for additional
medical diagnostic testing is probably useful.
We're considering recommending medical followup for cross-reacting
diseases because there has some evidence of cross reactivity with other
parasitic diseases.
In the arena of
product management, we are considering whether establishments should quarantine
and label their index donations from repeatedly reactive donors. Prior collections from that same donor should
be retrieved and quarantined and labeled.
We're also considering
the appropriate lookback, which could be to notify consignees to enable
notification of recipients of prior donations from a repeatedly reactive donor
who is, one, repeatedly reactive on the screening test and for whom there is
additional information indicating risk of T. cruzi infection, such as a positive
test result on a licensed T. cruzi supplemental test when such test is
available. Until such test is available,
geographic risk for exposure in an endemic area or other medical diagnostic
testing may provide additional information.
The autologous
donation that we're considering is pretty much standard by the regs, and, also,
labeling and circular information, biological product deviation report, and
fatality report are also standard according to the regs. And we're considering whether implementation
of the test should be reported in the annual report.
And that's it for
today. Thank you.
CHAIR SIEGAL: Thank you, Dr. Duncan. Now, we'll hear from Melissa Greenwald again
from FDA.
COMMANDER
GREENWALD: Not quite finished with me
yet, but if you thought the last one was brief, wait until you hear this
one. So I'm here to present our current
considerations for T. cruzi for cell and tissue donors.
Almost a year ago
today, just a few days off, I presented a talk to this committee about T.
cruzi considerations for HCT/P donors and asked a few questions for
consideration of the committee. So just
the reminder about what is relevant communicable disease in our regulations,
and I'm not going to read through those to you, but I described that in the
last talk, and then these slides are included only to prove to you that, in
fact, T. cruzi is not a relevant communicable disease and, unless it
were so, we cannot recommend donor screening or testing.
So we have stated
several times and wrote that in our guidance that any time we intend to make a
new relevant communicable disease, we will publish it in guidance and allow for
comment.
So currently we are
considering whether or not we should make T. cruzi a relevant
communicable disease H or disease and recommend any donor screening and/or
testing. So any recommendations would be
published in draft guidance ahead of time.
I think that's very important to put forth to everyone hear.
And that is it. So if there are any questions for either Dr.
Duncan or myself, we'll be able to move on after that. Thank you.
CHAIR SIEGAL: Thank you very much. So, questions?
DR. KULKARNI: Roshni Kulkarni. You know, as I listened to these about donor
testing, I think what goes through my mind is, what about the recipient? For example, patients with hemophilia, sickle
cell disease, bone marrow failure syndromes, and all, to me are like canary in
the mine who get a lot of these blood products and would be the first on hand
to have these diseases. So I know at the
CDC we do do testing for West Nile virus for and we have specimen saved from
many years actually, since 1998, for doing
But I was wondering,
is there any requirement as far as the recipient is concerned as to what do we
do with them, especially these groups
which are multiply transfused? I'm even
worried about parvo virus in this population because that's another one which
is normally not tested.
CHAIR SIEGAL: You guys want to comment on that? Dr. Greenwald?
Anybody? Jay?
DR. EPSTEIN: Matt, you may be in a better position to
comment, but there is a surveillance program established through the hemophilia
treatment care centers that are funded under the child health component of HRSA
and where they have determined that they should be monitoring the hemophilia
patients for acquiring certain infectious diseases they do routinely
screen. So I think it's a question that
might want to come back to the CDC. Do
the average risk, based on seroprevalence in donors is only 1:29,000, and if
you look at the transmission data, we're already 95 percent confident that the
transmission risk is under 5 percent. So
we're looking at really a very low risk situation. But, certainly, one could consider whether
surveillance in that population is warranted.
The Chagas Disease is
very difficult to treat. I'm sure most
people know this. There's greater
success in the acute stage than in the indeterminate or symptomatic stage, but
there are recent CDC guidelines on treatment according to stage of Chagas
Disease. So given that there might be
suitable intervention, also, a pregnant woman, of course, can transmit to a
fetus. So I think it's a very good point
and we'll just have to think about it in collaboration with our CDC colleagues.
