UNITED STATES OF AMERICA

P-R-O-C-E-E-D-I-N-G-S

8:35 a.m.

CHAIR SIEGAL: Good morning and welcome to BPAC. We have a number of new members to welcome. Over the last two days some of us had the opportunity to revisit the issue of hemoglobin-based oxygen carriers at a fascinating meeting that was co-sponsored by CBER and NHLBI, and I personally look forward to a slightly less contentious meeting today, but, anyway, welcome.

I'd like to welcome the new members, Dr. Katherine McComas from Cornell; Dr. Rentas from Walter Reed; Dr. Troxel from the University of Pennsylvania; Dr. Ann Zimrin also from the University of Maryland; and Don Trunkey, who won't be here, from Oregon Health and Science University.

In addition, we have several temporary voting members. I'd like to welcome back Dr. Irma Szymanski and Tom Fleming, who've been here many times before. And Tom Atkinson of the University of Alabama at Birmingham; Dr. Andrea Apter, University of Pennsylvania; Larry Borish, University of Virginia; and Gail Macik, also from the University of Virginia who are temporary voting members.

I hope I haven't left anybody out. We'll go around the room and introduce ourselves. I'm Fred Siegal. I'm, obviously, the chair. I'm a clinical immunologist with a background in immunodeficiency diseases in AIDS, and I'm particularly interested in mechanisms of immune deficiency, particularly cellular.

To my right, Don, want to introduce yourself?

MR. JEHN: Yes. I'm Don Jehn, the designated federal official for the Blood Products Advisory Committee.

CHAIR SIEGAL: Dr. Macik?

DR. MACIK: Good morning. I'm Gail Macik, or Mah-chik is the correct pronunciation actually from the University of Virginia. I'm a hematologist.

DR. SZYMANSKI: Hi. I'm Dr. Irma Szymanski, currently at Boston University.

DR. FLEMING: Thomas Fleming, Department of Biostatistics, University of Washington.

DR. KULKARNI: Roshni Kulkarni, pediatric hematologist from Michigan State University and also currently Director of Division of Blood Disorders at the CDC.

DR. McCOMAS: Katherine McComas from the Department of Communication at Cornell University and a specialist in risk communication.

DR. RENTAS: Frank Rentas, the Chief of Blood Services at Walter Reed Army Medical Center in Washington, D.C.

DR. TROXEL: Andrea Troxel from the Department of Biostatistics at the University of Pennsylvania.

DR. ZIMRIN: Ann Zimrin, hematology/oncology, University of Maryland.

MS. BAKER: Judith Baker, Federal Hemophilia Treatment Centers, Region Nine, based at UCLA, Los Angeles.

DR. KATZ: Louis Katz, Mississippi Valley Regional Blood Center.

DR. KUEHNERT: Matt Kuehnert, I'm the Director of the Office of Blood, Organ and Other Tissue Safety at CDC.

DR. GLYNN: Simone Glynn, NHLBI.

DR. FINNEGAN: Maureen Finnegan, orthopaedic surgeon, U.T. Southwestern in Parkland.

DR. BISCEGLIE: Adrian Bisceglie, I'm a hematologist at St. Louis University.

DR. CRYER: Gill Cryer, Department of Surgery, UCLA in Los Angeles.

DR. BALLOW: I'm Mark Ballow, allergy immunology, SUNY, Buffalo.

CHAIR SIEGAL: Thank you, everybody. Mr. Jehn, do you have some announcements?

MR. JEHN: Yes. I wanted to welcome everybody again, and this is the 91^st meeting of the Blood Products Advisory Committee. I have the conflict of interest statement to read today. It's rather lengthy, so bear with me.

The Food and Drug Administration is convening the May 1-2, 2008, meeting of the Blood Products Advisory Committee under the authority of the Federal Advisory Committee Act, FACA, of 1972. With the exception of the industry representative, all participants of the committee are special government employees or regular federal employees from other agencies and are subject to the federal conflict of interest laws and regulations.

The following information on the status of this advisory committee's compliance with federal ethics and conflict of interest laws including, but not limited to, 18 U.S. Code, Section 208 and 712 of the Federal Food and Drug Cosmetic Act are being provided to participants at this meeting and to the public. FDA has determined that all members of the advisory committee are in compliance with federal ethics and conflicts of interest laws.

Under 18 U.S. Code 208, Congress has authorized FDA to grant waivers to special government employees and regular government employees who have financial conflicts when it is determined that the agency's need for a particular individual's service outweighs his or her potential conflict of interest.

Under 712 of the Food and Drug and Cosmetic Act, Congress has authorized FDA to grant waivers to special government employees and regular government employees with potential financial conflicts when necessary to afford the committee their essential expertise.

Related to the discussions at this meeting, members and consultants of this committee have been screened for potential financial conflicts of interest of their own, as well as those imputed to them, including those of their spouses and minor children, and for the purposes of 18 U.S. Code 208, their employers. These interests may include investments, consulting, expert witness testimony, contract and grants, CRADAs, teaching, speaking, writing, patents and royalties, and primary employment.

The committee will discuss the Biomedical Excellence for Safer Transfusion, BEST, committee report on blood cell recovery. This is a particular matter of general applicability, Topic 1. For Topic 2, the committee will discuss, review and make recommendations on Lev Pharmaceuticals, Incorporated clinical trial for the use of plasma drive C1S trace inhibitors, Cinryze, for the prophylaxis of hereditary angioedema attacks. This is a particular matter involving specific parties' product discussion.

For Topic 3, the committee will hear an overview of the research programs in the laboratory of hepatitis and related emerging agents, division of emerging and transfusion transmitted diseases. There is no conflict of interest involved with this overview.

In addition, the committee will hear updates and informational presentations on several topics. There is no conflict of interest involved with these informational updates.

Based on the agenda and all financial interest reported by members and consultants, conflict of interest waivers have been issued to Dr. Ballow in accordance with 18 U.S. Code 208, Section 3 and 712 of the Food and Drug and Cosmetic Act. Dr. Ballow's waivers include a consulting arrangement with the firm that could be affected by the committee's discussion of Topic 2. The waivers allow Dr. Ballow to participate fully and vote on the committee discussion.

FDA's reason for issuing waivers are described in the waivers documents, which are posted on FDA's website at www.fda.gov OHRMS dockets default at HTM. Copies of the written waivers may obtain by submitting a written request to the agency's Freedom of Information Office, Room 6-30 of the Parklawn Building, Rockville, Maryland.

With regard to FDA's guest speakers, the agency has determined that the information being provided is essential. The following information is being made public to allow the audience to objectively evaluate any presentation and/or comments.

For Topic 1, Dr. Larry Dumont was formerly employed by Gambro BCT, Incorporated, where he was the project leader for 7-day platelets and the PASSPORT study. In addition, he is the co-leader of the clinical studies team and a member of the executive committee for the BEST collaborative. He is also a consultant for and receives research support from several firms that could be affected by the committee discussions.

Dr. Louis Katz is serving at the industry representative, acting on behalf of all related industry, and is employed by the Mississippi Valley Regional Blood Center. In addition, Dr. Katz is employed part time with the Scott County Health Department, Iowa, and the Genesis Health System in Davenport. Dr. Katz is a member of and chair of various committees with the American Blood Center and the American Association of Blood Banks. Industry representatives are not special government employees and do not vote.

This conflict of interest statement will be available for review at the registration table. We would like to remind members, consultants, and participants that if discussions involve any other products or firms not already on the agenda for which an FDA participant has a personal or imputed financial interest, the participant's need to exclude themselves from such involvement and their exclusion will be noted for the record.

FDA encourages all other participants to advise the committee of any financial relationships that you have with a sponsor, its product, and, if known, its direct competitors. Thank you.

I now turn over to the Chair.

CHAIR SIEGAL: Thank you, Mr. Jehn.

We have a number of updates today and Don's already mentioned all of them in passing, so we might as well get started directly. I've been asked to point out that committee members are encouraged to ask questions between and after each presentation.

So we'll start with Jerry Holmberg, Ph.D., Executive Secretary of the Advisory Committee on Blood Safety and Availability, who's going to talk about the August '07 and January '08 meetings of the DHHS Advisory Committee on Blood Safety and Availability. Dr. Holmberg.

