ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

This transcript has not been edited or corrected, but appears as received from the commercial transcribing service. Accordingly the Food and Drug Administration makes no representation as to its accuracy.

BLOOD PRODUCTS ADVISORY COMMITTEE

76TH MEETING

Thursday, June 19, 2003

8:00 a.m.

Hilton Gaithersburg

620 Perry Parkway

Gaithersburg, Maryland

PARTICIPANTS

Kenrad E. Nelson, M.D., Chairman

Linda A. Smallwood, Ph.D., Executive Secretary

Pearline K. Muckelvene, Committee Management Specialist

Carolyn D. McMillan, B.B.A., Committee Management Specialist

MEMBERS:

James R. Allen, M.D.

Charlotte Cunningham-Rundles, M.D., Ph.D.

Kenneth Davis, Jr., M.D.

Donna M. DiMichele, M.D.

Samuel H. Doppelt, M.D.

G. Michael Fitzpatrick, Ph.D.

Jonathan C. Goldsmith, M.D.

Harvey G. Klein, M.D.

Daniel L. McGee, Ph.D.

Paul J. Schmidt, M.D.

CONSUMER REPRESENTATIVE:

Robert J. Fallat, M.D.

NON-VOTING INDUSTRY REPRESENTATIVE:

Michael D. Strong, Ph.D.

TEMPORARY VOTING MEMBER:

Liana Harvath, Ph.D.

GUEST SPEAKERS:

Anton P. Andonov, Ph.D.

Mark R. Denison, M.D.

Anthony A. Marfin, M.D., M.P.H., M.A.

C O N T E N T S

Welcome, Statement of Conflict of Interest,

Linda A. Smallwood, Ph.D. 5

Committee Updates:

Medical Device User Fee and Modernization Act

(MDUFMA), Mary Elizabeth Jacobs, Ph.D. 9

White Particulate Matter in Blood Bags,

Sharyn Orton, Ph.D. 13

Safety Reporting Requirements for Human Drug and

Biological Products, Richard Lewis, Ph.D. 26

Bovine Spongiform Encephalopathy (BSE) in Canada,

Pedro Piccardo, M.D. 38

Risk Assessment for Products Utilizing Bovine Material in the Production Process,

Baxter Presentation 46

Open Committee Discussion:

Severe Acute Respiratory Syndrome (SARS) - Informational:

Introduction and Background,

Alan Williams, Ph.D. 54

Epidemiology and Pathogenesis,

Mark Denison, M.D. 63

SARS: Canadian Studies (Epidemiology and

Virology), Anton Andonov, M.D. 88

FDA Current Thinking, Alan Williams, Ph.D. 107

Open Public Hearing

Kay Gregory, AABB 133

George J. Dawson, M.D., Abbott Laboratories 155

II. West Nile Virus - Informational

A. Introduction

Hira Nakhasi, Ph.D. 160

B. Epidemiology and Surveillance Update

Anthony Marfin, M.D. 166

C. Status of WNV Test, Lot Release and Validation

Panel Development

Indira Hewlett, Ph.D. 192

C O N T E N T S

D. Revised WNV Guidance

Sharyn Orton, Ph.D. 212

Open Public Hearing

Presentations from Manufacturers

George J. Dawson, M.D., Abbott Labs 224

Sherrol McDonough, Gen-Probe 232

William A. Heaton, M.D., Chiron 236

James L. Gallarda, Ph.D., Roche 247

Kay Gregory, Blood Banking Organizations 261

Mary Gustafson, PPTA 275

Miriam O'Day, Immune Deficiency Foundation 280

Committee Discussion 284

P R O C E E D I N G S

Welcome Statement and Conflict of Interest

DR. SMALLWOOD: Good morning and welcome to the 76th meeting of the Blood Products Advisory Committee. I am Linda Smallwood, the Executive Secretary. At this time I will read the conflict of interest statement that applies to this meeting.

This announcement is part of the public record for the Blood Products Advisory Committee meeting on June 19th and 20th, 2003. Pursuant to the authority granted under the Committee Charter, the Director of FDA's Center for Biologics Evaluation and Research has appointed Dr. Liana Harvath as a temporary voting member.

Based on the agenda, it has been determined that there are no products being approved at this meeting. The committee participants have been screened for their financial interests. To determine if any conflicts of interest existed, the agency reviewed the agenda and all relevant financial interests reported by the meeting participants. The Food and Drug Administration has prepared general matter waivers for the special government employees participating in this meeting who required a waiver under Title 18, United States Code 208.

Because general topics impact on so many entities, it is not prudent to recite all potential conflicts of interest as they apply to each member. FDA acknowledges that there may be potential conflicts of interest but, because of the general nature of the discussions before the committee, these potential conflicts are mitigated.

We would like to note for the record that Dr. Michael Strong is participating in this meeting as a non-voting industry representative acting on behalf of regulated industry. Dr. Strong's appointment is not subject to Title 18 United States Code 208. He is employed by Puget Sound Blood Center and, thus, has a financial interest in his employer. He also is a researcher for Roche Molecular Diagnostics. In addition, in the interest of fairness, FDA is disclosing that his employer, Puget Sound Blood Center, has associations with regional hospitals and medical centers that store platelets that could be affected by today's committee discussions. Also, the Puget Sound Blood Center is a participating blood center for the West Nile Virus research.

With regards to FDA's invited guests, the agency has determined that the services of these guests are essential. The guests were screened for conflict of interest and reported no relevant interest to their topic.

In addition, there are speakers making industry presentations and speakers giving committee updates on regulated industry and other outside organizations. These speakers have financial interests associated with their employer and with other regulated firms. They were not screened for these conflicts of interest.

FDA participants are aware of the need to exclude themselves from the discussions involving specific products or firms for which they have not been screened for conflicts of interest. Their exclusion will be noted for the public record.

With respect to all other meeting participants, we ask in the interest of fairness that you state your name, affiliation and address and any current or previous financial involvement with any firm whose products you wish to comment upon.

Waivers are available by written request under the Freedom of Information Act. At this time, if there are any declarations to be made by any of our participants, please do so or please do so prior to making your presentation.

I would just like to announce that the next Blood Products Advisory Committee meeting is tentatively scheduled for September 18th and 19th, 2003. The site will be this hotel.

I would like now to introduce the members of the committee. As I call your name, would you please raise your hand? Dr. Kenrad Nelson, Chairman, Dr. Liana Harvath, Dr. Jonathan Goldsmith, Dr. Charlotte Cunningham-Rundles, Dr. Kenneth Davis, Dr. Samuel Doppelt, Dr. Fallat, Dr. Michael Strong, Dr. Fitzpatrick, Dr. Allen, Dr. Klein, Dr. McGee. Members absent are Dr. Chamberland, Dr. Stuver, Dr. Lew and Dr. Laal.

We have added for this meeting a lighted timer for our speakers so you will be placed on a timer and we will have the light to assist you through your presentation.

At this time I will turn the proceedings of this meeting over to the committee chairman, Dr. Nelson.

DR. NELSON: Thank you, Dr. Smallwood. The first item on the agenda is discussion of the Medical Device User Fee and Modernization Act by Dr. Mary Elizabeth Jacobs, also called MDUFMA.

Medical Device User Fee and Modernization Act

DR. JACOBS: Thank you, Dr. Nelson.

[Slide]

This is a short update for you. We have been doing these at every BPAC this year.

[Slide]

We would like to give you our performance so far for the first eight months, through May.

[Slide]

As you see on our device receipts at the bottom, the critical factors, we have met all the FY05 goals so far this year, which don't kick in officially under the Act until 05. We have had PMAs which are traditional, meaning they are not supplements but they actually are modular PMAs, two of those. We have had more 510(k)s than we ordinarily have and we have had quite a few manufacturing supplements, 70 of those.

[Slide]

We are looking at the number here for 510(k)s because those are the most in volume. Of these, we have had 42. Twenty-six are traditional; six abbreviated and ten special, which are much shorter, with a 30-day deadline.

[Slide]

This is a projection of the numbers we are receiving. If we receive as many in FY03 as we did in the fist six months, you are seeing we are having a substantially larger volume.

[Slide]

Of these, for the traditional ones which have been completed--we have a number that are pending, and we have indicated here that these times may increase with the completion of these. The traditional have an FDA average of about 57 days; abbreviated also approximately 57 days; and special approximately 19 days. We have a 30-day time clock on those.

[Slide]

Of the cycles, the average one for traditional is 1.12 cycles.

[Slide]

We want to reiterate what are the improvements that have led to the better performance. One of these is taking a very active problem solving approach, finishing our reviews earlier and spending the rest of the time solving problems; training in what is called least burdensome way of demonstrating what needs to be demonstrated; and we have much faster document handling with the new courier service that also covers counter-terrorism documents and a barcoded delivery system.

[Slide]

There are three new guidances since the last BPAC meeting. The first one is 31 pages long and it is inspection by accredited persons program, which is called third-party inspection. That guidance is rather complex but it has Q&A in it. So, I would encourage anybody who is interested in that topic, even though they may not be immediately looking at being involved in it, to look at that guidance.

The second one is the pediatric expertise for advisory panels. There are special provisions for devices that are being developed for pediatric populations. There is going to be a companion guidance coming out relatively soon on all the aspects of considering pediatric devices.

The final one is how do we file PMA applications. I would encourage everyone who is filing a PMA to review that because that will give you in some detail how we make that decision.

[Slide]

We also have an instrument that we call the "blue book memo." It is kind of like a light guidance. This describes for you the electronic labeling for prescription devices in healthcare facilities. If you are interested in that for your device you can call the RPM branch chief, who is Dr. Sayah Nedjar and will discuss with you the provisions on that.

[Slide]

We have two expected reports at the end of the year, one on CBER and one on the program as a whole.

[Slide]

There has been a new announcement of a meeting for all stakeholders. I want to make you aware of this. Many of you will be receiving invitations from our normal list for BPAC. We send all the invitations to everyone who is invited to this meeting. It is going to be on December 3, right here. It is going to be following both of these reports that go to the Congress, and it is going to address how we have done in our progress in the first year.

[Slide]

I want to make you aware again that we have an electronic docket. Any concerns that you have about the program can be sent into that. As well, you can read the concerns that other people have addressed, and please let us know what your concerns are. Thank you.

DR. NELSON: Thank you. Any comments or questions?

[No response]

The next item is a report on white particulate matter in blood bags, DR. Sharyn Orton.

White Particulate Matter in Blood Bags

DR. ORTON: Good morning.

[Slide]

I am going to give you an update on the white particulate matter task force. This is going to be a general summary of the studies that have been done so far and the study results.

[Slide]

As you are probably all aware, in February of 2003 the American Red Cross Southern Region, Atlanta, Georgia reported unusual particulate matter in red blood cells prepared from whole blood drawn in bags manufactured by Baxter. This was followed by reports from other blood centers, and included bags manufactured by Terumo and Medsep as well.

[Slide]

This particulate matter was reported primarily in red cells prepared using a hard spin method, and was found less frequently in red cells prepared using a soft spin or post leukofiltration.

[Slide]

FDA required visual inspection procedures during storage and immediately before distribution, and our current thinking is that as part of this visual inspection centers should perform an enhanced visual inspection, commonly called the 10-minute hold, of red cells after preparation.

[Slide]

Suspect units should be either leuko-filtered prior to release to transfusion services, or they should be quarantined. These recommendations are still in effect at this time.

[Slide]

I am going to be describing studies that were done by Baxter, within FDA, our Forensic Chemistry Center, the Center for Devices and Radiological Health.

[Slide]

Within CBER, the Division of Hematology did some work. They also worked with the American Red Cross Holland Laboratory and the NIH Transfusion Service. Division of Blood Applications worked with Gulfcoast Regional Blood Center, Florida Blood Services and Centers for Disease Control.

[Slide]

At Baxter--and this is a slight update from the slides that are on the web and the information that you have; I just received this information from Baxter yesterday--they did analytical methods for PM development due to solution instability, degradation or precipitation. They did final product release testing for implicated and non-implicated lots and they looked at the established container system entities. They did characterization of delineated organic compounds, both leachables and impurities. They were able, using the Red Cross Southern Region procedure, to reproduce particulate development.

[Slide]

The FCC at the FDA analyzed the anticoagulants. They tested fill volumes. They analyzed for impurities, degradation products or exotic elements. They examined interior surfaces of the bags and raw material and sheeting, and they examined particles to identify whether there was any seed material involved.

[Slide]

They also examined and compared bag materials from control, heated and cooled bags.

[Slide]

At CBER, the Division of Hematology photographed and classified particles. They asked for representative examples from any of the blood centers that were finding these particles. The American Red Cross Holland Laboratory evaluated particulate matter formation. They looked at donor blood-related and blood-processing factors. They looked at the influence of leukoreduction on the matter removal. They did total protein, total fibrinogen and lipid profiles. They looked at donor medications and meals in 24 hours prior to donation. They also were using the Red Cross method to reproduce the particles.

[Slide]

They also did a plasma study and looked at both platelet and plasma parameters, and the different parameters are listed here.

[Slide]

Within the Division of Blood Applications for infectious agents we worked with the CDC. We looked and pre and post filtration white cell and platelet counts with Gulfcoast Regional Blood Center and Florida Blood Services. That data was shown previously at BPAC. I will have it again in a later slide. We also looked at adverse event rates, and this was with CDC, Gulfcoast Regional Blood Center and Florida Blood Services.

[Slide]

For the results, the particles appeared to be comprised of normal blood constituents. There were reports from some blood centers that particulate matter can normally be found in red blood cell preparation. There was quite a bit of literature from the late '80s and '90s that supports this.

[Slide]

This is the information that I just received from Baxter. It was a very large document. I tried to summarize it. Again, they could reproduce the particulates. These particulates were removed after leukofiltration. They found no process of material abnormalities. The implicated and non-implicated lots had no discernible material differences in any of the system entities or parameters that were studied. The implicated lots met all the relevant compositional specifications, and the particulate development was not correlated with any of the parameters tested.

[Slide]

At the CDC forensic lab all the anticoagulant associated solutions that were tested were as expected. All the fill volumes were as stated on the label. No impurities, degradation products or exotic elements were identified, and no seed material was identified either.

[Slide]

At CDRH the study on the control, heated and cooled bags showed no differences. Suspected lots were not measurably different from non-implicated lots. There was consistent molecular weight between the bags; consistent plasticizer weight fractions; and all the bulk material parameters were confirmed.

[Slide]

This is preliminary data from the American Red Cross Holland Laboratory. The studies are ongoing. They found no apparent association between the particulates and high platelet or white cell counts. Leukofiltration was observed to remove the particulates. Subsequent filtration with 170 micron mesh filter did not isolate any additional material from these leuko-filtered units. Additional particulate development was not observed during subsequent storage of these units after 42 days. In the plasma study they found comparable platelet and plasma parameters between units that had particles and units that did not.

[Slide]

Within the Division of Blood Applications, working with the CDC on infectious agents, there was no evidence of an infectious agent involved. For the pre and post platelet and white cell counts of particulates on leuko-filtered red cells, which was done by Florida Blood Services, all of the white cell counts post filtration were acceptable, and 80 percent of the platelets were removed after filtration.

[Slide]

For adverse events CDC reported data from the Georgia Department of Health. This was also described at the previous BPAC. There was no increase in adverse event reporting for transfused red cells comparing January of 2002 with January of 2003, nor was there any trend in adverse event reporting between those two time periods.

[Slide]

Gulfcoast Regional Blood Center and Florida Blood Services tracked both particulate units that were leuko-filtered and subsequently transfused, and Florida Blood Services also looked at units that had particulates that they determined to be normal in the process of the red cell. There were no adverse events reported and of the particulate units, 135 leuko-filtered were tracked and 187 noon-leuko-filtered. In the control group which did not have particulates observed at any phase, there were 176 leuko-filtered and 695 non-leuko-filtered, again with no adverse events reported.

[Slide]

In conclusion, there were no detectable aberrant results associated with the collection bags, and there does not appear to be an increase in adverse event rates associated with the transfusion of red cells that are either leuko-filtered or that have normal particulate matter. However, I do need to note that the sample size here is small relative to the power to really detect a substantial difference. I would like to thank Florida Blood Services. They are continuing to track these so we can get more data. Thank you.

DR. NELSON: Questions? What is the conclusion as to what the particulates were?

DR. ORTON: They are normal. They are platelets. They are normal constituents from blood.

DR. KLEIN: My conclusion from what you presented and what I know from elsewhere is that this doesn't appear to be a new problem if we review the literature. There doesn't to be clinical import and, certainly, the leukoreduction filters remove the particulate matter which appears to be blood constituents. So, I am wondering what the current thinking is about the enhanced inspection, which was clearly important at a time when we didn't know what was occurring but seems somewhat less important now.

DR. ORTON: We have discussed this fairly recently, and I think our current thinking at this point is that until we have a little bit more information on adverse events I don't think we are going to make any change in our recommendations. I am not disagreeing with anything you have said so far but we would like to get a little bit more information before we make any other statement.

DR. STRONG: I would agree with Dr. Klein. I think also those with a little more grey hair in the audience, they may remember that this is a phenomenon that has been seen probably since the onset of transfusion, and if you inspect the transfusion filter at the bedside you will find that they are also removed by that process. So, it seems like we are putting an awful lot of effort into this that probably won't gain very much.

DR. ORTON: One of the studies that Holland Lab is conducting is to look at the regular units not being leuko-filtered that have particulates, and just looking at what the 170 micron filter removes, which is part of exactly what you are talking about.

DR. EPSTEIN: Harvey, our current policy is that if units are leuko-filtered you can discontinue the extra 10-minute inspection. But the underlying problem here is that if you are not leuko-filtering we know that current manufacturing procedures will produce these particulates. It may not be new but the question is whether it is or is not contributory to adverse reactions to transfusion. That is the point that we would like to continue to clarify. I mean, we could roll back the clock and say, well, we didn't know before so it is still okay now. On the other hand, we now know that these things do occur with a significant frequency and they are removable. So, what we are concerned about is the noon-filtered unit.

DR. KLEIN: That makes some sense if you are going to be looking at large numbers in a controlled study of the leukoreduced versus the non-leukoreduced. If that is the case, that is going to take a couple of years but perhaps that is worth doing.

DR. FITZPATRICK: As Harvey said, we need a large controlled study if that is the goal because those institutions that are doing the inspection, they don't release the unit so there is no adverse event because the unit hasn't been transfused, and the units that are released pass the inspection so there is no way to track anything there.

Because it is current thinking, my understanding is it is not a guidance; it is not a regulation; it is a recommendation. So, it is up to local policy whether to do the 10-minute inspection or not. So, I think the implication of the current thinking based on this is that what we have been doing is probably effective and we observed a phenomenon, studied it and determined that we have naturally occurring products in the red cells. So, without a large controlled study the impact of continuing to do the 10-minute inspection is becoming, from our centers, a significant impact on their ability to do their work.

Also, you are not seeing results of what they are doing; they are doing something. At the beginning they understood why they were doing it. Now, with this report, they will think it even less important to continue to do it. So, it is going to be difficult to continue to tell a local medical director that it is important for him to do it because the data are not supporting them doing the 10-minute inspection.

DR. ORTON: I would just like to add one thing about sample size. I have sat down and worked with many of the figures and it is not as large a study, I think, as you would think, particularly if we had multiple blood centers with their transfusion services participating. As I said, Florida Blood Services was able to do 800 or 900 for me in about a little over a month's time. So, if we were looking at between 2,000 and 3,000, which was the figure I was looking at with the controlled group, at multiple blood centers we could knock it off in less than years. So, again, I would ask that any blood center that has a transfusion service, if they feel they could get this information please contact me so we can get more information.

DR. NELSON: I think Kay Gregory wanted to make a comment.

DR. GREGORY: Thank you. I will just speak from here because it is a short statement and, actually, I am not even going to read the statement because I think the gist of our statement has already been expressed by the panel members. We would simply encourage FDA to come to some kind of conclusion as quickly as possible. Thank you.

DR. NELSON: Any other comments?

[No response]

The next item is safety reporting requirements for human drug and biological products, Dr. Richard Lewis.

Safety Reporting Requirements for Human Drug and

Biological Products

DR. LEWIS: Good morning. Thank you, Dr. Nelson. Good morning, committee members.

[Slide]

I wanted to take the opportunity to introduce to you a regulation that has been proposed and published in March, and is still currently open for comment.

[Slide]

This is the safety reporting proposed rule. I said I could do this in five minutes but that was before I knew there was going to be a timer.

[Laughter]

Thank you, Dr. Smallwood, for the pleasant surprise!

This safety reporting proposed rule encompasses drugs, biologics as well as blood and blood components. Most of my comments this morning will focus on the blood and blood components but there are parts of the proposed rule that also address biological therapeutic products.

[Slide]

As I said, the proposed rule has requirements for premarketing expedited safety reporting; postmarketing safety reporting, and these reports are in two groups, both expedited reports as well as periodic reports; and then, as I mentioned, safety reporting for blood and blood components.

[Slide]

For the blood and blood components the proposal suggests that it would require the reporting of serious adverse reactions, in addition to fatalities, that are related to the collection or transfusion of blood and blood components.

[Slide]

Currently biologics manufacturers, including blood manufacturers, are required to report within 45 days any deviation from current good manufacturing practices, applicable regulations, applicable or established standard, or an unexpected or unforeseeable event which may affect the safety, purity or potency of a product.

[Slide]

Also required currently are fatality reports, and these reports must come in as soon as possible, and then a written report of the investigation within seven days of the fatality.

[Slide]

In the proposed regulation the current requirement would continue that a fatal reaction be reported within seven calendar days.

[Slide]

Currently adverse reactions related to blood transfusion--the blood establishment is required to investigate the adverse reactions and to prepare and maintain a written report of the investigation, including any follow-up and conclusions, and that report is to be sent to the collection facility.

[Slide]

In the proposal the particular adverse event would still be investigated and conclusions drawn, however, at the end of that investigation there would be a decision on whether or not the particular event was serious or not serious. If it were serious, it would then be reported to the FDA.

In the preamble to the proposed reg the FDA has provided a number of examples, and those examples fit into four categories, examples related to the collection of blood products and examples related to transfusion. We have also provided examples of whether or not there were things that we thought were important to be reported, as well as examples of things that did not need to be reported.

[Slide]

This is a list of some of the things that we thought were important: Vasovagal reactions with syncope; citrate reactions; anaphylaxis; seizures; cerebrovascular accidents; and others. I believe committee members have copies of the slides and there are other copies at the table outside.

[Slide]

Some of the things not included related to collection include self-limited vasovagal reactions; self-limited citrate reactions; localized hematoma; localized skin irritation.

[Slide]

Regarding transfusion complications from the use of an unsuitable unit, include infusion of hemolyzed blood; complications from improper blood administration; induced hemolysis; and others.

[Slide]

Things that would probably not need to be reported related to transfusion would be febrile nonhemolytic transfusion reactions; related hypersensitivity without respiratory insufficiency or hypotension; induced alloimmunization; and others.

[Slide]

This summarizes the part of the proposed regulation related to blood and blood components. Currently, fatality reporting is required. In the proposed regulation fatalities would be reported and, in the same time frame as currently required, the proposed report would include all serious suspected adverse drug reactions, except fatalities, and the time frame for these reports would be 45 calendar days. The 45 calendar days was selected so it would coincide with the biological product deviation reporting because we thought that there may be some of these reports that would overlap and this would allow the investigations to proceed concomitantly and the reports to come in at the same time.

[Slide]

This relates to other drug and biological products and summarizes the expedited safety reports. I mentioned that there are expedited reports premarketing. Currently, safety reports are expected for an unexpected fatal or life-threatening experience in seven calendar days, and in the proposed reg it would change the definition of what should be reported. This would be unexpected, fatal or life-threatening suspected drug reactions. And then, a written IND safety report would change slightly the definition of what is reported. It would still maintain the same time frame.

[Slide]

In postmarketing--this would be the largest change--there would be some expedited safety reports. There would be initial reports within 15 days predominantly. Some of those reports would also be required within 45 calendar days.

[Slide]

Some of these reports would have a later follow-up, and again we are talking about postmarketing. This has to do with new information expedited follow-up reports.

[Slide]

Then postmarketing, there are two separate reports that would be required, a descriptive information report as well as individual case reports. As in the previous slides, the yellow shows the new components of the regulation. Currently there are periodic safety reports. The new regulation would require updates, as well as interim and individual case safety reports.

[Slide]

The frequency would change in the proposed regulation. This is a little bit more complicated scheme but over the life of a drug product the numbers of reports would actually be reduced. It is not easy to see that from this. It proposes that after a product is approved or licensed there would be semi-annual reporting for two years after approval, and then for the next three years reports would come in annually, and then two and a half years for the next ten years and then five years, every five years after the first ten years of a drug life. Individual case safety reports related to specific adverse reactions would come in semi-annually after U.S. approval.

[Slide]

The definition of adverse drug experience was very descriptive in our current regulations. In the new regulations it becomes a little bit more broad and the decision-making is left up to the drug manufacturer, with a noxious and unintended response to any dose of a drug product for which there is a reasonable possibility that the product caused the response. In this definition the phrase "a reasonable possibility" means that the relationship cannot be ruled out.

Let me just comment that on the blood and blood component part of the regulation we have begun efforts to have in place a mechanism to receive those reports electronically. They would come in on the 3500 report form that is used for MedWatch reporting. There would be a computer system that would allow them to be entered immediately. We think that this would also facilitate analysis so that we could address things that look like they were having an effect on blood and blood components nationally. Thank you.

DR. NELSON: Comments? Yes, go ahead.

DR. STRONG: Our handouts are missing the last set of slides. Could we go back to the very first slide on the blood products so that we could just see that one more time? DR. LEWIS: Sure, I think we can.

DR. STRONG: It is out of order I think. We have blank pages after about six slides. It was the one that had the vasovagal reactions on it.

[Slide]

DR. LEWIS: I have already received some comments on this. I italicized "requiring medical intervention" and I think we are going to have to do some work to define exactly what medical intervention is. From the two extremes, it doesn't mean that the individual fainted but, on the other extreme, if the individual had to be taken by ambulance to the hospital that would be medical intervention. But where we draw the line between those two extremes we will probably have to put some effort into defining when this becomes a final regulation.

DR. STRONG: That actually was my question, the definition of medical intervention, citrate reactions.

DR. LEWIS: Citrate reactions requiring medical intervention? I presume it would be the same difficulty, yes, what is medical intervention.

DR. NELSON: Does the FDA have any data on how complete reporting has been, or what the compliance has been or is with the current requirements?

DR. LEWIS: Unfortunately, the only requirements now are fatalities, the only reports that we get. The other investigations are evaluated by the field inspection force when they go to a particular center. So, there is no accumulation of data.

DR. NELSON: You might want to consider some sort of QC procedure where you evaluate how effective this is and how complete because having data that is only 20 percent accurate or something like that is not very useful. It can give you false information and it looks like a fair number of things might need to be reported that aren't now. Jim?

DR. ALLEN: Yes, that was exactly the question I was going to ask. In a very diffuse medical care system such as ours, I mean even if a hospital is trying to find out what kind of adverse events are happening within that--I mean here, whether it is the bedside physician who would be responsible for reporting or the transfusion service or the hospital infection control quality assurance program, however it is set up, I think it is often unclear. I assume that most transfusion services would take the responsibility if they become aware of it, and there can be events that occur that they, for whatever reason, don't ever become aware of.

You know, I commend the FDA for its efforts to try and get this kind of information. I know that physicians are routinely or periodically sent information and fliers about the requirements for adverse event reporting. It would, indeed, be useful to consider, if funds and resources are available perhaps through other public health agencies, some sort of evaluation of what is the completeness of reporting even for fatalities because I will bet it is considerably less than 100 percent complete. Whether hospital discharge data might be useful as a proxy to kind of cross-evaluate, I don't know, but it is an interesting problem that does need to be considered.

DR. NELSON: These data are on blood collection facilities but you had another one, didn't you, on transfusion? I suspect that the blood collection serious reactions could be readily reported, and probably pretty accurately. But I suspect transfusion, when you are transfusing a person with multiple underlying illnesses, trying to figure out what is due to the transfusion, a serious adverse event that might be related to transfusion "could not be ruled out" might be more difficult.

DR. LEWIS: Thank you.

DR. HARVATH: Richard, I was wondering if FDA has considered, or maybe already done this--considered the NCI toxicity criteria that were recently updated because they have gone very systematically through every organ system and it may be a starting point to help sort of quantify this more easily, and most clinical trials that are sponsored by NIH are using this for their adverse event scoring. So, it might help; it might save you a lot of work.

DR. LEWIS: Honestly, we haven't discussed that but that is a very good suggestion. Thank you very much.

DR. GOLDSMITH: On the last slide you changed the definition about serious adverse events and you took out the idea that there is a lack of therapeutic effect. That was removed I think from the definition. I was just trying to understand that a little better.

DR. LEWIS: Can we go to the last slide?

[Slide]

DR. GOLDSMITH: Yes, failure of pharmacologic action. The way I read the new definition, that is not part of it.

DR. LEWIS: I had not focused on that. I see that you are correct. I presume that this is because the regulation is trying to focus on safety rather than efficacy. A lot of the impetus for this particular regulation is to harmonize with some of the reporting requirements in Europe. It is part of ICH initiatives.

DR. GOLDSMITH: Not to overdo this, but lack of efficacy can lead to safety problems.

DR. LEWIS: Thanks.

DR. NELSON: Thank you. The next report is on bovine spongiform encephalopathy in Canada, Dr. Piccardo.

Bovine Spongiform Encephalopathy (BSE) in Canada

DR. PICCARDO: Thank you.

[Slide]

I will summary recent events related to the discovery of a cow with bovine spongiform encephalopathy in Canada, and I will also present briefly some background information.

[Slide]

BSE, bovine spongiform encephalopathy, was first described in the U.K. in 1986, and BSE is present in most countries of Western Europe. The peak of the epidemic was in the U.K. in 1992-1993 and surveillance in Canada began in 1992. BSE was detected and reported in Canada in 1993. It is very important to note that this one animal was imported from the U.K. BSE was recently found in Japan, in Israel, Slovakia and the Czech Republic and Poland.

[Slide]

In the transmissible spongiform encephalopathy field there are some basic assumptions. This is one of those, that BSE first arose in the U.K. and was propagated through the recycling of infected bovine tissue into ruminant feed, meaning meat and bone meal. The export of infected animals and infected feed from the U.K. spread the BSE agent to other countries where it was recycled and propagated via the animal food chain.

[Slide]

One critical issue, a landmark in the field is 1997 with the ruminant feed ban in North America. Canada implemented a rule that prohibits the feeding of most mammalian proteins to ruminant animals, what we call the feed ban. The U.S. implemented a similar rule the same year.

[Slide]

The importance of the occurrence of bovine spongiform encephalopathy was highlighted when variant Creutsfeldt-Jakob disease was found. Variant Creutsfeldt-Jakob disease is a neurological disease in humans attributed to the consumption of meat products from BSE-affected animals.

Most vCJD cases have been detected in the U.K. The last figure I could find was 135. But vCJD was also found in five other countries, Canada, France, Ireland, Italy and the U.S. now. It is very important to note that patients in Ireland, the U.S. and Canada have spent extended time in the U.K. so for all purposes the Canadian case can be considered as a case from the U.K. Regarding France, some of these patients in France and the Italian patient had not visited the U.K. It is also important to know that France imported a significant amount of beef from the U.K.