CHAIR SIEGAL: Thank you, Dr. Epstein. Are there any other comments or questions?
DR. EDWARDS: Yes.
Willarda Edwards.
Thank you very much
for addressing that question because it is a major issue, not only in
hemophilia, but those with thalassemia where transfusion therapy is basically
part of the care, as well, obviously, with sickle cell. And I'm hoping that as a result of raising
this question, and as we've heard, that we'll talk with our friends at CDC and
I'm asking this Chair whether or not we're talking about having a report back
regarding that issue?
CHAIR SIEGAL: I need a little guidance here. I imagine that there will be a response. If there is no one else, let's move on. Now we're going to hear from Dorothy Scott
from FDA on the proposal to lower the minimum recommended lot release titer for
measles antibodies and immunoglobulin.
DR. SCOTT: Good morning.
This is an issue that you addressed last August and that was our request
for your advice on lowering the measles antibody lot release specification in
IGIV and IG subcutaneous use for treating primary immune deficiency. I'm going to refer to both of these as immune
globulin products.
This is just a
background summary and I'll go through it very quickly. As you probably recall, measles antibody
titers serve as a potency test for lot release of all immune globulin products
licensed in the
However, the failure
of potency testing at lot release, including this particular test, measles
antibody titers, results in lot rejection.
So in the setting of declining titers, as these go down, there's a
potential large negative impact on immune globulin product availability for
primary immune deficiency because these lots would be manufactured but not
used.
We propose to lower
the minimum measles antibody titer in IGIV and IGSC to levels still expected to
be effective in pre-exposure protection in patients with primary immune
deficiency.
So we sought your
guidance and further information about the potential clinical impact of
lowering the measles antibody specification in these products. We heard from Dr. Seward of the CDC some
epidemiological information that they have gathered showing that measles is
uncommon in the
Measles in
Primary immune
deficient patients with measles have been very rarely observed and none have
been reported through an informal survey of primary immune deficiency treaters
in recent years. Dr. Moss from Johns
Hopkins presented data showing that people with combined B and T cell defects
are at most risk of serious complications and he also showed us an animal model
in primates that demonstrated that.
Just to continue,
protective antibody levels against clinical measles disease in normal people
are estimated to be 120 mIU/ml in the sera, but sterilizing immunity that is
altogether a prevention of infection probably requires much higher titers in
the sera. However, the protective level
needed for primary immune deficient patients is unstudied and unknown, but it
is likely to vary depending on the specific type of immune deficiency that they
have and the relative contribution of T cells to their immunity.
We proposed a
specification based on our pharmacokinetic modeling to go from 0.6 x CBER
standard, which it currently is set at, to 0.48 x CBER standard, and at this
specification we estimated that IGIV given at a typical dose of 400 mg/kg for
primary immune deficiency should provide serum trough levels of at least 240
mIU/ml, which is double that needed to protect normal individuals against
clinical disease.
We sought data from
CSL Behring for their IGIV and IG subcutaneous products at least affirmed the
likelihood of achieving trough levels greater than 240 mIU/ml with standard
doses of their products. However,
obviously, those were at the current 0.6 x CBR standard or greater.
So we asked you
whether you concurred with our proposal to lower the minimum measles antibody
specification for the IG products and you voted yes, 13, and the 1, no, vote
was request really for more trough titer data.
I'm going to go very
briefly through this and just cover the first and the third points because the
other one I'll come back to later. But
some members stated that the risk to supply of rejecting lots exceeds the
current risk of serious measles infection in primary immune deficiency
patients. In other words, this is a low
likelihood event, but this actually is a high likelihood event if we continue
at the 0.6 x CBER standard lot release specification.
You also felt that
surveillance would be important to identify and investigate breakthrough cases
in recipients of immune globulin products.
I should mention that measles is a nationally notifiable disease. Reporting of cases is required by all
states. Those reports go to CDC and our
CDC colleagues have assured us that they would notify us if they had any immune
deficient patients that had measles.
We also asked you
since we were considering requesting additional studies to confirm that immune
deficiency patients will receive trough titer levels -- I'm sorry -- achieve
trough titer levels of measles antibodies above this lower limit of 120 mIU/ml
if treated with IGIV and IGSC products that met this lower revised
standard. Basically, we're asking you,
do we need more studies? The vote was
13, yes, and 1, no.