DR. HOLMBERG: Good morning. Welcome to those people returning to the BPAC and also welcome to the new members of the Blood Products Advisory Committee.

What I would like to do is to give a quick overview of some of the last two recommendations, meeting recommendations, for the Advisory Committee for some of you that are new to the BPAC. The Advisory Committee on Blood Safety and Availability is an advisory committee at the secretarial level. It has the responsibility to look at various issues, including safety and availability, but also transfusion and transplantation safety.

Since our last meeting we've had some changes in the administration in the Office of the Secretary, and especially the Assistant Secretary for Health. Dr. Garcia joined us in February/March. He was confirmed by the Senate. He is an admiral in the United States Public Health Service, four-star admiral, and was just commissioned last week.

We also have a non-political appointee, Dr. Don Wright, who came to us from the Bureau of Labor, or I should say OSHA, Health Safety, and he is the principal Deputy Assistant Secretary for Health. And then we also have Dr. Parekh, who is the Deputy Assistant Secretary for Health for Science and Medicine.

Some of the recommendations over the period of 2000 to 2008 I want to quickly give you an update on some of those, not specific, but an overview. Our recommendations are posted on the website, hhs.gov/blood safety. I think this is very remarkable. Most recently my office went through and looked at the various recommendations since 2000, year 2000. There were 42 recommendation topic groups, in other words, a subject where there were several recommendations under one topic, and I have to say that over 100 actions by the department and the operating divisions have been noted on those 42 recommendation topic groups.

Now, when I say about operating divisions within the Office of the Secretary and the HHS, we do have the public health services that represent or have something to do with tissues or transplantation safety, CDC, CMS, FDA, HRSA, and NIH, and specifically not only with various institutes within NIH, but also NHLBI.

At the August meeting of the Advisory Committee on Blood Safety and Availability, the main topic that was discussed during this period was to look at the flexibility or the elasticity of the blood supply when it's faced with various challenges. And the first challenge that we were asked to comment about was primarily the impact of erythropoiesis stimulating agents.

In the summer of last year, CMS came forward with a proposed national coverage determination that would lower the trigger for use of the ESAs down to 10 grams of hemoglobin and also over a period of eight weeks. This caused a lot of concern and our committee was asked to take a look at the availability of blood products if this national coverage determination was reduced down to 10 grams of hemoglobin.

The committee actually came forward and said that, first of all, that there needs to be a review of the perspective data collection data and that we need to do some data collection. The specific recommendation was that the committee believes that there is inadequate information to accurately assess the impact of CMS's national coverage determination for ESAs on the management of anemia in the general patient population and in cancer patients.

Since this recommendation has come out, the Secretary has communicated to CMS officially with the findings of the committee, and also within the department. We've had various meetings with CMS and also with FDA. One of the most recent meetings that FDA held was the Oncological Drug Advisory Committee, and I believe that was back on April 13^th or March 13^th. I can't remember the day. They seem to all blur together. But it was in the last couple of months that the ODAC met and some of the recommendations that came out of that were basically to come in line with the 10 grams of hemoglobin for the trigger and also to recommend that the labeling be changed to discourage the use of ESAs in breast and head and neck cancers, especially metastatic cancers.

Also the committee was asked to look at the elasticity of the blood supply, especially in light of different scenarios that may take place as far as being prepared in response to the natural disaster or manmade disaster that may present itself, and that the committee felt that the blood supply is a critical part of the nation's health care infrastructure. The advisory committee believes that the knowledge of the realtime national blood and blood product inventory and its dynamics is essential for emergency preparedness and response.

The committee finds that the blood center data are extensive but not comprehensively aggregated nor available to HHS. Hospital data reporting is essential but limited. Although the blood supply is elastistic, it is unclear whether it is sufficient elastic to address potential disasters and the committee recommended that there be established sufficient hospital and blood donor center participation, and the inventory reporting develop comprehensive models and also to define shortage scenarios that would require implementations of alternative strategies, support operational research to characterize and to recruit potential donors who do not now routinely donate.

Since August we have moved quite rapidly on this. There were some things that were already in the works, such as the Blood Availability Safety Information System, which is a nationwide system to collect data on blood centers and also hospitals to look at the supply and demand.

We've worked a little bit more, and I'll show you a graph, we've worked with the blood community, the blood centers, and I have to say that starting after the first of the year this year we are now getting an aggregate report from the American Red Cross, the Americas Blood Centers, and the Blood Centers of America through the AABB as an aggregated report.

We're also working with the Biomedical Advance Research and Development Authority, which is within HHS, to work on various scenarios and also to work on modeling that would be required to be able to predict how much blood we would need in a scenario.

I'll show you the next slide. This may be a little bit difficult to read. But this data actually is representative of what was presented yesterday to me. This is an aggregated report from all three blood organizations through the AABB. And the second one, the lowest column there, is actually the group O^-s, and you can see we're at about 2.1 day supply of O^-s in this country.

Now, this is really only an estimate of what is available in the blood centers, and down below is actually an attempt to give us an estimate of what is available within the blood centers and what might be available within the hospitals, and this is based on an assumption that the hospitals have about an eight day blood supply.

Even though the 2.1 day supply of group O^- looks serious, and it is serious, the blood supply is able to respond and we believe, that between the two-day supply within the blood center and the eight-day supply which might be in the hospital, is sufficient. Also what we're seeing at the present time, and at one point last month, this was actually down to less than two days. It was down to about 1.9 days of group O^- blood available. And what we're seeing right now is that there is a response, a seasonal response, in donations.

We're also trying to work on getting more data for the hospitals and we've been in contact and discussions with various states to try to get more hospital participation so we can have a better reflection of what is happening.

Now, let me turn to January 2008's meeting. At that meeting we looked quite a bit at the infectious diseases and the emerging infectious diseases, and what new technologies and what were the barriers to advancing technology to reduce the risk of infectious disease and safety issues to the blood supply.

This may be a little bit hard to read, but let me just read it to you. The Advisory Committee on Blood Safety and Availability finds that accumulating evidence for the efficacy and safety of pathogen reduction warrants a commitment and concerted effort to add this technology as a broadly applicable safeguard, which additionally would provide a reasonable protection against potential emerging infectious diseases.

This would result in a proactive, preeminent strategy that would broadly render most known agents noninfectious and preventing emerging agents from becoming transfusion risk. To achieve this goal, government, industry, blood organizations, and public stakeholders need to work in concert to commit the required financial and technical resources.

The committee went on to recommend to the Secretary that the Secretary adopt as a high priority the urgent development of safe and effective pathogen reduction technologies for all blood transfusion products and implementation as they become available; provide resources to overcome current barriers to development and validation of pathogen reduction technologies; to ensure adequate safety monitoring of pathogen reduced blood products, post marketing using an active national hemovigilant system and to ensure that other efforts to improve blood safety and availability are not compromised by those efforts.

I'd like to say that since the January meeting we've made great progress on this, but I have to be honest with you and say that the department is still working on these recommendations. We're having discussions internally on what this means and how we can put our hands around this, but it is out there in the public domain as a recommendation to the Secretary.

In finishing up, I just want to let you know that our next meeting is going to be on May 29^th and 30^th of this month. We will have updates on safety in transfusion and transplantation.

We're also going to have an update on the HBOC meeting and the rule making associated with the vascularized composite allographs, and we're also going to have discussion on the transfusions associated with older red cells. And some of us that were at the meeting yesterday for the HBOC, a lot of that was a good preliminary to the discussion at the end of May.

I also would like to make known to the committee, and also to the audience, is that we are seeking nominations to the Advisory Committee on Blood Safety and Availability. The notice went in the April 15^th Federal Registry and the nominations are due June 30^th. And thank you very much.

CHAIR SIEGAL: Thank you, Dr. Holmberg. Next we'll hear from Maria Rios of FDA on the West Nile epidemiology and current considerations for the use of NAT testing for transmission reduction. Dr. Rios.

I should say, are there any questions for Dr. Holmberg? I apologize for forgetting that. DR. RIOS: Okay.

