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]{.underline}
>
> 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]{.underline}
>
> 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]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline}
>
> \[1:30 p.m.\]
>
> 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 10^7^ and 10^8^ 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 10^8^, 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 10^7^, we still
> were generating positive CT values, at 3 times 10^8^, one started to
> drop out, and one remained positive, so we were comfortably detecting
> the lysate at 10^7^ 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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