[Slide]

Regarding BSE in Canada, as you might know, on January 31, 2003 an older breeder cow, meaning six to eight years old, in Alberta was condemned with a diagnosis of possible pneumonia and it was slaughtered. It is important to note that BSE was not suspected at that time. The head was collected and stored and the carcass was sent for inedible rendering for pet food, industrial use. The brain was not examined immediately due to backlog.

On May 16 BSE was diagnosed in Alberta, in a laboratory in Alberta, and it was diagnosed by immunohistochemistry, meaning there was recognized the presence of abnormal prion protein in the medulla.

On May 18 BSE was confirmed in another lab in Winnipeg. The material was sent to the United Kingdom and on May 20 BSE was confirmed, and it was confirmed in the U.K. as typical BSE, typical BSE in terms of the pattern by the pathology, the pattern by immunohistochemistry and the Western Blot pattern. Canada announced the case and the USDA started the import prohibition.

[Slide]

Canadian authorities assured that the carcass had not entered the human food chain and the rendered products went to eight feed mills, two farms and a pet food manufacturer in Alberta. Regarding the feed mills, all the farms that received the feed, whiich was not intended for ruminants, were contacted to determine if any ruminants were present on the premises. If so, they were further investigated. Two farms have been depopulated because it could not be ruled out if inadvertent feeding of poultry feed to cattle occurred on the same premises.

Regarding the pet food manufacturer, it was dog food. Dog food was shipped to one firm in the U.S. and there is no evidence that dogs can contract transmissible spongiform encephalopathies. However, the U.S. firm asked customers to return the food to the distributors for proper disposal.

[Slide]

What was the Canadian response plan? There were several lines of inquiry. Regarding feed, over 200 farms have been investigated and were found in compliance with the required feeding practices. Regarding the animals, for the case herd there is no information available about the use of meat and bone meal on the last farm where the BSE-positive cow lived. However, the farm was depopulated and all the animals have been tested.

There was another line of inquiry which they call the trace-back, meaning a search for the possible birthplace of the positive BSE-affected cow, and the probability was that this cow was born in Saskatchewan and possibly in Alberta. Herds where the BSE cow co-mingled were investigated. The trace-forward means that herds where the offspring from the case herd might have lived were also investigated.

[Slide]

Regarding U.S. follow-up, several federal agencies are following up five bulls imported into the U.S. from one possible herd of origin of the BSE-positive cow. It was stated that these animals might have gone to Montana and at this time information that I gathered from the USDA is that the investigation is undergoing.

[Slide]

The results--approximately 2,700 cattle brains have been analyzed by the rapid test and by immunohistochemistry and all tested negative, of course except the single positive index cow. Approximately 25 farms have been investigated in Alberta, Saskatchewan and British Columbia. On June 9 the Canadian Food Inspection Agency announced that the active investigation of the case is ending. At this point they are evaluating data and they are also evaluating recommendations that were made by an international panel that assessed the situation.

It is important to note that the recent risk assessment, in December, 2002, has indicated that the likelihood of BSE affecting cattle in Canada was very low. The current prevalence of BSE in Canada, however, must be very low risk, probably lower than before 1997. I remind you that 1997 was the time when the feed ban was imposed.

[Slide]

So, what is next? Well, BSE in Canada will be a topic of discussion at the next meeting of the Transmissible Spongiform Encephalopathies Advisory Committee next July. Here you can see the Canadian Food Inspection Agency website in case there is some further information that would be forthcoming.

[Slide]

Regarding the agenda for the next TSE advisory committee, the agenda includes safety of bovine gelatin; BSE in Canada which will be a topic of discussion, as I said before; and decontamination of medical equipment and facilities.

The next speaker will be Dr. Baker, from Baxter International, who will present on risk assessment for products utilizing bovine material in the production process.

DR. NELSON: Thank you. Any questions? Maybe I didn't hear it right, but initially I think you said this cow was born in the U.K. and then later on you said it was born in Saskatchewan. Was it born actually in Canada?

DR. PICCARDO: This cow was born in Canada, yes.

DR. NELSON: That would imply that the infection actually occurred in Canada.

DR. PICCARDO: Well, yes.

DR. FITZPATRICK: The first slide says it was imported from the U.K.

DR. PICCARDO: In 1993 there was a case that was recognized in Canada and that animal was from the U.K. It was imported from the U.K. That was in 1993. The case that was reported recently was a Canadian case, and Alberta was the site that was suspected to be the origin of that cow, although Saskatchewan could not be ruled out.

DR. NELSON: Thank you. Dr. Baker?

Risk Assessment for Products Utilizing Bovine

Material in the Production Process

DR. BAKER: Good morning.

[Slide]

Dr. Nelson, members of the committee, I appreciate the opportunity this morning to discuss Baxter's response to this Canadian BSE episode.

[Slide]

As Dr. Piccardo has described, on May 20th a report was received by Baxter of this finding of a Canadian BSE case from Canada. For those of you who might be interested in terms of how a company like Baxter manages these kinds of things, we have a standing threat management committee which is comprised of members of senior management representing all functionalities.

This report happened to come to me. I am a member of the threat management committee. I immediately initiated a risk assessment for all of our products globally which utilize bovine materials in the production process. In that assessment we determined that only one product, recombinate antihemophilic factor, utilized bovine materials in the manufacturing process.

[Slide]

The materials used in recombinate processing comprise two categories. One is what we term direct contact materials. These are materials that actually come in direct contact with the active agent, recombinate Factor VIII. This includes serum albumin, bovine insulin and bovine aprotinin.

There are also a number of indirect process materials that are utilized in the manufacture of this material, and one of the things that I want to make clear is that there are probably only six degrees of separation from the cow in any therapeutic product that you run into. An example is this material, Ventrex, which is a medium supplement. Now, there is a very small amount, trace amount essentially of bovine protein in that product so there is a purified bovine protein in that product. That product is used to produce the antibody which is used to produce the immunoaffinity resin which is used to purify the Factor VIII in the process. So, you can see that there is a significant degree of separation.

The products that I am going to talk about are only going to be the direct contact products. Although we did do a risk assessment on all of these, just to keep this presentation manageable I am going to talk about these ones. Clearly, for the very indirect products there is a lot less risk associated with these because there are many purification removal steps that occur between that and the final product.

[Slide]

A recombinate is produced through certified suppliers. Obviously, this TSE risk is a known risk and the for two materials we are talking about serum albumin is Canadian sourced. It has a certificate of suitability in accordance with the European regulations. The bovine insulin was a more complicated story. That pancreas that went into the production of the material was sourced from Canada and the United States. There were 12 slaughterhouses used and I think one of the 12 was a Canadian slaughterhouse.

[Slide]

Inasmuch as our product is globally licensed, it must meet the global regulatory requirements with respect to bovine sourcing. The European Union has the most definitive and well-described requirements. They deal with country of origin, the part of the animal used, the manufacturing process, and bovine materials used have to have a certificate of suitability from the EDQM. In the U.S., the guidance is primarily in the CBER letter to manufacturers. In Japan, only draft requirements are available, although this slide is now out of date. Coincidentally, on May 20th Japan published its final requirements with respect to bovine materials and they are somewhat similar to the European requirements in terms of the issues considered.

[Slide]

At the outset, I would like to say that the index animal could not and did not enter into the manufacture of production materials for our products. We source all of our bovine materials from relatively young animals, less than 30 months of age, and there is a requirement that there be a veterinary inspection pre and post mortem to ensure that the animals are in good health. So, those animals that exhibit clinical signs of disease are not used in the production of bovine materials.

The serum albumin is produced from a category IV tissue, bovine plasma obviously, which is considered to have no detectable infectivity. The manufacturing process has been validated by the supplier using the hamster scrapie model. There is a validated 16.2 log clearance of the hamster scrapie agent, which gives you very good assurance that were there any TSE agents present in the plasma they would be well cleared by the manufacturing process.

[Slide]

The situation with insulin is a little more complicated. Pancreas is a low infectivity tissue. It is the second lower category. The manufacturing process has not been validated for the TSE removal, however, there are manufacturing steps, particularly the low pH and the 7M urea, that could be reasonably expected to dramatically reduce the concentration of any prion infectivity. This material was also manufactured in 1998. Part of the reason why there is no validation for the process is that this product is no longer produced--the plant has been actually bulldozed--and the source tissue was collected in 1996.

[Slide]

The recombinate manufacturing process itself has been evaluated by us for the removal of the TSE agent. There are two steps that are responsible for most of the clearance, the immunoaffinity chromatography step, which has been demonstrated to give a 5.4 log clearance, and the combination of the two anion exchange steps, which have been demonstrated to give a 3.2 log clearance. So, in the actual manufacturing process we end up with a combined 8.6 log removal of the TSE agent.

[Slide]

Obviously, even though we don't believe that there is any risk associated with this event, we are taking steps in response to this event. For the serum albumin we are going to replace the Canadian sourced bovine plasma with U.S. sourced bovine plasma. We will be replacing the current bovine insulin with recombinant insulin.

[Slide]

In summary, the bovine materials that we use did not come from the index animal and are in the lowest risk categories. The manufacturing processes were shown to, or can be reasonably expected to have significant TSE agent reduction capability, and the recombinate manufacturing process itself has been shown to have significant clearance of the TSE agent. Thank you.

DR. NELSON: Thank you. Questions? Yes?

DR. FITZPATRICK: With the relatively high volume of exchange between U.S. and Canada, have you done a risk assessment? Is there really any difference between U.S. sourced and Canadian sourced material?

DR. BAKER: That is a very provocative question. You know, I think the prudent thing for a manufacturer to do, and I don't care what biologic product you are making, is to assume that the materials, the raw materials, could carry some sort of infection; evaluate the possibility for the source of infection and take appropriate steps. So, that is why we have the validated clearance during the manufacture of the product. I think it is just the prudent thing to do and I don't care what you are making.

DR. NELSON: Jay?

DR. EPSTEIN: Yes, I just want to respond also to that point, which we think is central. The FDA is engaged in examining the risk assessment both for BSE in the U.S. and BSE in Canada with the question of whether there is any significant difference in estimated risk, as well as with the question of what is the possible contribution to U.S. risk of risk in Canada. We are hoping to have that analysis completed in time to present it at the TSEC meeting in July.

DR. NELSON: Has there been any difference in the importation of meat and bone meal from the U.K. by Canada and the U.S. because apparently that is probably how the Canadian cow got infected? If there is not a difference in importation, I suspect the U.S. may have a risk.

DR. EPSTEIN: I can't answer that question at this time but that is one of the facts that will be entered into the model.

DR. DIMICHELE: I know that it is in category IV but just for completeness sake, the bovine serum from which the albumin in recombinate is coming, when was that harvested? You talked about the insulin but what about the bovine serum? Is that more recent?

DR. BAKER: Yes, that is manufactured on a continuing basis. We get the materials in on a regular basis. I think the last shipment we got from Canada was probably March, or something like that.

DR. DIMICHELE: So, is there additional surveillance of the product itself? Are you testing the product at all beyond sort of the guidelines that you have put in place to ensure removal of the prion? Are you doing any further testing of these lots right now?

DR. BAKER: You know, I guess I would give a standard quality response to that. We don't test quality in; we have assurance that an agent would be excluded or removed.

DR. NELSON: Thank you. The next discussion will be on severe acute respiratory syndrome, with Alan Williams.

Severe Acute Respiratory Syndrome (SARS) -

Informational Interpretation and Background

DR. WILLIAMS: Thank you, Ken, and good morning.

[Slide]

The concept of emerging infections and emerging diseases has kind of been a set of buzz words for about the past decade in infectious diseases. I think SARS is really showing itself to kind of be the epitome of what a truly emerging infection can look like, even made more incredible by the fact that since the original identification it has been recognized as a distinct clinical disease.

It has shown rapid spread to a number of countries around the world. It has been identified that standard infectious disease precautions are very effective in preventing the droplet spread. The etiologic agent has been identified as a coronavirus. That virus has ben sequenced. There are early development diagnostic tests available based on that virus. There have been donor eligibility recommendations published by the FDA, and those recommendations have been implemented. Now the epidemic or what had the potential to be an epidemic is in apparent decline and there is talk of vaccine development actively under way. It is made incredible by the fact that all this has occurred since the last meeting of this committee.

[Slide]

In this session I will review some aspects of SARS with an emphasis on blood safety. I am going to introduce the session and provide some background. We had actually lined up Dr. Matt Cunart from the CDC to present a CDC perspective on SARS. Unfortunately, he was called away to the field and is currently working on monkey pox in Indiana and so was unable to join us today. But he was able to share some slides.

We will then have a presentation by Mark Denison, Vanderbilt University, on epidemiology and pathogenesis, and then a discussion on SARS and Canadian studies, particularly surrounding the Toronto cases, by Dr. Anton Andonov who is with the Canadian Science Center for Human and Animal Microbiology in Winnipeg, affiliated with Health Canada. I have not actually seen Dr. Andonov yet; I hope he is here.

[Slide]

Following that, I will return and present some of the elements on the guidance document that was published by FDA in April. In addition, I will address some of the questions and answers that have come up surrounding that document and some of the comments received to the docket, and a few comments on the general concept of introducing new donor questionnaires and finding the most efficient and effective way of conducting that process.

[Slide]

As I said and Dr. Fauci detailed in a very elegant talk yesterday that this is a fascinating story. The original infection appears to have arisen from an animal handler in Guangdong Province in China who appeared to pick up a respiratory illness from small rodents being raised for a food source. A physician who left China and stayed at a hotel in Hong Kong appeared to spread that respiratory infection to a number of individuals within that hotel who then went on to multiple other sites and there was additional spread. The first report of this as a new entity occurred on March 12 from the World Health Organizations as cases of atypical pneumonia.

[Slide]

As of June 12, data about a week old, there have been a total of 8,445 probable SARS cases, with almost 800 deaths. These numbers have increased just slightly in the past week. Finally, most of the cases and the deaths have occurred in China and Hong Kong but additional countries impacted have been Taiwan, Canada, Singapore, the United States, Vietnam, the Philippines and a handful of other countries.

[Slide]

The case definition is described both on the U.S. CDC website, as well as the World Health Organization website. I am going to emphasize the CDC materials which FDA has referenced in its guidance document. The clinical criteria for SARS is respiratory illness of unknown etiology with an onset, since February 1 of this year, which meets the following criteria: A measured temperature of greater than 100.4 and one or more clinical findings of respiratory illness, for example a cough, shortness of breath, difficulty breathing, hypoxia or radiographic findings of either pneumonia or acute respiratory distress syndrome.

[Slide]

That needs to be combined with epidemiologic criteria which encompasses travel within ten days of symptoms to an area with documented or suspected community transmission of SARS, or close content within ten days of onset of symptoms with either a person with respiratory illness who traveled to a SARS-affected area or a person known to be a suspect SARS case.

[Slide]

In addition, now with the identification of the virus, there are antibody tests that are available. These are of limited usefulness for diagnostic purposes because it takes a while for the antibody to actually develop. There are now also nucleic acid-based tests. So, there are laboratory criteria which can be plugged into the diagnostic scheme.

Currently, case classifications are designated as suspect SARS, and that would be the case meeting the clinical definition for which there is not yet radiographic evidence of pneumonia or death from an apparent acute respiratory cause. The next stage, which encompass all of the factors leading to a suspect case, would be probable SARS. This would include the radiographic findings of pneumonia.

Most of the data that are reported, particularly from the World Health Organization reports, are probable cases. Now there is a new designation emerging, which is confirmed infection and this is infection that, in fact, has laboratory evidence of infection with the SARS agent, generally by nucleic acid testing.

[Slide]

Throughout the United States, as of June 11, there were 70 cases identified. The numbers are a little hard to see here but there is a smattering of between one and three cases for the most part in the yellow designated states, the bulk of the cases occurring in California, as one might expect for reasons I will show in the next slide. Most of these cases are due to travel to Asia and SARS areas where potential exposure occurred, but 70 cases were identified in the United States as of June 11, and these are probable cases. If you see higher numbers in the United States, up in the 300 to 350 range, these are suspect cases.

[Slide]

The epidemic curve for the United States shows a typical bell shape. Early in the recognition of the disease cases were brought into the States. The peak of cases were recognized in late March and then there was a gradual decline. In fact, standard infectious disease precautions for prevention of respiratory spread are very effective and the United States was particularly fortunate in that the Canadian experience and experiences around the world had actually educated healthcare providers that these precautions were necessary and prevented a much worse situation in the United States. In the U.S., as well as worldwide, one can see a gradual drop-off of cases now and it has been relatively quiet for the past couple of weeks.

[Slide]

Of the probable SARS cases identified in the U.S., 97 percent of those cases reported travel to the affected areas mentioned before. One case is a healthcare worker who cared for a SARS patient; one case of a household contact of a SARS patient. Considering that the disease is effectively spread by droplets--which generally means an individual working within a three to six foot range of an infected person would potentially come into contact with those droplets--it is understandable how these cases occurred and, in fact, remarkable that the numbers aren't higher.

[Slide]

There already is a tremendous amount of information available both from the World Health Organization website, which can be found at this site, as well as the CDC website, really very extensive information regarding travel, diagnosis, patient care, etc.

[Slide]

So, as you hear these subsequent talks, which will deal with some of the interesting epidemiology and virologic findings considering those in relation to blood donor eligibility, the points to consider are whether or not viremia occurs in the asymptomatic phase. Do we know that? Do we not know it? What are assurances in either direction? What is the incubation period prior to symptomatic disease? What is the duration of infection? What is the potential for relapse with infection? What treatments are available and how might these treatments impact eligibility of the donor? If there are interventions taken, what is the impact on the blood supply? I think a question, given the information coming out of Kuala Limpur this week that the epidemic is on the decline, is there a definable endpoint where we can be reasonably assured that new cases are not occurring and some of the precautionary measures could be reevaluated?

So, with that, I am looking forward to some interesting talks and discussion. Thank you.

DR. NELSON: Thanks. My understanding is that the CDC and the MMWR, about a week or two ago, evaluated that there have been no fatalities in the U.S., and they evaluated over 100 of these probable and suspect cases and were actually only able to confirm about eight or ten of them as actually infected with the coronavirus. Is that correct or is there any update on how many have been studied and confirmed?

DR. WILLIAMS: Jim may want to add but I know from Dr. Fauci's talk yesterday that there is evidence for PCR positivity for the SARS virus in eight cases in the United States. I don't know the denominator as to how many have been tested to this point and how many samples were available for testing. So, yes, there have been eight. I don't know that the rest were negative or even tested.

DR. NELSON: I thought there were, like, 100 tested either by PCR or antibodies after recovery and that there were only something like eight. But it was clear that including the suspect cases was quite different than, let's say, in Taiwan or Singapore or places where there was an epidemic and that it really wasn't a different virus. It may have been that our isolation facilities are no better than the Canadians, is my suspicion.

DR. WILLIAMS: I think the other thing is the distinction between the suspect cases and the probable cases. We know that probable cases have radiographic evidence of pneumonia, but I have not seen information as to how many of the suspect cases were actually looked at with x-rays and found to be negative or positive. I have just not seen that information available.

DR. NELSON: Dr. Denison?

Epidemiology and Pathogenesis

DR. DENISON: Good morning.

[Slide]

I appreciate the opportunity to be here and to speak before the committee. I was concerned on my way here yesterday when I picked up USA Today and they informed me that SARS has been stopped. I was concerned I was going to get called and they were going to cancel my talk. But reading the rest of the article doesn't reflect the title quite as much.

There are some issues, as a coronavirus investigator for the last 20 years, that I think are worth addressing. So, what I first want to do is talk to you about a few issues related to the other animal coronaviruses and their relationship and leave some open questions. I am anticipating that Dr. Andonov is going to answer all the questions that I have at the end of my talk.

[Slide]

First I want to acknowledge the people in my lab, the students and the post docs who have worked in my lab. There are four from the NIH and particularly the assistance of Linda Saif--who is an investigator at Ohio State who works with many of the animal coronaviruses and just recently was nominated to the National Academy of Sciences--for use of her slides. I have no additional disclosures because prior to March of this year no one was particularly interested in coronaviruses.

[Slide]

Briefly, what I want to do today is review for you the pathogenesis of respiratory enteric coronaviruses and then compare some of the known features of the SARS coronavirus transmission and pathogenesis and, finally, list questions relevant to SARS and its impact on blood and blood-related products.

[Slide]

What I have done here is I put up a schematic which I would use for teaching many of my first year medical students. I am using many terms these days like I am sure all of you know a lot about coronaviruses. That is not anything I thought I would ever say to anybody. What I wanted to go through real briefly is this issue and where are we in terms of understanding other coronaviruses and where are we in understanding SARS.

So, if we think about a general scheme or model for coronavirus and/or SARS pathogenesis, typically obviously this would begin with the issue of transmission and infection. I am going to sort of present what I call a straw virus or a straw model for thinking about this, with some of the things to fill in where we know and what we know about other coronaviruses.

If we think about coronaviruses and SARS particularly, these issues have come up already in transmission and infection with inhalation; question of inoculation and/or ingestion; followed by a primary replication typically in epithelial cells of the respiratory tract or the GI tract and lymphatics--tonsils Peyer's patches and the lymph nodes. This might lead to a direct pneumonia or a direct gastroenteritis. This has probably been the sort of general feeling that has been promulgated. I think that is based on the fact that there is sort of a little bit of a prodrome and then a late progression to pneumonia, and virus has been recognized in the GI tract.

But in the typical scheme and the model that I would like to present in terms of thinking about this, particularly related to blood products, is the issue of thinking about SARS as a systemic disease with a progressive pulmonary component. So, it is more like a model that would be consistent with, say, measles virus or some other systemic disease that may have late pulmonary complications.

In that case then, primary replication would be followed by primary viremia or blood-borne spread which would then be followed by secondary replication, particularly in the reticuloendothelial system, the liver, spleen and lymph nodes, followed by another round of viremia which could then lead back to disease in the lungs, the GI tract and/or other complications of systemic disease. Such has been reflected, at least biochemically, in some SARS patients, suggesting hepatitis, possibly nephritis and certainly cytopenias or blood-borne complications of the disease.

In terms of its implications or relationship to blood products, the issue of transmission during the primary viremia would have implications for blood products for its presence in cells for issues of maternal-infant transmission and for sexual transmission. I think we can address a little bit about these and then ask questions about what we don't know.

[Slide]

If we think about coronavirus diseases, what I am going to tell you--I will tell you now what I am going to tell you--is that I would like to think about these diseases as what I will call either pneumoenteric or enterorespiratory. If we think about coronaviruses as a big group, it is a reasonable way to develop a scaffolding that we can then present subsequent data into.

If we look at the human coronaviruses, those of mice which is what I have worked with, and those of other domestic animals of which these are very important pathogens, we can see some general diseases or general strategies emerging. Those that have significant gastroenteritis and/or respiratory disease. Then, there are some things that are more enteric or systemic, such as hepatitis and encephalitis with MHV, peritonitis with feline infectious peritonitis virus, and renal disease associated with infectious bronchitis virus of chickens, as well, as you can see, other sort of pneumonic or respiratory diseases such as colds in human coronaviruses, tracheitis, pneumonia and others.

SARS, we feel, in some ways looks very different because of the way it emerges, but if you look at the general strategies and the data that have emerged both in humans and potentially now in animals such as the palm civet, we can see that certainly there has been recovery of virus from the gastrointestinal tract and there certainly is evidence of pneumonia.

[Slide]

I want to present just a couple of very brief models for you of how this has been known in animal coronavirus for a long time, and what relationship it might have as we think about how we want to think about SARS.

The first one is for transmissible gastroenteritis virus of pigs. This is a devastating disease in young pigs and can lead to high death rates and enzootics in pig populations. It basically replicates in the small intestinal villous enterocytes. It can lead to villous atrophy, vomiting and rapid serious and fatal diarrhea.

Interestingly, this is principally a gastrointestinal disease but a disease recently emerged called porcine respiratory coronavirus, which has a deletion in the spike protein on the surface of the virus that led to a mutant of TGEV which now has limited replication in the GI tract but now replicates in the upper and lower respiratory tract of pigs, leading to interstitial pneumonia.

This in fact, interestingly, is leading to the decline of this disease because it retains the same epitopes and immunizes against this disease. But now it is a respiratory disease instead of gastrointestinal.

[Slide]

The second model I want to show you for pathogenesis is that of the bovine coronaviruses, a similar kind of disease. Basically, the basic disease has been severe enteric disease of young cattle, less than four weeks of age, with infection of epithelial cells of calves, intestinal villous atrophy, diarrhea and dehydration--sounds familiar. But there were multiple point mutations that occurred and a new disease has recently emerged which is called bovine coronavirus respiratory, which leads to respiratory disease of young cattle, or the disease called shipping fever or shipping pneumonia in stressed adult feed-lot animals that is now respiratory and retains some of the same epitopes but is a little different disease but, nevertheless, demonstrates this respiratory and enteric access that occurs in the changes of diseases over time.

[Slide]

Finally, I want to talk about two other diseases that may perhaps have some other relevance to the issue of blood-borne transmission. The first is infectious bronchitis virus of chickens. This is what I would call a model of a disease that is a systemic disease with a pulmonary component. That is, it can have a primary infection in the upper respiratory tract that involves the tracheae and bronchi of chickens so it is a severe tracheitis. Virus detection, however, can be found certainly with a viremia and in multiple secretions, including nasal secretions and feces and urine, suggesting either that it is spread in swallowing or it is replication and/or transmission hematogenously. Certainly, that has been consistent with the issue with other organs being infected, such as the kidneys, the oviducts and the intestine with some late disease occurring in these animals.

[Slide]

The next model is that of feline infectious peritonitis virus. This is the one that is the cautionary tale and that is very concerning to everybody and I think provides the most concerning model for the issue of blood products. That is, a primary infection in cats that may be primarily pharyngeal or respiratory or intestinal epithelial cells but clearly can spread hematogenously and end up resulting in a severe, progressive and fatal peritonitis in cats, in animals that get this, with a persistent infection.

Now, virus detection can be in the peritoneum. It can be gastrointestinal and viremic, and viremia is cell-associated. That is, it is the infection of monocytes and macrophages. This can be continuous and, in fact, there is an enhanced disease that is based on increased uptake and replication in the presence of some non-neutralizing antibody. So, this is a model of pathogenesis which suggests a concern for viremia.

[Slide]

If we look at this overall--and I am sorry, I didn't know how big the room is but I will just go through these very, very quickly--the issue of viremia is certainly not consistent and, for the most part, has not been tested. In the cases where it has been looked at it is either moderate to low level, with the exception of feline peritonitis virus that has a cell-associated viremia that seems to be consistent and continuous. The replication in the upper and lower respiratory tract depends on the strain, as does the intestinal replication. Then, there is evidence of systemic disease with many of the viruses.

[Slide]

So, in the summary of the coronaviruses as a group there is this issue of pneumoenteric or enterorespiratory disease. This is Linda Saif's terminology. Systemic disease certainly does occur. It occurs in infectious bronchitis virus, the feline disease, and in mouse hepatitis virus viremia can be detected. Viremia is cell-associated in the case of FIPV but shedding and transmission can be by multiple routes. There is no data really; it has never been investigated in animal models for many reasons, this issue of parenteral, sexual or vertical transmission. So, there is not good direct data for any correlates or parallels.

[Slide]

What I want to do now is just talk briefly about some of the known features of SARS transmission of pathogenesis to relate it to these.

[Slide]

I am going to do a tremendous summarization here of things with some of my opinions. I don't want to rumor monger but a lot of this is based on phone conversations and interactions, and much of this data obviously is not out yet in an organized form. That will still take some time.

But in terms of overall clinical disease, it is a concept of a prolonged incubation period with late development of progressive respiratory disease; lack of upper respiratory symptoms in humans; lack of rhinorrhea and coryza, suggesting that this is a different model than that of other respiratory diseases that may have a prodrome of the upper respiratory tract.

Certainly gastroenteritis has been reported. It has sort of been overlooked and it is not included in the case definition but definitely virus is shed. There is as much, in some studies out of Hong Kong, as 60-70 percent of who will report diarrhea or gastrointestinal symptoms.

Children's disease, interestingly, appears to be much milder, particularly those younger than adolescents, without air hunger and without respiratory failure and certainly with basically no mortality in young children. Then, development of antibody response, as Alan said, is delayed for 10-20 days.

[Slide]

What is the evidence for systemic disease? Well, there is evidence. It is provocative. When I say evidence, I could have put "suggestion" because there is no absolute data that says this is a systemic infection.

There is liver enzyme elevation in a significant number of patients, as well as that of creatinine phosphokinase for a suggestion perhaps of muscle involvement or inflammation. Virus isolates have been obtained from organs. Some of the earliest isolates were from kidneys at autopsy. There is possible viral cytopathic effect seen in organs such as the liver and kidney, although this has not been consistent and these were late autopsies done in the earlier patients. So, it is not clear if those were contaminants or issues of late disease in people who had hypoxemia and other disease.

Urine has been a source for positive RT-PCR reactions. I couldn't find the data; I thought there was some data that there have been some positive viral isolates from urine as well but I don't have that, I am sorry.

This is also an issue of discussion, that is, that USAMRAD was looking at animal models of a macaque and there was one where there was a pneumonia that was produced quickly after IV inoculation of a macaque. That animal died possibly of a complicating bacterial infection so it was not possible to determine that this was actually true but there is suggestive evidence that IV inoculation could lead to pneumonia, suggesting a hematogenous route or blood-borne route.

[Slide]

So, possible modes of transmission, coming back to some of what Alan talked about, are large droplet aerosol contacts, with direct contact or fomite contact. Small particle aerosol has been considered, particularly because of some of the outbreaks such as in the emergency department in Toronto where a patient was passing through the emergency department and ultimately 12 people in that emergency department became infected and there wasn't a clear issue of contact. The person wasn't in the ED for a long period of time. So, the issue of small particle aerosol has been raised.

Certainly stool isolates have been found in humans in some of the cases such as the vertical transmission in Hong Kong, suggesting the possibility of a contaminated water supply.

Then this issue of the palm civet, or the civet cat which is not a cat but is more related to the mongoose, comes to this issue of animal vectors in transmission. Was it possible the source was ingestion, the source of these initial infections. The finding of people who are antibody positive without disease suggests that there may be some intestinal disease or replication.

What I can say though is that viremia, to my knowledge, has not yet been detected by culture in any of these systems. If Dr. Andonov has additional information, I would like to see that but my understanding is that viremia has not yet been detected by culture in any circumstance and cell-associated virus has not been reported. That doesn't mean it is not being investigated. I know that in Canada particularly there are tremendous efforts to accumulate these data and to get the samples and look and see if they can find cell-associated virus.

Is the time red on your side too?

[Laughter]

I am almost there. I figure I have been working on this 18 years, I should get at least 18 minutes!

[Laughter]

[Slide]

Just a couple of issues of virus stability and survival. I want to talk first about mouse hepatitis virus. Clearly, its stability is pH dependent. You can't see this clearly but I will tell you what this says. This is survival at 37 degrees at different pH's over time. It was 48 hours on this curve. This is percent. These are log scale survivals of MHV at 37 degrees at different pH's. So, this is 4; this is 5; 6 and 7; and then 8, 9 and 10 down here.