DR. FLEMING: Just one clarification. You were talking the erythropoietin stimulating agents, ESAs, and the ODAC recommendation that came through recently about head, neck and breast cancer. I think you said particularly in the advanced disease setting. My understanding is that was true, but there principal focus was on low risk, the surgical adjuvant disease settings given the venothrombotic events at six to seven percent increase in a five to 20 percent potential increase in mortality that they had actually first discouraged the use in the lower risk adjuvant setting and then also added the breast cancer and head and neck advanced disease setting. Isn't that correct?

DR. HOLMBERG: Yes, it is. Thank you.

CHAIR SIEGAL: Any other questions?

DR. FINNEGAN: As far as the supply of O^- is concerned, has anyone looked at user usage and can that be altered so that perhaps the supply is not as low as it is?

DR. HOLMBERG: Well, the committee has grappled with that many times as far as utilization guidelines and it really comes down to an issue of the Secretary making recommendations to the practicing physicians, is that really appropriate. And so we're really looking to a scientific body, the peer review process, to hopefully implement some of those utilization guidelines. But, yes, there are attempts at the present time to look at the various guidelines issues and that's all I can say at the present time.

DR. FINNEGAN: Because there are multiple medical associations that the Secretary could deal with that would be happy to -- hematology, American College of Surgeons, blood bank people, I mean I think all of those people could educate if they knew that this was --

DR. HOLMBERG: Yes. And we have worked with some of those groups and we continue to work with them.

CHAIR SIEGAL: Okay. Anyone else? Dr. Szymanski?

DR. SZYMANSKI: I'd like to ask, is there any understanding why ESAs are harmful in those conditions described?

CHAIR SIEGAL: Dr. Holmberg?

DR. HOLMBERG: I thought I was finished. I didn't hear that question.

DR. SZYMANSKI: Is there any understanding why ESAs are harmful in those conditions you stated?

DR. HOLMBERG: Well, without getting into a lot of the specifics, at least with some of the high risk such as the breast, the metastatic breast, and also the head and neck, it's my understanding as far as the erythropoiesis or the EPO receptors that may be on some of those cancers and the risk of spreading the metastasis of that, but also I have to say that there is also the risk of, especially higher than the 12 grams, the increased thrombosis that was presented by Dr. Fleming, clarified by Dr. Fleming.

CHAIR SIEGAL: If there are no others, Dr. Rios.

DR. RIOS: Okay. I will present an update to you on West Nile season and then I will present to you the guidance on blood donor screening for infection with West Nile.

In an update in 2007, it's the ninth consecutive year of West Nile outbreak in the U.S. and this has resulted in 3,623 human cases, and these human cases of disease are serious enough to be diagnosed as West Nile and reported to the CDC.

Please remember that about 80 percent of the infections by West Nile are asymptomatic and the disease case can lead to neurological infection and invasion with serious consequence, and there has been 1,213 cases of neuroinvasion disease this year and a total of 124 deaths.

So in the ninth year of consecutive outbreaks, West Nile is still really active in the west. It has been distributed throughout the country and positive in 47 of the 48 contiguous states of the U.S., including D.C. and then Puerto Rico. The neuroinvasive cases are most closer to the center of the country, and USGS reports the number of 3,628 animal cases, including veterinary cases, birds, et cetera, and 8,625 positive mosquito pools. So West Nile is still here.

This shows the number of human cases from 1999 to 2007. You can see that it peaked in 2002 and 2003, which the largest number of neuroinvasive cases and cases in general, and close to 3,000 cases of neuroinvasive disease. And that dropped in 2004 to lower than 1,200 cases of neuroinvasive disease, but sustained above the 1,000 number throughout these six years.

And one can calculate the number of cases that occur of infection based on neuroinvasive cases if CDC considers 1:150 neuroinvasive case, 1:150 is a neuroinvasive case. More recent data show that these number is actually low estimation and it's more accurate 1:353 cases.

Taking that into account, there has been between 1.7 and 3.9 million infections in the U.S. in the past nine years. And the fatality cases have been close to 300 in 2002 and 2003, but not lower than 100 in subsequent years in the last six years.

So West Nile is important in the U.S. The infection is notifiable to the CDC. It has occurred throughout the year. CDC says since 2005 the onset of clinical cases has been reported to them from January to December every single year and then peaks high between spring and fall, and that since 2002 over 1,000 neuroinvasive cases. This is serious just like Japanese encephalitis seen in the far east in Japan and over 100 cases of death yearly.

This year West Nile started really early. The first human case was reported in January. We have already four human cases reported mid April, and they are one in Tennessee; one in Arizona; and two in Mississippi, one in March, one in April. There is one horse case, 12 dead birds from West Nile, and that's interesting because it's from South Carolina to California. It's east and west coasts, ten mosquito pool positive and four sentinel chickens. And so West Nile has begun and it's hot as ever.

Blood screening for West Nile using MP-NAT has been implemented as you well know from 2003 and now and has been extremely successful and it's a joint collaborative effort between test kit manufactures, the public health department's blood centers and it's incredible cooperation to get to this. To date there has been 2,600 interdicted units due to reactivity to NAT to West Nile virus. That led to the prevention of between 2,600 to 7,800 of potential transmission by transfusion. This is really a tremendous effort and a great success.

There is a task force of West Nile that AABB believes that discuss this date is an update what's to be done. This is the summary of transfusion transmission cases that where 23 cases -- a total of 32 cases confirmed to be transmitted by transfusion to date, plus 56 cases that were inconclusive because they couldn't be resolved for several reasons.

You can see that the drop from 23 cases in 2002 to six cases after implementation of NAT shows the efficacy of the assay to prevent blood transmission by

-- West Nile transmission by transfusion. There was another case in 2004, none in 2005 that has been documented. We don't know if there are any that has not been, and two cases in 2002 and I'll address this a little bit later.

The current test algorithm means that the assays is performed around using MP-NAT six of 16 specimens, the test kit manufacturer, and if the pool is negative and the unit is suitable for transfusion, then the unit is released. If the MP is reactive, then the units are tested independently to identify the positive.

We will just go quickly because I will address these later to show that further testing, repeating the same NAT plus antibody has a positive predictive value of 98 percent and sensitivity of 98 percent, and these data was provided to or generated by the blood establishments and discussed thoroughly in the West Nile Virus Task Force and has been provided to us.

So the further testing, the repeat NAT and antibody testing as well leads to the definition of what the donor has to be told. And if it's ID-NAT reactive unit repeating in the repeat NAT, then it's positive regardless of antibody. If it's antibody positive and not repeat NAT, then it's considered positive regardless of the NAT.

There is a portion, however, that does not repeat ID-NAT and it's subset for West Nile antibody. And these are considered false positive or true negative. However, in follow-up studies, two percent of these portions have been shown to be true positive showing clearly that the absence of repeat NAT in the absence of antibody coming from an ID-NAT reactive has a two percent risk of being true infection. Additionally, ten percent of the initial reactive units that do not repeat NAT, they have antibody either in screening or follow up.

We mentioned some issues, we had some issues. I have been told that the time is short so I will skip a lot of these slides now. But in any case, MP-NAT would lose a lot of reactive units, 25 percent of reactive units.

Last year we presented that in the blood establishment have been testing for ID-NAT in the situation where the peak, the West Nile is active in the region and there is 1:1,000 or two MP reactive NAT.

I'm sorry. I have to skip a lot here. I have been told to speed up.

Based on the lack of sensitivity of or perfect sensitivity of MP-NATs, ID-NAT has been used, as I said, to detect additional units. A uniform criteria is desirable. There is automated system and last year there was a paucity of data to recommend uniform criteria.

So AABB issued bulletins in 2007 and again in 2008, which is available and I have to just say briefly to you that the West Nile Virus Task Force discussed the issue and they actually took the lead the investigate the appropriateness of the criteria used to ID-NATs, to implement ID-NAT.

And the ARC study was presented the task force and Dr. Stramer kindly provided her data for us to present here. The ID-NAT was required to detect 27 percent of the cases in 2002 and 2003 and these were retrospective assays tests; 29 in 2005; 36 in 2006, and in some cases here ID-NAT was implement with 2 PVD only and without the ratio; and 44 percent in 2007 when the criteria was evaluated.

I'm going to put just these here that the evaluated criteria was 1 PVD. That it's presumptive viremic donor and the PVD is defined by signal to cut off higher than 17 and all repeat reactivity if not is the signal to cut off is below 17.

