DEPARTMENT 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

 

78th Meeting

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Thursday, December 11, 2003

 

8:00 a.m.

 

 

 

 

 

 

 

 

 

 

 

Hilton Gaithersburg

620 Perry Parkway

Gaithersburg, Maryland 20877

PARTICIPANTS

 

   Kenrad E. Nelson, M.D., Chairman

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

   Pearline K. Muckelvene, Committee Management

   Specialist

 

MEMBERS:

 

   James R. Allen, M.D., M.P.H.

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

   Kenneth Davis, Mr., M.D.

   Donna M. DiMichele, M.D.

   Samuel H. Doppelt, M.D.

   Jonathan C. Goldsmith, M.D.

   Harvey G. Klein, M.D.

   Suman Laal, Ph.D.

   Judy F. Lew, M.D.

 

NON-VOTING INDUSTRY REPRESENTATIVE:

 

   D. Michael Strong, Ph.D.,

 

TEMPORARY VOTING MEMBERS:

 

   Charles Bolan, M.D.

   John M. Boyle, Ph.D.

   Peter L. Callero, Ph.D.

   Liana Harvath, Ph.D.

   Katharine E. Knowles

   Matthew J. Kuehnert, M.D.

 

SPEAKERS:

 

   Mary Beth Bassett

   Paul C. Beatty, Ph.D.

   Michael F. Busch, M.D., Ph.D.

   Peter Hellstern, M.D.

   Barbara L. Herwaldt, M.D., M.P.H.

   Anthony A. Marfin, M.D., M.P.H.

   Stacy L. Sime

   Susan L. Stramer, Ph.D.

   Ruth D. Sylvester, Literature. Col. USAF, BSC

   Mary J. Townsend, M.D.

 

C O N T E N T S

 

Conflict of Interest Statement and Committee Member

   Introductions, Linda A. Smallwood,

   Executive Secretary     6

 

Update: Use of Secure E-Mail, Michael Fauntleroy     12

 

Topic I: AABB Abbreviated Questionnaire:

 

A. Introduction and Background,

   Judy Ciaraldi, MT(ASCP)SBB,

   Consumer Safety Officer, OBRR     17

 

B. AABB UDHQ Task Force Perspective on Abbreviated

   Questionnaires, Mary Townsend, M.D., Chair, UDHQ

   Task Force, AABB     30

 

C. FDA Regulatory and Review Issues,

   Judy Ciaraldi, MT(ASCP)SBB,

   Consumer Safety Officer, OBRR     61

 

   Sharon O'Callaghan, MT(ASCP),

   Consumer Safety Officer, OCBQ     70

 

D. Experience Using Abbreviated Questionnaires,

   Mary Beth Bassett, MS, MT(ASCP)SBB, Vice

   President, Quality Management and Regulatory

   Affairs, Blood Systems, Inc.     91

 

   Stacy Sime, MS, MT(ASCP)SBB,

   The Blood Center of Iowa     113

 

F. Validation of Donor Screening Procedures,

   Alan Williams, Ph.D., Director, Division of

   Blood Applications, OBRR     126

 

E. Can Abbreviated Questionnaires be

   Studied/Tested, Paul Beatty, Ph.D., NCHS, CDC     144

 

Open Public Hearing:

 

   Steven Kleinman, M.D., AABB     157

   Celso  Bianco, M.D., ABC     162

   Peter Page, M.D., ARC     165

   Susan Rothman, M.D. Gulf Coast Blood Center     172

   Debra Kessler, New York Blood Center     174

   Dorothy Kowalski, New York Blood Center     176

   Mary Gustafson, PPTA     178

 

C O N T E N T S (Continued)

 

G. FDA Current Thinking and Questions for the

   Committee, Judy Ciaraldi, MT(ASCP)SBB,

   Consumer Safety Officer, OBRR     180

 

H. Committee Discussion and Recommendations      181

Topic II:  Potential Recommendations on Blood Donor

           Deferral for Leishmaniasis and its

           Exposure:

 

A. Interpretation and Background,

   Robert Duncan, Ph.D. Staff Scientist,

   DETTD, OBBR     211

 

B. Leishmania Pathogenesis and Epidemiology,

   Barbara Herwaldt, M.D., M.P.H.,

   Medical Epidemiologist, CDC     218

 

C. Department of Defense Leishmaniasis Donor

   Deferral Policy, Lt. Col. Ruth D. Sylvester,

   USAF, BSC, Director of Operations, Armed

   Services Blood Program     256

 

D. Impact of Leishmaniasis Donor Deferral Policy on

   the Blood Supply, Sharyn Orton, Ph.D., Acting

   Chief, Blood and Plasma Branch, DBA, OBRR     266

 

Open Public Hearing:

 

   Steven Kleinman, M.D., AABB     271

   Kirt Love, Desert Storm War Battle Registry     274

   Venus Hammack     282

 

E. FDA Current Thinking, Questions for the

   Committee, Committee Discussion and

   Recommendations       285

 

Topic III: Update on West Nile Virus Epidemic and

           Donor Testing in 2003

 

A. Introduction and Background, Hira Nakhasi,

   Ph.D., Director, Division of Emerging and

   Transfusion-Transmitted Diseases, OBRR, CBER     318

 

B. Update on Epidemiology Including Reports of

   Transfusion-Transmitted Cases, Anthony Marfin,

   M.D., Acting Deputy Director, Division of

   Vector-Borne Infectious Diseases, CDC  329

 

C O N T E N T S (Continued)

 

C. Updates on WNV Testing Under IND and Plans

   for 2004:

 

   Susan Stramer, Ph.D., Executive Scientific

   Director, The American Red Cross     365

 

   Jeff Linnen, Gen-Probe     386

 

   Jim Gallarda, Roche     394

 

D. Status Reports:

 

   Prospective and Retrospective Testing Using

   ID-NAT and Update on Relative Sensitivity Study

   for WNV NAT Testing, Michael Busch, M.D., Ph.D.,

   Blood Centers of the Pacific     408

 

   Prospective and Retrospective Testing Using

   ID-NAT, Susan Stramer, Ph.D., Executive

   Scientific Director, The American Red Cross     425

 

   Follow-up Testing of Canadian Donors who Tested

   Positive for WNV RNA by Routine Screening/

   Establishment of a Reference Reagent for WNV

   NAT Assays, John Saldhanha, Executive Director,

   Infectious Diseases, Canadian Blood Services     444

 

   Update on Infectivity Study, Indira Hewlett,

   Ph.D., Chief, Molecular Virology Branch,

   DETTD, OBRR     455

 

Open Public Hearing:

 

   Andrew Heaton, Ph.D., Chiron   463

 

   Celso Bianco, M.D., ABC     467

 

   Steven Kleinman, M.D., AABB     471


P R O C E E D I N G S

Conflict of Interest Statement

     DR. SMALLWOOD:  Good morning.  We are ready to convene.  Welcome to the 78th meeting of the Blood Products Advisory Committee.  I am Linda Smallwood, the Executive Secretary.

     At this time, for your hearing pleasure, I will read the conflict of interest statement.

     [Laughter]

     This announcement is part of the public record for the Blood Products Advisory Committee meeting on December 11th and 12th, 2003.

     Pursuant to the authority granted under the Committee Charter, the Director of FDA's Center for Biologics Evaluation and Research has appointed the following individuals as temporary voting members: Dr. Charles Bolan, Dr. John Boyle, Dr. Peter Callero, Dr. Liana Harvath, Ms. Katharine Knowles and Dr. Matthew Kuehnert.

     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 18 U.S.C. 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 discussion 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 the non-voting industry representative acting on behalf of regulated industry.  Dr. Strong's appointment is not subject to 18 U.S.C. 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 are involved with West Nile Virus research.

     With regard to FDA's invited guests, the Agency has determined that the services of these guests are essential.  There are interests that are being made public to allow meeting participants to objectively evaluate any presentation and/or comments made by the guests.

     For the discussion of Topic 1 related to the abbreviated questionnaire form for donor screening, Ms. Mary Beth Bassett is employed by Blood Systems, Inc.  Mr. Paul Beatty is employed by the National Center for Health Statistics.  His agency receives funds from NHLBI to evaluate questionnaires.  Ms. Stacy Sime is employed by the Blood Center of Iowa.  Dr. Mary Townsend is employed by the America's Blood Centers.

     For the discussion of Topic II on blood donor deferral for individuals exposed to leishmaniasis, Dr. Barbara Herwaldt is employed by CDC.  Lt. Col Ruth Sylvester is employed by the Armed Services Blood Program.

     For the discussion of Topic III on the current status of West Nile Virus, Dr. Michael Busch is employed by the Blood Systems Research Institute.  He is a scientific advisor, is a principal investigator on a contract, and receives speaker fees from firms that could be affected by the discussions.  Dr. Antony Marfin is employed by the Division of Vector-Borne Infectious Diseases, Center for Disease Control in Fort Collins, Colorado.  Dr. Susan Stramer is employed by the American Red Cross, National Reference Laboratory of Infectious Disease.  She is a researcher, a scientific advisor, and has financial interests in firms that could be affected by the discussions.

     For the discussions of Topic IV on plasma collection nomograms, Dr. Charles Bolan is employed by the Division of Transfusion Medicine, Clinical Center, National Institutes of Health.  Dr. Peter Hellstern is employed by the Academic City Hospital as Professor of Internal Medicine and Head of the Institute of Hemostaseology and Transfusion Medicine in Germany.  The Institute includes a non-profit blood donor center.  Dr. Hellstern is also a member of the Plasma Protein Therapeutic Association and is involved in a study of the safety of intensified plasmapheresis for the improvement of the quality of source plasma and source plasma products.

     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 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.

     The statement that I have just read will be available for your review, if you so desire.  At this time are there any declarations to be made relative to any potential conflicts of interest?

     [No response]

     Again, all individuals participating in the public hearing are reminded that before you present you must state your name and your affiliation and any potential conflict you may have, and you will be reminded again at the time of the open public hearing.

     At this time I would like to introduce to your the members of the Blood Products Advisory Committee.  As I call your name, would you please raise your hand?  The Chairman, Dr. Kenrad Nelson.  Seated to his right is Dr. DiMichele; Dr. Goldsmith; Dr. Allen; Dr. Cunningham-Rundles; Dr. Davis; Dr. Callero; Ms. Knowles; Dr. Strong; Dr. Doppelt; Dr. Laal; Dr. Klein; Dr. Harvath; Dr. Boyle and Dr. Kuehnert.

     I would just like to announce that there will be a new schedule for the BPAC meetings in 2004.  The tentative new dates are March 18 and 19; July 12 and 13; October 21 and 22.  Again, these are tentative and we will confirm them at a later date but for your planning, you have those.

     We have a very full agenda today.  I would like to remind everyone speaking to please stay within your limits.  I do have a timer and I will use it--

     [Laughter]

     --I also have a pointer that you may use if you so desire.  I have it at my table so if you ask to use it, I will allow you to.  I don't want you to walk away with it; it does have an alarm on it.

     [Laughter]

     So, at this time I would like to turn the proceedings of the meeting over to the Chairman, Dr. Kenrad Nelson.

     DR. NELSON:  Thank you, Dr. Smallwood.  Welcome to the 78th meeting.  The first item on the agenda is an update by Michael Fauntleroy on use of secure e-mail.

Update: Use of Secure E-Mail

     MR. FAUNTLEROY:  Hello.  We are going to get directly into this in the interest of time.  I will be very brief.

     Next slide, please.  At FDA, CBER this is what we are dealing with.  I want you to understand why we are here, talking about secure e-mail and the ability to transmit information to us in a secure fashion for us to facilitate discussions.

     This is what our document control looks like.  We spent quite a bit of money on housing and archiving paper and it does not facilitate the review process because it takes days to move information versus minutes in access.

     Next slide, please.  With our security e-mail program we have scope, delivery and receipt of regulatory documents, focused receipt of regulatory submissions to preexisting electronic applications, as well as the exchange of information to facilitate decision-making for all applications translation.  We have the ability to do this for paper submissions.  Please make a note of that.  All security mail messages received and sent out are archived.

     Next.  From the industry point of view, I would like to tell you what is in it for you.  You have the ability to deliver amending regulatory submissions to existing electronic BLAs, IDEs and INDs in a matter of minutes to the RPM, Regulatory Project Manager, versus spending days for one-day delivery, logging into DCC, routing up to the office and then having it routed after administrative action has been done to take the data, put it in the system and then move to the reviewer.  We are talking about a matter of 10, 12 minutes for a 20 megabyte file versus 5 days.  Also, as of December 5 this year, for PMAs, 510(k)s, IDEs, as well as BLAs and INDs which we already have, you have the ability now to interact with FDA reviewers on both electronic and paper submissions via this method.

     Next slide.  This basically lays out the structure for a regulatory amendment and regulatory communications.  These are the two options that you have.  So, even if you do not have an electronic submission, you can interact with us in this manner.  We do recommend it.  We are trying to get away from the burden and bane of faxes.  This allows usable documents to be delivered to the Agency quickly and easily.

     Next slide.  This details the structure.  I would like to note for you, because most of you do not have electronic submissions here, that the communications allow a wide variety of files to be attached and delivered to the Center for discussion.  It is not an official regulatory submission because it does not have a signature.  You will have to follow it up with an official regulatory document for your paper submission but this facilitates the communication and allows you to move documents back and forth six, seven times a day if needs be, PDF, Word, Excel, down the list that is a binary file.

     Next slide.  Understand that we have the instructions now being posted to CBER's web page for the establishment of this communication method.  We have the instructions to industry for the electronic submissions template put forward, and for regulatory correspondence the instructions to establish that connection also.  You will be contacting Joseph Montgomery or Dan Offringa within CBER's Office of Information Management to establish these connections.  Those are important numbers.

     Next slide.  That is just the technical information.  I wanted it in the document so that those who do access the Power Point presentation will have some background for IT shops.

     Next slide.  This is the freebie; this is what it is really about.  In the absence of a formal guidance document, we are now within CBER allowing the industry to submit electronic copies of the paper submission in PDF format for 510(k)s and PMAs.  We will post this to a server area for the review team to access.  So, not only do you have the ability now to establish a secure e-mail connection but an electronic document.

     Well, what is the benefit here?  Instead of making seven copies of a submission to send in for review to be disseminated, which is five over and above what the regulations state in some cases.  I think it is the PMA or is it the 510(k)--one of the two, I am not exactly sure; I have heard quite a bit about it.  Now you can give us an electronic document.  You cut your paper cost; you cut your delivery cost and it cuts our handling cost.  We have a viable secure e-mail program for all applications and submissions, both paper and electronic, and all messages are archived.

     Next slide.  Thank you.  Questions?

     [No response]

     Okay, everybody is still waking up on a Thursday morning at 8:00-something in the morning, but at this point in time please note we now have all the capability to address and facilitate the MDUFA requirement and goals quickly and in an archivable fashion.  Yes, sir?

     DR. BIANCO:  Celso Bianco, America's Blood Centers.  Does this system include electronic submissions of the common applications that blood centers and blood banks provide like CB-30s by prior approval supplements and these type of systems, not the BLAs?        MR. FAUNTLEROY:  Well, CB-30 is a BLA supplement and it will be eligible for the amending submission or communications for this type of submission if you send it in electronically.  We presently already allow for BLA supplements to be submitted to the Agency in electronic format.

     DR. NELSON:  Thank you.  The next item is discussion of the abbreviated donor questionnaire.  Judy Ciaraldi will give us an introduction.

Topic I: AABB Abbreviated Questionnaire

Introduction

     MS. CIARALDI:  Good morning, everybody.  Thank you very much for being here and happy holidays.

     Next slide, please.  The abbreviated donor history questionnaire is a component of the donor screening procedures or process which includes educating the donor about the risk of transmitting diseases and allowing them options for self-deferring, questioning the donor about their medical history and behavior and performing a physical examination on the donors, as well as testing the donors for evidence of infection due to communicable diseases.

     Next slide, please.  The purpose of doing these is to ensure that the donation procedure is safe for the donor and that the product is safe and effective for transfusion or for protecting the staff within a blood center.  Besides making sure that the product is safe for transfusion, we want to make sure it is also safe before it is further manufactured into plasma derivatives.

     Now, the FDA donor selection criteria are described in our regulations and in our guidance documents but, as you probably know from looking at the regulations, they do not include specific required questions.  Instead, the regulations include information that the blood center must obtain from the donor and, when tests are not available, asking a question and getting information.  That way is one method.

     Next slide, please.  We also don't have a required questionnaire.  Besides not having required questions, we also don't have a required questionnaire that FDA has developed but we have approved various questionnaires.  The last AABB uniform donor history questionnaire that we approved--reviewed and approved--was in 1998.  It is a full-length questionnaire that is currently being used with updates to include the new donor deferral recommendations.  We have been told that we can no longer officially approve industry standard questionnaires so we are seeking out other methods to inform everybody that we have reviewed the questionnaires and consider them acceptable documents.

     We also review Center developed questionnaires.  Licensed blood establishments send in their questionnaires to CBER for us to review.  We look at them to make sure they include all of our regulations and to see if they do have our recommendations in there, and if they do address all of our concerns we will approve them.

     We have also approved abbreviated questionnaires for two licensed blood establishments and you are going to hear about them today.

     Lastly, we approve both the abbreviated and full-length questionnaires for source plasma establishments, and the source plasma establishments routinely administer the full-length questionnaire on an annual basis.

     Next slide, please.  Besides reviewing Center developed questionnaires, we also support the uniform donor history task force by providing liaisons and funding for some of their studies.  We spend a lot of time and effort reviewing the uniform donor history questionnaire material sent in by the American Association of Blood Banks representing the full inter-organizational task force.  It is our current thinking that we will prepare a guidance document that will accept the full-length questionnaire that the AABB has prepared.

     Lastly, we are continuing our review on the Plasma Protein Therapeutic Association Questionnaire materials that will be used for screening source plasma donors.

     Next slide.  Just to briefly go over our review process, in 2001 the AABB submitted a proposed revised full-length questionnaire and asked for our input.  This questionnaire was shared with individuals within the Office of Blood, Office of Compliance and Office of Regulatory Affairs.  When the comments were gathered they were forwarded back to the task force which used them to prepare their final materials, and sent those in, in 2002, to the FDA.  These materials included a full-length quality assurance and an abbreviated questionnaire, a user brochure, educational materials, as well as cognitive study results and focus group study results.  These were reviewed within the same offices in FDA, and we also included four industry members from past and present BPACs.

     We gathered those comments and submitted them back to the task force which used them to revise their materials.  Earlier this year they submitted their materials to us.  We reviewed them to make sure that they addressed all of our concerns.  At this time we were able to look at the abbreviated questionnaire in its more final format and we highlighted some concerns and questions that we wanted to discuss.  We also found some small edits that needed to be made on the other materials.  We called the task force with our comments and with our concerns.  They made the revisions and submitted those in the summer of this year.  We did one quick review of the revised materials to make sure that all of the comments had been included and we notified the task force that we had completed the review on the full-length questionnaire but we were still discussing the abbreviated questionnaire.

     Next slide, please.  Abbreviated questionnaires are used for established frequent repeat donors.  They are used to reduce both the donor and the staff frustration with repeatedly asking the same information time and time again at every donation.  They focus on collecting new eligibility information that may have changed just since the previous donation.  The historical information, as provided on initial donations, are not re-ascertained in that the questions for getting the historical information are not included on the abbreviated questionnaires.

     Next slide, please.  We have had several FDA discussions on abbreviated questionnaires.  The earliest ones led to including in our 1990 HIV memoranda an allowance for using abbreviated questionnaires or abbreviated materials to obtain information about HIV high risk behavior from repeat source plasma donors and autologous donors.  The guidance document didn't specify how the materials could be abbreviated and we have seen a variety of methods that were submitted by licensed blood and plasma establishments to FDA for our review.

     Next slide, please.  We also commissioned a study by the American Institutes of Research in the early '90s to study ways to increase the safety of the blood supply by screening donors more effectively.  An outcome of the study was development of an interactive computer-donor interview process that included as a component an abbreviated questionnaire for repeat donors.  This particular format for administering questions to donors was field-tested in three donor centers.

     Next slide, please.  The investigators from the AIR report presented their initial findings at a 1993 BPAC.  I sent you the transcripts from that BPAC meeting, much to Dr. Smallwood's consternation.  She gave me the "stink eye" when I came with all the transcripts that she had to copy and mail to you.  The AIR report summarized the use of the abbreviated questionnaires by saying that the abbreviated interview deferred and accepted the same donors as did the longer version.