So, the pH stability is sort of between 5-7 for MHV; less at low pH and certainly less at very high pH. Also, heat inactivation may be variable and may be spike dependent. This is an issue of different MHV strains with their own spikes and then chimeric spike proteins that were made showing that they may enhance the stability of the virus. It looks like there are some differences with the SARS agent in terms of its stability. It may have a higher pH optimum. It can survive in diarrheal stools for longer periods of times and possibly drying for longer periods of time.

[Slide]

If we look at SARS then, what do we know about it? Well, it has been recovered from surfaces at greater than 24 hours. This is from data that I did in collaboration with Konde Subarau at the NIH.

It has been recovered from infected Vero cell lysates that that had been lysed in two percent SDS buffer. She put it in the freezer and I assured her that this would get rid of the infectivity but, being a good scientist, she did the test. She went back and scraped the surface after this was lysed and put it in the freezer and got about three logs of virus back. So, I think there are some issues about its ability to be killed easily from cell lysates in detergent and that needs to be investigated.

It is stable for greater than 24 hours in stool, particularly reduced pH, and it is recovered from non-ill animals, the civets, which is also concerning. Finally, it is likely rapidly inactivated by heat, at lest 60 degree heat and methanol because we have done fixation studies looking at organics, suggesting its ability to be inactivated.

[Slide]

So, if we put all this data together, what can we say about SARS? Well, it is still more in the category of what we think rather than what we know, but what we can say is that there is yet no evidence for straightforward viremia, either cell-associated or in serum; that replication can occur in multiple systems, or at least virus can be recovered; and there is some suggestive evidence for systemic disease, suggesting its possible transmission that way.

[Slide]

I will skip this. We are coming to the end.

[Slide]

Then what questions are remaining? Well, is SARS established in humans? I think that remains to be determined. The evidence of milder disease suggests that we may have some surprises. The late emergence of cases in Toronto suggests there may be some surprises and less severe disease and more of a spectrum.

Is there transmission by blood or blood products? There is certainly no evidence; there are no reports that that has occurred.

Persistent infection in the presence of antibody, persistent infection in coronaviruses--and I didn't go into this--is the rule. It is the rule almost in bovine and porcine and murine diseases. Persistent infection after animals recover is the rule, as is some recurrence of disease.

Is there serum viremia or cell-associated virus? This needs to be answered and should be able to be addressed as the tests improve.

Inactivation of virus, I think this just needs to be done in an organized way, and with different strains, but obviously you would like to do that from products that are relevant to the blood system.

Finally, the sensitivity of diagnostic tests for viremia, even the nucleic acid-based tests, may not be as good as we would like them to be yet. So, there will be a co-evolution of the tests and our ability to understand if there is virus even in products that were obtained from earliest patients.

I will stop there. Thank you very much.

DR. NELSON: Thank you, Dr. Denison, for a comprehensive review. You mentioned that persistence is the rule. For how long?

DR. DENISON: Well, it depends on the animal. In the mouse model, if the animals survive acute infection they will be persistently infected. Once a population of mice is infected, in the population and in the individuals that survive, they may be infected and shedding virus for the life of the animal. So, that may be with late development of disease or without late development of disease. You also can see intermittent shedding in young animals that survive acute disease as well. Clearly in tissue culture persistence is the rule. So, if the tissue culture is destroyed the cells will survive and you continue to recover virus from the supernatant after that.

DR. NELSON: Persistence is in the intestinal tract?

DR. DENISON: In the animals it is not known. Wherever the primary disease is you can find persistence. Some of that is thought perhaps to be sort of immune surveillance shutdown or that it is in the immune system too, in circulating cells. But, you know, this hasn't been investigated in that much detail in the animal models.

DR. NELSON: One of the reports, I think it was from the German investigators, found SARS coronavirus in stool 25 days after the acute illness. Probably it has been studied beyond that, but the epidemic isn't that old so maybe not.

DR. DENISON: I think that needs to be reproduced much more carefully, and I think the relevance of that or the relationship of that to disease in the blood system--I don't want to go into my pathogenesis 101 or 102, but many, many of viruses, respiratory, systemic viruses have a very limited low level transient viremia with systemic disease but it won't come back into the blood; you won't find it in the blood. So, I think that those are questions that have to be addressed.

DR. GOLDSMITH: Do you have any more information about host factors, besides age?

DR. DENISON: Well, there are other issues related to disease. There is some relationship for diseases like, for example, diabetes to hepatitis B surface antigen positivity. There haven't been enough patients with HIV yet to know what the relationship is to immunocompromise or what the basis of lymphopenia is. But age is clearly the issue. I just passed the age that moved me into the higher risk category so I am concerned about that.

DR. FALLAT: You mentioned a lot of animal viremias or virus infections. You have been studying it for 18 years. Is there any data that any of these other viruses could vertically affect humans, and why did this one affect humans?

DR. DENISON: I have had a slide I have shown to try to justify my NIH grants for the last 15 years about risk for trans-species adaptation because there have been animal and laboratory data. In fact, they have tried to immunize and the cat vaccines really stink. They don't have a high efficacy as a general rule. So, people have shown that they can actually infect cats with other coronaviruses and get them to infect and get antibodies, but it is not protective. In the laboratory, nature and vaccine trials trans-adaptation or trans-species infections have been demonstrated.

There are some questions that some human coronaviruses may have caused a recent new disease in pigs, called porcine enteric diarrhea virus, PEDV, that looks more similar to a human virus. So, it may go in both directions. So, the biologic barriers probably aren't that high for movement into humans. There are probably a lot of other barriers in terms of adaptation and transmission of disease and maintenance in populations. I think we are seeing some of that play out with SARS. So we, as a community, probably weren't so shocked that this happened--amazed but not so shocked based on what is already known about these viruses in animals and in the laboratory.

DR. STRONG: I was interested in the immune response to these viruses. This is primarily a cellular response, and is there any role for passive immunoglobulin therapy?

DR. DENISON: The issue of passive immunoglobulin therapy--gosh, I wish I had lots of time--depends on the model. If you give passive immunoglobulin to the cats and then infect them, they get much worse disease. So, you get actually immune-mediated enhancement of disease, probably uptake into macrophages and monocytes. There may be some role in other animals for that. The correlates of protection are not that well defined. Cell-mediated immunity appears to be critical for clearance and recovery and usually there is also an immunopathogenic determinant. But antibodies alone in the animal models so far have not been protective. So, it may lessen possibly but it could also enhance. So, that is a concern and that is why we need to look quickly at whether this can replicate in macrophages or monocytes and what happens in the presence of antibody. Even if antibody looks like it is neutralizing in tissue culture in those environments, is it neutralizing in an animal model? That is a question that has to be addressed.

DR. STRONG: The immunoglobulin not being protective would support an FC-mediated macrophage uptake which would enhance the infection. So, it sounds like the cellular immune response is probably Class I mediated. Is there any evidence for that?

DR. DENISON: Yes, cell-mediated immunity clearly is important for recovery in the mouse model. That is the main one that has been looked at. In the animal models IgA is protective in young animals so maternally transferred by IgA is protective--lactogenic immunity is protective in young animals. So, immunize the mother at late times, get good GI immunization and they pass on IgA antibodies in the milk. That is the goal actually of that. Cell-mediated immunity has only been looked at in the animal models, a pathogenesis model, not as a protection model.

DR. NAKHASI: Mark, thanks very much for the nice presentation. You mentioned that some of these viruses, the feline or other animal viruses, remain in the tissues. The question is how long they remain, and is it a possibility that coronavirus, even though it may not be viremic through blood, can remain after an acute phase and go into tissues, organ transplantation and other things? Will that be a problem?

DR. DENISON: Yes, I don't want to overstate the data that is available because things have been studied for pathogenesis. Disease, pathogenesis and vaccine have sort of all been separated into different models depending on the needs. The murine model is the best one for the issue of persistence and disease. It depends on the strain, the animal, their age, etc. There is both a continuous infection model of encephalitis in mice where you can continue to get virus isolated, and there is also an immune model where you don't get virus but you can get RNA by PCR suggesting increased replication but you can't recover virus anymore and you get progressive immunopathologic disease. So, there are certainly suggestions of continuous replication. There is no model or no basis for the issue of transplantation or movement into materials and then re-initiation of infection in another host, as far as I know. I can certainly recommend to you people who could address those issues very clearly, and I would be happy to do so.

DR. NELSON: Dr. Andonov?

SARS: Canadian Studies (Epidemiology and Virology)

DR. ANDONOV: Thank you, Dr. Nelson. This presentation has been assembled on very short notice and I didn't have enough time to send it to Alan and to Dr. Smallwood but I have it here so if there is a copier copies could be made.

[Slide]

In my discussion with Alan we decided that I will briefly update you on the Toronto SARS outbreak and then share with you our laboratory data that we have accumulated so far, and as well address some issues that might have indirect or direct impact on blood safety, such as viremia, whatever we know about it, as well as asymptomatic or subclinical state of infection and some animal experiments that we have conducted in our place.

[Slide]

On February 23, a couple arrived from Hong Kong, from Chinese origin, and later on, on March 2, a 78-year old woman had respiratory disease with fever, cough and later progressed to dyspnea. She infected five of her family members. On March 5 she collapsed at home. Her son tried to resuscitate her but she succumbed to infection. Several days later her son ended up in the emergency ward of one of the community hospitals in Toronto and started a chain of events that resulted in the largest outbreak of SARS outside of Asia.

Currently, we have 259 probable cases. A lot of them are already confirmed by lab testing in Ontario and 133 suspect cases; 34 deaths.

[Slide]

The outbreak in Toronto has been publicized relatively well. There are three published reports. The last one was just published last week, I believe, in the MMWR issue on Friday.

What I would like to point out here is some of the difficulties that we were facing in Toronto, especially with something that we dubbed SARS-2, as it is shown here, the second phase of the SARS outbreak. By April 20 there were no more new cases in Toronto. At the end of April, April 30th, WHO lifted the travel ban on Toronto.

Later, in early May and in mid-May the health officials decided to suspend the expanded precautionary measures that were in place. By May 14, WHO stated that for the last 20 days there was no transmission in Toronto so it took it off the list of places where SARS is occurring. Then a disaster happened two days later. There was a cluster in a rehabilitation hospital. Retrospectively, the investigation showed that actually the outbreak was still lingering.

Just to give you an example of how difficult it is to actually try to say that, yes, there are no cases, there were only two cases, we believe, that actually were linked with the first outbreak and transmitted infection later in the rehabilitation hospital.

One of these two was a 96-year old man who was hospitalized on March 22 with a broken pelvis. On April 2 he had respiratory disease, mild respiratory disease, then developed pneumonia but he responded very well to antimicrobial treatment and, because he had not been exposed to any of the contacts or to any of the people that had been infected with SARS, he was not considered a probable or even a suspect case. He improved. Then, on April 19 the same patient developed a second bout of respiratory disease, fever, diarrhea. He was tested again. All the lab findings were negative and there was Clostridium difficile in his stool. So, again, he was dismissed as a case that was not SARS.

Now we know that actually it was a SARS case and that kind of patient-to-patient, patient-to-visitor transmission occurred in that period, between late April and the beginning of May in that rehabilitation hospital. As a result of that, the latest big cluster was among the healthcare personnel.

[Slide]

In the second SARS outbreak, as we call it, more than 90 percent of all the cases resulted directly from exposure in that rehabilitation hospital. There were only a few household members that had secondary infections from healthcare personnel.

[Slide]

This is an interesting comparison of what might happen or what might not happen with SARS and imported cases. At the same time that Toronto had its first importation of SARS from Hong Kong, the Chinese couple arrived in Vancouver and the husband immediately went to the emergency ward. He was sick with severe respiratory disease.

Now, there was really an astute physician in the emergency ward and he thought that this was an influenza H-5 case and essentially he sent the patient immediately into isolation and requested testing for H. influenzae H-5. As it turned out, it was not influenza H-5; it was SARS. But the most important thing was that, unlike Toronto, that patient was immediately isolated and there was no big outbreak in Vancouver.

The wife of that first patient, which is also an interesting case, was never isolated. I am not sure if she was even under quarantine because when she came to Canada with her husband she didn't have any symptoms. She was not sick and she never developed any significant symptoms. She recalls, however, that she had a mild febrile episode while visiting Hong Kong. Later her samples were tested and were positive both by PCR and serology for SARS coronavirus. So, apparently she was not infectious or maybe was not able to transmit the infection to some of her close relatives.

Another interesting case that underscores the difficulty of proper diagnostics of SARS cases is the North Carolina man who got infected while visiting his father in a Toronto hospital. This is a very interesting case again, and WHO blamed Canada for not properly doing surveillance on that case, which may or may not be exactly the case.

What happened is that he visited his father who was with another patient in a room. Actually, at the time of the visit both patients were okay. There was no respiratory illness. When the North Carolina man went back, approximately at the same time not his father but the other patient got sick. So, what the epidemiological investigation of our colleagues in Toronto uncovered was that the wife of the second patient was sick and probably she infected her husband.

The interesting part is that while the wife was visiting her husband they never met, the North Carolina man and the wife who eventually infected him never met in the same room. They were never in the same place. The other interesting thing is that his father, who was in the same room all the time, never got infected. So, in a way it is a little bit of a mystery. I guess all big mysteries in life have a simple explanation but right now we don't have it.

[Slide]

What do we know about the incubation period? Based on work on 44 patients, it is about between three and ten days, based on the prodrome with headache, malaise or myalgia. Based on fever, it is a little bit longer, seven days median; based on diarrhea, eight days; and coughing and dyspnea, nine days.

Health Canada did its own investigation because all these cases had probably multiple exposures. So, what we did, we investigated 42 patients with a single point exposure, and the median here was 4.2 days and 95 percent of all these 42 patients fell within that range of 4.2 days--sorry, of ten days total. But there were about five percent outliers. That is a statistical estimation.

Now, we had three cases. One is confirmed and three are under investigation. One case was a medical resident who was quarantined for ten days. On day 11 he came to the hospital and worked for 24 hours delivering babies. On the next day he had fever and was sick. So, we have more or less about 12 days definitely in that particular case of an incubation period. We have three more cases where the incubation period is between 11 and 15 days, but these are still being investigated.

[Slide]

This is the history of how we got involved. Early in March we were notified about these cases in Toronto and started receiving samples, and we are still receiving samples, more than 10,000 samples and most of them probably have nothing to do with SARS.

[Slide]

Our initial results discovered metapneumovirus in five of the eight cases of the initial cluster. So, we thought that might be one of the causes but later Hong Kong and CDC reported isolates in coronavirus. Later we were able to isolate coronavirus within four days after initial culture.

[Slide]

This is apparently not a very good slide but here you can see the immuno-gold by electron microscopy of coronavirus with a relatively early serum from a patient. That is not exactly convalescent but still it reacts with the virus-like particles.

[Slide]

This may be a little better picture of the immuno-gold particles.

[Slide]

In the early stages of our laboratory testing and investigation we stumbled across a category that we named "neither." You know the so-called "probable" and "suspect" case and their definitions. The "neither" group had laboratory evidence of coronavirus infection but the were never included in these suspect or probable groups, partly because we didn't at that time have enough data and I guess they are moving up the scale to suspect or getting discarded. So, 14 percent of our initial cases that were not probable or suspect had laboratory evidence of SARS infection.

[Slide]

Just to give you an example of some of these cases, there are seven symptomatic cases, one of which was coronavirus positive by PCR. There were cases with fever but not respiratory symptoms or the other way around, respiratory symptoms, no fever, positive by PCR, some of them. There was no difference whether they were exposed or whether they were not exposed, at least to our knowledge, to infected people.

So, at this time it was really puzzling. That was more or less a month ago. It was really puzzling what was going on, and do we really have something which is more than the typical SARS outbreak or do we have infection going on in the community?

[Slide]

The picture gets clearer now that we have more convalescent samples. I think this is important data in terms of lab diagnostics for SARS coronavirus. As you see, out of the total number of 144 patients with probable SARS, 62 percent are positive for coronavirus. This includes serology and PCR of the original samples or PCR or the cultured samples from these patients. If you look only at the PCR-positive results, it is 44 percent. So, PCR is not the best diagnostic test, especially in the early stages of the disease.

Now, out of these 144, for 43 cases we have the complete set of samples which means the original first samples, late in the middle of the disease and convalescent samples. So, here the correlation gets much better and 41 out of these 43 probable cases, or 95 percent, have evidence of SARS corona. So, here you can say that the diagnostic really works. Only seroconversion, no PCR positivity was discovered in 35 percent of the patients and only PCR in 60 percent of that group with complete sets of samples. Similar, though not exactly the same, was the picture in the suspect cases. Overall, 39 against 62 and then 49 percent positivity in PCR against 60 percent in the probable group, and again very high serology.

I think that serological testing may be one of the most important, currently at least. What we are lacking right now is a good IgM serology test to be able to find out early in the infection. Most of these are convalescent results.

Going again to the "neither" group, the results are really very preliminary but what I can say is that when I left the number was 112 people that we think are in that group. Today I have heard that the number has risen up close to 200. In 14 percent of these we have evidence of infection and they are not suspect or probable.

So, we are starting an investigation in 92 of these persons and, hopefully, we will have all the follow-up serum samples to be able to say exactly what is going on with that "neither" group. So far we have only six people with full sets of samples, and these are all serology positive and two of these are PCR positive. As I said, they fall outside the category of typical suspect and probable cases.

[Slide]

I just want to share some of the data that we have obtained so far. What I can say is that the viral load in the samples that we received is quite low. Maybe that is why the PCR is failing to detect, in at least 50 percent of the acute stage of cases, the nucleic acid of SARS corona. In some of these the NP, the nasopharyngeal swabs in a few patients--I don't know if you can dub them super-spreaders or not but the viral load is extremely high. The bronchoalveolar lavage is a very good source for PCR testing, again with very high viral loads. The oropharyngeal samples, again, had extremely low viral load. Some of the stool samples have a relatively high viral load but, again, most of them are low.

Then, coming to the EDTA blood, at the beginning we tested serum samples and whole EDTA blood and we found that in EDTA blood we get positive nested PCR. So far, out of 1,900 samples of whole blood we have 67 positive results. Of these--not of all of them; we have the real-time PCR recently established--of these, there are four samples here and, again, the viral load is extremely low. Our limit of detection is 0.05, 0.025 plaque-forming units. I don't know how that relates to copy number. But as you can see, in two of them we have about 0.5; in the other ones 3 plaque-forming units concentration, and in another two who are actually borderline negative, I would say, 0.01 and 0.02 but these two, when we tested them in nested PCR were confirmed positive.

So, the bottom line is, yes, apparently you can detect the virus but if there is any viremia it is very short because we have never been able to discover a patient where we have two consecutive samples of whole blood positive. Usually that was in the beginning, first stages of the illness.

[Slide]

We were concerned because in some of the samples we were receiving, let's say, there was a difference of ten days between day of collection and when they arrived in our lab so we were concerned how long the virus can be preserved in samples like that, and what we have found out essentially is that even at 37 degrees cell culture virus is pretty stable in terms of PCR detection and there is no problem detecting it on day ten; maybe less than one log reduction.

[Slide]

Dr. Denison has already shown a similar slide about the stability of the virus. What is interesting here is that with cultured virus without any preservant the reduction of titer is negligent. So, the virus can survive on surfaces pretty well.

[Slide]

The initial experiments that we have done on animals included mice, newborn mice, rabbits and guinea pigs and they did not result in any illness in these animals.

[Slide]

At approximately the same time we started experiments with pigs and chickens. They were all inoculated at the same time intranasally, intravenously, ocularly and orally with approximately two million plaque-forming units.

[Slide]

The result of that animal experiment is that we were able to find evidence of the virus in the animals by PCR. We were never able to isolate the virus from these animals. The viremia was very short, about two days.

[Slide]

The next experiment that we designed was again in mice, and here the route of inoculation was intraperitoneal, intranasal, and they were separated. We are still doing the virus isolation but what was surprising was that the oral route in these animals seems to be quite good.

[Slide]

The animals were sacrificed one hour after peritoneal infection and then one day, three, five, seven and nine days after infection. As you can see, after one hour infection you can see it in the liver in two of two mice. In the kidney, similar findings one day after infection; and spleen again appears. On day three it is the same more or less as on day two, and then if that is any kind of evidence of replication, I am not sure, it fades off.

Now, the oral route in this experiment at least was the best in terms of number of animals. In all animals essentially liver, kidney, lung and spleen were positive on day three post inoculation for SARS corona. What is interesting from this, and again it is preliminary data, is that we couldn't find it the blood anywhere. Again, this is only real-time PCR and our real-time PCR is five to ten times less sensitive than the nested. So, we are going to continue to test them by nested PCR probably next week or sometime this week. But so far only one sample I think here was found positive by PCR.

The interesting thing is that the spleen seems to be the organ where you can find it quite often and it persists almost to the end of the experiment, day nine.

I think I should stop here. Thank you.

DR. NELSON: Thank you. Comments or questions? Jay?

DR. EPSTEIN: Thank you, Dr. Andonov. I appreciate you doing this on short notice. One question, in your studies of contacts have you done any investigations to look for viremia in persons either during an incubation period post exposure or during the convalescent period? Essentially, I am asking whether there is any study of viremia in an asymptomatically infected person.

DR. ANDONOV: We have our PCR-positive results only from NPs, from that group. So far we have no evidence of EDTA whole blood being positive in these patients.

DR. EPSTEIN: But how many samples have been studied in those same patients that had positive nasopharyngeal PCR?

DR. ANDONOV: The ones that we have the complete set of samples for--and the group is quite small; only six--all six are seropositive and two of them are PCR positive. However, in that 112 patient group that I showed, there were 14 positive by PCR. In the so-called "neither" group the numbers are changing quite often because some of them eventually, as the epidemiologists do more proper work are able to shift them to suspect, to the list of the suspect, but we still have a large group of about 190 that we consider "neither" plus about 1,000 so-called unclassified that we just don't have enough information for, epi or any other, to be able to say that there is any relevance of asymptomatic or subclinical SARS. We are hoping that these 92 cases, 92 people that have agreed to be followed, that they and their relatives, family, relatives, will give us a better picture. Again, I would say we it mostly depend on serology.

DR. NELSON: Actually, the "neither" group are people that are all asymptomatic but mostly they have had contact with a case, or are they controls without any contact with a case?

DR. ANDONOV: Some of them are asymptomatic and we don't know why we ended up with samples from asymptomatic people. But at the beginning of the outbreak everybody was sending samples and we were testing which, at the end, turned out to be quite interesting and will give us maybe some interesting data. I don't know why anyone would send an asymptomatic sample from an asymptomatic person unless he feels that he may have been in contact. So, what we are trying to uncover is what the reason was for sending the asymptomatic people. They were people, however, who had mild respiratory illness and for some reason ended up in our place as well. There were others who didn't have any respiratory illness but just had fever and they ended up as well in our database. In March, when we tested all of them we just stumbled on that, that there are positive PCR findings on these. In some of these, when we collected serum samples later, there was seroconversion. So, there definitely is some sort of infection.

DR. NELSON: Is it known that the SARS virus, coronavirus--that PCR and serology does not cross-react with the U2 human coronaviruses that were present before SARS?

DR. ANDONOV: The data that I know is that in CDC they have looked into that and they have not found in ELISA cross-reactivity. Cross-reactivity in histology, yes, they have found and it is published. Not in ELISA so I think that the ELISA results are accurate. The PCR cross-reactivity--definitely there is no cross-reactivity in PCR. So, PCR from that point of view is very good. The only problem with PCR that we are a little bit concerned with right now is that we are testing samples with nested PCR. As you all know, even in the best places contamination happens, especially when you have a huge number of samples to test and there is huge pressure to get faster results. So, I would say that in a month or two when we are able to collect some of the sera from people who have tested PCR positive, if they seroconvert I would say this would be the ultimate proof whether PCR was specific but we have to wait for that.

DR. NELSON: Thank you. Now Alan.

FDA Current Thinking

DR. WILLIAMS: I would also like to extend my thanks to Dr. Andonov and Dr. Denison for their very interesting presentations, both done on relatively short notice.

[Slide]

What I would like to do is end this session by discussing some of the precautionary measures taken by FDA in response to the emerging SARS epidemic, specifically the guidance document which was published in April of this year, entitled, recommendations for the assessment of donor suitability and blood product safety in cases of suspected severe acute respiratory syndrome, SARS, or exposure to SARS. Following that, I would like to highlight some of the common questions and answers that have come into our office with respect to this guidance document, in addition to some comments to the docket.

[Slide]

I want to stress that, in fact, almost on a daily basis there are ongoing inter-agency and international discussions reviewing emerging scientific data about this epidemiology of this epidemic, the virology and natural history, particularly in terms of factors that impact blood supply. So, there is tremendous effort going on to basically stay current with developments as they occur and much of the information, obviously, that you have heard already this morning is emerging and not yet published.

[Slide]

Now, I think this is an example where FDA recommendations with respect to donor eligibility have interacted perhaps more than ever before with the emerging epidemiology that has been put onto the CDC website. In fact, we have a dynamic reference to the SARS case definition that CDC has on its site. The site is referenced in the guidance document and for those who don't have web access, there is also access by telephone, and the hours for that access are underlined in the document itself.

[Slide]

I think in many of the situations that we encounter the first protection is that, in fact, donor screening measures already in place provide a healthy donor. So, an individual who has symptomatic infection would not meet the criteria that are currently in place to define a healthy donor. Generally, what we are most concerned about is an asymptomatic individual who would appear healthy but still be capable of transmitting infection. So, with respect to SARS, the guidance document specifically recommends questions to be asked of individuals to capture certain information. For wording in the guidance document at donor interview, we recommend that you ask orally or in writing potential donors about--and the first area of inquiry is a history of SARS, suspected SARS or treatment for SARS within the previous 28 days.

For the first time in a guidance document, instead of putting wording for a question into the guidance directly, we used the wording for example, in the past 28 days have you been ill with SARS or suspected SARS? The intent of this was not to give blood centers the option to develop their own questions, we have a lot of different questions being used by blood collection establishments, but more to give freedom to groups, like the uniform donor history questionnaire task force, to work with this model question, do cognitive testing and build a question that would then be relevant to put into a standardized form. So, that is the explanation for this nomenclature and you will see this in the subsequent questions as well.

[Slide]

The second question, the area you wish to capture information about is close contact within the previous 14 days with persons with SARS or suspected SARS and, again, there is an example question closely allied with that information.

[Slide]

An additional question, travel to or residence in areas affected by SARS within the previous 14 days and, again, with reference to the CDC website which dynamically lists those countries. In this situation, because there are travel questions currently asked, and have been for some time, many blood centers have gone to using capture questions, something as simple as asking a donor have you been out of the United States in the past three years. In that way, as many as half of the donors would say no and they don't have to go through the subsequent questions. So, since that is common and to the extent that that capture question would meet and identify donors who would be potentially in a SARS-affected area, it would be obviously appropriate to continue within that blood center to use that capture question. If there isn't a capture question in place, then we again give an example of a way to uniquely ask that information.

[Slide]

The recommended deferral actions related to these criteria for history of SARS--there is recommended deferral for at least 28 days after complete symptom resolution and the cessation of any treatment. Some of the rationale for the 28-day period is recognition of the fact that virus can be shed for a prolonged period of time. Information known at that time captured the length of period that was recognized, and there have been some isolated instances of longer fecal shedding. I think 43 days is the longest period at this point but, again, those are not fully worked out and accepted as potentially having fecal shedding of virus for that length of period and currently FDA uses 28 days as a period.

History of contact with persons with SARS or suspected SARS, deferral is for a period of at least 14 days after last exposure. The 14 days is based on the estimated three to ten-day range of incubation periods with some margin. Similarly for travel of residence, deferral for 14 days after arrival back in the United States.

[Slide]

In addition, it is recommended that donors be encouraged to report post donation any evidence that they, in fact, had a SARS illness within the 28-day period prior to donation; had any known exposure within 14 days prior to donation; or a SARS illness within 14 days after donation. If this information is then reported back to the blood establishment, there is a recommendation for prompt product retrieval and quarantine, with the exception of pooled plasma given that current fractionation procedures and viral inactivation would be presumed to inactivate a SARS-like agent.

[Slide]

Some of the questions and comments, and there were a fair number of questions that came in with respect to this guidance document--the general categories were the rationale for the facilities; questions about implementation of the procedures; issues related to the burden of donor screening modifications and the rapid time frame in which they were both introduced as recommendations and recommended for implementation; and mechanisms for implementation in the context of this very large and very effective program to build a standardization questionnaire. I am going to touch on each of these because I think it is relevant; there has been a lot of interaction in these areas.

[Slide]

Specific to the scientific rationale and, remember this occurred in early April for the most part, I think some of the key scientific observations used as a basis for the recommendations do hold and, obviously, we are reviewing this on a regular basis. But there was limited PCR evidence of SARS coronavirus in the blood of symptomatic SARS cases and reasonable question as to whether there existed a potential for viremia in a symptomatic infection certainly could not be ruled out at that time and I think can't be ruled out at this time.

In addition, there are not alternative preventive measures readily available to prevent an asymptomatic donor from donating a unit of blood when they might be viremic. One measure that was considered and discussed extensively was with you could get at precautionary measures from another direction, i.e., since the CDC hands out donor cards to individuals returning from SARS-affected areas whether this travel questionnaire could contain a contraindication for blood, tissue or related donation.

For various reasons, including the amount of space available, the need to keep such information current, and so forth, CDC made the determination that it was not appropriate to include a contraindication for donation on that card and most likely, anyway, it would be felt that the donor would need to be qualified on the day of donation and that really is the most direct means of preventing inappropriate donation by an exposed individual.

[Slide]

It was recognized at that time that SARS was spreading rapidly worldwide and the United States certainly has has a SARS experience but I think the general consensus is it could have been a lot worse. Based on the Canadian experience and others, all SARS under care here had aggressive infection control measures implemented by their healthcare personnel. The availability of this knowledge and a certain amount of luck I think prevented a much more extensive SARS epidemic in the United States. This knowledge was fortunately in place at the right time. This is not a direct quote from Dr. Fauci's grand rounds presentation yesterday but it is essentially the conclusion that was made, that the United States could have had a much worse outbreak.

Finally, in any precautionary measures, the perceived value of that measure in relation to the cost of implementation in terms of donor loss and burden on ultimately manufacturing a product is going to differ among stakeholders and that calls for healthy debate. However, this doesn't negate the fact that, particularly in today's world, we really need to have a rapid response capability to protect the blood supply. Be it a donor questionnaire or test implementation, we need to keep in mind rapid implementation.

[Slide]

A couple of the questions that came in for increased standardization of the donor form screening asked can we, in fact, extend the deferral period for SARS to harmonize with some of the other deferrals that are in place. The answer to that is yes, certainly any donor eligibility action that is more conservative or more constrictive than FDA recommendations is acceptable.

A concept of immediate implementation of the guidance document--the face page of the document says, when it is issued, for immediate implementation. That is the document as a whole. Then, within the guidance document itself it generally gives a time period for implementation of those individual recommendations. Unfortunately, both terms are called implementation so there is some confusion but, in fact, the time period specified by the document is when those recommendations should be put into place.

