1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
BLOOD PRODUCTS ADVISORY COMMITTEE
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.
Friday, July 23, 2004
8:00 a.m.
Gaithersburg Holiday
Inn
2 Montgomery Village
Avenue
Gaithersburg, Maryland
20877
2
PARTICIPANTS
Kenrad E. Nelson, M.D., Chair
Linda A. Smallwood, Ph.D., Executive
Secretary
Pearline K. Muckelvene, Scientific
Advisors
& Consultants Staff
MEMBERS:
James R. Allen, M.D., M.P.H.
Kenneth Davis, Jr., M.D.
Donna M. DiMichele, M.D.
Samuel H. Doppelt, M.D.
Jonathan C. Goldsmith, M.D.
Harvey G. Klein, M.D.
Suman Laal, Ph.D.
Katherine E. Knowles,
Acting Consumer Representative
D. Michael Strong,
Non-Voting Industry Representative
TEMPORARY VOTING MEMBERS:
Liana Harvath, Ph.D.
F. Blaine Hollinger, M.D.
Katharine E. Knowles
Matthew J. Kuehnert, M.D.
Susan F. Leitman, M.D.
Keith C. Quirolo, M.D.
George B. Schreiber, Sc.D.
Donna S. Whittaker, Ph.D.
3
C O N T E N T S
PAGE
Update on West Nile Virus, Hira Nakhasi,
Ph.D. 6
IV. Hepatitis B Virus Nucleic Acid
Testing (NAT)
for Donors of Whole
Blood:
A. Introduction and
Background,
Gerardo Kaplan, Ph.D.,
Laboratory
of Hepatitis and Related
Emerging
Viruses, DETTD, OBRR, FDA 28
B. Serological Course of
Hepatitis B,
F. Blaine Hollinger, M.D.,
Baylor College of
Medicine 32
C. Preclinical and Clinical
Data for
HBV MP NAT, Steven Herman, Ph.D.,
Roche Molecular
Systems 51
Allan Frank M.D., M.S.,
Roche Molecular
Systems 65
Open Public Hearing:
Michael Busch, Blood Centers
of the Pacific 103
William Andrew Heaton,
Chiron 121
Sherrol McDonough,
Gen-Probe 129
Richard Smith, NGI 136
Harvey Alter, AABB 144
IV. Hepatitis B Virus Nucleic Acid
Testing (NAT)
for Donors of Whole
Blood:
E. Committee Discussion and
Recommendations 154
V. Current Trends in Plasma Product
Manufacturing
A. Introduction and
Background,
Mark Weinstein, Ph.D.,
Associate
Deputy Director, OBRR, FDA 223
B. Presentation, Jan M.
Bult, CEO,
Plasma Protein
Therapeutics
Association 225
Open Public Hearing:
Patrick Schmidt, CEO, FFF
Enterprises 258
4
1 P R O C E E D I N G S
2 DR. SMALLWOOD:
May I ask all advisory
3
committee members to, please, take your seats?
4
Welcome to the second day of the Blood Products
5
Advisory Committee meeting.
Yesterday I read the
6
conflict of interest statement that applies to this
7
meeting, however, we have a new process now and we
8
will read a conflict of interest statement for each
9
day.
10 So, if you will indulge me, I will read
11
that at this point. This brief
announcement is in
12
addition to the conflict of interest statement read
13
at the beginning of the meeting yesterday, and is
14
part of the public record for the Blood Products
15
Advisory Committee meeting on July 23, 2004. This
16
announcement addresses conflicts of interest for
17
topic V.
18 Drs. Liana Harvath, Blaine Hollinger,
19
Matthew Kuehnert, Susan Leitman, Keith Quirolo,
20
George Schreiber, Donna Whittaker and Ms. Katherine
21
Knowles have been appointed as temporary voting
22
members for this meeting
5
1
Dr. Michael Strong is participating in this meeting
2
as the non-voting industry representative, acting
3
on behalf of regulated industry.
The Food and Drug
4
Administration has prepared general matters waivers
5
for the special government employees participating
6
in this meeting who required a waiver under Title
7
XVIII, United States Code 208.
8 In addition, there are regulated industry
9
and other outside organization speakers making
10
presentations. These speakers
have financial
11
interests associated with their employers and with
12
other regulated firms. They were
not screened for
13
these conflicts of interest. I
would just like to
14
remind everyone participating to, please, make
15
known, if you have not already done so, any
16
affiliation you may have and your status with that
17
affiliation prior to speaking.
18 Our committee chairman, Dr. Kenrad Nelson
19
has joined us this morning, and we also have Dr.