So 42 were identified with 1 PVD; 31 with 2 PVD; and five, 2 PVD plus 1:1000. So if you go from 2 PVDs in 1:1000 to 1 PVD there is 8.4-fold increase in the detection. And 2 PVD in 1:100 to 2 PVD, it's 6.2-fold increase.

There is also consideration that if the unit is positive for IgG but not IgM donation, those IgG, not IgM are being considered false positive. So if you retrieve the so-called false positive, there is still an increase of 6.4 from 2 PVD in 1:1000 to 1 PVD, or an increase of 4-folds from 2 PVD in 1:1000 to 1 PVD.

What I will present to you now is what we have in the West Nile NAT guidance to the industry, and please note that this is a draft guide and it's for comment purposes only, not for implementation. The draft guidance was published for comments on April 28 and the 90-day comment period closes in July 27, '08. Please submit any comments that you may have and they will be considered. Please also submit any additional data that may support your comments for proper evaluation and consideration.

The recommendations on tests is that the screen for West Nile should be performed year-round using licensed NAT on donor samples of whole blood and blood components intended for transfusion. It's to be performed either by MP- or ID-NAT, and the ID-NAT should replace MP-NAT during the activity in your region. That has to be previously defined.

I'm just going to go quickly through this screening. The algorithmics, the same thing, you test ID-NAT. It's either six or 16. If the units are nonreactive and suitable for transfusion, they're released. If MP-NAT is reactive, it goes the same path as when screening ID-NAT. If the sample is reactive, further tests need to be done, and MP-NAT is resolved to identify single unit that caused the reactivity in the pool. The ID-NAT nonreactive units, if suitable, are released for transfusion.

In the ID-NAT positive units go down to further testing for donor counseling, the unit should be discarded, defer the donor for 120 days, retrieving date product prior to the collection during the period back to 120 days and initiate

ID-NAT for that region.

ID-NAT, we're waiting for ID-NAT implementation. MP reactive test specimens, if in the pool, if you get one ID-NAT reactive unit, you should initiate ID-NAT within 24 hours of the collection. If more than 24 hours, it's taken to initiate ID-NAT retrospective test of the units between the date of collection and the date of results are encouraged should the study unit defer the donor and retrieve in-date products.

If blood establishment used as an assay that does not discriminate between West Nile virus and other virus from the same family, it should be resolved for donor counseling. And if a blood establishment wish to revert back to MP-NAT, then they do so in these high activity in the defined geographic area as long as the MP-NAT -- the reactivity has subsided, the activity in the area has subsided a minimum of seven days has passed without single ID-NAT reactive.

Additional tests are waiting for donor counseling purposes. I have mentioned to you before that perform additional tests is recommended, repeat NAT using the same assay or equal sensitivity assay, and perform antibody using a cleared antibody assay.

If ID-NAT reactive, MP antibody to positive O, ID-NAT reactive with West Nile antibody positive or negative, the donor is to be notified as positive, deferred and follow all the procedure. If ID-NAT is nonreactive, but antibody is positive, the donor should be considered positive as well.

If ID-NAT nonreactive in West Nile antibody negative, then the donor should be notified of deferred and should be counseled as inconclusive because I showed you that two percent of these population here may, in fact, have a true infection, and we encourage the donor to return for follow up and be tested in 30 days after the initial testing.

Also, one has to keep in mind that the virus has cross reactivity with JE serocomplex West Nile virus. Therefore, if the NAT assay used for counseling does not discriminate between West Nile and other JE members, that should be taken into account.

The recommendation regarding label, is that the container label and instruction circular should be changed to reflect the West Nile test result consistent for labeling of all infectious disease markers. And the West Nile reactive unit not to be shipped or used except as provided in the FDA provided programs and all research or autologous use and such units be labeled with appropriate warnings.

Thank you.

CHAIR SIEGAL: Thank you, Dr. Rios. Let's hold the questions under after Melissa Greenwald speaks. As of now, you have -2.5 minutes to talk. That's a joke.

COMMANDER GREENWALD: Good morning, everyone. Maria had the hard part and I think I have a much easier part to talk about West Nile virus today. I really just need to update you on what the office's cellular, tissue, and gene therapies is doing with donors of human cells, tissues and cellular and tissue-based products, which I prefer to say cells and tissues because it's just too long to say it otherwise.

So as a little bit of background to remind you of what's been going on with us that, along with office of blood, CBER has also been considering cell and tissue donors ever since the first workshop back in November 2002. And we didn't have our 1271 regulations in place at that time, so, obviously, West Nile virus was not a relevant communicable disease because we didn't have those at the time. At the time we required donor screening and testing for HIV, hepatitis B, and hepatitis C.

But West Nile virus is now a relevant communicable disease agent or disease. It was proposed back in May of 2004 in draft guidance and it became a relevant communicable disease upon implementation of our final guidance on donor eligibility this past August.

And this is just a reminder of the relevant communicable disease agents or diseases for all cell and tissue donors and these are the ones that are defined by the regulations themselves. So they're specifically listed in the regulations.

And then we also had a provision in the definition of a relevant communicable disease that gives us criteria to use to define new relevant communicable diseases as we have new emerging infectious diseases. And these, including West Nile virus, were the ones that were implemented in August of 2007.

We had originally also proposed SARS as a relevant communicable disease, but since, unlike West Nile virus, it sort of seemed to fizzle out. We didn't really think that it met the criteria set forth for cell and tissue relevant communicable diseases.

So through the guidance where we made West Nile virus a relevant communicable disease, we recommended donor screening. At that time did not recommend any donor testing. We have several different ways that we screen cell and tissue donors, and donor screening does not include testing in our regulations.

So one of them is reviewing other medical records for risk factors, as well as a donor medical history interview. And these are the criteria that we require regarding the medical history interview and review of medical records for West Nile virus, and these are consistent with the ones that have been recommended for blood donors.

Then we also look for clinical evidence of West Nile virus. And the main reason why that I want to point out about reviewing clinical evidence is that you'll see in the next couple of slides these are just the descriptions that are given by CDC. But given that West Nile virus is very nonspecific, it was difficult to say if you meet these criteria for West Nile virus without any positive test results you definitely can't donate.

So we gave the description as basically information and then the medical directors, or the person making donor eligibility determination, may take that information in light of other information obtained about the donor. So we described the mild symptoms and then possible severe symptoms of West Nile virus in our guidance.

And we did sort of try to give clues in our guidance. Of course, we reconsider testing recommendations in the future. At that time we weren't prepared to make testing recommendations.

But we have published draft guidance with the office of blood, and so we've made, for the first time, a guidance for both of our offices at the same time so that everyone can be on the same page and not wonder if we're going to do something different.

So in the draft guidance for cell and tissue donors we recommend year-round testing by individual donor NAT for all HCT/P donors. And, just like for blood, according to good guidance practices, you know we publish draft guidance to allow public comment and we will take those into consideration before we make final recommendations.

Thank you.

CHAIR SIEGAL: Thank you, Commander Greenwald. Time is very late. Are there any essential questions before we move on to T. cruzi? All right. We'll be hearing from Commander Greenwald again.

So now we're going to hear from Robert Duncan of FDA, and eventually, again, Dr. Greenwald on screening for T. cruzi. Dr. Duncan?

DR. DUNCAN: Good morning. In the interest of time I'm going to go fairly quickly over my slides. Some of them have been presented to BPAC in the past, beginning with not reading the title to my talk.

But I want to just show the background of the disease to make the point that our current considerations on use of testing for Chagas Disease in the blood donor population is based on an understanding of the disease, the likely nature of an infected donor based on studies that have been going on for many years, primarily in Central and South America.

Our current considerations are also based on an assessment of the risk of transfusion transmission of Trypanosoma cruzi and based on the best knowledge from studies of U.S. blood donors as well as blood donors around the world, and actual confirmed cases of transfusion transmission.

But more to the point, our current considerations are based on the fact that the FDA approved a blood donor screening assay, the Ortho T. cruzi ELISA test system for testing blood donors for infection with T. cruzi. Up to now there is no supplemental test for T. cruzi antibodies, which means there's no possibility of a re-entry algorithm without the availability of a supplemental test.

