ATDEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
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.
BLOOD PRODUCTS ADVISORY COMMITTEE
76TH MEETING
Thursday, June 19, 2003
8:00 a.m.
Hilton Gaithersburg
620 Perry Parkway
Gaithersburg, Maryland
PARTICIPANTS
Kenrad E. Nelson, M.D., Chairman
Linda A. Smallwood, Ph.D., Executive Secretary
Pearline K. Muckelvene, Committee Management Specialist
Carolyn D. McMillan, B.B.A., Committee Management Specialist
MEMBERS:
James R. Allen, M.D.
Charlotte Cunningham-Rundles, M.D., Ph.D.
Kenneth Davis, Jr., M.D.
Donna M. DiMichele, M.D.
Samuel H. Doppelt, M.D.
G. Michael Fitzpatrick, Ph.D.
Jonathan C. Goldsmith, M.D.
Harvey G. Klein, M.D.
Daniel L. McGee, Ph.D.
Paul J. Schmidt, M.D.
CONSUMER REPRESENTATIVE:
Robert J. Fallat, M.D.
NON-VOTING INDUSTRY REPRESENTATIVE:
Michael D. Strong, Ph.D.
TEMPORARY VOTING MEMBER:
Liana Harvath, Ph.D.
GUEST SPEAKERS:
Anton P. Andonov, Ph.D.
Mark R. Denison, M.D.
Anthony A. Marfin, M.D., M.P.H., M.A.
C O N T E N T S
Welcome, Statement of Conflict of Interest,
Linda A. Smallwood,
Ph.D. 5
Committee Updates:
Medical Device User Fee and Modernization Act
(MDUFMA), Mary Elizabeth
Jacobs, Ph.D. 9
White Particulate Matter in Blood Bags,
Sharyn Orton, Ph.D. 13
Safety Reporting Requirements for Human Drug and
Biological Products,
Richard Lewis, Ph.D. 26
Bovine Spongiform Encephalopathy (BSE) in Canada,
Pedro Piccardo, M.D. 38
Risk Assessment for Products Utilizing Bovine Material in the
Production Process,
Baxter Presentation 46
Open Committee Discussion:
Severe Acute Respiratory Syndrome (SARS) - Informational:
Introduction and
Background,
Alan Williams, Ph.D. 54
Epidemiology and
Pathogenesis,
Mark Denison, M.D. 63
SARS: Canadian Studies
(Epidemiology and
Virology), Anton
Andonov, M.D. 88
FDA Current Thinking, Alan Williams, Ph.D. 107
Open Public Hearing
Kay Gregory, AABB 133
George J. Dawson, M.D.,
Abbott Laboratories 155
II. West Nile Virus - Informational
A. Introduction
Hira Nakhasi, Ph.D. 160
B. Epidemiology and
Surveillance Update
Anthony Marfin, M.D. 166
C. Status of WNV Test, Lot
Release and Validation
Panel Development
Indira Hewlett, Ph.D. 192
C O N T E N T S
D. Revised WNV Guidance
Sharyn Orton, Ph.D. 212
Open Public Hearing
Presentations from Manufacturers
George J. Dawson, M.D.,
Abbott Labs 224
Sherrol McDonough,
Gen-Probe 232
William A. Heaton,
M.D., Chiron 236
James L. Gallarda,
Ph.D., Roche 247
Kay Gregory, Blood
Banking Organizations 261
Mary Gustafson, PPTA 275
Miriam O'Day, Immune
Deficiency Foundation 280
Committee Discussion 284
P R O C E E D
I N G S
Welcome Statement and Conflict of
Interest
DR.
SMALLWOOD: Good morning and welcome to
the 76th meeting of the Blood Products Advisory Committee. I am Linda Smallwood, the Executive
Secretary. At this time I will read the
conflict of interest statement that applies to this meeting.
This
announcement is part of the public record for the Blood Products Advisory
Committee meeting on June 19th and 20th, 2003.
Pursuant to the authority granted under the Committee Charter, the
Director of FDA's Center for Biologics Evaluation and Research has appointed
Dr. Liana Harvath as a temporary voting member.
Based
on the agenda, it has been determined that there are no products being approved
at this meeting. The committee
participants have been screened for their financial interests. To determine if any conflicts of interest
existed, the agency reviewed the agenda and all relevant financial interests
reported by the meeting participants.
The Food and Drug Administration has prepared general matter waivers for
the special government employees participating in this meeting who required a
waiver under Title 18, United States Code 208.
Because
general topics impact on so many entities, it is not prudent to recite all
potential conflicts of interest as they apply to each member. FDA acknowledges that there may be potential
conflicts of interest but, because of the general nature of the discussions
before the committee, these potential conflicts are mitigated.
We
would like to note for the record that Dr. Michael Strong is participating in
this meeting as a non-voting industry representative acting on behalf of
regulated industry. Dr. Strong's
appointment is not subject to Title 18 United States Code 208. He is employed by Puget Sound Blood Center
and, thus, has a financial interest in his employer. He also is a researcher for Roche Molecular Diagnostics. In addition, in the interest of fairness,
FDA is disclosing that his employer, Puget Sound Blood Center, has associations
with regional hospitals and medical centers that store platelets that could be
affected by today's committee discussions.
Also, the Puget Sound Blood Center is a participating blood center for
the West Nile Virus research.
With
regards to FDA's invited guests, the agency has determined that the services of
these guests are essential. The guests
were screened for conflict of interest and reported no relevant interest to
their topic.
In
addition, there are speakers making industry presentations and speakers giving
committee updates on regulated industry and other outside organizations. These speakers have financial interests
associated with their employer and with other regulated firms. They were not screened for these conflicts
of interest.
FDA
participants are aware of the need to exclude themselves from the discussions
involving specific products or firms for which they have not been screened for
conflicts of interest. Their exclusion
will be noted for the public record.
With
respect to all other meeting participants, we ask in the interest of fairness
that you state your name, affiliation and address and any current or previous
financial involvement with any firm whose products you wish to comment upon.
Waivers
are available by written request under the Freedom of Information Act. At this time, if there are any declarations
to be made by any of our participants, please do so or please do so prior to
making your presentation.
I
would just like to announce that the next Blood Products Advisory Committee
meeting is tentatively scheduled for September 18th and 19th, 2003. The site will be this hotel.
I
would like now to introduce the members of the committee. As I call your name, would you please raise
your hand? Dr. Kenrad Nelson, Chairman,
Dr. Liana Harvath, Dr. Jonathan Goldsmith, Dr. Charlotte Cunningham-Rundles,
Dr. Kenneth Davis, Dr. Samuel Doppelt, Dr. Fallat, Dr. Michael Strong, Dr.
Fitzpatrick, Dr. Allen, Dr. Klein, Dr. McGee.
Members absent are Dr. Chamberland, Dr. Stuver, Dr. Lew and Dr. Laal.
We
have added for this meeting a lighted timer for our speakers so you will be
placed on a timer and we will have the light to assist you through your
presentation.
At
this time I will turn the proceedings of this meeting over to the committee
chairman, Dr. Nelson.
DR.
NELSON: Thank you, Dr. Smallwood. The first item on the agenda is discussion
of the Medical Device User Fee and Modernization Act by Dr. Mary Elizabeth
Jacobs, also called MDUFMA.
Medical Device User Fee and
Modernization Act
DR.
JACOBS: Thank you, Dr. Nelson.
[Slide]
This
is a short update for you. We have been
doing these at every BPAC this year.
[Slide]
We
would like to give you our performance so far for the first eight months,
through May.
[Slide]
As
you see on our device receipts at the bottom, the critical factors, we have met
all the FY05 goals so far this year, which don't kick in officially under the
Act until 05. We have had PMAs which
are traditional, meaning they are not supplements but they actually are modular
PMAs, two of those. We have had more
510(k)s than we ordinarily have and we have had quite a few manufacturing
supplements, 70 of those.
[Slide]
We
are looking at the number here for 510(k)s because those are the most in
volume. Of these, we have had 42. Twenty-six are traditional; six abbreviated
and ten special, which are much shorter, with a 30-day deadline.
[Slide]
This
is a projection of the numbers we are receiving. If we receive as many in FY03 as we did in the fist six months,
you are seeing we are having a substantially larger volume.
[Slide]
Of
these, for the traditional ones which have been completed--we have a number
that are pending, and we have indicated here that these times may increase with
the completion of these. The
traditional have an FDA average of about 57 days; abbreviated also
approximately 57 days; and special approximately 19 days. We have a 30-day time clock on those.
[Slide]
Of
the cycles, the average one for traditional is 1.12 cycles.
[Slide]
We
want to reiterate what are the improvements that have led to the better
performance. One of these is taking a
very active problem solving approach, finishing our reviews earlier and
spending the rest of the time solving problems; training in what is called
least burdensome way of demonstrating what needs to be demonstrated; and we
have much faster document handling with the new courier service that also covers
counter-terrorism documents and a barcoded delivery system.
[Slide]
There
are three new guidances since the last BPAC meeting. The first one is 31 pages long and it is inspection by accredited
persons program, which is called third-party inspection. That guidance is rather complex but it has
Q&A in it. So, I would encourage
anybody who is interested in that topic, even though they may not be
immediately looking at being involved in it, to look at that guidance.
The
second one is the pediatric expertise for advisory panels. There are special provisions for devices
that are being developed for pediatric populations. There is going to be a companion guidance coming out relatively
soon on all the aspects of considering pediatric devices.
The
final one is how do we file PMA applications.
I would encourage everyone who is filing a PMA to review that because
that will give you in some detail how we make that decision.
[Slide]
We
also have an instrument that we call the "blue book memo." It is kind of like a light guidance. This describes for you the electronic
labeling for prescription devices in healthcare facilities. If you are interested in that for your
device you can call the RPM branch chief, who is Dr. Sayah Nedjar and will
discuss with you the provisions on that.
[Slide]
We
have two expected reports at the end of the year, one on CBER and one on the
program as a whole.
[Slide]
There
has been a new announcement of a meeting for all stakeholders. I want to make you aware of this. Many of you will be receiving invitations
from our normal list for BPAC. We send
all the invitations to everyone who is invited to this meeting. It is going to be on December 3, right
here. It is going to be following both
of these reports that go to the Congress, and it is going to address how we
have done in our progress in the first year.
[Slide]
I
want to make you aware again that we have an electronic docket. Any concerns that you have about the program
can be sent into that. As well, you can
read the concerns that other people have addressed, and please let us know what
your concerns are. Thank you.
DR.
NELSON: Thank you. Any comments or questions?
[No
response]
The
next item is a report on white particulate matter in blood bags, DR. Sharyn
Orton.
White Particulate Matter in Blood Bags
DR.
ORTON: Good morning.
[Slide]
I
am going to give you an update on the white particulate matter task force. This is going to be a general summary of the
studies that have been done so far and the study results.
[Slide]
As
you are probably all aware, in February of 2003 the American Red Cross Southern
Region, Atlanta, Georgia reported unusual particulate matter in red blood cells
prepared from whole blood drawn in bags manufactured by Baxter. This was followed by reports from other
blood centers, and included bags manufactured by Terumo and Medsep as well.
[Slide]
This
particulate matter was reported primarily in red cells prepared using a hard
spin method, and was found less frequently in red cells prepared using a soft
spin or post leukofiltration.
[Slide]
FDA
required visual inspection procedures during storage and immediately before
distribution, and our current thinking is that as part of this visual
inspection centers should perform an enhanced visual inspection, commonly
called the 10-minute hold, of red cells after preparation.
[Slide]
Suspect
units should be either leuko-filtered prior to release to transfusion services,
or they should be quarantined. These
recommendations are still in effect at this time.
[Slide]
I
am going to be describing studies that were done by Baxter, within FDA, our
Forensic Chemistry Center, the Center for Devices and Radiological Health.
[Slide]
Within
CBER, the Division of Hematology did some work. They also worked with the American Red Cross Holland Laboratory
and the NIH Transfusion Service.
Division of Blood Applications worked with Gulfcoast Regional Blood
Center, Florida Blood Services and Centers for Disease Control.
[Slide]
At
Baxter--and this is a slight update from the slides that are on the web and the
information that you have; I just received this information from Baxter
yesterday--they did analytical methods for PM development due to solution
instability, degradation or precipitation.
They did final product release testing for implicated and non-implicated
lots and they looked at the established container system entities. They did characterization of delineated
organic compounds, both leachables and impurities. They were able, using the Red Cross Southern Region procedure, to
reproduce particulate development.
[Slide]
The
FCC at the FDA analyzed the anticoagulants.
They tested fill volumes. They
analyzed for impurities, degradation products or exotic elements. They examined interior surfaces of the bags
and raw material and sheeting, and they examined particles to identify whether
there was any seed material involved.
[Slide]
They
also examined and compared bag materials from control, heated and cooled bags.
[Slide]
At
CBER, the Division of Hematology photographed and classified particles. They asked for representative examples from
any of the blood centers that were finding these particles. The American Red Cross Holland Laboratory
evaluated particulate matter formation.
They looked at donor blood-related and blood-processing factors. They looked at the influence of
leukoreduction on the matter removal.
They did total protein, total fibrinogen and lipid profiles. They looked at donor medications and meals
in 24 hours prior to donation. They
also were using the Red Cross method to reproduce the particles.
[Slide]
They
also did a plasma study and looked at both platelet and plasma parameters, and
the different parameters are listed here.
[Slide]
Within
the Division of Blood Applications for infectious agents we worked with the
CDC. We looked and pre and post
filtration white cell and platelet counts with Gulfcoast Regional Blood Center
and Florida Blood Services. That data
was shown previously at BPAC. I will
have it again in a later slide. We also
looked at adverse event rates, and this was with CDC, Gulfcoast Regional Blood
Center and Florida Blood Services.
[Slide]
For
the results, the particles appeared to be comprised of normal blood
constituents. There were reports from
some blood centers that particulate matter can normally be found in red blood
cell preparation. There was quite a bit
of literature from the late '80s and '90s that supports this.
[Slide]
This
is the information that I just received from Baxter. It was a very large document.
I tried to summarize it. Again,
they could reproduce the particulates.
These particulates were removed after leukofiltration. They found no process of material
abnormalities. The implicated and
non-implicated lots had no discernible material differences in any of the
system entities or parameters that were studied. The implicated lots met all the relevant compositional
specifications, and the particulate development was not correlated with any of
the parameters tested.
[Slide]
At
the CDC forensic lab all the anticoagulant associated solutions that were
tested were as expected. All the fill
volumes were as stated on the label. No
impurities, degradation products or exotic elements were identified, and no
seed material was identified either.
[Slide]
At
CDRH the study on the control, heated and cooled bags showed no
differences. Suspected lots were not
measurably different from non-implicated lots.
There was consistent molecular weight between the bags; consistent
plasticizer weight fractions; and all the bulk material parameters were
confirmed.
[Slide]
This
is preliminary data from the American Red Cross Holland Laboratory. The studies are ongoing. They found no apparent association between
the particulates and high platelet or white cell counts. Leukofiltration was observed to remove the
particulates. Subsequent filtration
with 170 micron mesh filter did not isolate any additional material from these
leuko-filtered units. Additional
particulate development was not observed during subsequent storage of these
units after 42 days. In the plasma
study they found comparable platelet and plasma parameters between units that
had particles and units that did not.
[Slide]
Within
the Division of Blood Applications, working with the CDC on infectious agents,
there was no evidence of an infectious agent involved. For the pre and post platelet and white cell
counts of particulates on leuko-filtered red cells, which was done by Florida
Blood Services, all of the white cell counts post filtration were acceptable,
and 80 percent of the platelets were removed after filtration.
[Slide]
For
adverse events CDC reported data from the Georgia Department of Health. This was also described at the previous
BPAC. There was no increase in adverse
event reporting for transfused red cells comparing January of 2002 with January
of 2003, nor was there any trend in adverse event reporting between those two
time periods.
[Slide]
Gulfcoast
Regional Blood Center and Florida Blood Services tracked both particulate units
that were leuko-filtered and subsequently transfused, and Florida Blood
Services also looked at units that had particulates that they determined to be
normal in the process of the red cell.
There were no adverse events reported and of the particulate units, 135
leuko-filtered were tracked and 187 noon-leuko-filtered. In the control group which did not have
particulates observed at any phase, there were 176 leuko-filtered and 695
non-leuko-filtered, again with no adverse events reported.
[Slide]
In
conclusion, there were no detectable aberrant results associated with the
collection bags, and there does not appear to be an increase in adverse event
rates associated with the transfusion of red cells that are either
leuko-filtered or that have normal particulate matter. However, I do need to note that the sample
size here is small relative to the power to really detect a substantial
difference. I would like to thank Florida
Blood Services. They are continuing to track these so we can get more
data. Thank you.
DR.
NELSON: Questions? What is the conclusion as to what the
particulates were?
DR.
ORTON: They are normal. They are
platelets. They are normal constituents
from blood.
DR.
KLEIN: My conclusion from what you
presented and what I know from elsewhere is that this doesn't appear to be a
new problem if we review the literature.
There doesn't to be clinical import and, certainly, the leukoreduction
filters remove the particulate matter which appears to be blood
constituents. So, I am wondering what
the current thinking is about the enhanced inspection, which was clearly
important at a time when we didn't know what was occurring but seems somewhat
less important now.
DR.
ORTON: We have discussed this fairly
recently, and I think our current thinking at this point is that until we have
a little bit more information on adverse events I don't think we are going to
make any change in our recommendations.
I am not disagreeing with anything you have said so far but we would
like to get a little bit more information before we make any other statement.
DR.
STRONG: I would agree with Dr.
Klein. I think also those with a little
more grey hair in the audience, they may remember that this is a phenomenon
that has been seen probably since the onset of transfusion, and if you inspect
the transfusion filter at the bedside you will find that they are also removed
by that process. So, it seems like we
are putting an awful lot of effort into this that probably won't gain very
much.
DR.
ORTON: One of the studies that Holland
Lab is conducting is to look at the regular units not being leuko-filtered that
have particulates, and just looking at what the 170 micron filter removes,
which is part of exactly what you are talking about.
DR.
EPSTEIN: Harvey, our current policy is
that if units are leuko-filtered you can discontinue the extra 10-minute
inspection. But the underlying problem
here is that if you are not leuko-filtering we know that current manufacturing
procedures will produce these particulates.
It may not be new but the question is whether it is or is not
contributory to adverse reactions to transfusion. That is the point that we would like to continue to clarify. I mean, we could roll back the clock and
say, well, we didn't know before so it is still okay now. On the other hand, we now know that these
things do occur with a significant frequency and they are removable. So, what we are concerned about is the
noon-filtered unit.
DR.
KLEIN: That makes some sense if you are
going to be looking at large numbers in a controlled study of the leukoreduced
versus the non-leukoreduced. If that is
the case, that is going to take a couple of years but perhaps that is worth
doing.
DR.
FITZPATRICK: As Harvey said, we need a
large controlled study if that is the goal because those institutions that are
doing the inspection, they don't release the unit so there is no adverse event
because the unit hasn't been transfused, and the units that are released pass
the inspection so there is no way to track anything there.
Because
it is current thinking, my understanding is it is not a guidance; it is not a
regulation; it is a recommendation. So,
it is up to local policy whether to do the 10-minute inspection or not. So, I think the implication of the current
thinking based on this is that what we have been doing is probably effective
and we observed a phenomenon, studied it and determined that we have naturally
occurring products in the red cells.
So, without a large controlled study the impact of continuing to do the
10-minute inspection is becoming, from our centers, a significant impact on
their ability to do their work.
Also,
you are not seeing results of what they are doing; they are doing
something. At the beginning they
understood why they were doing it. Now,
with this report, they will think it even less important to continue to do
it. So, it is going to be difficult to
continue to tell a local medical director that it is important for him to do it
because the data are not supporting them doing the 10-minute inspection.
DR.
ORTON: I would just like to add one
thing about sample size. I have sat
down and worked with many of the figures and it is not as large a study, I
think, as you would think, particularly if we had multiple blood centers with
their transfusion services participating.
As I said, Florida Blood Services was able to do 800 or 900 for me in
about a little over a month's time. So,
if we were looking at between 2,000 and 3,000, which was the figure I was
looking at with the controlled group, at multiple blood centers we could knock
it off in less than years. So, again, I
would ask that any blood center that has a transfusion service, if they feel
they could get this information please contact me so we can get more
information.
DR.
NELSON: I think Kay Gregory wanted to
make a comment.
DR.
GREGORY: Thank you. I will just speak from here because it is a
short statement and, actually, I am not even going to read the statement
because I think the gist of our statement has already been expressed by the
panel members. We would simply
encourage FDA to come to some kind of conclusion as quickly as possible. Thank you.
DR.
NELSON: Any other comments?
[No
response]
The
next item is safety reporting requirements for human drug and biological
products, Dr. Richard Lewis.
Safety Reporting Requirements for Human
Drug and
Biological Products
DR.
LEWIS: Good morning. Thank you, Dr. Nelson. Good morning, committee members.
[Slide]
I
wanted to take the opportunity to introduce to you a regulation that has been
proposed and published in March, and is still currently open for comment.
[Slide]
This
is the safety reporting proposed rule.
I said I could do this in five minutes but that was before I knew there
was going to be a timer.
[Laughter]
Thank
you, Dr. Smallwood, for the pleasant surprise!
This
safety reporting proposed rule encompasses drugs, biologics as well as blood
and blood components. Most of my
comments this morning will focus on the blood and blood components but there
are parts of the proposed rule that also address biological therapeutic
products.
[Slide]
As
I said, the proposed rule has requirements for premarketing expedited safety
reporting; postmarketing safety reporting, and these reports are in two groups,
both expedited reports as well as periodic reports; and then, as I mentioned,
safety reporting for blood and blood components.
[Slide]
For
the blood and blood components the proposal suggests that it would require the
reporting of serious adverse reactions, in addition to fatalities, that are
related to the collection or transfusion of blood and blood components.
[Slide]
Currently
biologics manufacturers, including blood manufacturers, are required to report
within 45 days any deviation from current good manufacturing practices,
applicable regulations, applicable or established standard, or an unexpected or
unforeseeable event which may affect the safety, purity or potency of a
product.
[Slide]
Also
required currently are fatality reports, and these reports must come in as soon
as possible, and then a written report of the investigation within seven days
of the fatality.
[Slide]
In
the proposed regulation the current requirement would continue that a fatal
reaction be reported within seven calendar days.
[Slide]
Currently
adverse reactions related to blood transfusion--the blood establishment is
required to investigate the adverse reactions and to prepare and maintain a
written report of the investigation, including any follow-up and conclusions,
and that report is to be sent to the collection facility.
[Slide]
In
the proposal the particular adverse event would still be investigated and
conclusions drawn, however, at the end of that investigation there would be a
decision on whether or not the particular event was serious or not serious. If it were serious, it would then be
reported to the FDA.
In
the preamble to the proposed reg the FDA has provided a number of examples, and
those examples fit into four categories, examples related to the collection of
blood products and examples related to transfusion. We have also provided examples of whether or not there were
things that we thought were important to be reported, as well as examples of
things that did not need to be reported.
[Slide]
This
is a list of some of the things that we thought were important: Vasovagal reactions with syncope; citrate
reactions; anaphylaxis; seizures; cerebrovascular accidents; and others. I believe committee members have copies of
the slides and there are other copies at the table outside.
[Slide]
Some
of the things not included related to collection include self-limited vasovagal
reactions; self-limited citrate reactions; localized hematoma; localized skin
irritation.
[Slide]
Regarding
transfusion complications from the use of an unsuitable unit, include infusion
of hemolyzed blood; complications from improper blood administration; induced
hemolysis; and others.
[Slide]
Things
that would probably not need to be reported related to transfusion would be
febrile nonhemolytic transfusion reactions; related hypersensitivity without
respiratory insufficiency or hypotension; induced alloimmunization; and others.
[Slide]
This
summarizes the part of the proposed regulation related to blood and blood
components. Currently, fatality
reporting is required. In the proposed
regulation fatalities would be reported and, in the same time frame as
currently required, the proposed report would include all serious suspected
adverse drug reactions, except fatalities, and the time frame for these reports
would be 45 calendar days. The 45
calendar days was selected so it would coincide with the biological product
deviation reporting because we thought that there may be some of these reports
that would overlap and this would allow the investigations to proceed
concomitantly and the reports to come in at the same time.
[Slide]
This
relates to other drug and biological products and summarizes the expedited
safety reports. I mentioned that there
are expedited reports premarketing.
Currently, safety reports are expected for an unexpected fatal or
life-threatening experience in seven calendar days, and in the proposed reg it
would change the definition of what should be reported. This would be unexpected, fatal or
life-threatening suspected drug reactions.
And then, a written IND safety report would change slightly the
definition of what is reported. It
would still maintain the same time frame.
[Slide]
In
postmarketing--this would be the largest change--there would be some expedited
safety reports. There would be initial
reports within 15 days predominantly.
Some of those reports would also be required within 45 calendar days.
[Slide]
Some
of these reports would have a later follow-up, and again we are talking about
postmarketing. This has to do with new
information expedited follow-up reports.
[Slide]
Then
postmarketing, there are two separate reports that would be required, a
descriptive information report as well as individual case reports. As in the previous slides, the yellow shows
the new components of the regulation.
Currently there are periodic safety reports. The new regulation would require updates, as well as interim and
individual case safety reports.
[Slide]
The
frequency would change in the proposed regulation. This is a little bit more complicated scheme but over the life of
a drug product the numbers of reports would actually be reduced. It is not easy to see that from this. It proposes that after a product is approved
or licensed there would be semi-annual reporting for two years after approval,
and then for the next three years reports would come in annually, and then two
and a half years for the next ten years and then five years, every five years
after the first ten years of a drug life.
Individual case safety reports related to specific adverse reactions
would come in semi-annually after U.S. approval.
[Slide]
The
definition of adverse drug experience was very descriptive in our current
regulations. In the new regulations it
becomes a little bit more broad and the decision-making is left up to the drug
manufacturer, with a noxious and unintended response to any dose of a drug
product for which there is a reasonable possibility that the product caused the
response. In this definition the phrase
"a reasonable possibility" means that the relationship cannot be
ruled out.
Let
me just comment that on the blood and blood component part of the regulation we
have begun efforts to have in place a mechanism to receive those reports
electronically. They would come in on
the 3500 report form that is used for MedWatch reporting. There would be a computer system that would
allow them to be entered immediately.
We think that this would also facilitate analysis so that we could
address things that look like they were having an effect on blood and blood
components nationally. Thank you.
DR.
NELSON: Comments? Yes, go ahead.
DR.
STRONG: Our handouts are missing the
last set of slides. Could we go back to
the very first slide on the blood products so that we could just see that one
more time? DR. LEWIS: Sure, I think
we can.
DR.
STRONG: It is out of order I
think. We have blank pages after about
six slides. It was the one that had the
vasovagal reactions on it.
[Slide]
DR.
LEWIS: I have already received some
comments on this. I italicized
"requiring medical intervention" and I think we are going to have to
do some work to define exactly what medical intervention is. From the two extremes, it doesn't mean that
the individual fainted but, on the other extreme, if the individual had to be
taken by ambulance to the hospital that would be medical intervention. But where we draw the line between those two
extremes we will probably have to put some effort into defining when this
becomes a final regulation.
DR.
STRONG: That actually was my question,
the definition of medical intervention, citrate reactions.
DR.
LEWIS: Citrate reactions requiring
medical intervention? I presume it
would be the same difficulty, yes, what is medical intervention.
DR.
NELSON: Does the FDA have any data on
how complete reporting has been, or what the compliance has been or is with the
current requirements?
DR.
LEWIS: Unfortunately, the only
requirements now are fatalities, the only reports that we get. The other investigations are evaluated by
the field inspection force when they go to a particular center. So, there is no accumulation of data.
DR.
NELSON: You might want to consider some
sort of QC procedure where you evaluate how effective this is and how complete
because having data that is only 20 percent accurate or something like that is
not very useful. It can give you false
information and it looks like a fair number of things might need to be reported
that aren't now. Jim?
DR.
ALLEN: Yes, that was exactly the
question I was going to ask. In a very
diffuse medical care system such as ours, I mean even if a hospital is trying
to find out what kind of adverse events are happening within that--I mean here,
whether it is the bedside physician who would be responsible for reporting or
the transfusion service or the hospital infection control quality assurance
program, however it is set up, I think it is often unclear. I assume that most transfusion services
would take the responsibility if they become aware of it, and there can be
events that occur that they, for whatever reason, don't ever become aware of.
You
know, I commend the FDA for its efforts to try and get this kind of
information. I know that physicians are
routinely or periodically sent information and fliers about the requirements
for adverse event reporting. It would,
indeed, be useful to consider, if funds and resources are available perhaps
through other public health agencies, some sort of evaluation of what is the
completeness of reporting even for fatalities because I will bet it is
considerably less than 100 percent complete.
Whether hospital discharge data might be useful as a proxy to kind of
cross-evaluate, I don't know, but it is an interesting problem that does need
to be considered.
DR.
NELSON: These data are on blood
collection facilities but you had another one, didn't you, on transfusion? I suspect that the blood collection serious
reactions could be readily reported, and probably pretty accurately. But I suspect transfusion, when you are
transfusing a person with multiple underlying illnesses, trying to figure out
what is due to the transfusion, a serious adverse event that might be related
to transfusion "could not be ruled out" might be more difficult.
DR.
LEWIS: Thank you.
DR.
HARVATH: Richard, I was wondering if
FDA has considered, or maybe already done this--considered the NCI toxicity
criteria that were recently updated because they have gone very systematically
through every organ system and it may be a starting point to help sort of
quantify this more easily, and most clinical trials that are sponsored by NIH
are using this for their adverse event scoring. So, it might help; it might save you a lot of work.
DR.
LEWIS: Honestly, we haven't discussed
that but that is a very good suggestion.
Thank you very much.
DR.
GOLDSMITH: On the last slide you
changed the definition about serious adverse events and you took out the idea
that there is a lack of therapeutic effect.
That was removed I think from the definition. I was just trying to understand that a little better.
DR.
LEWIS: Can we go to the last slide?
[Slide]
DR.
GOLDSMITH: Yes, failure of
pharmacologic action. The way I read
the new definition, that is not part of it.
DR.
LEWIS: I had not focused on that. I see that you are correct. I presume that this is because the
regulation is trying to focus on safety rather than efficacy. A lot of the impetus for this particular
regulation is to harmonize with some of the reporting requirements in
Europe. It is part of ICH initiatives.
DR.
GOLDSMITH: Not to overdo this, but lack
of efficacy can lead to safety problems.
DR.
LEWIS: Thanks.
DR.
NELSON: Thank you. The next report is on bovine spongiform
encephalopathy in Canada, Dr. Piccardo.
Bovine Spongiform Encephalopathy (BSE)
in Canada
DR.
PICCARDO: Thank you.
[Slide]
I
will summary recent events related to the discovery of a cow with bovine
spongiform encephalopathy in Canada, and I will also present briefly some
background information.
[Slide]
BSE,
bovine spongiform encephalopathy, was first described in the U.K. in 1986, and
BSE is present in most countries of Western Europe. The peak of the epidemic was in the U.K. in 1992-1993 and
surveillance in Canada began in 1992.
BSE was detected and reported in Canada in 1993. It is very important to note that this one
animal was imported from the U.K. BSE
was recently found in Japan, in Israel, Slovakia and the Czech Republic and
Poland.
[Slide]
In
the transmissible spongiform encephalopathy field there are some basic
assumptions. This is one of those, that
BSE first arose in the U.K. and was propagated through the recycling of
infected bovine tissue into ruminant feed, meaning meat and bone meal. The export of infected animals and infected
feed from the U.K. spread the BSE agent to other countries where it was
recycled and propagated via the animal food chain.
[Slide]
One
critical issue, a landmark in the field is 1997 with the ruminant feed ban in
North America. Canada implemented a
rule that prohibits the feeding of most mammalian proteins to ruminant animals,
what we call the feed ban. The U.S.
implemented a similar rule the same year.
[Slide]
The
importance of the occurrence of bovine spongiform encephalopathy was
highlighted when variant Creutsfeldt-Jakob disease was found. Variant Creutsfeldt-Jakob disease is a
neurological disease in humans attributed to the consumption of meat products
from BSE-affected animals.
Most
vCJD cases have been detected in the U.K.
The last figure I could find was 135.
But vCJD was also found in five other countries, Canada, France,
Ireland, Italy and the U.S. now. It is
very important to note that patients in Ireland, the U.S. and Canada have spent
extended time in the U.K. so for all purposes the Canadian case can be
considered as a case from the U.K.
Regarding France, some of these patients in France and the Italian
patient had not visited the U.K. It is
also important to know that France imported a significant amount of beef from
the U.K.