20
Blaine Hollinger who will also be part of the
21
committee this morning.
22 I just wanted to announce to those who
6
1
were not here yesterday that the next date, which
2
is tentative however pretty much firm, for the next
3
Blood Products Advisory Committee meeting will be
4
October 21st and 22nd, 2004.
5 At this time I will turn over the
6
proceedings of the meeting to the chairman, Dr.
7
Kenrad Nelson.
8 Update on West Nile Virus
9 DR. NELSON:
Thank you, Dr. Smallwood. I
10
will try to keep awake after the 24-hour airplane
11
ride. I came in last night but I
feel really
12
pretty good and I am very interested in the topic
13
today so I think that will help.
14 The first topic is an update on West Nile
15
virus by Hira Nakhasi.
16 DR. NAKHASI:
Good morning. I just want
17
to give you an update, as Dr. Kenrad Nelson
18
mentioned, on the West Nile epidemic and donor
19
testing which is happening now, in 2004. First I
20
will try to wrap up last year's things and then
21
come up to 2004.
22 Next slide, please.
The topics which I
7
1
will update you on are, as I said, last year's
2
epidemiology and the investigational West Nile
3
testing outcome of that, and some of the
4
transfusion-transmitted cases, and then the trigger
5
for the ID-NAT testing. Then I
will update you on
6
the West Nile donor and product management
7
recommendations with the recent revelations we have
8
got. Then I will update you on
the 2004 epidemic
9
and investigational West Nile testing, and also our
10
efforts in-house on the panel development and other
11
scientific issues--you know, the variation among
12
the strains of viruses infectivity of these
13
studies.
14 Next slide, please.
If you summarize in
15
one slide the last year's epidemic, it really
16
basically sums up that we had approximately 1000
17
[sic] cases or, to be precise, 9862 cases, human
18
cases, and 264 deaths. And, the
proportion of the
19
West Nile meningitis/encephalitis was 29 percent,
20
whereas, the fever was 69 percent in the human
21
cases.
22 Forty-six states, including
Washington,
8
1
D.C., were endemic, and donor testing started, as
2
all of you know, in July of 2003, using two
3
investigational NAT testing. In
some cases, a
4
small proportion started in the middle of June.
5
Despite this testing, I think these two
6
investigational NAT testing--these are minipool and
7
the two tests were the Gen-Probe test and the Roche
8
test, and Roche tested, as you know, in pools of 6
9
and the Gen-Probe test involves a pool of 16.
10 Despite testing, there were some
11
transfusion-transmitted cases and CDC had
12
investigated a total of 23 cases.
They were
13 confirmed by NAT and IgM reactivity and also by
14
follow-up of both the donor and the recipient. Out
15
of the 23, 6 were confirmed cases.
Only 4/6, you
16
may recall, had very low viremia, around 0.1
17
pfu/ml. Eleven cases did not confirm;
3 were
18
inconclusive because of the follow-up situation;
19
and 3 were open investigations.
20 Next slide, please.
As I said, since it
21
started on July 1 of last year, screening using
22
minipool NAT and IND, all geographic regions of the
9
1
U.S. were screening at that time.
With that, what
2
happened 1000 units of West Nile infected blood
3
donors were interdicted after screening
4
approximately 8 million donations.
So, I think it
5
was a very, very vast improvement over the year
6
before when there was no testing.
The last
7
positive donation was reported in the middle of
8
December in 2003.
9
Despite this testing, as you
see, the
10
majority of cases were interdicted, more than 75
11
percent, but there was a small percentage which
12
went through because, as you know, this was done in
13
minipool NAT.
14 Next slide, please.
This slide is Mike
15
Busch's slide where he showed why we were missing
16
some of these cases, and we knew that minipool NAT
17
sensitivity was such. The areas,
you know, where
18
the wrap-up takes place when--you know, he calls it
19
stage I, II, III, IV and V, and in stage I and II
20
they are ID-NAT positive but minipool NAT negative,
21
IgM negative. So, it could be
plus/minus. So,
22
during that stage they become IgM positive but they
10
1
become minipool negative and they are still ID-NAT
2
positive. So, this region and
this region were the
3
ones where they went through.
But, you know, these
4
were IgM negative and these were IgM positive so
5
the question is what is the infection of these
6
types of samples.
7 Next slide, please.
So there was a
8
potential for transmission of West Nile through
9
minipool NAT negative blood of low viremia in some
10
patients. Therefore, what
happened at that time is
11
that limited prospective ID-NAT testing started in
12
high incidence areas. If you
remember last year,
13
Colorado, Kansas and certain other areas, and
14
Nebraska were hot spots and ID-NAT was triggered at
15
that time, and the trigger was based on if the
16
preceding the rate of 1/200 minipool NAT positive
17
rate of 1/250, then they would start testing with
18
ID-NAT testing. Also, what happened
at that time
19
is that there was voluntary withdrawal of the
20
frozen transfusables in the high incidence areas
21
before the ID-NAT was initiated by some blood
22
establishments.