     FDA statisticians had also looked at the AIR report materials and their study data and had determined that there were problems or faults with the design of the studies and the data themselves.  Two examples that they listed were that it was hard to compare the abbreviated questionnaire in a computerized form with the paper questionnaires because they really were devised by two different groups and really contained two different sets of material.  It was hard to compare apples and oranges.

     They also noted that in at least one of the field-tested centers donors were counted twice so that skewed some of the data and it was hard to determine the true validity of the data.

     BPAC expressed concern about the validity of the data but believed that the concept in the abbreviated questionnaire could have an advantage to the repeat donor.  A vote was taken at this time that asked if there was sufficient information provided to demonstrate the equivalence of the abbreviated questionnaire for repeat donors and whether or not we could recommend it.  The vote at that time was no/yes votes.  Six no votes and one abstained.

     Next slide, please.  The AIR report was presented again at the '94 BPAC.  At this time, the BPAC members supported the concept of an abbreviated questionnaire but still expressed concerns about the study design and the data.  FDA made a statement that blood centers may use the AIR material, any or all of it; may use the abbreviated questionnaire with or without a component of a computer program, and that we will accept individual proposals for abbreviated questionnaires from blood centers.

     In 2000, we sponsored a workshop with the American Association of Blood Banks to define and discuss methods for streamlining the blood donor questionnaire.  Sharon O'Callaghan represented the FDA's point of view on abbreviated questionnaires by providing a list of concerns about the questionnaire and the impact it would have on the safety of the blood supply.

     Next slide.  We have had other BPAC discussions about donor history questionnaires in general.  One included a discussion in 1999 about the validation of the donor history questionnaire.  At this one, FDA said that we were concerned about the post-donation information and biological product deviation reports due to information presented on subsequent donations.  BPAC realized that this is an important issue but they wanted FDA and industry to find a way to recognize and encourage donations from repeat donors.

     In 2001, representatives from the task force described their efforts which got full support from the BPAC.  In their presentations they stressed the need to define what a repeat donor was, and they have done that in their user brochure and you will hear that from Dr. Townsend.

     In 2002, we went over the status of our review, at the time of the AABB's UDHQ materials.  We hadn't completed our evaluation of the abbreviated questionnaires but we did say that we had some concerns about its implementation.

     Next slide, please.  During this meeting we are going to continue our discussion on abbreviated questionnaires.  We are seeking your recommendation on the extent to which the data that currently exist demonstrate the risk/benefit of the AABB's abbreviated questionnaire to be at least equivalent to the current donor screening instruments that are being used, either in its proposed format or as a pilot program.  We are also asking for recommendations on strategies for pilot implementation for abbreviated questionnaires in regulated blood and plasma center environments that would allow us an opportunity to collect data.

     Next slide, please.  Today you will hear presentations from representatives from the task force that developed the AABB uniform donor history questionnaire.  Dr. Mary Townsend is the chair of that task force.  They will give their perspective on the implementation of abbreviated questionnaires.  I will come back describing our concerns and proposed implementation policies or procedures.  Ms. O'Callaghan, representing the FDA Office of Compliance, will evaluate the biological product deviation reports that apply to donor history questionnaire procedures.  Then the two blood establishments that have approved abbreviated questionnaires will give us their experiences.  Mary Beth Bassett is representing Blood Systems and Stacy Sime is representing the Blood Center of Iowa.

     One of the concerns that you heard me talk about is the lack of studies and a lack of efficient, effective studies on the abbreviated questionnaire.  What is an appropriate study and what will address the risk/benefit concerns that we have?  Dr. Paul Beatty, from NCHS, will talk about this.  Dr. Williams, from FDA, will follow-up with a validation of the donor screening procedures.

     Next slide, please.  We are proposing the following questions for your consideration, and I will display them again at the end of the presentations:

     Do current data support the use of the AABB UDHQ abbreviated questionnaire as equivalent to the donor screening process?

     Number two, if not, does the committee believe that the current data support approval of pilot programs to evaluate performance of the abbreviated questionnaire in a regulated blood environment?

     Next slide, please.  If so, please comment on the design of the pilot program.  In other words, should there be a pilot readministration of the full-length questionnaire annually to repeat donors and consideration of conversion to a biannual administration based on submitted data?  If not, what additional information is needed prior to approval of an abbreviated donor questionnaire pilot program in a regulated blood collection environment?  Thank you very much.

     DR. NELSON:  Thank you.  Questions?  Comments?  Your one slide said that FDA was not allowed to approve a questionnaire but then you went on to sort of suggest that it approved questionnaires.

     MS. CIARALDI:  Well, we can approve an industry standard questionnaire, one that was developed independent of a licensed blood establishment.  So, that is the difference.  We can't approve individual questionnaires that come in from licensed blood establishments because it is part of their biologics license application and supplements that they report to that.  But an industry standard developed questionnaire is what we can't officially approve and we have to find another mechanism for saying that it is an acceptable instrument.

     DR. EPSTEIN:  Kenrad?

     DR. NELSON:  Yes, Jay?

     DR. EPSTEIN:  Yes, if I could comment, when we issue guidance documents, which are non-binding on the Agency or the industry, what we are saying is what operations or procedures would be acceptable to the Agency to meet regulatory requirements.  So, we have the mechanism through a guidance document to state that the uniform donor history questionnaire is acceptable to the Agency as a way to comply with regulatory requirements.  So, the distinction that is being made here is between an approvals process which is linked to licenses versus a guidance process through which we can declare the acceptability of procedures.  So, it is a technical distinction, if you will, but we needed a legal mechanism to give some status to UDHQ from a regulatory point of view so we have found it to be acceptable to the Agency.

     DR. NELSON:  Thank you.  Any other comments?  If not, Dr. Townsend, AABB uniform donor history questionnaire task force chairman.

AABB UDHQ Task Force Perspective on

Abbreviated Questionnaires

     DR. TOWNSEND:  Good morning and thank you for inviting me to discuss the abbreviated questionnaire, and thank you for your consideration of this exciting new improvement in donor screening.  I will apologize to begin with, I know I have been given 15 minutes but I was asked to cover a lot of material and there is no way I am going to do this in 15 minutes, not to mention that I am a Southerner and everybody knows it takes twice as long for us to say something.

     Next slide.  I have been asked to cover a lot of territory in a short time so I will only briefly summarize the history of the project and, in the interest of time, will refer you to the documents that were sent in advance of this meeting.  I will spend the bulk of my time reviewing the rationale, development and use of the abbreviated questionnaire, address issues and concerns and discuss some proposed post-implementation monitoring strategies.

     Next slide.  Previous BPAC meetings have discussed the full-length questionnaire at length.  The process started in 2000 and employed new approaches and methodologies in developing a streamlined donor questionnaire that is intended to make the screening process easier and more understandable to donors and to those who screen them and, at the same time, maintain the safety of the blood.

     The major changes include the use of capture questions with simplified language and a time-bounded format.  Standardized materials, including a medication list and donor education materials, were also developed and tested using focus groups followed by cognitive interviewing.  A user brochure that describes the use of the questionnaire in more detail was also developed and tested by donor screeners, and you have a copy of that in your materials.  BPAC has already endorsed the use of the full-length donor questionnaire and we are eagerly awaiting the promised FDA guidance permitting use of the new questionnaire.

     However, before moving on to today's topic, the abbreviated questionnaire, I want to emphasize to this committee that this is the first time a blood donor screening document has been systematically evaluated and it is this new evaluated, validated questionnaire that is the basis for the abbreviated questionnaire.

     Next slide.  It is important to start by defining "why" behind the abbreviated questionnaire.  Where did this concept arise?

     Next slide.  First, a shorter, more focused questionnaire for frequent donors has been a top request of donors for years.

     Next slide.  A 2002 nationwide study to determine why donors stop donating or become lapsed donors was performed by mailing surveys to current and previous Red Cross and ABC donors.

     Next slide.  The top three reasons lapsed donors give for no longer donating all have to do with the length of the process--too busy, too inconvenient or too much time.

     Next.  In their conclusion, the authors stated efficiency of the collection and convenience of the collection are perceived as important variables to facilitate or impede blood donation and should be integrated into blood center recruitment and retention strategies.

     Next slide.  The same group performed a similar nationwide study among a random group of non-donors or people who had never donated by conducting random telephone interviews of 1,673 persons.

     Next slide.  Again, three of the top five reasons given for never having donated were related to the perceived length of time and inconvenience.  Clearly, if we want to get new donors in the door we must find ways to make this process more convenient.

     Next.  It is interesting to note that among these non-donors perceived inefficiency ranked even higher than the fear of needles as primary factors in impeding donations.  These two studies cited are small but studies on this important aspect of blood donation are sadly lacking.  The more we know about why donors donate or do not donate, the better able we will be to improve the process and maintain repeat frequent donors, a group that has been shown through multiple studies to have a significantly lower risk of infection and deferrable risk.

     Next slide.  Such a study has been conducted by the REDS group but that is currently being evaluated and is not available for our review today.  The REDS study was designed to examine barriers to donation return in lapsed donors and to assess whether reasons varied by race and ethnicity or by first time versus repeat donors.  We are looking forward to having this data available in the future and encourage similar studies.

     Next slide.  Donor complaints regarding repetitiveness were confirmed by a 2000 survey conducted by AABB as a pilot project of the donor history task force to determine issues of concern for blood collection facilities and donors to be addressed by the task force in developing the new questionnaire.

     Next slide, please.  Comments most frequently noted were repetitive questions and the personal nature of the questions.  There is little that the task force could do about the personal nature of the questions but we attempted to address repetitiveness through development of an abbreviated questionnaire.

     Next slide.  Blood donors and collection facilities are not the only participants crying out for change.  FDA and even BPAC have considered the appropriate use of an abridged donor screening questionnaire as early as 1994.  The FDA sponsored the American Institutes of Research study to determine if safety in the blood supply could be improved by using a more effective process, specifically an abridged questionnaire and/or computer-assisted screening.  It was reported to BPAC in 1994.  A subcommittee of that group was charged with evaluation of the study and reported back to BPAC in 1995 and endorsed the concept of use of an abbreviated questionnaire for repeat donors.

     Next slide.  Further, the concept of an abbreviated questionnaire was suggested and partially endorsed by FDA at the October 16, 2000 workshop on streamlining the donor questionnaire.  To kick off the work of the task force, in his charge to the task force Dr. Epstein posed the challenge to FDA and the blood community to devise a donor selection process which optimizes both blood safety and availability.  He went on to state that the donor selection process should contribute significantly toward preventing disease transmission, yet, it should not discourage donors nor result in unnecessary deferral.

     Next slide.  Dr. Epstein went on to add that we have questions whether we maintain valid screening when we keep asking the same questions over and over and over again to repeat donors.  He concluded with stating that certainly one modification, which I suppose could be a standard modification, is that of an abbreviated questionnaire of a repeat donor.

     Next slide.  Finally, FDA has set a precedent by approving two abbreviated questionnaires and you will hear from both centers today regarding their experience with an abbreviated questionnaire.

     Next slide.  So, what did the task force hope to accomplish with an abbreviated questionnaire?

     Next slide.  Obviously, we must focus on safety since donor screening is the first layer of the proverbial onion of safety.  We designed the abbreviated questionnaire to be at least as efficient as the new full-length questionnaire for detecting deferrable risk in qualifying frequent donors.  In addition, in order to impact the other half of the safety/availability equation as defined by Dr. Epstein, we designed the abbreviated questionnaire to increase donor satisfaction and, hence, enhance availability of blood.

     Next slide, please.  First and foremost, this committee should note that the abbreviated questionnaire was not created in a vacuum.  It was developed starting with validated questions taken from a new simplified, reformatted validated full-length questionnaire.  Furthermore, during the final phase of cognitive testing of the final documents a small test of the travel capture question and the health capture question from the abbreviated questionnaire were performed by one-on-one cognitive testing.  Granted, this was a very small group.  The conclusion of the evaluator was that the process was conceptually sound and seemed to have the desired effect.

     If you came here today, however, hoping for overwhelming volumes of data specific to the abbreviated questionnaire, I am afraid you are in for a disappointment.  Although you will hear data today from the two centers with approved abridged questionnaires, large-scale studies have not been performed.  Furthermore, the appropriate studies cannot be completed until both the new full-length questionnaire and the abbreviated questionnaire are in place since they are companion documents and were designed to be used one after the other.  I will discuss task force proposals for such studies in this presentation.

     Next slide.  However, survey design theory holds that the efficiency of a questionnaire goes beyond mere questions.  These sound theoretical premises were applied to assure safety efficacy of the abbreviated questionnaire.  I am not an expert on survey design so I can only briefly note these principles but you will hear from such an expert later today and you may want to address some questions his way.

     Briefly, studies suggest that recall of current or recent events is easier than for remote events, enabling survey responders to focus and remember more accurately and to focus on recent risk behavior.  The application of this concept was eloquently summarized by Drs. Williams and Orton in their chapter on donor screening in which they concluded that behavioral risk screening needs to be optimized to query donors about factors that best predict recent infection.

     Next slide.  Beyond focusing donors' attention to recent behavior, donor attention in general is increased when the time required to complete a questionnaire is reduced.  Satisficing is the behavior of survey respondents who simply provide an answer to avoid the burden of pure concentration required to answer complex questionnaires.  Satisficing occurs in donor screening when the donor fatigues and becomes disinterested as the questioning goes on and on and on.  Krosnik describes the result of satisficing and he notes a respondent's motivation to optimize or focus in answering a particular question is determined by how long the interview has been going on.  Motivation to optimize or focus is probably greatest at the beginning of a questionnaire and decreases as more and more questions are asked and answered.  Common sense dictates that when donors are able to concentrate more fully screening will be more effective and should positively impact safety.

     Next slide.  We have already emphasized that safety is only one half of the equation and availability is the other half.  By holding on to our safest donors, the repeat frequent donors, and attracting new donors we should positively impact both halves of the equation.

     Next slide.  I now want to turn to how the abbreviated questionnaire was actually developed.  Having established sound theoretical rationale, the task force appointed a committee to develop the abbreviated questionnaire.  Again, I remind BPAC that the basis of the abbreviated questionnaire was a new clear, concise, revalidated full-length questionnaire.  The subcommittee went through this validated questionnaire question by question to determine which questions target a single risk in the remote past and could be eliminated, for instance, questions about travel and military service in the 1980-1996 period.

     They went on to consider which questions could be consolidated and to capture questions either for medical health issues or travel.  Please note that the HIV and hepatitis risk questions remain intact on the abbreviated questionnaire.

     Next slide.  The task force then tackled the question of who should qualify as a frequent donor.  The task force determined that a qualified frequent donor is one who had successfully completed the new full-length questionnaire at least twice, with one donation in the last six months.  The two donation limit was set based on anecdotal evidence that suggests donors may remember information at the second donation that they did not remember at the first donation since they were less familiar with the process.  We are aware that one of the two alternative abridged questionnaires, already approved by FDA that you will hear about today, requires three donations using their full-length questionnaire to qualify for their abbreviated questionnaire and that this requirement was based on evidence that some donors may not recall information until as many as three donations.  However, I remind you that this high rate of donor memory failure is documented for the hodge-podge of long, complicated, unvalidated questionnaires currently being used around the nation.  The task force determined that the new validated reformatted questionnaire should result in better recall and better detection of deferral of risk, and that administering such an improved document should suffice if done twice.

     Next slide.  So, who exactly are we talking about?  We are talking about donors like this whole blood donor who has come in regularly from two to four times a year for the past 14 years.  Why should this donor be asked each and every time if he or she spent time in the military from 1980 to 1996?  The answer is clearly not going to change.

     Next slide.  This is a regular apheresis donor who comes in from 3 to 16 times a year.  Why should she be asked if she has taken human-derived growth hormone that hasn't even been available since the mid-1980s?

     Next slide.  Given questions that have been posed regarding exact use of abbreviated questionnaire, I have been asked to briefly point out the differences between the two screening documents.

     Next slide.  You do have copies of these documents.  The full-length questionnaire contains 48 questions; the abbreviated questionnaire 29 questions.  There are five questions on current health and medications.  These have been distilled to two current questions with the medication questions incorporated into the capture questions.  There are six specified time questions and these are questions like "in the last eight weeks have you donated whole blood?"  These are identically worded on both questionnaires.

     There are two distinct questions that I have already talked about that were eliminated on the abbreviated questionnaire.  There are 17 direct questions that ask about risk activity.  These same 17 questions are asked about on the abbreviated questionnaire except they have been changed to, "since your last donation," to focus on recent risk.  Finally, the 14 health-related questions and four travel questions were distilled into three capture questions about changes in health risk and medications and treatments and one about travel.

     Next slide.  So, what does the comparison look like?  We will just take one example.  On the full-length questionnaire, "have you ever used needles to take drugs, steroids or anything not prescribed by your doctor" becomes "since your last donation have you ever used needles to take drugs, steroids or anything not prescribed by your doctor."  You can see that we have simply changed the prefix to focus on recent behavior.

     Next slide.  You should have copies of these two screening documents highlighted for comparison between the full-length and the abbreviated questionnaire.  This is a copy of the full-length questionnaire and you can see that questions highlighted in yellow are included in both documents.  The ones starred in red are worded identically in both documents.

     Next slide, please.  This is the abbreviated questionnaire showing the same questions.

     Next slide.  Again, the full-length questionnaire and again the yellow questions are asked in both documents.  The ones with the blue star are asked identically except for the prefix which on the abbreviated questionnaire becomes "since your last donation."  You can see these numbers, outlined here to the side, are the capture questions on the abbreviated questionnaire that capture the health and medication risk.

     Next slide, please.  Again the full-length questionnaire, these are the two remote questions that were taken off and, again, you can see the questions that are asked that are the same and the questions that are distilled into recent health questions.

     Next slide.  Again, the abbreviated questionnaire is showing these two capture questions and the travel question.

     Next slide, please.  Many questions and concerns have been voiced in public fora by FDA staff members and others.  Many of these issues were specifically considered and addressed by the task force in developing and testing the abbreviated questionnaire, and many of the answers are available in the user brochure but I was asked to specifically address these with you today.

     Next slide.  One concern that has been voiced is that direct questions are omitted in the abbreviated questionnaire.  The task force disagrees with this assertion.  Direct questions are asked for HIV and hepatitis risk as well as for other health risks.  However, by changing the time frame the focus is changed for frequent donors to recent health changes.  The only indirect questions that are asked are the capture questions that focus on recent changes on health and travel status.

     Next slide.  Another question is must a full-length questionnaire be administered periodically?  Once the donor qualifies for the abbreviated questionnaire there is no need to readminister the questionnaire as long as the donor continues to qualify for the abbreviated questionnaire, that is, comes in at least every six months.  If the donor is deferred, at the end of the deferral period he or she must then be rescreened using the full-length questionnaire and then must requalify for the abbreviated questionnaire.

     Next slide.  How will the blood collection facility track whether the full-length questionnaire or the abbreviated questionnaire should be administered, especially at mobile collection units?  The user brochure states that blood collection facilities must have a system to determine when it is appropriate to administer the abbreviated questionnaire.  Some of the factors include the total number of donations; the time since the last donation; which questionnaire was used at the last donation; and whether the donor was deferred at the last donation.  The user brochure further stresses that only those facilities that can track this information should use both questionnaires.

     Next slide.  What action should be taken when it is determined that an incorrect questionnaire was administered?  The blood collection facility must have an SOP describing actions in this circumstance.  If the full-length questionnaire was administered, then no action is indicated.  However, if the abbreviated questionnaire was administered in error the SOP must ensure the unit is not made available for distribution until donor suitability is determined in compliance with regulations.  If the unit has already been distributed, then it should be treated as an error including submission of a biologic product deviation report to FDA.

     Next slide.  How will the addition of new questions be handled?  Must the full-length questionnaire be readministered with new questions?  The new questionnaire will be added to both the full-length and the abbreviated questionnaire at the same time.  A new question will be retained on the abbreviated questionnaire for one full year from the date the question is adopted.  If the question must be asked at each donation, it will be retained indefinitely on both questionnaires.  This determination should be made by FDA at the time new questions are recommended.  A precedent for this one-year time frame has been set by the July, 2003 FDA guidance for the use of self-administered questionnaires that established one year as the time frame period required for highlighting new questions on the questionnaire.  The task force applied the rationale to this decision.