And much of this information was presented one year ago at a BPAC, so I'm just updating things that have changed. And the biggest thing that has changed is we have been watching the progress of blood donor screening. These data are available to us, very thankfully, to the AABB, which has made a tremendous effort to post the information. I updated this as of yesterday with April 25^th data. So up to that time, more than 11.8 million donors have been screened. And in that actual clinical experience the characteristics of the test that were identified in the clinical trials have pretty much held up. We're very happy about that.

One thousand four hundred ninety-two (1,492) repeatedly reactive donors represents about 0.01 percent of the donor pool. That's pretty close to the estimate of what would happen and that repeat reactive rate is low enough that even without re-entry there has not been a significant effect on blood availability as a result of this testing.

These donors are also retested on a more specific, but unlicensed T. cruzi radioimmune precipitation assay, and by looking at that data we can make some other estimates about the performance of the test. Nine hundred eighty (980) of those 1,400 are nonreactive or false positives. Three were indeterminate. Four hundred and fifty-two (452), however, were positive with the RIPA assay or 31 percent of the repeated reactives, which is a pretty good positive predictive value for a screening test.

The other thing about those 452, those are the true positives that have been detected to date, which calculates approximately to 0.0038 percent prevalence among blood donors, and that's a little lower than some of the estimates that I showed in the earlier slide for previous data. But it still represents a substantial number of potentially true positive cases that have been interdicted and are making the blood supply safer.

This map shows a little bit about how those 452 cases are distributed across the country, and though there are some clusters in California and Florida, the major message for us is that it is spread widely throughout the country making any kind of strategy for a geographically focused screening unlikely, both with the mobility of the population as well as the mobility of blood and the wide distribution of the RIPA reactive cases. The prevalence is widespread throughout the country.

There's two other points that I'd like to make that comes from my scrutiny of data that's made available to us from the American Red Cross, and on two points:

1) Is there evidence for vector borne transmission in the U.S.?

And I highlight this point because it will really make a difference in how we view implementation of testing. A situation where all the reactive cases are long term, chronic, asymptomatic individuals that acquire their infection earlier in life in the endemic area dictates one sort of situation. If there are newly acquired cases, potentially window period cases, potentially early infection, the test that we're using, the Ortho T. cruzi ELISA test system, has not particularly been validated with a newly acquired infection, so there are some -- those are questions that will arise if there's substantial evidence for endemic transmission in the United States.

To date there are about 15 cases that I've been able to glean out of the study that had no history of immigration or travel to or parents who immigrated from an endemic area. Some of those have been followed up quite extensively and some risk factors have been identified, a time in the forest, a time in areas of the country where it is known that there are insect vectors that are infected, where there are animals in the wild that are infected. So the possibility is there that there is a very low level of the long term is autochthonous transmission.

2) Is there new evidence of transfusion transmission?

This, of course, will be something we're watching as the testing continues to unfold. And this is the information develops from a lookback of repeat reactive or confirmed positive donors who have had prior donations. From that study 65 recipients of blood products from 37 seropositive donors have been tested. The recipients have been tested. Among them, 57 of the recipients tested negative on all tests, indicating no transfusion transmission.

One of the recipients is seropositive, but his birthplace in El Salvador suggests that he was pre-infected and this was, in fact, not a transfusion transmission. There are six recipients that have a single reactive test either by RIPA or by PCR, not by the ELISA test, and they've been judged to be false positive because that one positive test does not repeat on other tests, and there's one case still pending.

So at this point the results would be that there's no clear case of transfusion transmission from lookback on the confirmed positive donors out of the 452 tested. And this would suggest a lower rate of transfusion transmission than has been documented in Central and South America.

There could be a lot of reasons for that. We are looking at long term, chronic blood donors as opposed to in an endemic area where there would be a mixed population of donors with different stages of the disease.

This whole lookback procedure also selects for the healthy recipient because of the transfused products that were identified from seropositive donors, about not quite half of them were transfused into recipients who are now deceased. The only ones that were followed up were the ones who are living. So there's a selection for the healthier recipient in the first place.

So there's a lot of factors not to conclude that this indicates there is no transfusion transmission. That has been documented. We will need to continue to look at this data as time goes on, but it's just one of the points to draw out of the testing that's been done.

So our current considerations for donor management would be that we're considering whether all donations should be tested for antibodies of T. cruzi, and we currently consider that for any kind of selective testing plan, that an appropriate methodology needs to be validated during a period of universal screening. Any repeat reactive we consider the possibility they should be deferred indefinitely and the re-entry will depend on a supplemental test.

However, for counseling purposes, the additional information can be used to communicate to the donor the medical significance of infection and referral for additional medical diagnostic testing is probably useful. We're considering recommending medical followup for cross-reacting diseases because there has some evidence of cross reactivity with other parasitic diseases.

In the arena of product management, we are considering whether establishments should quarantine and label their index donations from repeatedly reactive donors. Prior collections from that same donor should be retrieved and quarantined and labeled.

We're also considering the appropriate lookback, which could be to notify consignees to enable notification of recipients of prior donations from a repeatedly reactive donor who is, one, repeatedly reactive on the screening test and for whom there is additional information indicating risk of T. cruzi infection, such as a positive test result on a licensed T. cruzi supplemental test when such test is available. Until such test is available, geographic risk for exposure in an endemic area or other medical diagnostic testing may provide additional information.

The autologous donation that we're considering is pretty much standard by the regs, and, also, labeling and circular information, biological product deviation report, and fatality report are also standard according to the regs. And we're considering whether implementation of the test should be reported in the annual report.

And that's it for today. Thank you.

CHAIR SIEGAL: Thank you, Dr. Duncan. Now, we'll hear from Melissa Greenwald again from FDA.

COMMANDER GREENWALD: Not quite finished with me yet, but if you thought the last one was brief, wait until you hear this one. So I'm here to present our current considerations for T. cruzi for cell and tissue donors.

Almost a year ago today, just a few days off, I presented a talk to this committee about T. cruzi considerations for HCT/P donors and asked a few questions for consideration of the committee. So just the reminder about what is relevant communicable disease in our regulations, and I'm not going to read through those to you, but I described that in the last talk, and then these slides are included only to prove to you that, in fact, T. cruzi is not a relevant communicable disease and, unless it were so, we cannot recommend donor screening or testing.

So we have stated several times and wrote that in our guidance that any time we intend to make a new relevant communicable disease, we will publish it in guidance and allow for comment.

So currently we are considering whether or not we should make T. cruzi a relevant communicable disease H or disease and recommend any donor screening and/or testing. So any recommendations would be published in draft guidance ahead of time. I think that's very important to put forth to everyone hear.

And that is it. So if there are any questions for either Dr. Duncan or myself, we'll be able to move on after that. Thank you.

CHAIR SIEGAL: Thank you very much. So, questions?

DR. KULKARNI: Roshni Kulkarni. You know, as I listened to these about donor testing, I think what goes through my mind is, what about the recipient? For example, patients with hemophilia, sickle cell disease, bone marrow failure syndromes, and all, to me are like canary in the mine who get a lot of these blood products and would be the first on hand to have these diseases. So I know at the CDC we do do testing for West Nile virus for and we have specimen saved from many years actually, since 1998, for doing West Nile virus testing which we are currently doing.

But I was wondering, is there any requirement as far as the recipient is concerned as to what do we do with them, especially these groups which are multiply transfused? I'm even worried about parvo virus in this population because that's another one which is normally not tested.

CHAIR SIEGAL: You guys want to comment on that? Dr. Greenwald? Anybody? Jay?

DR. EPSTEIN: Matt, you may be in a better position to comment, but there is a surveillance program established through the hemophilia treatment care centers that are funded under the child health component of HRSA and where they have determined that they should be monitoring the hemophilia patients for acquiring certain infectious diseases they do routinely screen. So I think it's a question that might want to come back to the CDC. Do the average risk, based on seroprevalence in donors is only 1:29,000, and if you look at the transmission data, we're already 95 percent confident that the transmission risk is under 5 percent. So we're looking at really a very low risk situation. But, certainly, one could consider whether surveillance in that population is warranted.

The Chagas Disease is very difficult to treat. I'm sure most people know this. There's greater success in the acute stage than in the indeterminate or symptomatic stage, but there are recent CDC guidelines on treatment according to stage of Chagas Disease. So given that there might be suitable intervention, also, a pregnant woman, of course, can transmit to a fetus. So I think it's a very good point and we'll just have to think about it in collaboration with our CDC colleagues.