Discuss that more data
would be useful to support our PK extrapolations and the data set that you saw
from one of the industry members, and I won't go through the details of this
for the sake of time.
We also requested your
comments on alternative strategies that we should consider to address the
measles titer problem in our products.
You also felt that
primary immune deficiency patients traveling to measles-endemic areas should be
infused prior to travel and preferably with high titer product. You felt that education of physicians would
be important so that immune deficient patients who have been exposed or may be
exposed to measles can have dosing or dose timing adjustments, or both. And, if exposed to measles, PID patients with
profound T cell deficiencies should receive doses that achieve sterilizing
immunity.
We went forward and
considered your additional discussion points and looked for a regulatory
pathway, which we've now defined.
Manufacturers can voluntarily propose to change their measles antibody
specification at lot release to 0.48 x CBER standard adjusted for IgG
concentration as a prior approval supplement.
Included in this prior approval supplement would be an agreement to
report measles in a primary immune deficiency patient that had been reported to
the company as a 15-day report to FDA, and this might be faster potentially
than going -- receiving reports through CDC simply because there may be a delay
between reporting to the state and reporting to CDC in recognition of the
measles. So we might hear of this sooner
and that would allow for investigation of the patient if possible.
We would also ask for
an agreement to a labeling change that reflects the potential need for dosing
alterations with respect to timing and total dose for an immune deficient
patient with potential or actual exposure to measles.
And we also request a
post marketing commitment to determine measles trough level titers in primary
immune deficient patients receiving a known dose of measles antibodies, in
other words, known titer in the product. This could be in the contact, and I'm
sorry this is so small, of an upcoming, ongoing, or completed clinical trial
that would have retention samples for primary immune deficiency with these
products.
Alternatively, a
separate stand- alone trial would also be acceptable, and measles titers, of
course, would have be measured by a functional assay, hemoglutination,
inhibition, or neutralization as always.
The outcomes I think
address the committee's concerns, and ours as well. They provide an expedited path to changing
the measles antibody lot release specification and minimize the change of loss
of a large amount of IG products to the market.
It enhances the likelihood that we'll find out about these cases early
enough to investigate if a measles case occurs in a primary immune deficient
patient.
It would provide
additional information about measles exposure and how to deal with that in the
package inserts. So this would provide
the educational aspect. It would also
provide a means of data collection to support that at least minimum protective
titers would be attained in these products.
Thank you very much
for your attention.
CHAIR SIEGAL: Thank you, Dr. Scott. Are there any questions for Dr. Scott? Yes.
DR. BALLOW: Mark Ballow.
I haven't read package inserts lately on these products, at least some
of the older products. But I recollect
that some of them still recommend a dose of like 200 mg per kilo, which
obviously wouldn't fulfill your recommended of 400. So I certainly applaud you, and as part of
your going forward is to revise some of the package inserts to take this into
consideration.
DR. SCOTT: In that particular instance, and I know
exactly what you are talking about, that's taken into consideration as part of
any submission that we would receive, and so the dosing recommendations, more
specifically, would be if somebody is on a 200 mg/kg dose, or 300 mg/kg dose
for that matter, that that dose be revised upward prior to travel or post
exposure so that they would actually receive more.
What that doesn't take
care of though is somebody who's exposed and you don't realize they're exposed,
and I think that's an important issue to address in the case of those lower
doses. I don't know clinically how often
they're being used, but the fact is, at least for one product, two products,
they're in the package insert.
DR. BALLOW: Yes. Well,
that's why I raised the issue because some physicians are still infusing at the
lower dose, which I don't advocate, but with that wording about travel exposure
may not take into account those patients that inadvertently may not know
they've been exposed for example.
DR. SCOTT: That's true, and that's something that with
those particular companies we're taking into account and addressing,
absolutely.
DR. BALLOW: Now, the other issue at the workshop that was
a measles issue that was coming up with other measures of specific antibodies
and the IVIG to guide clinicians on the whole protective ability or efficacy of
some of these products or lots of particular products.