     Next slide.  In order to continue qualifying for the abbreviated questionnaire donors must come in at least twice a year, and would be exposed to the new questions at least twice before the question could be even removed from the questionnaire.  Further, it is not practical to reset the clock and revert to the full-length questionnaire for all donors each and every time a new question is added.  Just in the last 12 months 6 new questions were recommended by FDA.  New questions are added so frequently that this approach would in effect negate the value of the abbreviated questionnaire.

     Next slide.  If a donor presents new information during the abbreviated screening process which is not necessarily included in the shortened procedure, how will that information be acted on?  Any information presented during donor screening, whether using a full-length or an abbreviated questionnaire, which impacts donor suitability will be considered in determination of acceptability.  A unit should not be collected from such a donor until suitability has been conclusively determined on the day of donation.

     Is it mandatory that a blood collection facility use the abbreviated donor history questionnaire?  As Dr. Epstein and Judy have already summarized, it is never mandatory that any given blood donor center use a specific donor screening tool.  If a blood collection facility opts to use the full-length questionnaire it is not mandatory that they also use the abbreviated questionnaire.  Even for blood centers that opt to use the abbreviated and the full-length questionnaire, either an individual donor or a donor screener may choose to use the full-length questionnaire if there is an issue of donor comprehension.

     Next slide.  Finally, I was asked to discuss our suggestions for post-implementation monitoring of the abbreviated form.

     Next slide.  Again, FDA has set a precedent of sorts by recommending possible measures for appropriate monitoring of effectiveness of a self-administered questionnaire.  We could consider similar measures for monitoring an abbreviated questionnaire.  They have suggested post-donation information rates, infectious disease markers, specific deferral trends, biologic product deviation reports and post-transfusion infectious disease reports.

     Next slide.  Post-donation information is a process whereby blood collection facilities find out about a deferrable risk after the donor has already given blood.  These do qualify as reportable errors and, in fact, represent the largest group of deferrable errors.  Indeed, the high rate of PDIs was one impetus for redesigning the donor questionnaire as an American Red Cross focus group study confirmed the chief contributor to post-donation information was poor comprehension of questions.

     We have already discussed the issue of satisficing and recall fatigue due to heavy memory burden of a long, complex questionnaire and its impact on high PDI rates.

     Next slide.  With that in mind, it is reasonable to consider that if PDI is to be used as one measure, then the appropriate comparison should be made.  Current PDI rates apply only to current donor screening documents which are obsolete and are demonstrated to be confusing due to complex questions and random time frames.  With implementation of a new validated questionnaire it is likely that PDI rates could even increase temporarily due to the increased clarity of the questions and more structured time frame, resulting in more effective detection of deferrable risk.  The task force suggested a more appropriate comparison would be to compare PDI rates in a qualified frequent donor screened with the new full-length questionnaire as compared to the same population screened with the abbreviated questionnaire.

     Next slide.  Another possible measure to consider is infectious marker rates.  Again however, current marker rates apply only to donors screened with current, flawed donor screening tools.  Any comparison of marker rates should target rates in qualified frequent donors screened with the new validated questionnaire as compared to the same group screened with the abbreviated questionnaire.  However, even if such a comparison may prove helpful, current serologic and nucleic acid testing has improved detection of infectious agents to the point that it would be exceedingly difficult from a statistical standpoint to determine if any increment or decrement in infectious disease rates would be observable.  Even if it were possible to ascertain a difference, the process would require such a lengthy surveillance period in evaluation of so many donors that this kind of undertaking would almost certainly be logistically and financially prohibitive.

     Next slide.  A very similar argument can be made in comparing deferral rates, biologic product deviation rates and post-transfusion disease rates.  Again, we should be prepared for the possibility that deferral rates could actually increase due to the use of a more understandable screening document that may be more effective in identifying deferrable risk.

     Next slide.  Finally, since one of the principal goals is to increase donor satisfaction and donation frequency, we should measure this also.  You will see the results of such studies from the two collection centers already using an abbreviated questionnaire today.

     Next slide.  In preparation of implementation of these new questionnaires we already have a commitment from blood organizations to participate in post-implementation monitoring.

     Next slide.  Isn't it nice to see "in conclusion?"  In conclusion, the abbreviated questionnaire was developed at the behest of donors, blood collection facilities and even FDA.  It was based on validated questions taken from new donor history questionnaire.  It makes use of direct queries for major behavioral risks.  Administration issues of variance and non-conformity have been addressed.  And, it is anticipated to have a positive impact on availability of blood as a direct result of a show of consideration to frequent blood donors.  By consideration, I mean old-fashioned courtesy, consideration of the donor's time.  We are all busy people and we hate it when someone wastes our time and we consider it rude when they do so.  It is no different for blood donors, even more so that they came in to do something good.  They should be treated with the respect and courtesy they deserve.

     Next slide.  Members of this BPAC hear routinely testimony from organizations such as AABB, ABC, American Red Cross and PPTA representing the interests of blood collection facilities and transfusion committees.  You hear from FDA representing the interests of blood recipients.  You hear from the National Hemophilia Association, from Immune Deficiency Foundation and the  Committee of 10,000 representing the interests of blood recipients.  There is no organization to represent the donors of America before this committee.  There is no American association of blood donors and there is no committee of 8 million for, indeed, that is how many people come in to donate blood every year.

     Next slide.  Today I stand before you in the name of blood donors of America and ask you to give them the respect and common courtesy they deserve.  As a committee you have already approved a new donor screening document that is clearer and more concise.  You have approved a process for donors to complete that questionnaire when appropriate on their own.  Today, I implore you to go the last step and give dedicated frequent donors the screening tool that they have asked for to make their screening process more efficient and time effective.  Thank you.

     DR. NELSON:  Thank you, Dr. Townsend.  Any comments or questions?  Yes?

     PARTICIPANT: Yes, on the abbreviated questionnaire one of the important differences is that donors are asked "since the last donation."  Has there been any consideration given to the memory of the donor in terms of when that last donation occurred?  Are we assuming that they know when their last donation was?

     DR. TOWNSEND:  No, we are not.  Actually, if you noticed on the list when we determine their eligibility we have to determine how many donations and when their last donation was.  So, we will know when their last donation was and they will know when their last donation was, including a date for them to even qualify.

     PARTICIPANT:  So they will be told when their last donation was.

     DR. TOWNSEND:  We will have a specific date, otherwise we could not qualify them.

     DR. WILLIAMS:  Alan Williams, FDA.  A quick comment and a question.  The comment is, Mary, you went through many of the implementation issues related to the abbreviated format.  We just wanted to reiterate for the committee that many of these are the position of the task force and are going to be the topic of discussions today.  In fact, FDA reserves its right to review these implementation issues and we will probably deal with those as recommendations and guidance in the future.

     The question is that in lead-off slides you mentioned the inconvenience factor of donation and the fact that it seemed to be inefficient and take a long time.  The question is at a typical collection site is it, in fact, the questionnaire that is the holdup?  My understanding is many sites are now using the self-administered process.  Is this a major contributor to the lines that you see at a collection site?

     DR. TOWNSEND:  It is a major consideration for time.  It is also a mental issue with donors.  The donors perceive even if it is only a difference of a few minutes, five, ten minutes--they perceive that you are asking them the same questions over and over and over again and they perceive that as an inconvenience, and they perceive that as inefficient because they don't see a reason for why you should have to ask the same questions every time.  So, it may not be a real difference but if it is a perceived difference it can still have a negative impact on that donor's willingness to come in and go through that again and again and again.

     DR. NELSON:  With regard to asking the same questions over and over, which is what has been done, I wonder what does the data show on how many people, like the fifth time they have been asked a question, are deferred on a question that they have answered differently the first four times.  I don't know, Alan, whether there are data on that.

     DR. GOLDSMITH:  I just have two brief questions.  One, has there been any study about information acquisition based on the ordering of the questions?  You raised that issue.  Because these questions are in a certain order and I see the first one is "are you in good health?" and that is when you have the highest attention.  Is that the most important question to ask first?  So, has anyone actually studied the order of these questions and the data that comes in as a result?

     The second is a quick one, what percentage of donors would be lost when these easier to understand questions are put in place?  What percentage is estimated by the blood industry?

     DR. TOWNSEND:  let me go to your second question.  I have no idea what percent.  We don't have the studies; I don't have the numbers for that.  I suppose that is something that we could try to get at.

     Your first question though was the order.  When we designed both questionnaires we put them in the time order from current going backwards so we could focus them on how you are feeling today.  Then, you will notice it goes to the last 2 weeks, the last 4 weeks and the last 8 weeks and the last 12 months and then ever.  So, we built that time frame in, in order to try to help donors focus on a specific time frame to help them remember.  As it is now, the time frames are a hodge-podge.  We may ask them about today and then 12 months ago and then last week, and they are jumping around trying to focus on time and it is very difficult.

     DR. GOLDSMITH:  I guess it isn't so much the time frame; it is the importance of the questions in terms of getting at safety information.  Which are the key questions to defer donors from historical information?  Are they being asked when the donor is paying the most attention?  It is a methodologic question.  I don't know the answer; I am not a statistician.

     DR. TOWNSEND:  I don't know the answer and I can't answer for FDA, though I have been told by FDA that no one question is more important than another question to them.  Maybe FDA would like to address that but we did not look at it that way.  We looked at it as a way to help donors remember.

     PARTICIPANT:  The way that they designed this as far as time-wise was a very standard methodology for health surveys and things like that.  I think your point is well taken, is a specific question more important so you want them to pay attention?  But they use very standardized methodology which had never been used in the past.

     DR. BOYLE:  This issue will come up again but the term validation has been used in these slides and the one thing we are not going to be able to do is to validate the questionnaire.  Validation requires an independent, non-biased source of information to compare with the question response and even before HIPAA it was virtually impossible to get that, and I think you are going to find it really impossible today.  So, I think we have to focus on reliability and other sources of error because validation is just not in the cards here.

     DR. ALLEN:  First of all, I just want to commend the process by the FDA and the AABB and all of the other organizations that have participated.  I think this is absolutely essential.  This is just a start.  It really needs to continue on into the future.

     Just a couple of other comments, not really questions.  I think we need a comparison of data collection methods, you know, the self-administered questionnaire versus having somebody read the questions and answer them.  I know I do better self-administered but I have a high reading level.  Many other people may not.  And, we need to be able to look at these.  I have enough hearing loss when somebody is trying to speak as rapidly as possible--you know, the words come out in a rush and I often have to say, wait a minute, can you repeat the question because I didn't hear everything that was in there.  You have five or six medications strung together into a single question.  So, I think this whole process has been extremely important.

     I will just say also that I think we need to look carefully at attempts to abbreviate things, such as, you know, have you taken any aspirin or medications that contain aspirin?  How many people know what other medications contain aspirin?  So, we have just begun to open a process.  There is a lot more work that needs to be done and I think we need to examine carefully the use of capture questions, which I think is probably a very good thing to do, versus starting out with the detailed questions.  So, thank you for this process and I hope it will continue.

     DR. TOWNSEND:  Thank you.

     DR. NELSON:  I would like to move on.  We are getting a little behind.  Thank you.  Judy Ciaraldi?

FDA Regulatory and Review Issues

     MS. CIARALDI:  I am going to make this talk very brief to allow time for other speakers.

     Next slide, please.  During our review of the AABB donor history questionnaire we asked the reviewers of the questionnaire materials to consider the following questions:

     Is the content of the questions and accompanying documents consistent with our regulations and recommendations?  Is the rationale for the revisions appropriate?  Is the proposed format for the questionnaire acceptable?  Does the user brochure provide adequate instructions for donor center personnel, and are the studies appropriate?

     Next slide.  The reviewers stated that the review questions were consistent with FDA regulations and recommendations; that the rationale for the revisions and studies were usually appropriate.  The proposed format was acceptable.  The accompanying documents did capture important issues and the overall method was an improvement over the current donor history questionnaire.  It offered a uniform process and the process had undergone some testing.  But there were still concerns about the implementation of the abbreviated questionnaire.

     Next slide, please.  The concerns included a definition of the repeat donor and how centers will track different types of donors, identify and track them.  Some of these concerns are ones that we may need to address in future guidance documents but they are definitely ones that we wanted to discuss.

     The center must manage two forms.  How will they ensure that updates are made properly and that the proper form is given to the proper donor?  If new questions are added, how will repeat donors see the new questions?

     As we mentioned, the questionnaire omits asking direct questions to get required information.  For instance, the regulations require the donor centers to know if the donors have had hepatitis or had a positive test for hepatitis.  The general question, the capture question on the questionnaire asks about any new medical diagnoses; it doesn't specifically ask about hepatitis.

     Next.  A repeat donor may not volunteer information if not asked directly.  So, we don't know what the answer to this is right now.  Our biological product deviation reports show that donors do present deferral information on third or later donation and, because there is no scheduled periodic readministration of the full-length questionnaire to repeat donors, there isn't an attempt to capture this information and the information may be missed.

     Next slide.  The available studies that are on abbreviated questionnaire are very limited.  When another colleague and I did a literature search on abbreviated questionnaires we found, of course, that there were none for blood donors who repeatedly take the same questionnaire.  There were some others, none of which were directly to point or could be transferable to applying to blood donors.

     The level of studies done on abbreviated right now is not the same as what has been done on the full-length and the testing of the broad capture questions on the abbreviated, as Dr. Townsend stated, were not in large numbers.  One set of reviewers commented that the question about medical diagnoses and medical treatments were tested.  That question was tested in a cognitive study, one-on-one cognitive study with four test subjects, one of which did not provide the expected information.  The reviewers wondered if a 25 percent failure rate was significant, taking into account there weren't large numbers, and whether this was enough to say that this question was an effective question.  Again, they were asking this question; they weren't making a decision but they wanted it brought to someone's attention.

     The rationale for using the abbreviated questionnaire, the large rationale that we are hearing is that it is easier for the donors and staff but FDA believes that the rationale should include a risk assessment.

     Next slide.  Previous BPAC meetings did not discuss any regulatory impact of the implementation of abbreviated questionnaires.  So, we are getting a lot deeper into discussing these.  Our concern is heightened because there will be a broad use of the abbreviated questionnaires by a lot of blood collection centers.  In other words, it will be a change from the current standard.  It may become a new standard.  Is it equivalent to the current screening procedures?  Will it compromise a center's ability to accurately determine donor eligibility?  Again, we don't feel we know this just yet and we would like to have more discussion in order to determine the impact on donor eligibility.

     Next slide.  We feel that there are several possible mechanisms for implementing abbreviated questionnaires where we can have an opportunity to collect data.  One, of course, is similar to what we are proposing for the full-length, to recognize an industry standard in an FDA guidance document or even to provide guidance, but we are not ready for that yet but maybe after today's meeting.

     We could also entertain licensed applicants to submit individual applications to us, and we could also implement a pilot program that includes a one-year readministration of the full-length questionnaire.  I am going to go into these last two a little more deeply.

     Next slide.  For licensed applicants submitting to FDA under the reporting requirement, they could be the AABB's questionnaire but oftentimes or recently they have been center developed a abbreviated questionnaire.  They are submitted as a prior approval supplement, which means we need to look at it and approve it before the product can be distributed, using it under a license.  We would like to have a look at it in length and depth because we want to see what has been submitted or what has been changed to make sure it still meets our requirements.

     We are proposing the possibility of requesting post-approval implementation data to be submitted to FDA.  This would be similar to a post-market commitment made on some other types of submissions.  I should bring to your attention that this only applies to licensed blood collection establishments.  It does not apply to unlicensed establishments.  Right now there is no application review process for any of their documents, but they do get some level of review during their FDA inspections.

     Next slide, please.  The pilot program, we feel, will address our concerns about donors providing deferral information on subsequent donations.  We would spell out the details of the pilot program in a guidance document.  Again, because licensed applicants are required to report important changes to us, they would make the request to use the pilot program in an application or supplement to FDA.  We propose that this pilot program would include a one-year readministration to full-time repeat donors, and that licensed applicants that have an approved pilot program could request that to extend the readministration to a two-year period.  Right now, again, we don't know what data we would like to see.  We need to make that determination.

     Next slide.  Currently there are two approved abbreviated questionnaires, one from the Blood Center of Iowa, which was approved by FDA in 1998, and one with Blood Systems, Inc. that was approved in spring of this year.

     The Blood Center of Iowa was one of the blood centers that participated in the AIR study.  After we announced that we would accept abbreviated questionnaires they made their first application or supplement of their questionnaire.  The Blood Systems, Inc. based the content of their questionnaire on the abbreviated questionnaire that AABB proposed and also included information they heard about Iowa's previous approval.  Both questionnaires were reviewed and approved on their own merit based on the material that was submitted to us, and they are approved for the specific use by that specific establishment.  At this time the approvals are still valid.

     So, FDA has completed the review of the AABB's full-length questionnaire and our current thinking is that we recognize it as an acceptable instrument in an FDA guidance document.  The abbreviated questionnaires are for use on frequent repeat donors and they only ask the donor about recent history.  Direct questions about more historical information are not asked but capture questions are used to get at this information.  FDA review of the abbreviated questionnaire continues.  We still need some more information and we have this heightened concern because of the potential for the broad use of the instrument.

     Next slide.  We need to define the appropriate studies and data to kind of ease some of our concerns and answer our questions that will help prepare our guidance document.  Licensed blood establishments may submit their own abbreviated questionnaire for our review.  We hope that their SOPs will address our concerns and, again, their approvals may include a post-market commitment process.

     We are also proposing our pilot program with a one-year readministration of the full-length questionnaire to address our concerns about deferral information that is volunteered on subsequent donations.  We are not saying that we won't approve abbreviated questionnaires but we feel that we need some additional information.  We are truly committed to supporting a more efficient donor screening process but we don't want to sacrifice the blood supply.  Thank you very much.

     DR. NELSON:  Thank you, Judy.  Comments?  Yes?

     DR. KLEIN:  Yes, you made a comment that donors give additional information after the third or later donation.  What kind of data do we have to support that?

     MS. CIARALDI:  That is the next speaker.  Sharon O'Callaghan is going to talk about that.  She has it all broken down.

     DR. KLEIN:  Okay.  Maybe she will address this too, but do we know whether that is because the current questionnaires are so lengthy and convoluted that people just stop reading them about half-way through?  I mean, has anyone looked at that issue?

     MS. CIARALDI:  She will talk a little bit about what the data mean.  I think that what she will tell you is that not all the questions can be answered with the data that we have.  So, those details may not be included in the data and in the discussion.

     DR. NELSON:  Sharon O'Callaghan from the FDA?

FDA Regulatory and Review Issues

     MS. O'CALLAGHAN:  I guess I have already gotten questions that I have to answer.  Right?

     Next slide, please.  I am going to present some data that we have obtained through the biological deviation reporting system.  This is just to show an overview of the reports that we received in fiscal year '03.  The information that I am going to be presenting is involved with the donor suitability section of these reports.  Out of the over 40,000 reports that we received last year, 80 percent of them were related to donor suitability.

     Next slide, please.  The donor suitability category has been broken down into post-donation information, donor screening and donor deferral.  You can see that the post-donation information represents the largest percentage of reports within the donor suitability category.  Now, a biological product deviation report is required when there is an event in associated manufacturing in which the safety, purity or potency of distributed product may be affected.  This could be either deviation in manufacturing or an unexpected event.  With the post-donation information reports, these are all basically considered unexpected events.

     Next slide, please.  Now, what post-donation information is, is that it is information that is provided by a donor or a third party that subsequent to the donation would have deferred the donor had that information been provided to the blood center.  This information is either provided shortly after the donation, usually within a few days.  Most of those involve post-donation illness or post-donation diagnosis of disease.  The majority of the post-donation information is provided at subsequent donations.

     Now, we have also broken down the post-donation information into three categories of information that is not known at the time of donation, which represents only about 6.5 percent of the reports; information that may or may not be known at the time of donation; and information that really is known at the time of donation and that is 85 percent of the reports.

     Next slide, please.  Of the information that is not known at the time of donation, this would include post-donation illness, post-donation diagnosis of disease or if a donor may go to his physician and end up being positive for a viral marker that he didn't know about before the donation.

     Next slide, please.  Information that may or may not be known would include situations in which the donor may not know the behavior of their sex partner.  In some cases it is known but in many cases they don't know until after the fact that their sex partner engaged in high risk behavior.  This would also include exposure to disease, especially things like hepatitis A.  This is a frequent one in this type of category where the donor may go to a restaurant and be exposed to hepatitis A but not find out until well after the donation.