CHAIR SIEGAL: Thank you, Dr. Epstein. Are there any other comments or questions?

DR. EDWARDS: Yes. Willarda Edwards.

Thank you very much for addressing that question because it is a major issue, not only in hemophilia, but those with thalassemia where transfusion therapy is basically part of the care, as well, obviously, with sickle cell. And I'm hoping that as a result of raising this question, and as we've heard, that we'll talk with our friends at CDC and I'm asking this Chair whether or not we're talking about having a report back regarding that issue?

CHAIR SIEGAL: I need a little guidance here. I imagine that there will be a response. If there is no one else, let's move on. Now we're going to hear from Dorothy Scott from FDA on the proposal to lower the minimum recommended lot release titer for measles antibodies and immunoglobulin.

DR. SCOTT: Good morning. This is an issue that you addressed last August and that was our request for your advice on lowering the measles antibody lot release specification in IGIV and IG subcutaneous use for treating primary immune deficiency. I'm going to refer to both of these as immune globulin products.

This is just a background summary and I'll go through it very quickly. As you probably recall, measles antibody titers serve as a potency test for lot release of all immune globulin products licensed in the U.S. And the antibody levels in products have been declining in recent years due to diminished titers in plasma donors. The reason is that the vaccinated population is now predominating over the naturally infected population.

However, the failure of potency testing at lot release, including this particular test, measles antibody titers, results in lot rejection. So in the setting of declining titers, as these go down, there's a potential large negative impact on immune globulin product availability for primary immune deficiency because these lots would be manufactured but not used.

We propose to lower the minimum measles antibody titer in IGIV and IGSC to levels still expected to be effective in pre-exposure protection in patients with primary immune deficiency.

So we sought your guidance and further information about the potential clinical impact of lowering the measles antibody specification in these products. We heard from Dr. Seward of the CDC some epidemiological information that they have gathered showing that measles is uncommon in the U.S. and that there is no endemic disease present here. Therefore, exposures are fairly unlikely. There were about just under 60 reported cases back in 2006. I think the 2007 data should be in by now.

Measles in U.S. residents is usually due to transmission from infected travelers returning from endemic regions of the world or their own travel to those regions in acquisition of measles.

Primary immune deficient patients with measles have been very rarely observed and none have been reported through an informal survey of primary immune deficiency treaters in recent years. Dr. Moss from Johns Hopkins presented data showing that people with combined B and T cell defects are at most risk of serious complications and he also showed us an animal model in primates that demonstrated that.

Just to continue, protective antibody levels against clinical measles disease in normal people are estimated to be 120 mIU/ml in the sera, but sterilizing immunity that is altogether a prevention of infection probably requires much higher titers in the sera. However, the protective level needed for primary immune deficient patients is unstudied and unknown, but it is likely to vary depending on the specific type of immune deficiency that they have and the relative contribution of T cells to their immunity.

We proposed a specification based on our pharmacokinetic modeling to go from 0.6 x CBER standard, which it currently is set at, to 0.48 x CBER standard, and at this specification we estimated that IGIV given at a typical dose of 400 mg/kg for primary immune deficiency should provide serum trough levels of at least 240 mIU/ml, which is double that needed to protect normal individuals against clinical disease.

We sought data from CSL Behring for their IGIV and IG subcutaneous products at least affirmed the likelihood of achieving trough levels greater than 240 mIU/ml with standard doses of their products. However, obviously, those were at the current 0.6 x CBR standard or greater.

So we asked you whether you concurred with our proposal to lower the minimum measles antibody specification for the IG products and you voted yes, 13, and the 1, no, vote was request really for more trough titer data.

I'm going to go very briefly through this and just cover the first and the third points because the other one I'll come back to later. But some members stated that the risk to supply of rejecting lots exceeds the current risk of serious measles infection in primary immune deficiency patients. In other words, this is a low likelihood event, but this actually is a high likelihood event if we continue at the 0.6 x CBER standard lot release specification.

You also felt that surveillance would be important to identify and investigate breakthrough cases in recipients of immune globulin products. I should mention that measles is a nationally notifiable disease. Reporting of cases is required by all states. Those reports go to CDC and our CDC colleagues have assured us that they would notify us if they had any immune deficient patients that had measles.

We also asked you since we were considering requesting additional studies to confirm that immune deficiency patients will receive trough titer levels -- I'm sorry -- achieve trough titer levels of measles antibodies above this lower limit of 120 mIU/ml if treated with IGIV and IGSC products that met this lower revised standard. Basically, we're asking you, do we need more studies? The vote was 13, yes, and 1, no.

Discuss that more data would be useful to support our PK extrapolations and the data set that you saw from one of the industry members, and I won't go through the details of this for the sake of time.

We also requested your comments on alternative strategies that we should consider to address the measles titer problem in our products.

You also felt that primary immune deficiency patients traveling to measles-endemic areas should be infused prior to travel and preferably with high titer product. You felt that education of physicians would be important so that immune deficient patients who have been exposed or may be exposed to measles can have dosing or dose timing adjustments, or both. And, if exposed to measles, PID patients with profound T cell deficiencies should receive doses that achieve sterilizing immunity.

We went forward and considered your additional discussion points and looked for a regulatory pathway, which we've now defined. Manufacturers can voluntarily propose to change their measles antibody specification at lot release to 0.48 x CBER standard adjusted for IgG concentration as a prior approval supplement. Included in this prior approval supplement would be an agreement to report measles in a primary immune deficiency patient that had been reported to the company as a 15-day report to FDA, and this might be faster potentially than going -- receiving reports through CDC simply because there may be a delay between reporting to the state and reporting to CDC in recognition of the measles. So we might hear of this sooner and that would allow for investigation of the patient if possible.

We would also ask for an agreement to a labeling change that reflects the potential need for dosing alterations with respect to timing and total dose for an immune deficient patient with potential or actual exposure to measles.

And we also request a post marketing commitment to determine measles trough level titers in primary immune deficient patients receiving a known dose of measles antibodies, in other words, known titer in the product. This could be in the contact, and I'm sorry this is so small, of an upcoming, ongoing, or completed clinical trial that would have retention samples for primary immune deficiency with these products.

Alternatively, a separate stand- alone trial would also be acceptable, and measles titers, of course, would have be measured by a functional assay, hemoglutination, inhibition, or neutralization as always.

The outcomes I think address the committee's concerns, and ours as well. They provide an expedited path to changing the measles antibody lot release specification and minimize the change of loss of a large amount of IG products to the market. It enhances the likelihood that we'll find out about these cases early enough to investigate if a measles case occurs in a primary immune deficient patient.

It would provide additional information about measles exposure and how to deal with that in the package inserts. So this would provide the educational aspect. It would also provide a means of data collection to support that at least minimum protective titers would be attained in these products.

Thank you very much for your attention.

CHAIR SIEGAL: Thank you, Dr. Scott. Are there any questions for Dr. Scott? Yes.

DR. BALLOW: Mark Ballow. I haven't read package inserts lately on these products, at least some of the older products. But I recollect that some of them still recommend a dose of like 200 mg per kilo, which obviously wouldn't fulfill your recommended of 400. So I certainly applaud you, and as part of your going forward is to revise some of the package inserts to take this into consideration.

DR. SCOTT: In that particular instance, and I know exactly what you are talking about, that's taken into consideration as part of any submission that we would receive, and so the dosing recommendations, more specifically, would be if somebody is on a 200 mg/kg dose, or 300 mg/kg dose for that matter, that that dose be revised upward prior to travel or post exposure so that they would actually receive more.

What that doesn't take care of though is somebody who's exposed and you don't realize they're exposed, and I think that's an important issue to address in the case of those lower doses. I don't know clinically how often they're being used, but the fact is, at least for one product, two products, they're in the package insert.

DR. BALLOW: Yes. Well, that's why I raised the issue because some physicians are still infusing at the lower dose, which I don't advocate, but with that wording about travel exposure may not take into account those patients that inadvertently may not know they've been exposed for example.

DR. SCOTT: That's true, and that's something that with those particular companies we're taking into account and addressing, absolutely.