[Slide]
Regarding
BSE in Canada, as you might know, on January 31, 2003 an older breeder cow,
meaning six to eight years old, in Alberta was condemned with a diagnosis of
possible pneumonia and it was slaughtered.
It is important to note that BSE was not suspected at that time. The head was collected and stored and the
carcass was sent for inedible rendering for pet food, industrial use. The brain was not examined immediately due
to backlog.
On
May 16 BSE was diagnosed in Alberta, in a laboratory in Alberta, and it was
diagnosed by immunohistochemistry, meaning there was recognized the presence of
abnormal prion protein in the medulla.
On
May 18 BSE was confirmed in another lab in Winnipeg. The material was sent to the United Kingdom and on May 20 BSE was
confirmed, and it was confirmed in the U.K. as typical BSE, typical BSE in
terms of the pattern by the pathology, the pattern by immunohistochemistry and
the Western Blot pattern. Canada
announced the case and the USDA started the import prohibition.
[Slide]
Canadian
authorities assured that the carcass had not entered the human food chain and
the rendered products went to eight feed mills, two farms and a pet food
manufacturer in Alberta. Regarding the
feed mills, all the farms that received the feed, whiich was not intended for
ruminants, were contacted to determine if any ruminants were present on the
premises. If so, they were further
investigated. Two farms have been
depopulated because it could not be ruled out if inadvertent feeding of poultry
feed to cattle occurred on the same premises.
Regarding
the pet food manufacturer, it was dog food.
Dog food was shipped to one firm in the U.S. and there is no evidence
that dogs can contract transmissible spongiform encephalopathies. However, the U.S. firm asked customers to
return the food to the distributors for proper disposal.
[Slide]
What
was the Canadian response plan? There
were several lines of inquiry.
Regarding feed, over 200 farms have been investigated and were found in
compliance with the required feeding practices. Regarding the animals, for the case herd there is no information
available about the use of meat and bone meal on the last farm where the
BSE-positive cow lived. However, the
farm was depopulated and all the animals have been tested.
There
was another line of inquiry which they call the trace-back, meaning a search
for the possible birthplace of the positive BSE-affected cow, and the
probability was that this cow was born in Saskatchewan and possibly in Alberta. Herds where the BSE cow co-mingled were
investigated. The trace-forward means
that herds where the offspring from the case herd might have lived were also
investigated.
[Slide]
Regarding
U.S. follow-up, several federal agencies are following up five bulls imported
into the U.S. from one possible herd of origin of the BSE-positive cow. It was stated that these animals might have
gone to Montana and at this time information that I gathered from the USDA is
that the investigation is undergoing.
[Slide]
The
results--approximately 2,700 cattle brains have been analyzed by the rapid test
and by immunohistochemistry and all tested negative, of course except the
single positive index cow.
Approximately 25 farms have been investigated in Alberta, Saskatchewan
and British Columbia. On June 9 the
Canadian Food Inspection Agency announced that the active investigation of the
case is ending. At this point they are
evaluating data and they are also evaluating recommendations that were made by
an international panel that assessed the situation.
It
is important to note that the recent risk assessment, in December, 2002, has
indicated that the likelihood of BSE affecting cattle in Canada was very
low. The current prevalence of BSE in
Canada, however, must be very low risk, probably lower than before 1997. I remind you that 1997 was the time when the
feed ban was imposed.
[Slide]
So,
what is next? Well, BSE in Canada will
be a topic of discussion at the next meeting of the Transmissible Spongiform
Encephalopathies Advisory Committee next July.
Here you can see the Canadian Food Inspection Agency website in case
there is some further information that would be forthcoming.
[Slide]
Regarding
the agenda for the next TSE advisory committee, the agenda includes safety of
bovine gelatin; BSE in Canada which will be a topic of discussion, as I said
before; and decontamination of medical equipment and facilities.
The
next speaker will be Dr. Baker, from Baxter International, who will present on
risk assessment for products utilizing bovine material in the production
process.
DR.
NELSON: Thank you. Any questions? Maybe I didn't hear it right, but initially I think you said this
cow was born in the U.K. and then later on you said it was born in
Saskatchewan. Was it born actually in
Canada?
DR.
PICCARDO: This cow was born in Canada,
yes.
DR.
NELSON: That would imply that the
infection actually occurred in Canada.
DR.
PICCARDO: Well, yes.
DR.
FITZPATRICK: The first slide says it
was imported from the U.K.
DR.
PICCARDO: In 1993 there was a case that
was recognized in Canada and that animal was from the U.K. It was imported from the U.K. That was in 1993. The case that was reported recently was a Canadian case, and
Alberta was the site that was suspected to be the origin of that cow, although
Saskatchewan could not be ruled out.
DR.
NELSON: Thank you. Dr. Baker?
Risk Assessment for Products Utilizing
Bovine
Material in the Production Process
DR.
BAKER: Good morning.
[Slide]
Dr.
Nelson, members of the committee, I appreciate the opportunity this morning to
discuss Baxter's response to this Canadian BSE episode.
[Slide]
As
Dr. Piccardo has described, on May 20th a report was received by Baxter of this
finding of a Canadian BSE case from Canada.
For those of you who might be interested in terms of how a company like
Baxter manages these kinds of things, we have a standing threat management
committee which is comprised of members of senior management representing all
functionalities.
This
report happened to come to me. I am a
member of the threat management committee.
I immediately initiated a risk assessment for all of our products
globally which utilize bovine materials in the production process. In that assessment we determined that only
one product, recombinate antihemophilic factor, utilized bovine materials in
the manufacturing process.
[Slide]
The
materials used in recombinate processing comprise two categories. One is what we term direct contact
materials. These are materials that
actually come in direct contact with the active agent, recombinate Factor
VIII. This includes serum albumin,
bovine insulin and bovine aprotinin.
There
are also a number of indirect process materials that are utilized in the
manufacture of this material, and one of the things that I want to make clear
is that there are probably only six degrees of separation from the cow in any
therapeutic product that you run into.
An example is this material, Ventrex, which is a medium supplement. Now, there is a very small amount, trace
amount essentially of bovine protein in that product so there is a purified
bovine protein in that product. That
product is used to produce the antibody which is used to produce the
immunoaffinity resin which is used to purify the Factor VIII in the
process. So, you can see that there is
a significant degree of separation.
The
products that I am going to talk about are only going to be the direct contact
products. Although we did do a risk
assessment on all of these, just to keep this presentation manageable I am
going to talk about these ones.
Clearly, for the very indirect products there is a lot less risk
associated with these because there are many purification removal steps that
occur between that and the final product.
[Slide]
A
recombinate is produced through certified suppliers. Obviously, this TSE risk is a known risk and the for two
materials we are talking about serum albumin is Canadian sourced. It has a certificate of suitability in
accordance with the European regulations.
The bovine insulin was a more complicated story. That pancreas that went into the production
of the material was sourced from Canada and the United States. There were 12 slaughterhouses used and I
think one of the 12 was a Canadian slaughterhouse.
[Slide]
Inasmuch
as our product is globally licensed, it must meet the global regulatory
requirements with respect to bovine sourcing.
The European Union has the most definitive and well-described
requirements. They deal with country of
origin, the part of the animal used, the manufacturing process, and bovine
materials used have to have a certificate of suitability from the EDQM. In the U.S., the guidance is primarily in
the CBER letter to manufacturers. In
Japan, only draft requirements are available, although this slide is now out of
date. Coincidentally, on May 20th Japan
published its final requirements with respect to bovine materials and they are
somewhat similar to the European requirements in terms of the issues
considered.
[Slide]
At
the outset, I would like to say that the index animal could not and did not
enter into the manufacture of production materials for our products. We source all of our bovine materials from
relatively young animals, less than 30 months of age, and there is a
requirement that there be a veterinary inspection pre and post mortem to ensure
that the animals are in good health.
So, those animals that exhibit clinical signs of disease are not used in
the production of bovine materials.
The
serum albumin is produced from a category IV tissue, bovine plasma obviously,
which is considered to have no detectable infectivity. The manufacturing process has been validated
by the supplier using the hamster scrapie model. There is a validated 16.2 log clearance of the hamster scrapie
agent, which gives you very good assurance that were there any TSE agents
present in the plasma they would be well cleared by the manufacturing process.
[Slide]
The
situation with insulin is a little more complicated. Pancreas is a low infectivity tissue. It is the second lower category.
The manufacturing process has not been validated for the TSE removal,
however, there are manufacturing steps, particularly the low pH and the 7M
urea, that could be reasonably expected to dramatically reduce the
concentration of any prion infectivity.
This material was also manufactured in 1998. Part of the reason why there is no validation for the process is
that this product is no longer produced--the plant has been actually
bulldozed--and the source tissue was collected in 1996.
[Slide]
The
recombinate manufacturing process itself has been evaluated by us for the
removal of the TSE agent. There are two
steps that are responsible for most of the clearance, the immunoaffinity
chromatography step, which has been demonstrated to give a 5.4 log clearance,
and the combination of the two anion exchange steps, which have been
demonstrated to give a 3.2 log clearance.
So, in the actual manufacturing process we end up with a combined 8.6
log removal of the TSE agent.
[Slide]
Obviously,
even though we don't believe that there is any risk associated with this event,
we are taking steps in response to this event.
For the serum albumin we are going to replace the Canadian sourced
bovine plasma with U.S. sourced bovine plasma.
We will be replacing the current bovine insulin with recombinant
insulin.
[Slide]
In
summary, the bovine materials that we use did not come from the index animal
and are in the lowest risk categories.
The manufacturing processes were shown to, or can be reasonably expected
to have significant TSE agent reduction capability, and the recombinate
manufacturing process itself has been shown to have significant clearance of
the TSE agent. Thank you.
DR.
NELSON: Thank you. Questions?
Yes?
DR.
FITZPATRICK: With the relatively high
volume of exchange between U.S. and Canada, have you done a risk
assessment? Is there really any
difference between U.S. sourced and Canadian sourced material?
DR.
BAKER: That is a very provocative
question. You know, I think the prudent
thing for a manufacturer to do, and I don't care what biologic product you are
making, is to assume that the materials, the raw materials, could carry some
sort of infection; evaluate the possibility for the source of infection and
take appropriate steps. So, that is why
we have the validated clearance during the manufacture of the product. I think it is just the prudent thing to do
and I don't care what you are making.
DR.
NELSON: Jay?
DR.
EPSTEIN: Yes, I just want to respond
also to that point, which we think is central.
The FDA is engaged in examining the risk assessment both for BSE in the
U.S. and BSE in Canada with the question of whether there is any significant
difference in estimated risk, as well as with the question of what is the
possible contribution to U.S. risk of risk in Canada. We are hoping to have that analysis completed in time to present
it at the TSEC meeting in July.
DR.
NELSON: Has there been any difference
in the importation of meat and bone meal from the U.K. by Canada and the U.S.
because apparently that is probably how the Canadian cow got infected? If there is not a difference in importation,
I suspect the U.S. may have a risk.
DR.
EPSTEIN: I can't answer that question
at this time but that is one of the facts that will be entered into the model.
DR.
DIMICHELE: I know that it is in
category IV but just for completeness sake, the bovine serum from which the
albumin in recombinate is coming, when was that harvested? You talked about the insulin but what about
the bovine serum? Is that more recent?
DR.
BAKER: Yes, that is manufactured on a
continuing basis. We get the materials
in on a regular basis. I think the last
shipment we got from Canada was probably March, or something like that.
DR.
DIMICHELE: So, is there additional
surveillance of the product itself? Are
you testing the product at all beyond sort of the guidelines that you have put
in place to ensure removal of the prion?
Are you doing any further testing of these lots right now?
DR.
BAKER: You know, I guess I would give a
standard quality response to that. We
don't test quality in; we have assurance that an agent would be excluded or
removed.
DR.
NELSON: Thank you. The next discussion will be on severe acute
respiratory syndrome, with Alan Williams.
Severe Acute Respiratory Syndrome
(SARS) -
Informational Interpretation and
Background
DR.
WILLIAMS: Thank you, Ken, and good
morning.
[Slide]
The
concept of emerging infections and emerging diseases has kind of been a set of
buzz words for about the past decade in infectious diseases. I think SARS is really showing itself to
kind of be the epitome of what a truly emerging infection can look like, even
made more incredible by the fact that since the original identification it has
been recognized as a distinct clinical disease.
It
has shown rapid spread to a number of countries around the world. It has been identified that standard
infectious disease precautions are very effective in preventing the droplet
spread. The etiologic agent has been
identified as a coronavirus. That virus
has ben sequenced. There are early
development diagnostic tests available based on that virus. There have been donor eligibility
recommendations published by the FDA, and those recommendations have been
implemented. Now the epidemic or what
had the potential to be an epidemic is in apparent decline and there is talk of
vaccine development actively under way.
It is made incredible by the fact that all this has occurred since the
last meeting of this committee.
[Slide]
In
this session I will review some aspects of SARS with an emphasis on blood
safety. I am going to introduce the
session and provide some background. We
had actually lined up Dr. Matt Cunart from the CDC to present a CDC perspective
on SARS. Unfortunately, he was called
away to the field and is currently working on monkey pox in Indiana and so was
unable to join us today. But he was
able to share some slides.
We
will then have a presentation by Mark Denison, Vanderbilt University, on
epidemiology and pathogenesis, and then a discussion on SARS and Canadian
studies, particularly surrounding the Toronto cases, by Dr. Anton Andonov who
is with the Canadian Science Center for Human and Animal Microbiology in
Winnipeg, affiliated with Health Canada.
I have not actually seen Dr. Andonov yet; I hope he is here.
[Slide]
Following
that, I will return and present some of the elements on the guidance document
that was published by FDA in April. In
addition, I will address some of the questions and answers that have come up
surrounding that document and some of the comments received to the docket, and
a few comments on the general concept of introducing new donor questionnaires
and finding the most efficient and effective way of conducting that process.
[Slide]
As
I said and Dr. Fauci detailed in a very elegant talk yesterday that this is a
fascinating story. The original
infection appears to have arisen from an animal handler in Guangdong Province
in China who appeared to pick up a respiratory illness from small rodents being
raised for a food source. A physician
who left China and stayed at a hotel in Hong Kong appeared to spread that
respiratory infection to a number of individuals within that hotel who then
went on to multiple other sites and there was additional spread. The first report of this as a new entity
occurred on March 12 from the World Health Organizations as cases of atypical
pneumonia.
[Slide]
As
of June 12, data about a week old, there have been a total of 8,445 probable
SARS cases, with almost 800 deaths.
These numbers have increased just slightly in the past week. Finally, most of the cases and the deaths
have occurred in China and Hong Kong but additional countries impacted have
been Taiwan, Canada, Singapore, the United States, Vietnam, the Philippines and
a handful of other countries.
[Slide]
The
case definition is described both on the U.S. CDC website, as well as the World
Health Organization website. I am going
to emphasize the CDC materials which FDA has referenced in its guidance
document. The clinical criteria for
SARS is respiratory illness of unknown etiology with an onset, since February 1
of this year, which meets the following criteria: A measured temperature of greater than 100.4 and one or more
clinical findings of respiratory illness, for example a cough, shortness of
breath, difficulty breathing, hypoxia or radiographic findings of either
pneumonia or acute respiratory distress syndrome.
[Slide]
That
needs to be combined with epidemiologic criteria which encompasses travel
within ten days of symptoms to an area with documented or suspected community
transmission of SARS, or close content within ten days of onset of symptoms
with either a person with respiratory illness who traveled to a SARS-affected
area or a person known to be a suspect SARS case.
[Slide]
In
addition, now with the identification of the virus, there are antibody tests
that are available. These are of
limited usefulness for diagnostic purposes because it takes a while for the
antibody to actually develop. There are
now also nucleic acid-based tests. So,
there are laboratory criteria which can be plugged into the diagnostic scheme.
Currently,
case classifications are designated as suspect SARS, and that would be the case
meeting the clinical definition for which there is not yet radiographic
evidence of pneumonia or death from an apparent acute respiratory cause. The next stage, which encompass all of the
factors leading to a suspect case, would be probable SARS. This would include the radiographic findings
of pneumonia.
Most
of the data that are reported, particularly from the World Health Organization
reports, are probable cases. Now there
is a new designation emerging, which is confirmed infection and this is
infection that, in fact, has laboratory evidence of infection with the SARS
agent, generally by nucleic acid testing.
[Slide]
Throughout
the United States, as of June 11, there were 70 cases identified. The numbers are a little hard to see here
but there is a smattering of between one and three cases for the most part in
the yellow designated states, the bulk of the cases occurring in California, as
one might expect for reasons I will show in the next slide. Most of these cases are due to travel to
Asia and SARS areas where potential exposure occurred, but 70 cases were
identified in the United States as of June 11, and these are probable
cases. If you see higher numbers in the
United States, up in the 300 to 350 range, these are suspect cases.
[Slide]
The
epidemic curve for the United States shows a typical bell shape. Early in the recognition of the disease
cases were brought into the States. The
peak of cases were recognized in late March and then there was a gradual
decline. In fact, standard infectious
disease precautions for prevention of respiratory spread are very effective and
the United States was particularly fortunate in that the Canadian experience
and experiences around the world had actually educated healthcare providers
that these precautions were necessary and prevented a much worse situation in
the United States. In the U.S., as well
as worldwide, one can see a gradual drop-off of cases now and it has been
relatively quiet for the past couple of weeks.
[Slide]
Of
the probable SARS cases identified in the U.S., 97 percent of those cases
reported travel to the affected areas mentioned before. One case is a healthcare worker who cared
for a SARS patient; one case of a household contact of a SARS patient. Considering that the disease is effectively
spread by droplets--which generally means an individual working within a three
to six foot range of an infected person would potentially come into contact
with those droplets--it is understandable how these cases occurred and, in
fact, remarkable that the numbers aren't higher.
[Slide]
There
already is a tremendous amount of information available both from the World
Health Organization website, which can be found at this site, as well as the
CDC website, really very extensive information regarding travel, diagnosis,
patient care, etc.
[Slide]
So,
as you hear these subsequent talks, which will deal with some of the
interesting epidemiology and virologic findings considering those in relation
to blood donor eligibility, the points to consider are whether or not viremia
occurs in the asymptomatic phase. Do we
know that? Do we not know it? What are assurances in either direction? What is the incubation period prior to
symptomatic disease? What is the
duration of infection? What is the
potential for relapse with infection?
What treatments are available and how might these treatments impact
eligibility of the donor? If there are
interventions taken, what is the impact on the blood supply? I think a question, given the information
coming out of Kuala Limpur this week that the epidemic is on the decline, is
there a definable endpoint where we can be reasonably assured that new cases
are not occurring and some of the precautionary measures could be reevaluated?
So,
with that, I am looking forward to some interesting talks and discussion. Thank you.
DR.
NELSON: Thanks. My understanding is that the CDC and the
MMWR, about a week or two ago, evaluated that there have been no fatalities in
the U.S., and they evaluated over 100 of these probable and suspect cases and
were actually only able to confirm about eight or ten of them as actually
infected with the coronavirus. Is that
correct or is there any update on how many have been studied and confirmed?
DR.
WILLIAMS: Jim may want to add but I
know from Dr. Fauci's talk yesterday that there is evidence for PCR positivity
for the SARS virus in eight cases in the United States. I don't know the denominator as to how many
have been tested to this point and how many samples were available for
testing. So, yes, there have been eight. I don't know that the rest were negative or
even tested.
DR.
NELSON: I thought there were, like, 100
tested either by PCR or antibodies after recovery and that there were only
something like eight. But it was clear
that including the suspect cases was quite different than, let's say, in Taiwan
or Singapore or places where there was an epidemic and that it really wasn't a
different virus. It may have been that
our isolation facilities are no better than the Canadians, is my suspicion.
DR.
WILLIAMS: I think the other thing is
the distinction between the suspect cases and the probable cases. We know that probable cases have
radiographic evidence of pneumonia, but I have not seen information as to how
many of the suspect cases were actually looked at with x-rays and found to be
negative or positive. I have just not
seen that information available.
DR.
NELSON: Dr. Denison?
Epidemiology and Pathogenesis
DR.
DENISON: Good morning.
[Slide]
I
appreciate the opportunity to be here and to speak before the committee. I was concerned on my way here yesterday
when I picked up USA Today and they informed me that SARS has been
stopped. I was concerned I was going to
get called and they were going to cancel my talk. But reading the rest of the article doesn't reflect the title
quite as much.
There
are some issues, as a coronavirus investigator for the last 20 years, that I
think are worth addressing. So, what I
first want to do is talk to you about a few issues related to the other animal
coronaviruses and their relationship and leave some open questions. I am anticipating that Dr. Andonov is going
to answer all the questions that I have at the end of my talk.
[Slide]
First
I want to acknowledge the people in my lab, the students and the post docs who
have worked in my lab. There are four
from the NIH and particularly the assistance of Linda Saif--who is an
investigator at Ohio State who works with many of the animal coronaviruses and
just recently was nominated to the National Academy of Sciences--for use of her
slides. I have no additional
disclosures because prior to March of this year no one was particularly
interested in coronaviruses.
[Slide]
Briefly,
what I want to do today is review for you the pathogenesis of respiratory
enteric coronaviruses and then compare some of the known features of the SARS
coronavirus transmission and pathogenesis and, finally, list questions relevant
to SARS and its impact on blood and blood-related products.
[Slide]
What
I have done here is I put up a schematic which I would use for teaching many of
my first year medical students. I am
using many terms these days like I am sure all of you know a lot about
coronaviruses. That is not anything I
thought I would ever say to anybody.
What I wanted to go through real briefly is this issue and where are we
in terms of understanding other coronaviruses and where are we in understanding
SARS.
So,
if we think about a general scheme or model for coronavirus and/or SARS
pathogenesis, typically obviously this would begin with the issue of
transmission and infection. I am going
to sort of present what I call a straw virus or a straw model for thinking
about this, with some of the things to fill in where we know and what we know
about other coronaviruses.
If
we think about coronaviruses and SARS particularly, these issues have come up
already in transmission and infection with inhalation; question of inoculation
and/or ingestion; followed by a primary replication typically in epithelial
cells of the respiratory tract or the GI tract and lymphatics--tonsils Peyer's
patches and the lymph nodes. This might
lead to a direct pneumonia or a direct gastroenteritis. This has probably been the sort of general
feeling that has been promulgated. I
think that is based on the fact that there is sort of a little bit of a
prodrome and then a late progression to pneumonia, and virus has been
recognized in the GI tract.
But
in the typical scheme and the model that I would like to present in terms of
thinking about this, particularly related to blood products, is the issue of
thinking about SARS as a systemic disease with a progressive pulmonary
component. So, it is more like a model
that would be consistent with, say, measles virus or some other systemic
disease that may have late pulmonary complications.
In
that case then, primary replication would be followed by primary viremia or
blood-borne spread which would then be followed by secondary replication,
particularly in the reticuloendothelial system, the liver, spleen and lymph
nodes, followed by another round of viremia which could then lead back to
disease in the lungs, the GI tract and/or other complications of systemic
disease. Such has been reflected, at
least biochemically, in some SARS patients, suggesting hepatitis, possibly
nephritis and certainly cytopenias or blood-borne complications of the disease.
In
terms of its implications or relationship to blood products, the issue of
transmission during the primary viremia would have implications for blood
products for its presence in cells for issues of maternal-infant transmission
and for sexual transmission. I think we
can address a little bit about these and then ask questions about what we don't
know.
[Slide]
If
we think about coronavirus diseases, what I am going to tell you--I will tell
you now what I am going to tell you--is that I would like to think about these
diseases as what I will call either pneumoenteric or enterorespiratory. If we think about coronaviruses as a big
group, it is a reasonable way to develop a scaffolding that we can then present
subsequent data into.
If
we look at the human coronaviruses, those of mice which is what I have worked
with, and those of other domestic animals of which these are very important
pathogens, we can see some general diseases or general strategies emerging. Those that have significant gastroenteritis
and/or respiratory disease. Then, there
are some things that are more enteric or systemic, such as hepatitis and
encephalitis with MHV, peritonitis with feline infectious peritonitis virus,
and renal disease associated with infectious bronchitis virus of chickens, as
well, as you can see, other sort of pneumonic or respiratory diseases such as
colds in human coronaviruses, tracheitis, pneumonia and others.
SARS,
we feel, in some ways looks very different because of the way it emerges, but
if you look at the general strategies and the data that have emerged both in
humans and potentially now in animals such as the palm civet, we can see that
certainly there has been recovery of virus from the gastrointestinal tract and
there certainly is evidence of pneumonia.
[Slide]
I
want to present just a couple of very brief models for you of how this has been
known in animal coronavirus for a long time, and what relationship it might
have as we think about how we want to think about SARS.
The
first one is for transmissible gastroenteritis virus of pigs. This is a devastating disease in young pigs
and can lead to high death rates and enzootics in pig populations. It basically replicates in the small
intestinal villous enterocytes. It can
lead to villous atrophy, vomiting and rapid serious and fatal diarrhea.
Interestingly,
this is principally a gastrointestinal disease but a disease recently emerged
called porcine respiratory coronavirus, which has a deletion in the spike
protein on the surface of the virus that led to a mutant of TGEV which now has
limited replication in the GI tract but now replicates in the upper and lower
respiratory tract of pigs, leading to interstitial pneumonia.
This
in fact, interestingly, is leading to the decline of this disease because it
retains the same epitopes and immunizes against this disease. But now it is a respiratory disease instead
of gastrointestinal.
[Slide]
The
second model I want to show you for pathogenesis is that of the bovine
coronaviruses, a similar kind of disease.
Basically, the basic disease has been severe enteric disease of young
cattle, less than four weeks of age, with infection of epithelial cells of
calves, intestinal villous atrophy, diarrhea and dehydration--sounds
familiar. But there were multiple point
mutations that occurred and a new disease has recently emerged which is called
bovine coronavirus respiratory, which leads to respiratory disease of young
cattle, or the disease called shipping fever or shipping pneumonia in stressed
adult feed-lot animals that is now respiratory and retains some of the same
epitopes but is a little different disease but, nevertheless, demonstrates this
respiratory and enteric access that occurs in the changes of diseases over
time.
[Slide]
Finally,
I want to talk about two other diseases that may perhaps have some other
relevance to the issue of blood-borne transmission. The first is infectious bronchitis virus of chickens. This is what I would call a model of a
disease that is a systemic disease with a pulmonary component. That is, it can have a primary infection in
the upper respiratory tract that involves the tracheae and bronchi of chickens
so it is a severe tracheitis. Virus
detection, however, can be found certainly with a viremia and in multiple
secretions, including nasal secretions and feces and urine, suggesting either
that it is spread in swallowing or it is replication and/or transmission
hematogenously. Certainly, that has
been consistent with the issue with other organs being infected, such as the
kidneys, the oviducts and the intestine with some late disease occurring in
these animals.
[Slide]
The
next model is that of feline infectious peritonitis virus. This is the one that is the cautionary tale
and that is very concerning to everybody and I think provides the most
concerning model for the issue of blood products. That is, a primary infection in cats that may be primarily
pharyngeal or respiratory or intestinal epithelial cells but clearly can spread
hematogenously and end up resulting in a severe, progressive and fatal
peritonitis in cats, in animals that get this, with a persistent infection.
Now,
virus detection can be in the peritoneum.
It can be gastrointestinal and viremic, and viremia is
cell-associated. That is, it is the
infection of monocytes and macrophages.
This can be continuous and, in fact, there is an enhanced disease that
is based on increased uptake and replication in the presence of some
non-neutralizing antibody. So, this is
a model of pathogenesis which suggests a concern for viremia.
[Slide]
If
we look at this overall--and I am sorry, I didn't know how big the room is but
I will just go through these very, very quickly--the issue of viremia is
certainly not consistent and, for the most part, has not been tested. In the cases where it has been looked at it
is either moderate to low level, with the exception of feline peritonitis virus
that has a cell-associated viremia that seems to be consistent and
continuous. The replication in the
upper and lower respiratory tract depends on the strain, as does the intestinal
replication. Then, there is evidence of
systemic disease with many of the viruses.
[Slide]
So,
in the summary of the coronaviruses as a group there is this issue of
pneumoenteric or enterorespiratory disease.
This is Linda Saif's terminology.
Systemic disease certainly does occur.
It occurs in infectious bronchitis virus, the feline disease, and in
mouse hepatitis virus viremia can be detected.
Viremia is cell-associated in the case of FIPV but shedding and
transmission can be by multiple routes.
There is no data really; it has never been investigated in animal models
for many reasons, this issue of parenteral, sexual or vertical transmission. So, there is not good direct data for any
correlates or parallels.
[Slide]
What
I want to do now is just talk briefly about some of the known features of SARS
transmission of pathogenesis to relate it to these.
[Slide]
I
am going to do a tremendous summarization here of things with some of my
opinions. I don't want to rumor monger
but a lot of this is based on phone conversations and interactions, and much of
this data obviously is not out yet in an organized form. That will still take some time.
But
in terms of overall clinical disease, it is a concept of a prolonged incubation
period with late development of progressive respiratory disease; lack of upper
respiratory symptoms in humans; lack of rhinorrhea and coryza, suggesting that
this is a different model than that of other respiratory diseases that may have
a prodrome of the upper respiratory tract.
Certainly
gastroenteritis has been reported. It
has sort of been overlooked and it is not included in the case definition but
definitely virus is shed. There is as
much, in some studies out of Hong Kong, as 60-70 percent of who will report
diarrhea or gastrointestinal symptoms.
Children's
disease, interestingly, appears to be much milder, particularly those younger
than adolescents, without air hunger and without respiratory failure and
certainly with basically no mortality in young children. Then, development of antibody response, as
Alan said, is delayed for 10-20 days.
[Slide]
What
is the evidence for systemic disease?
Well, there is evidence. It is
provocative. When I say evidence, I
could have put "suggestion" because there is no absolute data that
says this is a systemic infection.
There
is liver enzyme elevation in a significant number of patients, as well as that
of creatinine phosphokinase for a suggestion perhaps of muscle involvement or
inflammation. Virus isolates have been
obtained from organs. Some of the
earliest isolates were from kidneys at autopsy. There is possible viral cytopathic effect seen in organs such as
the liver and kidney, although this has not been consistent and these were late
autopsies done in the earlier patients.
So, it is not clear if those were contaminants or issues of late disease
in people who had hypoxemia and other disease.
Urine
has been a source for positive RT-PCR reactions. I couldn't find the data; I thought there was some data that
there have been some positive viral isolates from urine as well but I don't
have that, I am sorry.
This
is also an issue of discussion, that is, that USAMRAD was looking at animal
models of a macaque and there was one where there was a pneumonia that was
produced quickly after IV inoculation of a macaque. That animal died possibly of a complicating bacterial infection so
it was not possible to determine that this was actually true but there is
suggestive evidence that IV inoculation could lead to pneumonia, suggesting a
hematogenous route or blood-borne route.
[Slide]
So,
possible modes of transmission, coming back to some of what Alan talked about,
are large droplet aerosol contacts, with direct contact or fomite contact. Small particle aerosol has been considered,
particularly because of some of the outbreaks such as in the emergency
department in Toronto where a patient was passing through the emergency
department and ultimately 12 people in that emergency department became
infected and there wasn't a clear issue of contact. The person wasn't in the ED for a long period of time. So, the issue of small particle aerosol has
been raised.
Certainly
stool isolates have been found in humans in some of the cases such as the
vertical transmission in Hong Kong, suggesting the possibility of a
contaminated water supply.
Then
this issue of the palm civet, or the civet cat which is not a cat but is more
related to the mongoose, comes to this issue of animal vectors in
transmission. Was it possible the
source was ingestion, the source of these initial infections. The finding of people who are antibody
positive without disease suggests that there may be some intestinal disease or
replication.
What
I can say though is that viremia, to my knowledge, has not yet been detected by
culture in any of these systems. If Dr.
Andonov has additional information, I would like to see that but my
understanding is that viremia has not yet been detected by culture in any
circumstance and cell-associated virus has not been reported. That doesn't mean it is not being
investigated. I know that in Canada
particularly there are tremendous efforts to accumulate these data and to get
the samples and look and see if they can find cell-associated virus.
Is
the time red on your side too?
[Laughter]
I
am almost there. I figure I have been
working on this 18 years, I should get at least 18 minutes!
[Laughter]
[Slide]
Just
a couple of issues of virus stability and survival. I want to talk first about mouse hepatitis virus. Clearly, its stability is pH dependent. You can't see this clearly but I will tell
you what this says. This is survival at
37 degrees at different pH's over time.
It was 48 hours on this curve.
This is percent. These are log
scale survivals of MHV at 37 degrees at different pH's. So, this is 4; this is 5; 6 and 7; and then
8, 9 and 10 down here.