     Donor self-deferred--in some cases, you know, there is generally not a lot of information as to why that donor chose to call the center back and say "I don't want my blood used."  So, there may or may not be information that the donor knew at the time of donation.  This is mostly related to plasma centers where the donors are deferred by another center.  In some cases the deferring center may not tell the donor that they were deferred for a particular reason and when the plasma centers check at other locations, that is when they get that information.

     Next slide, please.  Now, information that is known at the time of donation but not provided at the time of donation includes the donor testing positive for a viral marker prior to the donation where the donor had a positive test for hepatitis, you know, ten years ago; history of disease or cancer; travel to malarial endemic area or variant CJD risk areas; received tattoo, piercing or needles stick exposures; received medication, vaccine; IV drug use, as well as male to male sex.  So, this is all information that the donor knows before he walks in the door but he is not providing that information.

     Next slide, please.  I broke this information down into three separate categories for when that information is provided.  So, the one I want to focus on is the first row where the information was actually known at the time of donation.  In the first column the information is presented to the blood center after the first donation.  This is after the first donation.  So, the donor was given the history question once.  At a subsequent donation they are now providing information that they knew at the previous donation, and 45 percent of the reports are in that category.

     After 2 donations, almost 13 percent of the reports where the donor was given the history questionnaire twice before they remember disqualifying information.

     After 3 donations or greater, 27 percent of the reports involve donors who have been given the donor history questionnaire at least 3 times and still have not provided that information until the fourth donation or sometimes fifth, sixth, seventh, all the way out.

     Next slide, please.  This is a breakdown of types of information provided in order of prevalence after the first donation.  We have the travel to vCJD risk areas and to malarial endemic areas that represents the largest percentage.  We have donor received tattoo; history of cancer; IV drug use.  We have male donor had sex with another male--very significant risk behaviors.

     Next slide, please.  This is for the information that is provided after the second donation.  Again, we still have the travel questions that the donors are not remembering when the second history question is being given; tattoo; we have IV drug use; male donor had sex with another male.

     Next slide, please.  After the third donation or later donor received a tattoo; travel; received ear and body piercing; incarcerated; again the travel to malarial endemic area and we still have the IV drug use.  So, that just represents the type of information that the donors are being asked on each donation but they are not remembering this information until the third or later donation.

     Next slide, please.  Now, we do know that there are some limitations to the data that we have.  You know, we don't know if the questionnaire was clear.  There are a lot of different questionnaires being used out there.  Some we have seen; some we haven't because this also includes data from unlicensed blood centers.  We don't know if there are flaws to the current questionnaire; if the wording is not clear; we don't know if the donors were screened properly at all donations.  This is a real big concern because a lot of times blood centers in general will just write this off as the donor didn't give us the information and that may be as far as their investigation goes when, in fact, they need to go back and look at were the questions even asked; was the documentation there that presented some additional questions that should have been followed up.  But the problem is that if you don't have the information documented even an audit is not going to catch the fact that the donor gave the information and it wasn't recognized as being a deferral criterion.

     Did the donor understand the questions?  You know, in most cases I know that there are some blood centers that will try to get some information from the donor of, you know, what made you give this information this time and not the five previous times that you donated?  But that doesn't happen consistently so we don't have the data to show if it is because the donor didn't understand or they just zoned out, or whatever.

     Next slide, please.  So, the issues that we have here are, you know, the abbreviated questionnaire may certainly help focus the donors on the current history and behavior but the abbreviated questionnaire may limit the information that we are able to get from the donors.  If the questions are not being asked, then they are not prompted to give any additional information.  You know, with the abbreviated questionnaire even if you give the full-length one for two donations you are assuming they are giving you all the appropriate information on those first two donations.  The donors can answer correctly using the abbreviated questionnaire that, no, nothing has changed since the last donation but they may remember, but they are not prompted to remember what happened before their first donation.  So, those are some of the issues that we need to think about.  I think that is it.

     DR. NELSON:  Thank you.  Questions or comments?  You gave us like numerators, three or more, but do you know what the denominators were?

     MS. O'CALLAGHAN:  How many donations there were to begin with?

     DR. NELSON:  Of 8,000 deferrals in 3 or more donations, how many people were included in that?

     MS. O'CALLAGHAN:  With the BPD reports we don't have a way to capture the numerator of how many donations were collected where the donors actually did give the information and were deferred at the first donation.  We don't get that information because there would be no report needing to be submitted if there is no previous product.

     DR. NELSON:  Right.  I guess it is complicated--

     MS. O'CALLAGHAN:  Yes.

     DR. NELSON:  --because it would be the number of people represented by five or six donations as opposed to the number of donations.  So, it is complicated.  The REDS study may have something on that?

     DR. DAVIS:  I wasn't clear when answers changed after the second, third or fourth time a question was asked, was it an actual change in the person's status or was this something preexisting that they didn't answer correctly the first time?

     MS. O'CALLAGHAN:  Most of it is preexisting.  What would be included in the information that was known at the time of the initial donation would be things like did you travel to a malarial endemic area?  They would say no because they only traveled to Cancun and stayed at a resort.  Then they would come back the next time and say, no, I only traveled to Cancun.  They would come back the third time and say, "you know what, I did take a side trip to the ruins."  Now the donor needs to be deferred.  They knew that they traveled there, they just didn't remember that they had this disqualifying information.

     DR. DAVIS:  You said that 8,262 were noted after 3 or more donations.  How far out are you going to get the majority of that 27 percent?

     MS. O'CALLAGHAN:  The way that I did the search was anything greater than 2 donations or 3 donations.

     DR. DAVIS:  Right, but is it--

     MS. O'CALLAGHAN:  You know, with some of the plasma centers where you have donors that are donating every two or three days, there is a number of donations and it is very typical in the plasma centers that they don't even realize the donor had a tattoo.  They don't have the information of tattoos and piercings until the annual physical.  They are asking the donors have you had a tattoo in the last 12 months and they say no, and when it comes time for the annual physical, they have the body map that shows where all the tattoos were and they find new tattoos.  So, these donors are being asked every single time, every two or three days and they are still saying no.  So, there could be a number of donations.

     DR. NELSON:  Harvey?

     DR. KLEIN:  I think these are important pieces of information but I suspect that this isn't something that there is one answer for, and I really suspect that it is not that the donor suddenly remembers something that they haven't thought about before.  This goes to much more than simply the abbreviated donor form.  For example, I think the fact that on the top of your list was the vCJD question and the malaria issues, which really are very complex and probably asked quite differently by different screeners, suggests that there is something perhaps fundamentally wrong with some of the way these questions are asked.  It is probably critical to find out just why this is happening because, again, I think it is much broader than the issue of the abbreviated form.

     DR. NELSON:  I can tell you from my own experience that they asked me to list all the places I have been to in the last year.  So, I listed the Republic of Georgia and China and India, etc. etc.  Then they asked me where were you in those places and then the guy went and said, "well, I have to call a center and find out"--and I visited a game park in South Africa which I found out was not in a malarial area but I was deferred based on the third phone call that the guy made.  You know, as a donor, if I were to go the next time I might just say no.

     [Laughter]

     It took an hour to get through the questionnaire based on my travel stuff.  The guy had a big book but said I am going to call the center on this.  So, I see that there is a problem.  On the other hand, there was a report from CDC on transfusion-transmitted malaria, and I think it was something like 50 or 60 percent.  It was a fair percentage of those that, had they answered correctly on the donor history, it would have been prevented.  So, it is an issue and there are some risks to this.

     DR. CALLERO:  I am wondering if we know about any patterns in those errors, male/female, other demographics, location, type of questionnaire that was used.

     MS. O'CALLAGHAN:  We don't capture that type of information.  It would be very difficult for us to match up.  I mean, we would end up having to have each facility submit their donor history questionnaire and compare that with the number of post-donation information reports that they received and compare it to each individual question to do an actual tally per question and see if there is a problem in the way that the question was asked, the wording of the question and things like that.  But we just don't capture that information.  We also don't capture whether the donor was male or female or, you know, anything like that either.

     DR. KUEHNERT:  The comment you made about the malaria case jogged my memory about a recent MMWR where there was a case of malaria that was in a donor that was not picked up both because the screener didn't apply the correct criteria but also because the donor did not recall that they had malaria.  So, there were at least two errors in that.  I wondered if you collect information on whether there was a screening error or whether there was a donor error.

     MS. O'CALLAGHAN:  Yes, as much as we can based on the information that is presented in the reports that we receive.  We have frequently received reports where they have identified this as post-donation information and in looking at the root cause and what they did, it really appears that there was a donor screening problem and not post-donation information.

     DR. KUEHNERT:  So, if the donor calls back and reports you go back and take out those that were screening errors?  Those are removed?

     MS. O'CALLAGHAN:  Yes, those are not included in there.  Yes, because frequently we get that it was post-donation information but then they find out that the donor had said that he went to Cancun but then there were no follow-up questions as to did he travel any place else.

     DR. BOYLE:  In response to the question about patterns, we did a test-retest six months later of medical conditions in a non-blood donation setting.  The good or bad news is that for medical conditions the reliability is about 97-99 percent.  The bad news is all the errors are the positives that move back and forth.

     The pattern for hepatitis was that hepatitis B tended to be more inconsistent, which might be a willingness to disclose.  The biggest changes for instance in cancer would be skin cancer, which is reported inconsistently, which is probably what does skin cancer mean?  The same thing with diabetes.  If it was not insulin dependent it tended to be more inconsistent.  I should say we also had inconsistency on vasectomy and I don't know what that was.

     [Laughter]

     But we certainly had at least three sources of error and these were all interviewer administered so you take away the screening issue.  You have basically comprehension, and for all I know vasectomy could be that.  You have the issues of the understanding of the question and that is what is cancer?  What is diabetes if I can control it with diet?  You also have recall error that we have talked about here, and then we have something else which is disclosure error and that is I just don't want to tell you because it is none of your business or it is embarrassing.  So, we are going to have to address all of those types of errors.  And, you are also going to have to accept some standard.  I mean, you are not going to get 100 percent so the question is what is reliable enough?

     MS. KNOWLES:  It really sounds like there is a true need for a standardized, uniform donor questionnaire to be used throughout the entire blood industry.  I think you would have less problems with your data collection and trying to figure out the answers, second-guessing, interpretations, etc.

     MS. O'CALLAGHAN:  Yes, it is very difficult when all we see is that the donor provided information of travel but we don't know exactly how that question was asked to begin with.  If we have the standardized form to begin with and everybody is using it, now we have a better baseline to compare everything else to.

     DR. NELSON:  I think there are some questions that probably could be parceled out into one of those four.  The malaria is probably confusing.  The history of drug use is probably disclosure.  Almost certainly that is probably true and the disclosure error is going to be hard to deal with, no matter what kind of questionnaire we come up with but an abbreviated, simpler questionnaire might help with it.

     DR. KUEHNERT:  You might not have this information off the top of your head but I saw repeatedly in there, towards the middle of the list, that donors did not recall that they had had a transplant or graft implantation.  I assume it is not a heart transplant that might have just slipped their mind.

     [Laughter]

     But do you have any information?

     MS. O'CALLAGHAN:  Most of it was bone grafts, bone transplant type things.  A lot of it has to do with dental work.  In some cases they knew that they had that; they just didn't think it applied to them and that is what you mean by this question.  And, there are probably a few cases where the donor didn't know that they actually had some type of graft until they went back and asked their doctor.

     DR. KUEHNERT:  To follow-up on that, for medical diagnoses do you also have information on situations where they had an illness, say a parasitic illness for instance that they found about later, and that is what prompted them to call back?

     MS. O'CALLAGHAN:  Yes, we get that with Lime's disease where they may not have felt very well but they don't think it is important at the time to tell the blood center because that was two months ago, but in the process they may have gone to their doctor because they still weren't feeling well, and got tested and now they have Lime's disease.  So, the blood centers would get the calls back.

     DR. KUEHNERT:  So, that is an example where a capture question might be more useful than the actual specific question--

     MS. O'CALLAGHAN:  That is right, they may not know that they actually had the disease.

     DR. KUEHNERT:  Right.

     MS. O'CALLAGHAN:  We do get some where the donors will provide information that they are being tested for something because they haven't been feeling well.  Yes, there is a fair number of those types of events.

     DR. NELSON:  Could you really be brief?  We are really falling way behind.

     MS. GUSTAFSON:  Mary Gustafson, Plasma Protein Therapeutics Association.  This was touched upon but, Sharon, I think it would probably be more fair to split out those conditions that were noted on physical examination rather than the questionnaire itself, and that was on the third or later where tattoos and piercings were very much highlighted.

     MS. O'CALLAGHAN:  Right.

     MS. GUSTAFSON:  And also if the BPAC ever wants to consider again the real risk of those--you did in the past two years--but I think in terms of disclosure the donor's perceived risk has a lot to do with their disclosing.

     DR. SAZMA:  Kathleen Sazma, M.D. Anderson Cancer Center.  Sharon, I have two comments to make.  The first is related to Mary's just now, and that is I think for purposes of our discussion here it really would be beneficial to separate out the whole blood reports from the plasma reports.  They are very different in most circumstances and I think it would be more informative if you could present the data in that way.

     The second is a question to you.  Because the focus of the discussion today is about the abbreviated donor history questionnaire, it would be very helpful to the committee I think to understand the time period between the donations.  Have you captured the interval of time?  Because the focus of the abbreviated is that the donors have to come back in within a six-month period of time and really be qualified as repeat donors, not as first time.  Based on our experience, it can be years between the first, second, third and fourth reports.  Do you have those data?

     MS. O'CALLAGHAN:  I don't have them with me.  I certainly could run a query to get some of that information.  But, for the most part, when the donors provide the information subsequent to a third donation they are fairly close, within a few years of donation not going back, you know, one donation ten years ago and then the next one five years ago, not spread out like that.  Some of the ones that we get with a history of cancer tend to go back a lot longer than most of the others.

     DR. SAZMA:  Well, just knowing that the average interval between donations is eight months or more, I think that one needs to keep that in mind in term of interpreting the impact of this for the purposes of this discussion.  I can only underscore the comments that were made by the members of the committee that until we have some sort of unified approach to doing this, I think none of us is going to be able to make sense out of the data.  Thank you.

     PARTICIPANT:  Blood Care, Dallas-Ft. Worth.  Sharon, I suppose I should be encouraged that in order to ensure maximal deferral you are not going to suggest we use your data to allow donors to donate only after they have, over a period of time, seen the donor questionnaire three times.  Against that background, those 25,000 individuals that might otherwise have been deferred had they recalled the information at the first donation, to what extent do we know that those are individuals who are linked to post-transfusion infection or some other mischief?  I know that for CJD it is zero.

     MS.  O'CALLAGHAN:  Right.

     PARTICIPANT:  What about for malaria?

     MS. O'CALLAGHAN:  That is probably pretty close to zero.  I don't have official data to support that but based on the number of reports that we get of post-transfusion malaria, HIV and hepatitis there are a lot more donors being deferred for this type of behavior, travel areas and such, than those that are actually transmitting disease.

     DR. NELSON:  Thank you.  Next, Mary Beth Bassett is going to talk about experience using abbreviated questionnaires.

Experience Using Abbreviated Questionnaires

Blood Systems, Inc.

     MS. BASSETT:  Good morning.  I would like to thank the FDA for inviting me to speak today on Blood Systems' experience using the abbreviated questionnaire.  We believe that the use of the abbreviated questionnaire is beneficial and very important to our organization.  I hope to provide you with information today for your consideration in allowing the process to have a broader application.

     Next slide, please.  So, today what I will be talking about is why our organization chose to implement an abbreviated process, some of the policy and criteria decisions that we made, a comparison of the abbreviated process and the full questionnaire, what we are doing to monitor this new process, and some real recent donor survey results of the abbreviated process.

     Next slide, please.  So, why did Blood Systems implement this process?  Certainly it was because donors for many years have been telling us that the donation process is too long.  In more recent time the donor group sponsors are telling us that the time away that their workers are spending from the workplace to give blood is unacceptable and are wanting to reduce the number of blood drives.  We had the opportunity to actually look at some donor survey information.  We perform quarterly donor surveys and in the second quarter we found that 36 percent of the donors that responded to this questionnaire, and that was just in the writing of response, they requested an abbreviated process.  This was unsolicited information and it was information that was not asked as a specific question.

     Next slide, please.  The goal we had for implementation was not unlike what the AABB's goals are or certainly any other blood center.  It is to improve customer satisfaction, increase donor retention, increase the donor frequency, and all of that would lead to an increased blood availability.

     Next slide, please.  I want to talk next about some of the policy decisions that we had to embark on as we were looking to implement this process.  One of the strong points that I would like to make is that the only thing that changed in the FDA's five layers of safety has to do with the medical history question.  No other process was abbreviated.  No other policy changes were made as we implemented this new process.

     Next slide, please.  Some of the rationale that we used as we were looking to determine our eligibility criteria was that in a collaborative study we actually reviewed that the viral marker rates among repeat donors--there was really no decrease in the viral marker rates with an increasing donation experience.  This was information that was published by Schreiber et al. in Transfusion.  Therefore, we felt comfortable selecting eligibility criteria that met our needs operationally and gave us a cushion of safety.  We looked for the simplest but the safest way to check and verify for donors' eligibility.  We did not make any assumptions that repeat frequent donors are less likely to have risk behaviors, and we believe that the abbreviated process focuses on the recent events from the last donation and, thus, reveals recent deferring conditions.

     Next slide, please.  So, using that rationale, our policy and our definition for repeat frequent donors is that we use three previous allogeneic donations.  We believed if we had three donations it had something to do with familiarity of the questionnaire.  They had to be successful interviews.  There could not be deferral in any of the interviews and id did not necessarily have to be a successful phlebotomy.  One of those donations had to be within the past six months.

     Next slide, please.  Another policy decision we had to make is what do we do when there is a change that needs to happen to the questionnaire.  In our SOP what we have done is left this open to an evaluation by our medical affairs staff and they will make the determination on a case-by-case basis.  They will either add the question to the abbreviated questionnaire or they may determine that our capture question includes the information.  We have had experience with this already since we have implemented this, which was August 5th for our organization.

     For smallpox, what we chose to do was to add this into what we call a medication deferring list.  This is a list that we give to the donors that describes for them all the medications that would defer them.  So, this was added to that medical list.  We also added the West Nile Virus to the form.  The determination was to add it specifically to the abbreviated questionnaire, as well as leishmaniasis.

     Next slide, please.  This is a comparison of our abbreviated process and our full-length questionnaire.  When it comes to risk behaviors and risk factors, the questions are the same.  So, the things that we really worry about we really didn't change in the questionnaire.  For current events, you can see that we reduced the questionnaire by two questions.  Those questions are, "do you understand if you have AIDS you can infect others?"  This information is now included in educational material that is given to each donor.  The other question was, "have you ever donated using another name?"  These are frequent donors and so that information is in the computer and could be identified by our donor ID or Social Security number.

     With regards to travel, we reduced the questionnaire by one.  It is a capture question, "have you been outside of the United States?"  Depending on the answer, the eligibility is evaluated for malaria, SARS, CJD and HIV-I group O.

     Medical conditions--this is where you can see a significant reduction.  We went from ten questions to one with a capture question, "have you had any new medical conditions or health problems?"  Again, this would relate to since your last donation.

     Under deferring medications, we went from eight questions to one.  It is a capture question, "have you taken any medications on the medications deferral list?"  As I explained, this is a list of medications that would defer them if they were taking one of those medications.

     You can see that for hepatitis we have not changed any of the questions.  For HIV risk we actually added a question, and the only reason we added the question is because we are actually doing a study to determine could we ask a capture question and reduce asking all of the higher risk questions.  That capture question that we are asking is "have you or your sex partner participated in any activity that puts you at risk of catching or spreading the AIDS virus?"

     We also reduced some miscellaneous questions just by one, and that is "have you read and understood all of the donor information presented to you?"  This is now included in the donor consent.

     So, you can see we reduced our numbers from 54 on the full questionnaire to 35, and 23 of the questions out of the 35 are linked to the period since the donor's last donation.