A question about application to autologous donors, in fact, the regulations do not address much eligibility requirements with relation to autologous donors. I believe it is only hematocrit and hemoglobin. So, in terms of applying donor suitability criteria, this is an area of medical discretion for SARS and most other donor screening.

[Slide]

In reference to the CDC website information, they use the term "last date of illness onset." In the chart included on that case definition slide it is actually based on the travel alert status of an individual country plus ten days. So, you may have read in the news recently that the only country still on travel advisory status is specifically Beijing, China. A travel advisory in CDC terms means that there is a precaution against travel and non-essential travel should be either curtailed or considered very carefully. A travel alert, on the other hand, simply means there is an ongoing potential threat and one should take measures to reduce exposure to that threat.

As of last night, in fact, the Chinese mainland is continuing on alert, with Beijing specifically being under travel advisory. Hong Kong also ongoing alert. Hanoi was removed from that list. The ten days after the alert was lifted was May 25. Singapore similarly was removed June 14; Toronto is ongoing and Taiwan is ongoing.

This does at times differ somewhat from the WHO affected areas list and we are specifically referencing the CDC list in our guidance document.

[Slide]

Now, there has also been discussion of the fact that the SARS guidance document and, in fact, several other recent guidance documents, the ones related to anthrax, vaccinia immunization and West Nile, are all issued as final guidance documents. There is a GGP, good guidance practice, regulation that, in fact, requires FDA, when public health is not potentially compromised, to put guidance documents out for draft and consider those comments to that draft in issuing final guidance. However, in situations like SARS there is language in the guidance that issued in final form, "agency has determined that seeking comments from the public prior to implementation is not appropriate since SARS may pose immediate safety risks to the blood supply," and similar language is in these other documents.

I think it is important to keep in mind that guidance documents can be the subject of comments to the docket at any time, and these comments are really distributed and taken quite seriously. So, not having a guidance document available in draft certainly does not rule out the opportunity for commenting.

There was a lot of comment from the field that rapid implementation, not only of donor questions but everything that is done in a blood center these days, takes training and takes SOP development. It takes computer software modification in some cases and in a GMP environment that is a handful to do in a short order. That is certainly recognized but, again, I would state that mechanisms need to be defined to allow us to respond rapidly to a threat. You know, I think that is something that really has to underlie some of our considerations in this area.

[Slide]

Finally, this committee has had several discussions about the evolution of the standardization questionnaire through the uniform donor history task force. A standardization questionnaire is almost in final approval stages and available. I think the emergence of these new questions through the recent guidance documents has kind of raised the specter of, okay, we have the final document, how do we handle new questions, particularly when they need to be implemented rapidly? So, we have tried through these guidance documents to develop mechanisms which would allow the questions to be used on an interim basis for a limited period of time so that experience can be gained with the questions and cognitive testing, or other relevant testing, can be done before they are integrated into a final standardization questionnaire.

The documents will use the "for example" questions and there was actually a comment from industry, well, can we use an interim form and document the response to the interim handout and reference that on the actual formal donor screening questionnaire? That was actually approved by FDA and referenced in the Q&A which was put on the FDA website in reference to the SARS guidance. We actually built on that with the West Nile guidance so that it is permissible to use an interim information sheet to put a question rapidly into place and put it into the questionnaire ultimately in a rational manner.

I think the bottom line here is FDA does strongly support the continuing uniform donor history questionnaire development process. The questions that have recently been recommended in the guidance are being subjected to cognitive testing early this summer, again through collaboration with the Center for Health Statistics that did the original work. FDA is funding this work and we are actively collaborating with the task force to keep this process going and make the questionnaire a rational, integrated whole, allowing that sometimes there do have to be modifications. Thank you very much.

DR. NELSON: Thanks. I am sure there are questions. Harvey?

DR. KLEIN: I only have two questions. I will separate them. The first one is short. Do you know what Canada has done in terms of the blood supply?

DR. WILLIAMS: The earliest recommendation from Health Canada was similar in terms of donor deferral but it specified a deferral period for case exposure and travel of ten days. In fact, the industry Canadian blood service has implemented a 14-day deferral voluntarily. Canada has recently modified their deferral period in response to some of the outlier cases that have been observed in Toronto. I don't recall exactly what that period is. Thirty days?

DR. ELSAADANY: Can I respond, please? I am Susie ElSaadany, Health Canada. I was really coming to ask you the same question, why Health Canada modified the donor deferral period to 21 days is based on the outliers of the incubation period and based on our statistical analysis using different scenarios for what would be the incubation period under what scenarios. We find that the outlier can go out to 17 days with 95 percent confidence interval. Also, in China the highest incubation period was 16 days, or the outlier was 16 days. So, to be prudent we recommended 21 days, adding an extra few days based on our experience with HIV when it was earlier discovered. So, it is 21 days.

DR. NELSON: Harvey, you had another question?

DR. KLEIN: The second question that I had related to the donor card and questions. I am delighted to hear that these questions are being validated because I think that is important. But the other point is that the questionnaires have gotten so long, and with every new emerging disease we have three or four more questions so that there is a real issue as to whether donors either listen to what is being asked of them or really answer these questions. When you get three or four sheets of questions it becomes an issue.

Just as an example, if one were to ask a question, as many donor centers do, have you been under a physician's care in the past year, it is very unlikely that anyone who has had SARS or West Nile virus or monkey pox, or a host of other things, would not have been so you can use that as a generic screen without having to ask questions about all of these which are, first of all, low likelihood positive answers and, second, possibly no risk at all. Secondly, we already have a geographic exclusion type of question and using that as a screen, as you pointed out, is much more efficient than trying to add all of the various subtleties onto the card.

So, I really would encourage the FDA, as well as the other people who develop questionnaires such as the AABB, to look at the entirety because anyone who donates blood can tell you that there is a great suspicion that this process is becoming so unwieldy as to defeat the intent of the screening card.

DR. WILLIAMS: I think I agree and that certainly is the sentiment of the task force that has been working on this. I think the new document will have increased use of capture questions that would make it a more efficient process.

I think one of the other problems is that typically it is not three or four pages, blood centers try to keep it on a single page and the type gets smaller. So, that has an additional problem.

But I think the concept is very much recognized and it is a goal of the task force to try and make it as efficient as possible. I think the other concept is that, hopefully, as the field begins moving toward computer interactive screening programs a lot of this skip pattern and capture questions and so forth could be built into a computer program, which would also simplify things. There is some of that work currently being done in blood centers but those are potential areas.

DR. NELSON: I think one of the real problems with the SARS, in contradistinction to malaria, is if your plan lands in Taipei on your way to Bangkok or somewhere else, you are supposed to be excluded for 14 days based on getting off one plane and on another, whereas that is not exclusion criteria for malaria. It becomes very complicated. I was just recently on a plane that landed several places in the Orient and in some places between Tokyo and Bangkok the stewardesses had masks on and had them for the passengers, and I didn't know whether they were suspect cases or just worried. I suspect they were worried. That, coupled with the fact that the sites keep going from one category to another, for a blood bank to figure out, you know, what is 14 days--from what?--May 14 or May 16? It is pretty unwieldy but I guess a guy that travels a lot through the Orient is probably not a blood donor for a month after he finishes that, pretty much.

DR. ALLEN: I don't want to belabor the point but I share many of the concerns that Harvey does. I will just ask specifically if you ask donors about the history of SARS, suspected SARS, I wonder how many donors really are going to have any idea if what you are trying to pick up something where they haven't yet been sick enough to go to a physician. But even many physicians may not suspect that diagnosis. I wonder if you perhaps wouldn't do better with a broader capture question, you know, in the last two weeks have you had history of fever with diarrhea or cough or other respiratory symptoms, if that may not be more effective than trying to ask them about SARS and other things about which they may have very little information, other than that they have heard it from the media.

The other question, you talked about the size of the type and so on, the counter point for that for blood collection centers that ask the questions orally is that the screeners speak more rapidly and those of us who have any degree of hearing impairment have great difficulty following what is actually being said.

DR. GOLDSMITH: On the post donation information and look-back pooled plasma is exempt from product retrieval and quarantine. Do you have information about the impact of cone fractionation, alcohol and sterilization regarding SARS in the end products?

DR. WILLIAMS: Someone else might want to address this but I will take a shot. I think in terms of other RNA envelope viruses there is good evidence that the fractionation process, as well as the inactivation procedures, have high degree of inactivation. I am not aware of work specific to SARS.

DR. GOLDSMITH: Is that going to be forthcoming?

DR. EPSTEIN: Well, we did look at the literature on inactivation of coronavirus and they do not appear to be stable viruses under the conditions common in fractionation, particularly with respect to heat, low pH. Of course, solvent detergent mixtures inactivate all envelope viruses. So, we didn't believe that there was evidence or, put it this way, high risk but it is a subject that could be explored further and will be if there proves to be viremia.

DR. STRONG: I have already been pointed out as having a major conflict of interest in these particular areas since I represent a blood center, but I can only amplify what has been stated before concerning the complexities of adding these questions. We are already dealing with a number of inconsistencies with the 7-day, 14-day, 28-day interpretations and these will only make it worse. For example, we have a question now about fever and headache 7 days prior to donation. If a donor comes in and has had a fever and headache a couple of days prior to that, they are okay to donate but if they call us two days after donation with fever and headache we have to quarantine and pull products for 28 days prior to donation. These are inconsistencies that are very difficult to track and you are dealing with blood collection services who aren't terribly educated about the various infectious disease issues. It really is beginning to come to a point where we are defeating the purpose of safety and it really needs I think an overall review of how we are approaching this. Because we keep adding new diseases, it is only going to get worse.

DR. ELSAADANY: Can I ask a question? This is Susie ElSaadany again from Health Canada. My question to you, Alan, is have you done a risk reduction analysis based on the 14 days, and how did you manage to deal with the tolerance level of blood loss when you do a donor deferral policy?

DR. WILLIAMS: A 14-day period was basically chosen based on knowledge that the majority--well, certainly all the cases recognized at the time the policy was being developed were in the 3-10 day period and allowing several days for a margin to reach a 2-week period.

In terms of donor loss, the estimates were derived based on some information received from CDC on the number of travelers who had, in fact, been approached by CDC with travel cards and where they had been located, and then calculations were made based on the likelihood that those individuals might have donated blood in the impacted period of time subsequent to that travel. Based on that, the estimate was made that the loss would be between 0.1 and 0.4 percent. We usually get feedback in terms of actual loss in terms of deferrals and we have not heard evidence that it has been anything higher than that in any particular sites, acknowledging that most donor loss probably occurs probably before the donor comes to the donation site. But the estimates were between 0.1 and 0.4 percent.

DR. EPSTEIN: I just want to add another comment about the deferral period post exposure in relation to the data available on the incubation period. At the time that we issued the guidance, as Alan stated, we had learned both from the data in China and in Canada that the average incubation period was 7-10 days. We were aware, however, of an outlier of 11 days in Canada and a report out to 16 days in China. However, most of those reports were time to fever, not time to first symptoms and the available data also indicated that a symptom prodrome did antecede fever. So, we felt reasonably comfortable that the 14-day period to first symptom likely would encompass the true incubation period. I think that remains the case. Even the current analysis in Canada is largely based on time to fever.

MR. CAVANAUGH: Dave Cavanaugh, with the Committee of Ten Thousand. In the early days before, say, April 1st, there was some discussion about is this going to be an influenza-like pattern with a resurgence the following winter of a more serious strain. Could you speak to the current reading on that? Also, I hear that WHO is now saying the virus is mutating. Could you speak to those issues?

DR. WILLIAMS: I guess I would basically be reiterating some of the substance from Dr. Fauci's talk yesterday. In fact, the initial recognition in China occurred in November or December and it was thought to be an atypical influenza and there was concern that there was potential confluence between two strains, one of which was easy to transmit but not as pathogenic and the second which was harder to transmit but more pathogenic. However, subsequent investigation showed that it was a different clinical entity.

I think in relation to influenza one of the differences is the necessity of the large droplet spread, which is one of those luck factors in the spread of this infection. As you have observed, most of the secondary infections have been to healthcare workers in close contact who are working with patients rather than individuals 20 ft, 30 ft away who may have had airborne small droplet exposure. I think it is reasonable to assume that the initial epidemic, as well as potential for subsequent outbreaks, would be far worse if the airborne spread was more effective for this agent, but it appears that large droplets are necessary and that closer exposure is necessary as well.

What hasn't perhaps been mentioned specifically is if there is an animal reservoir human infection could potentially erupt again at any time.

DR. NAKHASI: I just wanted to respond to the mutation of the virus. I don't think there is any evidence at this point that there is mutation occurring because recently, last week, two Science papers which was published on the sequence of various isolates showed that mutation is not happening.

DR. NELSON: One last comment and then let's take a break for 15 minutes. Yes?

DR. ELSAADANY: Yes, I would just like to comment about the time to fever versus time to symptoms. One of the symptoms is fever so really our calculation was based on the onset data. The onset data was not agreed upon and nobody agrees on what is the onset date of SARS. It is still a controversial issue, however, I don't understand time to fever versus time to symptoms. Fever is one of the symptoms of the disease, or one of the case definitions.

DR. NELSON: Yes, okay. We are arguing about a few days and the risk, as far as blood transfusion, I think is well defined at the moment probably, nothing like with Nile virus I think. Let's take a 15-minute break.

[Brief recess]

DR. NELSON: We are going to continue the discussion on SARS. There were two people that wanted to testify in the open public hearing. First was Kay Gregory from the American Association of Blood Banks.

Open Public Hearing

MS. GREGORY: Thank you. The American Association of Blood Banks is a professional society for over 8,000 individuals involved in blood banking and transfusion medicine and represents approximately 2,000 institutional members including blood collection centers, hospital-based blood banks and transfusion services as they collect, process, distribute and transfuse blood and blood components and hematopoietic stem cells.

Our members are responsible for virtually all of the blood collected and more than 80 percent of the blood transfused in this country. For over 50 years, the AABB's highest priority has been to maintain and enhance the safety and availability of the nation's blood supply.

On April 17, 2003, the FDA suddenly issued its final guidance on SARS-related blood deferrals requiring temporary deferrals for recent travel to SARS-affected areas, contact with a person who had probable or suspected SARS or illness due to SARS.

While the AABB and other blood-banking organizations from the outset shared FDA's concerns about the possibility of transmission of SARS through the blood supply, the AABB is concerned about both the practicality of implementing the final guidance and the process by which the guidance was issued.

The FDA proposed addition of a minimum of three additional donor history questions, which are complex and difficult to understand. There was no effort to consult blood banks about donor comprehension and understanding of these questions, nor was there an understanding of the difficulty of adding new questions to donor history questionnaires within a 30-day implementation period.

As a response to these concerns, the blood banking community quickly developed an alternate proposal to present these questions using an information sheet. Fortunately, the FDA showed flexibility in agreeing to permit this alternate method, but the time to devise the alternate approach and secure FDA approval further strained the ability of blood banks to implement the guidance within the prescribed 30 days.

The FDA guidance advised that blood banks consult the CDC web site to obtain updated information on SARS-affected areas and the case definition of SARS, and to update their travel deferral accordingly. However, the CDC web site is very difficult to interpret. The distinction between SARS and "probable" and "suspected" SARS is confusing, as is the definition of a travel advisory and a travel alert.

This is further compounded by differences in CDC and WHO recommendations, all of which are being discussed by the news media, leaving the general public and, more specifically, blood donors extremely confused.

Further, the instruction for each blood collection facility to monitor this web site on a regular basis and make changes in procedures and information sheets each time the information changes, demonstrates a major lack of understanding of blood bank operations. Such a procedure is very impractical.

Before a change in procedure is implemented, the SOP must be rewritten and the staff trained. In the case of donor suitability, this involves training of large numbers of staff as well as preparation of new donor history questionnaires and donor materials.

In addition, the CDC has understandably posted changes to the web site to meet the CDC needs, without appreciating the impact such changes would have on blood collection, and without notifying the blood safety officer at the CDC.

For example, due to rapidly changing conditions in Toronto, there have been three updates to the CDC web page involving Toronto - first adding Toronto as a SARS-affected area, then announcing a last date of illness onset of May 30, 2003--this was done on a Friday afternoon prior to the Memorial Day weekend--only to be followed by changing the last date of illness back to "ongoing" (based on a second SARS outbreak in Toronto), and this was done on the Tuesday following the Memorial Day weekend.

While we appreciate FDA's attempt to be flexible and create a mechanism for blood centers to respond rapidly to changes in information, this is extremely difficult for blood centers to implement and creates a system where policy is likely to be misinterpreted and errors are very likely to occur. It puts the burden of interpretation on individual blood establishments rather than on the FDA.

In addition to our logistical concerns, the AABB also is concerned about the process by which FDA interacted with the blood community prior to the issuance of this guidance.

On April 15, 2003, the AABB convened the first of several conference calls with other blood banking organizations and invited the CDC and FDA to participate in the discussions. At that time, the task force requested that CDC include information about blood donation deferral on the SARS information cards that were being distributed to travelers returning from SARS-affected areas.

The rationale for this request was that this would be a targeted, and therefore, better way to reach affected individuals than requiring changes to donor history questionnaires and asking questions of millions of potential blood donors annually.

However, when it was quickly obvious that this recommendation was not going to be adopted, the blood banking community agreed that deferral of travelers returning from a SARS-affected area should be implemented.

We also discussed the possibility of deferring donors who might have had contact with SARS, and concluded that such deferral was not indicated. During these task force discussions, we specifically queried FDA about measures they might be planning, and were told that they were unable to provide any information, but that our plan of action would not be contrary to FDA thinking.

We understand that FDA is constrained by the Administrative Procedures Act, but their inability to hold discussions with the blood banking community is certainly not in the best interests of patient and donor safety.

In conclusion, the AABB is concerned about the safety of patients and donors. We recognize that new infectious agents require policy decisions to be made, sometimes before all of the scientific information is available.

The blood banking community has demonstrated that it can be convened on a very short notice and stands ready to interact with FDA as needed. We are happy to provide input and data, but, in turn, ask that this information be given serious consideration and not just ignored.

Early interaction would permit devising recommendations that are practical and possible to implement, and would avoid needless confusion. It would also avoid the need to submit alternate procedures for FDA approval and thus permit blood banks to begin planning for implementation in a timelier manner.

While we appreciate the need to respond to a perceived threat to the blood supply, the AABB requests development of a mutually satisfactory approach to improve FDA recommendations, so that the most appropriate and effective interventions can be established on behalf of patient safety and blood availability.

Finally, on issues specific to SARS, we request that FDA and/or CDC initiate studies to determine whether there is viremia during the asymptomatic period of SARS. This information is vital in deciding whether these donor deferral criteria should be continued.

Thank you.

DR. NELSON: Thank you.

Any questions or comments? I am sure Jay has a comment.

DR. EPSTEIN: I think the question at hand is whether the AABB has a better strategy to deal with rapidly changing epidemiological information above and beyond the issue that FDA can't be selectively influenced by a particular constituency.

MS. GREGORY: Jay, I appreciate that, but when you remember that we can convene a task force that represents the entire blood banking community, and can do so very rapidly, it would be useful if we could at least have some dialogue.

I realize that you can't be influenced by one particular constituent, but certainly I think we could do more in the way of communication. For example, I learned things from Alan's presentation this morning that I really didn't realize before, and had he communicated some of those a little earlier, perhaps some of our confusion and misunderstanding could have been alleviated.

DR. BIANCO: Celso Bianco, America's Blood Centers.

I want to support very much what Kay said, representing AABB and all of us, but there is one point and probably a couple triggered by Dr. Epstein's comment. I wish that if there are restrictions from administrative law that prevent us from talking to each other, and really coming to discussions that just help public health, that there was, for instance, an emergency meeting of this committee where all issues could be aired publicly, everybody could make public comments, and we could have found a more balanced view.

The other thing that I am searching for, and that's the only point that I don't agree entirely with what Kay put in the statement, is the search for more data in SARS.

I think that like we heard earlier in white particulate matter, like we have now the question in SARS, we are looking for endpoints, conclusions, and we don't have endpoints in the mathematical sense of a point. We have end continuous because we are always searching for some more data or some more data or somewhat I think that will bring us the opportunity to say yes, this is a negative result, it's final, we are happy, and we stop.

I think that we have to have a little bit more energy and courage, and I would like to encourage FDA to, for instance, in case of the SARS, that everything seems to be under control at this point, that we could have a suspension of the guidance for a period of time.

If the epidemic comes back, as some people talk about in November, with the winter, let's reinstate it, but it is not something that has to be permanently made part of our lives.

The white particulate matter, again, since it has been there for 50 years, yes, not all safety questions have been answered, but it's not such a yelling thing that we have there, that we cannot make a decision, let's stop that so-called enhanced inspection that is not even part of guidance, let's continue those studies, and if something different happens, let's go back and implement some more rigid measures.

Sorry if I said more than I should, but thank you very much, Dr. Nelson.

MS. GREGORY: No, Celso, I would actually agree with what you said. It is very easy to jump into jump into doing things and then it seems like we are left with forever doing them because we haven't thought out an endpoint strategy, so we just keep on doing them for years and years, and I think that is one thing we need to take a good, solid look at.

DR. EPSTEIN: We do periodically revisit our current policies. We do that as a matter of routine practice. I think the historic record will show that we have done this for numerous things, either through advisory committee meetings or through workshops, the list is very long.

We have looked at our hemoglobin standard, we have looked at deferrals for history of hepatitis, we have looked at the syphilis test, we have looked at the male sex with male deferral, I mean the list goes on and on and on.

So, I don't think it is true that the continuation of current standards is due to lack of reflection. Generally, the problem has been lack of data. That is a problem, and I do accept the charge that was made earlier that we have to re-examine the system as a whole, because despite good intentions, it is becoming unwieldy and perhaps ineffective.

So, we understand that, but the problem doesn't lie in having failed to re-examine our recommendations and requirements, we do this periodically.

But again I come back to the question of is there a better answer, because I haven't heard one, and the problem is that when we are dealing with an urgent situation, we don't really have the tools available for rapidly obtaining input from all potentially interested parties.

It is true that we can convene Blood Product Advisory Committee meetings ad hoc, but the process for clearing the members, let alone clearing their calendars, is not as straightforward as you might think. You know, we do have requirements for posting notices in the Federal Register, we have requirements for assuring that there is freedom from conflict of interest for the subjects that will be discussed, et cetera.

We may need better mechanisms, but we are doing the best with the tools we have.

DR. NELSON: Celso.

DR. BIANCO: Jay, I totally respect what you said and understand the constraints, but we have to find a way, and even if there is all these constraints in terms of this committee, maybe you have to generate recommendations that are more flexible and that allow continued discussion and modification as we acquire more knowledge.

I think that the value of this committee is too big and this committee has to be part of helping us make those decisions and giving us a forum to present our points of view. So, actually, I would ask if the committee would ask FDA, would make a recommendation to FDA that they be more involved in those issues and that we search for mechanisms for more flexible guidances that could vary as I know that there are legal restrictions and all that, and I don't want to get entangled in that, more flexible guidances and opportunities in a public forum for us to interact and discuss.

When a final guidance is published, yes, we can send comments to the docket, however, the FDA, from the administrative point of view, has no time limits for when to respond to those comments, differently from guidance studies, a draft guidance, for instance. So, we need a public forum.

Thank you.

DR. NELSON: Comments? Yes.

DR. FITZPATRICK: I agree that the industry needs a way to discuss with FDA in some forum when there is an immediate perceived threat to the blood supply and how to deal with that in a reasonable manner, but, Kay and Celso, I hear two conflicting things.

One is provide us more flexibility, yet in the statement, when the FDA provided you flexibility in how to word questions and monitor the CDC web site, and that sort of thing, there was a complaint that there was too much flexibility, so that there is kind of a conflicting statement there in that.

I understand that it was problematic and difficult to deal with and that there may be a better way to do it, but there is a balance here that we haven't reached yet and maybe there should just be an open forum on that, how do you suggest that FDA provide wording that allows you flexibility, but still gives them regulatory authority because that is two very conflicting messages, and it is very difficult to balance those two conflicting messages.

MS. GREGORY: I think you are absolutely right, and it wasn't the flexibility that we were objecting to, it was the fact of the complexity of what we were being asked to interpret. So, I think there are other issues where there could be more flexibility where it wouldn't be quite so difficult to figure out what you were doing, and we definitely do appreciate the flexibility.

One of the things that frankly I personally did not understand until Alan's presentation this morning was the purpose of the examples of the questions that were given in the guidance, because frankly, we all interpreted that to mean that any blood center would come up with whatever question you wanted to because they were going to be really flexible, when, in effect, as he said this morning, what they were really trying to do was you give us an example or that the Donor History Task Force could take the question, work on it, and come back maybe with a better wording or a better question.

But once again, it wasn't clear to me and I don't think it was clear to any of us who were reading the guidance. So, yes, we do want flexibility, but, you know, when it is really complex, sometimes it is better to have a little more guidance than just say, well, read the web site and figure out what to do.

DR. NELSON: I would be interested to find out, Kay, how did the blood banks implement this and was it immediately implemented or were there differences, or do you have any information on this, because it is complex because, in part, it wasn't only, you know, have you had SARS or been diagnosed, et cetera, but there is a 14-day deferral for having traveled through, not being in, but traveled through an area that was on that SARS list, and the dates kept changing.

I tried to figure out whether I was in that category or not, and I guess I wasn't, but I could have been. I just wondered how, in fact, it was, do you have any information on how the blood banks went about implementing this?

MS. GREGORY: I don't have any specific data to show you. I think there were lots of different ways of doing it, and you are right, traveling through was one of the things that was different from anything we had before.

In trying to put all this together in 30 days, I suspect that there were many different ways of doing it, and maybe Celso can explain the way it was done using an information sheet in a number of blood centers.

DR. BIANCO: We all worked very fast and the best we could to try to find simpler ways of doing it, and one of them, that Alan mentioned, was to have an information sheet that actually could be changed from time to time.

But I just want to touch on travel deferrals that you mentioned. That is probably one of the most difficult areas that we have in medical history. If we look at the post-donation information report that are submitted to FDA, and are reported always, those are on top of the list, because like you did, you went to donate blood, you remembered that you stopped at that airport, but not that airport, and then you go home and you look at your passport or you look at your ticket, and you see you changed and you call back the blood center, and we recall the unit.

So, I think that actually, it is one of the few areas where despite the complexities, most of the time medical history works, and the fact of our donor reports and recalls is a victory for the system, but the complexity is immense, and the donor history questionnaire group, the AABB Task Force has actually come to a very rational way of timelines, that is ordering the time and the questions, and all that, so that if you remember from previous presentations, to make it a little bit easier.

DR. NELSON: I think overall, the public health response to the SARS epidemic in total has been really remarkable. This is really a global pandemic, you know, that occurred dramatically within a couple months, and everybody in the world practically knows about it and have been pretty rational and effective, and the communication on this has been amazing.

In the airplane on the way to Asia, I was able to read all these stories about people went through. It was really remarkable.

DR. ALLEN: I think certainly one of the broader questions that this raises for the FDA and blood banking in general is to spend time now reflecting on how exactly to do this. My personal feeling is that it's impractical to expect, let's say, I would think even an organization such as the National Red Cross or Blood Systems, Incorporated, headquarters to go on line even once a week to get updates and then try to get that information out uniformly to all the donor collection centers and the mobile units and everything, it is a daunting process.

If you try to push it further down the line than that, I suspect that you are going to get more difficulty trying to apply it than not. So, I think that we need to look at how we are going to handle this information.

Just as importantly, however, is to look at what the time frame is for an area to be designated. I mean it is absolutely astounding that within weeks of the time that this disease was first reported as an unusual occurrence, or if you go back to the earliest cases, perhaps months, we had a putative agent, there were diagnostic tests available although we haven't defined how good those diagnostic tests are, and we have already heard information this morning that the antibody test data differs from the PCR data, and so on, nonetheless, it has been remarkable.

However, in a given area, if you have patients or people with onset of disease for a diagnosis to be established, for that to get to the public health authorities, from the hospitals to the public health authorities, and on then to the WHO authorities who would finally post it, my guess is that we aren't talking about something that happens within 48 or 72 hours of diagnosis.

So, in actual fact, cases are occurring in a given area before the posting ever occurs. It is never going to be a perfect system, and I think we have to look at how we can best take the information that's available, make it work within the system, and apply it on a uniform basis. It is going to be a real challenge.

DR. NELSON: I just wonder, you know, one, there is a movement both toward a standard donor questionnaire, it's a revision of that, but there is also a movement toward as opposed to paper to a CASI or computer-derived interview.

It seems to me that to the extent that this becomes uniform in blood donor collection facilities throughout the U.S., it conceivably could be easier to make a quick modification. I mean you could send electronically, you could alter a donor questionnaire and probably electronically send it to 3,000 blood collection facilities within the U.S. You might be able to change it overnight.

It may be that that is what we need, but my understanding is that the blood collection facilities are at least moving in that direction and that there is now more of an interest in that possibility.

MS. GREGORY: I think you are right that blood centers are going to start moving toward CASI or something like that, but I would just remind you that even that won't allow us to change things overnight because it has to be programmed, it has to be validated. We have to train our people, we have to write our SOPs, so people know about it

So, yes, it will make it a little easier, but we are still going to have some of the same issues even with that.

DR. NELSON: Once it is changed, you can send it an awful lot of places quickly.

MS. GREGORY: That is true, you can send it, and that will help to be able to do it electronically, not having to do everything on a piece of paper, so that part of it will be easier, but really the major hold-up things are I think still probably going to be in play.

DR. STRONG: Just to amplify that once again, it often takes us several weeks to make a change of that magnitude, because of the writing, reviewing SOPs, document review, boards, implementation, training, et cetera. This is not a logistically easy thing to accomplish.

DR. NELSON: I have collected some data by CASI in Thailand, and there you had to start, you know, you had the translation in the middle and a back translation, and all this kind of stuff, and it took a few months to get that really working.

But I think as opposed to writing a whole document, adding a question or two, you might be able to do it more quickly once the systems were in place. At least I am optimistic about that.

MS. GREGORY: My colleagues from the Red Cross just reminded me that we may also have the issue of if these computer systems need to have 510(k) approval, any changes will have to go through that process, as well.

DR. NELSON: So, that gets back to the first presentation today.

DR. KLEIN: With all due respect, I think we need to focus on the issue of what this process does, and not on the technology. The donor history questionnaire is a relatively crude screen. It can be quite effective when you use the appropriate questions that screen out high-risk individuals.

Adding additional things because you can add additional things, even if the technology allows you to do that more quickly, is not going to necessarily do what we want it to do, and I think we have to really focus on the purpose of this particular tool, and not on how technology can make it do things more quickly.

DR. NELSON: I agree. It's a good point.

There was another person that wanted to testify. Dr. George Dawson from Abbott Labs.

DR. DAWSON: I am George Dawson here representing Abbott Laboratories, and I will talk about a very quick presentation on some of the work done in Germany actually by Dr. Thomas Laue and researchers at Artus.

[Slide.]