So,
the pH stability is sort of between 5-7 for MHV; less at low pH and certainly
less at very high pH. Also, heat
inactivation may be variable and may be spike dependent. This is an issue of different MHV strains
with their own spikes and then chimeric spike proteins that were made showing
that they may enhance the stability of the virus. It looks like there are some differences with the SARS agent in
terms of its stability. It may have a
higher pH optimum. It can survive in
diarrheal stools for longer periods of times and possibly drying for longer
periods of time.
[Slide]
If
we look at SARS then, what do we know about it? Well, it has been recovered from surfaces at greater than 24
hours. This is from data that I did in
collaboration with Konde Subarau at the NIH.
It
has been recovered from infected Vero cell lysates that that had been lysed in
two percent SDS buffer. She put it in
the freezer and I assured her that this would get rid of the infectivity but,
being a good scientist, she did the test.
She went back and scraped the surface after this was lysed and put it in
the freezer and got about three logs of virus back. So, I think there are some issues about its ability to be killed
easily from cell lysates in detergent and that needs to be investigated.
It
is stable for greater than 24 hours in stool, particularly reduced pH, and it
is recovered from non-ill animals, the civets, which is also concerning. Finally, it is likely rapidly inactivated by
heat, at lest 60 degree heat and methanol because we have done fixation studies
looking at organics, suggesting its ability to be inactivated.
[Slide]
So,
if we put all this data together, what can we say about SARS? Well, it is still more in the category of
what we think rather than what we know, but what we can say is that there is
yet no evidence for straightforward viremia, either cell-associated or in
serum; that replication can occur in multiple systems, or at least virus can be
recovered; and there is some suggestive evidence for systemic disease,
suggesting its possible transmission that way.
[Slide]
I
will skip this. We are coming to the
end.
[Slide]
Then
what questions are remaining? Well, is
SARS established in humans? I think
that remains to be determined. The
evidence of milder disease suggests that we may have some surprises. The late emergence of cases in Toronto
suggests there may be some surprises and less severe disease and more of a
spectrum.
Is
there transmission by blood or blood products?
There is certainly no evidence; there are no reports that that has
occurred.
Persistent
infection in the presence of antibody, persistent infection in
coronaviruses--and I didn't go into this--is the rule. It is the rule almost in bovine and porcine
and murine diseases. Persistent
infection after animals recover is the rule, as is some recurrence of disease.
Is
there serum viremia or cell-associated virus?
This needs to be answered and should be able to be addressed as the
tests improve.
Inactivation
of virus, I think this just needs to be done in an organized way, and with
different strains, but obviously you would like to do that from products that
are relevant to the blood system.
Finally,
the sensitivity of diagnostic tests for viremia, even the nucleic acid-based
tests, may not be as good as we would like them to be yet. So, there will be a co-evolution of the
tests and our ability to understand if there is virus even in products that
were obtained from earliest patients.
I
will stop there. Thank you very much.
DR.
NELSON: Thank you, Dr. Denison, for a
comprehensive review. You mentioned
that persistence is the rule. For how
long?
DR.
DENISON: Well, it depends on the
animal. In the mouse model, if the
animals survive acute infection they will be persistently infected. Once a population of mice is infected, in
the population and in the individuals that survive, they may be infected and
shedding virus for the life of the animal.
So, that may be with late development of disease or without late
development of disease. You also can
see intermittent shedding in young animals that survive acute disease as
well. Clearly in tissue culture
persistence is the rule. So, if the
tissue culture is destroyed the cells will survive and you continue to recover
virus from the supernatant after that.
DR.
NELSON: Persistence is in the intestinal
tract?
DR.
DENISON: In the animals it is not
known. Wherever the primary disease is
you can find persistence. Some of that
is thought perhaps to be sort of immune surveillance shutdown or that it is in
the immune system too, in circulating cells.
But, you know, this hasn't been investigated in that much detail in the
animal models.
DR.
NELSON: One of the reports, I think it
was from the German investigators, found SARS coronavirus in stool 25 days
after the acute illness. Probably it
has been studied beyond that, but the epidemic isn't that old so maybe not.
DR.
DENISON: I think that needs to be
reproduced much more carefully, and I think the relevance of that or the
relationship of that to disease in the blood system--I don't want to go into my
pathogenesis 101 or 102, but many, many of viruses, respiratory, systemic
viruses have a very limited low level transient viremia with systemic disease
but it won't come back into the blood; you won't find it in the blood. So, I think that those are questions that
have to be addressed.
DR.
GOLDSMITH: Do you have any more
information about host factors, besides age?
DR.
DENISON: Well, there are other issues
related to disease. There is some
relationship for diseases like, for example, diabetes to hepatitis B surface
antigen positivity. There haven't been
enough patients with HIV yet to know what the relationship is to
immunocompromise or what the basis of lymphopenia is. But age is clearly the issue.
I just passed the age that moved me into the higher risk category so I
am concerned about that.
DR.
FALLAT: You mentioned a lot of animal
viremias or virus infections. You have
been studying it for 18 years. Is there
any data that any of these other viruses could vertically affect humans, and
why did this one affect humans?
DR.
DENISON: I have had a slide I have
shown to try to justify my NIH grants for the last 15 years about risk for
trans-species adaptation because there have been animal and laboratory data. In fact, they have tried to immunize and the
cat vaccines really stink. They don't
have a high efficacy as a general rule.
So, people have shown that they can actually infect cats with other
coronaviruses and get them to infect and get antibodies, but it is not
protective. In the laboratory, nature
and vaccine trials trans-adaptation or trans-species infections have been
demonstrated.
There
are some questions that some human coronaviruses may have caused a recent new
disease in pigs, called porcine enteric diarrhea virus, PEDV, that looks more
similar to a human virus. So, it may go
in both directions. So, the biologic
barriers probably aren't that high for movement into humans. There are probably a lot of other barriers
in terms of adaptation and transmission of disease and maintenance in
populations. I think we are seeing some
of that play out with SARS. So we, as a
community, probably weren't so shocked that this happened--amazed but not so
shocked based on what is already known about these viruses in animals and in
the laboratory.
DR.
STRONG: I was interested in the immune
response to these viruses. This is
primarily a cellular response, and is there any role for passive immunoglobulin
therapy?
DR.
DENISON: The issue of passive
immunoglobulin therapy--gosh, I wish I had lots of time--depends on the
model. If you give passive
immunoglobulin to the cats and then infect them, they get much worse
disease. So, you get actually
immune-mediated enhancement of disease, probably uptake into macrophages and
monocytes. There may be some role in
other animals for that. The correlates
of protection are not that well defined.
Cell-mediated immunity appears to be critical for clearance and recovery
and usually there is also an immunopathogenic determinant. But antibodies alone in the animal models so
far have not been protective. So, it
may lessen possibly but it could also enhance.
So, that is a concern and that is why we need to look quickly at whether
this can replicate in macrophages or monocytes and what happens in the presence
of antibody. Even if antibody looks
like it is neutralizing in tissue culture in those environments, is it
neutralizing in an animal model? That
is a question that has to be addressed.
DR.
STRONG: The immunoglobulin not being
protective would support an FC-mediated macrophage uptake which would enhance
the infection. So, it sounds like the
cellular immune response is probably Class I mediated. Is there any evidence for that?
DR.
DENISON: Yes, cell-mediated immunity
clearly is important for recovery in the mouse model. That is the main one that has been looked at. In the animal models IgA is protective in
young animals so maternally transferred by IgA is protective--lactogenic
immunity is protective in young animals.
So, immunize the mother at late times, get good GI immunization and they
pass on IgA antibodies in the milk.
That is the goal actually of that.
Cell-mediated immunity has only been looked at in the animal models, a
pathogenesis model, not as a protection model.
DR.
NAKHASI: Mark, thanks very much for the
nice presentation. You mentioned that
some of these viruses, the feline or other animal viruses, remain in the
tissues. The question is how long they
remain, and is it a possibility that coronavirus, even though it may not be
viremic through blood, can remain after an acute phase and go into tissues,
organ transplantation and other things?
Will that be a problem?
DR.
DENISON: Yes, I don't want to overstate
the data that is available because things have been studied for
pathogenesis. Disease, pathogenesis and
vaccine have sort of all been separated into different models depending on the
needs. The murine model is the best one
for the issue of persistence and disease.
It depends on the strain, the animal, their age, etc. There is both a continuous infection model
of encephalitis in mice where you can continue to get virus isolated, and there
is also an immune model where you don't get virus but you can get RNA by PCR
suggesting increased replication but you can't recover virus anymore and you
get progressive immunopathologic disease.
So, there are certainly suggestions of continuous replication. There is no model or no basis for the issue
of transplantation or movement into materials and then re-initiation of
infection in another host, as far as I know.
I can certainly recommend to you people who could address those issues
very clearly, and I would be happy to do so.
DR.
NELSON: Dr. Andonov?
SARS:
Canadian Studies (Epidemiology and Virology)
DR.
ANDONOV: Thank you, Dr. Nelson. This presentation has been assembled on very
short notice and I didn't have enough time to send it to Alan and to Dr.
Smallwood but I have it here so if there is a copier copies could be made.
[Slide]
In
my discussion with Alan we decided that I will briefly update you on the
Toronto SARS outbreak and then share with you our laboratory data that we have
accumulated so far, and as well address some issues that might have indirect or
direct impact on blood safety, such as viremia, whatever we know about it, as
well as asymptomatic or subclinical state of infection and some animal
experiments that we have conducted in our place.
[Slide]
On
February 23, a couple arrived from Hong Kong, from Chinese origin, and later
on, on March 2, a 78-year old woman had respiratory disease with fever, cough
and later progressed to dyspnea. She
infected five of her family members. On
March 5 she collapsed at home. Her son
tried to resuscitate her but she succumbed to infection. Several days later her son ended up in the emergency
ward of one of the community hospitals in Toronto and started a chain of events
that resulted in the largest outbreak of SARS outside of Asia.
Currently,
we have 259 probable cases. A lot of
them are already confirmed by lab testing in Ontario and 133 suspect cases; 34
deaths.
[Slide]
The
outbreak in Toronto has been publicized relatively well. There are three published reports. The last one was just published last week, I
believe, in the MMWR issue on Friday.
What
I would like to point out here is some of the difficulties that we were facing
in Toronto, especially with something that we dubbed SARS-2, as it is shown
here, the second phase of the SARS outbreak.
By April 20 there were no more new cases in Toronto. At the end of April, April 30th, WHO lifted
the travel ban on Toronto.
Later,
in early May and in mid-May the health officials decided to suspend the
expanded precautionary measures that were in place. By May 14, WHO stated that for the last 20 days there was no
transmission in Toronto so it took it off the list of places where SARS is
occurring. Then a disaster happened two
days later. There was a cluster in a
rehabilitation hospital.
Retrospectively, the investigation showed that actually the outbreak was
still lingering.
Just
to give you an example of how difficult it is to actually try to say that, yes,
there are no cases, there were only two cases, we believe, that actually were
linked with the first outbreak and transmitted infection later in the
rehabilitation hospital.
One
of these two was a 96-year old man who was hospitalized on March 22 with a
broken pelvis. On April 2 he had
respiratory disease, mild respiratory disease, then developed pneumonia but he
responded very well to antimicrobial treatment and, because he had not been
exposed to any of the contacts or to any of the people that had been infected
with SARS, he was not considered a probable or even a suspect case. He improved. Then, on April 19 the same patient developed a second bout of
respiratory disease, fever, diarrhea.
He was tested again. All the lab
findings were negative and there was Clostridium difficile in his
stool. So, again, he was dismissed as a
case that was not SARS.
Now
we know that actually it was a SARS case and that kind of patient-to-patient,
patient-to-visitor transmission occurred in that period, between late April and
the beginning of May in that rehabilitation hospital. As a result of that, the latest big cluster was among the
healthcare personnel.
[Slide]
In
the second SARS outbreak, as we call it, more than 90 percent of all the cases
resulted directly from exposure in that rehabilitation hospital. There were only a few household members that
had secondary infections from healthcare personnel.
[Slide]
This
is an interesting comparison of what might happen or what might not happen with
SARS and imported cases. At the same
time that Toronto had its first importation of SARS from Hong Kong, the Chinese
couple arrived in Vancouver and the husband immediately went to the emergency
ward. He was sick with severe
respiratory disease.
Now,
there was really an astute physician in the emergency ward and he thought that
this was an influenza H-5 case and essentially he sent the patient immediately
into isolation and requested testing for H. influenzae H-5. As it turned out, it was not influenza H-5;
it was SARS. But the most important
thing was that, unlike Toronto, that patient was immediately isolated and there
was no big outbreak in Vancouver.
The
wife of that first patient, which is also an interesting case, was never
isolated. I am not sure if she was even
under quarantine because when she came to Canada with her husband she didn't
have any symptoms. She was not sick and
she never developed any significant symptoms.
She recalls, however, that she had a mild febrile episode while visiting
Hong Kong. Later her samples were
tested and were positive both by PCR and serology for SARS coronavirus. So, apparently she was not infectious or
maybe was not able to transmit the infection to some of her close relatives.
Another
interesting case that underscores the difficulty of proper diagnostics of SARS
cases is the North Carolina man who got infected while visiting his father in a
Toronto hospital. This is a very
interesting case again, and WHO blamed Canada for not properly doing
surveillance on that case, which may or may not be exactly the case.
What
happened is that he visited his father who was with another patient in a
room. Actually, at the time of the
visit both patients were okay. There
was no respiratory illness. When the
North Carolina man went back, approximately at the same time not his father but
the other patient got sick. So, what
the epidemiological investigation of our colleagues in Toronto uncovered was
that the wife of the second patient was sick and probably she infected her
husband.
The
interesting part is that while the wife was visiting her husband they never
met, the North Carolina man and the wife who eventually infected him never met
in the same room. They were never in
the same place. The other interesting
thing is that his father, who was in the same room all the time, never got
infected. So, in a way it is a little
bit of a mystery. I guess all big
mysteries in life have a simple explanation but right now we don't have it.
[Slide]
What
do we know about the incubation period?
Based on work on 44 patients, it is about between three and ten days,
based on the prodrome with headache, malaise or myalgia. Based on fever, it is a little bit longer,
seven days median; based on diarrhea, eight days; and coughing and dyspnea,
nine days.
Health
Canada did its own investigation because all these cases had probably multiple
exposures. So, what we did, we
investigated 42 patients with a single point exposure, and the median here was
4.2 days and 95 percent of all these 42 patients fell within that range of 4.2
days--sorry, of ten days total. But
there were about five percent outliers.
That is a statistical estimation.
Now,
we had three cases. One is confirmed
and three are under investigation. One
case was a medical resident who was quarantined for ten days. On day 11 he came to the hospital and worked
for 24 hours delivering babies. On the
next day he had fever and was sick. So,
we have more or less about 12 days definitely in that particular case of an
incubation period. We have three more
cases where the incubation period is between 11 and 15 days, but these are
still being investigated.
[Slide]
This
is the history of how we got involved.
Early in March we were notified about these cases in Toronto and started
receiving samples, and we are still receiving samples, more than 10,000 samples
and most of them probably have nothing to do with SARS.
[Slide]
Our
initial results discovered metapneumovirus in five of the eight cases of the
initial cluster. So, we thought that
might be one of the causes but later Hong Kong and CDC reported isolates in
coronavirus. Later we were able to
isolate coronavirus within four days after initial culture.
[Slide]
This
is apparently not a very good slide but here you can see the immuno-gold by
electron microscopy of coronavirus with a relatively early serum from a
patient. That is not exactly
convalescent but still it reacts with the virus-like particles.
[Slide]
This
may be a little better picture of the immuno-gold particles.
[Slide]
In
the early stages of our laboratory testing and investigation we stumbled across
a category that we named "neither."
You know the so-called "probable" and "suspect" case
and their definitions. The
"neither" group had laboratory evidence of coronavirus infection but
the were never included in these suspect or probable groups, partly because we
didn't at that time have enough data and I guess they are moving up the scale
to suspect or getting discarded. So, 14
percent of our initial cases that were not probable or suspect had laboratory
evidence of SARS infection.
[Slide]
Just
to give you an example of some of these cases, there are seven symptomatic
cases, one of which was coronavirus positive by PCR. There were cases with fever but not respiratory symptoms or the
other way around, respiratory symptoms, no fever, positive by PCR, some of
them. There was no difference whether
they were exposed or whether they were not exposed, at least to our knowledge,
to infected people.
So,
at this time it was really puzzling.
That was more or less a month ago.
It was really puzzling what was going on, and do we really have
something which is more than the typical SARS outbreak or do we have infection
going on in the community?
[Slide]
The
picture gets clearer now that we have more convalescent samples. I think this is important data in terms of
lab diagnostics for SARS coronavirus.
As you see, out of the total number of 144 patients with probable SARS,
62 percent are positive for coronavirus.
This includes serology and PCR of the original samples or PCR or the
cultured samples from these patients.
If you look only at the PCR-positive results, it is 44 percent. So, PCR is not the best diagnostic test,
especially in the early stages of the disease.
Now,
out of these 144, for 43 cases we have the complete set of samples which means
the original first samples, late in the middle of the disease and convalescent
samples. So, here the correlation gets
much better and 41 out of these 43 probable cases, or 95 percent, have evidence
of SARS corona. So, here you can say
that the diagnostic really works. Only
seroconversion, no PCR positivity was discovered in 35 percent of the patients
and only PCR in 60 percent of that group with complete sets of samples. Similar, though not exactly the same, was
the picture in the suspect cases.
Overall, 39 against 62 and then 49 percent positivity in PCR against 60
percent in the probable group, and again very high serology.
I
think that serological testing may be one of the most important, currently at
least. What we are lacking right now is
a good IgM serology test to be able to find out early in the infection. Most of these are convalescent results.
Going
again to the "neither" group, the results are really very preliminary
but what I can say is that when I left the number was 112 people that we think
are in that group. Today I have heard
that the number has risen up close to 200.
In 14 percent of these we have evidence of infection and they are not
suspect or probable.
So,
we are starting an investigation in 92 of these persons and, hopefully, we will
have all the follow-up serum samples to be able to say exactly what is going on
with that "neither" group. So
far we have only six people with full sets of samples, and these are all
serology positive and two of these are PCR positive. As I said, they fall outside the category of typical suspect and
probable cases.
[Slide]
I
just want to share some of the data that we have obtained so far. What I can say is that the viral load in the
samples that we received is quite low.
Maybe that is why the PCR is failing to detect, in at least 50 percent
of the acute stage of cases, the nucleic acid of SARS corona. In some of these the NP, the nasopharyngeal
swabs in a few patients--I don't know if you can dub them super-spreaders or
not but the viral load is extremely high.
The bronchoalveolar lavage is a very good source for PCR testing, again
with very high viral loads. The
oropharyngeal samples, again, had extremely low viral load. Some of the stool samples have a relatively
high viral load but, again, most of them are low.
Then,
coming to the EDTA blood, at the beginning we tested serum samples and whole
EDTA blood and we found that in EDTA blood we get positive nested PCR. So far, out of 1,900 samples of whole blood
we have 67 positive results. Of
these--not of all of them; we have the real-time PCR recently established--of
these, there are four samples here and, again, the viral load is extremely
low. Our limit of detection is 0.05,
0.025 plaque-forming units. I don't
know how that relates to copy number.
But as you can see, in two of them we have about 0.5; in the other ones
3 plaque-forming units concentration, and in another two who are actually
borderline negative, I would say, 0.01 and 0.02 but these two, when we tested
them in nested PCR were confirmed positive.
So,
the bottom line is, yes, apparently you can detect the virus but if there is
any viremia it is very short because we have never been able to discover a
patient where we have two consecutive samples of whole blood positive. Usually that was in the beginning, first
stages of the illness.
[Slide]
We
were concerned because in some of the samples we were receiving, let's say,
there was a difference of ten days between day of collection and when they
arrived in our lab so we were concerned how long the virus can be preserved in
samples like that, and what we have found out essentially is that even at 37
degrees cell culture virus is pretty stable in terms of PCR detection and there
is no problem detecting it on day ten; maybe less than one log reduction.
[Slide]
Dr.
Denison has already shown a similar slide about the stability of the
virus. What is interesting here is that
with cultured virus without any preservant the reduction of titer is
negligent. So, the virus can survive on
surfaces pretty well.
[Slide]
The
initial experiments that we have done on animals included mice, newborn mice,
rabbits and guinea pigs and they did not result in any illness in these
animals.
[Slide]
At
approximately the same time we started experiments with pigs and chickens. They were all inoculated at the same time
intranasally, intravenously, ocularly and orally with approximately two million
plaque-forming units.
[Slide]
The
result of that animal experiment is that we were able to find evidence of the
virus in the animals by PCR. We were
never able to isolate the virus from these animals. The viremia was very short, about two days.
[Slide]
The
next experiment that we designed was again in mice, and here the route of
inoculation was intraperitoneal, intranasal, and they were separated. We are still doing the virus isolation but
what was surprising was that the oral route in these animals seems to be quite
good.
[Slide]
The
animals were sacrificed one hour after peritoneal infection and then one day,
three, five, seven and nine days after infection. As you can see, after one hour infection you can see it in the
liver in two of two mice. In the
kidney, similar findings one day after infection; and spleen again
appears. On day three it is the same
more or less as on day two, and then if that is any kind of evidence of
replication, I am not sure, it fades off.
Now,
the oral route in this experiment at least was the best in terms of number of
animals. In all animals essentially
liver, kidney, lung and spleen were positive on day three post inoculation for
SARS corona. What is interesting from
this, and again it is preliminary data, is that we couldn't find it the blood
anywhere. Again, this is only real-time
PCR and our real-time PCR is five to ten times less sensitive than the
nested. So, we are going to continue to
test them by nested PCR probably next week or sometime this week. But so far only one sample I think here was
found positive by PCR.
The
interesting thing is that the spleen seems to be the organ where you can find
it quite often and it persists almost to the end of the experiment, day nine.
I
think I should stop here. Thank you.
DR.
NELSON: Thank you. Comments or questions? Jay?
DR.
EPSTEIN: Thank you, Dr. Andonov. I appreciate you doing this on short
notice. One question, in your studies
of contacts have you done any investigations to look for viremia in persons
either during an incubation period post exposure or during the convalescent
period? Essentially, I am asking
whether there is any study of viremia in an asymptomatically infected person.
DR.
ANDONOV: We have our PCR-positive
results only from NPs, from that group.
So far we have no evidence of EDTA whole blood being positive in these
patients.
DR.
EPSTEIN: But how many samples have been
studied in those same patients that had positive nasopharyngeal PCR?
DR.
ANDONOV: The ones that we have the
complete set of samples for--and the group is quite small; only six--all six
are seropositive and two of them are PCR positive. However, in that 112 patient group that I showed, there were 14
positive by PCR. In the so-called
"neither" group the numbers are changing quite often because some of
them eventually, as the epidemiologists do more proper work are able to shift
them to suspect, to the list of the suspect, but we still have a large group of
about 190 that we consider "neither" plus about 1,000 so-called
unclassified that we just don't have enough information for, epi or any other,
to be able to say that there is any relevance of asymptomatic or subclinical
SARS. We are hoping that these 92
cases, 92 people that have agreed to be followed, that they and their
relatives, family, relatives, will give us a better picture. Again, I would say we it mostly depend on
serology.
DR.
NELSON: Actually, the
"neither" group are people that are all asymptomatic but mostly they
have had contact with a case, or are they controls without any contact with a
case?
DR.
ANDONOV: Some of them are asymptomatic
and we don't know why we ended up with samples from asymptomatic people. But at the beginning of the outbreak
everybody was sending samples and we were testing which, at the end, turned out
to be quite interesting and will give us maybe some interesting data. I don't know why anyone would send an
asymptomatic sample from an asymptomatic person unless he feels that he may
have been in contact. So, what we are
trying to uncover is what the reason was for sending the asymptomatic
people. They were people, however, who
had mild respiratory illness and for some reason ended up in our place as
well. There were others who didn't have
any respiratory illness but just had fever and they ended up as well in our
database. In March, when we tested all
of them we just stumbled on that, that there are positive PCR findings on
these. In some of these, when we
collected serum samples later, there was seroconversion. So, there definitely is some sort of
infection.
DR.
NELSON: Is it known that the SARS
virus, coronavirus--that PCR and serology does not cross-react with the U2
human coronaviruses that were present before SARS?
DR.
ANDONOV: The data that I know is that
in CDC they have looked into that and they have not found in ELISA
cross-reactivity. Cross-reactivity in
histology, yes, they have found and it is published. Not in ELISA so I think that the ELISA results are accurate. The PCR cross-reactivity--definitely there
is no cross-reactivity in PCR. So, PCR
from that point of view is very good.
The only problem with PCR that we are a little bit concerned with right
now is that we are testing samples with nested PCR. As you all know, even in the best places contamination happens,
especially when you have a huge number of samples to test and there is huge
pressure to get faster results. So, I
would say that in a month or two when we are able to collect some of the sera
from people who have tested PCR positive, if they seroconvert I would say this
would be the ultimate proof whether PCR was specific but we have to wait for
that.
DR.
NELSON: Thank you. Now Alan.
FDA Current Thinking
DR.
WILLIAMS: I would also like to extend
my thanks to Dr. Andonov and Dr. Denison for their very interesting
presentations, both done on relatively short notice.
[Slide]
What
I would like to do is end this session by discussing some of the precautionary
measures taken by FDA in response to the emerging SARS epidemic, specifically
the guidance document which was published in April of this year, entitled,
recommendations for the assessment of donor suitability and blood product
safety in cases of suspected severe acute respiratory syndrome, SARS, or
exposure to SARS. Following that, I
would like to highlight some of the common questions and answers that have come
into our office with respect to this guidance document, in addition to some
comments to the docket.
[Slide]
I
want to stress that, in fact, almost on a daily basis there are ongoing
inter-agency and international discussions reviewing emerging scientific data
about this epidemiology of this epidemic, the virology and natural history,
particularly in terms of factors that impact blood supply. So, there is tremendous effort going on to
basically stay current with developments as they occur and much of the
information, obviously, that you have heard already this morning is emerging
and not yet published.
[Slide]
Now,
I think this is an example where FDA recommendations with respect to donor
eligibility have interacted perhaps more than ever before with the emerging
epidemiology that has been put onto the CDC website. In fact, we have a dynamic reference to the SARS case definition
that CDC has on its site. The site is
referenced in the guidance document and for those who don't have web access,
there is also access by telephone, and the hours for that access are underlined
in the document itself.
[Slide]
I
think in many of the situations that we encounter the first protection is that,
in fact, donor screening measures already in place provide a healthy
donor. So, an individual who has
symptomatic infection would not meet the criteria that are currently in place
to define a healthy donor. Generally,
what we are most concerned about is an asymptomatic individual who would appear
healthy but still be capable of transmitting infection. So, with respect to SARS, the guidance
document specifically recommends questions to be asked of individuals to
capture certain information. For
wording in the guidance document at donor interview, we recommend that you ask
orally or in writing potential donors about--and the first area of inquiry is a
history of SARS, suspected SARS or treatment for SARS within the previous 28
days.
For
the first time in a guidance document, instead of putting wording for a
question into the guidance directly, we used the wording for example, in the
past 28 days have you been ill with SARS or suspected SARS? The intent of this was not to give blood
centers the option to develop their own questions, we have a lot of different
questions being used by blood collection establishments, but more to give
freedom to groups, like the uniform donor history questionnaire task force, to
work with this model question, do cognitive testing and build a question that
would then be relevant to put into a standardized form. So, that is the explanation for this
nomenclature and you will see this in the subsequent questions as well.
[Slide]
The
second question, the area you wish to capture information about is close
contact within the previous 14 days with persons with SARS or suspected SARS
and, again, there is an example question closely allied with that information.
[Slide]
An
additional question, travel to or residence in areas affected by SARS within
the previous 14 days and, again, with reference to the CDC website which
dynamically lists those countries. In
this situation, because there are travel questions currently asked, and have
been for some time, many blood centers have gone to using capture questions,
something as simple as asking a donor have you been out of the United States in
the past three years. In that way, as
many as half of the donors would say no and they don't have to go through the
subsequent questions. So, since that is
common and to the extent that that capture question would meet and identify
donors who would be potentially in a SARS-affected area, it would be obviously
appropriate to continue within that blood center to use that capture
question. If there isn't a capture
question in place, then we again give an example of a way to uniquely ask that
information.
[Slide]
The
recommended deferral actions related to these criteria for history of
SARS--there is recommended deferral for at least 28 days after complete symptom
resolution and the cessation of any treatment.
Some of the rationale for the 28-day period is recognition of the fact
that virus can be shed for a prolonged period of time. Information known at that time captured the
length of period that was recognized, and there have been some isolated
instances of longer fecal shedding. I
think 43 days is the longest period at this point but, again, those are not
fully worked out and accepted as potentially having fecal shedding of virus for
that length of period and currently FDA uses 28 days as a period.
History
of contact with persons with SARS or suspected SARS, deferral is for a period
of at least 14 days after last exposure.
The 14 days is based on the estimated three to ten-day range of
incubation periods with some margin.
Similarly for travel of residence, deferral for 14 days after arrival
back in the United States.
[Slide]
In
addition, it is recommended that donors be encouraged to report post donation
any evidence that they, in fact, had a SARS illness within the 28-day period
prior to donation; had any known exposure within 14 days prior to donation; or
a SARS illness within 14 days after donation.
If this information is then reported back to the blood establishment,
there is a recommendation for prompt product retrieval and quarantine, with the
exception of pooled plasma given that current fractionation procedures and
viral inactivation would be presumed to inactivate a SARS-like agent.
[Slide]
Some
of the questions and comments, and there were a fair number of questions that
came in with respect to this guidance document--the general categories were the
rationale for the facilities; questions about implementation of the procedures;
issues related to the burden of donor screening modifications and the rapid
time frame in which they were both introduced as recommendations and
recommended for implementation; and mechanisms for implementation in the
context of this very large and very effective program to build a
standardization questionnaire. I am
going to touch on each of these because I think it is relevant; there has been
a lot of interaction in these areas.
[Slide]
Specific
to the scientific rationale and, remember this occurred in early April for the
most part, I think some of the key scientific observations used as a basis for
the recommendations do hold and, obviously, we are reviewing this on a regular
basis. But there was limited PCR evidence
of SARS coronavirus in the blood of symptomatic SARS cases and reasonable
question as to whether there existed a potential for viremia in a symptomatic
infection certainly could not be ruled out at that time and I think can't be
ruled out at this time.
In
addition, there are not alternative preventive measures readily available to
prevent an asymptomatic donor from donating a unit of blood when they might be
viremic. One measure that was
considered and discussed extensively was with you could get at precautionary
measures from another direction, i.e., since the CDC hands out donor cards to
individuals returning from SARS-affected areas whether this travel
questionnaire could contain a contraindication for blood, tissue or related
donation.
For
various reasons, including the amount of space available, the need to keep such
information current, and so forth, CDC made the determination that it was not
appropriate to include a contraindication for donation on that card and most
likely, anyway, it would be felt that the donor would need to be qualified on
the day of donation and that really is the most direct means of preventing
inappropriate donation by an exposed individual.
[Slide]
It
was recognized at that time that SARS was spreading rapidly worldwide and the
United States certainly has has a SARS experience but I think the general
consensus is it could have been a lot worse.
Based on the Canadian experience and others, all SARS under care here
had aggressive infection control measures implemented by their healthcare
personnel. The availability of this
knowledge and a certain amount of luck I think prevented a much more extensive
SARS epidemic in the United States.
This knowledge was fortunately in place at the right time. This is not a direct quote from Dr. Fauci's
grand rounds presentation yesterday but it is essentially the conclusion that
was made, that the United States could have had a much worse outbreak.
Finally,
in any precautionary measures, the perceived value of that measure in relation
to the cost of implementation in terms of donor loss and burden on ultimately
manufacturing a product is going to differ among stakeholders and that calls
for healthy debate. However, this
doesn't negate the fact that, particularly in today's world, we really need to
have a rapid response capability to protect the blood supply. Be it a donor questionnaire or test
implementation, we need to keep in mind rapid implementation.
[Slide]
A
couple of the questions that came in for increased standardization of the donor
form screening asked can we, in fact, extend the deferral period for SARS to
harmonize with some of the other deferrals that are in place. The answer to that is yes, certainly any
donor eligibility action that is more conservative or more constrictive than
FDA recommendations is acceptable.
A
concept of immediate implementation of the guidance document--the face page of
the document says, when it is issued, for immediate implementation. That is the document as a whole. Then, within the guidance document itself it
generally gives a time period for implementation of those individual
recommendations. Unfortunately, both
terms are called implementation so there is some confusion but, in fact, the
time period specified by the document is when those recommendations should be
put into place.