DR. BALLOW: Now, the other issue at the workshop that was a measles issue that was coming up with other measures of specific antibodies and the IVIG to guide clinicians on the whole protective ability or efficacy of some of these products or lots of particular products.

DR. SCOTT: Well, we would really like to be forward looking with respect to especially looking at antibody titers to H. Influenza and to pneumococcus by a functional assay, and WHO has a group that's been working on standardizing the opsonophagocytosis assays. We are in contact through a colleague at CBER about this and those studies have been progressing. I think once we have the methodology that can be validated and some standards that this will be possible for those pathogens that particularly affect the primary immune deficient population, especially those two which, I think, were identified at the workshop as being among the very most important.

We haven't forgotten. We're quite keen on it.

CHAIR SIEGAL: Dr. Kulkarni?

DR. KULKARNI: Just a point of clarification. The trough level titers, when would they be obtained, and if those are low, then is the recommendation to give a second dose? I just wanted to know.

DR. SCOTT: I think if those were low, the recommendation would be to give higher doses just on a routine basis.

DR. KULKARNI: When would they be dosed?

DR. SCOTT: And the trough level titers are usually obtained right before the next dose. So a typical dosing pattern for immune deficient patients who are receiving IV would be to get dosed every three to every four weeks and the trough level is right before that. Likewise, for subcutaneous, which is given more often, it would be prior to the next dose so you know what the lowest possible level is in that patient.

CHAIR SIEGAL: I have a question. Has there been any proactive effort made to actually collect a bank of trough levels in a variety of patients with primary immunodeficiencies who are getting regular infusions of immunoglobulin? That might be something that we really ought to initiate.

DR. SCOTT: I think that would be very interesting to pursue. Maybe Dr. Ballow has a comment. The immune deficiency foundation might be in a position to help accomplish that.

DR. BALLOW: I don't think we need to do that because there's been a number of products that have come before the FDA for approval in the past few years, plus some that are in progress now, and most of those studies I think collect extra sera to stock away.

DR. SCOTT: They do, they do.

DR. BALLOW: And I would just ask them to go back and just measure those trough levels of measles antibody. So the material I believe is available. It's just a matter of asking them to go back and measure those.

CHAIR SIEGAL: The issue, of course, isn't just trough levels of measles antibody, but of some of the more relevant antibodies that aren't indicators usually of efficacy. Because those haven=t been --

DR. BALLOW: Okay. But I thought the issue was more data for the measles trough level.

CHAIR SIEGAL: Is there any more discussion on this issue? All right. Then let's move on.

Now we're going to hear from Larry Dumont, Director of Cell Labeling Laboratory at Dartmouth Medical School on Post Marketing Studies of 7-day Platelets in the PASSPORT study. Dr. Dumont?

DR. DUMONT: Mr. Chairman, members of the committee, Dr. Epstein, and members of the FDA, thank you for your invitation this morning to come from cold New Hampshire to the nation's capital. I want to talk this morning about a project on 7-day platelets and bacteria project that seems like it's become a career project.

I do have some conflicts of interest. I do personal consulting for these companies. These companies supply some type of research support to my laboratory at Dartmouth and the taxpayers of the United States paid for my ticket down here.

So there's a couple of things that I want to point out that, amazingly to me, seem to be continually confusing to everybody about this project and I think they're very important.

Number one, 7-day platelets are 510(k) cleared by FDA. Two companies hold clearances for those products.

PASSPORT is the post-marketing surveillance of 7-day platelets, that is to say a Phase IV type trial of, if you will, an approved product. This is not an IND or an IDE study that is a prerequisite for a clearance.

PASSPORT does have an explicitly stated primary hypothesis with a written analysis plan which was reviewed and accepted by FDA. The planned analysis has not been conducted and the primary hypothesis has not been tested.

A couple of other items. Going into this whole program there were some assumptions made. One, we made the assumption that the true bacterial contamination rate in platelets was somewhere between 178 and 349/M, or roughly 1/5000, and this was based on one bottle aerobic testing of platelets at 24 hours past collection.

We also assumed that the release test would detect at least 50 percent of these, and that, therefore, the residual risk of released platelets would be about 100/M or 1/10,000.

Based on these assumptions, we did a sample size calculation where we came up with <4 positive out of 50,000 surveillance tests, and I'll show you what a surveillance test is in a second, would be detectable here. And that's the upper 90 percent confidence that no more than 1/5000 or 200/M residual risk would be in the blood supply.

Note that these risks do not weight the data in any way for clinical risks that may be associated with what the organism is or the day that it might be detected or it's titer. Well, what we know right now is that these assumptions were wrong.

So 7-day platelets has a long history. To cut it short, in 2005 FDA approved a combination approach using apheresis platelets and a bacterial detection method, the BacT/ALERT, to approve 7-day platelets, and the first one was made under this program in 2005 by New York Blood Center.

Following that was the initiation of the PASSPORT, this post marketing surveillance by Gambro, and that was joined in 2006 by Fenwal. And I think everybody knows that that has been suspended as of actually last week I believe.

So the 7-day platelet release test, and this is a release test, I'll emphasize that, is that the platelet product is sampled at 24 to 36 hours post apheresis collection; 4 to 5 mL aliquots of the single donor platelet in both are placed in one aerobic and one anaerobic culture bottle; and the platelets are released if there's no growth indicated after 24 hours on test in the BacT/ALERT; and then the culture bottles remain on test until they either turn positive or the platelets expire; and then, of course, standard practices are indicated for microbiology and any clinical follow-up for positive cultures.

But the scheme looks like this: 7-day apheresis platelets, if they're collected at this point, they're held for 24 to 36 hours in quarantine, then they're sampled and the bottles are inoculated, and things are incubated for 24 hours. If after 24 hours we still have a negative test, then the products are released into inventory and then we have 7-day platelets that progress through their potential life. So that's a 7-day platelet.

The PASSPORT post marketing surveillance study takes advantage of the fact that some of these products will outdate, they won't be used, and we wanted to recapture and retest 50,000 of these with the two bottle test. And, again, we would incubate those recultures seven days and analyze the data the end.

There's been some confusion in the vernacular here for types of centers that participate. One type of center is the Tier 1 center and they're the type of center that either they're small enough, or for some other reason, they can only supply release test data.

There are other participants in PASSPORT that are called Tier 2 participants, and they actually supply both the release test data and surveillance data on any products that they're able reculture.

The primary hypothesis is listed here. I won't read the whole thing, but, basically, we're comparing 7-day platelets, and this is a non-inferiority test where we're saying it will not present a greater risk than 5-day platelets that are untested.

Specific aims of PASSPORT study were to determine specificity, sensitivity, negative predictive value, positive predictive value of the 2-bottle release test and to determine the prevalence of bacterial contamination for untested and for 2-bottle tested single donor platelets, because, remember, we only guessed at this at the beginning. And there's also some questions related to should we also include the anaerobic bottle long term for a release test.

As of March 2008 there were 51 centers across the United States that were participating. An accrual for the number of sites is shown from 2005 to 2007. This is the number of centers that are participating up to 51. This was certainly slower than we anticipated. We thought it would be a little steeper than that.

This has led to accumulative, over 320,000 release tests that have been conducted and 4,369 surveillance tests of expire products to date.

This is important. This is the criteria that we use to evaluate products and this is from AABB recommendations where we have the type of event, a true positive, false positive, indeterminate, true negative, false negative, and this is for products that are not transfused. This is for platelets that end up being transfused.

Of course, a true positive is one where we can confirm with another test or that we can confirm, perhaps, in the patient a septic event with a bug that matches. False positive is one where we cannot confirm it. Indeterminates are those where we can't actually do the test. True negatives are those where we don't get an initial release test positive and we just get information from the clinic.

What's important about this is that products where we get initial positives, which would be this group and part of the indeterminates, the clinic data actually comes from a phone call from the blood center to the clinical service to say how's the patient doing. Some of the indeterminates and some of the true negatives and false negatives, that comes from passive surveillance at the clinical site calling the blood center to say we have a sick patient.

Results to date are shown here out of 320,983 single donor platelet collections. We have interdicted all of these products, 62 true positives, and these are the event rate per million shown over here. And then there were, of course, some that we didn't catch in time, some true positives, some false positives, and some indeterminates that were transfused to patients. And there were two false negatives shown here, and I'll show you them again in a second. One was a double platelet product where they both were transfused on day six. One patient had a fever, the other patient did not. There was another double platelet product that had staph aureus in it.