As we have heard, there is two types of tests. One could use the diagnosed exposure to the SARS virus. We heard mostly on molecular testing, RT-PCR, but also serologic testing, I think you will hear a lot about in the future. It looks like both types of tests will be required to make diagnostics, and most likely one test will complement the other. Both types of tests will need to be improved over time.

[Slide.]

Abbott has made an agreement with Artus to market and distribute their RT-PCR test, real-time PCR. This test was introduced by Artus actually in Asia and Europe under direction of WHO and has been used for several of the studies on SARS.

The basic plan is that Artus will manufacture the test and that Abbott would distribute it, and in places like the U.S., would only be distributed after appropriate regulatory approval.

[Slide.]

The test can be utilized on various types of specimens including sputum, serum, native body fluids, swabs, fecal material, and tissues. The extraction is external to the kit, and they recommend using the QIAamp viral RNA mini-kit or the QIAamp ultra-sensitive virus kit.

It is a one-step RT-PCR test and includes the Master Mix reagents and internal control, and is run on the LightCycler. The total assay time is about two hours.

[Slide.]

I was just going to go through a few of the studies that have been done very briefly in Germany. In this one study, 22 postmortem lung tissues were received from one of the sites, from 11 patients, and RNA was detected in all 22 specimens. It was not detected in any of 23 lung control specimens that were not associated suspect SARS cases.

[Slide.]

The second study done in Southeast Asia indicated that of 43 specimens that were patients who were classified as meeting the WHO case definition, 42 were positive with the Artus test. Among 14 patients who partially met the definition, 14 were positive in the Artus test. Of 1,060 patient tested kind of as a general survey, 935 were clearly negative, the remainder, 125, are still under investigation.

[Slide.]

In the third study, a blood bank study, this one is a little different in that it was not conducted in a SARS endemic area, and utilized pools of 96 specimens. 338 pools were tested for SARS virus, as well as other viruses.

The internal control was detected in all the sample pools. SARS virus was not detected in any of the pools, and the sensitivity of the test was about 140 copies/ml. This study doesn't really indicate that SARS virus does or does not include a viremic stage because it's from a non-endemic area.

[Slide.]

So, to summarize, this Artus SARS assay does appear to detect the coronavirus RNA in clinical specimens. Additional studies are in progress. Research activities will continue and in my lab, we will do some of the work to look at different regions of the viral genome for improved detection of RNA by RT-PCR.

We will also be looking to express recombinant proteins to look and see if we can develop IgM and IgG class-specific antibody tests to see if we can detect exposure to the virus earlier than what has been shown in the existing serologic assays.

Thank you.

DR. NELSON: So, the specimens that were tested and positive were lung samples from people who died.

DR. DAWSON: That's correct.

DR. NELSON: You don't have blood samples from the same people?

DR. DAWSON: I believe that we do have blood samples from the same people, but I don't know what the results of those tests are.

DR. KLEIN: Given what we know about the viral load, how likely is it that even if you were testing in an endemic area, you would pick up positives in pools of 96?

DR. DAWSON: I agree, pools of 96 is probably not the way to go. I think I would go NEET or pools of 16, and then go from there and find out--once you find a positive, find out how far you can dilute it, find out what the viral load is, yes, I agree.

DR. NELSON: Any other? If not, we will break for lunch. We will be back at 1:30. Thank you.

[Whereupon, at 12:20 p.m., the proceedings were recessed, to be resumed at 1:30 p.m.]

A F T E R N O O N P R O C E E D I N G S

[1:30 p.m.]

DR. NELSON: Good afternoon. The topic now is West Nile Virus. Again, there aren't any questions, but it's an important issue with regard to transfusion. Here, there is some data on transfusion transmission.

To open the session, Dr. Hira Nakhasi from FDA will introduce it.

II. West Nile Virus - Informational

A. Introduction

DR. NAKHASI: Good afternoon. I guess everybody has had a good lunch. Let's talk about now having talked about this morning SARS, let's talk about the West Nile, another favorite subject of ours.

This is an informational session only just to update you where we stand with regard to the epidemiology, pathogenesis, and also with regard to the testing, development, and also our blood donor guidances.

[Slide.]

The three major issues which we will be discussing this afternoon will be the current status of the West Nile epidemiology and surveillance. Dr. Tony Marfin from CDC will talk about that and will bring us up to date as of today how the surveillance and epidemiology of West Nile virus is happening, and will also compare it with last year's epidemiology.

Then, we will hear from Dr. Indira Hewlett about the progress in West Nile test development including FDA's in-house effort on lot release and validation panel development, and also in the open public hearing, you will hear from industry their success story about the West Nile test development.

I think the last topic will be discussion of the guidance document and the recommendations which last year we had two of these guidances put out, one was in October and another one was in May of this year, and Dr. Sharyn Orton will be talking about revisions in the guidance.

[Slide.]

Just to orient you or disorient you from the SARS to now West Nile virus and what it is, West Nile virus is an enveloped, single-stranded RNA virus and is a mosquito-borne flavivirus, primarily infects birds, and you will hear now other animals may also get infected, but occasionally infects humans.

About 80 percent of the human infections are asymptomatic and 20 percent develop mild febrile illnesses, flu-like illnesses. Approximately 1 in 150 infections result in meningitis or encephalitis.

As I said last time, and I am saying again, advanced age is by far the most significant risk for severe neurological disease, so we watch out, those who are older people.

Viremic period can occur up to two weeks prior to symptoms and can last up to a month from the initiation of the infection.

[Slide.]

In last year's outbreak in the United States, besides mosquito bites, other modes of transmission were detected, for example, blood transmission through RBC plasma and platelets, transplantation, breast-feeding, transplacental, as well as occupational mishaps.

The magnitude of the risk from transfusion was not known, and still the magnitude if not known how much it can be.

The virus titer, another important thing to remember is that virus titer is low compared to other transmissible diseases, bloodborne like HIV and HCV, and viremia results rapidly after seroconversion to IgM, and IgM can persist for a long period of time up to two years, and Tony tells me it is a long period of time, up to 500 days or so.

No chronic stage of West Nile infection has been reported so far.

[Slide.]

You will hear more from Tony's presentation here, but just to give you a quick update what happened last year. In 2002, 4,156 cases of West Nile were reported. Out of these, 284 deaths and approximately 3,000 cases of West Nile meningitis and encephalitis.

It is endemic now in 40 states including Washington, D.C.

The average risk of West Nile by transfusion was throughout the United States, was 0.4 per 10,000 donations, but in certain high endemic areas, it could go as high as 10.5/10,000 donations in the State of Michigan and, in fact, in Detroit, it was much higher than that, the City of Detroit, that area.

Last year, in that period, there were 61 possible transfusion transmitted cases reported, 23 were confirmed from 16 blood donations. Out of these 61, 19 were not transfusion related, 19 were inconclusive because of incomplete donor follow-up.

There were 6 deaths reported in this group, but the causal relationship with West Nile virus has not been established definitely.

[Slide.]

Now, what did we do during the last year or so? At the FDA, as you heard last time also, we issued several alert notices, we encouraged industry to develop the donor screening as a supplemental test, and we had several congressional briefings as late as June 6th. This was a congressional staff hearing basically apprising what the status of this test is.

Then, we had various meetings with the test manufacturers, and I am very, very thankful to test manufacturers to really have a good collaborative approach in developing this test.

FDA issued, as I said, several guidances. One was in October 25th, and another one was May 1st, and you will hear more in detail from Dr. Orton.

[Slide.]

I am happy to report that FDA has approved three INDs, one Gen-Probe's IND. This was in Phase I and Phase II, which Phase I was repository samples and the second phase was the prospective samples. The American Red Cross, which is using Gen-Probe's test, also had an IND separately, and this was approved. Roche's IND for West Nile was also approved.

So, again, this is very timely. I guess the industry folks will tell themselves, but yesterday, they released a press release that I guess yesterday or the day before yesterday, both Roche and Gen-Probe has started testing in some places already. They were telling us by the beginning of July 1st, but I guess testing has now in certain areas started right now. So, congratulations to both of these companies.

FDA is again in contact with the CDC to determine the areas where the activity could start earlier and we have been in contact with them, as well as with the blood organizations.

We have biweekly meetings with them, and we are very proactively interacting with these blood organizations, as well as with CDC and NIH, to coordinate epidemiological data on West Nile infection and see where implementation of West Nile testing could be expedited, so as to reduce the risk of transfusion and transmission.

This is one of the success stories which I am really proud of, because it was only last year, around November, when we had the first workshop and asked for the field to developing this test, and is now June and we already have a test. Thank you very much.

I will ask Dr. Tony Marfin to start the session. He will talk about the epidemiology and pathogenesis.

DR. NELSON: Thanks, Hira.

Are there any questions or comments?

Dr. Marfin.

B. Epidemiology and Surveillance Update

DR. MARFIN: Good afternoon. This is actually my second visit to BPAC. The first one was about eight to nine months ago when I was first talking to you about the first cases of transfusion-associated transmission of West Nile virus.

It kind of underscores exactly what Hira said. People have moved very quickly on this. It has been a tremendous response. I have never been on so many conference calls in my life as I have over the past eight to nine months, and it is nice to see that something has come out of it.

Today, though, my presentation is going to be somewhat different. I am going to be talking about surveillance primarily. If there is time at the end, I will just mention the transfusion story, but I think Hira did a very good job of overseeing that.

[Slide.]

Now, working at Fort Collins used to be great when I was an EIS officer back in the early '90s because you worked very hard for six months of the year, during summer, all your diseases went away and then you got to ski during winter.

Now, the only way that I know that the year is changing is that last year, this used to be my last slide, now, it's my first slide, so that is the only way that I know that we are going into another season.

But this is a very, very important question, and it is a very, very important question to people who are developing tests, it is a very, very important question to people who are developing new questions for questionnaires, it is a very important question for blood banks, because as I laid out last year in a lot of the meetings, we had two choices. West Nile virus was either going to become like Japanese encephalitis, which we call hyperendemic disease, where there would be hundreds to thousands of cases every single year in the United States, or it would become like St. Louis encephalitis virus, which we have known about for 70 years and causes periodic large outbreaks.

Obviously, the economic factors are very, very important if you are trying to develop a test for something like Japanese encephalitis hyperendemic disease as opposed to a periodic large outbreak disease like St. Louis, so there are large implications with trying to figure out what that pattern is.

I am here to tell you that I think at least for a while, it is going to be like Japanese encephalitis, so if you have to go to the rest room, you don't have to wait for the final story.

[Slide.]

2002. You may have seen Lyle Petersen's slide because this is where I grabbed this one from, was the season of surprises. This was the largest arbovirus meningoencephalitis outbreak that ever occurred in the western hemisphere. That is not an understatement. These are not extrapolations as arbovirologists often do, multiply it by 10, divide by 5, and come up with some number that is not realistic.

The 3,000 cases of meningitis and/or encephalitis that we measured is truly the largest epidemic that has ever occurred. It is the largest West Nile meningoencephalitis epidemic ever documented ever in the world. So, this was really very, very serious.

When you look at the number of cases of neuroinvasive disease, that is, encephalitis and/or meningitis, and you multiply it by the 150 or 170 or 180, whatever number you want to use, you figure out that there may have been as many as half a million infections in the United States last year alone.

Now, these are not illnesses, these aren't going to come to anyone's attention except potentially blood banks because these people do have viremia. It may be very, very low, it may be very short, but because they are asymptomatic, they are potential donors, and that is something that you people have to think about more than a lot of the clinicians that I talk with.

One of the absolutely unbelievable stories is the geographic spread, and I will show you some maps that show the rapid spread in only four years, the four modes of transmission that Hira already talked about, in fact, occupational has been well described of West Nile virus, it is just that we are seeing more and more of it, and, in fact, there will be a new MMWR coming out in a bit about a whole group of workers who may have been infected because of their work.

Then, of course, there is a lot of the new clinical syndromes.

[Slide.]

Here is what West Nile virus has done since it has been in the United States, and in 1999, there were only four states that were affected. There were 59 cases of neuroinvasive disease. You are going to see variations on this slide, but I always refer to neuroinvasive disease.

There were only 6 fatalities. God only knows how many birds were killed in that first year, but people have described them falling out of the sky as they walked down the street. There were a few positive pools and there was one large flock of horses out on Long Island that were infected.

Now, over the next two years, you can see why there was never a great deal of concern from people. You know, it looked like it was going to be here, there was going to be an occasional infection, you know, low level endemic, although it sure appeared that it could kill a lot of birds, and then we started to appreciate that it could infect a lot of horses.

Then, in 2002, as Hira already mentioned, we had 44 states reporting neuroinvasive West Nile viral illnesses, almost 3,000 cases and about 284 deaths or 9 percent case fatality ratio, lots of birds, lots of mosquito pools, and I haven't spoken to this group about the epidemiology with regards to mosquitoes, but some something that is inherently different about West Nile virus from St. Louis encephalitis virus is that we have a large number of mosquito species that are involved.

That means that this virus has a lot of flexibility, inherent flexibility. It may be able to adapt to a lot of situations. When I show you the map on the number of counties that have reported West Nile virus in 2002, I think I will come back to that theme.

[Slide.]

I am showing you a little more graphically what we had in 1999. Shown in red are all the counties that reported any West Nile virus infections, and that is either in humans or animals.

[Slide.]

2000, and we are starting to get a good appreciation for the spread, but in 2000, there were only 19 cases of encephalitis and/or meningitis, and we beat the bushes for them. So, although we were seeing lots of animal activity, we just did not see all that much human activity.

[Slide.]

This is 2001, and this is when we realized that West Nile virus was here to stay. The very first areas that were reporting animal and human disease were in the Northeast, which had been the traditional two years stronghold of West Nile virus, but then we saw a second outbreak in the Southeast along the Georgia-Florida border, and then at the end of the season, almost all of the spots that you see in Ohio, Michigan, Illinois, Indiana, and Wisconsin, those all came at the end of the year. In fact, it set up very clearly what was to happen the next year.

[Slide.]

These are the number of counties that were affected in 2002, over 2,500 counties. The only thing that stopped it was the Rocky Mountains. As you can see, there is a few counties even on the other side of the Rocky Mountains.

This is where I want to emphasize the large number of bird species that the West Nile virus can infect, the large number of mosquito species that the West Nile virus can affect, because it gives it the ability to have activity in all of these very, very different geographic areas.

I mean we are talking about Maine compared to Corpus Christi, and yet the virus was active in all of those places and very active in all of those places.

It was at this point that we should have--and we did actually--when we walked around, we started saying this isn't going to act like St. Louis encephalitis.

In fact, last year, there were about 8 cases of St. Louis encephalitis. They were all down in the Southeast, in Texas, or Southwest, in Texas, and it wasn't reported anywhere else. Why not? They are closely related viruses, there is something inherently different about West Nile virus.

I don't think it's a big stretch of anyone's imagination to think that the weather, the winters, all of these things are very, very different if there was activity in all of these counties.

[Slide.]

This is showing the incidence of human West Nile meningoencephalitis by county. In red are the high incidence counties, those counties that had greater than 100 cases of meningoencephalitis per million population; in yellow, 10 to about 99; in gray, less than 10.

Now, I actually loaded the wrong slide because what I wanted to show you were the cases of infectious donors, and if I had loaded the right slide, you would have seen that most of the infectious donors came from this area and this area, the cases where there was high incidence.

Now, it is no surprise, then, that we never saw any donor-related problems in the previous years because we just didn't have the level of human infections, the rates of human infections that we see here. I think it goes without say that we used the incidence of meningoencephalitis as a rough surrogate for the total number of infections in these counties.

[Slide.]

This is the epi curve for 2002. The very first infection had illness onset on May the 19th, and that was actually here in the District of Columbia or down the road in the District of Columbia, and the last case had illness onset in the middle of December. This is another reason why we don't get as much skiing in anymore, it has become a much longer season.

But what I really want to emphasize is this five-week period right here. This five-week period accounts for two-thirds of the cases. This is the same thing that we have seen now for four years in a row.

I applaud the activity of the blood banks and everyone getting ready, and I can tell you that you were probably about five or six weeks ahead of the curve, and that is just terrific, because I think that our first cases of viremic donors are still coming up. And what do I base that on?

[Slide.]

Well, here is the time period when those 16 infectious units were collected. The very first donor donated on July the 22nd, and the very last one came on October the 6th. Again, I don't think it is any coincidence that this period coincides with the peak of the human epidemic.

This is not likely to be a disease that we are going to see at the end of June or early July, and yet all of the blood bank, all of the testing that is going to have to go in place, it's all there already, so I think that is remarkable.

[Slide.]

So, let's come back to this. So, what is going to happen in 2003? Now, to think about what is going to happen in 2003, we have advantages over SARS. I mean we may be number 3 in the emerging infection list now, after SARS and Monkeypox, but we have an advantage over them, and that is that we have a better surveillance system than they do, because we don't wait around for human infections.

[Slide.]

For people who don't think about the fact that animal infections occur before human infections, this is a paper that came out last year. It is by one of my EIS officers that I had. She just loved to model, so what she said is, you know, in 1999, there was a very impressive crow die-off that came before the human epidemic. In 2000, we established something called ArboNET. This is a real-time electronic animal and human surveillance system. We have 54 co-operators, 54 local and state health departments that help us detect West Nile virus activity.

So, she hypothesized that if we could assess the intensity and timing of crow epizootics that we should be able to predict human disease. In fact, she spent about eight months doing this, and just as an overall general comment, if you look at the density of dead crow sightings of reports, or you look at the proportion of dead crows, especially in counties with larger populations, you are going to find the counties that are going to subsequently report lots of human cases.

In fact, if a county has both of those things, they were 50 times more likely to report human cases than counties that had neither of those things.

Now, she based her work on the 2000 data. She looked at 2002 data, she found out that her model was robust, and she concluded that detecting early season West Nile virus activities in animals may allow timely interventions to reduce human risk.

Now, I will underline "may," because you have to be able to do something with that information if you are going to intervene. This is a very, very complex paper. I can't believe a journal gave her 10 pages, and it just went on and on. So, Steve Guptill, a partner of ours from the U.S. Geologic Survey, did the next paper.

[Slide.]

This came out in Emerging Infectious Diseases just a few months ago, and what Steve said is either they have animal events before humans, when humans are reported, or after humans. So, he looked at the 2001 data and he found out that counties that had animal events, in this case only crow events, that if they had a positive crow prior to humans, they were 6 to 7 times more likely to have human cases in the subsequent year.

Now, something I forgot to emphasize in Kathleen's paper and something I want to point out here, we are talking about early season. We are talking about identifying animal infections that occur from mid-June to the end of July, which we used to consider early, and I will show you in a bit that that is no longer true. But this gives people time to intervene and potentially lower human risk.

He, too, looked at 2000 data, he looked at a preliminary dataset of ours, and he found out that his model was robust, as well.

[Slide.]

Now, I can say well, if I know what is happening in the animal population, I should be able to at least speculate as to what is going to happen in the human population.

[Slide.]

The next three slides, I am going to talk about three aspects of our surveillances. It could be dead birds, mosquitoes, and horses. Each one of them brings a different quality to surveillance although I am not going to go into that now.

What we have is a comparison of 2002 and 2003. We are going to talk about when the first bird, the total number of birds, the number of counties and the states that have reported by a particular date.

Now, inherently, these two systems are different. For 2002, these are all the events that occurred by June the 17th. It doesn't matter that some of them reported it to us in April of 2003, it still occurred on June the 17th, so this is going to be a more complete dataset.

This dataset here is subject to both testing lag and reporting lag, and, in fact, these are the number of events that were reported to CDC by June the 17th. Now, for those of you that have copies of my slides, you can see that this is different. That is how rapidly our surveillance dataset is changing right now.

We are at a point where it is changing, if you pull out information six hours apart, you are getting radically different values. So, this is midnight on June the 17th. In fact, we can see that the number of counties that were involved in 2002 and 2003, it is about the same number. The states are about the same.

There are some qualitative differences here in the states. What we are seeing this year, we are not seeing the Northeast states as we had seen last year, and, in fact, we are starting to see states like Wyoming, North Dakota, Colorado, showing up very, very early on. We didn't see that last year.

[Slide.]

In mosquitoes, mosquito surveillance is very, very expensive. It is very, very useful because you know exactly what vectors are out there and you can tell when you are starting to see what we call "bridge" vectors or those vectors that like to feed both on birds and mammals specifically humans, so it's very, very valuable, but very few states are performing it.

I am just going to draw your attention to this last line here, that we have lots of positive mosquito pools already in Georgia, Indiana, New Jersey, and a tremendous number already out of Louisiana.

Now, Louisiana performs mosquito surveillance very well, they have been doing it for years, yet this year it is heads and heels above what we saw last year.

[Slide.]

The last slide then on this are the horses. Now, horses are important because they are fed upon by what we call "bridge" vectors, and as I said, they are vectors that will feed on mammals preferentially to birds. As a result, this is a really rough surrogate for human-biting mosquitoes. It tells me that human-biting mosquitoes are out there.

I can see already that we have twice as many states, despite the lag in reporting, despite the lag in testing, I already have 8 states that are reporting positive horses. In fact, one state, Wisconsin, has already reported 2 positive horses from the same county.

You will also see that these are some northern states. Minnesota has already reported. This horse was infected in late April. So, we are starting out at a very, very high level compared to last year.

[Slide.]

What we are showing here is kind of an epi curve. It is the number of positive West Nile virus surveillance events in the United States through an MMWR week. Now, this is MMWR week 23 in 2002 ended on June the 8th, and in 2003 ended on June the 7th, so they are roughly comparable.

I am going to draw your attention to the weeks 1 through 20. As I have mentioned,there may be some problems with interpreting this. This may be due to testing lag or reporting lag. But look at the rest of the year, very, very comparable, if not, an increase in terms of the number of surveillance events.

Now, why am I especially impressed with the fact that this might be 8 and that might be 4? Well, I can tell you that a lot of states don't even have their surveillance up and running yet. I can tell you that a lot of states are getting really tired of animal surveillance, it is very expensive, very intensive, and yet I am still seeing lots and lots of activity.

[Slide.]

Where were we on June the 8th of 2002? Well, in 2002, we had the Northeast activity, we had the Southeast activity, and we had moved over into the Midwest, and we had about 70 counties involved.

What happened when the country used to look like this?

[Slide.]

We went to that. That is just a reminder. That is a slide that you saw earlier. We expanded from those few foci and it rapidly expanded probably due to birds, probably along the rivers, and it involved all of these areas.

So, where are we now in 2003?

[Slide.]

Very, very, very similar. Again, the Midwest is there, the Southeast is already there. There are some states--and this is just because I made the dataset about 12 hours apart--but North Dakota should have a county colored, Colorado should, Ohio should, and Virginia should, as well.

Now, this looks very, very similar to last year's map except that we haven't seen the activity in the Northeast yet, and we are starting to see more activity out of the West. This is very, very important where are our first human case is going to occur. They are going to probably occur in the Gulf Coast, and, in fact, we are working on some samples from that area right now.

This is something we have been working with FDA and the blood banks to let them know that if we are going to deploy early, this is where we really should be deploying. It looks like that is not going to become an issue, and that is very, very good.

We also work with NIH to let them know that if they are going to get a controlled clinical trial up, that these will be the first cases, and these will be the largest number of cases here and up here in the Midwest.

Now, something that just came to me this morning, these are the areas where we should also be reinforcing to our general population the importance of personal protection, but it is something that we haven't really addressed yet, and that is should we be addressing personal protection with our blood donors especially in these areas and the importance of DEET in setting up those programs.

We put a lot of emphasis on deferring on the basis of questions, deferring, doing the testing, and that's great, but maybe these are the people we should say, you know, you have got to get in the habit of using some DEET if you are going to be our donors.

[Slide.]

I don't think I have time to go into a discussion of the transfusion story, but Hira did an excellent job with that already.

Thank you very much, and I will take questions.

DR. NELSON: Thank you, Dr. Marfin, that was very good.

Yes, Paul.

DR. SCHMIDT: What is a mosquito pool?

DR. MARFIN: The question is what is a mosquito pool. We don't test individual mosquitoes. What we do is we will trap several of them and we will make pools, so we will make pools of 50, once in a while they make pools of 100, so in the night, say, last night you went out to site X and you collected 1,300 Culex pipiens, you would make those into 26 pools. From that, we can calculate a minimum mosquito infection rate.

I can tell you that, in fact, the minimum mosquito infection rates that we saw last year were the highest that we have ever seen in an arbovirus, much higher than we have ever seen in SLE.

DR. SCHMIDT: Do you mash them all up and test them?

DR. MARFIN: I don't, but--

DR. SCHMIDT: Is that how it is done?

DR. MARFIN: Yeah, they put them in a shaker with a beebee, and they pulverize them and they liquify them.

Any other questions, questions that I can probably answer better than that?

DR. NELSON: The other thing that I understand is that there were like 40 or 50 different species of mosquitoes that were infected, which is quite different.

DR. MARFIN: If you look at West Nile virus in North Africa or Israel, for that matter, or South Africa, you usually see one predominant species. Here, we see 37 from the time that it has come in here in 1999.

Now, the predominant one are the bird-feeding species, Culex pipiens, Culex quinquefasciatus, Culex tarsalis, but what is very, very impressive are the number of Aedes, and you probably don't know it, but they have subdivided Aedes now into two genera, and it is now Aedes and Ochlerotatus, and there are a tremendous number of Aedes and Ochlerotatus species that we are finding positive including Aedes egypti, which is very, very bothersome, as well.

DR. NELSON: Knowing something about the entomology and the feeding habits of the mosquitoes, is the prevalence in different species useful in predicting a human epidemic, or is it just too gross a measure?

DR. MARFIN: In fact, that would be the best proximate value that we have, and that is why I point out, well, if it's so good, why aren't more people doing it. It is really expensive. You have to have good expertise out there.

It requires lots of molecular tools, some that are being constantly developed and refined, so it is very, very expensive, but, yes, if I lived in a community where Aedes albopictus had a very high infection rate, Aedes albopictus is a very, very vigorous daytime biter, and it likes feeding on humans, it likes feeding on mammals, but it really likes humans, and so, yes, I would be very, very concerned as opposed to, say, finding a similar infection rate in Culex restuans, say, which almost feeds entirely on birds.

So, understanding that is very, very important and hopefully, we are going to be able to get more information on that from those mosquito pools.

DR. ALLEN: The weather that we see outside today, that has been certainly up and down the East Coast all summer long, have you been working with NOAA and the National Weather Service, and others, to do some modeling on what this might do to potential mosquito populations and how that might affect the transmission overall, the epidemic overall?

DR. MARFIN: We have been working with NASA primarily. They also have a similar process, as well as the National Weather Service and NOAA, and that's great, but I can tell you that when people first discovered St. Louis encephalitis in 1933, that there were a lot of smart arbovirologists that came all along and they made the same assumption, and it is a good assumption, it has to be true that weather affects the number of mosquitoes, therefore, can have influence on the outbreak.

That is a good overall model and when people look at it, it is mild winter, cool, wet spring, hot, dry summer that is perfect for growing mosquitoes. Now, you have to have virus in there. We have the virus. This virus doesn't go away, there is lots of overwintering that is going on. That is something that we haven't seen with St. Louis encephalitis, so we have the virus ready to go, and so now I think what is really the proof in the pudding will be what the summer does.

Now, one of the reasons that I pointed out how many counties were involved, all of those counties had different weather patterns. All of those counties had a tremendous number of events, animal events and human events, so there must be more to the picture than that because they are very, very different settings.

DR. STRONG: You mentioned St. Louis encephalitis in Texas. There was also an earlier reported case in Washington State. Is there any evidence that there is any increase in SLE?

DR. MARFIN: No, and that is another piece of information that we use when we talk about what is going to happen with West Nile virus. The big outbreak in '33, in St. Louis, caused about 1,200 cases.

There was a large outbreak in 1975, that caused about 2,000 cases of encephalitis, and then it essentially disappeared until, let's see, '91, my first outbreak was in Arkansas, then nothing until two years ago in Monroe, Louisiana, and then they had a large outbreak.

Now, over that time, they always have cases in Houston, it is a persistent focus. We had one case out of Colorado, very, very sporadic, but we haven't seen that really big epidemic. We wait for it all the time, we always think that there can be some focal conditions that allow that. We have not seen that to date.

With regards to the Yakima person, that is St. Louis encephalitis and people say, gosh, Yakima, Washington, well, in fact, if you look at migrant farm workers over the years, there has always been some cases of St. Louis encephalitis periodically in the Yakima Valley.

If you look at the mosquito populations of the southern Great Central Valley in California and the Imperial Valley of California, there is always St. Louis activity, there is always Western Equine encephalitis activity, and periodically, you see human cases, so it's not that big a surprise although April is pretty early for Yakima.

DR. EPSTEIN: What are the prospects for controlling West Nile through control of mosquitoes this year?

DR. MARFIN: This is the big question. We now have, there is probably seven or eight papers out there that say when crows do this, this is going to happen. Despite knowing that, it is very hard for somebody to stand up and absolutely guarantee a county board of supervisors or a mosquito control district board and say we have to start doing the following things now, especially when it is very, very expensive.

Unfortunately, that describes a lot of the situations in a lot of counties right now, so there has been a great deal of emphasis on personal protection. There has been some hesitancy in a lot of areas to get involved in adulticiding, which is killing adult mosquitoes.

There has been a good emphasis on larvaciding, there has been good emphasis on reducing wetland areas that are producing especially the Culex mosquitoes, so I think that those interventions will be helpful, but despite that, and getting back to the question about different mosquito species, some of them are just not amenable to aerial spraying or larvaciding. You know, Aedes albopictus likes little tree holes that we find all throughout our neighborhoods, so it is very, very difficult to control those.

Thank you very much.

DR. NELSON: Thanks for a great presentation.

Dr. Hewlett is going to talk about status of the West Nile virus test, lot release and validation panel development.

C. Status of West Nile Virus Test, Lot Release, and

Validation Panel Development

DR. HEWLETT: Good afternoon. We are going to be switching gears, switching from testing mosquito pools to testing human donor pools.

What I am going to present today is an update on the status of the development of West Nile virus tests and the development of lot release and validation panels for approval and licensure of these tests.

[Slide.]

To briefly recap FDA's previous actions, at the March BPAC, we discussed and presented an FDA proposal for clinical study design for assay validation. We talked about unit and donor management strategies, and a plan for development of lot release and qualification panels.

[Slide.]

We also talked about a study design for test sensitivity determination, which included testing of repository specimens from transfusion and community-acquired West Nile virus illness samples, any positive cases that were identified in prospective studies, and testing of seroconversion panels. All of these samples would contribute to the sensitivity determination of West Nile virus tests.

[Slide.]

Because of the limited number of samples that would be available for assay validation, we also discussed an additional approach for validation of tests. This would be testing a common set of pedigreed specimens by all candidate investigational tests, and testing all reactive specimens identified during IND studies by all manufacturer's assays. The expectation here is that this approach would help us evaluate the relative sensitivities of the different tests and to examine whether they have equivalent sensitivity.

[Slide.]

At the March BPAC, we stated that FDA's current standard for West Nile virus NAT assays was 100 copies/ml for the individual donation when tested in a pool, and this continues to be the standard at this time.

The standard may be revised as assay sensitivity improves and additional data on viremia and infectivity become available in future studies, and it is our hope that such studies are in progress.