A
question about application to autologous donors, in fact, the regulations do
not address much eligibility requirements with relation to autologous
donors. I believe it is only hematocrit
and hemoglobin. So, in terms of
applying donor suitability criteria, this is an area of medical discretion for
SARS and most other donor screening.
[Slide]
In
reference to the CDC website information, they use the term "last date of
illness onset." In the chart
included on that case definition slide it is actually based on the travel alert
status of an individual country plus ten days.
So, you may have read in the news recently that the only country still
on travel advisory status is specifically Beijing, China. A travel advisory in CDC terms means that
there is a precaution against travel and non-essential travel should be either
curtailed or considered very carefully.
A travel alert, on the other hand, simply means there is an ongoing
potential threat and one should take measures to reduce exposure to that threat.
As
of last night, in fact, the Chinese mainland is continuing on alert, with
Beijing specifically being under travel advisory. Hong Kong also ongoing alert.
Hanoi was removed from that list.
The ten days after the alert was lifted was May 25. Singapore similarly was removed June 14;
Toronto is ongoing and Taiwan is ongoing.
This
does at times differ somewhat from the WHO affected areas list and we are
specifically referencing the CDC list in our guidance document.
[Slide]
Now,
there has also been discussion of the fact that the SARS guidance document and,
in fact, several other recent guidance documents, the ones related to anthrax,
vaccinia immunization and West Nile, are all issued as final guidance
documents. There is a GGP, good
guidance practice, regulation that, in fact, requires FDA, when public health
is not potentially compromised, to put guidance documents out for draft and
consider those comments to that draft in issuing final guidance. However, in situations like SARS there is
language in the guidance that issued in final form, "agency has determined
that seeking comments from the public prior to implementation is not
appropriate since SARS may pose immediate safety risks to the blood
supply," and similar language is in these other documents.
I
think it is important to keep in mind that guidance documents can be the
subject of comments to the docket at any time, and these comments are really
distributed and taken quite seriously.
So, not having a guidance document available in draft certainly does not
rule out the opportunity for commenting.
There
was a lot of comment from the field that rapid implementation, not only of
donor questions but everything that is done in a blood center these days, takes
training and takes SOP development. It
takes computer software modification in some cases and in a GMP environment
that is a handful to do in a short order.
That is certainly recognized but, again, I would state that mechanisms
need to be defined to allow us to respond rapidly to a threat. You know, I think that is something that
really has to underlie some of our considerations in this area.
[Slide]
Finally,
this committee has had several discussions about the evolution of the
standardization questionnaire through the uniform donor history task
force. A standardization questionnaire
is almost in final approval stages and available. I think the emergence of these new questions through the recent
guidance documents has kind of raised the specter of, okay, we have the final
document, how do we handle new questions, particularly when they need to be
implemented rapidly? So, we have tried
through these guidance documents to develop mechanisms which would allow the
questions to be used on an interim basis for a limited period of time so that
experience can be gained with the questions and cognitive testing, or other
relevant testing, can be done before they are integrated into a final
standardization questionnaire.
The
documents will use the "for example" questions and there was actually
a comment from industry, well, can we use an interim form and document the
response to the interim handout and reference that on the actual formal donor
screening questionnaire? That was
actually approved by FDA and referenced in the Q&A which was put on the FDA
website in reference to the SARS guidance.
We actually built on that with the West Nile guidance so that it is
permissible to use an interim information sheet to put a question rapidly into
place and put it into the questionnaire ultimately in a rational manner.
I
think the bottom line here is FDA does strongly support the continuing uniform
donor history questionnaire development process. The questions that have recently been recommended in the guidance
are being subjected to cognitive testing early this summer, again through
collaboration with the Center for Health Statistics that did the original
work. FDA is funding this work and we
are actively collaborating with the task force to keep this process going and
make the questionnaire a rational, integrated whole, allowing that sometimes
there do have to be modifications.
Thank you very much.
DR.
NELSON: Thanks. I am sure there are questions. Harvey?
DR.
KLEIN: I only have two questions. I will separate them. The first one is short. Do you know what Canada has done in terms of
the blood supply?
DR.
WILLIAMS: The earliest recommendation
from Health Canada was similar in terms of donor deferral but it specified a
deferral period for case exposure and travel of ten days. In fact, the industry Canadian blood service
has implemented a 14-day deferral voluntarily.
Canada has recently modified their deferral period in response to some
of the outlier cases that have been observed in Toronto. I don't recall exactly what that period
is. Thirty days?
DR.
ELSAADANY: Can I respond, please? I am Susie ElSaadany, Health Canada. I was really coming to ask you the same
question, why Health Canada modified the donor deferral period to 21 days is
based on the outliers of the incubation period and based on our statistical
analysis using different scenarios for what would be the incubation period
under what scenarios. We find that the
outlier can go out to 17 days with 95 percent confidence interval. Also, in China the highest incubation period
was 16 days, or the outlier was 16 days.
So, to be prudent we recommended 21 days, adding an extra few days based
on our experience with HIV when it was earlier discovered. So, it is 21 days.
DR.
NELSON: Harvey, you had another
question?
DR.
KLEIN: The second question that I had
related to the donor card and questions.
I am delighted to hear that these questions are being validated because
I think that is important. But the other
point is that the questionnaires have gotten so long, and with every new
emerging disease we have three or four more questions so that there is a real
issue as to whether donors either listen to what is being asked of them or
really answer these questions. When you
get three or four sheets of questions it becomes an issue.
Just
as an example, if one were to ask a question, as many donor centers do, have
you been under a physician's care in the past year, it is very unlikely that
anyone who has had SARS or West Nile virus or monkey pox, or a host of other
things, would not have been so you can use that as a generic screen without
having to ask questions about all of these which are, first of all, low
likelihood positive answers and, second, possibly no risk at all. Secondly, we already have a geographic
exclusion type of question and using that as a screen, as you pointed out, is
much more efficient than trying to add all of the various subtleties onto the
card.
So,
I really would encourage the FDA, as well as the other people who develop
questionnaires such as the AABB, to look at the entirety because anyone who
donates blood can tell you that there is a great suspicion that this process is
becoming so unwieldy as to defeat the intent of the screening card.
DR.
WILLIAMS: I think I agree and that
certainly is the sentiment of the task force that has been working on
this. I think the new document will
have increased use of capture questions that would make it a more efficient
process.
I
think one of the other problems is that typically it is not three or four
pages, blood centers try to keep it on a single page and the type gets
smaller. So, that has an additional
problem.
But
I think the concept is very much recognized and it is a goal of the task force
to try and make it as efficient as possible.
I think the other concept is that, hopefully, as the field begins moving
toward computer interactive screening programs a lot of this skip pattern and
capture questions and so forth could be built into a computer program, which
would also simplify things. There is
some of that work currently being done in blood centers but those are potential
areas.
DR.
NELSON: I think one of the real
problems with the SARS, in contradistinction to malaria, is if your plan lands
in Taipei on your way to Bangkok or somewhere else, you are supposed to be
excluded for 14 days based on getting off one plane and on another, whereas
that is not exclusion criteria for malaria.
It becomes very complicated. I
was just recently on a plane that landed several places in the Orient and in
some places between Tokyo and Bangkok the stewardesses had masks on and had
them for the passengers, and I didn't know whether they were suspect cases or
just worried. I suspect they were
worried. That, coupled with the fact
that the sites keep going from one category to another, for a blood bank to
figure out, you know, what is 14 days--from what?--May 14 or May 16? It is pretty unwieldy but I guess a guy that
travels a lot through the Orient is probably not a blood donor for a month
after he finishes that, pretty much.
DR.
ALLEN: I don't want to belabor the
point but I share many of the concerns that Harvey does. I will just ask specifically if you ask
donors about the history of SARS, suspected SARS, I wonder how many donors
really are going to have any idea if what you are trying to pick up something
where they haven't yet been sick enough to go to a physician. But even many physicians may not suspect
that diagnosis. I wonder if you perhaps
wouldn't do better with a broader capture question, you know, in the last two
weeks have you had history of fever with diarrhea or cough or other respiratory
symptoms, if that may not be more effective than trying to ask them about SARS
and other things about which they may have very little information, other than
that they have heard it from the media.
The
other question, you talked about the size of the type and so on, the counter
point for that for blood collection centers that ask the questions orally is
that the screeners speak more rapidly and those of us who have any degree of
hearing impairment have great difficulty following what is actually being said.
DR.
GOLDSMITH: On the post donation
information and look-back pooled plasma is exempt from product retrieval and
quarantine. Do you have information
about the impact of cone fractionation, alcohol and sterilization regarding
SARS in the end products?
DR.
WILLIAMS: Someone else might want to
address this but I will take a shot. I
think in terms of other RNA envelope viruses there is good evidence that the
fractionation process, as well as the inactivation procedures, have high degree
of inactivation. I am not aware of work
specific to SARS.
DR.
GOLDSMITH: Is that going to be
forthcoming?
DR.
EPSTEIN: Well, we did look at the
literature on inactivation of coronavirus and they do not appear to be stable
viruses under the conditions common in fractionation, particularly with respect
to heat, low pH. Of course, solvent
detergent mixtures inactivate all envelope viruses. So, we didn't believe that there was evidence or, put it this
way, high risk but it is a subject that could be explored further and will be
if there proves to be viremia.
DR.
STRONG: I have already been pointed out
as having a major conflict of interest in these particular areas since I
represent a blood center, but I can only amplify what has been stated before
concerning the complexities of adding these questions. We are already dealing with a number of
inconsistencies with the 7-day, 14-day, 28-day interpretations and these will
only make it worse. For example, we
have a question now about fever and headache 7 days prior to donation. If a donor comes in and has had a fever and
headache a couple of days prior to that, they are okay to donate but if they
call us two days after donation with fever and headache we have to quarantine
and pull products for 28 days prior to donation. These are inconsistencies that are very difficult to track and
you are dealing with blood collection services who aren't terribly educated
about the various infectious disease issues.
It really is beginning to come to a point where we are defeating the
purpose of safety and it really needs I think an overall review of how we are
approaching this. Because we keep
adding new diseases, it is only going to get worse.
DR.
ELSAADANY: Can I ask a question? This is Susie ElSaadany again from Health
Canada. My question to you, Alan, is
have you done a risk reduction analysis based on the 14 days, and how did you
manage to deal with the tolerance level of blood loss when you do a donor
deferral policy?
DR.
WILLIAMS: A 14-day period was basically
chosen based on knowledge that the majority--well, certainly all the cases
recognized at the time the policy was being developed were in the 3-10 day
period and allowing several days for a margin to reach a 2-week period.
In
terms of donor loss, the estimates were derived based on some information
received from CDC on the number of travelers who had, in fact, been approached
by CDC with travel cards and where they had been located, and then calculations
were made based on the likelihood that those individuals might have donated
blood in the impacted period of time subsequent to that travel. Based on that, the estimate was made that
the loss would be between 0.1 and 0.4 percent.
We usually get feedback in terms of actual loss in terms of deferrals
and we have not heard evidence that it has been anything higher than that in
any particular sites, acknowledging that most donor loss probably occurs
probably before the donor comes to the donation site. But the estimates were
between 0.1 and 0.4 percent.
DR.
EPSTEIN: I just want to add another
comment about the deferral period post exposure in relation to the data
available on the incubation period. At
the time that we issued the guidance, as Alan stated, we had learned both from
the data in China and in Canada that the average incubation period was 7-10
days. We were aware, however, of an
outlier of 11 days in Canada and a report out to 16 days in China. However, most of those reports were time to
fever, not time to first symptoms and the available data also indicated that a
symptom prodrome did antecede fever.
So, we felt reasonably comfortable that the 14-day period to first
symptom likely would encompass the true incubation period. I think that remains the case. Even the current analysis in Canada is
largely based on time to fever.
MR.
CAVANAUGH: Dave Cavanaugh, with the
Committee of Ten Thousand. In the early
days before, say, April 1st, there was some discussion about is this going to
be an influenza-like pattern with a resurgence the following winter of a more
serious strain. Could you speak to the
current reading on that? Also, I hear
that WHO is now saying the virus is mutating.
Could you speak to those issues?
DR.
WILLIAMS: I guess I would basically be
reiterating some of the substance from Dr. Fauci's talk yesterday. In fact, the initial recognition in China
occurred in November or December and it was thought to be an atypical influenza
and there was concern that there was potential confluence between two strains,
one of which was easy to transmit but not as pathogenic and the second which
was harder to transmit but more pathogenic.
However, subsequent investigation showed that it was a different
clinical entity.
I
think in relation to influenza one of the differences is the necessity of the
large droplet spread, which is one of those luck factors in the spread of this
infection. As you have observed, most
of the secondary infections have been to healthcare workers in close contact
who are working with patients rather than individuals 20 ft, 30 ft away who may
have had airborne small droplet exposure.
I think it is reasonable to assume that the initial epidemic, as well as
potential for subsequent outbreaks, would be far worse if the airborne spread
was more effective for this agent, but it appears that large droplets are
necessary and that closer exposure is necessary as well.
What
hasn't perhaps been mentioned specifically is if there is an animal reservoir
human infection could potentially erupt again at any time.
DR.
NAKHASI: I just wanted to respond to
the mutation of the virus. I don't
think there is any evidence at this point that there is mutation occurring
because recently, last week, two Science papers which was published on
the sequence of various isolates showed that mutation is not happening.
DR.
NELSON: One last comment and then let's
take a break for 15 minutes. Yes?
DR.
ELSAADANY: Yes, I would just like to
comment about the time to fever versus time to symptoms. One of the symptoms is fever so really our
calculation was based on the onset data.
The onset data was not agreed upon and nobody agrees on what is the
onset date of SARS. It is still a
controversial issue, however, I don't understand time to fever versus time to
symptoms. Fever is one of the symptoms
of the disease, or one of the case definitions.
DR.
NELSON: Yes, okay. We are arguing about a few days and the
risk, as far as blood transfusion, I think is well defined at the moment
probably, nothing like with Nile virus I think. Let's take a 15-minute break.
[Brief
recess]
DR.
NELSON: We are going to continue the
discussion on SARS. There were two
people that wanted to testify in the open public hearing. First was Kay Gregory from the American
Association of Blood Banks.
Open Public Hearing
MS.
GREGORY: Thank you. The American Association of Blood Banks is a
professional society for over 8,000 individuals involved in blood banking and
transfusion medicine and represents approximately 2,000 institutional members
including blood collection centers, hospital-based blood banks and transfusion
services as they collect, process, distribute and transfuse blood and blood
components and hematopoietic stem cells.
Our
members are responsible for virtually all of the blood collected and more than
80 percent of the blood transfused in this country. For over 50 years, the AABB's highest priority has been to
maintain and enhance the safety and availability of the nation's blood supply.
On
April 17, 2003, the FDA suddenly issued its final guidance on SARS-related
blood deferrals requiring temporary deferrals for recent travel to
SARS-affected areas, contact with a person who had probable or suspected SARS
or illness due to SARS.
While
the AABB and other blood-banking organizations from the outset shared FDA's
concerns about the possibility of transmission of SARS through the blood
supply, the AABB is concerned about both the practicality of implementing the
final guidance and the process by which the guidance was issued.
The
FDA proposed addition of a minimum of three additional donor history questions,
which are complex and difficult to understand.
There was no effort to consult blood banks about donor comprehension and
understanding of these questions, nor was there an understanding of the
difficulty of adding new questions to donor history questionnaires within a
30-day implementation period.
As
a response to these concerns, the blood banking community quickly developed an
alternate proposal to present these questions using an information sheet. Fortunately, the FDA showed flexibility in
agreeing to permit this alternate method, but the time to devise the alternate
approach and secure FDA approval further strained the ability of blood banks to
implement the guidance within the prescribed 30 days.
The
FDA guidance advised that blood banks consult the CDC web site to obtain
updated information on SARS-affected areas and the case definition of SARS, and
to update their travel deferral accordingly.
However, the CDC web site is
very difficult to interpret. The
distinction between SARS and "probable" and "suspected"
SARS is confusing, as is the definition of a travel advisory and a travel
alert.
This
is further compounded by differences in CDC and WHO recommendations, all of
which are being discussed by the news media, leaving the general public and,
more specifically, blood donors extremely confused.
Further,
the instruction for each blood collection facility to monitor this web site on
a regular basis and make changes in procedures and information sheets each time
the information changes, demonstrates a major lack of understanding of blood
bank operations. Such a procedure is
very impractical.
Before
a change in procedure is implemented, the SOP must be rewritten and the staff
trained. In the case of donor
suitability, this involves training of large numbers of staff as well as
preparation of new donor history questionnaires and donor materials.
In
addition, the CDC has understandably posted changes to the web site to meet the
CDC needs, without appreciating the impact such changes would have on blood
collection, and without notifying the blood safety officer at the CDC.
For
example, due to rapidly changing conditions in Toronto, there have been three
updates to the CDC web page involving Toronto - first adding Toronto as a
SARS-affected area, then announcing a last date of illness onset of May 30,
2003--this was done on a Friday afternoon prior to the Memorial Day
weekend--only to be followed by changing the last date of illness back to
"ongoing" (based on a second SARS outbreak in Toronto), and this was
done on the Tuesday following the Memorial Day weekend.
While
we appreciate FDA's attempt to be flexible and create a mechanism for blood
centers to respond rapidly to changes in information, this is extremely
difficult for blood centers to implement and creates a system where policy is
likely to be misinterpreted and errors are very likely to occur. It puts the burden of interpretation on
individual blood establishments rather than on the FDA.
In
addition to our logistical concerns, the AABB also is concerned about the
process by which FDA interacted with the blood community prior to the issuance
of this guidance.
On
April 15, 2003, the AABB convened the first of several conference calls with
other blood banking organizations and invited the CDC and FDA to participate in
the discussions. At that time, the task
force requested that CDC include information about blood donation deferral on
the SARS information cards that were being distributed to travelers returning
from SARS-affected areas.
The
rationale for this request was that this would be a targeted, and therefore,
better way to reach affected individuals than requiring changes to donor history
questionnaires and asking questions of millions of potential blood donors
annually.
However,
when it was quickly obvious that this recommendation was not going to be
adopted, the blood banking community agreed that deferral of travelers
returning from a SARS-affected area should be implemented.
We
also discussed the possibility of deferring donors who might have had contact
with SARS, and concluded that such deferral was not indicated. During these task force discussions, we
specifically queried FDA about measures they might be planning, and were told
that they were unable to provide any information, but that our plan of action
would not be contrary to FDA thinking.
We
understand that FDA is constrained by the Administrative Procedures Act, but
their inability to hold discussions with the blood banking community is
certainly not in the best interests of patient and donor safety.
In
conclusion, the AABB is concerned about the safety of patients and donors. We recognize that new infectious agents require
policy decisions to be made, sometimes before all of the scientific information
is available.
The
blood banking community has demonstrated that it can be convened on a very
short notice and stands ready to interact with FDA as needed. We are happy to provide input and data, but,
in turn, ask that this information be given serious consideration and not just
ignored.
Early
interaction would permit devising recommendations that are practical and
possible to implement, and would avoid needless confusion. It would also avoid the need to submit
alternate procedures for FDA approval and thus permit blood banks to begin
planning for implementation in a timelier manner.
While
we appreciate the need to respond to a perceived threat to the blood supply,
the AABB requests development of a mutually satisfactory approach to improve
FDA recommendations, so that the most appropriate and effective interventions
can be established on behalf of patient safety and blood availability.
Finally,
on issues specific to SARS, we request that FDA and/or CDC initiate studies to
determine whether there is viremia during the asymptomatic period of SARS. This
information is vital in deciding whether these donor deferral criteria should
be continued.
Thank
you.
DR.
NELSON: Thank you.
Any
questions or comments? I am sure Jay
has a comment.
DR.
EPSTEIN: I think the question at hand
is whether the AABB has a better strategy to deal with rapidly changing
epidemiological information above and beyond the issue that FDA can't be selectively
influenced by a particular constituency.
MS.
GREGORY: Jay, I appreciate that, but
when you remember that we can convene a task force that represents the entire
blood banking community, and can do so very rapidly, it would be useful if we
could at least have some dialogue.
I
realize that you can't be influenced by one particular constituent, but
certainly I think we could do more in the way of communication. For example, I learned things from Alan's
presentation this morning that I really didn't realize before, and had he
communicated some of those a little earlier, perhaps some of our confusion and
misunderstanding could have been alleviated.
DR.
BIANCO: Celso Bianco, America's Blood
Centers.
I
want to support very much what Kay said, representing AABB and all of us, but
there is one point and probably a couple triggered by Dr. Epstein's
comment. I wish that if there are
restrictions from administrative law that prevent us from talking to each
other, and really coming to discussions that just help public health, that
there was, for instance, an emergency meeting of this committee where all
issues could be aired publicly, everybody could make public comments, and we
could have found a more balanced view.
The
other thing that I am searching for, and that's the only point that I don't
agree entirely with what Kay put in the statement, is the search for more data
in SARS.
I
think that like we heard earlier in white particulate matter, like we have now
the question in SARS, we are looking for endpoints, conclusions, and we don't
have endpoints in the mathematical sense of a point. We have end continuous because we are always searching for some
more data or some more data or somewhat I think that will bring us the
opportunity to say yes, this is a negative result, it's final, we are happy,
and we stop.
I
think that we have to have a little bit more energy and courage, and I would
like to encourage FDA to, for instance, in case of the SARS, that everything
seems to be under control at this point, that we could have a suspension of the
guidance for a period of time.
If
the epidemic comes back, as some people talk about in November, with the
winter, let's reinstate it, but it is not something that has to be permanently
made part of our lives.
The
white particulate matter, again, since it has been there for 50 years, yes, not
all safety questions have been answered, but it's not such a yelling thing that
we have there, that we cannot make a decision, let's stop that so-called
enhanced inspection that is not even part of guidance, let's continue those
studies, and if something different happens, let's go back and implement some
more rigid measures.
Sorry
if I said more than I should, but thank you very much, Dr. Nelson.
MS.
GREGORY: No, Celso, I would actually
agree with what you said. It is very
easy to jump into jump into doing things and then it seems like we are left
with forever doing them because we haven't thought out an endpoint strategy, so
we just keep on doing them for years and years, and I think that is one thing
we need to take a good, solid look at.
DR.
EPSTEIN: We do periodically revisit our
current policies. We do that as a
matter of routine practice. I think the
historic record will show that we have done this for numerous things, either
through advisory committee meetings or through workshops, the list is very
long.
We
have looked at our hemoglobin standard, we have looked at deferrals for history
of hepatitis, we have looked at the syphilis test, we have looked at the male
sex with male deferral, I mean the list goes on and on and on.
So,
I don't think it is true that the continuation of current standards is due to
lack of reflection. Generally, the
problem has been lack of data. That is
a problem, and I do accept the charge that was made earlier that we have to
re-examine the system as a whole, because despite good intentions, it is
becoming unwieldy and perhaps ineffective.
So,
we understand that, but the problem doesn't lie in having failed to re-examine
our recommendations and requirements, we do this periodically.
But
again I come back to the question of is there a better answer, because I
haven't heard one, and the problem is that when we are dealing with an urgent
situation, we don't really have the tools available for rapidly obtaining input
from all potentially interested parties.
It
is true that we can convene Blood Product Advisory Committee meetings ad hoc,
but the process for clearing the members, let alone clearing their calendars,
is not as straightforward as you might think.
You know, we do have requirements for posting notices in the Federal
Register, we have requirements for assuring that there is freedom from conflict
of interest for the subjects that will be discussed, et cetera.
We
may need better mechanisms, but we are doing the best with the tools we have.
DR.
NELSON: Celso.
DR.
BIANCO: Jay, I totally respect what you
said and understand the constraints, but we have to find a way, and even if
there is all these constraints in terms of this committee, maybe you have to
generate recommendations that are more flexible and that allow continued
discussion and modification as we acquire more knowledge.
I
think that the value of this committee is too big and this committee has to be
part of helping us make those decisions and giving us a forum to present our
points of view. So, actually, I would
ask if the committee would ask FDA, would make a recommendation to FDA that
they be more involved in those issues and that we search for mechanisms for
more flexible guidances that could vary as I know that there are legal
restrictions and all that, and I don't want to get entangled in that, more
flexible guidances and opportunities in a public forum for us to interact and
discuss.
When
a final guidance is published, yes, we can send comments to the docket,
however, the FDA, from the administrative point of view, has no time limits for
when to respond to those comments, differently from guidance studies, a draft
guidance, for instance. So, we need a
public forum.
Thank
you.
DR.
NELSON: Comments? Yes.
DR.
FITZPATRICK: I agree that the industry
needs a way to discuss with FDA in some forum when there is an immediate
perceived threat to the blood supply and how to deal with that in a reasonable
manner, but, Kay and Celso, I hear two conflicting things.
One
is provide us more flexibility, yet in the statement, when the FDA provided you
flexibility in how to word questions and monitor the CDC web site, and that
sort of thing, there was a complaint that there was too much flexibility, so
that there is kind of a conflicting statement there in that.
I
understand that it was problematic and difficult to deal with and that there
may be a better way to do it, but there is a balance here that we haven't
reached yet and maybe there should just be an open forum on that, how do you
suggest that FDA provide wording that allows you flexibility, but still gives
them regulatory authority because that is two very conflicting messages, and it
is very difficult to balance those two conflicting messages.
MS.
GREGORY: I think you are absolutely
right, and it wasn't the flexibility that we were objecting to, it was the fact
of the complexity of what we were being asked to interpret. So, I think there are other issues where
there could be more flexibility where it wouldn't be quite so difficult to
figure out what you were doing, and we definitely do appreciate the
flexibility.
One
of the things that frankly I personally did not understand until Alan's
presentation this morning was the purpose of the examples of the questions that
were given in the guidance, because frankly, we all interpreted that to mean
that any blood center would come up with whatever question you wanted to
because they were going to be really flexible, when, in effect, as he said this
morning, what they were really trying to do was you give us an example or that
the Donor History Task Force could take the question, work on it, and come back
maybe with a better wording or a better question.
But
once again, it wasn't clear to me and I don't think it was clear to any of us
who were reading the guidance. So, yes,
we do want flexibility, but, you know, when it is really complex, sometimes it
is better to have a little more guidance than just say, well, read the web site
and figure out what to do.
DR.
NELSON: I would be interested to find
out, Kay, how did the blood banks implement this and was it immediately
implemented or were there differences, or do you have any information on this,
because it is complex because, in part, it wasn't only, you know, have you had
SARS or been diagnosed, et cetera, but there is a 14-day deferral for having
traveled through, not being in, but traveled through an area that was on that
SARS list, and the dates kept changing.
I
tried to figure out whether I was in that category or not, and I guess I
wasn't, but I could have been. I just
wondered how, in fact, it was, do you have any information on how the blood
banks went about implementing this?
MS.
GREGORY: I don't have any specific data
to show you. I think there were lots of
different ways of doing it, and you are right, traveling through was one of the
things that was different from anything we had before.
In
trying to put all this together in 30 days, I suspect that there were many
different ways of doing it, and maybe Celso can explain the way it was done
using an information sheet in a number of blood centers.
DR.
BIANCO: We all worked very fast and the
best we could to try to find simpler ways of doing it, and one of them, that
Alan mentioned, was to have an information sheet that actually could be changed
from time to time.
But
I just want to touch on travel deferrals that you mentioned. That is probably one of the most difficult
areas that we have in medical history.
If we look at the post-donation information report that are submitted to
FDA, and are reported always, those are on top of the list, because like you
did, you went to donate blood, you remembered that you stopped at that airport,
but not that airport, and then you go home and you look at your passport or you
look at your ticket, and you see you changed and you call back the blood
center, and we recall the unit.
So,
I think that actually, it is one of the few areas where despite the
complexities, most of the time medical history works, and the fact of our donor
reports and recalls is a victory for the system, but the complexity is immense,
and the donor history questionnaire group, the AABB Task Force has actually
come to a very rational way of timelines, that is ordering the time and the
questions, and all that, so that if you remember from previous presentations,
to make it a little bit easier.
DR.
NELSON: I think overall, the public
health response to the SARS epidemic in total has been really remarkable. This is really a global pandemic, you know,
that occurred dramatically within a couple months, and everybody in the world
practically knows about it and have been pretty rational and effective, and the
communication on this has been amazing.
In
the airplane on the way to Asia, I was able to read all these stories about
people went through. It was really
remarkable.
DR.
ALLEN: I think certainly one of the
broader questions that this raises for the FDA and blood banking in general is
to spend time now reflecting on how exactly to do this. My personal feeling is that it's impractical
to expect, let's say, I would think even an organization such as the National
Red Cross or Blood Systems, Incorporated, headquarters to go on line even once
a week to get updates and then try to get that information out uniformly to all
the donor collection centers and the mobile units and everything, it is a
daunting process.
If
you try to push it further down the line than that, I suspect that you are
going to get more difficulty trying to apply it than not. So, I think that we need to look at how we
are going to handle this information.
Just
as importantly, however, is to look at what the time frame is for an area to be
designated. I mean it is absolutely
astounding that within weeks of the time that this disease was first reported
as an unusual occurrence, or if you go back to the earliest cases, perhaps
months, we had a putative agent, there were diagnostic tests available although
we haven't defined how good those diagnostic tests are, and we have already
heard information this morning that the antibody test data differs from the PCR
data, and so on, nonetheless, it has been remarkable.
However,
in a given area, if you have patients or people with onset of disease for a diagnosis
to be established, for that to get to the public health authorities, from the
hospitals to the public health authorities, and on then to the WHO authorities
who would finally post it, my guess is that we aren't talking about something
that happens within 48 or 72 hours of diagnosis.
So,
in actual fact, cases are occurring in a given area before the posting ever
occurs. It is never going to be a
perfect system, and I think we have to look at how we can best take the
information that's available, make it work within the system, and apply it on a
uniform basis. It is going to be a real
challenge.
DR.
NELSON: I just wonder, you know, one,
there is a movement both toward a standard donor questionnaire, it's a revision
of that, but there is also a movement toward as opposed to paper to a CASI or
computer-derived interview.
It
seems to me that to the extent that this becomes uniform in blood donor
collection facilities throughout the U.S., it conceivably could be easier to
make a quick modification. I mean you
could send electronically, you could alter a donor questionnaire and probably
electronically send it to 3,000 blood collection facilities within the
U.S. You might be able to change it
overnight.
It
may be that that is what we need, but my understanding is that the blood
collection facilities are at least moving in that direction and that there is
now more of an interest in that possibility.
MS.
GREGORY: I think you are right that
blood centers are going to start moving toward CASI or something like that, but
I would just remind you that even that won't allow us to change things
overnight because it has to be programmed, it has to be validated. We have to train our people, we have to
write our SOPs, so people know about it
So,
yes, it will make it a little easier, but we are still going to have some of
the same issues even with that.
DR.
NELSON: Once it is changed, you can
send it an awful lot of places quickly.
MS.
GREGORY: That is true, you can send it,
and that will help to be able to do it electronically, not having to do
everything on a piece of paper, so that part of it will be easier, but really
the major hold-up things are I think still probably going to be in play.
DR.
STRONG: Just to amplify that once
again, it often takes us several weeks to make a change of that magnitude,
because of the writing, reviewing SOPs, document review, boards,
implementation, training, et cetera.
This is not a logistically easy thing to accomplish.
DR.
NELSON: I have collected some data by
CASI in Thailand, and there you had to start, you know, you had the translation
in the middle and a back translation, and all this kind of stuff, and it took a
few months to get that really working.
But
I think as opposed to writing a whole document, adding a question or two, you
might be able to do it more quickly once the systems were in place. At least I am optimistic about that.
MS.
GREGORY: My colleagues from the Red
Cross just reminded me that we may also have the issue of if these computer
systems need to have 510(k) approval, any changes will have to go through that
process, as well.
DR.
NELSON: So, that gets back to the first
presentation today.
DR.
KLEIN: With all due respect, I think we
need to focus on the issue of what this process does, and not on the
technology. The donor history
questionnaire is a relatively crude screen.
It can be quite effective when you use the appropriate questions that
screen out high-risk individuals.
Adding
additional things because you can add additional things, even if the technology
allows you to do that more quickly, is not going to necessarily do what we want
it to do, and I think we have to really focus on the purpose of this particular
tool, and not on how technology can make it do things more quickly.
DR.
NELSON: I agree. It's a good point.
There
was another person that wanted to testify.
Dr. George Dawson from Abbott Labs.
DR.
DAWSON: I am George Dawson here
representing Abbott Laboratories, and I will talk about a very quick
presentation on some of the work done in Germany actually by Dr. Thomas Laue
and researchers at Artus.
[Slide.]
As
we have heard, there is two types of tests.