     Next slide, please.  Now I want to talk to you about the process we use to measure the effectiveness and the safety of this new questionnaire.  This is an ongoing process for us.  Our data is pretty limited.  I will share with you what we have to date.  The time period for this data is from August 5th to October 15th.  So, it is only approximately 10 weeks.  We began implementation of the abbreviated questionnaire on August 5th but not at all of our locations.  We tried to select measures that would detect any change in the safety of blood donated by donors by using the abbreviated questionnaire.  So, we looked at medical deferral; temporary deferrals which is pulse, blood pressure, temperature and hemoglobin; viral marker rates; post-donation information; and certainly the number of errors that have been related to the use of the wrong form.       Next slide, please.  This slide has a lot of information so bear with me as I kind of walk you through the information or at least the highlighted information on this.  I also will have some additional slides which will give you a little more detail.  So far we have data on 182,383 donations.  This was given, again, between August 5th and October 15th.

     As I mentioned, we wanted to look at surrogate markers for blood safety, and to do this successfully we constructed a control group.  We were able to compare both our control group and our experimental group with donations from those donors that were ineligible for the abbreviated process.  So, if you look at columns three and four, this is those donors that were not eligible for the abbreviated questionnaire.  You can see that for repeat donors we had about 75,000 donors; first time donors were 39,000.  If you go over to columns one and two, you can see that these were the donors that were eligible for using the abbreviated questionnaire and 24,000 donors actually were given the abbreviated questionnaire and 44,000 did not receive the full questionnaire.  This became an ideal control group for us.  The reason they did not all get that questionnaire is because, again, we didn't implement this across our entire system so we were able to search the database and determine those donors that were eligible at other centers that had not implemented the process.  Then, within each group we assessed the rate of the medical history deferrals; our temporary deferrals; viral marker rates with the repeat reactive and confirmed positive; and then post-donation information.

     Next slide, please.  This slide I just wanted to show because I think there is a key observation and a key point that I would like to make, and that is that 37 percent of our donors were eligible for the abbreviated process and we think that is a very large number of donors that would use this abbreviated process.

     Next slide, please.  These next few slides just give you a little additional information from the previous slide that I showed.  Each of these slides will show you a mean and they also show you a 95 percent confidence interval.  What you can see here for medical history deferrals is that there really is no difference in the frequency of medical history deferrals between the users of the abbreviated form and the people that used the full questionnaire.  You can see that there really is no difference.  Certainly, where you are going to see the most difference--this is our first time donors and they have the highest number of medical history deferrals.

     Next slide, please.  Temporary deferrals--these are deferrals again for pulse, blood pressure, hemoglobin, temperature and also the response to the question "do you feel well and healthy today?"  As you can see, there really is a downward trend from the first time donors all the way to those that had obviously more experience in donation.  Probably we are culling out some individuals with cardiovascular disease.  There is also a bit of a difference here, as you can see, between our experimental group and our control group, not highly significant but there is a difference.  I don't believe it is really probably related to the use of the questionnaire.

     Next slide.  This is repeat reactives.  As expected, there really is no difference between our control group and our experimental group.  Certainly, our first time donors have the highest repeat reactive rate.

     Next slide.  The same phenomena here, again really no difference between our control and experimental and our first time donors are significantly higher.

     Next slide.  For post-donation information, as you can see here and we believe this was very interesting information, we are not seeing anything that is really very significant between the experimental group and the control group.  These are the people that were all eligible for the abbreviated process but this group here didn't use the abbreviated form.  Certainly, we have most of our donor call-backs coming from our first time donors.

     Next slide, please.  Looking at the errors related to the abbreviated questionnaire, you can see, as with any new process, we started out with a number of errors.  We had an error rate of 0.31 percent and you can see that through the middle of October, which is what this data really represents, we had reduced to 0.09 percent.  The four-month data I was able to get for you and we actually did about 12,000 abbreviated interviews and our error rate was 0.08 percent.

     Next slide, please.  Lastly what I want to talk to you about is some very recent, in fact as of Monday, donor survey results.  We do quarterly survey results system-wide and so we were fortunate to be able to have that as comparison data because the next thing we did is have the company telephone and do interviews of 600 people that had used the abbreviated questionnaire, and these were donations collected between 10/1 and 10/15.  These donors were randomly selected from all of the donors that used the abbreviated questionnaire, and this work was done by an organization called West Group Research, in Phoenix.

     Next slide, please.  Just some highlights because the information is really new for us, and I did provide all of you, members of BPAC, an actual full set of the survey results but I just extrapolated some information that I thought would be important to present to all of you.  We had a response from the donors that greater than 80 percent perceived the donation to be shorter.  We all know that the process really isn't a whole lot shorter even if it is a few minutes shorter but their perception, as Dr. Townsend talked about, really is that it was a better process.

     Then we had the baseline data to be able to compare additional responses to.  What we saw was that 20 percent more rated the overall process as excellent.  What was also interesting was that they also rated parts of the process that didn't change as better.  For instance, the phlebotomy, they rated that as 21 percent better.  For the reception, they rated that 10 percent better.  Certainly, the 20 percent more that rated the interview process as excellent was what we were expecting.  So, what that really told us is that they thought the whole process was better, not just the abbreviated questionnaire part of the process.

     The last bullet here we were pretty excited about because they also stated that 8 percent more are likely to donate in the next 12 months.  If that really did happen, that would have a huge impact on blood availability.

     Next slide, please.  We also asked them to respond to some statements and actually either agree or not agree.  We gave the donors four statements.  The first statement was "I prefer the shorter interview because it makes the entire experience more positive."  Eighty percent agreed with this statement.

     The second statement was "being able to do the shorter interview will motivate me to donate more frequently."  Forty percent agreed with this statement.

     "Because the interview is shorter it is easier to concentrate and give complete answers," and 71 percent of the donors agreed.

     The last statement was "am I concerned that the shorter interview might miss critical information?"  Only seven percent of the donors agreed with this statement.

     Next slide, please.  I have shared some preliminary data with you, data which we generated to assess the safety and effectiveness of our new abbreviated process.  My overall message is that we have found no data to suggest that we are doing something which affects risk.  We believe that shortening the interview process has the potential to increase donor satisfaction which could improve blood availability.  Thirty-seven percent of our donors are eligible to use the abbreviated questionnaire.  Review of the selected markers, the positive tests, deferrals and post-donation information indicates no reason to be concerned about increased level of risk associated with use of the abbreviated questionnaire.  Donor satisfaction is enhanced.  We have had errors seen in the implementation but they are being reduced, and we will continue to monitor this process to confirm our initial impressions and to continue to improve the effectiveness of the system.  Thank you.

     DR. NELSON:  Thank you very much.  Questions?  Jay?

     DR. EPSTEIN:  Thank you very much, Mary Beth.

     MS. BASSETT:  You are welcome.

     DR. EPSTEIN:  Can you just comment whether there are any significant differences between the abbreviated questionnaire that was used at United Blood Systems versus the one that the UDHQ has developed?

     MS. BASSETT:  The one that who has developed?

     DR. EPSTEIN:  The AABB task force, the UDHQ.

     MS. BASSETT:  You know, there really aren't many significant differences.  I don't know, Mary, if you have the actual breakdown of what those differences are.

     MS. TOWNSEND:  I did make a comparison and they are very, very similar.  I have it with me but I would have to dig it out and you can look at it.  Probably most of the major differences are the new questions that have been added.  Headache and fever have been added and we have not added those questions to our card until we have those tested and validated.  That is the major difference.

     DR. NELSON:  You had a comment?

     DR. CALLERO:  Yes, I am sorry but could you tell me the location of your center and where the blood was collected?

     MS. BASSETT:  The centers that have implemented the abbreviated questionnaire?

     DR. CALLERO:  Right.  Just in general.

     MS. BASSETT:  Well, United Blood Services has 18 blood centers in the western part of the United States and at the end we probably had implemented it in most of our centers but at the beginning of the process we really had a limited use of the form.  I know we implemented it in El Paso, Cheyenne, Wyoming.

     PARTICIPANT:  Yes, but within each center not all eligible donors are screened, whether they were mobile or in a blood center.  So, even within centers that implemented it, there was not full implementation in one location.

     DR. NELSON:  For the record, could you give your name?

     DR. CAMELLE:  Hani Cammelle, from Blood Systems.

     DR. CALLERO:  Thank you.  I have just seen a map.

     MS. BASSETT:  Did you see the map?

     DR. CALLERO:  Right.

     MS. BASSETT:  We collect about a million units a year.

     DR. CALLERO:  The other question is was the collection of this information the same procedure used at all of these locations?  Were they self-administered?  Were they face-to-face?  Were they computer?

     MS. BASSETT:  We use a computer process for our screen.  It is not self-administered.  It is face-to-face but we directly enter the information into the computer.

     DR. CALLERO:  And that is the same at all locations?

     MS. BASSETT:  All locations.

     DR. CALLERO:  And what was the reaction of the staff to this change, the blood collection staff?  Do you have any sense?  Were they interviewed or were data collected from them, or do you have any anecdotal responses?

     MS. BASSETT:  You know, we didn't actually do any survey but they get the front-line hit of the donors who want this abbreviated process.  So, for them to be able to offer something that they know the donors have been asking for was a real plus.

     DR. NELSON:  Matt?

     DR. KUEHNERT:  You had these comparisons of variables, medical history deferrals, temporary deferrals, repeat reactive units, etc.  As an epidemiologist, I had trouble seeing the error bars and wonder if you had p values.  You don't have to list them if they were greater than 0.1 but if there are any that were less than 0.1, particularly 0.05, and I know there was one you said was significant under temporary deferral, and I wondered if you could expand on that and try to speculate on reasons why there might have been a significant difference, especially on that particular variable.

     MS. BASSETT:  I don't have that information right here with me.  I don't know if Dr. Busch is here.  He and his colleagues were kind enough to put that information together.  There he comes to the microphone.  I am sure he can help explain that in greater detail.

     DR. BUSCH:  Yes, obviously there were significant differences in most of the comparisons between first time donors, repeat non-eligible and then the eligible for UDHQ.  With respect to the UDHQ who qualified, who got it and didn't, there were some of those comparisons that were significant.  Actually, the confirmed positive marker rate was lower in the donors who got the UDHQ versus those who didn't in the qualified group.  Some of the other comparisons were also significant.  We need to dig into this more.

     As indicated, the UDHQ was implemented regionally, predominantly at fixed sites initially, predominantly I suspect apheresis donors.  So, we need to sort the donors into donation type and further examine these comparisons.  I believe that once we do so we will see that there will be no significant difference once we properly stratify the difference.

     DR. KUEHNERT:  Okay.  And, the temporary deferral refers to what, again?

     MS. BASSETT:  It is hemoglobin, blood pressure, pulse and "are you feeling well and healthy today?"

     DR. BUSCH:  Again, that was significantly lower in the donors that got the UDHQ.  You know, other than the fact that that probably over-represents apheresis donors--you know, we can do both donation type and demographic stratifications.

     DR. KUEHNERT:  Thanks.

     DR. NELSON:  Donna?

     DR. DIMICHELE:  Actually, as a follow-up to that question, one of the questions that I had is whether the statistical significance was not observed because of the low number of overall donations that are represented by this study compared to the national average since my calculation is that it is only about 2.5 percent of the national donations.

     DR. BUSCH:  Right, I mean when you get into tens of thousands of donors you get significance where the medical significance is questionable.  I think, clearly, when you get into millions of donations very, very small differences become statistically significant but then you have to question whether that is medically relevant.

     DR. DIMICHELE:  My question is, if I can also ask a question, as you were implementing the questionnaire was there any reason why it couldn't have been implemented among eligible donors in a prospective, randomized way rather than, you know, just administered to eligible patients as the centers came on line?  Let me just clarify, in other words, as you are sort of implementing this in a particular center you are going to have a pool of eligible donors.  Is there any reason, from a logistical standpoint, that this couldn't have been implemented in a prospective, randomized way in any of those centers as opposed--

     MS. BASSETT:  Just letting them come in as they will?

     DR. DIMICHELE:  --kind of whoever got it, got it; whoever didn't; didn't.

     MS. BASSETT:  Yes, there should be no difference between that.  In fact, one of the things that might be is to actually let these donors know, and that is something we are looking at, that this is now an option and they are eligible to participate in this program.

     DR. DIMICHELE:  Just because from an ideal study design--

     MS. BASSETT:  Sure.

     DR. DIMICHELE:  --that would obviously be preferable unless there are logistical problems that would prevent that from happening.

     MS. BASSETT:  No.

     DR. NELSON:  Could you make it brief?  We are getting way behind and I would like to move on.

     DR. ALLEN:  Again an implementation question, your error rate did go up.  Were there any significant errors and do you have any concerns about that?

     MS. BASSETT:  Well, the errors really related to the actual determination of the criteria so that at the six-month interval what we saw is that they got the sixth month right but they missed looking at the year.  So, it was the year 2001 or 2002.  Some of the other errors that occurred I think was just people getting used to what three donations means, three allogeneic acceptable donations.  You cannot include autologous.  You cannot include deferrals, therapeutics.  So that was I think just part of the learning curve.  But those are the basic errors that we saw.

     DR. NELSON:  I would like to move on and have the data from Iowa and then we will take a break.  Stacy Sime?

Experience Using Abbreviated Questionnaires

The Blood Center of Iowa

     MS. SIME:  My name is Stacy Sime.  I am the Director of Collections at the Blood Center of Iowa.  We are a community blood center that is located in Des Moines.  We collect blood from a population base of 1.3 million, covering the central part of Iowa, touching the Minnesota, Wisconsin and Missouri borders.  We will collect approximately 85,000 units of blood this year.

     Ten years ago we began our submission process for an abbreviated history.  Based on that AIR study, BPAC meeting comments, combined with findings from the focus group meetings with our occasional, frequent and lapsed donors, we determined that an abbreviated history could have an impact on donor perception regarding the blood collection process.

     Next slide, please.  We received our approval to use the abbreviated history in November of 1998.  Implementation did wait 15 months for a number of reasons not related to the license approval or the submission.  Our original submission was for whole blood donors only.  This was intentional on our part.  At that time we were going through the process to bring the abbreviated history submission together we had two factors that prevented us from including apheresis donors.

     First and foremost, our apheresis program, in 1994, drew about 100 units of apheresis products a year.  Secondly, we were beginning a process of major SOP and process redesign in that area that we felt would be complicated by taking it through the process that needed to occur with our submission.  We expanded our license to include apheresis donors in 2002, with the first apheresis donors being screened with the abbreviated history in November of that year.

     The committee has been provided with copies of both our regular and abbreviated donor history questionnaire.  The regular history is based on the AABB uniform donor history.  If you count each question, there are 57 questions.  The abbreviated history questionnaire has 43.  Laying the two questionnaires side by side, it is easy to detect the questions that are not included because they are left blank on the abbreviated questionnaire.

     The benefit in the abbreviated questionnaire is not in the number of questions but in the time frame the question focuses on, the time period since the donor's last donation instead of the donor's entire life.

     Next slide, please.  The basic donor criteria to qualify a donor for an abbreviated history mimics our definition of a frequent donor.  A donor who has donated at least two times with us and at least once in the last 12 months is eligible for the abbreviated history, as long as the donor has donated since the last time a question was added to a regular history questionnaire and the donor was not deferred during or since their last donation.

     Next slide, please.  The actual determination of donor eligibility is made by our computer system.  The history questionnaire that the donor qualifies for prints on the donor card.  By SOP, staff are not allowed to switch donors from the regular donor questionnaire to the abbreviated history.

     Next slide.  Both questionnaires are available in a screening booth.  The staff chooses the history based on the information printed on the donor card.  Both the regular and the abbreviated questionnaire are supported by flow charts for follow-up questioning.

     Next slide, please.  The addition of a question to the regular history will revert the entire donor base to the regular history for one donation.  I provided an additional document to the committee that describes the occurrences that have forced the whole blood donor base to return to the regular history.  All occurrences, with the exception of removing the use of the confidential unit exclusion sticker, relate to FDA or AABB guidance.  Individual donors will return to the regular history if for any reason the screening staff feel that the donor should have the full questionnaires or following an individual donor deferral.

     Next slide.  Since starting, we have seen over 300,000 donors with over 125,000 of them being screened with the abbreviated history.  We have had a total of nine errors, all related to human error:  Four situations where the wrong history questionnaire was selected in the history booth; five situations where the donor was registered in error as a whole blood donor instead of an apheresis donor.  This resulted in abbreviated printing on the donor card and the wrong questionnaire being selected by the staff.  Once apheresis donors were included and were eligible to be used on the abbreviated history, these issues have gone away.  We have had two situations where our staff believed the computer determination was incorrect.  This resulted in staff opting to use a history questionnaire not matching the computer determination.  In all situations the computer has performed correctly.

     Next slide, please.  As we have implemented the abbreviated history we have focused on three areas for an indication of impact on quality, our deferral rates, post-donation information rates and viral marker rates.  Our analysis has focused on the times when we have switched our entire donor base between the regular and the abbreviated donor history.  Statistically, we wanted to see no difference between the means of the data sets in these rates when donors are eligible for the abbreviated history versus when the entire donor base was forced back to the regular history questionnaire.  ANOVA analysis of the means of the data sets have been used to determine that with a 95 percent confidence level we can say that there is no correlation between deferral, post-donation information and viral marker rates.

     Next slide.  Just to give you some perspective, our blood collections have increased approximately 9-13 percent a year every year since 2000.  On each of the upcoming charts the periods of time when our whole blood donors are eligible for the abbreviated questionnaire are highlighted in green.

     Next slide.  Looking at the whole blood donor deferral statistics, you can see that when the whole blood donor is eligible for the abbreviated history there is an indication that there is an upward trend in the deferral statistics.  However, this does match deferral trends that are consistent with blood centers across the nation.  As we did the ANOVA analysis, there was no indication that there was a difference in the mean of the data sets included.  Approximately 48 percent of the donors in our whole blood donor base will qualify for the abbreviated history when it is in play.

     Next slide, please.  The apheresis deferral statistics again show no correlation between deferral rate and the abbreviated history.  You will note one significant change in this chart from the previous chart, and that is that there are no significant breaks in the period of time when the apheresis donors are eligible for the abbreviated history.  The reason for this is that a whole blood donor, when they are forced back to the regular history--it takes 56 days to qualify anyone in our donor base to be eligible for the abbreviated history.  With the apheresis donor base it only takes three days.  So, basically, we have no significant breaks in the sequence.

     One other important point to note is that 48 percent of our whole blood donors qualify but 85 percent of our apheresis donors are screened by the abbreviated donor history.

     Next slide.  This chart represents the number of post-donation information reports that we have received versus the periods of time when the whole blood donor base was eligible for the abbreviated history.  We chose the whole blood donor base because this comprises approximately 90 percent of our total collections.  Again, through doing an ANOVA analysis, there was no difference in the mean of the data sets when we looked at the time periods when the abbreviated history was in use versus the time periods when it was not.

     Next slide.  In light of time constraints I did not bring all of the viral marker charts.  This is the hepatitis B core and it does have both the initial reactive, the non-reactive and the repeat reactive.

     Next slide.  This particular one focuses on just the repeat reactivity rate of the hepatitis B core.  These viral marker slides prove to be much more difficult for us to analyze for a couple of reasons.  We have inconsistency between lab-to-lab performance and the initial and repeat reactive and non-reactive rates.  Additionally, because we have very few confirmed positives during the entire course of HIV testing, being in the State of Iowa, we have only had three donors that have ever tested positive for HIV so it was very difficult to correlate monthly statistics on viral markers.

     Next slide, please.  We have also looked at how the abbreviated history has benefited donor satisfaction.  Our initial application was submitted because of donor feedback.  Our apheresis donor base did campaign to be included.  This is a strong indication that the abbreviated history at least perceptually is important to the donor.  Our donor satisfaction surveys are conducted annually.  Our scores have been consistently around 9 on a scale of 10.  Our scores on both overall satisfaction as well as satisfaction in the history process jumped to 9.8 and 9.7 the first year after the abbreviated history was in use.  These scores have remained consistently higher than pre-abbreviated history scores.  Consistently since then, we have no received any comments from our donors requesting a shortened history although prior to implementation that was a comment that was made by a significant number of donors.

     Next slide, please.  One of the last indications of success of the abbreviated history is donor retention.  Our monitor for donor retention is really a donor frequency measure.  Donor frequency is calculated by determining the average number of donations each donor in our donor base donates.  Prior to implementation, each donor donated approximately 1.5 donations per year.  In 2003 we anticipate finishing with a frequency rate between 2.1 or 2.2 donations per donor.  This has resulted in several thousand additional donations each year.  Although we feel confident that the abbreviated history has contributed to this, it is really only one of several initiatives we have put in place since 2000 to increase donor retention and frequency.