DR. SCOTT: Well, we would really like to be forward
looking with respect to especially looking at antibody titers to H. Influenza
and to pneumococcus by a functional assay, and WHO has a group that's been
working on standardizing the opsonophagocytosis assays. We are in contact through a colleague at CBER
about this and those studies have been progressing. I think once we have the methodology that can
be validated and some standards that this will be possible for those pathogens
that particularly affect the primary immune deficient population, especially
those two which, I think, were identified at the workshop as being among the
very most important.
We haven't
forgotten. We're quite keen on it.
CHAIR SIEGAL: Dr. Kulkarni?
DR. KULKARNI: Just a point of clarification. The trough level titers, when would they be
obtained, and if those are low, then is the recommendation to give a second
dose? I just wanted to know.
DR. SCOTT: I think if those were low, the recommendation
would be to give higher doses just on a routine basis.
DR. KULKARNI: When would they be dosed?
DR. SCOTT: And the trough level titers are usually
obtained right before the next dose. So
a typical dosing pattern for immune deficient patients who are receiving IV
would be to get dosed every three to every four weeks and the trough level is
right before that. Likewise, for
subcutaneous, which is given more often, it would be prior to the next dose so
you know what the lowest possible level is in that patient.
CHAIR SIEGAL: I have a question. Has there been any proactive effort made to
actually collect a bank of trough levels in a variety of patients with primary
immunodeficiencies who are getting regular infusions of immunoglobulin? That might be something that we really ought
to initiate.
DR. SCOTT: I think that would be very interesting to
pursue. Maybe Dr. Ballow has a
comment. The immune deficiency
foundation might be in a position to help accomplish that.
DR. BALLOW: I don't think we need to do that because
there's been a number of products that have come before the FDA for approval in
the past few years, plus some that are in progress now, and most of those
studies I think collect extra sera to stock away.
DR. SCOTT: They do, they do.
DR. BALLOW: And I would just ask them to go back and just
measure those trough levels of measles antibody. So the material I believe is available. It's just a matter of asking them to go back
and measure those.
CHAIR SIEGAL: The issue, of course, isn't just trough
levels of measles antibody, but of some of the more relevant antibodies that
aren't indicators usually of efficacy.
Because those haven=t been --
DR. BALLOW: Okay.
But I thought the issue was more data for the measles trough level.
CHAIR SIEGAL: Is there any more discussion on this
issue? All right. Then let's move on.
Now we're going to
hear from Larry Dumont, Director of Cell Labeling Laboratory at
DR. DUMONT: Mr. Chairman, members of the committee, Dr.
Epstein, and members of the FDA, thank you for your invitation this morning to
come from cold
I do have some
conflicts of interest. I do personal
consulting for these companies. These
companies supply some type of research support to my laboratory at
So there's a couple of
things that I want to point out that, amazingly to me, seem to be continually
confusing to everybody about this project and I think they're very important.
Number one, 7-day
platelets are 510(k) cleared by FDA. Two
companies hold clearances for those products.
PASSPORT is the
post-marketing surveillance of 7-day platelets, that is to say a Phase IV type
trial of, if you will, an approved product.
This is not an
PASSPORT does have an
explicitly stated primary hypothesis with a written analysis plan which was
reviewed and accepted by FDA. The
planned analysis has not been conducted and the primary hypothesis has not been
tested.
A couple of other
items. Going into this whole program there
were some assumptions made. One, we made
the assumption that the true bacterial contamination rate in platelets was
somewhere between 178 and 349/M, or roughly 1/5000, and this was based on one
bottle aerobic testing of platelets at 24 hours past collection.
We also assumed that
the release test would detect at least 50 percent of these, and that,
therefore, the residual risk of released platelets would be about 100/M or
1/10,000.
Based on these
assumptions, we did a sample size calculation where we came up with <4
positive out of 50,000 surveillance tests, and I'll show you what a
surveillance test is in a second, would be detectable here. And that's the upper 90 percent confidence
that no more than 1/5000 or 200/M residual risk would be in the blood supply.
Note that these risks
do not weight the data in any way for clinical risks that may be associated
with what the organism is or the day that it might be detected or it's
titer. Well, what we know right now is
that these assumptions were wrong.