One could use the diagnosed exposure to the SARS virus. We heard mostly on molecular testing,
RT-PCR, but also serologic testing, I think you will hear a lot about in the
future. It looks like both types of
tests will be required to make diagnostics, and most likely one test will
complement the other. Both types of
tests will need to be improved over time.
[Slide.]
Abbott
has made an agreement with Artus to market and distribute their RT-PCR test,
real-time PCR. This test was introduced
by Artus actually in Asia and Europe under direction of WHO and has been used
for several of the studies on SARS.
The
basic plan is that Artus will manufacture the test and that Abbott would
distribute it, and in places like the U.S., would only be distributed after
appropriate regulatory approval.
[Slide.]
The
test can be utilized on various types of specimens including sputum, serum,
native body fluids, swabs, fecal material, and tissues. The extraction is external to the kit, and
they recommend using the QIAamp viral RNA mini-kit or the QIAamp
ultra-sensitive virus kit.
It
is a one-step RT-PCR test and includes the Master Mix reagents and internal
control, and is run on the LightCycler.
The total assay time is about two hours.
[Slide.]
I
was just going to go through a few of the studies that have been done very
briefly in Germany. In this one study,
22 postmortem lung tissues were received from one of the sites, from 11
patients, and RNA was detected in all 22 specimens. It was not detected in any of 23 lung control specimens that were
not associated suspect SARS cases.
[Slide.]
The
second study done in Southeast Asia indicated that of 43 specimens that were
patients who were classified as meeting the WHO case definition, 42 were
positive with the Artus test. Among 14
patients who partially met the definition, 14 were positive in the Artus
test. Of 1,060 patient tested kind of
as a general survey, 935 were clearly negative, the remainder, 125, are still
under investigation.
[Slide.]
In
the third study, a blood bank study, this one is a little different in that it
was not conducted in a SARS endemic area, and utilized pools of 96
specimens. 338 pools were tested for
SARS virus, as well as other viruses.
The
internal control was detected in all the sample pools. SARS virus was not detected in any of the
pools, and the sensitivity of the test was about 140 copies/ml. This study doesn't really indicate that SARS
virus does or does not include a viremic stage because it's from a non-endemic
area.
[Slide.]
So,
to summarize, this Artus SARS assay does appear to detect the coronavirus RNA
in clinical specimens. Additional studies are in progress. Research activities will continue and in my
lab, we will do some of the work to look at different regions of the viral
genome for improved detection of RNA by RT-PCR.
We
will also be looking to express recombinant proteins to look and see if we can
develop IgM and IgG class-specific antibody tests to see if we can detect
exposure to the virus earlier than what has been shown in the existing
serologic assays.
Thank
you.
DR.
NELSON: So, the specimens that were
tested and positive were lung samples from people who died.
DR.
DAWSON: That's correct.
DR.
NELSON: You don't have blood samples
from the same people?
DR.
DAWSON: I believe that we do have blood
samples from the same people, but I don't know what the results of those tests
are.
DR.
KLEIN: Given what we know about the
viral load, how likely is it that even if you were testing in an endemic area,
you would pick up positives in pools of 96?
DR.
DAWSON: I agree, pools of 96 is
probably not the way to go. I think I
would go NEET or pools of 16, and then go from there and find out--once you
find a positive, find out how far you can dilute it, find out what the viral
load is, yes, I agree.
DR.
NELSON: Any other? If not, we will break for lunch. We will be back at 1:30. Thank you.
[Whereupon,
at 12:20 p.m., the proceedings were recessed, to be resumed at 1:30 p.m.]
A F T E R N O O N P R O C
E E D I N G S
[1:30 p.m.]
DR.
NELSON: Good afternoon. The topic now is West Nile Virus. Again, there aren't any questions, but it's
an important issue with regard to transfusion.
Here, there is some data on transfusion transmission.
To
open the session, Dr. Hira Nakhasi from FDA will introduce it.
II.
West Nile Virus - Informational
A.
Introduction
DR.
NAKHASI: Good afternoon. I guess everybody has had a good lunch. Let's talk about now having talked about
this morning SARS, let's talk about the West Nile, another favorite subject of
ours.
This
is an informational session only just to update you where we stand with regard
to the epidemiology, pathogenesis, and also with regard to the testing,
development, and also our blood donor guidances.
[Slide.]
The
three major issues which we will be discussing this afternoon will be the
current status of the West Nile epidemiology and surveillance. Dr. Tony Marfin from CDC will talk about
that and will bring us up to date as of today how the surveillance and
epidemiology of West Nile virus is happening, and will also compare it with
last year's epidemiology.
Then,
we will hear from Dr. Indira Hewlett about the progress in West Nile test
development including FDA's in-house effort on lot release and validation panel
development, and also in the open public hearing, you will hear from industry
their success story about the West Nile test development.
I
think the last topic will be discussion of the guidance document and the
recommendations which last year we had two of these guidances put out, one was
in October and another one was in May of this year, and Dr. Sharyn Orton will
be talking about revisions in the guidance.
[Slide.]
Just
to orient you or disorient you from the SARS to now West Nile virus and what it
is, West Nile virus is an enveloped, single-stranded RNA virus and is a
mosquito-borne flavivirus, primarily infects birds, and you will hear now other
animals may also get infected, but occasionally infects humans.
About
80 percent of the human infections are asymptomatic and 20 percent develop mild
febrile illnesses, flu-like illnesses.
Approximately 1 in 150 infections result in meningitis or encephalitis.
As
I said last time, and I am saying again, advanced age is by far the most
significant risk for severe neurological disease, so we watch out, those who
are older people.
Viremic
period can occur up to two weeks prior to symptoms and can last up to a month
from the initiation of the infection.
[Slide.]
In
last year's outbreak in the United States, besides mosquito bites, other modes
of transmission were detected, for example, blood transmission through RBC
plasma and platelets, transplantation, breast-feeding, transplacental, as well as occupational mishaps.
The
magnitude of the risk from transfusion was not known, and still the magnitude
if not known how much it can be.
The
virus titer, another important thing to remember is that virus titer is low
compared to other transmissible diseases, bloodborne like HIV and HCV, and
viremia results rapidly after seroconversion to IgM, and IgM can persist for a
long period of time up to two years, and Tony tells me it is a long period of
time, up to 500 days or so.
No
chronic stage of West Nile infection has been reported so far.
[Slide.]
You
will hear more from Tony's presentation here, but just to give you a quick
update what happened last year. In 2002, 4,156 cases of West Nile were
reported. Out of these, 284 deaths and
approximately 3,000 cases of West Nile meningitis and encephalitis.
It
is endemic now in 40 states including Washington, D.C.
The
average risk of West Nile by transfusion was throughout the United States, was
0.4 per 10,000 donations, but in certain high endemic areas, it could go as
high as 10.5/10,000 donations in the State of Michigan and, in fact, in
Detroit, it was much higher than that, the City of Detroit, that area.
Last
year, in that period, there were 61 possible transfusion transmitted cases
reported, 23 were confirmed from 16 blood donations. Out of these 61, 19 were not transfusion related, 19 were
inconclusive because of incomplete donor follow-up.
There
were 6 deaths reported in this group, but the causal relationship with West
Nile virus has not been established definitely.
[Slide.]
Now,
what did we do during the last year or so?
At the FDA, as you heard last time also, we issued several alert
notices, we encouraged industry to develop the donor screening as a
supplemental test, and we had several congressional briefings as late as June
6th. This was a congressional staff
hearing basically apprising what the status of this test is.
Then,
we had various meetings with the test manufacturers, and I am very, very
thankful to test manufacturers to really have a good collaborative approach in
developing this test.
FDA
issued, as I said, several guidances.
One was in October 25th, and another one was May 1st, and you will hear
more in detail from Dr. Orton.
[Slide.]
I
am happy to report that FDA has approved three INDs, one Gen-Probe's IND. This was in Phase I and Phase II, which
Phase I was repository samples and the second phase was the prospective
samples. The American Red Cross, which
is using Gen-Probe's test, also had an IND separately, and this was
approved. Roche's IND for West Nile was
also approved.
So,
again, this is very timely. I guess the
industry folks will tell themselves, but yesterday, they released a press
release that I guess yesterday or the day before yesterday, both Roche and
Gen-Probe has started testing in some places already. They were telling us by the beginning of July 1st, but I guess
testing has now in certain areas started right now. So, congratulations to both of these companies.
FDA
is again in contact with the CDC to determine the areas where the activity
could start earlier and we have been in contact with them, as well as with the
blood organizations.
We
have biweekly meetings with them, and we are very proactively interacting with
these blood organizations, as well as with CDC and NIH, to coordinate
epidemiological data on West Nile infection and see where implementation of
West Nile testing could be expedited, so as to reduce the risk of transfusion
and transmission.
This
is one of the success stories which I am really proud of, because it was only
last year, around November, when we had the first workshop and asked for the
field to developing this test, and is now June and we already have a test. Thank you very much.
I
will ask Dr. Tony Marfin to start the session. He will talk about the
epidemiology and pathogenesis.
DR.
NELSON: Thanks, Hira.
Are
there any questions or comments?
Dr.
Marfin.
B.
Epidemiology and Surveillance Update
DR.
MARFIN: Good afternoon. This is actually my second visit to
BPAC. The first one was about eight to
nine months ago when I was first talking to you about the first cases of
transfusion-associated transmission of West Nile virus.
It
kind of underscores exactly what Hira said.
People have moved very quickly on this.
It has been a tremendous response.
I have never been on so many conference calls in my life as I have over
the past eight to nine months, and it is nice to see that something has come
out of it.
Today,
though, my presentation is going to be somewhat different. I am going to be talking about surveillance
primarily. If there is time at the end,
I will just mention the transfusion story, but I think Hira did a very good job
of overseeing that.
[Slide.]
Now,
working at Fort Collins used to be great when I was an EIS officer back in the
early '90s because you worked very hard for six months of the year, during
summer, all your diseases went away and then you got to ski during winter.
Now,
the only way that I know that the year is changing is that last year, this used
to be my last slide, now, it's my first slide, so that is the only way that I
know that we are going into another season.
But
this is a very, very important question, and it is a very, very important
question to people who are developing tests, it is a very, very important
question to people who are developing new questions for questionnaires, it is a
very important question for blood banks, because as I laid out last year in a
lot of the meetings, we had two choices.
West Nile virus was either going to become like Japanese encephalitis,
which we call hyperendemic disease, where there would be hundreds to thousands
of cases every single year in the United States, or it would become like St.
Louis encephalitis virus, which we have known about for 70 years and causes
periodic large outbreaks.
Obviously,
the economic factors are very, very important if you are trying to develop a
test for something like Japanese encephalitis hyperendemic disease as opposed
to a periodic large outbreak disease like St. Louis, so there are large
implications with trying to figure out what that pattern is.
I
am here to tell you that I think at least for a while, it is going to be like
Japanese encephalitis, so if you have to go to the rest room, you don't have to
wait for the final story.
[Slide.]
2002. You may have seen Lyle Petersen's slide
because this is where I grabbed this one from, was the season of
surprises. This was the largest
arbovirus meningoencephalitis outbreak that ever occurred in the western
hemisphere. That is not an
understatement. These are not
extrapolations as arbovirologists often do, multiply it by 10, divide by 5, and
come up with some number that is not realistic.
The
3,000 cases of meningitis and/or encephalitis that we measured is truly the
largest epidemic that has ever occurred.
It is the largest West Nile meningoencephalitis epidemic ever documented
ever in the world. So, this was really
very, very serious.
When
you look at the number of cases of neuroinvasive disease, that is, encephalitis
and/or meningitis, and you multiply it by the 150 or 170 or 180, whatever
number you want to use, you figure out that there may have been as many as half
a million infections in the United States last year alone.
Now,
these are not illnesses, these aren't going to come to anyone's attention
except potentially blood banks because these people do have viremia. It may be very, very low, it may be very
short, but because they are asymptomatic, they are potential donors, and that
is something that you people have to think about more than a lot of the
clinicians that I talk with.
One
of the absolutely unbelievable stories is the geographic spread, and I will
show you some maps that show the rapid spread in only four years, the four
modes of transmission that Hira already talked about, in fact, occupational has
been well described of West Nile virus, it is just that we are seeing more and
more of it, and, in fact, there will be a new MMWR coming out in a bit about a
whole group of workers who may have been infected because of their work.
Then,
of course, there is a lot of the new clinical syndromes.
[Slide.]
Here
is what West Nile virus has done since it has been in the United States, and in
1999, there were only four states that were affected. There were 59 cases of neuroinvasive disease. You are going to see variations on this
slide, but I always refer to neuroinvasive disease.
There
were only 6 fatalities. God only knows
how many birds were killed in that first year, but people have described them
falling out of the sky as they walked down the street. There were a few positive pools and there
was one large flock of horses out on Long Island that were infected.
Now,
over the next two years, you can see why there was never a great deal of
concern from people. You know, it
looked like it was going to be here, there was going to be an occasional
infection, you know, low level endemic, although it sure appeared that it could
kill a lot of birds, and then we started to appreciate that it could infect a
lot of horses.
Then,
in 2002, as Hira already mentioned, we had 44 states reporting neuroinvasive
West Nile viral illnesses, almost 3,000 cases and about 284 deaths or 9 percent
case fatality ratio, lots of birds, lots of mosquito pools, and I haven't
spoken to this group about the epidemiology with regards to mosquitoes, but
some something that is inherently different about West Nile virus from St.
Louis encephalitis virus is that we have a large number of mosquito species
that are involved.
That
means that this virus has a lot of flexibility, inherent flexibility. It may be able to adapt to a lot of
situations. When I show you the map on
the number of counties that have reported West Nile virus in 2002, I think I
will come back to that theme.
[Slide.]
I
am showing you a little more graphically what we had in 1999. Shown in red are all the counties that
reported any West Nile virus infections, and that is either in humans or
animals.
[Slide.]
2000,
and we are starting to get a good appreciation for the spread, but in 2000,
there were only 19 cases of encephalitis and/or meningitis, and we beat the
bushes for them. So, although we were
seeing lots of animal activity, we just did not see all that much human
activity.
[Slide.]
This
is 2001, and this is when we realized that West Nile virus was here to
stay. The very first areas that were
reporting animal and human disease were in the Northeast, which had been the
traditional two years stronghold of West Nile virus, but then we saw a second
outbreak in the Southeast along the Georgia-Florida border, and then at the end
of the season, almost all of the spots that you see in Ohio, Michigan,
Illinois, Indiana, and Wisconsin, those all came at the end of the year. In fact, it set up very clearly what was to
happen the next year.
[Slide.]
These
are the number of counties that were affected in 2002, over 2,500
counties. The only thing that stopped
it was the Rocky Mountains. As you can
see, there is a few counties even on the other side of the Rocky Mountains.
This
is where I want to emphasize the large number of bird species that the West
Nile virus can infect, the large number of mosquito species that the West Nile
virus can affect, because it gives it the ability to have activity in all of
these very, very different geographic areas.
I
mean we are talking about Maine compared to Corpus Christi, and yet the virus
was active in all of those places and very active in all of those places.
It
was at this point that we should have--and we did actually--when we walked
around, we started saying this isn't going to act like St. Louis encephalitis.
In
fact, last year, there were about 8 cases of St. Louis encephalitis. They were all down in the Southeast, in
Texas, or Southwest, in Texas, and it wasn't reported anywhere else. Why not?
They are closely related viruses, there is something inherently
different about West Nile virus.
I
don't think it's a big stretch of anyone's imagination to think that the
weather, the winters, all of these things are very, very different if there was
activity in all of these counties.
[Slide.]
This
is showing the incidence of human West Nile meningoencephalitis by county. In red are the high incidence counties,
those counties that had greater than 100 cases of meningoencephalitis per
million population; in yellow, 10 to about 99; in gray, less than 10.
Now,
I actually loaded the wrong slide because what I wanted to show you were the
cases of infectious donors, and if I had loaded the right slide, you would have
seen that most of the infectious donors came from this area and this area, the
cases where there was high incidence.
Now,
it is no surprise, then, that we never saw any donor-related problems in the
previous years because we just didn't have the level of human infections, the
rates of human infections that we see here.
I think it goes without say that we used the incidence of
meningoencephalitis as a rough surrogate for the total number of infections in
these counties.
[Slide.]
This
is the epi curve for 2002. The very
first infection had illness onset on May the 19th, and that was actually here
in the District of Columbia or down the road in the District of Columbia, and
the last case had illness onset in the middle of December. This is another reason why we don't get as
much skiing in anymore, it has become a much longer season.
But
what I really want to emphasize is this five-week period right here. This five-week period accounts for
two-thirds of the cases. This is the
same thing that we have seen now for four years in a row.
I
applaud the activity of the blood banks and everyone getting ready, and I can
tell you that you were probably about five or six weeks ahead of the curve, and
that is just terrific, because I think that our first cases of viremic donors
are still coming up. And what do I base
that on?
[Slide.]
Well,
here is the time period when those 16 infectious units were collected. The very first donor donated on July the
22nd, and the very last one came on October the 6th. Again, I don't think it is any coincidence that this period
coincides with the peak of the human epidemic.
This
is not likely to be a disease that we are going to see at the end of June or
early July, and yet all of the blood bank, all of the testing that is going to
have to go in place, it's all there already, so I think that is remarkable.
[Slide.]
So,
let's come back to this. So, what is
going to happen in 2003? Now, to think
about what is going to happen in 2003, we have advantages over SARS. I mean we may be number 3 in the emerging
infection list now, after SARS and Monkeypox, but we have an advantage over
them, and that is that we have a better surveillance system than they do,
because we don't wait around for human infections.
[Slide.]
For
people who don't think about the fact that animal infections occur before human
infections, this is a paper that came out last year. It is by one of my EIS officers that I had. She just loved to model, so what she said
is, you know, in 1999, there was a very impressive crow die-off that came
before the human epidemic. In 2000, we
established something called ArboNET.
This is a real-time electronic animal and human surveillance
system. We have 54 co-operators, 54
local and state health departments that help us detect West Nile virus
activity.
So,
she hypothesized that if we could assess the intensity and timing of crow
epizootics that we should be able to predict human disease. In fact, she spent about eight months doing
this, and just as an overall general comment, if you look at the density of
dead crow sightings of reports, or you look at the proportion of dead crows,
especially in counties with larger populations, you are going to find the
counties that are going to subsequently report lots of human cases.
In
fact, if a county has both of those things, they were 50 times more likely to
report human cases than counties that had neither of those things.
Now,
she based her work on the 2000 data.
She looked at 2002 data, she found out that her model was robust, and
she concluded that detecting early season West Nile virus activities in animals
may allow timely interventions to reduce human risk.
Now,
I will underline "may," because you have to be able to do something
with that information if you are going to intervene. This is a very, very complex paper. I can't believe a journal gave her 10 pages, and it just went on
and on. So, Steve Guptill, a partner of
ours from the U.S. Geologic Survey, did the next paper.
[Slide.]
This
came out in Emerging Infectious Diseases just a few months ago, and what Steve
said is either they have animal events before humans, when humans are reported,
or after humans. So, he looked at the
2001 data and he found out that counties that had animal events, in this case
only crow events, that if they had a positive crow prior to humans, they were 6
to 7 times more likely to have human cases in the subsequent year.
Now,
something I forgot to emphasize in Kathleen's paper and something I want to
point out here, we are talking about early season. We are talking about identifying animal infections that occur
from mid-June to the end of July, which we used to consider early, and I will
show you in a bit that that is no longer true.
But this gives people time to intervene and potentially lower human
risk.
He,
too, looked at 2000 data, he looked at a preliminary dataset of ours, and he
found out that his model was robust, as well.
[Slide.]
Now,
I can say well, if I know what is happening in the animal population, I should
be able to at least speculate as to what is going to happen in the human
population.
[Slide.]
The
next three slides, I am going to talk
about three aspects of our surveillances.
It could be dead birds, mosquitoes, and horses. Each one of them brings a different quality
to surveillance although I am not going to go into that now.
What
we have is a comparison of 2002 and 2003.
We are going to talk about when the first bird, the total number of
birds, the number of counties and the states that have reported by a particular
date.
Now,
inherently, these two systems are different. For 2002, these are all the events
that occurred by June the 17th. It
doesn't matter that some of them reported it to us in April of 2003, it still
occurred on June the 17th, so this is going to be a more complete dataset.
This
dataset here is subject to both testing lag and reporting lag, and, in fact,
these are the number of events that were reported to CDC by June the 17th. Now, for those of you that have copies of my
slides, you can see that this is different.
That is how rapidly our surveillance dataset is changing right now.
We
are at a point where it is changing, if you pull out information six hours
apart, you are getting radically different values. So, this is midnight on June the 17th. In fact, we can see that the number of counties that were
involved in 2002 and 2003, it is about the same number. The states are about the same.
There
are some qualitative differences here in the states. What we are seeing this year, we are not seeing the Northeast
states as we had seen last year, and, in fact, we are starting to see states
like Wyoming, North Dakota, Colorado, showing up very, very early on. We didn't see that last year.
[Slide.]
In
mosquitoes, mosquito surveillance is very, very expensive. It is very, very useful because you know
exactly what vectors are out there and you can tell when you are starting to
see what we call "bridge" vectors or those vectors that like to feed
both on birds and mammals specifically humans, so it's very, very valuable, but
very few states are performing it.
I
am just going to draw your attention to this last line here, that we have lots
of positive mosquito pools already in Georgia, Indiana, New Jersey, and a
tremendous number already out of Louisiana.
Now,
Louisiana performs mosquito surveillance very well, they have been doing it for
years, yet this year it is heads and heels above what we saw last year.
[Slide.]
The
last slide then on this are the horses.
Now, horses are important because they are fed upon by what we call
"bridge" vectors, and as I said, they are vectors that will feed on
mammals preferentially to birds. As a
result, this is a really rough surrogate for human-biting mosquitoes. It tells me that human-biting mosquitoes are
out there.
I
can see already that we have twice as many states, despite the lag in
reporting, despite the lag in testing, I already have 8 states that are
reporting positive horses. In fact, one
state, Wisconsin, has already reported 2 positive horses from the same county.
You
will also see that these are some northern states. Minnesota has already reported.
This horse was infected in late April.
So, we are starting out at a very, very high level compared to last
year.
[Slide.]
What
we are showing here is kind of an epi curve. It is the number of positive West
Nile virus surveillance events in the United States through an MMWR week. Now, this is MMWR week 23 in 2002 ended on
June the 8th, and in 2003 ended on June the 7th, so they are roughly
comparable.
I
am going to draw your attention to the weeks 1 through 20. As I have mentioned,there may be some
problems with interpreting this. This
may be due to testing lag or reporting lag.
But look at the rest of the year, very, very comparable, if not, an
increase in terms of the number of surveillance events.
Now,
why am I especially impressed with the fact that this might be 8 and that might
be 4? Well, I can tell you that a lot
of states don't even have their surveillance up and running yet. I can tell you that a lot of states are
getting really tired of animal surveillance, it is very expensive, very
intensive, and yet I am still seeing lots and lots of activity.
[Slide.]
Where
were we on June the 8th of 2002? Well,
in 2002, we had the Northeast activity, we had the Southeast activity, and we
had moved over into the Midwest, and we had about 70 counties involved.
What
happened when the country used to look like this?
[Slide.]
We
went to that. That is just a
reminder. That is a slide that you saw
earlier. We expanded from those few
foci and it rapidly expanded probably due to birds, probably along the rivers,
and it involved all of these areas.
So,
where are we now in 2003?
[Slide.]
Very,
very, very similar. Again, the Midwest
is there, the Southeast is already there.
There are some states--and this is just because I made the dataset about
12 hours apart--but North Dakota should have a county colored, Colorado should,
Ohio should, and Virginia should, as well.
Now,
this looks very, very similar to last year's map except that we haven't seen
the activity in the Northeast yet, and we are starting to see more activity out
of the West. This is very, very
important where are our first human case is going to occur. They are going to
probably occur in the Gulf Coast, and, in fact, we are working on some samples
from that area right now.
This
is something we have been working with FDA and the blood banks to let them know
that if we are going to deploy early, this is where we really should be
deploying. It looks like that is not going to become an issue, and that is
very, very good.
We
also work with NIH to let them know that if they are going to get a controlled
clinical trial up, that these will be the first cases, and these will be the
largest number of cases here and up here in the Midwest.
Now,
something that just came to me this morning, these are the areas where we
should also be reinforcing to our general population the importance of personal
protection, but it is something that we haven't really addressed yet, and that
is should we be addressing personal protection with our blood donors especially
in these areas and the importance of DEET in setting up those programs.
We
put a lot of emphasis on deferring on the basis of questions, deferring, doing
the testing, and that's great, but maybe these are the people we should say,
you know, you have got to get in the habit of using some DEET if you are going
to be our donors.
[Slide.]
I
don't think I have time to go into a discussion of the transfusion story, but
Hira did an excellent job with that already.
Thank
you very much, and I will take questions.
DR.
NELSON: Thank you, Dr. Marfin, that was
very good.
Yes,
Paul.
DR.
SCHMIDT: What is a mosquito pool?
DR.
MARFIN: The question is what is a
mosquito pool. We don't test individual
mosquitoes. What we do is we will trap
several of them and we will make pools, so we will make pools of 50, once in a
while they make pools of 100, so in the night, say, last night you went out to
site X and you collected 1,300 Culex pipiens, you would make those into 26
pools. From that, we can calculate a
minimum mosquito infection rate.
I
can tell you that, in fact, the minimum mosquito infection rates that we saw
last year were the highest that we have ever seen in an arbovirus, much higher
than we have ever seen in SLE.
DR.
SCHMIDT: Do you mash them all up and
test them?
DR.
MARFIN: I don't, but--
DR.
SCHMIDT: Is that how it is done?
DR.
MARFIN: Yeah, they put them in a shaker
with a beebee, and they pulverize them and they liquify them.
Any
other questions, questions that I can probably answer better than that?
DR.
NELSON: The other thing that I
understand is that there were like 40 or 50 different species of mosquitoes
that were infected, which is quite different.
DR.
MARFIN: If you look at West Nile virus
in North Africa or Israel, for that matter, or South Africa, you usually see
one predominant species. Here, we see
37 from the time that it has come in here in 1999.
Now,
the predominant one are the bird-feeding species, Culex pipiens, Culex
quinquefasciatus, Culex tarsalis, but what is very, very impressive are the
number of Aedes, and you probably don't know it, but they have subdivided Aedes
now into two genera, and it is now Aedes and Ochlerotatus, and there are a
tremendous number of Aedes and Ochlerotatus species that we are finding
positive including Aedes egypti, which is very, very bothersome, as well.
DR.
NELSON: Knowing something about the
entomology and the feeding habits of the mosquitoes, is the prevalence in
different species useful in predicting a human epidemic, or is it just too
gross a measure?
DR.
MARFIN: In fact, that would be the best
proximate value that we have, and that is why I point out, well, if it's so
good, why aren't more people doing it.
It is really expensive. You have
to have good expertise out there.
It
requires lots of molecular tools, some that are being constantly developed and
refined, so it is very, very expensive, but, yes, if I lived in a community
where Aedes albopictus had a very high infection rate, Aedes albopictus is a
very, very vigorous daytime biter, and it likes feeding on humans, it likes
feeding on mammals, but it really likes humans, and so, yes, I would be very,
very concerned as opposed to, say, finding a similar infection rate in Culex
restuans, say, which almost feeds entirely on birds.
So,
understanding that is very, very important and hopefully, we are going to be
able to get more information on that from those mosquito pools.
DR.
ALLEN: The weather that we see outside
today, that has been certainly up and down the East Coast all summer long, have
you been working with NOAA and the National Weather Service, and others, to do
some modeling on what this might do to potential mosquito populations and how
that might affect the transmission overall, the epidemic overall?
DR.
MARFIN: We have been working with NASA
primarily. They also have a similar
process, as well as the National Weather Service and NOAA, and that's great,
but I can tell you that when people first discovered St. Louis encephalitis in
1933, that there were a lot of smart arbovirologists that came all along and
they made the same assumption, and it is a good assumption, it has to be true
that weather affects the number of mosquitoes, therefore, can have influence on
the outbreak.
That
is a good overall model and when people look at it, it is mild winter, cool,
wet spring, hot, dry summer that is perfect for growing mosquitoes. Now, you have to have virus in there. We have the virus. This virus doesn't go away, there is lots of overwintering that
is going on. That is something that we haven't seen with St. Louis
encephalitis, so we have the virus ready to go, and so now I think what is
really the proof in the pudding will be what the summer does.
Now,
one of the reasons that I pointed out how many counties were involved, all of
those counties had different weather patterns.
All of those counties had a tremendous number of events, animal events
and human events, so there must be more to the picture than that because they
are very, very different settings.
DR.
STRONG: You mentioned St. Louis
encephalitis in Texas. There was also
an earlier reported case in Washington State.
Is there any evidence that there is any increase in SLE?
DR.
MARFIN: No, and that is another piece
of information that we use when we talk about what is going to happen with West
Nile virus. The big outbreak in '33, in
St. Louis, caused about 1,200 cases.
There
was a large outbreak in 1975, that caused about 2,000 cases of encephalitis,
and then it essentially disappeared until, let's see, '91, my first outbreak
was in Arkansas, then nothing until two years ago in Monroe, Louisiana, and
then they had a large outbreak.
Now,
over that time, they always have cases in Houston, it is a persistent
focus. We had one case out of Colorado,
very, very sporadic, but we haven't seen that really big epidemic. We wait for it all the time, we always think
that there can be some focal conditions that allow that. We have not seen that to date.
With
regards to the Yakima person, that is St. Louis encephalitis and people say,
gosh, Yakima, Washington, well, in fact, if you look at migrant farm workers
over the years, there has always been some cases of St. Louis encephalitis
periodically in the Yakima Valley.
If
you look at the mosquito populations of the southern Great Central Valley in
California and the Imperial Valley of California, there is always St. Louis
activity, there is always Western Equine encephalitis activity, and
periodically, you see human cases, so it's not that big a surprise although
April is pretty early for Yakima.
DR.
EPSTEIN: What are the prospects for
controlling West Nile through control of mosquitoes this year?
DR.
MARFIN: This is the big question. We now have, there is probably seven or
eight papers out there that say when crows do this, this is going to happen. Despite knowing that, it is very hard for
somebody to stand up and absolutely guarantee a county board of supervisors or
a mosquito control district board and say we have to start doing the following
things now, especially when it is very, very expensive.
Unfortunately,
that describes a lot of the situations in a lot of counties right now, so there
has been a great deal of emphasis on personal protection. There has been some hesitancy in a lot of
areas to get involved in adulticiding, which is killing adult mosquitoes.
There
has been a good emphasis on larvaciding, there has been good emphasis on
reducing wetland areas that are producing especially the Culex mosquitoes, so I
think that those interventions will be helpful, but despite that, and getting
back to the question about different mosquito species, some of them are just
not amenable to aerial spraying or larvaciding. You know, Aedes albopictus likes little tree holes that we find
all throughout our neighborhoods, so it is very, very difficult to control
those.
Thank
you very much.
DR.
NELSON: Thanks for a great
presentation.
Dr.
Hewlett is going to talk about status of the West Nile virus test, lot release
and validation panel development.
C. Status of West Nile Virus Test, Lot
Release, and
Validation Panel Development
DR.
HEWLETT: Good afternoon. We are going to be switching gears,
switching from testing mosquito pools to testing human donor pools.
What
I am going to present today is an update on the status of the development of
West Nile virus tests and the development of lot release and validation panels
for approval and licensure of these tests.
[Slide.]
To
briefly recap FDA's previous actions, at the March BPAC, we discussed and
presented an FDA proposal for clinical study design for assay validation. We talked about unit and donor management
strategies, and a plan for development of lot release and qualification panels.
[Slide.]
We
also talked about a study design for test sensitivity determination, which
included testing of repository specimens from transfusion and
community-acquired West Nile virus illness samples, any positive cases that
were identified in prospective studies, and testing of seroconversion
panels. All of these samples would
contribute to the sensitivity determination of West Nile virus tests.
[Slide.]
Because
of the limited number of samples that would be available for assay validation,
we also discussed an additional approach for validation of tests. This would be testing a common set of
pedigreed specimens by all candidate investigational tests, and testing all
reactive specimens identified during IND studies by all manufacturer's
assays. The expectation here is that
this approach would help us evaluate the relative sensitivities of the
different tests and to examine whether they have equivalent sensitivity.
[Slide.]
At
the March BPAC, we stated that FDA's current standard for West Nile virus NAT
assays was 100 copies/ml for the individual donation when tested in a pool, and
this continues to be the standard at this time.
The
standard may be revised as assay sensitivity improves and additional data on
viremia and infectivity become available in future studies, and it is our hope
that such studies are in progress.
[Slide.]