     Next slide.  As we have evaluated our abbreviated donor history, the benefits have been a decrease in the time period that the donor is questioned on.  The biggest impact has been on the donor perception and ultimately satisfaction related to the short form.  Our process could be improved.  Our questions could be streamlined.  There are question changes that would decrease the number of questions in the abbreviated history.  Additionally, it would benefit us to have potentially a different approach when questions are added.  The process of setting the entire donor base back to the regular history each time a question is added has proven to be frustrating for our frequent donors.

     Next slide.  In conclusion, the message I would like to leave you with is that the abbreviated history at the Blood Center of Iowa has a positive impact on our donors' perception of donating blood.  Additionally, we can make no correlation between the use of the abbreviated history and our deferral rates, post-donation information rates or viral marker rates.  Thank you.

     DR. NELSON:  Thank you very much.  Yes, Donna?

     DR. DIMICHELE:  Thank you for that.  Actually, I noted that your abbreviated questionnaire is significantly longer than the task force's and also the one that was previously--in fact, actually if you look at it, there is only like 16 percent--I mean, it has only been reduced by 16 percent, a very small amount.  So, it would be good to know what is included in yours that hasn't been included in some of the others.  But besides that, I guess given that it is not that much significantly abbreviated, do you have any data on how much less time it takes to administer than the full-length questionnaire?

     MS. SIME:  We do cycle time studies and when we are on a full regular history our average cycle time is 12 minutes for a donor history, and we do face-to-face questions.  When we have done cycle times on only the donors doing the abbreviated donor history, the cycle time is 9.8 minutes.  It is not that much different but perceptually to that donor it is huge.

     I would also comment that the reason you see such a big change in the questionnaires that are out there now, the one from Blood Systems and the AABB one, is kind of the time period.  If you think about this, we were submitting ten years ago and haven't changed ours, waiting to see what the rest of the industry would do.

     DR. GOLDSMITH:  Do you have any idea about the impact of literacy and the education rate in Iowa on the performance of these tests?  Iowa is a very literate place, a place with a very high education level.  Do you have any concept about that?

     MS. SIME:  I don't.  I do know that we do not use self-administered histories so we still do 100 percent face-to-face interviews.  So, I can't comment on that, I am sorry.

     DR. KUEHNERT:  I noticed that part of the reason why your abbreviated questionnaire is a little longer is that you have a few more questions about sort of medical care and treatment questions.  Was there a particular reason for that, that you have it in there?  Was there some pre-testing that you did that showed that capturing wasn't quite what you thought it might be?

     MS. SIME:  You know, back as the submission was going through in the time period between 1994 and 1998, we did no pre-testing of our questionnaire at that time period.  I believe the questionnaire that we ended up with was based on various discussions back and forth with the FDA, and I did not bring that up but I know some of those questions came back because it was the only way we could assure at that time that we could get that information.

     DR. KUEHNERT:  Thanks.

     DR. STRONG:  Do you expect that you will accept the more abbreviated abbreviated questionnaire?

     MS. SIME:  Our intent would be to see where that goes.  We would love to go to a more abbreviated form than we have had.  We did not feel though that it was beneficial for us to take that and run with it individually so we are waiting to see what will happen with the AABB.

     DR. NELSON:  If there are no further questions, let's take a break for maybe 20 minutes, until maybe 11:10.

     [Brief recess]

     DR. SMALLWOOD:  We are ready to reconvene.  We are going to reconvene at this time.  We are sorry for the delay.  We will try to catch up but we do know we have a very full agenda so I hope that you all will be relaxed and expect to stay overnight.

     [Laughter]

     DR. NELSON:  With that encouraging note, the next issue is Dr. Paul Beatty from CDC who is going to talk about can abbreviated questionnaires be studied or tested.  Is here?

     PARTICIPANT:  I don't think he has walked back into the room yet.

     DR. SMALLWOOD:  Shall we go out of order and call on the next person?

     DR. NELSON:  Dr. Williams, from FDA, talking about validation of donor screening procedures.

Validation of Donor Screening Procedures

     DR. WILLIAMS:  We are late; I am losing my voice and my topic has already billed as impossible so I am going to try to be brief.

     [Laughter]

     But seriously, there has been a lot of talk about the need for data and validation studies, and the predictive accuracy of these questionnaires is a very important topic.  Although there are limited external measures that can be brought to bear, I think there are some and I hope to make the case that validation studies aren't necessarily impossible but they are difficult and they are expensive.

     Next, please.  I want to make one point, that the qualification of blood donors is really a continuous process.  In fact, quantitatively, most of it occurs by self-deferral of the donors before the blood drive even occurs.  That is based on education materials either provided by the media or the blood center or some form of contact with blood center staff.

     This is an area ripe for further study and evaluation in the future because, as I said, this is where most of the deferral actually occurs.  Additional stages are on site self-deferral prior to the formal screening; formal screening itself which involves the questionnaire and may or may not involve the confidential unit exclusion process; then, after the fact assessment of donor qualifications through post-donation information and look-back activities.

     Next slide.  There is a lot of emphasis on the questionnaire itself, including regulatory emphasis.  The reasons are that the procedures themselves are readily definable in the regulated environment of blood collection, and the documented administration of the questionnaire satisfies the regulations that require documented donor qualification on the day of donation.

     Next slide.  What are the ways to look at the validity of a questionnaire process?  Some of the terms used here are not necessarily standardized in the methodological literature but what I have based it on is a book by Fowler on proving survey questionnaires, which is part of a series on research methods.  He deals with the concepts of construct validity, namely, designing questionnaires and questions for reliable and accurate interpretation.  In other words, does the subject understand what you are asking to be the same thing that you think you are asking?  A lot of that then relates to what has already been done with this questionnaire in terms of the focus group development of the questions and the one-on-one cognitive interviews.

     There is some overlap, to be sure, but what I am actually going to speak about mostly is what is known as the predictive validity or the predictive accuracy of the questions, that is, comparison to some sort of independent standard.  If you were to look at a gold standard, what you would want to measure is ability to have some sort of adverse outcome in a recipient of that blood, obviously a very difficult measure to get to and we use many surrogates to try to approach that but that would be the gold standard for an external measure.

     Next slide.  Now, while the overall process that I mentioned is known to be a key layer of blood safety and I think there are data which say that, including passive and some limited active surveillance of recipients, it creates overall a very high degree of blood and plasma safety in the United States.  Some specific studies that have been done and some of the data presented previously to the committee show that if you compare infectious disease marker prevalence and risk factors between first time blood donors who have not been pre-screened versus general population figures from other sources, you generally see between a 7-15 fold reduction in incoming blood donors before they ever reach the blood center, and that is a function of that pre-donation education factor.

     Next slide.  However, although the overall process is pretty well defined, the predictive validity of individual elements within the process has been difficult.  In an ideal world what you would want to do is run a clinical trial.  Optimally, you could conduct it by modifying, adding or removing a question from one arm of a study and assessing the outcome.  As was mentioned earlier, you could take a random sample and administer an abbreviated questionnaire and then have a built-in control group.  What is difficult in this environment, however, is the outcome measure because the gold standard for outcome resides with the recipient rather than with the donor in most cases.  In a regulated situation, manufactured products intended for release need to meet current standards so there isn't a lot of room for variation.  The recipient risk/benefit equation may not be balanced, i.e., the benefit may be societal and the risk may be individual and that forms a very difficult consent process.  And, the post-transfusion adverse outcomes tend to be rare and may not be evident for some time.  Therefore, they are difficult and expensive and time consuming to measure.

     Next slide.  But what I wanted to mention to you is three potential areas for data collection.  Some of them have been touched on already, and I will just mention some of the potential ways data could be collected and some of the difficulties that might be associated.

     These are broken into two categories, the first being operational data, data that are collected anyhow that could simply be captured and used for evaluation.  Then the second set would be ad hoc observational data collection.  These are post-donation variations in marker prevalence and incidence, comparison of deferral numbers, and then for the observational data comparison to alternate modes of questioning, follow-up laboratory testing and recipient surveillance.

     Next slide.  In terms of PDI or post-donation information, an advantage is that the data are maintained routinely in blood collection centers and should be available for comparison.  They may be useful in both directions when comparing the predictive value of an abbreviated format against the full-length version.  There could be an increase in PDIs or there could be a decrease in PDIs depending on the effectiveness of the questionnaire.  Obviously, as many other associated factors as possible that can be assessed and built into that comparison would help to inform the conclusion.

     What are the downsides?  In terms of data available to FDA, only a proportion of the PDIs are reported to FDA as biological product deviations and that is when the products have actually been released.  And, the BPD reports that we do get, as has been discussed, are difficult to interpret out of context because often we just don't have some of the associated factors that we would need to make accurate comparisons.  In addition, as a measure of outcome probably only a fraction of post-donation information is actually recognized and identified at the blood center.  So, there is a large body of data probably missing and we don't know how representative what we get is.

     Next slide.  A second potential way of looking at things is variations and marker prevalence and incidence.  This is something that commonly comes up as a way to compare operational changes.  An advantage is that prevalence data obviously is readily available.  Incidence data, at least over the last ten years, have become available and incidence, in particular, correlates pretty well with blood safety at least for some of the known agents.

     But on the downside, the variations in prevalence over time, as you have seen from some of the blood center presentations, are such that picking up what was probably a minor difference due to an operational change with any sort of statistical power is going to be very difficult, if not in fact impossible.  So, while it is a convenient measure, it is often just not practical to try to look for comparisons.

     Next slide.  There have been some studies of this subject done which simply compared deferral numbers, either a crossover design where one technique is used and then an alternate technique is used and crossed over for comparison.  There could be a serial administration, a pre/post design, in other words, a center putting a full-length questionnaire into place and then an abbreviated questionnaire, comparing deferral numbers.  Or, it could be done by a site which puts a new procedure into place and then identifies an external site with the same general characteristics and uses that as an external control site.

     Operationally, these techniques tend to be feasible.  The problem is that in the absence of additional follow-up you don't know if deferrals in each arm are the same people, and you don't know if either one is the people that you really need to defer.  So, these types of studies would be more powerful if they could be combined with some sort of follow-up technique even if it is just on a sample population.  In addition, the data can be confounded by other operational variables that may be at play in addition to changes in the questionnaire.

     Next slide.  In terms of looking at some of the larger, more comprehensive studies, there has been some work over the past ten years in comparing donors who have gone through the standard screening process standard with alternate modes of questioning.  One that is pretty well-known is the REDS behavioral study where an anonymous donor survey was done by mail, asking donors if in fact they had risk factors that should have prevented their donation in the first place.  These were done in 1993 and 1997, and found between 2 and about 3.5 percent of donors cumulatively who identified risk factors through this external process.  That is actually a pretty powerful way to get at these types of measures because the prevalence of risk is quite a bit higher than the prevalence of markers so there are more individuals to deal with.

     There have also been many studies which get at one specific factor.  If you identify a blood donor who is seropositive for a marker you can certainly interview that donor and determine what the risk factors were.

     The third one I am almost even hesitant to mention, but you have kind of a natural experiment if the NAT-positive confirmed donor is identified because that donor will have been screened a very short time previously.  By doing an intensive follow-up investigation, one can actually determine in a pretty short time frame why that donor may have not been identified as having a risk related to that positive test result.

     Advantages--as a survey method it has improved power to derive such estimates.  A disadvantage is external validation still remains a problem.  The studies are expensive.  In terms of the last possibility, there are possible staff retention problems if you start that sort of in depth look at a screening process.

     Next slide.  Follow-up laboratory testing is also a possibility.  We explored this within the Red Cross several years ago and found out that to do a study without bias, one way we might do it is to pre-sample all first time donors coming in and hold that sample until you see what their donation status is and then, assuming approval consent, one could do the testing on those retained samples for deferred donors and develop appropriate data.  It is operationally feasible, if the funding were available, but those studies have to be very large and tend to be expensive.

     In addition, one could run a large study like that and actually find that the data were not sufficiently compelling to result in a policy change.  So, that is an additional consideration.

     Next slide.  Finally, I think probably the most powerful way of assessing changes is through recipient surveillance activities.  One way to get at this is to improve adverse event reporting, as FDA has been considering, not only to have fatalities reported but other adverse events that may be related to transfusion.  There have been studies of active surveillance of a representative sample, such as National Heart, Lung and Blood Institute's FACT study and the REDS repository which combines recipient blood samples with donation blood samples and follow-up measures.  These have good statistical power, particularly if the association with transfusion is well defined, but they tend to be very large-scale studies, very expensive.

     Next slide.  So, just to summarize on the topic at hand, FDA is very interested in seeing data related to this issue.  We have not placed on the table for the committee's consideration the cognitive testing that has been done with the abbreviated questionnaire because we do intend to ask for some additional assessment on the abbreviated questionnaire, and we think the methods used are appropriate but the studies are somewhat small and we would like some additional assessment.

     Next slide.  But the question posed for the committee is, in the absence of other supporting data, should the abbreviated format be considered as acceptable for broad implementation as a pilot program with annual readministration of the full-length questionnaire?  If this is then acceptable as a pilot, FDA would consider alternate procedures for use of the abbreviated format by licensed manufacturers as prior appropriate supplements and we would encourage supporting data related to that submission.

     So, what I wanted to do is just summarize some of the potential ways that data could be captured.  Obviously, it would help to get the ear of some of the major funding organizations which would have a role in this, but also I will just conclude by saying that if studies are anticipated, obviously, we would appreciate your approaching FDA for discussion as well.  Thank you.

     DR. NELSON:  Thank you, Alan.  Questions?  Yes, John?

     DR. BOYLE:  Just an issue of clarification, my earlier comment was on item validity where we basically are trying to find out what percentage of men who had sex with men in the past, whatever the time period is, say yes to the question and what percentage say no.  Similarly, what proportion of people with hepatitis say yes.

     You are talking about something totally different with your construct validity, and that is with some kind of combination of questions how well does this predict some kind of outcome measure?  Even if we knew that question, we wouldn't know what any changes in individual items or format would actually do in terms of improving or reducing the predictiveness of the test.  Right?  Are you in agreement?

     DR. WILLIAMS:  Yes.

     DR. KLEIN:  We may be getting into this later, Alan, but I am not sure that I understand why you are recommending and annual full-length?  Is that for study purposes or because you think that that is a better procedure?

     DR. WILLIAMS:  A couple of reasons.  What I will mention first but not necessarily of the highest priority is that it does harmonize with what is currently the practice in the plasma industry.  They use an abbreviated questionnaire format with an annual readministration of the full-length questionnaire.

     Given the post-donation information observations that have been made, there might be alternate explanations for those data, but based on the current data we can't rule out the possibility that there is added value to some sort of repeated administration of the full-length questionnaire.  In terms of serial administration of an abbreviated questionnaire followed by a full-length questionnaire in standard format, one should actually be able to produce data which would help to evaluate the equivalence of those two processes.

     DR. NELSON:  Yes, Liana?

     DR. HARVATH:  Alan, I just would like to ask a question of clarification.  Is the proposal then that all of the blood centers would be required to follow your plan, that is, the annual administration of the full questionnaire, even if they already have been approved to use a shorter questionnaire and they are doing a study that may be a bit different approach?

     DR. WILLIAMS:  No, the current thinking is that the sites that have been approved for an abbreviated questionnaire, that approval would stand and, as you see, they have done some post-implementation studies which I think are very encouraging.  Obviously, we would not require an abbreviated format to be used but, in keeping with the standardization goal of the task force, if the abbreviated was used it would be FDA's recommendation to follow certain implementation procedures, which have yet to be determined but one proposal put on the table for discussion is this annual readministration of the full-length.

     DR. NELSON:  Thank you.  Is Dr. Beatty here?

Can Abbreviated Questionnaires be Studied/Tested?

     DR. BEATTY:  First, thanks for the opportunity to be here and be a part of this important discussion.  I have gotten to talk with a lot of people in this room over the last couple of years but I am still probably somewhat of an outsider so let me just spend a minute telling you about where I come from, both organizationally and methodologically.

     The group that I work with at the National Center for Health Statistics is in the business of evaluating questionnaires but generally for surveys, and that is a little different than the screening questionnaires that we are talking about here.  Survey researchers tend to accept that there is a certain amount of individual error that goes into a report and that is okay because we are really dealing with aggregate statistics.  We assume that in general these things just sort of even out.

     With this sort of an instrument we are really raising the bar to a much higher level.  We are talking about extremely accurate individual level measurement.  Errors that kind of even out in the long haul may be overestimated or underestimated somewhere else.  That is not going to be acceptable.  I do recognize the difference.  We are talking about something a little bit different than what usually goes on here with our usual surveys.

     Next slide, please.  So, the question at hand is can the abbreviated questionnaire capture the quality information that is necessary to protect the blood supply?  I think there is another question underlying that one that has kind of been addressed by some others but I will kind of give you my take on it, is there a good reason to even really attempt it?  Clearly, there are reasons why people want this to happen.  There are very pragmatic concerns here otherwise we wouldn't be talking about.  But I am kind of approaching it from a science of measurement perspective.  Is there any compelling reason from that perspective that an abbreviated questionnaire might be better than the full-length one?  Or, at a minimum, that it doesn't have any serious disadvantages or any liabilities associated with it?  If so, how do we determine the quality of that information captured in the abbreviated one?  So, let's begin with the first issue.

     Is the shorter questionnaire better?  Well, one thing we might argue is that the shorter one minimizes the burden and perhaps minimizes the mental fatigue of donors.  That is not exactly on the right track though and I want to kind of make some distinctions here.  The full-length questionnaire, by any survey standard and any study that we know of that talks about burden, is not burdensome.  You know, if you are talking about something that takes five minutes to fill out, hey, in surveys we will show up at your door unannounced and ask for 45 minutes to an hour of your time and not think twice about it, and we are only concerned about things that go to a much higher level.  Or, we will call you blind on the telephone for 20 minutes.  No big deal.  We are concerned about things that are really on a different scope.

     But there are some ideas worth considering here.  Even if absolute length is not the issue, as I think several speakers have pointed out, we do know that the quality of response can be influenced by motivation and perceived relevance of the response task, and those thing can, I think, be threatened by a full-length questionnaire that in its current design could undermine both of those factors.

     Next slide, please.  So, let's think about a few questions that are vital in the scheme of blood donor screening but are a little inefficient and frequent ones.  If you haven't spent time that adds up to five years in Europe as of six months ago, the chances are pretty unlikely that you will have reached that threshold in the last couple of months.  I mean, it is possible.  But if you have, it might be possible to determine the same bit of information just by a more general question that says "have you traveled outside the U.S. at all?"  If you haven't, then you couldn't possibly have reached that quota.

     Or, if you had a brain graft or babesiosis or Chagas disease or any of these other things--if you have never had those, then it is pretty unlikely that the last several months would have been that magic window where it happened to show up but, again, if you had, and it could happen, then presumably a much simpler question could do the same job, the one asks more about general noteworthy medical conditions.

     Next, please.  That is all fine and well but you say, well, what is the harm of asking these things anyway just to be safe?  And, there is a downside.  It opens it up to the possible perception of doing something really irrelevant.  I mean, if you ask people questions they perceive as pointless they lose their respect for the process.  That means minimal effort not only reading the details of the questions that we crafted very carefully over a period of many months, but also not spending much time thinking about them if they bothered to read all the details.

     Why do we think this might happen?  Well, one angle that might be relevant is thinking of the work of Paul Grice who developed sort of norms that are followed in any communication, including answering questions.  When you violate one of these norms--for example, one of the norms you could violate is asking a question that has no relevance, the person who you are engaged with in this communication then has to take a step back and say, "why are you asking me that?"  One obvious conclusion that they can reach is that it is not that important that you really provide a serious answer.  It is the old "ask a silly question" and they feel entitled to respond with not the same level of commitment that they would respond to a question that they perceive as fully legitimate.

     By the same token, we also have reason to think that people don't necessarily spend the optimal amount of time answering questions as we would necessarily think they should, and this is the idea of satisficing that Mary mentioned earlier.  They do what they perceive to be an adequate amount of effort.  If you ask questions that have very little probability of happening it sends a signal that the level of effort that is adequate is truly not very high.  "This is the same list of stuff I answer no to every time so I don't really need to pay attention to it."

     Next, please.  So, the point of all this is that it is not necessarily better that a more detailed, longer, more intensive questionnaire is necessarily better.  In fact, there is ample reason to make the questionnaire as short as it can reasonably be while still fulfilling its objectives, but that is the rub.  It is worth it absolutely to make a questionnaire that is abbreviated for frequent donors if it works.  Now you have to figure out if it actually works.