So 7-day platelets has
a long history. To cut it short, in 2005
FDA approved a combination approach using apheresis platelets and a bacterial
detection method, the BacT/ALERT, to approve 7-day platelets, and the first one
was made under this program in 2005 by
Following that was the
initiation of the PASSPORT, this post marketing surveillance by Gambro, and
that was joined in 2006 by Fenwal. And I
think everybody knows that that has been suspended as of actually last week I
believe.
So the 7-day platelet
release test, and this is a release test, I'll emphasize that, is that the
platelet product is sampled at 24 to 36 hours post apheresis collection; 4 to 5
mL aliquots of the single donor platelet in both are placed in one aerobic and
one anaerobic culture bottle; and the platelets are released if there's no
growth indicated after 24 hours on test in the BacT/ALERT; and then the culture
bottles remain on test until they either turn positive or the platelets expire;
and then, of course, standard practices are indicated for microbiology and any
clinical follow-up for positive cultures.
But the scheme looks
like this: 7-day apheresis platelets, if
they're collected at this point, they're held for 24 to 36 hours in quarantine,
then they're sampled and the bottles are inoculated, and things are incubated
for 24 hours. If after 24 hours we still
have a negative test, then the products are released into inventory and then we
have 7-day platelets that progress through their potential life. So that's a 7-day platelet.
The PASSPORT post
marketing surveillance study takes advantage of the fact that some of these
products will outdate, they won't be used, and we wanted to recapture and
retest 50,000 of these with the two bottle test. And, again, we would incubate those
recultures seven days and analyze the data the end.
There's been some
confusion in the vernacular here for types of centers that participate. One type of center is the Tier 1 center and
they're the type of center that either they're small enough, or for some other
reason, they can only supply release test data.
There are other
participants in PASSPORT that are called Tier 2 participants, and they actually
supply both the release test data and surveillance data on any products that
they're able reculture.
The primary hypothesis
is listed here. I won't read the whole
thing, but, basically, we're comparing 7-day platelets, and this is a
non-inferiority test where we're saying it will not present a greater risk than
5-day platelets that are untested.
Specific aims of
PASSPORT study were to determine specificity, sensitivity, negative predictive
value, positive predictive value of the 2-bottle release test and to determine
the prevalence of bacterial contamination for untested and for 2-bottle tested
single donor platelets, because,
remember, we only guessed at this at the beginning. And there's also some questions related to
should we also include the anaerobic bottle long term for a release test.
As of March 2008 there
were 51 centers across the United States that were participating. An accrual for the number of sites is shown
from 2005 to 2007. This is the number of
centers that are participating up to 51.
This was certainly slower than we anticipated. We thought it would be a little steeper than
that.
This has led to
accumulative, over 320,000 release tests that have been conducted and 4,369
surveillance tests of expire products to date.
This is
important. This is the criteria that we
use to evaluate products and this is from AABB recommendations where we have
the type of event, a true positive, false positive, indeterminate, true
negative, false negative, and this is for products that are not
transfused. This is for platelets that
end up being transfused.
Of course, a true
positive is one where we can confirm with another test or that we can confirm,
perhaps, in the patient a septic event with a bug that matches. False positive is one where we cannot confirm
it. Indeterminates are those where we
can't actually do the test. True
negatives are those where we don't get an initial release test positive and we
just get information from the clinic.
What's important about
this is that products where we get initial positives, which would be this group
and part of the indeterminates, the clinic data actually comes from a phone
call from the blood center to the clinical service to say how's the patient
doing. Some of the indeterminates and
some of the true negatives and false negatives, that comes from passive
surveillance at the clinical site calling the blood center to say we have a
sick patient.
Results to date are
shown here out of 320,983 single donor platelet collections. We have interdicted all of these products, 62
true positives, and these are the event rate per million shown over here. And then there were, of course, some that we
didn't catch in time, some true positives, some false positives, and some
indeterminates that were transfused to patients. And there were two false negatives shown
here, and I'll show you them again in a second.
One was a double platelet product where they both were transfused on day
six. One patient had a fever, the other
patient did not. There was another
double platelet product that had staph aureus in it.