We
also proposed a scheme for donor and unit management whereby reactive
investigational NAT results on the individual donation could be confirmed by
follow-up testing with an investigational NAT, an alternate NAT, and an IgM
test, and the donor could be retested prior to 28 days, and if the follow-up
sample is reactive by an investigational NAT or an alternate NAT, the donor
would continue to remain deferred for an additional 28 days.
The
donor may be eligible for reinstatement if the follow-up sample prior to 28
days is NAT-negative and IgM positive, however the donor would continue to
remain deferred for the 28-day period.
[Slide.]
Today,
I would like to report on the progress in test development, and we are glad to
report, as you have heard from Hira in his introductory remarks, that multiple
IND studies are in progress.
Two
manufacturers have publicly acknowledged their existing INDs, Gen-Probe and
Roche Molecular Systems. These IND
tests are based on NAT using pooled or individual samples, and they are
intended for use with whole blood, blood components, and source plasma at this
time, although additional claims for bone marrow, cord blood, hematopoietic
progenitor cells, tissue and organ donors will be added as these studies
progress.
[Slide.]
The
expected start date for nationwide testing is early July 2003, however, some
centers have already initiated prospective testing. All samples will be collected under approved IRBs with the
necessary informed consent.
I
would like to point out the analytical sensitivities of these IND tests are
comparable, in fact, very good, they are between 5 and 7 copies/ml.
[Slide.]
Now,
I am going to provide a few details on each of these tests, but the
manufacturers will actually be discussing this in greater detail in their
presentation.
The
first test, Gen-Probe, the Procleix West Nile virus assay is a TMA-based
screening assay for West Nile virus RNA.
It uses existing instrument platforms as Gen-Probe's licensed HIV-1 and
HCV NAT blood screening assay, which is essentially a semi-automated system.
Obviously,
the fact that these platforms were already in place has played a major role in
enhancing and expediting the implementation of new tests, such as tests for
West Nile virus.
The
assay also uses existing formulations as much as possible.
[Slide.]
The
Procleix West Nile virus assay has an analytical sensitivity, 95 percent
detection rate, about 7 copies with a range of 7 to 15 copies.
The
specificity in preclinical studies was evaluated by testing 1,180 blood
donations, and the observed specificity was very good.
No
cross-reactivity to other bloodborne viruses was observed. This includes a battery of viruses that are
usually tested, such as HTLV, HIV-1/2, HCV, HBV, HGV, and a number of other
viruses.
[Slide.]
The
Procleix West Nile virus IND consists of a two-phased clinical study. Phase I consists of a retrospective
prevalence study where about 89,000 archived specimens from the Red Cross, from
6 high incidence areas collected during the 2002 season will be tested. In fact, they are being tested.
Phase
II consists of a prospective donor screening analysis. This consists of testing voluntary donations
of whole blood and source plasma at 25 testing sites. They could be testing either individual samples or pools, and
this is site dependent. Nationwide
testing is expected to begin July 1st, and as you just heard from the earlier
presentation and my own previous slides, this testing is already in place in
some centers.
[Slide.]
In
case of a regional West Nile virus outbreak,
samples will be shipped and prospective testing will be initiated at both
Phase I and Phase II sites. Samples are
being archived from June 1st onward.
Testing of samples will be based on regional prevalence, and, of course,
these studies are contingent on IRB approvals and West Nile virus informed
consent.
[Slide.]
The
Roche Molecular Systems West Nile virus NAT assay is a PCR-based screening
assay for use with pooled samples. The
analytical sensitivity is between 5 and 7 copies/ml.
No
cross-reactivity has been seen with the other bloodborne viruses that are
non-West Nile virus related, and clinical specificity has been preliminarily
evaluated by testing 400 random volunteer donor sample from West Nile virus low
and high prevalence areas. Again, the
specifically observed has been very good.
The
manufacturer will be speaking in the open public hearing and will provide more
details on the clinical study design and the emergency testing plan, so I am
not going to discuss that in my presentation.
[Slide.]
Next,
I would like to switch to talking about FDA's panel development efforts. This work is actually being conducted by
Maria Rios and her group in our laboratory.
We are putting together a lot release panel for licensure and
post-market surveillance of NAT and IgM tests, potential IgM tests, and a
qualification panel for evaluation of the relative sensitivities of
investigational NAT and IgM assays.
[Slide.]
We
are working on an FDA NAT panel, which will be composed of two isolates, the
FDA NY99, which is a flamingo isolate, and the FDA Hu2002 isolate. Both of these isolates are being
characterized by genetic sequencing.
Viral infectivity has been determined at both FDA and the New York
Department of Health laboratories and by cytopathic assays at the FDA. I should mention that these isolates have,
in fact, been obtained from the CDC and the New York Department of Health
although human isolate was, in fact, cultured in our laboratory at the FDA.
RNA
concentration measurements include fluorescence and optical density
determination and TaqMan assays. These
are in-house TaqMan assays that Maria has developed in our lab.
Final
panel specifications are being established through collaborative studies.
[Slide.]
This
slide shows the PDU results on the FDA isolates. Again, these isolates were tested both at FDA and the New York
Department of Health in Laura Kramer's laboratory. I would just like to point out that there is good agreement
between the two labs and the numbers come out between 107 and 108
PFU/ml depending on the isolate.
[Slide.]
These
two isolates were then distributed to four different laboratories in a
dilutional series, either untreated or heat-treated at 60 degrees for 2 hours
for an analysis of a quantitation of virus in terms of copies/ml, and the two
points that I would like to make on the slide are that there was generally very
good agreement between the different laboratories.
We
observed a 2- to 3-log difference in the untreated versus the heat-treated
material, so although heat treatment does affect copy number determination, the
differences are not as significant as we thought it would be, so, in fact, this
may allow us to use heat-treated material for panel development.
[Slide.]
The
reason this is important is because upon heat treatment, we observed a complete
loss of activity, so infectivity is completely destroyed as indicated by the
PFUs on the very far righthand column.
As you can see, there is no infectious virus that could be isolated from
an isolate that had been subjected to heat treatment.
Again,
this is encouraging because this allows us to develop inactivated materials
that would still have quantifiable viral RNA in them.
[Slide.]
We
also have a plan for developing a qualification panel. At this point, we are trying to acquire
specimens to develop this panel. The
plan is to put together at least 100 pedigreed clinical specimens that may be
either RNA positive only, IgM positive only, or dually positive for both RNA
and IgM.
To
date, we have obtained some samples from the Red Cross, from the CDC and the
State Public Health Laboratories. We
are also recommending that reactive specimens identified in IND clinical trials
be made available possible to FDA and to all manufacturers through sharing of
samples since this would create a sample bank that would allow expedited assay
validation.
[Slide.]
This
qualification panel will be evaluated in collaborative studies using various
candidate NAT and IgM assays, and the specifications for these panels will be
established based on the results of these collaborative studies.
[Slide.]
In
summary, at this point, we are really glad to report that two test kit
manufacturers' IND studies for West Nile virus NAT on pools or individual
samples are in progress. These are IND
tests, but they have an excellent analytical sensitivity between 5 and 7
copies/ml.
Prospective
testing is already underway in some blood centers. Nationwide testing is expected to begin in early July, and a
contingency plan is being developed for early testing in case of a regional
outbreak prior to nationwide testing.
[Slide.]
The
lot release panels are also being developed and these are based on a high-titer
Flamingo and Human Viral Isolates. The
viral stocks have been quantitated in preliminary collaborative studies
involving a few participating laboratories.
A
prototype panel is being formulated to evaluate the performance of the panel in
a larger collaborative study involving more participating laboratories.
A
qualification panel for NAT and IgM assays based on clinical specimens is also
under development.
[Slide.]
I
would like to close by acknowledging the people who made this possible. Of course, most importantly are the test kit
manufacturers Gen-Probe and Roche Molecular Systems, who were very responsive
and responded to FDA's request to develop products in an expedited manner, and
the blood organizations for helping initiate implementation of the test.
I
would like to thank Maria and acknowledge Maria and her team and Dr. Shimi
Vasen who, in fact, cultured some of the virus, these people in our laboratory at
CBER-FDA. I would also like to thank
Robert Lanciotti from the CDC and Laura Kramer from the New York Department of
Health for providing us with the specimens.
That has really helped us with our panel development work.
Thank
you.
DR.
NELSON: Thanks, Dr. Hewlett. That is remarkable progress in the last six
months or less.
Questions. Paul.
DR.
SCHMIDT: Dr. Hewlett, in the handout
you gave us, it is noted that the Gen-Probe assay, there is no cross-reactivity
to other flaviviruses, dengue and St. Louis encephalitis, don't have that
information for Roche, but last March, Dr. Petersen was talking about the
transfusion/transmission of dengue on the basis of marrow. I just don't know about experience with bone
marrow.
I
don't know anything about St. Louis encephalitis and transfusion, but since we
are not here as epidemiologists, but trying to keep the blood clean, wouldn't
cross-reactivity with other flaviviruses be good? Do you have any comments?
DR.
HEWLETT: In fact, at the time we held
our workshop, we made the point that it would actually be desirable to have
some cross-reactivity with some of the other flaviviruses, but we have left it
up to the manufacturers to develop what would be easy to implement and would be
also expeditious for validation.
So,
some of the companies, actually, the companies are going to talk about this in
the open public hearing, so you will hear some more and have an opportunity to
probe that issue a bit further, but what we understand is that at least with
those types of studies that were done, a very limited number of samples were
tested, so it is really too early to say that, in fact, they are either
cross-reactive or not.
This
is one of the things we would like to do at FDA is we would like to collect
some isolates that represent the non-West Nile virus, flaviviruses, to look for
potential cross-reactivity with other members of the sera complex, and that is
something we would like to pursue in-house, but we also recommend that
manufacturers try to acquire as many samples as possible of these other viruses
to, in fact, either pursue a claim or to not have a claim for the other
viruses, but this is tricky issue because many of these primers do, in fact,
cross-react with the other viruses.
DR.
SCHMIDT: Is there any history of
transmission of St. Louis encephalitis by transfusion?
DR.
HEWLETT: No. I see Tony says they don't.
DR.
NELSON: From what region of the virus
do the primers come from, is it a conserved?
DR.
HEWLETT: I am not sure I can talk about
that. I think the companies would.
DR.
STRONG: A couple of problems have
cropped up in implementation because we are doing it so quickly, and I wanted
your comments about this. One is the
requirement that there be IRB approval.
There are a number of IRBs that are holding up approvals for a variety
of reasons, and what position the blood centers should take should they not
have IRB approval, but be ready to test.
Secondly,
I know of at least a couple of examples of places who think that they shouldn't
be testing and don't want to test.
These would be hospital collection sites and how that would be dealt
with.
DR.
HEWLETT: Yes, that is actually a bigger
issue and we did face this dilemma also with HIV and HCV NAT testing, and our
FDA position is that we would be looking for IRB approvals to be in place or at
least being negotiated at the time that the studies are put in place.
As
far as the hospital IRBs, I know that issue has come up about the local IRBs
and the single IRBs, and so on, and we are looking into this, and we hope to
have something worked out for the blood industry, but at this point, what I
recall with the HIV and HCV was that, in fact, we recommended that waivers be
sought, and that is another option.
Jay,
I don't know if you would like to comment on that.
DR.
EPSTEIN: I am afraid the subject is
complicated because there is no one rule that applies. The rule is that it is subject to IRB
approval. We do recognize national
IRBs, but the local IRB has the discretion to act or not act. FDA's requirement is only that there is an
IRB approval.
DR.
NELSON: I have gotten in the middle of
research projects where there are 20 different IRBs that disagree with each
other, and they can delay implementation for years if they are clever enough. I hope that doesn't happen here.
DR.
KLEIN: Jay, I recognize that this is a
research project and therefore should go through IRB, but given what we said
this morning about a disease that we have no idea is even transmitted via
blood, and here we know that we have a disease that is transmitted via blood,
and we have absolutely outstanding evidence that there is going to be another
epidemic coming up very soon, do you not have the authority to waive that
particular requirement in terms of public health because, in fact, this is a
public health issue and one that I think we need to be concerned about?
DR.
EPSTEIN: Well, I will think we will
take that up with the lawyers.
DR.
HEWLETT: Yes, good answer.
DR.
KLEIN: As long at it's on the record.
DR.
NELSON: I think BPAC could perhaps
recommend that the ethical issues and the issues that relate to donors and that
the public health issues maybe supersede or are important enough that this
should be taken into consideration.
DR.
KLEIN: It is also the scientific and
medical data support this as best I can see.
DR.
EPSTEIN: I think the legal framework is
that the current regulation for donor testing is agent and disease specific,
and so it would require promulgation of new regulation to require test for West
Nile. That doesn't mean it couldn't be
recommended.
It
would be unusual for us to recommend unapproved tests, however, so there would
be a legal distinction while we are in the phase of test development versus
post-approval. We do have broad
authority under the communicable disease control provisions of the Public
Health Service Act, so-called Part 361, but that section of the Act also
requires rulemaking, which as you know is not a rapid process.
I
think that we can get a message out there, we can encourage it. Whether there are other mechanisms that
could be exercised to actually require it short or rulemaking, I am just not sure there are.
DR.
ALLEN: One question which I will get to
in a minute, but a comment on this. I
appreciate the bureaucratic dilemma in which you find yourself, but with regard
to the rulemaking, certainly when the HIV antibody test was first licensed in
March of 1985, the Agency didn't wait for rulemaking. They put out guidance which was very quickly acted on by blood
centers, and the rulemaking, if I remember, was delayed by several years before
it was actually finally accomplished.
Can
I move on to anther question at this point?
It is with regard to implementation of testing in blood collection
centers.
Given
that everything we have heard is that the level of viremia tends to be very low
even though these are highly sensitive tests in terms of their ability to pick
up low levels, do you have a sense in terms of what the recommendations are
going to be in terms of individual versus small pool testing in blood
collection centers?
DR.
HEWLETT: At this point, our standard is
100 copies/ml, and that is, of course, for the individual donation when tested
in a pool, but we are essentially holding to that standard at this point.
Unless
we find that there is a need, in fact, to lower that to something in the range
of 10 copies or 20, at this point, we don't have a good sense for what that
number should be below 100 copies.
The
100 copies seems to be it is achievable, and also we feel, I mean at this
point, we have no idea about the infectivity of titers that are below 100
copies, not that we want to find out, but hopefully, that is a number that will
stay as it has for the HIV pool and HCV pool test, but obviously, as tests
become more sensitive and as individual donation testing platforms get put in
place, because that is another issue, we don't really have high throughput
individual donation testing platforms in place as yet.
When
that happens, we may have to revisit the issue of the standard for a single
donation test, but at this point, I think we are going to stick with 100 copies
unless there is a need to re-evaluate that on the basis of any infectivity
studies and results that come out of those studies.
DR.
EPSTEIN: Just back to Dr. Allen's
earlier point, your recollections are exactly correct about HIV, however, do
recall that the recommendation for testing was for use of a licensed test, and
the current situation is that we are talking about investigational West Nile
testing.
DR.
NELSON: Revised West Nile virus
guidelines by Dr. Sharyn Orton.
D. Revised West Nile Virus Guidance
DR.
ORTON: I have been asked to go over the
revised recommendations for the assessment of donor suitability and blood and
blood product safety in cases of known or suspected West Nile virus infection
and just to give you a brief summary of how this differs from the document that
was published in October 2002. I also
included at the end of my presentation, a few of the questions and answers that
we have received on the document.
[Slide.]
As
background, in October of 2002, CBER released the final guidance for industry
dealing with West Nile at that time, and in May 2003, a revised final guidance
was released, and this guidance supersedes the October 2002 release.
[Slide.]
As
highlights of the current guidance, the recommendations that are in here were
worked on very extensively with recommendations from the CDC based on the
transfusion-transmitted cases from last year.
These
recommendations apply to whole blood and blood components intended for
transfusion and blood components intended for use in further manufacturing into
injectable or non-injectable products, including recovered plasma, source
leukocytes and source plasma.
[Slide.]
For
donor deferral, for current disease, clearly, donors should be in good health
as required and consistent with the CFR, but for diagnosed acute West Nile
virus illness, or infection, donors should be deferred for 28 days from onset
of symptoms or until 14 days after the condition is considered resolved,
whichever is the later date, and the 28 days allows for potential prolonged
viremia from studies that were done in cancer patients quite a few years ago.
In
the absence of West Nile virus compatible illness, an IgM-positive antibody
test result should not be grounds for deferral, and this is the same as was in
the previous guidance.
[Slide.]
For
suspected acute West Nile virus illness or infection, this is where the
guidance differs substantially. There is a predonation question to ask donors
about fever with headache in the week prior to donation.
If
yes, the deferral for the donor would be 28 days from the date of that
interview. This should be implemented
no later than June 1st of this year, and earlier if there were local reports of
epizootic or human infections.
This
question could be discontinued no earlier than November 30th of this year, and
later if human cases were still being reported in the area in November. If there were cases reported in November,
the deferral question should continue until there were two consecutive weeks
without human cases.
[Slide.]
This
question should be asked annually using the same time periods and the same
criteria. It is noted this question is
new from the previous guidance.
The
rationale for this was again working with CDC. Donors implicated in
transfusion-transmitted West Nile virus in 2002 were asymptomatic at the time
of donation, however, 9 of 14 reported symptoms compatible with West Nile virus
infection prior to or after donation.
[Slide.]
Fever
and headache were reported by approximately 57 percent versus less than 2
percent in non-implicated donors, and there was a survey that was conducted in
blood donor centers that suggested that the inclusion of this kind of question
related to fever with headache in the week prior to donation would result in a
less than 1 percent donor loss.
[Slide.]
For
potential association with transfusion-related West Nile virus transmission,
the donor should be deferred from 28 days from the date of the implicated
donation. This is the same as in the
previous guidance.
[Slide.]
For
post-donation information, any donor that reports a post-donation febrile
illness suggestive of West Nile virus infection particularly during the June 1
and November 30 time period, but keeping in mind the potential for those time
periods being changed as noted before based on local activity, these donors
should be deferred from 28 days from the onset of illness or 14 days after the
condition is considered to be resolves, whichever is the later date, and again
this date range is slightly new from the previous guidance.
[Slide.]
For
retrieval and quarantine of blood components, for diagnosed West Nile virus
infection or illness in the donor, in-date components from relevant collections
should be quarantined and retrieved promptly.
Relevant
collections are those occurring between 14 days prior to onset of illness and
either 28 days subsequent to illness or 14 days after the condition is
considered to be resolved, whichever is the later date, as previously noted. This is the same as the previous guidance.
[Slide.]
Donors
associated with a potential case of transmission to a transfusion
recipient. A donor is considered
potentially associated or suspect if a recipient of blood or transfusible blood
components is diagnosed with West Nile virus and received blood components from
that donor within the 28 days prior to the onset of the symptoms in the
recipient.
[Slide.]
Quarantine
and retrieval of in-date components from the suspected donor collected in the
period between 28 days before the suspect donation and 28 days after the
suspect donation. This is the same as
in the previous guidance.
[Slide.]
For
undiagnosed post-donation illness in potentially exposed individuals. Medical directors in general should use
their judgment particularly during the West Nile virus transmission dates or
local activity to determine what would and would not apply at their own
individual center.
The
symptoms should be consistent with West Nile virus infection. Current donation and any others that date
back to 14 days prior to the onset of symptoms in the donor. Pooled source
plasma, recovered plasma or source leukocytes already pooled for fractionation
do not need to be retrieved.
It
is believed that the viral inactivation methods are believed to inactivate
flaviviruses although validation has not been completed, and this is the same
as in the previous guidance.
[Slide.]
For
notification of prior transfusion recipients, when there is diagnosed West Nile
virus illness in a donor relevant to prior donations, the relevant units would
again be those dating from 14 days prior through 28 days after onset of illness
in the donor.
Establishment
trace records are recommended to be done notifying the transfusion
service. Again, recommendation that the
transfusion service notify physicians of prior recipients of blood or blood
components from that donor.
[Slide.]
If
the donor is a likely source of transfusion-transmitted West Nile virus, the
relevant units would be those dating from 28 days prior through 28 days after
the donation that was implicated.
Again,
the same process of establishing trace records, notifying the transfusion
service, and the transfusion service notifying physicians of any prior
recipients. Again, this is the same as
the previous guidance document.
[Slide.]
So
far, we have received four questions related to this guidance. The first was does the guidance apply to
autologous blood donors.
The
use of the question and deferral standards defined in the guidance for
autologous donors is entirely a matter of discretion of the individual medical
director, as is recommended in most of our guidance documents.
FDA
recommends that the medical director at each blood bank assess the risk and
make decisions about the autologous donation with the donor and the donor's
physician.
[Slide.]
The
next question was must the blood banks make changes in their donor interview
forms.
As
discussed in the guidance, temporary use of a separate printed sheet,
independent of the usual donor history questionnaire, will be acceptable in the
interim, however, SOPs must clearly specify how the donor will be instructed to
respond and how the response will be documented, and this is laid out in the
CFR.
[Slide.]
The
next question was if an establishment asks blood donors the question,
"Have you had a medical diagnosis of West Nile virus," would they
have to submit as a supplement because they weren't following the guidance
specifically?
The
FDA intentionally did not recommend that establishments specifically ask
potential donors about West Nile virus infection. If the establishment wants to ask about the infection, this would
be more than we recommended, and can be submitted in the next annual report
from the blood center.
[Slide.]
This
is not on the slides on the web site. I
just received this question yesterday, which is why it is included here. Once testing under IND begins, what is the
recommendation for product retrieval and quarantine upon receipt of a reactive
West Nile virus NAT result, because this is not addressed in the guidance.
We
specifically did not address it in the guidance because at the time we were
writing it, there was no test even under IND.
Our
current thinking is that a reactive West Nile virus NAT result on an individual
donation is consistent with evidence of West Nile virus infection and that the
recommendations under the diagnosed West Nile virus infection or illness in the
donor in the Retrieval and Quarantine Section should be followed.
[Slide.]
This
current guidance is located at this web site for anybody who needs access to
it.
Thank
you.
DR.
NELSON: Thank you.
Are
there any questions and comments? Yes.
DR.
CUNNINGHAM-RUNDLES: I am just puzzled
by that counterintuitive statement on one of those slides about donor deferral
in the absence of West Nile virus compatible illness and IgM-positive antibody
test should not be grounds for deferral.
That
just seems counterintuitive, no?
DR.
ORTON: Well, the antibody test, in and
by itself, it would be no, because IgM test can be positive for very long
periods of time without the donor being viremic, so someone just having a
positive antibody test would not preclude them from donating.
DR.
CUNNINGHAM-RUNDLES: That doesn't seem
to make immunological sense to me.
DR.
NELSON: It has been the finding that
IgM can persist for a year or more--
DR.
ORTON: Right, and the donor would not
be viremic.
DR.
NELSON: --after infection, but the
chronic viremic state has not been documented yet. Because of the frequency, if there are, in fact, 500,000 people
infected with West Nile virus in the United States, that is a substantial
proportion who might be IgM positive, and yet they are not viremic, you know,
past the first couple of weeks or 28 days of illness or at most.
DR.
CUNNINGHAM-RUNDLES: But if the IgM was
positive, that would be the situation where you want to either confirm or deny
it with the NAT.
DR.
NELSON: Yes.
DR.
CUNNINGHAM-RUNDLES: So, that is
eventually what will happen?
DR.
ORTON: No, we are saying, for instance,
if a donor came in and said, well, you know, I was sick and I had the test done
and it was positive, yes, you would need more information than just the IgM
test in and of itself. It, by itself,
would not defer a donor.
DR.
CUNNINGHAM-RUNDLES: I see. It would put them on a suspect list until
you knew more, I presume.
DR.
NAKHASI: No.
DR.
NELSON: I think all of the donors
during the time of an epidemic are all going to be tested, so you will have NAT
results on everybody. But IgM
positivity alone will not be a transfer deferral. That is my interpretation.
DR.
NAKHASI: You are right, Dr.
Nelson. As I mentioned in my
presentation, as soon as the IgM positivity comes up, there is no detection of
the virus, and therefore, as I said also, and Tony also suggested that the IgM
positivity can remain for two years and without the presence of the virus, so I
think all these points, that IgM positivity does not mean it in infective.
DR.
MARFIN: Just to add to Hira's comments,
when we look at the cases of documented encephalitis over the years, and we
look for virus in the serum, there have only been two cases over the past four
years in which we have found simultaneous IgM positivity and PCR positivity,
and that is hundreds and hundreds of samples, so it is a very, very unlikely
event, and, in fact, both of those events, the person was immunologically
suppressed, so there were very unusual conditions.
Our
rule of thumb is when the IgM is positive, there is not going to be any virus.
DR.
EPSTEIN: I just want to reiterate back
to Dr. Cunningham-Rundles' point that the expectation is that the vast majority
of units will be least be screened with investigational NAT.
DR.
NELSON: We will move to the industry
presentations and Dr. Dawson from Abbott.
Open Public Hearing
Presentations from Manufacturers
DR.
DAWSON: I am going to give a brief
update on Abbott's activities in regard to West Nile virus detection.
[Slide.]
The
last time I spoke we had a three-step overnight assay, and we have reduced the
assay format to a two-step, 3.5 hour test, and we maintained the robust signals
that we saw in the overnight test, as you will see in the next slides.
I
am going to talk just briefly about our performance on a CDC performance panel,
some confirmed antibody positives, and just a quick overview of an experimental
animal study that we did.
[Slide.]
Here
is the assay format. It's a two-step
assay, an anti-mu coated solid phase captures IgM in the first step after a
wash step, antigen and conjugate are both added, and the complexed IgM antigen
and conjugate are detected, and this takes 3 hours incubation and then a
half-hour exposure to substrate.
[Slide.]
Here
is the 2-step assay compared to the two-step assay on the 20-member CDC
proficiency panel where members 2, 4, 7, 9, 11, 13, 17, 19, and 20 are supposed
to be negative for IgM, and you can see in the dark blue, light blue, and
purple, the three assays being the Abbott 3-step, in the middle the CDC assay,
and on the right, the purple, on these different panel members, and on the Y
axis you have the S/N values.
You
can see on most of the samples, the S/N value on the 2-step assay is as high or
higher than on the 3-step assay, so we feel that reducing the timing of the
assay is not affecting our sensitivity.
[Slide.]
Here
is the 2-step assay versus the CDC assay in terms of S/N on the Y axis on
several different samples that were IgM positive only, we see a very robust
signal for IgM.
[Slide.]
Here
are samples that are positive both for IgG and IgM. Again, the Abbott test sample to negative values are very high,
very robust signals for most of the samples. Even after IgG has kicked in, you
still see a very strong IgM response.
[Slide.]
We
were involved in an experimental study infecting macaques intradermally with
West Nile virus, and we are seeing here the serologic profile. I am not showing you the entire testing that
has been done, but just focusing here on the IgM S/N values and the positive or
negative signal with RT-PCR. We use a
nested PCR for our assay.
In
this particular animal, you see that the PCR results are positive on days 1
through 7, and 9 and 10 post-inoculation.
The antibodies come up on days 9 and 10, so we get co-detection of IgM
and RNA on days 9 and 10. I am certain
you are going to see this in human cases.
I
think the CDC's experience last year was all on symptomatic cases and here you
are dealing with a different situation where these individuals are not
symptomatic that are blood donors, so you are likely to see co-detection of IgM
and RNA.
[Slide.]
Here
is a second animal where we see a clear distinction between the RNA detection
between days 1 and 6 and the IgM detection beginning on day 9. You see the IgM values go up to about day
21, where it peaks, and then goes down in the next days.
[Slide.]
We
are continuing studies with the American Red Cross. We have looked at some of the donor transfusion-transmitted
samples for IgM, and we will be look at the quarantined plasma units with both
the American Red Cross and the American Blood Centers with Dr. Michael Busch.
In
addition, we will be looking to be involved in both the Roche and Gen-Probe IND
studies. We are on the IND actually
with Gen-Probe and American Red Cross to look at the IgM status of nucleic acid
testing positive samples.
[Slide.]
So,
to summarize, we finalized our assay format.
It's an enzyme immunoassay on polystyrene beads. It has reduced it to a 2-step, 3.5 hour
assay.
For
IgM, we feel and we have heard from CDC that IgM is the preferred method for
diagnostics, and we see that the IgM response is fairly robust in the
symptomatic individuals that we have looked at, and we do see in experimental
infected animals that IgM is detected by about day 10, and we do see in some
instances co-detection of IgM and RNA during the infection process.
That
concludes my presentation. Thank you.
DR.
NELSON: Thank you.
Questions? Mike.
DR.
STRONG: For the dancing impaired, I am
sure 2-step is better than 3-step, but you didn't mention what hardware
platform your filter is on, what is your hardware platform for the assay?
DR.
DAWSON: It's Quantum or Commander, our
EIA system, polystyrene beads.
DR.
CUNNINGHAM-RUNDLES: I guess I am just
getting redundant, but I am wondering, you are looking at the IgM and the virus
test in parallel, and that seems like a good idea, but going back to what we
were saying a moment ago, if people are going to be remaining IgM positive for
a long period of time, wouldn't that unnecessarily exclude individuals, or am I
just missing the point on that?
DR.
DAWSON: Well, we are not suggesting to
exclude individuals based on IgM detection.
We are looking at the kinetics of infection in experimental animals,
looking to see what comes up what when and whether there is co-detection, how
long virus persists, and things like that.
DR.
CUNNINGHAM-RUNDLES: Right, but you do
say co-detection that you see, so that was in contradistinction to what was
said a moment ago.
DR.
DAWSON: Yes, and I think that there is
a difference in the studies. I think
that when you see people that are ill, they probably do have IgM already and
probably have cleared the virus from the bloodstream, although very likely it
is still present in CNS or else they wouldn't be having symptoms.
DR.
NELSON: I guess one of the arguments
you are trying to make is that you can't use the presence of IgM to be assured
that the donor is not still viremic because of the short overlap, but certainly
during most of the persistence of the IgM, the donor is not viremic, but there
may be a short overlap at least in this monkey model and maybe in some humans.
DR.
DAWSON: Yes. I am sure you will see it in humans.
DR.
EPSTEIN: I think the unifying principle
here is the idea that the viremia resolves quickly when the IgM appears, but
that the IgM then persists. So, if what
you are trying to detect is infectivity, the problem is that IgM is a
nonspecific marker because of persistence.
On
the other hands, it is a very highly specific marker for showing that someone
had a West Nile infection, therefore, it certainly plays a useful or will play
a useful diagnostic role.
Let
me just comment that there are some studies that I don't believe have been made
public yet, looking at samples from asymptomatic individuals during peak
outbreaks in certain areas in 2002. I
believe some of those samples have shown positivity concurrently for RNA and
IgM, and that is, in fact, not surprising based on earlier data and now your data.
DR.
DAWSON: Yes, and another part of our
data is that we did not find during the bleeds that RNA and IgM were
co-detected, these were not infectious.
We could not isolate virus from those.
DR.
NELSON: Do you plan to study samples
from plasmapheresis donors, because the interval between which the samples
would be collected could be rather short as opposed to whole blood donors where
you might not pick up this overlap?
DR.
DAWSON: I think perhaps we would study
them. If we did, it would be in association with the Roche or Gen-Probe
studies, we would be interested in doing those, yes.
DR.
FALLAT: What about the persistence of
the virus in Oregon related to organ transplantation?
DR.
DAWSON: We don't have any data on
those. I am sure that is very good
topic to bring up because, you know, in spite of being unable to find viremia
in patients that are having meningoencephalitis, they do have virus in their
brain, so it is not predictive of what is happening in other organs.
DR.
NELSON: Dr. Sherrol McDonough from
Gen-Probe.
DR.
McDONOUGH: Thanks to the committee for
the chance to present today.
[Slide.]
I
will be discussing the assay performance of the Procleix West Nile virus assay,
this is to detect West Nile virus RNA, discussing sensitivity and specificity,
reproducibility, consistent detection of true positives with the assay, and
some validation work we have done with anticoagulants.
[Slide.]
As
you heard already this morning, the analytical sensitivity for this assay is
quite high with sensitivity between 9 and 18 copies/ml using 95 percent
confidence intervals, and this was determined using both Lineage 1 and Lineage
2 virus from BBI, as well as transcripts.
Specificity
determined in our laboratory was 99.8 percent using initial reactive rate, and
upon retest, specificity was 100 percent.
[Slide.]
Now,
I would like to discuss the reproducibility study that has been performed at
Gen-Probe. The study includes results
from three different operators, two different reagent lots, three different
instrument sets, and was performed over six days.
The
study included four West Nile virus panel members, the first containing 100
copies/ml of heat-inactivated West Nile virus at 100 copies/ml, the second
transcript at 100 copies/ml, the third, 30 copies/ml, and the final panel
member contained negative plasma.