     Next, please.  There are some characteristics of some kind of problem questions and if this is true of the items that we have put in the abbreviated questionnaire, then it probably doesn't cut it for our purposes.  One, it would fail to prompt memory.  This is actually a point where detail can have a really strong advantage.  Sometimes wordiness actually has the unexpected but pleasant benefit of stirring things up that don't come to your mind immediately.  It is possible that a nice, pithy item like have you had any medical problems at all just doesn't dig into your brain deep enough to get it out.  Questions themselves could lack detail.  That is, in addition to failing to stir memories, new questions could be just so short that they don't have enough detail to be comprehensible.

     Another issue is that questions don't work entirely in isolation.  They come in a context.  The meaning is shaped by questions that come before and in some cases afterwards if it is a self-administered questionnaire.  So, in dropping questions you could actually change the meaning of something that was perfectly clear to begin with and all of a sudden it is not that clear anymore.

     Next slide, please.  Well, how do we find out if these things are actually happening?  Well, a term that is often tossed out is validation.  How do we validate the questionnaire?  As several have pointed out, true validation is really difficult to achieve.  The term suggests you have the answers to the question that you compare to some external data source that you have more confidence in than the questions themselves.  Those gold standards are really hard to come by.  In the pre-HIPAA era you might have been able to do it for some things.  That is increasingly difficult today and for some things there really is no external data source.  I mean, people who have been to a prostitute in the last six months, there is nothing to compare that to.  They didn't sign up for a list somewhere or frequent prostitution card, or whatever you might do to be able to get them to participate.

     [Laughter]

     Generally, the only way you can find out about those things is by asking them the question, and if you ask them the question you have blown your opportunity to really test it on a naive face.

     Let me go to the next point.  Similarly, even if you find the people, generally we rely on volunteers.  We get people that we know might be likely to have these things happen to them and get them to sign up and then we ask them the questions.  But if you approach someone yourself you have to have a reason for doing it.  They might reasonably ask, "you know, why are you asking me these questions?  How did you approach me?  How did you pick me?"  "Well, because we know you have been to a prostitute in the last six months."  You can't really say that or any of a number of other things.

     Next point, please.  For any of these items we are dealing with pretty rare populations, which makes it real difficult to test them adequately.

     The next one.  Finally, there is also the fact that for each one finding people who would really qualify for multiple items, that is even tougher.  You know, here you had to find someone that actually has had hepatitis, had a tattoo, been to jail and had sex with a prostitute--

     [Laughter]

     --I don't know where to find them.  Maybe some of you do know where to find these people but that is pretty tough.

     Next, please.  But these are the problems we always face in questionnaire evaluation.  So, rather than compare respondents to an external source of data, our trick that we tend to rely on is to get two separate reports from the same people.  One is their answer to the question and one is another kind of more general narrative response that tells about their circumstances.  We then evaluate whether the answer that they provided us to the yes/no question winds up with the experience they explained to us in more detail.  We also probe in depth to find out things that were missed, improperly left out of responses, forgotten.  That is basically the same thing that we did with the full-length questionnaire.  It is basically one version of a kind of conglomeration of techniques, known as cognitive interviewing, and we do that all the time.

     Next slide, please.  The next thing I want to address is that the usual way that we do cognitive interviewing doesn't exactly meet our needs, and that is sort of a problem.  One thing is that cognitive interviewing is really great at finding the limitations behind one way of asking the question, what doesn't work.  It is a really efficient way of hunting down these problems and just nailing them.  It is less effective in demonstrating that a questionnaire does work.  In other words, we can show very easily what is wrong.  It is not as easy to show that this is actually quite good.  It also tends to focus on usually one questionnaire and the research question, as I understand it, is that we want to see does this abbreviated questionnaire fulfill the same function that the larger questionnaire does.

     Next, please.  But we ought to be able to learn some interesting things through sort of a modified testing plan that uses multiple questionnaire administrations.  So, the general strategy that I had in mind would be to first give participants the abbreviated questionnaire, then kind of reset the clock and say, okay, forget that you just did that and give them the full questionnaire.  You kind of help them understand that this is repetitive but, you know, please answer this in a fresh manner.  Then we do a debriefing and probing in depth where we try to find out everything we can about their circumstances recently.  The idea behind that, of course, is to see whether each successive wave of collecting data picks up something that was missed in the one before it.

     Again, that doesn't guarantee that the questionnaire is good but that is almost impossible to do.  What we can do is poke it, prod it, try to make it break in any way that we can and if we fail to find problems through a test of that type, then that would constitute a pretty good case in favor of it working.  When there are glaring problems with a questionnaire it doesn't really take thousands of people to talk to; they come to the surface pretty quickly.  You tend to find out through an evaluation of their actual circumstances things that just don't work.

     Next, please.  There are a few other considerations that we would want to make sure that this is, in fact, a quality test.  One is appropriate people.  I alluded to that a little bit earlier.  The questionnaire assumes that you have donated blood in the past six months at a minimum.  So, you need a pool of frequent blood donors but you also, as I said, want to find people who are going to likely answer yes to some of these questions.  That makes it difficult because the frequent donors are probably even less likely than the general population to be excluded.

They tend to be people who know the rules and aren't so likely to trip these deferral characteristics.  They are out there, for sure, but they are just harder to find.  If everyone answers no to the questions, well, that is not really a good test.  We have to get some people who would fall on both sides of the response categories.

     Next point, please.  It is also important to administer the questionnaire under more or less realistic circumstances.  So, if we are planning to do this in a self-administered mode, which I think is a good idea given that some of the questions are pretty sensitive, then we would want the test to be self-administered as well.  It would not hurt--in fact, it would probably be a good idea even to do it in a realistic setting of a blood donor setting so that you really make the circumstance seem realistic.

     The next point, please.  It should also be completed on an individual basis and it would be important to go through it first without interruption.  You don't want to put ideas in people's minds that will influence the way they are answering the questions.  It is important that the answer be based on their experiences, drawn on their own autobiographical memory.  By that token, we don't want to focus so much on probing what their interpretations of the questions are.  Some of that is okay but the focus should really be on kind of matching their answer to the question with their own actual experience.  We also would probably be less well served by "group think" that sort of comes from hypothetical discussions of other people and one-on-one I think is more appropriate.

     Next.  To wrap up, the final slide.  What is the appropriate test to evaluate whether this abbreviated questionnaire is as good as the full one?  I don't know of any one that is an "out of the box" answer to that question that we can readily apply.  I do think we could design an evaluation based on some pretty solid principles.  If we accept the fact that, first of all, true validation is unlikely, we can still put together a test that is explicitly designed to break the thing if it is, in fact, breakable and find out what characteristics of it don't work.  I think that could be rigorous and I think it would be a reasonable test.  It wouldn't be proof, as I have said, that the thing is flawless but if we are really looking for that level of proof we will really never be able to get anywhere; we will never be satisfied with any product that we produced including the full-length questionnaire.  And, there is good reason to try the abbreviated approach.  I think one of the best ones is that it really does the best to ensure donor commitment.

     There are other ways you can ensure donor commitment.  I mean, I am not trying to say that donor education is unimportant.  I think exactly the opposite.  You need to explain constantly the importance of why people should pay attention to these questions and that will help, but nothing will do as good of a job as asking questions that reflect realistic circumstances as they see them.  If you are being as efficient as possible with donors, they will recognize that and the rest will be maximizing their attention and their motivation.  Thanks.

     DR. NELSON:  Thank you.  Questions?

     [No response]

     Thanks very much, Paul.

     DR. BEATTY:  Thank you.

Open Public Hearing

     DR. NELSON:  We are now at the open public hearing and there were several people that wanted to--

     DR. SMALLWOOD:  You have to read this.

     DR. NELSON:  Do you want to read it?

     DR. SMALLWOOD:  No, you have to read it.

     DR. NELSON:  I have to read it.  I have to read something out of Genesis.

     [Laughter]

     Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision-making.  To ensure such transparency at the open public hearing session of the advisory committee meeting, FDA believes that it is important to understand the context of an individual's presentation.  For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting.  For example, this financial information may include a company's or a group's payment of your travel, lodging or other expenses in connection with your attendance at the meeting.  Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationships.  If you choose not to address this issue of financial relationships at the beginning of your statement it will not preclude you from speaking.

     So, that is Genesis 1:7 or something.  At any rate, Kay Gregory, from American Association of Blood Banks?  You don't look like Kay.  Steve Kleinman.  You have aged well.

     DR. KLEINMAN:  Either I aged or you aged, Ken, if you think that I am Kay.

     [Laughter]

     My name is Dr. Steve Kleinman and I am here on behalf of the American Association of Blood Banks.  In response to that statement, they have paid for me to be here today.  My position is I am Chair of the Transfusion-Transmitted Disease Committee.  I also have been a member of the UDHQ task force since its inception, and I have been interested in the issue of donor screening for about 20 years and I have published extensively in the area.  That is by way of background.

     So, I will read the statement that the committee has.  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.

     Now on to the statement and, obviously, the AABB supports the implementation of an abbreviated donor history questionnaire for frequent donors, as you heard in Dr. Townsend's presentation.  As you heard in that presentation, the proposed abbreviated questionnaire was developed in response to requests from the blood banking community, donors themselves and even the FDA.

     Similar to the process used to develop the full-length donor history questionnaire that has previously been endorsed by BPAC, the development of an abbreviated questionnaire has been the subject of unprecedented attention by a panel of experts.  The data that we have heard today from the two blood centers that have been using FDA approved abbreviated donor questionnaires indicate that blood safety is not compromised by this procedure.

     However, given the very low risks of transfusion-transmitted infections, it is virtually impossible to collect enough data to conclusively prove that a change in the donor questionnaire will not affect donor safety.  The AABB believes that there is already enough experience to justify approval of the abbreviated donor history questionnaire for use by the entire blood banking community.  The AABB urges the BPAC to look beyond the data and to use common sense in reviewing this issue.  Let's not create a situation where theoretical statistical principles of proof are used as an impediment to obvious progress.

     I just want to repeat the last two sentences because I think it is the crux.  We urge the BPAC to look beyond the data and to use common sense in reviewing this issue.  Let's not create a situation where theoretical statistical principles of proof are used to impede obvious progress.

     The use of the questions on the abbreviated questionnaire cannot compromise safety given that all questions relevant to new donor risk exposures are still being asked.  The only questions that are eliminated are those related to remote risk.  It is highly unlikely that donors will give positive responses to questions that they have previously answered negatively on two occasions, and I would say that is true despite the data we heard this morning because I think there are quite a bit of flaws in the data.  It includes plasma donor data and it hasn't been broken out I think in the kind of detail that should influence the committee in evaluating it.

     So, the only questions that are eliminated--as I said, it is highly unlikely that donors will give positive responses to questions they have previously answered negatively on two occasions or, given the non-specific nature of the questions, it is also unlikely that a positive response actually represents a risk to the recipient.

     Now, one valid concern about the safety impact of the abbreviated questionnaire relates to whether a blood center that chooses to implement it can appropriate ensure that it is administered only to those donors who are eligible to receive it.  To this end, the task force has consistently recommended that the abbreviated questionnaire be used only by blood collection facilities that have a system in place to determine that the appropriate questionnaire is administered.

     The process of developing an abbreviated questionnaire has now spanned over almost four years.  There appears to be no reason to further delay implementation of this questionnaire in those blood centers that choose to use it and can manage the process effectively.  Donors understand that the primary aim of blood banking procedures is to ensure the safety of the recipient.  Donors endorse this concept.  However, donors do not understand why they have to continue to answer the same questions about remote risk over and over again.  There are no data to support this need and both rational thinking and common sense argue against it.

     It is time to be responsive to the needs of donors who are, after all, the foundation of blood transfusion.  There are clearly benefits to be gained in increasing satisfaction among frequent donors, as will occur with the use of the abbreviated questionnaire.  This may translate to more donors making more donations, thereby improving blood availability.  At the very least, it shows that the blood banking agencies and the FDA are trying to improve the frequent donors' donation experience.

     The AABB requests that the BPAC endorse the use of the abbreviated donor history questionnaire.  Thank you.

     DR. NELSON:  Thank you.  Celso  Bianco for Americas Blood Centers.  You made it with the yellow light on still, Steve.  That is great!

     DR. BIANCO:  I am speaking on behalf of America's Blood Centers.  That is a national network of locally controlled, not-for-profit community blood centers with collections that exceeded 7 million donations, 7.5 million collections in 2002.  ABC members operate in 45 states and in Quebec, Canada and serve more than half of the 6,000 U.S. hospitals.

     The ABC strongly supports the implementation of an abbreviated donor history questionnaire for frequent donors.  The length of time taken to screen a volunteer blood donor has become painfully long.  This is especially true for regular donors who answer the same questions over and over.  They are tired, bored, annoyed.  There have been several presentations to this committee regarding the benefits of the abbreviated questionnaire over the past several years.

     The abbreviated questionnaire is the successful product of an unprecedented effort to harness the energy of the entire blood collection community and a panel of respected experts.  The proposed questionnaire was developed in response to requests from our members, from donors themselves and even FDA.  The data we have heard today from blood centers that have been using the abbreviated questionnaire indicate that blood safety is not compromised by the procedure.  ABC and our members feel that the continued collection of data may even show that use of the abbreviated questionnaire may reduce recalls and withdrawals as a result of post-donation information from donor call-backs because it focuses the attention of the donor on individual health and high risk information that has changed since the last time he or she donated, rather than forcing the donor to go through the entire process once more, diverting his or her attention from the most relevant issues of recent risk behavior.

     We want to note that the risk of transmission of infections by transfusion is extremely low and that testing of the hypothesis that the abbreviated donor history questionnaire may actually improve safety can only be accomplished in a reasonable amount of time if it is approved and all centers in the U.S. have the choice of using it.  ABC joins the AABB in urging the committee to recommend that FDA approve the abbreviated donor history questionnaire for use by the entire blood banking community.

     I actually was somewhat disappointed by the presentations made by FDA indicating that they want to see more data.  I think that we have enough data; that there is evident documentation that donors do not pay attention anymore to the long donor history questionnaires that we present to them; and that the post-donation information reports that we see submitted to FDA just reflect the defects of the current donor history questionnaire.  We need to help our donors better understand donor history.  We need to reduce the post-donation information and we urge this committee to help us do that.  We will improve safety.  We will increase donations and we will better serve our recipient public.  Thank you.

     DR. NELSON:  Thank you, Celso.  Dr. Peter Page, from American Red Cross?

     DR. PAGE:  Good morning.  I am Dr. Peter Page, from the American Red Cross.  I am Senior Medical Officer at the headquarters here, in the DC area.  I appreciate the opportunity to represent Red Cross' view on the uniform donor history questionnaire and the abbreviated version.

     In the last fiscal year, Red Cross made over 8 million suitability evaluations of individuals who presented as potential blood donors.  From those 8 million, over 7 million donations were collected, enabling Red Cross to provide about half of the nation's blood supply for transfusion.

     The Red Cross is vitally concerned with initiatives that improve the process for donating blood, maintain or improve the safety of blood products and encourage more people to donate and donate more frequently.  To that end, Red Cross has been supportive of the efforts of the blood industry to develop a uniform simplified approach to donor history screening since the original AIR study, and has been an active participant in the AABB's interagency task force on the UDHQ.

     I just said that we have over 7 million donations per year.  Those come from 4.2 million different individual donors.  About 1.5 of these 4.2 million donors who gave blood to the Red Cross in 2002 were first time donors.  These first time donors gave blood on an average of 1.25 times that year, for a total of almost 2 million donations from first time donors.  The remaining 2.7 million repeat donors provided 4.6 million donations.  Most important, about 1.1 million of those repeat donors, or about 27 percent of the Red Cross total donor base, were what we call loyal donors who had donated at least one time each year for the past 3 years and averaged 2.3 donations in fiscal year 2002.

     These loyal donors, who donate more than 1.5 times as frequently as other donors, provided about 2.5 million donations in '02--a large portion of the resources needed to meet the transfusion needs of patients, or about 40 percent that might be eligible for the abbreviated version.  Patients depend upon the willingness of a relatively small percentage of the population to donate blood, and especially on the smaller number of loyal donors who donate frequently year after year.

     Donors give not only their blood but also a significant amount of their time in order to make their donations available.  A major concern on the part of many donors is the length of time it takes to donate.  In fact, the time that it takes to donate was the top reason given by donors who have not given blood in the past three years in a 2002 mail survey of lapsed donors.  Red Cross has received many letters from donors expressing concern about the apparent inefficiency of the donation process.  I hope the BPAC members received a two-sided printout of a number of these particular comments that donors have sent to us at our headquarters.  We limited those to the donors who complain about having to answer the same questions on repeated occasions, and I think the donors speak very well for themselves and demonstrate that a number of multi-gallon donors have stopped donating because of their unhappiness with the process.

     The current pre-donation qualification process, including the health history interview given by a trained supervisor, takes about 18 minutes.  Regardless of whether they have donated before, potential donors are asked at least 39 questions about their health behaviors to qualify as donors.  Our 39 minimum questions include a number of compound questions and nested questions.  Many of these questions focus on risk behaviors that occurred even once, sometimes many years earlier.  Since all potential donors answer these questions prior to each donation, the frequent donors must provide the same information over and over and over.

     New questions are added as appropriate and so occasionally frequent donors must provide new information.  For example questions about West Nile and SARS were added in the last year.  However, by and large, the information obtained from frequent donors is the same.  Critics of the current health history interview process note that frequent donors may pay less attention to the questions and may not focus on new questions sufficiently because of the sheer number and complexity of the questions to be answered.

     Clearly, there is great benefit to be gained by improving the donation process in order to preserve the loyalty of frequent donors.  The abbreviated UDHQ format proposed by the AABB task force would benefit both blood collection organizations and frequent donors by making the pre-donation qualification process take less time for the donor, and be more efficient for the collection organization itself, and also more relevant to focusing on the potential donor's recent activities and risk behaviors.  The format of the questions on the abbreviated UDHQ as "since your last donation have you..." allows the potential donor to focus on recent activities and eliminates the need to reiterate the lack of a number of risk factors in the distant past.  The use of a reduced number of capture questions about travel and recent medical events also simplifies the process and expedites the potential donor's qualification.

     While not all repeat donors would be eligible to use the abbreviated UDHQ, Red Cross would consider adopting this approach for most of its loyal donors and other repeat donors who meet the accepted donation frequency criteria.  This would enable an estimated 3 million donations per year, close to half of the total Red Cross collections, to be accepted using the abbreviated donor interview process based on our current donor base analytical and collection volumes.  The impact on lessening the number of lapsed donors can only be contemplated, but our most loyal donors would certainly appreciate the fact that their top-most concern has been addressed.

     Red Cross appreciates the need to collect data to evaluate these new approaches as they are adopted by various participants in the blood industry.  We are extremely interested in the experience of other blood collection agencies already using abbreviated questionnaires, especially with respect to the impact on post-donation information and any changes in viral marker rates or deferral rates.  It will be most valuable to learn about the impact of an abbreviated questionnaire on donor retention and donation frequency rates, and we look forward to hearing updates on these issues as more experience is gained with the abbreviated format.

     Red Cross is very supportive of continuing efforts to implement both the standard UDHQ and the abbreviated UDHQ, and plans to implement the standard UDHQ as soon as it is approved by FDA.  However, we are concerned about the need to select the appropriate questionnaire for each potential donor based on the persons past donation record.  Therefore, Red Cross will consider implementing the abbreviated UDHQ only after our health history process, including selection of the appropriate questionnaire format for each donor, is more fully automated.

     CBER initiated a blood action plan in July, '97 to increase the effectiveness of its scientific and regulatory actions.  This action plan addresses highly focused areas of concern such as emergency operations, response to emerging diseases, and updating regulations.  One initiative associated with monitoring and increasing the blood supply is, quote, FDA will coordinate a joint government/industry initiative on simplifying and abbreviating the donor questionnaire to commence by January 1, 2001, close quote.

     Red Cross is pleased that the blood industry and FDA have advanced on this goal and encourages the members of the BPAC to support the completion of this initiative to enable the use of a UDHQ and, hopefully, an abbreviated UDHQ for appropriate donors.  The completion of this project will likely have a positive impact on both blood availability and safety.  It is Red Cross' intention to continue to support efforts in this regard to completion and to cooperate fully with the Agency and other blood collection agencies to make this goal a reality.  Thank you for the opportunity to speak on this important issue.