Surveillance test,
which is the main aim of PASSPORT, with the 4,369 tested after day 7, there
were three true positives for a rate of 868/M with a very wide confidence
interval because of the low number here.
The specific positives, one was with staph aureus. This is the aerobic bottle. This is the anaerobic bottle. This is how long it took for the machine to
turn positive, 3.7 hours, and these were confirmed as true positive.
There was another one,
split donation, that came up with staph epidermidis. And the second bag, actually, was transfused
on day 4 and there was no adverse reaction reported from that patient. And the third was a strep veridans. You can see the results there.
The confirmatory test
came up with diphtheroid like gram positive rods. So that's not strep veridans, but
because of our definitions that turned out to be a true positive.
To give you a little
perspective on what these numbers might mean, I tried to compare the PASSPORT
data to other data that had been reported.
This shows the one bottle test.
This is only the aerobic bottle, and that's all that the American Red
Cross uses. They've reported on over a
million tests and they have a rate of 185/M here. This is the PASSPORT evaluated for only the
one bottle test. It looks like we're
about the same number there.
The studies to the
right are
two bottle tests, so this is the anaerobic and the aerobic
bottles. PASSPORT, we have some data
from the Irish, some data from the Welsh.
These are a little bit apples and oranges because the test conditions,
sample size, time of collection, those types of things, are not exactly the
same between these three studies, but I still think it's instructive to look at
them.
These are platelets
that are prepared by the buffy coat method in
Now, the last three
studies have actually done some surveillance testing and this shows the
surveillance test for PASSPORT with confidence, 95 percent confidence
interval. The Irish surveillance, and,
of course, this is for apheresis and for buffy coat products, and this is the
Welsh surveillance, again, for both types of products.
So with the caveat
that this is a little bit apples and oranges, it kind of seems like we're
comparable across studies.
Just real briefly to
show you the two bottle test results because there's a lot of questions about
do we need two bottles, the main point of this slide is that if we look at the
totals for the number that come up in aerobic only, the anaerobic only bottle,
or both bottles at the same time, there's quite a number of discordant bottles
where we actually pick up true positives or false positives for that matter or
indeterminates.
So some would say that
this might be an argument for using two bottles. It's not clear of the cause of this is
because of this sample volume or because of the characteristic of the anaerobic
bottle.
This is a list of the
actual organisms that have been identified for true positives in both
bottles. And I do want to point out that
probably as early as some time in 2003 all of these products would have been
transfused to patients. They were
caught.
So these are gram
negative organisms, citrobacter, E. coli, Klebsiella, Serratia marcescens. This shows the number of products and this is
the time to detection in the aerobic and the anaerobic bottles. So you can see that list for yourself. Some not nice organisms to have in your
bloodstream.
These are organisms
that were detected in only one or the other bottle. This is the aerobic bottle, Bacilius,
Corynebacteriums, Staphus Aureus, et cetera, with the same presentation of
the number of events and the time to detection.
If you notice in the
anaerobic bottle, one of the controversial issues is we have these Corynebacteria
species, diptheroids, and Propionibacterium, and maybe these are all
the same thing. Depends on what lab
you're in. There's a lot of questions
about what does that mean clinically. We
don't know.
Clinical outcomes,
we've transfused 13 true positives.
There were 202 indeterminates transfused. There have been no deaths reported. Fourteen (14) transfusion reactions that were
related to bacterial contamination for a rate of 44/M.
And this shows the
clinical outcomes. These are the first
two false negatives that I showed you on the previous slide. The first one was the release test was
negative. There were two products made
from this collection. They were both
transfused on day 6.
The first product, there
was no reaction. The second one, there
was a febrile reaction. The followup
with the blood culture and the confirmatory test, the product showed coagulates
negative staph.
Another false negative
where clearly there was a sepsis related to staph aureus and there was a
fever with staph aureus.
We have some true
positives with P. acnes, Corynebacteria species. Several indeterminates where we really
couldn't tell if it was a true positive or not shown here. I'm not going to go through the whole list. You have it in your handout I think.