[Slide.]
The
overall results for this study are shown here. Out of the 360 negative panel
members that were tested, all 360 gave nonreactive results in the study under
all conditions. Of the 1,080 known
positive panel members tested in this study, all of those panel members gave
reactive results in the study, for overall agreement of 100 percent with
negative and positive panel members.
[Slide.]
Sources
of variability in the assay are further analyzed in this slide. We have looked at inter-lot, inter-operator
and inter-instrument variability, and those are shown on the right columns. You can see there is very low CVs from all
of these different factors.
The
highest CVs actually come from the inter-run and intra-run data, and all CVs
are less than 16 percent, so we feel that there is very high reproducibility
with the Procleix West Nile virus assay under the conditions that have been
tested.
[Slide.]
We
wanted to go ahead and test some known positive samples, so we went back and
looked at the positive samples that we tested, that were derived from the CDC
case investigations.
The
results on the left side were already shown at a previous BPAC meeting, and
indicate detection of different dilutions of these panel members, and the
results shown on the right side, that are boxed in, in green, indicate we have
equivalent results with our second scale-up lot.
I
would like to stop and mention at this point that we do have results starting
to come in from the Phase I testing with Red Cross, and testing of those
samples suggest that there are some extremely low viral load samples in that
population.
In
the case of extremely low viral load samples, pool testing may miss some
infected donations that will most likely be detected NEET [?]. It is not known if these low viral loads
units would cause transmission, as we have already discussed here at the
meeting, and will continue to gather data and provide that as it is available.
[Slide.]
We
have also looked at a number of anticoagulants for use in the assay. As you can see, we have tested K2 and K3
EDTA, PPT tubes, ACD, sodium citrate and heparin, all tested in plastic and in
certain cases, we have also looked at glass tubes.
As
shown at the bottom of the slide, whole blood and plasma units collected in
CPD. CDPA1 and CP2 are also fine to use
in the assay.
[Slide.]
So,
in summary, the Procleix West Nile virus assay has excellent sensitivity and
specificity. We have shown reproducible
performance between operators, lots, and instruments over time. Testing of known West Nile virus-positive
samples from CDC case investigations indicate consistent performance between
lots, and a range of anticoagulants has been validated for us.
Thank
you.
DR.
NELSON: Thank you.
Any
questions?
DR.
STRONG: Have you tested serum?
DR.
McDONOUGH: No.
DR.
BIANCO: Sherrol, just a definition of
extremely very low, is it 1, 2, 10, 1,000?
DR.
McDONOUGH: That is the question we
would all like to be able to answer today.
I don't have a definitive number for you yet.
DR.
NELSON: It is below 100 copies/ml
apparently.
DR.
McDONOUGH: That's a good guess.
DR.
NELSON: The pool size for the Procleix
is 16, pools of 16?
DR.
McDONOUGH: Yes.
DR.
NELSON: Next is Andrew Heaton from
Chiron.
DR.
HEATON: Good afternoon. Thank you for the opportunity to present an
update from the Procleix West Nile virus assay introduction, which I am sure
you are aware is a collaborative development between Chiron and Gen-Probe.
During
the next few minutes, I plan to comment on the development process, recognize
critical success factors, and draw attention to the regulatory approaches that
greatly assisted in this rapid development.
[Slide.]
Obviously,
the general goal was to develop a specific blood safety assay to prevent new
and previously undescribed blood safety risk in an extraordinarily short time.
[Slide.]
The
specific development goals of the current Gen-Probe collaboration included
development of an assay specific to the West Nile virus since this is the only
flavivirus associated with post-transfusion mortality in the U.S. We wanted to achieve a turnaround time that
would support timely product release testing and achieve a sensitivity adequate
to maintain the existing pooling strategy.
At
the request of our customers, we focused also on a test that could be used on
existing equipment to minimize the cost and to minimize the need for new blood
center space requirements which would have delayed the introduction.
We
also wanted the test to be similar enough to capitalize on our existing
operator expertise to minimize the need for new training. All of this had to be achieved by the
mosquito season.
With
only nine months available, assay development had to be rapid, and indeed it
was. An R&D assay was available in
just three months, a pilot in four months, and an IND with two amendments was
filed in March, April, and May.
Since
the software to export the laboratory results was so important, a NAT Tracker
upgrade was undertaken, and NAT Tracker 2.0 software was 510(k) cleared in May
of this year.
The
initial CDC comparison results have already been presented to this group, but
they showed improved sensitivity and specificity over the prototype CDC assay,
and currently, as you have heard, ARC repository samples are now completing
testing.
I
am delighted to report the development lot materials were shipped to blood
centers, which test more than 80 percent of the U.S. blood supply, last week,
and the first center, which is a Central Indiana blood center, started testing
with our Procleix test today.
[Slide.]
This
complex project benefited greatly from the earlier Procleix HIV-1, HCV assay
development. It started with customer
education and feedback which resulted in a full survey identifying customer
needs.
We
had a meeting with the customers in January to review equipment, space,
software needs, planed the workflow, and identify training needs.
Then,
we developed a timeline and shared that with our customers, so they could
integrate it into their planning process, and from this we identified the need
to develop a very comprehensive training program to train new operators and
existing operators in high-frequency throughput. In fact, we have trained 300 operators in the last six weeks.
Draft
instructions were provided to the customers for SOP development and equipment
was ordered in advance to mitigate the long lead time items, and this finally
was followed by installation and qualification, and over the last three weeks,
training has been completed, proficiency established, and the test kits now are
available for the customers to use.
I
am delighted to report that the assay performance has been generally similar to
the previous HIV/HCV Procleix assay.
There were minor changes in the materials, and we added color coding
both to improve compliance to procedures and to separate the two Procleix
assays. Throughput was maintained by
two rack training, which maintained the turnaround time.
[Slide.]
Not
a lot of compiled data is available, but there is enough available to assure
that performance results are similar to the introduction that we had with HIV
and HCV when we started some four years ago.
The
assay copy number sensitivity is similar to the Procleix assay and the reactive
rate is generally within the range predicted.
As
with any new assay, a supplemental test is critical. One wants to avoid inappropriate donor loss either for
cross-reactivity or positivity to viruses that do not cause post-transfusion
morbidity.
In
order to support this, we have developed an orthogonal confirmatory assay which
has a sensitivity and specificity comparable to the TMA assay. This is now available, we have a service
provided in a GLP facility with a turnaround time on the throughput requirement
that will be adequate to meet customer needs and to avoid unnecessary delay in
notifying donors.
[Slide.]
What
were the critical success factors?
Well, first, clear goals. We had a clearly expressed need and a
defined timeline, and a defined target sensitivity which greatly helped our
project team.
We
were greatly assisted by CBER availability to answer questions and indeed the
regulatory support was excellent. CBER
provided discretion to us to distribute draft materials to allow SOP development,
they abbreviated the requirement for multi-lot requirements, and they supported
the use above all of an IND approach to support IUO testing.
CBER
facilitated the process with a modular license application, pre-IND meetings,
ready availability of guidance, and rapid software review.
We
also benefited from very strong blood bank relationships. We worked with the blood banks to educate
them, we solicited their feedback and indeed received it in spades. We worked with the blood centers for support
and planning, and we secured their commitment and flexibility in
implementation.
The
TMA assay appears to be sensitive enough to meet the pooling requirement and
meet the FDA standard, and it was developed rapidly to a highly specific
assay. It has turned out to be robust
in practice and our dedicated development team, which was a multi-disciplinary
and very hard-working group, ensured our success.
What
do we believe are the lessons to be learned going forward?
[Slide.]
Well,
first, the TMA assay is extremely robust.
It is developable and could cover other viruses as needed, it has proved
to be sensitive and virologically very specific, and the modularity of the
equipment that we use supports flexibility.
NAT
also allowed fast-track development at a rate that could never have been
achieved with previous generations of NAT or EIA technologies, and indeed the
only outstanding issue is the need for FDA guidance under the blood center
obligation to seek local donor IRB approval in addition to national IRB approval.
As
we heard earlier, FDA enforcement discretion may be needed to help resolve this
if we are to meet the July 1 timeline.
It required investment and commitment by the CDC for analysis, FDA for
assigning the goal and helping us develop a team to support it, CBER for their
regulatory support, the companies for a massive investment in increase in
priority, together with the NIH who took the lead in providing funding, and
lastly, the blood bank support to get it done.
It
was this combination from all sectors of the blood bank industry that allowed
us, Chiron and Gen-Probe, to have a Procleix test available in time to meet the
mosquito season.
Thank
you.
DR.
NELSON: Thank you.
Questions?
DR.
ALLEN: Let me just play the devil's
advocate for a second, Andrew. If you
are looking at blood collection centers only, and I realize that your market
share is going to go well beyond that, I could argue that in actual fact, a
second-level confirmatory test is unnecessary for West Nile virus, unlike HIV
and some of the others, in that the diagnosis itself doesn't really carry any
social stigmata, the deferral is for a temporary period of time, and in actual
fact, it doesn't matter if you have got a few false positives that are in
there, it is not going to really affect the donor population much.
I
certainly understand beyond that, that the confirmatory test probably is a very
important tool to have.
DR.
HEATON: That is true to an extent. If you take our Procleix HIV/HCV assay, we
have I think about a 1 in 30,000 false positive rate, well, a positive rate
that cannot be confirmed, but nevertheless, if you think of it in donor terms,
you like to have an orthogonal assay to confirm whether the donor is really
infected or not.
For
consignee notifications, certainly the hospital would like to know whether the
unit was truly positive, and then for lookback notifications with the
significant medical-legal issues, to have that confirmatory assay is pretty
critical, so we very much took the position that we wanted to have a good,
solid GLP-supported confirmatory assay as we launch the product.
DR.
NELSON: The thing I am still a little
confused about is all the IRB issues and how many IRBs have to approve
this. I know that I have had research
projects that were held up for a long time by an IRB that didn't understand
what was being done, or didn't meet very often, or if they met and approved it,
they couldn't get people to sign the approval letter, and that delayed it for
months.
Is
that a real problem here?
DR.
HEATON: Well, the critical issue here
is there is a national IRB, and it has approved the study and the consent form,
so that worked very well.
DR.
NELSON: The national being the American
Red Cross?
DR.
HEATON: No, in this case, the Western
IRB.
DR.
NELSON: Oh, the Western.
DR.
HEATON: They have approved the
protocol, however, because of new regulations, they added a rider in their
approval and said that where there was a local IRB that was applicable, by
donor group, local approval should be sought.
Well, obviously, if you are running blood drives, some companies have
IRBs.
If
you went to a hospital, obviously, they would have an IRB, but if you went to
Chiron Manufacturing to collect our employees, we wouldn't have an IRB, so that
forces the blood center to find out does the donor group have an IRB, and, of
course, the moment you communicate with them, they would want to look over the
information, and they will delay the approval process. So, this is really a bureaucratic
requirement rather than a specific research or medical question.
DR.
NELSON: Well, presumably, every
university and government hospital in the country probably has an IRB, all of
which could interfere hopefully. I mean
they are designed to improve or to review issues of research subjects, but to
me, even though it is an unapproved test, it is a different issue. I mean these aren't in a way research
subjects, they are blood donors.
DR.
HEATON: One of the points that was made
earlier is the implementation of this type of assay, it's so much part of
routine blood banking, it is scarcely research, it is really operational
implementation under very controlled circumstances, but nevertheless, by virtue
of the IUO regulations, it does require IRB approval, and that then rolls you into
all the sequence of IRB cross coverage issues.
DR.
NELSON: Do you have to specifically
notify the donors that they are being tested for West Nile virus, as well as
hep C, HIV, syphilis, and other things?
DR.
HEATON: Yes, indeed, you do.
DR.
NELSON: That's not a bad thing, that's
okay, that's easy enough, but I can see where it could be delayed.
DR.
HEATON: So, currently, at this point, I
believe the Western IRB, the chairman of the IRB is in contact with the FDA
attorney to seek clarification on the law, and that is the only thing that
might hold up implementation on July the 1st.
DR.
NELSON: The final industry
presentation, Dr. Jim Gallarda from Roche.
DR.
GALLARDA: I would like to start by
reading a headline from a news article that came out two days ago from
Newsday. This is by a staff writer
Delthia Ricks, and her article is entitled, "Virus hits blood supply. Donations to be checked for West Nile."
The
staff writer says, "As teams of federal health investigators were probing
the new viral threat of Monkeypox last week, others were quietly racing to
track an increasingly familiar one that has stalked the nation for four years
running West Nile disease."
Delthia
goes on to say, "This year, however, in a stunning example of fast-track
scientific development, blood collection agencies will have for the first time
a way to screen donated blood for the virus."
Nine
months ago, these tests were nonexistent, so I agree with Andrew, the past nine
months have been more than fast-track, they have been frantically tracked, and
for Roche, this was all the more remarkable because it was January 31st when we
had a big meeting, and we decided to provide a fully automated solution for
sample prep and kinetic PCR for West Nile.
So,
what I would like to do is give you kind of highlights of what we have been up
to since the last March BPAC.
[Slide.]
So,
in March at BPAC, we had three things we were talking about. We were talking about filing an IND and we
were talking about the phases of that IND.
We filed the IND on April 21st, and the Agency worked rapidly to provide
guidance and ultimately approve that IND later.
In
our IND, we have described two phases.
One is Phase I where we were really looking at issues related to
workflow and training, and these were testing panels provided by Roche that had
both positive and negative members, as well as unlinked samples.
We
tackled five sites, three in the U.S. and two in Canada, and we completed those
studies in the end of May, after which we immediately began our second phase
activities to train and install the rest of the sites, so there are a total of
11 sites in the U.S. and three in Canada.
That
is the Phase II testing, which really is to assess the safety and effectiveness
of the system and detecting West Nile virus, however, based upon the
discussions at the November BPAC and also at the November workshop and the
March BPAC, to not only go after West Nile but to see if we could deliberately
design the assay to include the other members of the Japanese encephalitis
family serocomplex.
So,
our intention is to really specifically try to get a claim for West Nile, but
to also hopefully show demonstrated effectiveness for other members of the JEV
family.
[Slide.]
Late
breaking developments. This is not in your
handouts or on the web site, but on Monday, June 16th, South Bend Medical
Foundation began prospective testing under the IND, and Gulf Coast Regional
Blood Center began yesterday to do the same thing, and during this morning's
session I got several phone calls from the NAT lab director at Gulf Coast who
said everything went flawlessly last night on their first run.
We
have the remaining sites targeted for July 1 or earlier start date.
[Slide.]
This
is the system that we put together, the basic components. We have a Hamilton Pipettor, which is
creating pools of 6. This is driven off
of software, which is Windows 2000 operating system, and the software is Part
11 compliant.
The
pools are transferred to the COBAS AmpliPrep, which is the automated sample
extraction device of the system. At the
end of an extraction, the AmpliPrep will automatically also add working Master
Mix to the extracted nucleic acid.
AmpliPrep extracts both DNA and RNA, so if we have to come back later to
develop Monkeypox assays, we would expect to have captured that nucleic acid
already with this system.
The
COBAS TaqMan then provides a kinetic PCR output for West Nile.
[Slide.]
I
would like to go over briefly the nonclinical performance studies and a
capacity analysis that we did in support of our IND filing.
[Slide.]
We
looked at 400 random volunteer donors in preclinical specificity studies from
both low and high prevalence areas. We
looked at analytical specificity studies with non-West Nile virus
microorganisms, and limit of detection studies with the CDC lysate.
In
addition, we looked at both Lineage 1 and Lineage 2 isolates for analytical
sensitivities, and also tested early studies with other members of the JEV
family.
[Slide.]
So,
for the 400 volunteer donors, this breaks down to 200 that were low-prevalence
sourced from California, 200 from the Chicago area. This is not during the peak of mosquito season of 2002. This is in the May time frame.
We
are going after a West Nile virus target, as well as an internal control in
each sample. This is a full process
control, which means it's an armored RNA, and it encapsulates the RNA, so it
mimics a virus, and this is important because it allows for us to conclude with
confidence that the entire process is working as expected from the lysis step
all the way through the amp detect step.
The
armored positive control is provided in each batch. We get CT values, which is the cycle number of where you start to
see fluorescence grow, so if a number is reported, that means it is a positive
result. The IC values for the positive
control was positive, as was the target, as you would expect. The negative control was negative for the
target, positive for the internal control.
All
samples were negative for the target, and yet positive for the armored internal
control, and we had very tight CVs around with a 1.18 standard deviation. One hundred percent of the negative samples
were negative, 100 percent of the ICs associated with those were positive. That pattern repeated itself for the 200
high prevalence donors.
[Slide.]
We
looked at several categories of viruses and bacteria, as well as Candida
albicans, to look for potential cross-reactivity to the system.
[Slide.]
Of
these categories, we tested 125 samples.
All of them were negative. There
were no false positive test results observed, and of the associated armored
internal controls were positive in each case.
[Slide.]
This
is a regression analysis looking at the limit of detection studies with the CDC
lysate. We looked at two different
systems and we made 10-fold dilutions starting at 1,000-fold down to 108,
and then we asked what kind of CT response would be generated in each of these
two systems.
So,
this shows a linear regression and with the TaqMan output, you see lower CT
values, that is, the growth curves appear earlier in the assay with high titer
samples, and then the CTs start to become larger as you get lower and lower
inputs. So, there is a very nice linear
regression.
The
bottom line is for each of the two systems, at 107, we still were
generating positive CT values, at 3 times 108, one started to drop
out, and one remained positive, so we were comfortably detecting the lysate at
107 dilution.
[Slide.]
Looking
at analytical sensitivity with the IMPATH/BCP Lineage 1 isolate, taking the
manufacturer's stated claim and diluting those from 25 copies down to 1
copy/ml, we were detecting 100 percent of 24 replicates in the small study even
at 5 copies/ml, and we started to see dropouts at 1 copy/ml.
We
didn't have sufficient information to generate probit on this for an
interpolative method, however, based on this, we would expect the estimated
sensitivity to be less than or equal to 5 copies/ml.
[Slide.]
For
the BBI Lineage 2 isolate, we again, based upon the manufacturer's claimed
titer, we made a similar dilution series, and we are testing replicates from 25
down to 1 copy/ml. We were positive
with 100 percent detection at 10 copies/ml.
We started to see dropouts at 5.
Doing
a probit on this, we generated a 7.4 copies/ml central tendency with a
confidence interval ranging from 5 to 16 copies/ml.
[Slide.]
We
were able to obtain additional isolates from ATCC. We got a third West Nile virus isolate, as well as a St. Louis
and a Murray Valley encephalitis virus, and all of these isolates were
detected. We are in the process now of
generating transcripts for Japanese encephalitis virus and additional isolates,
and we are trying to procure clinical samples, as well, to expand this data.
[Slide.]
Gulf
Coast did a really nice capacity analysis, oh, I think it's probably now four
weeks ago, where they started pooling at 6:30 in the morning, and they reported
an average pooling time, it wasn't 20 minutes, it was 19.5 minutes.
They
put their first extractions on the COBAS AmpliPrep at 0649. Amplifications began at 0900. The total throughput with two FTE operating
two systems was about 1,600 samples in 12 hours. This is a correction.
If
you extrapolate, you are looking at a system that has two shifts, that's
running 16 hours using two of these Taq screen West Nile systems with two FTEs
working on the systems, we would expect those to accommodate 700,000 samples
per year.
[Slide.]
So,
the current status and issues with our IND is that all 11 U.S. sites and 3
Canadian sites are installed and they are preparing for linked testing on or
before July 1. We are doing a software
upgrade right now to the pooling and data management system that has been
successfully installed in about three quarters of our sites.
We
have interest in expanding to other sites, and we have had some discussions to
pursue that further. We have had
several sites request can they assist local public health labs in testing
non-blood bank applications or testing patient samples, and our IND right now
doesn't allow that, although I was asked to bring it up with the Agency to see
if that might be in the interest of public health, something that would be
possible to do.
There
is also a need to have national prevalence data that would be very useful to
capture what is happening on a nationwide basis with both prevalence and
incidence in West Nile. I know Mike
Busch and Steve Kleinman have been working through REDS and NIH to put together
a means by which we can capture that in timely fashion.
There
was an issue with USDA permits for West Nile virus panels. We got that cleared up. We have an umbrella license for us to ship
samples to the sites, as well as them to ship positive samples to the
confirmatory lab.
I
think Maria and Indira have been working on standardizing a much needed West
Nile virus panel, which is encouraging to see.
Getting
back to the fast-track scientific development, this was an enormous undertaking
for Roche.
[Slide.]
However, we really called upon resources all over the
world. We had an outstanding instrument
and software group out of Penzberg, Germany, and Rotkreuz, Switzerland. We had development and marketing in
Pleasanton. The design of the system
for West Nile, as well as the broader JEV, came out of our Alameda folks. Indianapolis has done an astounding job in
stepping up and getting involved in supporting the sites, because this is a
rather enormous undertaking, as you can imagine.
Branchberg
is our site of manufacturing and also our outstanding colleagues in Laval,
Quebec, Canada, for the Canadian customers.
Thank
you very much.
DR.
NELSON: Thank you.
Questions? Jim.
DR.
ALLEN: Two questions. First, do I understand that your
implementation, you are recommending small pools of 6 samples?
DR.
GALLARDA: Yes. When we were going to these early meetings
last year, and we were trying to understand what does a plaque-forming unit
mean in copies, everyone's consensus was, well, it's low. So, we were debating whether to keep pools
of 24 or do something lower, and we decided that in order to try to maximize
the sensitivity, but still maintain the throughput required for our sites,
pools of 6 on that system would do it.
So,
if we are bouncing around 10 copies/ml, then, you would expect to detect a
sample pretty readily at 60 copies/ml if it's diluted 6-fold in a pool of 6, so
that was our rationale for that.
DR.
ALLEN: The second question. You showed a couple of slides on the
analytical sensitivity, and as you went on out to the dilutions and dropped
below 5 copies/ml down to about 1 copy/ml, that you began to get loss of
specimen detection.
Yet,
your internal controls, you were still at 100 percent detection.
DR.
GALLARDA: Right. That's a good question. I think, first of all, on that 1 copy/ml, I
think that is not going to be the standard.
I expect that data to look more like the Lineage 2, so we will be at 7
and 10 copies/ml.
With
regards to the internal control, we want to make sure that we have a level of
control that statistically, would not cause failures because of a Poisson
effect, whereas, 5 percent of the time, you would expect to have a negative
result simply because you didn't sample an armored particle, but at the same
time, be informative, so if there is a process failure, that internal control
is going to be able to tell you, you have a failure, so you shouldn't trust the
result.
So,
this is why we would expect to have a level of internal control that ensures
that we can detect a process failure, but not a failure because of stochastic
variation.
DR.
KLEIN: Will your license application
provide for eventually using single specimens, as well as pools of 6?
DR.
GALLARDA: Right. We are going after both minipool and a
single unit testing strategy
DR.
NELSON: I know the viruses in a JE complex
are JE, there is dengue, there is St. Louis, there is West Nile, and Murray
Valley, and all of these I think are pathogens, but there are arboviruses that
aren't really pathogenic, are they? Are
there others in this complex that might be NOIS?
DR.
GALLARDA: That's a good question. We searched the entire gene bank database
for homologies to do potential cross-reactivities, and the nice thing about
this is that you really need three independent sites to work together to get a
hit. You have two primers at the end,
either one of which is not sufficient to generate a result. Together, they are
not sufficient to generate a result.
Then,
you need a third target area that the probe lights on, and so the nice thing
about this strategy is you have a multiplicative requirement in order to
generate a result, so I would expect that unless it has those three
requirements where you have significant homology, they will not be detected in
the assay.
DR.
FALLAT: Did I understand you that you
are able to test for more than one virus in a single throughput?
DR.
GALLARDA: Correct.
DR.
NELSON: Thanks. Very good.
We
has some people who wanted to testify in the open public hearing.
First,
Kay Gregory.
MS.
GREGORY: Thank you. You have been hearing from test
manufacturers, and we wanted you to hear from the blood banking community, as
well.
The
American Association of Blood Banks, America's Blood Centers, the American Red
Cross, and the Armed Services Blood Program have taken a number of actions over
the past several months with regard to West Nile virus. These actions relate to increasing blood
safety, education, communication, and ongoing monitoring.
First,
let's talk about testing. Since
November 2002, the national blood banking organizations have committed to
implementing nucleic acid screening tests for West Nile virus as they were
developed by commercial manufacturers for implementation under investigational
new drug exemptions.
Two
manufacturers you have heard from, Roche and Gen-Probe/Chiron, have been
successful in obtaining such FDA approval and it now appears that most, if not
all, U.S. blood banks will have minipool West Nile virus NAT donor screening in
place on or about July 1, 2003.
It
is estimated that approximately 25 to 30 laboratories will be performing this
test nationwide. Implementation of donor screening by early July represents an
extraordinary effort to develop and implement this testing in only seven months
under cGMP constraints, so as to reduce the risk of West Nile virus transfusion
transmission during the 2003 mosquito season.
Some
of our other measures. To our
knowledge, most blood collection facilities have now added an additional
screening question about fever and headache in the past week to their donor
questionnaire as recommended in the May 2003 FDA Final Guidance entitled,
"Revised Recommendations for the Assessment of Donor Suitability and Blood
and Blood Product Safety in Cases of Known or Suspected West Nile virus
infection."
Subsequent
to the 2002 mosquito transmission season, blood collection facilities have been
stockpiling frozen products for use in the event of local human West Nile virus
infections prior to the availability of West Nile virus screened frozen plasma
this summer.
In
the area of communication and information sharing, the blood banking
organizations have established a task force that meets by telephone conference
with the PHS agencies, FDA, CDC, NIH, in order to share the most recent
epidemiologic data on West Nile virus infection and to discuss policies to
reduce the risk of transfusion transmission.
This task force has been meeting regularly since early May, so if you
wonder what I do with my time.
Blood
collection organizations have been active in disseminating information to
hospital transfusion services,
clinicians, and the public about the risks of acquiring West Nile virus
infection via transfusion.
Materials
distributed to hospitals have advised that there will remain a small risk that
West Nile virus could be transmitted by transfusion in 2003; that, prior to
West Nile virus donor screening, hospitals should review their current
transfusion policies, and that any small risk of West Nile virus transfusion
should be balanced against the benefits of the indicated transfusion.
We
have been coordinating blood bank activities with the Public Health
community. We have worked actively with
the CDC and representatives of state health departments on several issues. A joint protocol is being developed to
investigate potential cases of transfusion-transmitted West Nile virus that
occur after July 1, 2003.
This
protocol will involve coordinated activities conducted by local health
departments, hospital transfusion services and blood collection facilities, the
CDC, and blood bank organizations and laboratories; its objective is to
determine if West Nile virus transfusion transmission is still occurring in
2003 despite the implementation of minipool West Nile virus NAT and enhanced
donor deferral policies.
A
national guidance document concerning the exchange of information between blood
collection agencies and state health departments is also under
development. This document is intended
to serve as a template for interactions that occur on a state-by-state level.
The
document addresses the anonymous reporting of West Nile viremic but clinically
well donors by the blood collection facility to the health department as well
as the reporting from the health department to the blood collector of a recent
blood donation in a person who is ill with suspected West Nile virus
illness. The latter activity is
important so that untransfused potentially infectious components can be
retrieved in a timely fashion.
In
summary, the national blood banking organizations will continue to monitor the
clinical epidemiology of West Nile virus in 2003 as well as the yield from West
Nile virus donor screening. It is
anticipated that measures that have been or will soon be implemented will
significantly reduce the risk of acquiring West Nile virus infection through
blood transfusion.
Thank
you.
DR.
NELSON: Thank you.
I
think the NAT data on blood donors is going to be very interesting. I mean if we would predict that 500,000
people infected is 0.25 percent of the U.S. population, and 3 to 5 percent of
the adult population donates blood, we may not see many, but we may, in fact,
see some cases, and we may be surprised by what we see, and we may be able to
actually improve the estimate of how many inapparent or subclinical infections
there are with West Nile virus.
So,
I think this is going to be important public health data, as well as very
important in protecting transfusion recipients. I am glad that there is a system to analyze it and hopefully look
at the data more carefully that we get.
DR.
DiMICHELE: I was just wondering if
there has been any financial analysis undertaken yet as to the implementation
of this and what it is going to add to the cost of a unit of blood.
MS.
GREGORY: I think we have all been so
busy doing everything else, we maybe haven't gotten to that yet.
DR.
STRONG: In terms of the state by state
communications, I don't think we have quite worked that one out yet. How do you see this information being
transferred to the state and local public health services?
MS.
GREGORY: You should see that document
probably Monday with a detailed explanation of how to do that. It is currently being approved by all the
various organizations. There will be
provision for you working it out individually in your area, so we are not
trying to say everybody has to do it exactly the same way. There is going to have to be a lot of
communication between you and the state health lab.
DR.
SCHMIDT: That is a very large
issue. I think the public is going to
be dealing with monkeys and SARS and prairie dogs and this, and I think the
result on what we are doing is going to grossly affect if people are going to
donate blood and if people are going to receive blood, and I don't think it is
something that can maybe just be taken care of by the blood bankers.
I
think this is a very high level someplace.
I don't know who is higher, but important public health thing that needs
to be addressed. Now, we have read some
information in medical journals that is kind of scary. I think everybody has to be very careful to
say the truth, but to say it in such a way that it doesn't cause a national
panic, and just the 500,000 data, well, that means that 500,000 units of blood
are contaminated and, of course, you don't control the press, but we really
need to help them out with how they do it.
I
just think a statement coming from the American Association of Blood Banks,
with a lot of other people, isn't going to do it.
MS.
GREGORY: I think you are probably
right, but we have been developing this in coordination with the CDC and with
the public health labs. There have been
a lot of people involved in it, it isn't just the blood banks, and believe me,
we are all very much aware of that kind of concern and we have the same concern
that we want to make sure we are doing the right thing, and not scaring people
to death at the same time.
DR.
DiMICHELE: I want to congratulate
everybody involved in how quickly this has proceeded with respect to blood
transfusion, but I wanted to ask what is going on with respect to surveillance
for organ transplantation because West Nile was also transmitted by organ
transplantation.
Earlier
today, we heard animal data suggesting that other viruses, such as SARS, may
actually remain in organ systems longer than animals will remain viremic, so
both of those viruses are very problematic with respect to organ
transplantation. I just wonder whether
that is where the attention is going to be turned to next or where the FDA
might go with that.
DR.
EPSTEIN: FDA doesn't regulate organs
for transplantation, but I know there is interest in West Nile testing.
DR.
FREIBERG: My name is Glen
Freiberg. I am with Gen-Probe. I would be happy to address your question.
I
think Dr. Hewlett's slides touched on it, and that is that our company does
plan to amend our INDs a little bit later this season to include it, and FDA
already has a guidance to follow for that indication. It is just going to take a little more time to get it together.
DR.
STRONG: Just to add to that, the
complication really is with cadaveric samples.
If we can get premortem plasma samples, they are really essentially
qualified for these assay, but for a cadaveric sample, which is essentially a
serum sample, which is why I asked the question earlier, and sometimes not the
best condition, that requires a different set of preclinical testing to qualify
them.
There
is now somewhere in the neighborhood of a million tissue transplants done per
year in this country, and we know that they are fully capable of transmitting
viral infection. I think that is even
more important.
DR.
CLEMENT: Tom Clement [ph], Roche.
I
would like to add to what Glen is saying.
Roche is also looking at expanding or amending our IND to cover cadaver
fluid and other things.
DR.
NELSON: At least non-cadaveric organ
donors, they have to undergo the same screening as a blood donor, right, in
terms of infectious screening?
DR.
STRONG: In general, that practice is
followed, but as has been pointed out, it is not regulated by FDA. It's a different organization, and it is not
quite as carefully regulated as blood is.
Good tissue practices are now still under consideration and haven't been
implemented, but should be soon.
DR.
NELSON: There is also the issue of
massive transfusion of a potential organ donor prior to death and a false negative
test, I guess.
DR.
STRONG: That's true, but everyone has
pretty much implemented hemodilution algorithms to take that into account.
DR.
EPSTEIN: Just to comment that with
regard to tissues in general, we have a policy on human cell tissue and cell-
and tissue-derived products, which calls for rulemaking in three domains -
registration and listing, which is already in effect with the Final Rule, donor
eligibility requirements for which there is a proposed rule, but not yet a
final rule, and good tissue practices, for which there is a proposed rule, and
not yet a final rule, and, of course, there will be a need for guidance
documents to be finalized in conjunction with those rulemakings.
So,
it is not that it is not going to be under a regulatory umbrella, however, the
regulatory schema is not yet fully in place.