Surveillance test, which is the main aim of PASSPORT, with the 4,369 tested after day 7, there were three true positives for a rate of 868/M with a very wide confidence interval because of the low number here. The specific positives, one was with staph aureus. This is the aerobic bottle. This is the anaerobic bottle. This is how long it took for the machine to turn positive, 3.7 hours, and these were confirmed as true positive.

There was another one, split donation, that came up with staph epidermidis. And the second bag, actually, was transfused on day 4 and there was no adverse reaction reported from that patient. And the third was a strep veridans. You can see the results there.

The confirmatory test came up with diphtheroid like gram positive rods. So that's not strep veridans, but because of our definitions that turned out to be a true positive.

To give you a little perspective on what these numbers might mean, I tried to compare the PASSPORT data to other data that had been reported. This shows the one bottle test. This is only the aerobic bottle, and that's all that the American Red Cross uses. They've reported on over a million tests and they have a rate of 185/M here. This is the PASSPORT evaluated for only the one bottle test. It looks like we're about the same number there.

The studies to the right are

two bottle tests, so this is the anaerobic and the aerobic bottles. PASSPORT, we have some data from the Irish, some data from the Welsh. These are a little bit apples and oranges because the test conditions, sample size, time of collection, those types of things, are not exactly the same between these three studies, but I still think it's instructive to look at them.

These are platelets that are prepared by the buffy coat method in Ireland and Wales and you can see what these rates are and the confidence intervals associated with those.

Now, the last three studies have actually done some surveillance testing and this shows the surveillance test for PASSPORT with confidence, 95 percent confidence interval. The Irish surveillance, and, of course, this is for apheresis and for buffy coat products, and this is the Welsh surveillance, again, for both types of products.

So with the caveat that this is a little bit apples and oranges, it kind of seems like we're comparable across studies.

Just real briefly to show you the two bottle test results because there's a lot of questions about do we need two bottles, the main point of this slide is that if we look at the totals for the number that come up in aerobic only, the anaerobic only bottle, or both bottles at the same time, there's quite a number of discordant bottles where we actually pick up true positives or false positives for that matter or indeterminates.

So some would say that this might be an argument for using two bottles. It's not clear of the cause of this is because of this sample volume or because of the characteristic of the anaerobic bottle.

This is a list of the actual organisms that have been identified for true positives in both bottles. And I do want to point out that probably as early as some time in 2003 all of these products would have been transfused to patients. They were caught.

So these are gram negative organisms, citrobacter, E. coli, Klebsiella, Serratia marcescens. This shows the number of products and this is the time to detection in the aerobic and the anaerobic bottles. So you can see that list for yourself. Some not nice organisms to have in your bloodstream.

These are organisms that were detected in only one or the other bottle. This is the aerobic bottle, Bacilius, Corynebacteriums, Staphus Aureus, et cetera, with the same presentation of the number of events and the time to detection.

If you notice in the anaerobic bottle, one of the controversial issues is we have these Corynebacteria species, diptheroids, and Propionibacterium, and maybe these are all the same thing. Depends on what lab you're in. There's a lot of questions about what does that mean clinically. We don't know.

Clinical outcomes, we've transfused 13 true positives. There were 202 indeterminates transfused. There have been no deaths reported. Fourteen (14) transfusion reactions that were related to bacterial contamination for a rate of 44/M.

And this shows the clinical outcomes. These are the first two false negatives that I showed you on the previous slide. The first one was the release test was negative. There were two products made from this collection. They were both transfused on day 6.

The first product, there was no reaction. The second one, there was a febrile reaction. The followup with the blood culture and the confirmatory test, the product showed coagulates negative staph.

Another false negative where clearly there was a sepsis related to staph aureus and there was a fever with staph aureus.

We have some true positives with P. acnes, Corynebacteria species. Several indeterminates where we really couldn't tell if it was a true positive or not shown here. I'm not going to go through the whole list. You have it in your handout I think.

And then this shows the age of the platelet, day 3 through day 7, the number of reactions that have been reported, septic transfusion reactions. The very difficult thing is we don't have good denominators for this, so to calculate rates is very difficult. We've tried to make some estimates based on distribution patterns. And based on that, it appears that the septic transfusion risk is about the same from day 4 to day 7. But, again, those are just estimates.

So, in summary, the 2-bottle release test, true positives were 234/M; if we add positives and indeterminates together, we're up at 1000/M or about 1/1000. These data are generally consistent with other reports.

Two hundred and fifty-six (256) collections were not interdicted prior to transfusion. Surveillance showed an estimated rate of 686/M; and, again, this is generally consistent with other reports. There have been no deaths reported and this one could contrast against reports from Hopkins in the late '90s with a rate of 15/M. Fourteen (14) transfusion reactions, you can contrast that, again, with the Hopkins data of about 70/M.

Thank you very much.

CHAIR SIEGAL: Thank you, Dr. Dumont. Are there any questions for Dr. Dumont? Dr. Epstein?

DR. EPSTEIN: Yes. Thank you very much, Larry.

Just one small point, on clinical outcomes three in the summary, you suggested that the rates of contamination might be the same for day 4, 5, 6, 7. But my understanding of PASSPORT is that we don't know the number or proportion of units transfused at each age.

DR. DUMONT: That's exactly true.

DR. EPSTEIN: So, therefore, we don't actually know the relative risk.

DR. DUMONT: We do not know the denominators. No, that statement was based on -- we do know some distribution patterns from large users and we try to make some estimates with obvious assumptions about usage based on distribution patterns. So we do not know denominators.

CHAIR SIEGAL: Anyone else? Thank you very much. Now, we're going to hear from our own Louis Katz talking about the PASSPORT study and risk analyses.

DR. KATZ: All right. So I'm going to try and do two things in I guess 10 or 15 minutes. The first is appended onto what I was asked to do.

So PASSPORT was the notice of bid suspension by the sponsors came in late January and since all the PASSPORT blood centers are ABC centers, we then asked Dr. Bianco at ABC to do a survey earlier this month to see whether we could begin to estimate any impact of the suspension on the participating centers.

Our 18 differs from the numbers you saw from Larry because we count only the corporate entity and he's counting all the individual blood regions, for example, within blood systems. So the numbers match if you add things up.

So there were 18 ABC PASSPORT centers representing the vast majority. There are some hospitals participating, hospital transfusion services participating, but the vast majority, 80 percent plus of the 7-day platelets being distributed were from these 18 ABC PASSPORT participants. And we also asked the nonparticipants in the U.S. part of ABC to tell us if they had or were aware of impact.

And I'm going to go through this very quickly. Ten of 16 said that to reach their planned levels of apheresis platelet production would require three to six months to get back to it with the loss of the day 6 and 7 platelets. So with the shorter outdate, more platelets are not usable at the end of the fifth day and five of 16 needing more than six months.

Five of the larger centers need to increase their collections from 1,000 to 6,000 units a year to compensate for increase outdate rates that will from probably an average of a three percent outdate rate of the 7-day platelets up toward ten percent. So, for example, at my center, which I wouldn't actually call a larger center, our outdate rate has gone from between one and two percent up to seven percent where it was before we were manufacturing 7-day platelets. It's based on only a couple of months of data and everybody is trying to do things in inventory management that will minimize that.

One center is going to replace the apheresis losses with prepooled platelets from whole blood that can be cultured. Three of 16 are going to increase their distribution of whole blood derived platelets by 20 to 30 percent and that will be important as we discuss risk. And five of the 40 non-participants who responded said the discontinuation of PASSPORT was affecting their operations and that's because those are centers that import platelets from places like mine that are making 7-day platelets.

Amongst the PASSPORT participants, four of the 15 have changed their bacterial detection procedure from two bottles to a single aerobic bottle because the only requirement for the anaerobic bottle was, in fact, to participate in PASSPORT, and so several have indicated that they're going to switch back to a single aerobic bottle.

We don't have details on the volume of culture that's going to be used, whether they're going to double the innoculum into the aerobic bottle or not and two more plan to change. Six of 15 have reduced the incubation after inoculation to product release from 24 hours to less.