[Slide.]

We also proposed a scheme for donor and unit management whereby reactive investigational NAT results on the individual donation could be confirmed by follow-up testing with an investigational NAT, an alternate NAT, and an IgM test, and the donor could be retested prior to 28 days, and if the follow-up sample is reactive by an investigational NAT or an alternate NAT, the donor would continue to remain deferred for an additional 28 days.

The donor may be eligible for reinstatement if the follow-up sample prior to 28 days is NAT-negative and IgM positive, however the donor would continue to remain deferred for the 28-day period.

[Slide.]

Today, I would like to report on the progress in test development, and we are glad to report, as you have heard from Hira in his introductory remarks, that multiple IND studies are in progress.

Two manufacturers have publicly acknowledged their existing INDs, Gen-Probe and Roche Molecular Systems. These IND tests are based on NAT using pooled or individual samples, and they are intended for use with whole blood, blood components, and source plasma at this time, although additional claims for bone marrow, cord blood, hematopoietic progenitor cells, tissue and organ donors will be added as these studies progress.

[Slide.]

The expected start date for nationwide testing is early July 2003, however, some centers have already initiated prospective testing. All samples will be collected under approved IRBs with the necessary informed consent.

I would like to point out the analytical sensitivities of these IND tests are comparable, in fact, very good, they are between 5 and 7 copies/ml.

[Slide.]

Now, I am going to provide a few details on each of these tests, but the manufacturers will actually be discussing this in greater detail in their presentation.

The first test, Gen-Probe, the Procleix West Nile virus assay is a TMA-based screening assay for West Nile virus RNA. It uses existing instrument platforms as Gen-Probe's licensed HIV-1 and HCV NAT blood screening assay, which is essentially a semi-automated system.

Obviously, the fact that these platforms were already in place has played a major role in enhancing and expediting the implementation of new tests, such as tests for West Nile virus.

The assay also uses existing formulations as much as possible.

[Slide.]

The Procleix West Nile virus assay has an analytical sensitivity, 95 percent detection rate, about 7 copies with a range of 7 to 15 copies.

The specificity in preclinical studies was evaluated by testing 1,180 blood donations, and the observed specificity was very good.

No cross-reactivity to other bloodborne viruses was observed. This includes a battery of viruses that are usually tested, such as HTLV, HIV-1/2, HCV, HBV, HGV, and a number of other viruses.

[Slide.]

The Procleix West Nile virus IND consists of a two-phased clinical study. Phase I consists of a retrospective prevalence study where about 89,000 archived specimens from the Red Cross, from 6 high incidence areas collected during the 2002 season will be tested. In fact, they are being tested.

Phase II consists of a prospective donor screening analysis. This consists of testing voluntary donations of whole blood and source plasma at 25 testing sites. They could be testing either individual samples or pools, and this is site dependent. Nationwide testing is expected to begin July 1st, and as you just heard from the earlier presentation and my own previous slides, this testing is already in place in some centers.

[Slide.]

In case of a regional West Nile virus outbreak, samples will be shipped and prospective testing will be initiated at both Phase I and Phase II sites. Samples are being archived from June 1st onward. Testing of samples will be based on regional prevalence, and, of course, these studies are contingent on IRB approvals and West Nile virus informed consent.

[Slide.]

The Roche Molecular Systems West Nile virus NAT assay is a PCR-based screening assay for use with pooled samples. The analytical sensitivity is between 5 and 7 copies/ml.

No cross-reactivity has been seen with the other bloodborne viruses that are non-West Nile virus related, and clinical specificity has been preliminarily evaluated by testing 400 random volunteer donor sample from West Nile virus low and high prevalence areas. Again, the specifically observed has been very good.

The manufacturer will be speaking in the open public hearing and will provide more details on the clinical study design and the emergency testing plan, so I am not going to discuss that in my presentation.

[Slide.]

Next, I would like to switch to talking about FDA's panel development efforts. This work is actually being conducted by Maria Rios and her group in our laboratory. We are putting together a lot release panel for licensure and post-market surveillance of NAT and IgM tests, potential IgM tests, and a qualification panel for evaluation of the relative sensitivities of investigational NAT and IgM assays.

[Slide.]

We are working on an FDA NAT panel, which will be composed of two isolates, the FDA NY99, which is a flamingo isolate, and the FDA Hu2002 isolate. Both of these isolates are being characterized by genetic sequencing. Viral infectivity has been determined at both FDA and the New York Department of Health laboratories and by cytopathic assays at the FDA. I should mention that these isolates have, in fact, been obtained from the CDC and the New York Department of Health although human isolate was, in fact, cultured in our laboratory at the FDA.

RNA concentration measurements include fluorescence and optical density determination and TaqMan assays. These are in-house TaqMan assays that Maria has developed in our lab.

Final panel specifications are being established through collaborative studies.

[Slide.]

This slide shows the PDU results on the FDA isolates. Again, these isolates were tested both at FDA and the New York Department of Health in Laura Kramer's laboratory. I would just like to point out that there is good agreement between the two labs and the numbers come out between 10⁷ and 10⁸ PFU/ml depending on the isolate.

[Slide.]

These two isolates were then distributed to four different laboratories in a dilutional series, either untreated or heat-treated at 60 degrees for 2 hours for an analysis of a quantitation of virus in terms of copies/ml, and the two points that I would like to make on the slide are that there was generally very good agreement between the different laboratories.

We observed a 2- to 3-log difference in the untreated versus the heat-treated material, so although heat treatment does affect copy number determination, the differences are not as significant as we thought it would be, so, in fact, this may allow us to use heat-treated material for panel development.

[Slide.]

The reason this is important is because upon heat treatment, we observed a complete loss of activity, so infectivity is completely destroyed as indicated by the PFUs on the very far righthand column. As you can see, there is no infectious virus that could be isolated from an isolate that had been subjected to heat treatment.

Again, this is encouraging because this allows us to develop inactivated materials that would still have quantifiable viral RNA in them.

[Slide.]

We also have a plan for developing a qualification panel. At this point, we are trying to acquire specimens to develop this panel. The plan is to put together at least 100 pedigreed clinical specimens that may be either RNA positive only, IgM positive only, or dually positive for both RNA and IgM.

To date, we have obtained some samples from the Red Cross, from the CDC and the State Public Health Laboratories. We are also recommending that reactive specimens identified in IND clinical trials be made available possible to FDA and to all manufacturers through sharing of samples since this would create a sample bank that would allow expedited assay validation.

[Slide.]

This qualification panel will be evaluated in collaborative studies using various candidate NAT and IgM assays, and the specifications for these panels will be established based on the results of these collaborative studies.

[Slide.]

In summary, at this point, we are really glad to report that two test kit manufacturers' IND studies for West Nile virus NAT on pools or individual samples are in progress. These are IND tests, but they have an excellent analytical sensitivity between 5 and 7 copies/ml.

Prospective testing is already underway in some blood centers. Nationwide testing is expected to begin in early July, and a contingency plan is being developed for early testing in case of a regional outbreak prior to nationwide testing.

[Slide.]

The lot release panels are also being developed and these are based on a high-titer Flamingo and Human Viral Isolates. The viral stocks have been quantitated in preliminary collaborative studies involving a few participating laboratories.

A prototype panel is being formulated to evaluate the performance of the panel in a larger collaborative study involving more participating laboratories.

A qualification panel for NAT and IgM assays based on clinical specimens is also under development.

[Slide.]

I would like to close by acknowledging the people who made this possible. Of course, most importantly are the test kit manufacturers Gen-Probe and Roche Molecular Systems, who were very responsive and responded to FDA's request to develop products in an expedited manner, and the blood organizations for helping initiate implementation of the test.

I would like to thank Maria and acknowledge Maria and her team and Dr. Shimi Vasen who, in fact, cultured some of the virus, these people in our laboratory at CBER-FDA. I would also like to thank Robert Lanciotti from the CDC and Laura Kramer from the New York Department of Health for providing us with the specimens. That has really helped us with our panel development work.

Thank you.

DR. NELSON: Thanks, Dr. Hewlett. That is remarkable progress in the last six months or less.

Questions. Paul.

DR. SCHMIDT: Dr. Hewlett, in the handout you gave us, it is noted that the Gen-Probe assay, there is no cross-reactivity to other flaviviruses, dengue and St. Louis encephalitis, don't have that information for Roche, but last March, Dr. Petersen was talking about the transfusion/transmission of dengue on the basis of marrow. I just don't know about experience with bone marrow.

I don't know anything about St. Louis encephalitis and transfusion, but since we are not here as epidemiologists, but trying to keep the blood clean, wouldn't cross-reactivity with other flaviviruses be good? Do you have any comments?

DR. HEWLETT: In fact, at the time we held our workshop, we made the point that it would actually be desirable to have some cross-reactivity with some of the other flaviviruses, but we have left it up to the manufacturers to develop what would be easy to implement and would be also expeditious for validation.

So, some of the companies, actually, the companies are going to talk about this in the open public hearing, so you will hear some more and have an opportunity to probe that issue a bit further, but what we understand is that at least with those types of studies that were done, a very limited number of samples were tested, so it is really too early to say that, in fact, they are either cross-reactive or not.

This is one of the things we would like to do at FDA is we would like to collect some isolates that represent the non-West Nile virus, flaviviruses, to look for potential cross-reactivity with other members of the sera complex, and that is something we would like to pursue in-house, but we also recommend that manufacturers try to acquire as many samples as possible of these other viruses to, in fact, either pursue a claim or to not have a claim for the other viruses, but this is tricky issue because many of these primers do, in fact, cross-react with the other viruses.

DR. SCHMIDT: Is there any history of transmission of St. Louis encephalitis by transfusion?

DR. HEWLETT: No. I see Tony says they don't.

DR. NELSON: From what region of the virus do the primers come from, is it a conserved?

DR. HEWLETT: I am not sure I can talk about that. I think the companies would.

DR. STRONG: A couple of problems have cropped up in implementation because we are doing it so quickly, and I wanted your comments about this. One is the requirement that there be IRB approval. There are a number of IRBs that are holding up approvals for a variety of reasons, and what position the blood centers should take should they not have IRB approval, but be ready to test.

Secondly, I know of at least a couple of examples of places who think that they shouldn't be testing and don't want to test. These would be hospital collection sites and how that would be dealt with.

DR. HEWLETT: Yes, that is actually a bigger issue and we did face this dilemma also with HIV and HCV NAT testing, and our FDA position is that we would be looking for IRB approvals to be in place or at least being negotiated at the time that the studies are put in place.

As far as the hospital IRBs, I know that issue has come up about the local IRBs and the single IRBs, and so on, and we are looking into this, and we hope to have something worked out for the blood industry, but at this point, what I recall with the HIV and HCV was that, in fact, we recommended that waivers be sought, and that is another option.

Jay, I don't know if you would like to comment on that.

DR. EPSTEIN: I am afraid the subject is complicated because there is no one rule that applies. The rule is that it is subject to IRB approval. We do recognize national IRBs, but the local IRB has the discretion to act or not act. FDA's requirement is only that there is an IRB approval.

DR. NELSON: I have gotten in the middle of research projects where there are 20 different IRBs that disagree with each other, and they can delay implementation for years if they are clever enough. I hope that doesn't happen here.

DR. KLEIN: Jay, I recognize that this is a research project and therefore should go through IRB, but given what we said this morning about a disease that we have no idea is even transmitted via blood, and here we know that we have a disease that is transmitted via blood, and we have absolutely outstanding evidence that there is going to be another epidemic coming up very soon, do you not have the authority to waive that particular requirement in terms of public health because, in fact, this is a public health issue and one that I think we need to be concerned about?

DR. EPSTEIN: Well, I will think we will take that up with the lawyers.

DR. HEWLETT: Yes, good answer.

DR. KLEIN: As long at it's on the record.

DR. NELSON: I think BPAC could perhaps recommend that the ethical issues and the issues that relate to donors and that the public health issues maybe supersede or are important enough that this should be taken into consideration.

DR. KLEIN: It is also the scientific and medical data support this as best I can see.

DR. EPSTEIN: I think the legal framework is that the current regulation for donor testing is agent and disease specific, and so it would require promulgation of new regulation to require test for West Nile. That doesn't mean it couldn't be recommended.

It would be unusual for us to recommend unapproved tests, however, so there would be a legal distinction while we are in the phase of test development versus post-approval. We do have broad authority under the communicable disease control provisions of the Public Health Service Act, so-called Part 361, but that section of the Act also requires rulemaking, which as you know is not a rapid process.

I think that we can get a message out there, we can encourage it. Whether there are other mechanisms that could be exercised to actually require it short or rulemaking, I am just not sure there are.

DR. ALLEN: One question which I will get to in a minute, but a comment on this. I appreciate the bureaucratic dilemma in which you find yourself, but with regard to the rulemaking, certainly when the HIV antibody test was first licensed in March of 1985, the Agency didn't wait for rulemaking. They put out guidance which was very quickly acted on by blood centers, and the rulemaking, if I remember, was delayed by several years before it was actually finally accomplished.

Can I move on to anther question at this point? It is with regard to implementation of testing in blood collection centers.

Given that everything we have heard is that the level of viremia tends to be very low even though these are highly sensitive tests in terms of their ability to pick up low levels, do you have a sense in terms of what the recommendations are going to be in terms of individual versus small pool testing in blood collection centers?

DR. HEWLETT: At this point, our standard is 100 copies/ml, and that is, of course, for the individual donation when tested in a pool, but we are essentially holding to that standard at this point.

Unless we find that there is a need, in fact, to lower that to something in the range of 10 copies or 20, at this point, we don't have a good sense for what that number should be below 100 copies.

The 100 copies seems to be it is achievable, and also we feel, I mean at this point, we have no idea about the infectivity of titers that are below 100 copies, not that we want to find out, but hopefully, that is a number that will stay as it has for the HIV pool and HCV pool test, but obviously, as tests become more sensitive and as individual donation testing platforms get put in place, because that is another issue, we don't really have high throughput individual donation testing platforms in place as yet.

When that happens, we may have to revisit the issue of the standard for a single donation test, but at this point, I think we are going to stick with 100 copies unless there is a need to re-evaluate that on the basis of any infectivity studies and results that come out of those studies.

DR. EPSTEIN: Just back to Dr. Allen's earlier point, your recollections are exactly correct about HIV, however, do recall that the recommendation for testing was for use of a licensed test, and the current situation is that we are talking about investigational West Nile testing.

DR. NELSON: Revised West Nile virus guidelines by Dr. Sharyn Orton.

D. Revised West Nile Virus Guidance

DR. ORTON: I have been asked to go over the revised recommendations for the assessment of donor suitability and blood and blood product safety in cases of known or suspected West Nile virus infection and just to give you a brief summary of how this differs from the document that was published in October 2002. I also included at the end of my presentation, a few of the questions and answers that we have received on the document.

[Slide.]

As background, in October of 2002, CBER released the final guidance for industry dealing with West Nile at that time, and in May 2003, a revised final guidance was released, and this guidance supersedes the October 2002 release.

[Slide.]

As highlights of the current guidance, the recommendations that are in here were worked on very extensively with recommendations from the CDC based on the transfusion-transmitted cases from last year.

These recommendations apply to whole blood and blood components intended for transfusion and blood components intended for use in further manufacturing into injectable or non-injectable products, including recovered plasma, source leukocytes and source plasma.

[Slide.]

For donor deferral, for current disease, clearly, donors should be in good health as required and consistent with the CFR, but for diagnosed acute West Nile virus illness, or infection, donors should be deferred for 28 days from onset of symptoms or until 14 days after the condition is considered resolved, whichever is the later date, and the 28 days allows for potential prolonged viremia from studies that were done in cancer patients quite a few years ago.

In the absence of West Nile virus compatible illness, an IgM-positive antibody test result should not be grounds for deferral, and this is the same as was in the previous guidance.

[Slide.]

For suspected acute West Nile virus illness or infection, this is where the guidance differs substantially. There is a predonation question to ask donors about fever with headache in the week prior to donation.

If yes, the deferral for the donor would be 28 days from the date of that interview. This should be implemented no later than June 1st of this year, and earlier if there were local reports of epizootic or human infections.

This question could be discontinued no earlier than November 30th of this year, and later if human cases were still being reported in the area in November. If there were cases reported in November, the deferral question should continue until there were two consecutive weeks without human cases.

[Slide.]

This question should be asked annually using the same time periods and the same criteria. It is noted this question is new from the previous guidance.

The rationale for this was again working with CDC. Donors implicated in transfusion-transmitted West Nile virus in 2002 were asymptomatic at the time of donation, however, 9 of 14 reported symptoms compatible with West Nile virus infection prior to or after donation.

[Slide.]

Fever and headache were reported by approximately 57 percent versus less than 2 percent in non-implicated donors, and there was a survey that was conducted in blood donor centers that suggested that the inclusion of this kind of question related to fever with headache in the week prior to donation would result in a less than 1 percent donor loss.

[Slide.]

For potential association with transfusion-related West Nile virus transmission, the donor should be deferred from 28 days from the date of the implicated donation. This is the same as in the previous guidance.

[Slide.]

For post-donation information, any donor that reports a post-donation febrile illness suggestive of West Nile virus infection particularly during the June 1 and November 30 time period, but keeping in mind the potential for those time periods being changed as noted before based on local activity, these donors should be deferred from 28 days from the onset of illness or 14 days after the condition is considered to be resolves, whichever is the later date, and again this date range is slightly new from the previous guidance.

[Slide.]

For retrieval and quarantine of blood components, for diagnosed West Nile virus infection or illness in the donor, in-date components from relevant collections should be quarantined and retrieved promptly.

Relevant collections are those occurring between 14 days prior to onset of illness and either 28 days subsequent to illness or 14 days after the condition is considered to be resolved, whichever is the later date, as previously noted. This is the same as the previous guidance.

[Slide.]

Donors associated with a potential case of transmission to a transfusion recipient. A donor is considered potentially associated or suspect if a recipient of blood or transfusible blood components is diagnosed with West Nile virus and received blood components from that donor within the 28 days prior to the onset of the symptoms in the recipient.

[Slide.]

Quarantine and retrieval of in-date components from the suspected donor collected in the period between 28 days before the suspect donation and 28 days after the suspect donation. This is the same as in the previous guidance.

[Slide.]

For undiagnosed post-donation illness in potentially exposed individuals. Medical directors in general should use their judgment particularly during the West Nile virus transmission dates or local activity to determine what would and would not apply at their own individual center.

The symptoms should be consistent with West Nile virus infection. Current donation and any others that date back to 14 days prior to the onset of symptoms in the donor. Pooled source plasma, recovered plasma or source leukocytes already pooled for fractionation do not need to be retrieved.

It is believed that the viral inactivation methods are believed to inactivate flaviviruses although validation has not been completed, and this is the same as in the previous guidance.

[Slide.]

For notification of prior transfusion recipients, when there is diagnosed West Nile virus illness in a donor relevant to prior donations, the relevant units would again be those dating from 14 days prior through 28 days after onset of illness in the donor.

Establishment trace records are recommended to be done notifying the transfusion service. Again, recommendation that the transfusion service notify physicians of prior recipients of blood or blood components from that donor.

[Slide.]

If the donor is a likely source of transfusion-transmitted West Nile virus, the relevant units would be those dating from 28 days prior through 28 days after the donation that was implicated.

Again, the same process of establishing trace records, notifying the transfusion service, and the transfusion service notifying physicians of any prior recipients. Again, this is the same as the previous guidance document.

[Slide.]

So far, we have received four questions related to this guidance. The first was does the guidance apply to autologous blood donors.

The use of the question and deferral standards defined in the guidance for autologous donors is entirely a matter of discretion of the individual medical director, as is recommended in most of our guidance documents.

FDA recommends that the medical director at each blood bank assess the risk and make decisions about the autologous donation with the donor and the donor's physician.

[Slide.]

The next question was must the blood banks make changes in their donor interview forms.

As discussed in the guidance, temporary use of a separate printed sheet, independent of the usual donor history questionnaire, will be acceptable in the interim, however, SOPs must clearly specify how the donor will be instructed to respond and how the response will be documented, and this is laid out in the CFR.

[Slide.]

The next question was if an establishment asks blood donors the question, "Have you had a medical diagnosis of West Nile virus," would they have to submit as a supplement because they weren't following the guidance specifically?

The FDA intentionally did not recommend that establishments specifically ask potential donors about West Nile virus infection. If the establishment wants to ask about the infection, this would be more than we recommended, and can be submitted in the next annual report from the blood center.

[Slide.]

This is not on the slides on the web site. I just received this question yesterday, which is why it is included here. Once testing under IND begins, what is the recommendation for product retrieval and quarantine upon receipt of a reactive West Nile virus NAT result, because this is not addressed in the guidance.

We specifically did not address it in the guidance because at the time we were writing it, there was no test even under IND.

Our current thinking is that a reactive West Nile virus NAT result on an individual donation is consistent with evidence of West Nile virus infection and that the recommendations under the diagnosed West Nile virus infection or illness in the donor in the Retrieval and Quarantine Section should be followed.

[Slide.]

This current guidance is located at this web site for anybody who needs access to it.

Thank you.

DR. NELSON: Thank you.

Are there any questions and comments? Yes.

DR. CUNNINGHAM-RUNDLES: I am just puzzled by that counterintuitive statement on one of those slides about donor deferral in the absence of West Nile virus compatible illness and IgM-positive antibody test should not be grounds for deferral.

That just seems counterintuitive, no?

DR. ORTON: Well, the antibody test, in and by itself, it would be no, because IgM test can be positive for very long periods of time without the donor being viremic, so someone just having a positive antibody test would not preclude them from donating.

DR. CUNNINGHAM-RUNDLES: That doesn't seem to make immunological sense to me.

DR. NELSON: It has been the finding that IgM can persist for a year or more--

DR. ORTON: Right, and the donor would not be viremic.

DR. NELSON: --after infection, but the chronic viremic state has not been documented yet. Because of the frequency, if there are, in fact, 500,000 people infected with West Nile virus in the United States, that is a substantial proportion who might be IgM positive, and yet they are not viremic, you know, past the first couple of weeks or 28 days of illness or at most.

DR. CUNNINGHAM-RUNDLES: But if the IgM was positive, that would be the situation where you want to either confirm or deny it with the NAT.

DR. NELSON: Yes.

DR. CUNNINGHAM-RUNDLES: So, that is eventually what will happen?

DR. ORTON: No, we are saying, for instance, if a donor came in and said, well, you know, I was sick and I had the test done and it was positive, yes, you would need more information than just the IgM test in and of itself. It, by itself, would not defer a donor.

DR. CUNNINGHAM-RUNDLES: I see. It would put them on a suspect list until you knew more, I presume.

DR. NAKHASI: No.

DR. NELSON: I think all of the donors during the time of an epidemic are all going to be tested, so you will have NAT results on everybody. But IgM positivity alone will not be a transfer deferral. That is my interpretation.

DR. NAKHASI: You are right, Dr. Nelson. As I mentioned in my presentation, as soon as the IgM positivity comes up, there is no detection of the virus, and therefore, as I said also, and Tony also suggested that the IgM positivity can remain for two years and without the presence of the virus, so I think all these points, that IgM positivity does not mean it in infective.

DR. MARFIN: Just to add to Hira's comments, when we look at the cases of documented encephalitis over the years, and we look for virus in the serum, there have only been two cases over the past four years in which we have found simultaneous IgM positivity and PCR positivity, and that is hundreds and hundreds of samples, so it is a very, very unlikely event, and, in fact, both of those events, the person was immunologically suppressed, so there were very unusual conditions.

Our rule of thumb is when the IgM is positive, there is not going to be any virus.

DR. EPSTEIN: I just want to reiterate back to Dr. Cunningham-Rundles' point that the expectation is that the vast majority of units will be least be screened with investigational NAT.

DR. NELSON: We will move to the industry presentations and Dr. Dawson from Abbott.

Open Public Hearing

Presentations from Manufacturers

DR. DAWSON: I am going to give a brief update on Abbott's activities in regard to West Nile virus detection.

[Slide.]

The last time I spoke we had a three-step overnight assay, and we have reduced the assay format to a two-step, 3.5 hour test, and we maintained the robust signals that we saw in the overnight test, as you will see in the next slides.

I am going to talk just briefly about our performance on a CDC performance panel, some confirmed antibody positives, and just a quick overview of an experimental animal study that we did.

[Slide.]

Here is the assay format. It's a two-step assay, an anti-mu coated solid phase captures IgM in the first step after a wash step, antigen and conjugate are both added, and the complexed IgM antigen and conjugate are detected, and this takes 3 hours incubation and then a half-hour exposure to substrate.

[Slide.]

Here is the 2-step assay compared to the two-step assay on the 20-member CDC proficiency panel where members 2, 4, 7, 9, 11, 13, 17, 19, and 20 are supposed to be negative for IgM, and you can see in the dark blue, light blue, and purple, the three assays being the Abbott 3-step, in the middle the CDC assay, and on the right, the purple, on these different panel members, and on the Y axis you have the S/N values.

You can see on most of the samples, the S/N value on the 2-step assay is as high or higher than on the 3-step assay, so we feel that reducing the timing of the assay is not affecting our sensitivity.

[Slide.]

Here is the 2-step assay versus the CDC assay in terms of S/N on the Y axis on several different samples that were IgM positive only, we see a very robust signal for IgM.

[Slide.]

Here are samples that are positive both for IgG and IgM. Again, the Abbott test sample to negative values are very high, very robust signals for most of the samples. Even after IgG has kicked in, you still see a very strong IgM response.

[Slide.]

We were involved in an experimental study infecting macaques intradermally with West Nile virus, and we are seeing here the serologic profile. I am not showing you the entire testing that has been done, but just focusing here on the IgM S/N values and the positive or negative signal with RT-PCR. We use a nested PCR for our assay.

In this particular animal, you see that the PCR results are positive on days 1 through 7, and 9 and 10 post-inoculation. The antibodies come up on days 9 and 10, so we get co-detection of IgM and RNA on days 9 and 10. I am certain you are going to see this in human cases.

I think the CDC's experience last year was all on symptomatic cases and here you are dealing with a different situation where these individuals are not symptomatic that are blood donors, so you are likely to see co-detection of IgM and RNA.

[Slide.]

Here is a second animal where we see a clear distinction between the RNA detection between days 1 and 6 and the IgM detection beginning on day 9. You see the IgM values go up to about day 21, where it peaks, and then goes down in the next days.

[Slide.]

We are continuing studies with the American Red Cross. We have looked at some of the donor transfusion-transmitted samples for IgM, and we will be look at the quarantined plasma units with both the American Red Cross and the American Blood Centers with Dr. Michael Busch.

In addition, we will be looking to be involved in both the Roche and Gen-Probe IND studies. We are on the IND actually with Gen-Probe and American Red Cross to look at the IgM status of nucleic acid testing positive samples.

[Slide.]

So, to summarize, we finalized our assay format. It's an enzyme immunoassay on polystyrene beads. It has reduced it to a 2-step, 3.5 hour assay.

For IgM, we feel and we have heard from CDC that IgM is the preferred method for diagnostics, and we see that the IgM response is fairly robust in the symptomatic individuals that we have looked at, and we do see in experimental infected animals that IgM is detected by about day 10, and we do see in some instances co-detection of IgM and RNA during the infection process.

That concludes my presentation. Thank you.

DR. NELSON: Thank you.

Questions? Mike.

DR. STRONG: For the dancing impaired, I am sure 2-step is better than 3-step, but you didn't mention what hardware platform your filter is on, what is your hardware platform for the assay?

DR. DAWSON: It's Quantum or Commander, our EIA system, polystyrene beads.

DR. CUNNINGHAM-RUNDLES: I guess I am just getting redundant, but I am wondering, you are looking at the IgM and the virus test in parallel, and that seems like a good idea, but going back to what we were saying a moment ago, if people are going to be remaining IgM positive for a long period of time, wouldn't that unnecessarily exclude individuals, or am I just missing the point on that?

DR. DAWSON: Well, we are not suggesting to exclude individuals based on IgM detection. We are looking at the kinetics of infection in experimental animals, looking to see what comes up what when and whether there is co-detection, how long virus persists, and things like that.

DR. CUNNINGHAM-RUNDLES: Right, but you do say co-detection that you see, so that was in contradistinction to what was said a moment ago.

DR. DAWSON: Yes, and I think that there is a difference in the studies. I think that when you see people that are ill, they probably do have IgM already and probably have cleared the virus from the bloodstream, although very likely it is still present in CNS or else they wouldn't be having symptoms.

DR. NELSON: I guess one of the arguments you are trying to make is that you can't use the presence of IgM to be assured that the donor is not still viremic because of the short overlap, but certainly during most of the persistence of the IgM, the donor is not viremic, but there may be a short overlap at least in this monkey model and maybe in some humans.

DR. DAWSON: Yes. I am sure you will see it in humans.

DR. EPSTEIN: I think the unifying principle here is the idea that the viremia resolves quickly when the IgM appears, but that the IgM then persists. So, if what you are trying to detect is infectivity, the problem is that IgM is a nonspecific marker because of persistence.

On the other hands, it is a very highly specific marker for showing that someone had a West Nile infection, therefore, it certainly plays a useful or will play a useful diagnostic role.

Let me just comment that there are some studies that I don't believe have been made public yet, looking at samples from asymptomatic individuals during peak outbreaks in certain areas in 2002. I believe some of those samples have shown positivity concurrently for RNA and IgM, and that is, in fact, not surprising based on earlier data and now your data.

DR. DAWSON: Yes, and another part of our data is that we did not find during the bleeds that RNA and IgM were co-detected, these were not infectious. We could not isolate virus from those.

DR. NELSON: Do you plan to study samples from plasmapheresis donors, because the interval between which the samples would be collected could be rather short as opposed to whole blood donors where you might not pick up this overlap?

DR. DAWSON: I think perhaps we would study them. If we did, it would be in association with the Roche or Gen-Probe studies, we would be interested in doing those, yes.

DR. FALLAT: What about the persistence of the virus in Oregon related to organ transplantation?

DR. DAWSON: We don't have any data on those. I am sure that is very good topic to bring up because, you know, in spite of being unable to find viremia in patients that are having meningoencephalitis, they do have virus in their brain, so it is not predictive of what is happening in other organs.

DR. NELSON: Dr. Sherrol McDonough from Gen-Probe.

DR. McDONOUGH: Thanks to the committee for the chance to present today.

[Slide.]

I will be discussing the assay performance of the Procleix West Nile virus assay, this is to detect West Nile virus RNA, discussing sensitivity and specificity, reproducibility, consistent detection of true positives with the assay, and some validation work we have done with anticoagulants.

[Slide.]

As you heard already this morning, the analytical sensitivity for this assay is quite high with sensitivity between 9 and 18 copies/ml using 95 percent confidence intervals, and this was determined using both Lineage 1 and Lineage 2 virus from BBI, as well as transcripts.

Specificity determined in our laboratory was 99.8 percent using initial reactive rate, and upon retest, specificity was 100 percent.

[Slide.]

Now, I would like to discuss the reproducibility study that has been performed at Gen-Probe. The study includes results from three different operators, two different reagent lots, three different instrument sets, and was performed over six days.