But we do have a lot of active dialogue with various parts of the tissue
industry and there is, of course, strong interest in trying to apply a suitable
test, such as NAT for HIV and HCV, as
well as the emerging test for West Nile.
DR.
STRONG: Might I ask FDA, is the plan,
once these regulations are implemented, to have that come before this advisory
committee, or will it be a separate advisory committee?
DR.
EPSTEIN: Well, I can't answer that at
this time. To date, the issues
pertinent to tissue regulation have been brought to the Blood Products Advisory
Committee as a matter of convenience, although some issues have been brought to
other advisory committees, for example, related issues affecting cell and gene
therapy have been brought to other committees, but there has been some
discussion whether another advisory committee would be needed, but I just can't
say that that will happen.
DR.
DiMICHELE: I have a slightly different
question, and it is actually for my own edification, and maybe this was
discussed in March since I wasn't here, but does anyone know why there is
persistence of IgM antibodies with this virus?
Is there a precedent, and what might be some of the immunological models
for this?
DR.
NELSON: I think IgM persists in
brucellosis for quite a while, for over a year, and there are other infections
where this happens, although it is usually a marker of a recent and an early
primary immune response.
DR.
GOLDSMITH: I think it depends on the
antigen, and I think there is actually a pattern, and it relates to the ability
of the antigen to stimulate B cells in a T-independent fashion, and that in
various infections, you do get persistence of IgM for very long periods of time. Brucellosis is a good example.
DR.
BIANCO: The other example is
pneumococcal polysaccharides. Actually,
there is no IgG formation in many of these, of some of the complex
polysaccharides when they are injected, and it is just IgM that stays
there. The antigen is retained in
macrophages and probably released in very small amounts, and you don't see the
switch.
DR.
STRONG: Just as a follow-up to that, in
that case, for example, that is a direct B-cell mitogen, and I suspect that
some of the fragments of this virus probably are acting the same way.
DR.
SCHMIDT: A comment on a different
subject. The reason that the blood
industry, if you want to call it that, survived HIV is that in states, we have
something called blood shield laws which protect blood transfusion against
implied warranty, and they came out as a result of hepatitis, that having a
virus in a bottle at that time of blood was different from having a mouse head
in your Coke can, which was bad under state laws.
DR.
NELSON: Probably safer.
DR.
SCHMIDT: Well, for example, the Florida
law says that if you do whatever is current scientific knowledge, you have done
the best you can.
Now,
one of the problems with HIV was there was this great discussion of surrogate
tests. Before there was a specific test
for HIV, there were surrogate tests, and a lot of trial lawyers really worked
this over very well, and there were very few, if any, successes. Jim, you may remember that better than I
would.
But
all the state laws are a little different. I am just thinking that there is some question which I guess
potentially could be raised about having to do a test under an IND versus a
licensed test, and I don't think it relates to the work of this panel, but it
is something that sometimes the Federal Government doesn't think about these
idiosyncrasies of state laws where you end up doing things to prevent yourself
from getting sued even if you are all right under the law.
But
it could happen again in some way or form or other because trial lawyers and
defense lawyers can come up with all sorts of things.
DR.
NELSON: Mary Gustafson from Plasma
Protein Therapeutics Association, PPTA.
MS.
GUSTAFSON: The Plasma Protein
Therapeutics Association appreciates the opportunity to provide comment to the
BPAC on the issue of West Nile virus.
PPTA
is the international trade association and standard-setting organization for
the world's major producers of plasma-derived and recombinant analogue
therapies. Our members provide 60
percent of the world's needs for source plasma and protein therapies.
These
include clotting therapies for individuals with bleeding disorders,
immunoglobulins to treat a complex of diseases in persons with immune
deficiencies, therapies for individuals who have alpha-1 antitrypsin
deficiency, albumin, which is used in emergency room settings to treat
individuals with shock, trauma, and burns, among other things.
PPTA
members are committed to assuring the safety and availability of these
medically needed life-sustaining therapies for people who depend on them.
At
the March BPAC, this committee voted on two questions that affect the
plasma-derived therapeutics industry.
Those questions involved the need to use specific West Nile virus and
viral inactivation studies and use of plasma donor testing to provide an added
measure of safety for West Nile virus.
In
response to these recommendations, PPTA requested a meeting with FDA to discuss
technical issues. On April 29th, PPTA
staff and members of the plasma therapeutics industry met with FDA.
For
one, we presented data packages to FDA that provided data that supported the
summary information presented to the committee at the BPAC.
In
addition, PPTA presented a three-part approach to addressing the West Nile
virus issue. The PPTA proposal includes
using risk assessment--and this is assessment of relevant epidemiological
factors--and worst case challenge to plasma therapies. We used the best available data at the time,
and truly used worst case, and one of our member companies called it "a hurricane
during an earthquake situation."
Also,
use of verification studies, and these would include studies demonstrating
efficacy of virus reduction with model and relevant viruses, donor screening
and surveillance in terms of continued surveillance of the West Nile virus
epidemic and sentinel parameters for evaluating industry actions using the
blood screening as a public health sentinel system for the disease.
FDA
did not say that they agreed with the three-part approach, however, they
provided feedback that was consistent with this approach. For one, they said the risk assessment could
be improved by having more data, that the data so far on donor titers and pool
titers was somewhat soft.
Also,
in terms of verification studies, FDA would like to see two independent process
steps each having a 4 log or greater reduction in virus.
Currently,
PPTA member companies are completing its risk assessment by evaluating West
Nile virus titers in plasma pools containing plasma collected during the height
of the 2002 epidemic, and initiating plans to participate in surveillance of
blood donors during the 2003 season in terms of looking at titer information
and hopefully, duration of viremia.
These
studies are in addition to studies conducted using relevant and model viruses
to verify that current plasma fractionation processes are effective in
inactivating West Nile virus.
In
conclusion, the plasma therapeutics industry works diligently to keep our
therapies safe. We look forward to
continuing our dialogue with FDA regarding the safety of our products with
respect to West Nile virus.
DR.
NELSON: Thank you.
Questions? Yes.
DR.
STRONG: You will be testing, correct,
the plasma pools?
MS.
GUSTAFSON: Yes. Member companies are going back and looking
at plasma pools from plasma collected primarily during the first three weeks of
September of last year.
DR.
STRONG: Are you doing pool testing,
what pool size?
MS.
GUSTAFSON: That is testing the plasma
pools that were used for fractionation.
DR.
STRONG: I was talking about screening
tests as the tests become available.
Generally, your pool sizes have been larger than--
MS.
GUSTAFSON: That is why our approach for
this season is to kind of piggyback with existing studies in blood donors using
the smaller pools, because you are right, the current technology for testing
plasma donors are 512 pool.
DR.
NELSON: So, you will test with smaller
pools?
MS.
GUSTAFSON: At the present time, what we
are going to have, what we have initiated discussions, is to look at the
testing that is being done in blood donors to provide an indicator of the
degree of positivity, the titers, and hopefully, the duration of viremia.
DR.
NELSON: It could provide some valuable
data, I think.
DR.
EPSTEIN: Could you just clarify, Mary,
what I hear you saying is that there is no plan to prospectively screen source
plasma donors, however, you will be cooperating in obtaining surveillance
donors, the surveillance data as whole blood donors are screened, is that a
correct statement?
MS.
GUSTAFSON: That is a correct statement.
DR.
NELSON: Miriam O'Day from the Immune
Deficiency Foundation.
MS.
O'DAY: Thank you very much. Good afternoon. I am Miriam O'Day. I am giving a statement today on behalf of
the Immune Deficiency Foundation.
The
statement is titled, "Forging an Effective and Practical Process to Ensure
the Safety of the Nation's Blood Supply: A Rational Approach of Emerging
Agents."
The
nation's blood supply is a lifesaving resource for patients in need of the
cellular components and/or plasma proteins of blood, however, the potential for
inadvertent viral transmission with the use of blood and its components
continues to be an area of significant concern for those receiving and those
administering these therapies.
Agents
known to be transmissible by blood are screened for in prospective donors
and/or in the donations themselves.
Traditional serological testing has been supplemented by the use of NAT
testing for several pathogens.
Currently,
as new bloodborne pathogens are identified, tests are developed and applied to
reduce the risk of transmission. The
addition of these new tests may add to the safety of blood and plasma, however,
the new tests add cost to the production of blood and blood derivatives. These incremental costs may ultimately
negatively impact the supply of blood derivatives as manufacturers assess the
financial viability of producing these lifesaving therapies.
Rising
costs may also impede patient access to care as reimbursement is adversely
affected. Using the plasma derivatives
as a model, there may be a new approach that assures safety regarding an
emerging agent, while keeping new screening costs in check.
Plasma
derivatives are produced by Cohn-Oncley fractionation or modification. The use of alcohol in the process can
inactivate viral agents. The separation
process itself can also partition potential pathogens away from the desired
plasma proteins.
Manufacturers
have also implemented dedicated viral removal and inactivation techniques
including enzyme treatment, pasteurization, solvent detergent treatments,
nanofiltration, et cetera. These
methods have been validated using laboratory-adapted model viruses and human
pathogens that permit assessment of several steps in the manufacturing process.
The
testing of model viruses can create a level of assurance if a new agent with
certain viral features emerges, such as a lipid envelope RNA virus.
We
recommend that the following algorithm be assessed on a demonstration basis to
determine if it is a rational approach to test for emerging agents in plasma
derivatives, and there are six steps.
The
first step is identification of a new agent potentially transmissible by blood.
Second
is epidemiologic and field assessment of cases to determine the risk of blood
transmission and the viral life cycle features included in the viral load.
Third
is implementation of additional donor screening measures or enhancement or
reemphasis of current measures to exclude potentially infectious donors.
Fourth
is development of tests, including NAT-based tests, to screen blood and plasma
units.
Fifth
is testing of viral inactivation removal techniques on a case-by-case basis,
manufacturer-by-manufacturer basis to determine efficacy against the emerging
agent.
Sixth,
if viral inactivation removal techniques are shown to be robust, and the viral
load known to be 4 to 6 logs less than the capacity of one step or the
cumulative reduction of the entire process, then, NAT testing of units or pools
can be abandoned or perhaps never initiated.
The
recent identification of the West Nile virus seems to fit this algorithm and
would be an excellent test for this new approach. Specifically, West Nile virus is transmitted by blood and can
cause morbidity and mortality in recipients especially those who are
immune-suppressed, therefore, it is a potential threat to those with primary
immune deficiency diseases who use plasma derivatives, such as IGIV.
Plasma
screening with NAT can eliminate some infectious units, however, the known
level of viremia, as we have heard here many times today, is low and would be
rendered noninfectious by dedicated viral inactivation technologies.
It
is incumbent on the manufacturers to demonstrate the robustness of their
technologies and for he regulatory authorities to review and approve the steps
that have been chosen.
The
Foundation looks forward to further discussions on this important topic and to
the continued improvements to blood and blood safety and product availability.
Thank
you.
DR.
NELSON: Thank you.
Questions
or comments?
Are
there any other questions of the panel about where we are with West Nile
virus? Harvey.
DR.
KLEIN: I don't have a question, but is
this the time for general discussion?
DR.
NELSON: Yes, that is where we are.
Committee Discussion
DR.
KLEIN: Since this is an advisory
committee, we haven't done too much advising today--
DR.
NELSON: We have been advised.
DR.
KLEIN: We have been advised. I am still very much concerned about this
issue of IRBs especially when a national IRB has already approved this IND, and
the issue of donor consent and whether some of these features of the research
process are somehow going to disturb the possibility of preventing infectious
transmission by blood.
So,
I would like to propose that this committee advise the FDA to use whatever
mechanisms are available within its authority to encourage universal adoption
of West Nile virus testing of all blood components collected in the U.S. for
transfusion by July of 2003.
DR.
ALLEN: Are you making that as a motion?
DR.
KLEIN: Yes, I am.
DR.
ALLEN: I second it.
DR.
NELSON: I, too, are concerned about the
IRB issue and I don't know to what extent this issue has or could delay a
public health issue or implementation.
I know I have had a personal experience with it, with a student who
wanted to do some research on hepatitis C virus epidemiology among prisoners
and using anonymous specimens to try to define the epidemiology, and that got
through two IRBs, one IRB refused to approve it only because it was prisoners,
but prisoners were the people that were at highest risk, and they not only had
a high risk of infection, but also there was transmission and treatment
possibilities for them, which were not being implemented.
So,
they suffered because of an IRB decision, and I think that there are other
examples where an IRB, in its important role to protect research subjects, has,
in fact, harmed either the research subjects or other populations or
misunderstood the issues.
I
see the possibility of that happening here although I hope this is not a real
issue, but I certainly agree we could, as a sense of this advisory committee,
give this advice to the FDA even though it wasn't sought, but we could still
give it.
DR.
ALLEN: I think I would add to what you
just said, that even if it does not result in delay or obstruction of getting
things done, that it certainly requires additional time and resources, and in
this instance, I can't think of a single reason in which it would protect, a
single way in which it would protect people, you know, the donor population,
further by going through multiple review at every single different site that
might possibly be affected.
It
seems to me that we need to look at marshaling our resources effectively as
long as people are adequately protected, and I think they are.
DR.
NELSON: It could well be that an
administrative or legal counsel for, let's say, a hospital or university
hospital or something might give advice that if they allowed the IRB to delay
implementation and during that time there was transmission at the hospital, the
Transfusion Service and everybody connected with it would, and should be,
legally liable if there was a test that could have prevented it.
I
hope that won't happen, but I think it probably would be useful for this
committee to vote on this proposition.
DR.
NELSON: Jay.
DR.
EPSTEIN: I would just comment, I mean,
of course, if the committee wants to make a recommendation, that's fine, but
the FDA is aware of this issue, and we are working with the Office of the Chief
Counsel to clarify the legal situation as it pertains both to the requirement
or non-requirement for IRB approvals and whatever authority we might be able to
exercise.
As
I said earlier, I don't believe we have the direct authority to require the
West Nile virus test even if it were approved, because that requires
rulemaking. It would be highly unusual
for us to issue a recommendation calling for the use of an unapproved
test. I think that that would be a
watershed event within the FDA, I see that as most unlikely.
On
the other hand, we can take steps to encourage and facilitate widespread
use. The mere fact that we have worked
cooperatively with the industry to enable large-scale testing, indeed, national
scale testing is proactive and is an effort to have testing done everywhere.
Short
of requiring it, we have some ability to work with IRBs and clarify their
concerns in exercising their role in approving investigational studies, and I
would just comment in that area that I think the situation for the donor and
therefore the IRB approval for the screening of the donor, is quite different
than the situation for the recipient, whether or not there is a need for an IRB
to approve use of a product that has been West Nile screened. That is far less
clear than whether you need to have a consented donor.
So,
we are aware of these issues and I think, as I said before, FDA's point of view
is that we can accept umbrella or national IRBs, we are not the ones requiring
that each and every local site have an IRB approval. I am not sure that there is any authority for us to prevent that
if that is the desire locally, and we are working with larger national
operating IRBs to clarify why they think they need to ask for local approvals.
So,
there are these several situations, the dialogue with the national IRB, the
dialogue with the IND holders, the dialogue with hospitals, and then there is
this issue of authorities, but I think that is pretty much off the table, but,
you know, never say never, but it would require some radically different
regulatory thinking.
DR.
NELSON: I am not exactly sure what the
exact specifications are, but there are, it seems to me, situations in which
the public health threat or issue outweighs the authority of a local IRB to
make an independent judgment.
Certainly,
in the context of a public health threat, there can be actions taken that are
not subject to review and approval by an IRB.
DR.
DiMICHELE: On the other hand, my
understanding is that this assay is just being validated, I mean this assay is
in the process of being validated. I am
not exactly sure how the study reads and what is being submitted to the IRB,
but, for instance, is there donor notification on the basis of these results,
because I mean certainly there needs to be some organized study and validation
of a test if there is going to be any kind of donor notification.
I
mean I don't know that you can get around this. I mean I think it has been
already fast-tracked and, you know, a season of validating the assay,
especially if you have got to get back to donors and counsel them on that
basis, it seems entirely appropriate to me.
DR.
DOPPELT: I was just going to say that I
believe most IRBs have a process for an expedited review, and if the FDA is
encouraging people to use this, that alone may be enough to push the IRBs to
review this quickly since really the risk is virtually nonexistent.
DR.
NELSON: Also, most IRBs have the
authority to accept the judgment of another IRB, and so I hope it won't be
necessary for each IRB to review this.
I guess the issue is that even though a national or local IRB can say
that they want to review it, but
hopefully, that won't happen or won't happen very often.
DR.
SCHMIDT: I support what Harvey is
saying and that is really why I brought up this other issue of state laws and
how they affect what happens locally and sometimes the Federal Government
forgets about that, but to carry it a little further and say yes, of course,
Jay, but if this really is called an advisory panel, are we allowed to make
unsolicited advice?
DR.
NELSON: Well, I think we are, and
whether we are or not, I suspect that we will.
DR.
HEATON: I wanted to make the point that
this isn't an issue of IRB approval or lack thereof. We have a good IRB, it has approved the protocol, and it does
have appropriate jurisdiction. The
issue is that the Central IRB, the Western IRB is nervous that it put a caveat
into its approval, that local IRB approval would be necessary.
Now,
with the HIV/HCV assay, which we introduced somewhat similarly, the Western IRB
was prepared to accept verbal assurances that where a local IRB wishes and had
jurisdiction, that we would get such IRB approval.
So,
if, for example, the Blood Centers of the Pacific had a local IRB, it would get
approval of those in order to implement the test, but it did not require, the
Western IRB at that time did not require in writing or issue a caveat that
wherever you collected a donor, you had to get IRB approval. At that time, it only focused on whether you
could implement testing, IOU testing.
So,
the issue here isn't so much that we don't have an IRB and an IRB approval,
it's this requirement that we contact an IRB where you collect a donor, that is
not the standard of practice and I believe that if the agencies supplied either
a statement or enforcement discretion statement to the Western IRB, they
probably would remit that requirement, and we could proceed as we did for HIV
and HCV, but I do believe that some form of statement will be necessary for the
Western IRB, otherwise, they are going to sit on their hands and point to this
regulation that they believe compels them to require this caveat.
MS.
ROSSMAN: Susan Rossman [ph], Gulf Coast
Regional Blood Center in Houston.
I
just wanted to say we just went live with this and our IRB, we do have an IRB
at our blood center which approved it.
We also do testing for about eight other collection facilities, either
other blood centers or hospital collection facilities. We got IRB approval from all of these. Some of them allowed us to go ahead with
just our IRB approval, some of them went to their own IRBs, in many cases an
expedited review.
The
concern is exactly what some members mentioned, which is donor not protesting
itself, I don't think, that's of no harm, but of donor notification, exactly
what you tell the donor, and the involvement of the donor in the enrollment for
follow-up studies, which are clearly going to be important for this test to be
validated and approved, and a secondary concern is also the retention of
specimens for future testing, which is frequently a concern of IRBs at this
time.
But
we didn't find it particularly onerous, but it is difficult, you do have a
number of steps if you are collecting for various centers, and they make their
own choice about whether to take your IRB or another one.
DR.
BIANCO: Just I think another comment to
clarify, I will say it instead of a British accent, I will have a Brazilian
accent.
The
issue that is concerning about the Western IRB approval, is that blood centers
will run multiple drives every day, in multiple sites, with different
hospitals, universities, schools and institutions that may have an IRB. Blood
centers are not even aware if those institutions have an IRB.
Those
drives are organized and you get there, and the only thing that the blood
center is utilizing in the space, is the cover on top, the electricity, and the
space, and the donors come to this drive.
All the responsibility, all the staff, all the informed consent, all the
questionnaires and everything, the PIs are the blood center, associated with
the blood center, not with that institution, there is no actual connection, so
even if that would be legally required for space rental that you have an IRB
approval.
DR.
DiMICHELE: Doesn't it depend on who is
doing the donor notification? You may
not need all these little IRB approvals if you are the one, if the blood center
is the one that is doing all the collection, the testing, and then the donor
notification.
DR.
BIANCO: That is correct, Donna, exactly
that, that is absolutely correct. The
issue was raised, that was raised with Western IRB, as some of the principal
investigators discussed it with them, us that they received in the past, with
the HIV/HCV implementation, complaints about some of the local IRBs, that
people were not asking for their approval under exactly the same circumstances,
so there is a little bit of this local power versus national power, and all
that.
But
in a situation like that, it should not delay implementation of the test.
DR.
FALLAT: I would like to get a sense
from Jay as to how long he thinks it would take, assuming we have an epidemic
this year equal to last year or greater than last year, how long will it take
do you anticipate to have approval and to go through those rule changes.
DR.
EPSTEIN: I think that, as Jim said
earlier, you know, we don't have to wait for the rulemaking. Once we approve a test, we will recommend
it. The industry is very likely to
implement an approved test once recommended, and rulemaking will come later.
I
don't think that the rulemaking is the issue that will resolve the IRB
question. I think that sort of has a
separate life than what would it take to get to a required West Nile test.
Again,
you know, we all think that we need to have a West Nile test in 03, but
requiring it is a little bit more tricky, because we don't know what is going
to happen in 04, 05, 06. We don't know
whether West Nile is here to day or whether it will burn out and appear more
like St. Louis encephalitis.
So,
I don't know what the logic will be about requiring it, and we will have that
debate, but for now we know we need it, and for now our mind-set is very much
to remove any obstacles to making it available.
I
think we hear the concern of the committee whether you vote on a recommendation
or not, you know, we are here and we hear you, and we are reviewing the legal
issues with the Office of Chief Counsel, so I think that is about as far as I
could go today.
DR.
FREIBERG: Thank you. I wanted to make a suggestion or two about
panel operations that hopefully will help you.
I heard earlier the start of a motion.
I was thrilled to hear it. I
also heard a comment about unsolicited advice.
My
suggestion is finish the motion, finish the vote, and be very specific about
asking FDA to use their enforcement or discretion and tell the Western IRB how
they feel about it. We are not
requiring the test, we are trying to allow the IRB system to work a little
smoother.
Similarly,
you talked a little bit about the 10-minute hold. You could also make a motion and a specific recommendation to
FDA. You all felt strongly about it,
but there was no formal recommendation.
If
there is a new product coming down the line you think should come before this
panel, make a formal motion and recommendation. If Dr. Epstein or FDA doesn't like it, you can rely on them to
get up and help guide you, but I would just suggest formalize your
recommendations, please.
DR.
NELSON: Well, that is what we plan to
do. Could you restate your motion?
DR.
KLEIN: Yes, and I would point out, Jay,
I worded this, so that it doesn't ask that you require anything or that you
rule-make or anything else, so let me just read this again. If there is something in the wording that
someone feels is inappropriate, then, let's change it.
The
committee advises the FDA to use whatever mechanisms are available within its
authority to encourage universal adoption of West Nile virus testing for all
blood components collected in the United States for transfusion by July of
2003.
DR.
NELSON: That sounds pretty good to me.
DR.
STRONG: The only caveat to that I would
suggest is that there are reasons why we operate under INDs, and that is with a
new test. We are making the assumption
that it works well and we don't run failures and false positives, and that sort
of thing, so I think we do have to consider that we are making the assumption
with that recommendation that these tests are working well.
DR.
KLEIN: I agree with you, Mike, 100
percent. It just seems to me that I find it very difficult to sit here, see the
data on the epidemic, see the scientific data on the test, and say, gee, if
someone doesn't feel they ought to use it in July of this year when we see the
epidemic coming in August, that's okay.
It wouldn't be okay for me if I were a patient or if it was one of my
patients in the hospital.
DR.
STRONG: I don't disagree with that, I
am just saying that the preclinicals look great, the studies that have been done
thus far look great, but we haven't put it through its final test, which is
putting 50,000 units a day through these things.
DR.
SCHMIDT: Harvey, that is exactly the
argument that the CDC used as to why surrogate testing should be done for HIV.
DR.
ALLEN: Correction, the CDC never
required, never recommended for it.
There were individuals who did, but the CDC never took that posture.
DR.
SCHMIDT: Thank you. I accept that.
DR.
KLEIN: Paul, in all due respect, I
don't think that there was a specific assay that appears to test for fewer than
100 copies. I think we are talking
about apples and oranges here.
Regardless
of the fact that the test is in IND, hasn't been licensed, hasn't been totally
validated as a screening test because that is why we are doing this, I think we
have enough confidence with what we know to say that it would probably not be a
reasonable thing to give untested blood when you have the capability of using
this particular assay.
The
worst that can happen in my mind is that you might toss out a couple of units
that weren't positive.
DR.
DOPPELT: I would like to know what has
to be done to validate the test in cadaveric samples, and although it is not an
approved test, would it be available to tissue bankers to use, as well.
DR.
NELSON: Do you want to answer that?
DR.
STRONG: Those studies are ongoing
actually and for all of the NAT assays.
West Nile virus is still new enough that studies haven't been
implemented yet, but there are reasons why they need to go through a different
process, and I guess I could give you the details later.
DR.
GOLDSMITH: Just to add one more
voice. Although I personally don't see
any real urgency to test source plasma that is used for further production and
undergoes manufacturing conditions for West Nile virus, we certainly would
think that there ought to be the earliest possible implementation and widest
possible application of this IND for the cellular components of blood.
So,
I think there are two paths here, I just want to say that again, and hopefully,
both paths can be recognized at the end of the day, so that we have the safest
and most available blood supply.
DR.
NELSON: Dr. Smallwood has copied your
motion and will project it. I like the
wording.
DR.
KLEIN: It is not exactly what I
said. I did say whatever mechanisms
within its authority, and I said for testing of all blood components, so that
might specifically exclude plasma that is collected for fractionation of source
plasma.
DR.
NELSON: You say "collected for
transfusion," does that mean--
DR.
KLEIN: Blood components collected for
transfusion.
DR.
NELSON: Okay.
DR.
KLEIN: So, that specifically refers to
cellular components and fresh frozen plasma made from whole blood.
DR.
NELSON: And platelets.
DR.
STRONG: Could I offer a friendly
amendment?
DR.
NELSON: Sure.
DR.
STRONG: I think it's investigational
testing, it's not a licensed test, using an investigational.
DR.
KLEIN: I would certainly accept that
myself.
DR.
FITZPATRICK: When you say July, are you
meaning July 1st, Harvey?
DR.
KLEIN: Looking at the data from the CDC
and knowing that we have four or five weeks, we think, and knowing that there
may not be availability of tests for the entire country, I didn't want to
specify it more tightly than July.
DR.
NELSON: You wanted to say
investigational testing of blood components?
Does anybody want to comment?
Yes.
MS.
FORD: Kendra Ford with the Oklahoma
Blood Institute.
I
read the Western IRB comments that came back out and I think the issue is, is
do we need to seek IRB approval from all the locations that we draw the blood
donors at. We have previously not done
that. We have gone to lots of
hospitals, other businesses that have IRBs.
We have never historically sought their approval to draw the donor, and
we, as the blood center, are in complete control of the process, donor
notification, and all of that.
The
issue is drawing blood, not testing.
That's brand-new language that came out. Whether it should or shouldn't be there, that is the concern. If one body starts doing it, we all then kind
of need to do it, and we have not done that at all in the past, right or wrong.
DR.
NELSON: Any discussion? Do you want to vote on this? Do you want it hand or roll call? Roll call, okay.
Jay.
DR.
EPSTEIN: Two comments, one on the draft
motion. I think rather than saying by
July of 2003, it would be better to say as soon as feasible, because we don't
quite know how kit availability will play out, nor do we really know how the
IRB issue will play out.
Just
as an aside, I mean FDA has expressed its willingness and interest to engage
Western IRB in a dialogue to clarify why Western IRB believes that there is a
need for local IRB approvals for points of collection, and as I said earlier,
we are also, at the same time, researching the legal situation.
It
is my expectation that we will get over this bump in the road. Again, I don't object to the recommendation
should it be voted on by the committee, but we are engaged.
DR.
NELSON: But I think the issue is that
this committee feels that the Western IRBs' approval is sufficient to cover the
research subjects' issues related to this and therefore, that we don't, you
know, we don't want to negate the role of local IRBs, and if everybody can
approve it within the next--what is today--the next two weeks, that's fine, but
maybe as soon as possible is okay.
I
mean obviously, it says the FDA is supposed to encourage, it doesn't say that
the testing has to be done by July, if it's not available.
DR.
KLEIN: I think that was the point. I know that you are engaged and perhaps a
strong statement from this committee might help you to make a strong statement
or help your lawyers understand that you need to make a strong statement.
Again,
I think having seen the epidemiologic data that suggests that July is the right
time, now, if it is not possible to do, that is still the advice of this
committee, I hope.
DR.
NELSON: Advice has not been followed in
the past, and it probably won't be in the future.
Why
don't we just vote.
DR.
KLEIN: The only additional was
investigational, which had been suggested by Dr. Strong, and had been accepted
by the proposer.
DR.
SMALLWOOD: I will read the question as
stated. Dr. Klein proposes that this
committee advise the FDA to use whatever mechanisms are available within its
authority to encourage universal adoption of investigational testing of all
blood components collected in the U.S. for transfusion by July of 2003.
DR.
SCHMIDT: Would the proposer be willing
to change that to just say the committee advises? I mean the proposal business is over, and the motion would be the
committee advises.
DR.
KLEIN: Yes.
DR.
SMALLWOOD: The correction is, The
committee advises the FDA to use whatever mechanisms are available within its
authority to encourage universal adoption of investigational testing of all
blood components collected in the U.S. for transfusion by July of 2003.
DR.
DOPPELT: One other question in regards
to the suggestion of "as soon as feasible" rather than July, because
you don't know about the availability of the test. I mean either way you want it as soon as possible.
DR.
KLEIN: I understand that, but I think
that since we have some data suggesting when we are likely to see the real
impact of the epidemic this year, that I think we need to advise them that July
is the time, and if that can't be done, it can't be done for whatever reason,
but I think to say "as soon as feasible," to me, is not being as
specific as the data suggest we ought to be.
DR.
NELSON: Yes, and for local IRBs, that
don't want to meet during the summertime or something like that, and don't want
to discuss this issue, as soon as feasible to them might be December. So, I think I would agree with leaving July
in there. If they want to review it,
fine, but they have to do it by July.
Well, we advise that the decisions, whatever roadblocks be dealt with by
July.
DR.
SMALLWOOD: The vote of the committee
will be taken by roll call.
Dr.
McGee.
DR.
McGEE: Aye.
DR.
SMALLWOOD: Dr. Klein.
DR.
KLEIN: Yes.
DR.
SMALLWOOD: Dr. Allen.
DR.
ALLEN: Yes.
DR.
SMALLWOOD: Dr. DiMichele.
DR.
DiMICHELE: Yes.
DR.
SMALLWOOD: Dr. Fitzpatrick.
DR.
FITZPATRICK: Yes.
DR.
SMALLWOOD: Dr. Nelson.
DR.
NELSON: Yes.
DR.
SMALLWOOD: Dr. Goldsmith.
DR.
GOLDSMITH: Yes.
DR.
SMALLWOOD: Dr. Cunningham-Rundles.
DR.
CUNNINGHAM-RUNDLES: Yes.
DR.
SMALLWOOD: Dr. Davis.
DR.
DAVIS: Yes.
DR.
SMALLWOOD: Dr. Doppelt.
DR.
DOPPELT: Yes.
DR.
SMALLWOOD: Dr. Fallat.
DR.
FALLAT: Yes.
DR.
SMALLWOOD: Dr. Schmidt.
DR.
SCHMIDT: Yes.
DR.
SMALLWOOD: Dr. Strong, how would you
have voted if you could?
DR.
STRONG: Yes.
DR.
SMALLWOOD: The vote is unanimous in
support of the proposal.
DR.
NELSON: So, we did actually advise the
FDA today. That's good.
I
guess we are adjourned until tomorrow morning.
One comment?
DR.
ALLEN: Yes, and I had thought that
perhaps for the first time since I have been on the committee that we would
actually adjourn within the time frame.
Some of us, this is a wonderful committee in terms of its diversity of
background, and that also means, however, that not all of us are expert in
every area.
I
personally, not being a laboratorian or specially trained in laboratory
science, find myself technologically challenged with the concepts and the
terminology including all of the acronyms used for these tests, and I would
request that the Executive Secretary consider either providing background
information on laboratory testing procedures to the committee, or perhaps our
having a background session at a future meeting just to provide some background
information on testing procedures, terminology, and so on, to enable us to
respond to the information better.
DR.
FITZPATRICK: Beyond that, I might
recommend that at some point, the FDA and the members of the committee actually visit a blood center.
DR.
ALLEN: Yes, a blood center and a
processing laboratory, I absolutely concur.
I think that would be wonderful.
[Whereupon,
the meeting was recessed at 4:45 p.m., to reconvene the following day, Friday,
June 20, 2003, at 8:30 a.m.]
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