11
1 Next slide, please.
There was also
2
another initiative started at that time. The
3
initiative was to go back to do the retrospective
4
study on the minipool NAT negative samples and test
5
them by ID-NAT to find out how many we missed. It
6
would also let us know what was the low level of
7
viremic high incidence samples in high incidence
8
areas where minipool NAT did not pick them up.
9 The other purpose of the study was also to
10
identify samples which are like minipool NAT low
11
titer, minipool NAT negative but ID-NAT positive
12
for infectivity studies. I told
you that we do not
13
know whether those samples are still infectious at
14
low levels, and what is the level of infectivity.
15
So, these samples would be tested in various animal
16
models including non-human primates.
Also, the
17
purpose of these samples is to really find out the
18
relative clinical sensitivity of various West Nile
19
investigational testing. I will
report in a minute
20
what is happening with the infectivity state.
21 Next slide, please.
Based on the
22
observation that we had minipool testing and we
12
1
missed some of the samples because the viremia was
2
low, and also in the ID-NAT testing in the high
3
incidence areas--based on those studies and based
4
on the logistics issues, the question was what
5
should be the trigger for ID-NAT, and also logistic
6
issues such the availability of adequate resources,
7
recruitment, reagents and trained technologists.
8 So, the discussion about the trigger for
9
ID-NAT was held in collaboration with the AABB task
10
force. By the way, we are very
indebted to the
11
AABB task force for the biweekly meetings almost
12
throughout the year, and weekly meetings with the
13
task force during the epidemic to update us and
14
jointly discuss the strategies for how to go
15
forward with the testing performance, as well as
16
the epidemic.
17 So, based on that discussion, which was
18
held in February, the recommendations were the
19
following for the ID-NAT trigger:
It was discussed
20
that we should monitor reactive rates by zones
21
daily, enrolled 7 days when the epidemic was
22
starting, which was usually, you know, around the
13
1
beginning of July and early June even and this year
2
even May some cases were found.
The trigger was
3
that if you have 2-4 cases in any geographic
4
area--that is the blood collection, and the
5
frequency of 1/1000. This was
based on the fact
6
that every 1/4 would be missed by minipool NAT and
7
require ID-NAT. This was the
study done by ARC and
8
BSL and they found out that that would be the
9
trigger. And, you go back to
minipool NAT only
10
when you see ID-NAT reactivity and you don't find
11
zero cases in a consecutive 3-4 day period or the
12
rate is less than 1/1000. So,
that was the trigger
13
because, you know, we wanted to be prepared this
14
year because last year it was on an ad hoc basis to
15
start ID-NAT testing in those hot areas. So, we
16
wanted to be prepared this year if these areas
17
become hot so that we get the logistics present
18
there so we can start without interruption of the
19
ID-NAT testing.
20 Next slide, please.
Now we come to 2004,
21
where are we now? As of July 20,
which is a couple
22
of days back--as you see, every week the numbers
14
1
keep changing. Last week there
were 108. This
2
week it is 182 human cases out of which there were
3 4
deaths. There are 2 from Arizona, 1
from Texas
4
and 1 from Iowa. Out of total
infections, 74
5
percent of cases are neuroinvasive West Nile
6
illness and 26 percent cases are West Nile fever.
7
At the moment there are 35 states endemic for West
8
Nile. This slide has been kindly
provided by Jen
9
Brown, from CDC, and other slides which I will
10
mention later.
11 The total number of presumptive West Nile
12
viremic donors reported to the CDC ArboNet--that is
13
why I highlighted this, is 23.
There are more
14
cases than that but, as you know, there is a delay
15
in reporting to the ArboNet from the health
16
departments. So, using minipool
NAT as well as
17
ID-NAT in select areas, starting on May 4. Out of
18
these 23 presumptive West Nile viremic donors, 21
19
are from Arizona. The majority
are from the
20
Maricopa county near Phoenix, in Arizona; 1 from
21
New Mexico and 1 from Iowa. But
this is the tip of
22
the iceberg.
15
1
Next slide, please. This slide, again, is
2
provided by Jen. You can see the
distribution of
3
the West Nile, both the animal, avian and mosquito
4
infection, which is in this color, and the blue
5
color shows you the human cases.
You can see it is
6
very high in Arizona and California.
I am telling