The study included four West Nile virus panel members, the first containing 100 copies/ml of heat-inactivated West Nile virus at 100 copies/ml, the second transcript at 100 copies/ml, the third, 30 copies/ml, and the final panel member contained negative plasma.

[Slide.]

The overall results for this study are shown here. Out of the 360 negative panel members that were tested, all 360 gave nonreactive results in the study under all conditions. Of the 1,080 known positive panel members tested in this study, all of those panel members gave reactive results in the study, for overall agreement of 100 percent with negative and positive panel members.

[Slide.]

Sources of variability in the assay are further analyzed in this slide. We have looked at inter-lot, inter-operator and inter-instrument variability, and those are shown on the right columns. You can see there is very low CVs from all of these different factors.

The highest CVs actually come from the inter-run and intra-run data, and all CVs are less than 16 percent, so we feel that there is very high reproducibility with the Procleix West Nile virus assay under the conditions that have been tested.

[Slide.]

We wanted to go ahead and test some known positive samples, so we went back and looked at the positive samples that we tested, that were derived from the CDC case investigations.

The results on the left side were already shown at a previous BPAC meeting, and indicate detection of different dilutions of these panel members, and the results shown on the right side, that are boxed in, in green, indicate we have equivalent results with our second scale-up lot.

I would like to stop and mention at this point that we do have results starting to come in from the Phase I testing with Red Cross, and testing of those samples suggest that there are some extremely low viral load samples in that population.

In the case of extremely low viral load samples, pool testing may miss some infected donations that will most likely be detected NEET [?]. It is not known if these low viral loads units would cause transmission, as we have already discussed here at the meeting, and will continue to gather data and provide that as it is available.

[Slide.]

We have also looked at a number of anticoagulants for use in the assay. As you can see, we have tested K2 and K3 EDTA, PPT tubes, ACD, sodium citrate and heparin, all tested in plastic and in certain cases, we have also looked at glass tubes.

As shown at the bottom of the slide, whole blood and plasma units collected in CPD. CDPA1 and CP2 are also fine to use in the assay.

[Slide.]

So, in summary, the Procleix West Nile virus assay has excellent sensitivity and specificity. We have shown reproducible performance between operators, lots, and instruments over time. Testing of known West Nile virus-positive samples from CDC case investigations indicate consistent performance between lots, and a range of anticoagulants has been validated for us.

Thank you.

DR. NELSON: Thank you.

Any questions?

DR. STRONG: Have you tested serum?

DR. McDONOUGH: No.

DR. BIANCO: Sherrol, just a definition of extremely very low, is it 1, 2, 10, 1,000?

DR. McDONOUGH: That is the question we would all like to be able to answer today. I don't have a definitive number for you yet.

DR. NELSON: It is below 100 copies/ml apparently.

DR. McDONOUGH: That's a good guess.

DR. NELSON: The pool size for the Procleix is 16, pools of 16?

DR. McDONOUGH: Yes.

DR. NELSON: Next is Andrew Heaton from Chiron.

DR. HEATON: Good afternoon. Thank you for the opportunity to present an update from the Procleix West Nile virus assay introduction, which I am sure you are aware is a collaborative development between Chiron and Gen-Probe.

During the next few minutes, I plan to comment on the development process, recognize critical success factors, and draw attention to the regulatory approaches that greatly assisted in this rapid development.

[Slide.]

Obviously, the general goal was to develop a specific blood safety assay to prevent new and previously undescribed blood safety risk in an extraordinarily short time.

[Slide.]

The specific development goals of the current Gen-Probe collaboration included development of an assay specific to the West Nile virus since this is the only flavivirus associated with post-transfusion mortality in the U.S. We wanted to achieve a turnaround time that would support timely product release testing and achieve a sensitivity adequate to maintain the existing pooling strategy.

At the request of our customers, we focused also on a test that could be used on existing equipment to minimize the cost and to minimize the need for new blood center space requirements which would have delayed the introduction.

We also wanted the test to be similar enough to capitalize on our existing operator expertise to minimize the need for new training. All of this had to be achieved by the mosquito season.

With only nine months available, assay development had to be rapid, and indeed it was. An R&D assay was available in just three months, a pilot in four months, and an IND with two amendments was filed in March, April, and May.

Since the software to export the laboratory results was so important, a NAT Tracker upgrade was undertaken, and NAT Tracker 2.0 software was 510(k) cleared in May of this year.

The initial CDC comparison results have already been presented to this group, but they showed improved sensitivity and specificity over the prototype CDC assay, and currently, as you have heard, ARC repository samples are now completing testing.

I am delighted to report the development lot materials were shipped to blood centers, which test more than 80 percent of the U.S. blood supply, last week, and the first center, which is a Central Indiana blood center, started testing with our Procleix test today.

[Slide.]

This complex project benefited greatly from the earlier Procleix HIV-1, HCV assay development. It started with customer education and feedback which resulted in a full survey identifying customer needs.

We had a meeting with the customers in January to review equipment, space, software needs, planed the workflow, and identify training needs.

Then, we developed a timeline and shared that with our customers, so they could integrate it into their planning process, and from this we identified the need to develop a very comprehensive training program to train new operators and existing operators in high-frequency throughput. In fact, we have trained 300 operators in the last six weeks.

Draft instructions were provided to the customers for SOP development and equipment was ordered in advance to mitigate the long lead time items, and this finally was followed by installation and qualification, and over the last three weeks, training has been completed, proficiency established, and the test kits now are available for the customers to use.

I am delighted to report that the assay performance has been generally similar to the previous HIV/HCV Procleix assay. There were minor changes in the materials, and we added color coding both to improve compliance to procedures and to separate the two Procleix assays. Throughput was maintained by two rack training, which maintained the turnaround time.

[Slide.]

Not a lot of compiled data is available, but there is enough available to assure that performance results are similar to the introduction that we had with HIV and HCV when we started some four years ago.

The assay copy number sensitivity is similar to the Procleix assay and the reactive rate is generally within the range predicted.

As with any new assay, a supplemental test is critical. One wants to avoid inappropriate donor loss either for cross-reactivity or positivity to viruses that do not cause post-transfusion morbidity.

In order to support this, we have developed an orthogonal confirmatory assay which has a sensitivity and specificity comparable to the TMA assay. This is now available, we have a service provided in a GLP facility with a turnaround time on the throughput requirement that will be adequate to meet customer needs and to avoid unnecessary delay in notifying donors.

[Slide.]

What were the critical success factors? Well, first, clear goals. We had a clearly expressed need and a defined timeline, and a defined target sensitivity which greatly helped our project team.

We were greatly assisted by CBER availability to answer questions and indeed the regulatory support was excellent. CBER provided discretion to us to distribute draft materials to allow SOP development, they abbreviated the requirement for multi-lot requirements, and they supported the use above all of an IND approach to support IUO testing.

CBER facilitated the process with a modular license application, pre-IND meetings, ready availability of guidance, and rapid software review.

We also benefited from very strong blood bank relationships. We worked with the blood banks to educate them, we solicited their feedback and indeed received it in spades. We worked with the blood centers for support and planning, and we secured their commitment and flexibility in implementation.

The TMA assay appears to be sensitive enough to meet the pooling requirement and meet the FDA standard, and it was developed rapidly to a highly specific assay. It has turned out to be robust in practice and our dedicated development team, which was a multi-disciplinary and very hard-working group, ensured our success.

What do we believe are the lessons to be learned going forward?

[Slide.]

Well, first, the TMA assay is extremely robust. It is developable and could cover other viruses as needed, it has proved to be sensitive and virologically very specific, and the modularity of the equipment that we use supports flexibility.

NAT also allowed fast-track development at a rate that could never have been achieved with previous generations of NAT or EIA technologies, and indeed the only outstanding issue is the need for FDA guidance under the blood center obligation to seek local donor IRB approval in addition to national IRB approval.

As we heard earlier, FDA enforcement discretion may be needed to help resolve this if we are to meet the July 1 timeline. It required investment and commitment by the CDC for analysis, FDA for assigning the goal and helping us develop a team to support it, CBER for their regulatory support, the companies for a massive investment in increase in priority, together with the NIH who took the lead in providing funding, and lastly, the blood bank support to get it done.

It was this combination from all sectors of the blood bank industry that allowed us, Chiron and Gen-Probe, to have a Procleix test available in time to meet the mosquito season.

Thank you.

DR. NELSON: Thank you.

Questions?

DR. ALLEN: Let me just play the devil's advocate for a second, Andrew. If you are looking at blood collection centers only, and I realize that your market share is going to go well beyond that, I could argue that in actual fact, a second-level confirmatory test is unnecessary for West Nile virus, unlike HIV and some of the others, in that the diagnosis itself doesn't really carry any social stigmata, the deferral is for a temporary period of time, and in actual fact, it doesn't matter if you have got a few false positives that are in there, it is not going to really affect the donor population much.

I certainly understand beyond that, that the confirmatory test probably is a very important tool to have.

DR. HEATON: That is true to an extent. If you take our Procleix HIV/HCV assay, we have I think about a 1 in 30,000 false positive rate, well, a positive rate that cannot be confirmed, but nevertheless, if you think of it in donor terms, you like to have an orthogonal assay to confirm whether the donor is really infected or not.

For consignee notifications, certainly the hospital would like to know whether the unit was truly positive, and then for lookback notifications with the significant medical-legal issues, to have that confirmatory assay is pretty critical, so we very much took the position that we wanted to have a good, solid GLP-supported confirmatory assay as we launch the product.

DR. NELSON: The thing I am still a little confused about is all the IRB issues and how many IRBs have to approve this. I know that I have had research projects that were held up for a long time by an IRB that didn't understand what was being done, or didn't meet very often, or if they met and approved it, they couldn't get people to sign the approval letter, and that delayed it for months.

Is that a real problem here?

DR. HEATON: Well, the critical issue here is there is a national IRB, and it has approved the study and the consent form, so that worked very well.

DR. NELSON: The national being the American Red Cross?

DR. HEATON: No, in this case, the Western IRB.

DR. NELSON: Oh, the Western.

DR. HEATON: They have approved the protocol, however, because of new regulations, they added a rider in their approval and said that where there was a local IRB that was applicable, by donor group, local approval should be sought. Well, obviously, if you are running blood drives, some companies have IRBs.

If you went to a hospital, obviously, they would have an IRB, but if you went to Chiron Manufacturing to collect our employees, we wouldn't have an IRB, so that forces the blood center to find out does the donor group have an IRB, and, of course, the moment you communicate with them, they would want to look over the information, and they will delay the approval process. So, this is really a bureaucratic requirement rather than a specific research or medical question.

DR. NELSON: Well, presumably, every university and government hospital in the country probably has an IRB, all of which could interfere hopefully. I mean they are designed to improve or to review issues of research subjects, but to me, even though it is an unapproved test, it is a different issue. I mean these aren't in a way research subjects, they are blood donors.

DR. HEATON: One of the points that was made earlier is the implementation of this type of assay, it's so much part of routine blood banking, it is scarcely research, it is really operational implementation under very controlled circumstances, but nevertheless, by virtue of the IUO regulations, it does require IRB approval, and that then rolls you into all the sequence of IRB cross coverage issues.

DR. NELSON: Do you have to specifically notify the donors that they are being tested for West Nile virus, as well as hep C, HIV, syphilis, and other things?

DR. HEATON: Yes, indeed, you do.

DR. NELSON: That's not a bad thing, that's okay, that's easy enough, but I can see where it could be delayed.

DR. HEATON: So, currently, at this point, I believe the Western IRB, the chairman of the IRB is in contact with the FDA attorney to seek clarification on the law, and that is the only thing that might hold up implementation on July the 1st.

DR. NELSON: The final industry presentation, Dr. Jim Gallarda from Roche.

DR. GALLARDA: I would like to start by reading a headline from a news article that came out two days ago from Newsday. This is by a staff writer Delthia Ricks, and her article is entitled, "Virus hits blood supply. Donations to be checked for West Nile."

The staff writer says, "As teams of federal health investigators were probing the new viral threat of Monkeypox last week, others were quietly racing to track an increasingly familiar one that has stalked the nation for four years running West Nile disease."

Delthia goes on to say, "This year, however, in a stunning example of fast-track scientific development, blood collection agencies will have for the first time a way to screen donated blood for the virus."

Nine months ago, these tests were nonexistent, so I agree with Andrew, the past nine months have been more than fast-track, they have been frantically tracked, and for Roche, this was all the more remarkable because it was January 31st when we had a big meeting, and we decided to provide a fully automated solution for sample prep and kinetic PCR for West Nile.

So, what I would like to do is give you kind of highlights of what we have been up to since the last March BPAC.

[Slide.]

So, in March at BPAC, we had three things we were talking about. We were talking about filing an IND and we were talking about the phases of that IND. We filed the IND on April 21st, and the Agency worked rapidly to provide guidance and ultimately approve that IND later.

In our IND, we have described two phases. One is Phase I where we were really looking at issues related to workflow and training, and these were testing panels provided by Roche that had both positive and negative members, as well as unlinked samples.

We tackled five sites, three in the U.S. and two in Canada, and we completed those studies in the end of May, after which we immediately began our second phase activities to train and install the rest of the sites, so there are a total of 11 sites in the U.S. and three in Canada.

That is the Phase II testing, which really is to assess the safety and effectiveness of the system and detecting West Nile virus, however, based upon the discussions at the November BPAC and also at the November workshop and the March BPAC, to not only go after West Nile but to see if we could deliberately design the assay to include the other members of the Japanese encephalitis family serocomplex.

So, our intention is to really specifically try to get a claim for West Nile, but to also hopefully show demonstrated effectiveness for other members of the JEV family.

[Slide.]

Late breaking developments. This is not in your handouts or on the web site, but on Monday, June 16th, South Bend Medical Foundation began prospective testing under the IND, and Gulf Coast Regional Blood Center began yesterday to do the same thing, and during this morning's session I got several phone calls from the NAT lab director at Gulf Coast who said everything went flawlessly last night on their first run.

We have the remaining sites targeted for July 1 or earlier start date.

[Slide.]

This is the system that we put together, the basic components. We have a Hamilton Pipettor, which is creating pools of 6. This is driven off of software, which is Windows 2000 operating system, and the software is Part 11 compliant.

The pools are transferred to the COBAS AmpliPrep, which is the automated sample extraction device of the system. At the end of an extraction, the AmpliPrep will automatically also add working Master Mix to the extracted nucleic acid. AmpliPrep extracts both DNA and RNA, so if we have to come back later to develop Monkeypox assays, we would expect to have captured that nucleic acid already with this system.

The COBAS TaqMan then provides a kinetic PCR output for West Nile.

[Slide.]

I would like to go over briefly the nonclinical performance studies and a capacity analysis that we did in support of our IND filing.

[Slide.]

We looked at 400 random volunteer donors in preclinical specificity studies from both low and high prevalence areas. We looked at analytical specificity studies with non-West Nile virus microorganisms, and limit of detection studies with the CDC lysate.

In addition, we looked at both Lineage 1 and Lineage 2 isolates for analytical sensitivities, and also tested early studies with other members of the JEV family.

[Slide.]

So, for the 400 volunteer donors, this breaks down to 200 that were low-prevalence sourced from California, 200 from the Chicago area. This is not during the peak of mosquito season of 2002. This is in the May time frame.

We are going after a West Nile virus target, as well as an internal control in each sample. This is a full process control, which means it's an armored RNA, and it encapsulates the RNA, so it mimics a virus, and this is important because it allows for us to conclude with confidence that the entire process is working as expected from the lysis step all the way through the amp detect step.

The armored positive control is provided in each batch. We get CT values, which is the cycle number of where you start to see fluorescence grow, so if a number is reported, that means it is a positive result. The IC values for the positive control was positive, as was the target, as you would expect. The negative control was negative for the target, positive for the internal control.

All samples were negative for the target, and yet positive for the armored internal control, and we had very tight CVs around with a 1.18 standard deviation. One hundred percent of the negative samples were negative, 100 percent of the ICs associated with those were positive. That pattern repeated itself for the 200 high prevalence donors.

[Slide.]

We looked at several categories of viruses and bacteria, as well as Candida albicans, to look for potential cross-reactivity to the system.

[Slide.]

Of these categories, we tested 125 samples. All of them were negative. There were no false positive test results observed, and of the associated armored internal controls were positive in each case.

[Slide.]

This is a regression analysis looking at the limit of detection studies with the CDC lysate. We looked at two different systems and we made 10-fold dilutions starting at 1,000-fold down to 10⁸, and then we asked what kind of CT response would be generated in each of these two systems.

So, this shows a linear regression and with the TaqMan output, you see lower CT values, that is, the growth curves appear earlier in the assay with high titer samples, and then the CTs start to become larger as you get lower and lower inputs. So, there is a very nice linear regression.

The bottom line is for each of the two systems, at 10⁷, we still were generating positive CT values, at 3 times 10⁸, one started to drop out, and one remained positive, so we were comfortably detecting the lysate at 10⁷ dilution.

[Slide.]

Looking at analytical sensitivity with the IMPATH/BCP Lineage 1 isolate, taking the manufacturer's stated claim and diluting those from 25 copies down to 1 copy/ml, we were detecting 100 percent of 24 replicates in the small study even at 5 copies/ml, and we started to see dropouts at 1 copy/ml.

We didn't have sufficient information to generate probit on this for an interpolative method, however, based on this, we would expect the estimated sensitivity to be less than or equal to 5 copies/ml.

[Slide.]

For the BBI Lineage 2 isolate, we again, based upon the manufacturer's claimed titer, we made a similar dilution series, and we are testing replicates from 25 down to 1 copy/ml. We were positive with 100 percent detection at 10 copies/ml. We started to see dropouts at 5.

Doing a probit on this, we generated a 7.4 copies/ml central tendency with a confidence interval ranging from 5 to 16 copies/ml.

[Slide.]

We were able to obtain additional isolates from ATCC. We got a third West Nile virus isolate, as well as a St. Louis and a Murray Valley encephalitis virus, and all of these isolates were detected. We are in the process now of generating transcripts for Japanese encephalitis virus and additional isolates, and we are trying to procure clinical samples, as well, to expand this data.

[Slide.]

Gulf Coast did a really nice capacity analysis, oh, I think it's probably now four weeks ago, where they started pooling at 6:30 in the morning, and they reported an average pooling time, it wasn't 20 minutes, it was 19.5 minutes.

They put their first extractions on the COBAS AmpliPrep at 0649. Amplifications began at 0900. The total throughput with two FTE operating two systems was about 1,600 samples in 12 hours. This is a correction.

If you extrapolate, you are looking at a system that has two shifts, that's running 16 hours using two of these Taq screen West Nile systems with two FTEs working on the systems, we would expect those to accommodate 700,000 samples per year.

[Slide.]

So, the current status and issues with our IND is that all 11 U.S. sites and 3 Canadian sites are installed and they are preparing for linked testing on or before July 1. We are doing a software upgrade right now to the pooling and data management system that has been successfully installed in about three quarters of our sites.

We have interest in expanding to other sites, and we have had some discussions to pursue that further. We have had several sites request can they assist local public health labs in testing non-blood bank applications or testing patient samples, and our IND right now doesn't allow that, although I was asked to bring it up with the Agency to see if that might be in the interest of public health, something that would be possible to do.

There is also a need to have national prevalence data that would be very useful to capture what is happening on a nationwide basis with both prevalence and incidence in West Nile. I know Mike Busch and Steve Kleinman have been working through REDS and NIH to put together a means by which we can capture that in timely fashion.

There was an issue with USDA permits for West Nile virus panels. We got that cleared up. We have an umbrella license for us to ship samples to the sites, as well as them to ship positive samples to the confirmatory lab.

I think Maria and Indira have been working on standardizing a much needed West Nile virus panel, which is encouraging to see.

Getting back to the fast-track scientific development, this was an enormous undertaking for Roche.

[Slide.]

However, we really called upon resources all over the world. We had an outstanding instrument and software group out of Penzberg, Germany, and Rotkreuz, Switzerland. We had development and marketing in Pleasanton. The design of the system for West Nile, as well as the broader JEV, came out of our Alameda folks. Indianapolis has done an astounding job in stepping up and getting involved in supporting the sites, because this is a rather enormous undertaking, as you can imagine.

Branchberg is our site of manufacturing and also our outstanding colleagues in Laval, Quebec, Canada, for the Canadian customers.

Thank you very much.

DR. NELSON: Thank you.

Questions? Jim.

DR. ALLEN: Two questions. First, do I understand that your implementation, you are recommending small pools of 6 samples?

DR. GALLARDA: Yes. When we were going to these early meetings last year, and we were trying to understand what does a plaque-forming unit mean in copies, everyone's consensus was, well, it's low. So, we were debating whether to keep pools of 24 or do something lower, and we decided that in order to try to maximize the sensitivity, but still maintain the throughput required for our sites, pools of 6 on that system would do it.

So, if we are bouncing around 10 copies/ml, then, you would expect to detect a sample pretty readily at 60 copies/ml if it's diluted 6-fold in a pool of 6, so that was our rationale for that.

DR. ALLEN: The second question. You showed a couple of slides on the analytical sensitivity, and as you went on out to the dilutions and dropped below 5 copies/ml down to about 1 copy/ml, that you began to get loss of specimen detection.

Yet, your internal controls, you were still at 100 percent detection.

DR. GALLARDA: Right. That's a good question. I think, first of all, on that 1 copy/ml, I think that is not going to be the standard. I expect that data to look more like the Lineage 2, so we will be at 7 and 10 copies/ml.

With regards to the internal control, we want to make sure that we have a level of control that statistically, would not cause failures because of a Poisson effect, whereas, 5 percent of the time, you would expect to have a negative result simply because you didn't sample an armored particle, but at the same time, be informative, so if there is a process failure, that internal control is going to be able to tell you, you have a failure, so you shouldn't trust the result.

So, this is why we would expect to have a level of internal control that ensures that we can detect a process failure, but not a failure because of stochastic variation.

DR. KLEIN: Will your license application provide for eventually using single specimens, as well as pools of 6?

DR. GALLARDA: Right. We are going after both minipool and a single unit testing strategy

DR. NELSON: I know the viruses in a JE complex are JE, there is dengue, there is St. Louis, there is West Nile, and Murray Valley, and all of these I think are pathogens, but there are arboviruses that aren't really pathogenic, are they? Are there others in this complex that might be NOIS?

DR. GALLARDA: That's a good question. We searched the entire gene bank database for homologies to do potential cross-reactivities, and the nice thing about this is that you really need three independent sites to work together to get a hit. You have two primers at the end, either one of which is not sufficient to generate a result. Together, they are not sufficient to generate a result.

Then, you need a third target area that the probe lights on, and so the nice thing about this strategy is you have a multiplicative requirement in order to generate a result, so I would expect that unless it has those three requirements where you have significant homology, they will not be detected in the assay.

DR. FALLAT: Did I understand you that you are able to test for more than one virus in a single throughput?

DR. GALLARDA: Correct.

DR. NELSON: Thanks. Very good.

We has some people who wanted to testify in the open public hearing.

First, Kay Gregory.

MS. GREGORY: Thank you. You have been hearing from test manufacturers, and we wanted you to hear from the blood banking community, as well.

The American Association of Blood Banks, America's Blood Centers, the American Red Cross, and the Armed Services Blood Program have taken a number of actions over the past several months with regard to West Nile virus. These actions relate to increasing blood safety, education, communication, and ongoing monitoring.

First, let's talk about testing. Since November 2002, the national blood banking organizations have committed to implementing nucleic acid screening tests for West Nile virus as they were developed by commercial manufacturers for implementation under investigational new drug exemptions.

Two manufacturers you have heard from, Roche and Gen-Probe/Chiron, have been successful in obtaining such FDA approval and it now appears that most, if not all, U.S. blood banks will have minipool West Nile virus NAT donor screening in place on or about July 1, 2003.

It is estimated that approximately 25 to 30 laboratories will be performing this test nationwide. Implementation of donor screening by early July represents an extraordinary effort to develop and implement this testing in only seven months under cGMP constraints, so as to reduce the risk of West Nile virus transfusion transmission during the 2003 mosquito season.

Some of our other measures. To our knowledge, most blood collection facilities have now added an additional screening question about fever and headache in the past week to their donor questionnaire as recommended in the May 2003 FDA Final Guidance entitled, "Revised Recommendations for the Assessment of Donor Suitability and Blood and Blood Product Safety in Cases of Known or Suspected West Nile virus infection."

Subsequent to the 2002 mosquito transmission season, blood collection facilities have been stockpiling frozen products for use in the event of local human West Nile virus infections prior to the availability of West Nile virus screened frozen plasma this summer.

In the area of communication and information sharing, the blood banking organizations have established a task force that meets by telephone conference with the PHS agencies, FDA, CDC, NIH, in order to share the most recent epidemiologic data on West Nile virus infection and to discuss policies to reduce the risk of transfusion transmission. This task force has been meeting regularly since early May, so if you wonder what I do with my time.

Blood collection organizations have been active in disseminating information to hospital transfusion services, clinicians, and the public about the risks of acquiring West Nile virus infection via transfusion.

Materials distributed to hospitals have advised that there will remain a small risk that West Nile virus could be transmitted by transfusion in 2003; that, prior to West Nile virus donor screening, hospitals should review their current transfusion policies, and that any small risk of West Nile virus transfusion should be balanced against the benefits of the indicated transfusion.

We have been coordinating blood bank activities with the Public Health community. We have worked actively with the CDC and representatives of state health departments on several issues. A joint protocol is being developed to investigate potential cases of transfusion-transmitted West Nile virus that occur after July 1, 2003.

This protocol will involve coordinated activities conducted by local health departments, hospital transfusion services and blood collection facilities, the CDC, and blood bank organizations and laboratories; its objective is to determine if West Nile virus transfusion transmission is still occurring in 2003 despite the implementation of minipool West Nile virus NAT and enhanced donor deferral policies.

A national guidance document concerning the exchange of information between blood collection agencies and state health departments is also under development. This document is intended to serve as a template for interactions that occur on a state-by-state level.

The document addresses the anonymous reporting of West Nile viremic but clinically well donors by the blood collection facility to the health department as well as the reporting from the health department to the blood collector of a recent blood donation in a person who is ill with suspected West Nile virus illness. The latter activity is important so that untransfused potentially infectious components can be retrieved in a timely fashion.

In summary, the national blood banking organizations will continue to monitor the clinical epidemiology of West Nile virus in 2003 as well as the yield from West Nile virus donor screening. It is anticipated that measures that have been or will soon be implemented will significantly reduce the risk of acquiring West Nile virus infection through blood transfusion.

Thank you.

DR. NELSON: Thank you.

I think the NAT data on blood donors is going to be very interesting. I mean if we would predict that 500,000 people infected is 0.25 percent of the U.S. population, and 3 to 5 percent of the adult population donates blood, we may not see many, but we may, in fact, see some cases, and we may be surprised by what we see, and we may be able to actually improve the estimate of how many inapparent or subclinical infections there are with West Nile virus.

So, I think this is going to be important public health data, as well as very important in protecting transfusion recipients. I am glad that there is a system to analyze it and hopefully look at the data more carefully that we get.

DR. DiMICHELE: I was just wondering if there has been any financial analysis undertaken yet as to the implementation of this and what it is going to add to the cost of a unit of blood.

MS. GREGORY: I think we have all been so busy doing everything else, we maybe haven't gotten to that yet.

DR. STRONG: In terms of the state by state communications, I don't think we have quite worked that one out yet. How do you see this information being transferred to the state and local public health services?

MS. GREGORY: You should see that document probably Monday with a detailed explanation of how to do that. It is currently being approved by all the various organizations. There will be provision for you working it out individually in your area, so we are not trying to say everybody has to do it exactly the same way. There is going to have to be a lot of communication between you and the state health lab.

DR. SCHMIDT: That is a very large issue. I think the public is going to be dealing with monkeys and SARS and prairie dogs and this, and I think the result on what we are doing is going to grossly affect if people are going to donate blood and if people are going to receive blood, and I don't think it is something that can maybe just be taken care of by the blood bankers.

I think this is a very high level someplace. I don't know who is higher, but important public health thing that needs to be addressed. Now, we have read some information in medical journals that is kind of scary. I think everybody has to be very careful to say the truth, but to say it in such a way that it doesn't cause a national panic, and just the 500,000 data, well, that means that 500,000 units of blood are contaminated and, of course, you don't control the press, but we really need to help them out with how they do it.

I just think a statement coming from the American Association of Blood Banks, with a lot of other people, isn't going to do it.

MS. GREGORY: I think you are probably right, but we have been developing this in coordination with the CDC and with the public health labs. There have been a lot of people involved in it, it isn't just the blood banks, and believe me, we are all very much aware of that kind of concern and we have the same concern that we want to make sure we are doing the right thing, and not scaring people to death at the same time.

DR. DiMICHELE: I want to congratulate everybody involved in how quickly this has proceeded with respect to blood transfusion, but I wanted to ask what is going on with respect to surveillance for organ transplantation because West Nile was also transmitted by organ transplantation.

Earlier today, we heard animal data suggesting that other viruses, such as SARS, may actually remain in organ systems longer than animals will remain viremic, so both of those viruses are very problematic with respect to organ transplantation. I just wonder whether that is where the attention is going to be turned to next or where the FDA might go with that.

DR. EPSTEIN: FDA doesn't regulate organs for transplantation, but I know there is interest in West Nile testing.

DR. FREIBERG: My name is Glen Freiberg. I am with Gen-Probe. I would be happy to address your question.

I think Dr. Hewlett's slides touched on it, and that is that our company does plan to amend our INDs a little bit later this season to include it, and FDA already has a guidance to follow for that indication. It is just going to take a little more time to get it together.

DR. STRONG: Just to add to that, the complication really is with cadaveric samples. If we can get premortem plasma samples, they are really essentially qualified for these assay, but for a cadaveric sample, which is essentially a serum sample, which is why I asked the question earlier, and sometimes not the best condition, that requires a different set of preclinical testing to qualify them.

There is now somewhere in the neighborhood of a million tissue transplants done per year in this country, and we know that they are fully capable of transmitting viral infection. I think that is even more important.

DR. CLEMENT: Tom Clement [ph], Roche.

I would like to add to what Glen is saying. Roche is also looking at expanding or amending our IND to cover cadaver fluid and other things.

DR. NELSON: At least non-cadaveric organ donors, they have to undergo the same screening as a blood donor, right, in terms of infectious screening?

DR. STRONG: In general, that practice is followed, but as has been pointed out, it is not regulated by FDA. It's a different organization, and it is not quite as carefully regulated as blood is. Good tissue practices are now still under consideration and haven't been implemented, but should be soon.

DR. NELSON: There is also the issue of massive transfusion of a potential organ donor prior to death and a false negative test, I guess.

DR. STRONG: That's true, but everyone has pretty much implemented hemodilution algorithms to take that into account.

DR. EPSTEIN: Just to comment that with regard to tissues in general, we have a policy on human cell tissue and cell- and tissue-derived products, which calls for rulemaking in three domains - registration and listing, which is already in effect with the Final Rule, donor eligibility requirements for which there is a proposed rule, but not yet a final rule, and good tissue practices, for which there is a proposed rule, and not yet a final rule, and, of course, there will be a need for guidance documents to be finalized in conjunction with those rulemakings.