And then this shows
the age of the platelet, day 3 through day 7, the number of reactions that have
been reported, septic transfusion reactions.
The very difficult thing is we don't have good denominators for this, so
to calculate rates is very difficult.
We've tried to make some estimates based on distribution patterns. And based on that, it appears that the septic
transfusion risk is about the same from day 4 to day 7. But, again, those are just estimates.
So, in summary, the 2-bottle release test, true positives were
234/M; if we add positives and indeterminates together, we're up at 1000/M or
about 1/1000. These data are generally
consistent with other reports.
Two hundred and
fifty-six (256) collections were not interdicted prior to transfusion. Surveillance showed an estimated rate of
686/M; and, again, this is generally consistent with other reports. There have been no deaths reported and this
one could contrast against reports from
Thank you very much.
CHAIR SIEGAL: Thank you, Dr. Dumont. Are there any questions for Dr. Dumont? Dr. Epstein?
DR. EPSTEIN: Yes.
Thank you very much, Larry.
Just one small point,
on clinical outcomes three in the summary, you suggested that the rates of
contamination might be the same for day 4, 5, 6, 7. But my understanding of PASSPORT is that we
don't know the number or proportion of units transfused at each age.
DR. DUMONT: That's exactly true.
DR. EPSTEIN: So, therefore, we don't actually know the
relative risk.
DR. DUMONT: We do not know the denominators. No, that statement was based on -- we do know
some distribution patterns from large users and we try to make some estimates
with obvious assumptions about usage based on distribution patterns. So we do not know denominators.
CHAIR SIEGAL: Anyone else?
Thank you very much. Now, we're
going to hear from our own Louis Katz talking about the PASSPORT study and risk
analyses.
DR. KATZ: All right.
So I'm going to try and do two things in I guess 10 or 15 minutes. The first is appended onto what I was asked
to do.
So PASSPORT was the
notice of bid suspension by the sponsors came in late January and since all the
PASSPORT blood centers are ABC centers, we then asked Dr. Bianco at ABC to do a
survey earlier this month to see whether we could begin to estimate any impact
of the suspension on the participating centers.
Our 18 differs from
the numbers you saw from Larry because we count only the corporate entity and
he's counting all the individual blood regions, for example, within blood
systems. So the numbers match if you add
things up.
So there were 18 ABC
PASSPORT centers representing the vast majority. There are some hospitals participating,
hospital transfusion services participating, but the vast majority, 80 percent
plus of the 7-day platelets being distributed were from these 18 ABC PASSPORT
participants. And we also asked the
nonparticipants in the
And I'm going to go
through this very quickly. Ten of 16
said that to reach their planned levels of apheresis platelet production would
require three to six months to get back to it with the loss of the day 6 and 7
platelets. So with the shorter outdate,
more platelets are not usable at the end of the fifth day and five of 16 needing
more than six months.
Five of the larger
centers need to increase their collections from 1,000 to 6,000 units a year to
compensate for increase outdate rates that will from probably an average of a
three percent outdate rate of the 7-day platelets up toward ten percent. So, for example, at my center, which I
wouldn't actually call a larger center, our outdate rate has gone from between
one and two percent up to seven percent where it was before we were
manufacturing 7-day platelets. It's
based on only a couple of months of data and everybody is trying to do things
in inventory management that will minimize that.
One center is going to
replace the apheresis losses with prepooled platelets from whole blood that can
be cultured. Three of 16 are going to
increase their distribution of whole blood derived platelets by 20 to 30
percent and that will be important as we discuss risk. And five of the 40 non-participants who
responded said the discontinuation of PASSPORT was affecting their operations
and that's because those are centers that import platelets from places like
mine that are making 7-day platelets.
Amongst the PASSPORT
participants, four of the 15 have changed their bacterial detection procedure
from two bottles to a single aerobic bottle because the only requirement for
the anaerobic bottle was, in fact, to participate in PASSPORT, and so several
have indicated that they're going to switch back to a single aerobic bottle.
We don't have details
on the volume of culture that's going to be used, whether they're going to
double the innoculum into the aerobic bottle or not and two more plan to
change. Six of 15 have reduced the
incubation after inoculation to product release from 24 hours to less.