So, it is not that it is not going to be under a regulatory umbrella, however, the regulatory schema is not yet fully in place. But we do have a lot of active dialogue with various parts of the tissue industry and there is, of course, strong interest in trying to apply a suitable test, such as NAT for HIV and HCV, as well as the emerging test for West Nile.

DR. STRONG: Might I ask FDA, is the plan, once these regulations are implemented, to have that come before this advisory committee, or will it be a separate advisory committee?

DR. EPSTEIN: Well, I can't answer that at this time. To date, the issues pertinent to tissue regulation have been brought to the Blood Products Advisory Committee as a matter of convenience, although some issues have been brought to other advisory committees, for example, related issues affecting cell and gene therapy have been brought to other committees, but there has been some discussion whether another advisory committee would be needed, but I just can't say that that will happen.

DR. DiMICHELE: I have a slightly different question, and it is actually for my own edification, and maybe this was discussed in March since I wasn't here, but does anyone know why there is persistence of IgM antibodies with this virus? Is there a precedent, and what might be some of the immunological models for this?

DR. NELSON: I think IgM persists in brucellosis for quite a while, for over a year, and there are other infections where this happens, although it is usually a marker of a recent and an early primary immune response.

DR. GOLDSMITH: I think it depends on the antigen, and I think there is actually a pattern, and it relates to the ability of the antigen to stimulate B cells in a T-independent fashion, and that in various infections, you do get persistence of IgM for very long periods of time. Brucellosis is a good example.

DR. BIANCO: The other example is pneumococcal polysaccharides. Actually, there is no IgG formation in many of these, of some of the complex polysaccharides when they are injected, and it is just IgM that stays there. The antigen is retained in macrophages and probably released in very small amounts, and you don't see the switch.

DR. STRONG: Just as a follow-up to that, in that case, for example, that is a direct B-cell mitogen, and I suspect that some of the fragments of this virus probably are acting the same way.

DR. SCHMIDT: A comment on a different subject. The reason that the blood industry, if you want to call it that, survived HIV is that in states, we have something called blood shield laws which protect blood transfusion against implied warranty, and they came out as a result of hepatitis, that having a virus in a bottle at that time of blood was different from having a mouse head in your Coke can, which was bad under state laws.

DR. NELSON: Probably safer.

DR. SCHMIDT: Well, for example, the Florida law says that if you do whatever is current scientific knowledge, you have done the best you can.

Now, one of the problems with HIV was there was this great discussion of surrogate tests. Before there was a specific test for HIV, there were surrogate tests, and a lot of trial lawyers really worked this over very well, and there were very few, if any, successes. Jim, you may remember that better than I would.

But all the state laws are a little different. I am just thinking that there is some question which I guess potentially could be raised about having to do a test under an IND versus a licensed test, and I don't think it relates to the work of this panel, but it is something that sometimes the Federal Government doesn't think about these idiosyncrasies of state laws where you end up doing things to prevent yourself from getting sued even if you are all right under the law.

But it could happen again in some way or form or other because trial lawyers and defense lawyers can come up with all sorts of things.

DR. NELSON: Mary Gustafson from Plasma Protein Therapeutics Association, PPTA.

MS. GUSTAFSON: The Plasma Protein Therapeutics Association appreciates the opportunity to provide comment to the BPAC on the issue of West Nile virus.

PPTA is the international trade association and standard-setting organization for the world's major producers of plasma-derived and recombinant analogue therapies. Our members provide 60 percent of the world's needs for source plasma and protein therapies.

These include clotting therapies for individuals with bleeding disorders, immunoglobulins to treat a complex of diseases in persons with immune deficiencies, therapies for individuals who have alpha-1 antitrypsin deficiency, albumin, which is used in emergency room settings to treat individuals with shock, trauma, and burns, among other things.

PPTA members are committed to assuring the safety and availability of these medically needed life-sustaining therapies for people who depend on them.

At the March BPAC, this committee voted on two questions that affect the plasma-derived therapeutics industry. Those questions involved the need to use specific West Nile virus and viral inactivation studies and use of plasma donor testing to provide an added measure of safety for West Nile virus.

In response to these recommendations, PPTA requested a meeting with FDA to discuss technical issues. On April 29th, PPTA staff and members of the plasma therapeutics industry met with FDA.

For one, we presented data packages to FDA that provided data that supported the summary information presented to the committee at the BPAC.

In addition, PPTA presented a three-part approach to addressing the West Nile virus issue. The PPTA proposal includes using risk assessment--and this is assessment of relevant epidemiological factors--and worst case challenge to plasma therapies. We used the best available data at the time, and truly used worst case, and one of our member companies called it "a hurricane during an earthquake situation."

Also, use of verification studies, and these would include studies demonstrating efficacy of virus reduction with model and relevant viruses, donor screening and surveillance in terms of continued surveillance of the West Nile virus epidemic and sentinel parameters for evaluating industry actions using the blood screening as a public health sentinel system for the disease.

FDA did not say that they agreed with the three-part approach, however, they provided feedback that was consistent with this approach. For one, they said the risk assessment could be improved by having more data, that the data so far on donor titers and pool titers was somewhat soft.

Also, in terms of verification studies, FDA would like to see two independent process steps each having a 4 log or greater reduction in virus.

Currently, PPTA member companies are completing its risk assessment by evaluating West Nile virus titers in plasma pools containing plasma collected during the height of the 2002 epidemic, and initiating plans to participate in surveillance of blood donors during the 2003 season in terms of looking at titer information and hopefully, duration of viremia.

These studies are in addition to studies conducted using relevant and model viruses to verify that current plasma fractionation processes are effective in inactivating West Nile virus.

In conclusion, the plasma therapeutics industry works diligently to keep our therapies safe. We look forward to continuing our dialogue with FDA regarding the safety of our products with respect to West Nile virus.

DR. NELSON: Thank you.

Questions? Yes.

DR. STRONG: You will be testing, correct, the plasma pools?

MS. GUSTAFSON: Yes. Member companies are going back and looking at plasma pools from plasma collected primarily during the first three weeks of September of last year.

DR. STRONG: Are you doing pool testing, what pool size?

MS. GUSTAFSON: That is testing the plasma pools that were used for fractionation.

DR. STRONG: I was talking about screening tests as the tests become available. Generally, your pool sizes have been larger than--

MS. GUSTAFSON: That is why our approach for this season is to kind of piggyback with existing studies in blood donors using the smaller pools, because you are right, the current technology for testing plasma donors are 512 pool.

DR. NELSON: So, you will test with smaller pools?

MS. GUSTAFSON: At the present time, what we are going to have, what we have initiated discussions, is to look at the testing that is being done in blood donors to provide an indicator of the degree of positivity, the titers, and hopefully, the duration of viremia.

DR. NELSON: It could provide some valuable data, I think.

DR. EPSTEIN: Could you just clarify, Mary, what I hear you saying is that there is no plan to prospectively screen source plasma donors, however, you will be cooperating in obtaining surveillance donors, the surveillance data as whole blood donors are screened, is that a correct statement?

MS. GUSTAFSON: That is a correct statement.

DR. NELSON: Miriam O'Day from the Immune Deficiency Foundation.

MS. O'DAY: Thank you very much. Good afternoon. I am Miriam O'Day. I am giving a statement today on behalf of the Immune Deficiency Foundation.

The statement is titled, "Forging an Effective and Practical Process to Ensure the Safety of the Nation's Blood Supply: A Rational Approach of Emerging Agents."

The nation's blood supply is a lifesaving resource for patients in need of the cellular components and/or plasma proteins of blood, however, the potential for inadvertent viral transmission with the use of blood and its components continues to be an area of significant concern for those receiving and those administering these therapies.

Agents known to be transmissible by blood are screened for in prospective donors and/or in the donations themselves. Traditional serological testing has been supplemented by the use of NAT testing for several pathogens.

Currently, as new bloodborne pathogens are identified, tests are developed and applied to reduce the risk of transmission. The addition of these new tests may add to the safety of blood and plasma, however, the new tests add cost to the production of blood and blood derivatives. These incremental costs may ultimately negatively impact the supply of blood derivatives as manufacturers assess the financial viability of producing these lifesaving therapies.

Rising costs may also impede patient access to care as reimbursement is adversely affected. Using the plasma derivatives as a model, there may be a new approach that assures safety regarding an emerging agent, while keeping new screening costs in check.

Plasma derivatives are produced by Cohn-Oncley fractionation or modification. The use of alcohol in the process can inactivate viral agents. The separation process itself can also partition potential pathogens away from the desired plasma proteins.

Manufacturers have also implemented dedicated viral removal and inactivation techniques including enzyme treatment, pasteurization, solvent detergent treatments, nanofiltration, et cetera. These methods have been validated using laboratory-adapted model viruses and human pathogens that permit assessment of several steps in the manufacturing process.

The testing of model viruses can create a level of assurance if a new agent with certain viral features emerges, such as a lipid envelope RNA virus.

We recommend that the following algorithm be assessed on a demonstration basis to determine if it is a rational approach to test for emerging agents in plasma derivatives, and there are six steps.

The first step is identification of a new agent potentially transmissible by blood.

Second is epidemiologic and field assessment of cases to determine the risk of blood transmission and the viral life cycle features included in the viral load.

Third is implementation of additional donor screening measures or enhancement or reemphasis of current measures to exclude potentially infectious donors.

Fourth is development of tests, including NAT-based tests, to screen blood and plasma units.

Fifth is testing of viral inactivation removal techniques on a case-by-case basis, manufacturer-by-manufacturer basis to determine efficacy against the emerging agent.

Sixth, if viral inactivation removal techniques are shown to be robust, and the viral load known to be 4 to 6 logs less than the capacity of one step or the cumulative reduction of the entire process, then, NAT testing of units or pools can be abandoned or perhaps never initiated.

The recent identification of the West Nile virus seems to fit this algorithm and would be an excellent test for this new approach. Specifically, West Nile virus is transmitted by blood and can cause morbidity and mortality in recipients especially those who are immune-suppressed, therefore, it is a potential threat to those with primary immune deficiency diseases who use plasma derivatives, such as IGIV.

Plasma screening with NAT can eliminate some infectious units, however, the known level of viremia, as we have heard here many times today, is low and would be rendered noninfectious by dedicated viral inactivation technologies.

It is incumbent on the manufacturers to demonstrate the robustness of their technologies and for he regulatory authorities to review and approve the steps that have been chosen.

The Foundation looks forward to further discussions on this important topic and to the continued improvements to blood and blood safety and product availability.

Thank you.

DR. NELSON: Thank you.

Questions or comments?

Are there any other questions of the panel about where we are with West Nile virus? Harvey.

DR. KLEIN: I don't have a question, but is this the time for general discussion?

DR. NELSON: Yes, that is where we are.

Committee Discussion

DR. KLEIN: Since this is an advisory committee, we haven't done too much advising today--

DR. NELSON: We have been advised.

DR. KLEIN: We have been advised. I am still very much concerned about this issue of IRBs especially when a national IRB has already approved this IND, and the issue of donor consent and whether some of these features of the research process are somehow going to disturb the possibility of preventing infectious transmission by blood.

So, I would like to propose that this committee advise the FDA to use whatever mechanisms are available within its authority to encourage universal adoption of West Nile virus testing of all blood components collected in the U.S. for transfusion by July of 2003.

DR. ALLEN: Are you making that as a motion?

DR. KLEIN: Yes, I am.

DR. ALLEN: I second it.

DR. NELSON: I, too, are concerned about the IRB issue and I don't know to what extent this issue has or could delay a public health issue or implementation. I know I have had a personal experience with it, with a student who wanted to do some research on hepatitis C virus epidemiology among prisoners and using anonymous specimens to try to define the epidemiology, and that got through two IRBs, one IRB refused to approve it only because it was prisoners, but prisoners were the people that were at highest risk, and they not only had a high risk of infection, but also there was transmission and treatment possibilities for them, which were not being implemented.

So, they suffered because of an IRB decision, and I think that there are other examples where an IRB, in its important role to protect research subjects, has, in fact, harmed either the research subjects or other populations or misunderstood the issues.

I see the possibility of that happening here although I hope this is not a real issue, but I certainly agree we could, as a sense of this advisory committee, give this advice to the FDA even though it wasn't sought, but we could still give it.

DR. ALLEN: I think I would add to what you just said, that even if it does not result in delay or obstruction of getting things done, that it certainly requires additional time and resources, and in this instance, I can't think of a single reason in which it would protect, a single way in which it would protect people, you know, the donor population, further by going through multiple review at every single different site that might possibly be affected.

It seems to me that we need to look at marshaling our resources effectively as long as people are adequately protected, and I think they are.

DR. NELSON: It could well be that an administrative or legal counsel for, let's say, a hospital or university hospital or something might give advice that if they allowed the IRB to delay implementation and during that time there was transmission at the hospital, the Transfusion Service and everybody connected with it would, and should be, legally liable if there was a test that could have prevented it.

I hope that won't happen, but I think it probably would be useful for this committee to vote on this proposition.

DR. NELSON: Jay.

DR. EPSTEIN: I would just comment, I mean, of course, if the committee wants to make a recommendation, that's fine, but the FDA is aware of this issue, and we are working with the Office of the Chief Counsel to clarify the legal situation as it pertains both to the requirement or non-requirement for IRB approvals and whatever authority we might be able to exercise.

As I said earlier, I don't believe we have the direct authority to require the West Nile virus test even if it were approved, because that requires rulemaking. It would be highly unusual for us to issue a recommendation calling for the use of an unapproved test. I think that that would be a watershed event within the FDA, I see that as most unlikely.

On the other hand, we can take steps to encourage and facilitate widespread use. The mere fact that we have worked cooperatively with the industry to enable large-scale testing, indeed, national scale testing is proactive and is an effort to have testing done everywhere.

Short of requiring it, we have some ability to work with IRBs and clarify their concerns in exercising their role in approving investigational studies, and I would just comment in that area that I think the situation for the donor and therefore the IRB approval for the screening of the donor, is quite different than the situation for the recipient, whether or not there is a need for an IRB to approve use of a product that has been West Nile screened. That is far less clear than whether you need to have a consented donor.

So, we are aware of these issues and I think, as I said before, FDA's point of view is that we can accept umbrella or national IRBs, we are not the ones requiring that each and every local site have an IRB approval. I am not sure that there is any authority for us to prevent that if that is the desire locally, and we are working with larger national operating IRBs to clarify why they think they need to ask for local approvals.

So, there are these several situations, the dialogue with the national IRB, the dialogue with the IND holders, the dialogue with hospitals, and then there is this issue of authorities, but I think that is pretty much off the table, but, you know, never say never, but it would require some radically different regulatory thinking.

DR. NELSON: I am not exactly sure what the exact specifications are, but there are, it seems to me, situations in which the public health threat or issue outweighs the authority of a local IRB to make an independent judgment.

Certainly, in the context of a public health threat, there can be actions taken that are not subject to review and approval by an IRB.

DR. DiMICHELE: On the other hand, my understanding is that this assay is just being validated, I mean this assay is in the process of being validated. I am not exactly sure how the study reads and what is being submitted to the IRB, but, for instance, is there donor notification on the basis of these results, because I mean certainly there needs to be some organized study and validation of a test if there is going to be any kind of donor notification.

I mean I don't know that you can get around this. I mean I think it has been already fast-tracked and, you know, a season of validating the assay, especially if you have got to get back to donors and counsel them on that basis, it seems entirely appropriate to me.

DR. DOPPELT: I was just going to say that I believe most IRBs have a process for an expedited review, and if the FDA is encouraging people to use this, that alone may be enough to push the IRBs to review this quickly since really the risk is virtually nonexistent.

DR. NELSON: Also, most IRBs have the authority to accept the judgment of another IRB, and so I hope it won't be necessary for each IRB to review this. I guess the issue is that even though a national or local IRB can say that they want to review it, but hopefully, that won't happen or won't happen very often.

DR. SCHMIDT: I support what Harvey is saying and that is really why I brought up this other issue of state laws and how they affect what happens locally and sometimes the Federal Government forgets about that, but to carry it a little further and say yes, of course, Jay, but if this really is called an advisory panel, are we allowed to make unsolicited advice?

DR. NELSON: Well, I think we are, and whether we are or not, I suspect that we will.

DR. HEATON: I wanted to make the point that this isn't an issue of IRB approval or lack thereof. We have a good IRB, it has approved the protocol, and it does have appropriate jurisdiction. The issue is that the Central IRB, the Western IRB is nervous that it put a caveat into its approval, that local IRB approval would be necessary.

Now, with the HIV/HCV assay, which we introduced somewhat similarly, the Western IRB was prepared to accept verbal assurances that where a local IRB wishes and had jurisdiction, that we would get such IRB approval.

So, if, for example, the Blood Centers of the Pacific had a local IRB, it would get approval of those in order to implement the test, but it did not require, the Western IRB at that time did not require in writing or issue a caveat that wherever you collected a donor, you had to get IRB approval. At that time, it only focused on whether you could implement testing, IOU testing.

So, the issue here isn't so much that we don't have an IRB and an IRB approval, it's this requirement that we contact an IRB where you collect a donor, that is not the standard of practice and I believe that if the agencies supplied either a statement or enforcement discretion statement to the Western IRB, they probably would remit that requirement, and we could proceed as we did for HIV and HCV, but I do believe that some form of statement will be necessary for the Western IRB, otherwise, they are going to sit on their hands and point to this regulation that they believe compels them to require this caveat.

MS. ROSSMAN: Susan Rossman [ph], Gulf Coast Regional Blood Center in Houston.

I just wanted to say we just went live with this and our IRB, we do have an IRB at our blood center which approved it. We also do testing for about eight other collection facilities, either other blood centers or hospital collection facilities. We got IRB approval from all of these. Some of them allowed us to go ahead with just our IRB approval, some of them went to their own IRBs, in many cases an expedited review.

The concern is exactly what some members mentioned, which is donor not protesting itself, I don't think, that's of no harm, but of donor notification, exactly what you tell the donor, and the involvement of the donor in the enrollment for follow-up studies, which are clearly going to be important for this test to be validated and approved, and a secondary concern is also the retention of specimens for future testing, which is frequently a concern of IRBs at this time.

But we didn't find it particularly onerous, but it is difficult, you do have a number of steps if you are collecting for various centers, and they make their own choice about whether to take your IRB or another one.

DR. BIANCO: Just I think another comment to clarify, I will say it instead of a British accent, I will have a Brazilian accent.

The issue that is concerning about the Western IRB approval, is that blood centers will run multiple drives every day, in multiple sites, with different hospitals, universities, schools and institutions that may have an IRB. Blood centers are not even aware if those institutions have an IRB.

Those drives are organized and you get there, and the only thing that the blood center is utilizing in the space, is the cover on top, the electricity, and the space, and the donors come to this drive. All the responsibility, all the staff, all the informed consent, all the questionnaires and everything, the PIs are the blood center, associated with the blood center, not with that institution, there is no actual connection, so even if that would be legally required for space rental that you have an IRB approval.

DR. DiMICHELE: Doesn't it depend on who is doing the donor notification? You may not need all these little IRB approvals if you are the one, if the blood center is the one that is doing all the collection, the testing, and then the donor notification.

DR. BIANCO: That is correct, Donna, exactly that, that is absolutely correct. The issue was raised, that was raised with Western IRB, as some of the principal investigators discussed it with them, us that they received in the past, with the HIV/HCV implementation, complaints about some of the local IRBs, that people were not asking for their approval under exactly the same circumstances, so there is a little bit of this local power versus national power, and all that.

But in a situation like that, it should not delay implementation of the test.

DR. FALLAT: I would like to get a sense from Jay as to how long he thinks it would take, assuming we have an epidemic this year equal to last year or greater than last year, how long will it take do you anticipate to have approval and to go through those rule changes.

DR. EPSTEIN: I think that, as Jim said earlier, you know, we don't have to wait for the rulemaking. Once we approve a test, we will recommend it. The industry is very likely to implement an approved test once recommended, and rulemaking will come later.

I don't think that the rulemaking is the issue that will resolve the IRB question. I think that sort of has a separate life than what would it take to get to a required West Nile test.

Again, you know, we all think that we need to have a West Nile test in 03, but requiring it is a little bit more tricky, because we don't know what is going to happen in 04, 05, 06. We don't know whether West Nile is here to day or whether it will burn out and appear more like St. Louis encephalitis.

So, I don't know what the logic will be about requiring it, and we will have that debate, but for now we know we need it, and for now our mind-set is very much to remove any obstacles to making it available.

I think we hear the concern of the committee whether you vote on a recommendation or not, you know, we are here and we hear you, and we are reviewing the legal issues with the Office of Chief Counsel, so I think that is about as far as I could go today.

DR. FREIBERG: Thank you. I wanted to make a suggestion or two about panel operations that hopefully will help you. I heard earlier the start of a motion. I was thrilled to hear it. I also heard a comment about unsolicited advice.

My suggestion is finish the motion, finish the vote, and be very specific about asking FDA to use their enforcement or discretion and tell the Western IRB how they feel about it. We are not requiring the test, we are trying to allow the IRB system to work a little smoother.

Similarly, you talked a little bit about the 10-minute hold. You could also make a motion and a specific recommendation to FDA. You all felt strongly about it, but there was no formal recommendation.

If there is a new product coming down the line you think should come before this panel, make a formal motion and recommendation. If Dr. Epstein or FDA doesn't like it, you can rely on them to get up and help guide you, but I would just suggest formalize your recommendations, please.

DR. NELSON: Well, that is what we plan to do. Could you restate your motion?

DR. KLEIN: Yes, and I would point out, Jay, I worded this, so that it doesn't ask that you require anything or that you rule-make or anything else, so let me just read this again. If there is something in the wording that someone feels is inappropriate, then, let's change it.

The committee advises the FDA to use whatever mechanisms are available within its authority to encourage universal adoption of West Nile virus testing for all blood components collected in the United States for transfusion by July of 2003.

DR. NELSON: That sounds pretty good to me.

DR. STRONG: The only caveat to that I would suggest is that there are reasons why we operate under INDs, and that is with a new test. We are making the assumption that it works well and we don't run failures and false positives, and that sort of thing, so I think we do have to consider that we are making the assumption with that recommendation that these tests are working well.

DR. KLEIN: I agree with you, Mike, 100 percent. It just seems to me that I find it very difficult to sit here, see the data on the epidemic, see the scientific data on the test, and say, gee, if someone doesn't feel they ought to use it in July of this year when we see the epidemic coming in August, that's okay. It wouldn't be okay for me if I were a patient or if it was one of my patients in the hospital.

DR. STRONG: I don't disagree with that, I am just saying that the preclinicals look great, the studies that have been done thus far look great, but we haven't put it through its final test, which is putting 50,000 units a day through these things.

DR. SCHMIDT: Harvey, that is exactly the argument that the CDC used as to why surrogate testing should be done for HIV.

DR. ALLEN: Correction, the CDC never required, never recommended for it. There were individuals who did, but the CDC never took that posture.

DR. SCHMIDT: Thank you. I accept that.

DR. KLEIN: Paul, in all due respect, I don't think that there was a specific assay that appears to test for fewer than 100 copies. I think we are talking about apples and oranges here.

Regardless of the fact that the test is in IND, hasn't been licensed, hasn't been totally validated as a screening test because that is why we are doing this, I think we have enough confidence with what we know to say that it would probably not be a reasonable thing to give untested blood when you have the capability of using this particular assay.

The worst that can happen in my mind is that you might toss out a couple of units that weren't positive.

DR. DOPPELT: I would like to know what has to be done to validate the test in cadaveric samples, and although it is not an approved test, would it be available to tissue bankers to use, as well.

DR. NELSON: Do you want to answer that?

DR. STRONG: Those studies are ongoing actually and for all of the NAT assays. West Nile virus is still new enough that studies haven't been implemented yet, but there are reasons why they need to go through a different process, and I guess I could give you the details later.

DR. GOLDSMITH: Just to add one more voice. Although I personally don't see any real urgency to test source plasma that is used for further production and undergoes manufacturing conditions for West Nile virus, we certainly would think that there ought to be the earliest possible implementation and widest possible application of this IND for the cellular components of blood.

So, I think there are two paths here, I just want to say that again, and hopefully, both paths can be recognized at the end of the day, so that we have the safest and most available blood supply.

DR. NELSON: Dr. Smallwood has copied your motion and will project it. I like the wording.

DR. KLEIN: It is not exactly what I said. I did say whatever mechanisms within its authority, and I said for testing of all blood components, so that might specifically exclude plasma that is collected for fractionation of source plasma.

DR. NELSON: You say "collected for transfusion," does that mean--

DR. KLEIN: Blood components collected for transfusion.

DR. NELSON: Okay.

DR. KLEIN: So, that specifically refers to cellular components and fresh frozen plasma made from whole blood.

DR. NELSON: And platelets.

DR. STRONG: Could I offer a friendly amendment?

DR. NELSON: Sure.

DR. STRONG: I think it's investigational testing, it's not a licensed test, using an investigational.

DR. KLEIN: I would certainly accept that myself.

DR. FITZPATRICK: When you say July, are you meaning July 1st, Harvey?

DR. KLEIN: Looking at the data from the CDC and knowing that we have four or five weeks, we think, and knowing that there may not be availability of tests for the entire country, I didn't want to specify it more tightly than July.

DR. NELSON: You wanted to say investigational testing of blood components? Does anybody want to comment?

Yes.

MS. FORD: Kendra Ford with the Oklahoma Blood Institute.

I read the Western IRB comments that came back out and I think the issue is, is do we need to seek IRB approval from all the locations that we draw the blood donors at. We have previously not done that. We have gone to lots of hospitals, other businesses that have IRBs. We have never historically sought their approval to draw the donor, and we, as the blood center, are in complete control of the process, donor notification, and all of that.

The issue is drawing blood, not testing. That's brand-new language that came out. Whether it should or shouldn't be there, that is the concern. If one body starts doing it, we all then kind of need to do it, and we have not done that at all in the past, right or wrong.

DR. NELSON: Any discussion? Do you want to vote on this? Do you want it hand or roll call? Roll call, okay.

Jay.

DR. EPSTEIN: Two comments, one on the draft motion. I think rather than saying by July of 2003, it would be better to say as soon as feasible, because we don't quite know how kit availability will play out, nor do we really know how the IRB issue will play out.

Just as an aside, I mean FDA has expressed its willingness and interest to engage Western IRB in a dialogue to clarify why Western IRB believes that there is a need for local IRB approvals for points of collection, and as I said earlier, we are also, at the same time, researching the legal situation.

It is my expectation that we will get over this bump in the road. Again, I don't object to the recommendation should it be voted on by the committee, but we are engaged.

DR. NELSON: But I think the issue is that this committee feels that the Western IRBs' approval is sufficient to cover the research subjects' issues related to this and therefore, that we don't, you know, we don't want to negate the role of local IRBs, and if everybody can approve it within the next--what is today--the next two weeks, that's fine, but maybe as soon as possible is okay.

I mean obviously, it says the FDA is supposed to encourage, it doesn't say that the testing has to be done by July, if it's not available.

DR. KLEIN: I think that was the point. I know that you are engaged and perhaps a strong statement from this committee might help you to make a strong statement or help your lawyers understand that you need to make a strong statement.

Again, I think having seen the epidemiologic data that suggests that July is the right time, now, if it is not possible to do, that is still the advice of this committee, I hope.

DR. NELSON: Advice has not been followed in the past, and it probably won't be in the future.

Why don't we just vote.

DR. KLEIN: The only additional was investigational, which had been suggested by Dr. Strong, and had been accepted by the proposer.

DR. SMALLWOOD: I will read the question as stated. Dr. Klein proposes that this committee advise the FDA to use whatever mechanisms are available within its authority to encourage universal adoption of investigational testing of all blood components collected in the U.S. for transfusion by July of 2003.

DR. SCHMIDT: Would the proposer be willing to change that to just say the committee advises? I mean the proposal business is over, and the motion would be the committee advises.

DR. KLEIN: Yes.

DR. SMALLWOOD: The correction is, The committee advises the FDA to use whatever mechanisms are available within its authority to encourage universal adoption of investigational testing of all blood components collected in the U.S. for transfusion by July of 2003.

DR. DOPPELT: One other question in regards to the suggestion of "as soon as feasible" rather than July, because you don't know about the availability of the test. I mean either way you want it as soon as possible.

DR. KLEIN: I understand that, but I think that since we have some data suggesting when we are likely to see the real impact of the epidemic this year, that I think we need to advise them that July is the time, and if that can't be done, it can't be done for whatever reason, but I think to say "as soon as feasible," to me, is not being as specific as the data suggest we ought to be.

DR. NELSON: Yes, and for local IRBs, that don't want to meet during the summertime or something like that, and don't want to discuss this issue, as soon as feasible to them might be December. So, I think I would agree with leaving July in there. If they want to review it, fine, but they have to do it by July. Well, we advise that the decisions, whatever roadblocks be dealt with by July.

DR. SMALLWOOD: The vote of the committee will be taken by roll call.

Dr. McGee.

DR. McGEE: Aye.

DR. SMALLWOOD: Dr. Klein.

DR. KLEIN: Yes.

DR. SMALLWOOD: Dr. Allen.

DR. ALLEN: Yes.

DR. SMALLWOOD: Dr. DiMichele.

DR. DiMICHELE: Yes.

DR. SMALLWOOD: Dr. Fitzpatrick.

DR. FITZPATRICK: Yes.

DR. SMALLWOOD: Dr. Nelson.

DR. NELSON: Yes.

DR. SMALLWOOD: Dr. Goldsmith.

DR. GOLDSMITH: Yes.

DR. SMALLWOOD: Dr. Cunningham-Rundles.

DR. CUNNINGHAM-RUNDLES: Yes.

DR. SMALLWOOD: Dr. Davis.

DR. DAVIS: Yes.

DR. SMALLWOOD: Dr. Doppelt.

DR. DOPPELT: Yes.

DR. SMALLWOOD: Dr. Fallat.

DR. FALLAT: Yes.

DR. SMALLWOOD: Dr. Schmidt.

DR. SCHMIDT: Yes.

DR. SMALLWOOD: Dr. Strong, how would you have voted if you could?

DR. STRONG: Yes.

DR. SMALLWOOD: The vote is unanimous in support of the proposal.

DR. NELSON: So, we did actually advise the FDA today. That's good.

I guess we are adjourned until tomorrow morning. One comment?

DR. ALLEN: Yes, and I had thought that perhaps for the first time since I have been on the committee that we would actually adjourn within the time frame. Some of us, this is a wonderful committee in terms of its diversity of background, and that also means, however, that not all of us are expert in every area.

I personally, not being a laboratorian or specially trained in laboratory science, find myself technologically challenged with the concepts and the terminology including all of the acronyms used for these tests, and I would request that the Executive Secretary consider either providing background information on laboratory testing procedures to the committee, or perhaps our having a background session at a future meeting just to provide some background information on testing procedures, terminology, and so on, to enable us to respond to the information better.

DR. FITZPATRICK: Beyond that, I might recommend that at some point, the FDA and the members of the committee actually visit a blood center.

DR. ALLEN: Yes, a blood center and a processing laboratory, I absolutely concur. I think that would be wonderful.

[Whereupon, the meeting was recessed at 4:45 p.m., to reconvene the following day, Friday, June 20, 2003, at 8:30 a.m.]

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