     DR. NELSON:  Thank you, Dr. Page.  Next is Dr. Susan Rothman, from Gulf Coast Blood Center.

     DR. ROTHMAN:  Thank you.  Gulf Cost Regional Blood Center is a member of ABC and AABB but they have paid for my presentation here.  There are no other financial considerations.

     In keeping with the principles of focus and concentration that we have heard about today, I am not going to read the statement that you have received.  I would like to emphasize two points.

     One is the importance of repeat and frequent donors to our donation base.  As all of you are aware, infrequent plasma donors can give plasma 12 times a year.  Plateletpheresis donors can give 24 times a year and, as plateletpheresis components are becoming increasingly important and plateletpheresis components are becoming the platelet of choice, this gains importance in the activities of the blood donor center.

     The other thing is the number of times this questionnaire would be used.  Our initial calculations, based upon the six-month interval of following successful donations that has been suggested by the AABB task force, is that approximately 36 percent of all our screening processes could use this abbreviated form, very similar to Blood Systems' numbers, and I think this would represent a significant improvement in the process.  At the same time, we feel that this would not impact donor safety as far as we are able to tell from our investigation of post-donation information and other similar events.

     We would like to make the process as short as is consistent with patient safety.  Thank you for your time.

     DR. NELSON:  Thank you, Dr. Rothman.  Next we have two people from the New York Blood Center.  I wonder if both are going to talk and if it could be fairly brief since we are way behind.  You are Debbie Kessler?

     MS. KESSLER:  Yes, I am.  I am Debbie Kessler, from the New York Blood Center.  I have no financial considerations to disclose.

     The New York Blood Center is pleased to have this opportunity to urge the Blood Products Advisory Committee to recommend the approval of the AABB abbreviated donor history questionnaire for frequent donors.  In recommending its approval, the BPAC would be responding to the need for an abbreviated process that has long been expressed by frequent donors, blood collection agencies and the FDA itself.

     The FDA came to the AABB to request their leadership in streamlining the donor screening process, recognizing that the questions as written were complicated, lacked clarity and that there was a need for an abbreviated donor history form to facilitate donations from frequent donors.  The AABB donor history task force first tackled the clarity of the questions as asked in the full-length questionnaire.  This committee recommended the full-length questionnaire for approval and the FDA has verbally said they would do so.

     The task force then used the validated questions from the full-length questionnaire and further refined them to develop the abbreviated donor history for frequent donors.  The FDA has previously approved two blood centers' abbreviated donor history forms.  These forms, as presented here this morning, are performing well in regards to donor satisfaction and safety.  We believe the AABB abbreviated donor form provides the same safety precautions as these previously approved forms.

     One concern we have is that the FDA might make implementation of an abbreviated questionnaire unfeasible by requiring an onerous system of flipping back and forth between the abbreviated and full-length forms based on a formula that would need to be applied donor by donor.  If the donor comes frequently enough, and this is well-defined in the AABB process, there should be no need to reapply the full-length form as long as new questions are added, whether permanently or temporarily, to both forms.  We believe that simplicity enhances safety through prevention of errors and focusing donor attention on key issues rather than inundating them with mind-numbing questions again and again.

     The New York Blood Center looks forward to the availability of the AABB abbreviated form and we would be committed to participating in post-implementation data collection. Thank you for your attention.

     DR. NELSON:  Thank you.  Next is Dorothy Kowalski.

     MS. KOWALSKI:  Thank you for the opportunity to address you today, and I will be very brief in my remarks.

     I come to you today as a volunteer donor.  I urge you to consider the appropriation of an abbreviated questionnaire for two reasons:  First of all, for safety.  I do believe that an abbreviated questionnaire can provide the same donor safety to both the donor and to the recipient, the consumer, and I ask you to look at a seamless process.

     I am a volunteer donor.  I have donated blood three times in the past year.  I am going to tell you quickly about an experience I had very recently.  I work in a large public university.  About two weeks ago we had our first cold spell.  I had to travel to another city.  The public university encompasses two cities in New Jersey.  I traveled to another city to donate.  As I looked around for a parking space, I thought, "it's so cold, do I really want to do this?  Okay, I really want to do this."  I parked.  I ran up the stairs.  I went to answer the questionnaire and thought one more time, yet again, I am answering the same questions.

     I ask you to think about the abbreviated questionnaire because I ask you to look at a seamless process, a seamless process for a certain group of cohort donors, who will always understand the deferral process, are intrinsically motivated to give of their time, effort and energy to donate and ask that you recognize that our time, effort and energy is as important to the process as in giving to the recipients.

     I am also chair of a university blood drive committee and what we have done in the committee is we have worked with students, faculty, staff and the surrounding community to educate people about the deferral process.  I ask that you consider an on-line questionnaire.  I ask you to understand that young people, especially first time donors, are taken aback about the confidentiality of the statements.  They would sooner self-defer than publicly defer over the questions again and again.  We have tried to educate the public so that they understand who is a deferral cohort group; educate the public to who is the group that may be able to donate blood; and then educate a group of people for life-long commitment to this process of blood donations.  Thank you.

     DR. NELSON:  Thank you.  Next, there was someone from the Plasma Protein Therapeutics Association, Chris Healy or Mary Gustafson.

     MS. GUSTAFSON:  I am May Gustafson.  I am a salaried employee of Plasma Protein Therapeutics Association.

     PPTA is an international trade association and standard-setting organization for the world's major producers of plasma-derived and recombinant analog therapies.  Our members provide 60 percent of the world's needs for source plasma and plasma protein therapy.

     PPTA supports the implementation of an abbreviated donor history questionnaire for frequent donors.  PPTA has been a participant in the AABB inter-organizational task force to develop the uniform donor history questionnaire or the UDHQ.

     The AABB task force developed the full-length questionnaire and abbreviated questionnaire to be used in tandem to enhance the donor interview process.  PPTA formed a subgroup of the task force to develop questionnaires to be used to screen donors of source plasma.

     It was recognized that separate documents were needed because of some differences in collection practices and donor screening requirements between whole blood donors and source plasma donors.  The PPTA subgroup used the AABB UDHQ and made modifications designed to elicit information relevant to source plasma donors.  PPTA submitted its UDHQ package, similar to AABB's proposed UDHQ, to the FDA for review on December 10, 2002.  Yes, that is a year ago yesterday.  To date, FDA has not provided PPTA with a review of its submission.

     PPTA not only encourages FDA to approve use of the AABB abbreviated questionnaire, but encourages FDA to promptly and favorably respond to PPTA's similar proposal.  Thank you.

     DR. NELSON:  Thank you very much.  Are there any other people who wanted to contribute to the open public hearing?  If not, we will close that and, Judy, could we discuss the questions for the committee?

FDA Current Thinking and Questions for

the Committee

     MS. CIARALDI:  The first question is do current data support the use of the AABB uniform donor history questionnaire, abbreviated questionnaire, is equivalent to the current donor screening process?

     DR. NELSON:  Is there discussion on this?  Why don't you show us the next question?

     MS. CIARALDI:  Next slide, please.  If not, does the committee believe that current data support approval of pilot programs to evaluate performance of an abbreviated questionnaire in a regulated blood collection environment?

     The next question, if so, please comment on the design of the pilot studies.  For instance, pilot readministration of the full-length questionnaire annually to repeat donors and consideration of conversion to biannual administration based on submitted data.

     Next question, if not, what additional data are needed prior to approval of an abbreviated donor questionnaire pilot program in a regulated blood collection environment?

     DR. NELSON:  So, go back to one then.

     MS. CIARALDI:  Could you flip back to number one, please?  Thank you.

Committee Discussion and Recommendations

     DR. NELSON:  John?

     DR. BOYLE:  In answering question one, one of the big changes between the abbreviated and non-abbreviated is "since the last donation."  The research literature is going to be split on that.  There are a number of major federal surveys--national crime victimization survey, the survey of income program participation--that have in the design phase demonstrated that the bounded interval since the last interview collection of data was more accurate than basically trying to get the lifetime, a year or whatever.  So, bounded interval is more accurate, although the accuracy tends to be keeping it in the interval than picking up additional stuff.

     On the other hand, surveys on sensitive topics, longitudinal surveys, particularly those in the drug field, indicate, number one, that lifetime drug use varies a whole lot but, even more dramatically, that recent drug use is even more variable in terms of reliability than basically lifetime.

     Having said that, that things seem to be going in different directions, if the deferral is based on "since your last donation" you had X, even if I ask the question have you ever had...and then if you say yes, the follow-up is "has it been since your last donation," the error is going to be the same.  So, I think the literature, including both the issue of disclosure of sensitive information and recall error, would basically support the bounded interval.

     DR. NELSON:  To me, I think one of the sets of questions that is probably the most difficult for donors is the travel history in that, you know, the areas that are endemic for malaria change and then we have leishmaniasis and all kinds of other things creeping in.  I think a more limited time period to recall that would probably be relevant even though for malaria risk it is a little artificial.  You could have malaria E. that would relapse after a long period of time.  Yet, you know, I think that since the last time period might deal more effectively with those questions.

     Then the issue of injection drug use and so forth, I think that there any injection drug use history is that the donor is deferred.  So, when those donors slip through it is not because they forget I think.  I mean, that is my sense.  Yes?

     DR. LAAL:  A related concern that I have is that you have no data coming from places like New York and New Jersey where, you know, there is a greater number of immigrants, a greater number of people traveling back and forth to countries which have malaria and leishmaniasis.  The data comes from Iowa which I think is a very clean place.

     [Laughter]

     Whereas the problems that you will have with immigrants and the large number of travelers is that we have no idea about viral markers, none of those things.

     DR. NELSON:  That is a good point.  Yes?

     DR. KUEHNERT:  I just wanted to try to get clarification on this question because it may help me think through this.  Is this asking do current data support the use of an abbreviated questionnaire, or is it support the use of the AABB UDHQ questionnaire?

     MS. CIARALDI:  The specific question is about the AABB uniform donor history questionnaire because that is the only one that we are reviewing right now.  We could certainly branch out and talk about it in a more general sense.

     DR. KUEHNERT:  But is it asking about the data that directly evaluate that questionnaire or is it data that evaluate other questionnaires that may apply to this questionnaire?

     MS. CIARALDI:  Well, that is the big question.  There isn't a wealth of data out there about the use of abbreviated questionnaires and what their equivalence is to the full-length questionnaire.  So, what we have to do and what we are asking is with what you have heard so far, with what you know so far, can we make a statement that what you heard about the AABB questionnaire and its ability to provide the same kind of donor screening capabilities as you might find with the full-length questionnaire, is that information there now?

     DR. NELSON:  And the other part of that question is, is this referring to a repeat donor?  That is, one who has already had the full-length questionnaire and donates within an interval?  Is that what you are talking about?

     MS. CIARALDI:  Well, according to AABB's protocol that is included within this.  In order to qualify for their abbreviated questionnaire you would have to take their full-length questionnaire twice first.  So, yes, the donors would have had experience with the full-length questionnaire and then they would get to see the abbreviated questionnaire that is developed from it.  Dr. Epstein wants to add some more information.

     DR. EPSTEIN:  I just want to make FDA's current thinking clear.  We are asking the committee's advice on approvability of the AABB task force uniform donor history questionnaire in its abbreviated form, period, full stop.  Our thinking is if, based on this deliberation and advice, FDA's reflection on the advice and so forth--if we go forward it would be through a guidance document that recognizes that questionnaire, that specific questionnaire, as an appropriate mechanism to comply with regulations and statutes.

     We would recognize the possibility for individual blood establishments to put forward alternative procedures.  That always exists.  However, that would then engage a separate review process.

     DR. NELSON:  Jim?

     DR. ALLEN:  I know time is short.  Let me make a couple of comments.  First of all, the existing long or full questionnaire has never really been adequately evaluated.  We have heard today that there are new questions that continue to be added on a regular basis.  I would venture to say that those are added without any validation or attempt to understand the ability to collect the data there.  The questionnaires certainly are not evaluated in any way that the FDA requires for a laboratory test to be implemented.

     Efforts to implement a uniform data collection system are highly commendable.  We do need to recognize that not all people process information efficiently in the same manner.  So, I think, you know, there is additional work that needs to be done.  We need to continue to evaluate the donor questionnaire and information collection process for the health history questions.

     The question about the need to go back to a full questionnaire, as was done in Iowa, every time a new question is added is another important issue.  I think the United Blood Services data suggest that familiarity of the collection process by the blood center personnel suggests that you can reduce errors once they become familiar with it, and I think continually to change back and forth should not be done.

     Finally, there is another question that came up, and that is the need to do a full data form periodically, for example annually.  I would suggest that that not be required unless there is data from a specially designed study that shows that this needs to be done.

     I think we have more information today than we have on any other questionnaire.  I am satisfied that we can move forward successfully with this, but that doesn't mean that the data collection should stop.

     DR. THOMPSON:  Can I answer one question?

     DR. NELSON:  Go ahead, Dr. Thompson.

     DR. THOMPSON:  I am from AABB.  Your question about as new questions do come along, are they validated, it is true that they weren't but we are in the process right now of validating the new questions.  So, all the new questions that have come along this year are undergoing a validation process and that will occur before they go on either or both of those questionnaires.

     DR. ALLEN:  Thank you for that clarification.  I meant to imply that when the FDA asks that additional data be collected by blood centers there isn't any validation of that or study of that before the process is implemented.

     DR. NELSON:  Charlotte?

     DR. CUNNINGHAM-RUNDLES:  Don't we have to change that word "equivalent" because it can't possibly be equivalent?  It has to be a different statement there.  It is not possibly equivalent and the answer now would be no but you don't mean that.

     MS. CIARALDI:  Well, I think what we are looking for here--you are right, physically it is different and the definition of donors is different.  Yes, they are different processes, different forms but what we are looking at here is the equivalence in the total impact it has on protecting the donor and the blood supply.  That is the type of equivalence that we are looking at, the broad equivalence of it.

     DR. CUNNINGHAM-RUNDLES:  So, it has to be re-written in any case.

     DR. EPSTEIN:  It is important not to get hung up on semantics.  The concept here is equivalent use.  We are not saying the instruments are the same; they can't be.  But the question is are we getting equally safe donations?  We are trying to qualify equivalent use.  Now, if the committee is happier with rewording, we can spend time on rewording but I think that the concept here ought to be clear.  We are really asking whether we have an equally appropriate, safe, equivalent, comparable screening tool.

     DR. KUEHNERT:  Are you saying then that if the answer is yes to this question, that means that no further data are needed?  Is that what that is saying?

     DR. EPSTEIN:  That would be correct.

     DR. NELSON:  Well, I am not sure.  I mean, even after the FDA licenses a drug for marketing there is Phase IV post-marketing surveillance, which oftentimes turns up stuff.  So, I would think that data should be collected if there is a change.

     DR. KUEHNERT:  I am just trying to figure out what the question is.

     DR. EPSTEIN:  Let me try to clarify that.  The difference, from the FDA perspective, is whether we would issue a guidance saying that the AABB UDHQ abbreviated questionnaire is appropriate for use.  If we say that as a stand-alone policy, then there may be opportunity to gather so-called Phase IV data but we would not be regarding implementation of the questionnaires as provisional based on a pilot program subject to a second level review.  So, it doesn't mean we can't gather additional information or that we wouldn't want to, but we wouldn't be regarding the implementation as provisional.

     DR. GOLDSMITH:  I just wanted to ask a question about recovered plasma and source plasma that result from blood collections.  Are we going to have a differential system for screening of donors for these two different products as these things are implemented?  If we have this implemented in the whole blood collection and not in the plasma industry is there some potential differential level of safety that might occur?  I would like to hear what people have to say about that.

     DR. NELSON:  I think this would apply for donor screening generally.  Yes?

     DR. STRONG:  Actually, PPTA, as you probably heard, has submitted an abbreviated questionnaire to address that issue.

     MS. CIARALDI:  I think the thing that he is asking about is the collection of recovered plasma from donors who meet whole blood donor suitability criteria, and some licensed blood centers also collect source plasma as a byproduct of plasmapheresis for other products.  So, there is source plasma being collected in a whole blood donor setting.  For those types of donors and recovered plasma donors that again come from donors who meet whole blood donor suitability criteria, we envision that the same donor form will be used and not the one proposed by PPTA.  We understand from what we have been told that the PPTA recommended or proposed materials will be used solely by the plasma centers that are manufacturing source plasma for further manufacturing under the PPTA auspices.

     DR. ALLEN:  Mr. Chairman, I suggest a slight wording change to the question, do current data support use of the AABB UDHQ abbreviated questionnaire as being as effective as the current donor screening process at eliciting important health history information in a selected repeat donor population?

     DR. NELSON:  That sounds okay.  I think that is the question.  Yes?

     DR. BOYLE:  There are three other pieces of current data that may bear upon this question.  One of them has to do with the repeated use of the term "sexual contact" and the data from the focus groups, as all other data, suggests that nobody agrees on what sexual contact means.  So, if you want to have some kind of uniformity or comprehensiveness you need a poster up that says, "here's what we mean by sexual contact."  It doesn't belong in the questionnaire but it certainly would be advisable to make people aware of what we are asking about, and that does come from the testing that was done of the revised instrument.

     The second thing that comes out of all of the literature on self-administered, and since some of these will be self-administered as I understand it, it would be important and that is, if you don't allow some way to say "not sure" you are going to get a "no."  If it is important to understand which of the questions people really don't understand--I don't suggest adding a "not sure" column because these are pretty good questions but I think there needs to be instruction that says if you are not sure about a question, just leave it blank so that the health screener can talk with you about it and I think that would improve the data quality.

     The last piece of what was presented to us since we are asked to talk about data that actually bears on this, appeared in the first data that we were seeing on the use of the abbreviated questionnaire.  The abbreviated questionnaire was reducing deferrals by 10 percent compared to the longer form but the rate of repeat reactives went up by 20 percent.  Fortunately, the confirmed positives were no different or actually slightly lower, but the idea that you are deferring more but getting more repeat reactives suggests that we really should understand a little bit more about what is going on.  And, the issue of not collecting data would bother me a little bit.

     DR. NELSON:  Sam?

     DR. DOPPELT:  The only thing I was going to say is if this is a stand-alone statement you have to say something about the fact that this applies to a specific group of people that have already filled out the full questionnaire one or more times.  But that was already addressed.

     DR. NELSON:  My understanding from your comment is that this questionnaire, the abbreviated questionnaire, could either be used as an interview--the issue is not the interview, not how it is administered and how it is administered may well affect some of the responses.  I think that was your point.  I mean, we are not asked to comment on that but, rather, the questions or the instrument; not the administration.

     MS. GREGORY:  Kay Gregory, from AABB.  I want to answer a couple of John's points and point out that this is defined in the user brochure that goes along with this document.  Furthermore, sexual contact is actually defined in the donor educational material.  So, I believe we have taken care of those two issues.

     MS. GUSTAFSON:  I am Mary Gustafson, from PPTA.  I know that our submission is not being discussed today but we also define sexual contact in the poster that is provided to the donor at each donation.

     DR. NELSON:  Celso?

     DR. BIANCO:  Celso Bianco, America's Blood Centers.  I would like to just make a suggestion in response to the challenge that Dr. Epstein made to us, saying that support of the abbreviated questionnaire would preclude the need for further studies.  I think that it is a prerogative of this committee to recommend what we, in the entire blood banking community, have committed to do.  That is, to perform those studies at least on the list of issues that were clearly presented by Mary Townsend and by Dr. Alan Williams.

     DR. DIMICHELE:  I just wanted to make a comment that I believe that the blood collection industry has really put forth a very important argument that repeat donors are a very valuable resource in this country, and they are population that should be respected, and that certainly their donations should be facilitated and I don't think that there is any question about that.  I think that there is a point to being responsive to these donor demands without sacrificing, of course, recipient safety and I think that that is well understood.

     It seems to me by what was presented that what the donors are asking for is a streamlined process that goes beyond the questionnaire, although there are some issues that are specific to the questionnaire.  Although the blood industry hasn't mentioned that, I am assuming that they are addressing other issues of inefficiency.  I mean, according to the time issues with respect to how long it takes to administer the full-length versus the abbreviated questionnaire, it is certainly not a tremendous amount of time difference.  So, I assume that there are other issues that need to be addressed to make sure that this population comes back and donates, and donates in a safe way.

     But with respect to the questionnaire itself, I really want to thank Dr. Beatty for his comments because it does seem to me that issues of motivation and relevance are the key here.  In thinking about that, my only questions with respect to the abbreviated questionnaire, especially after looking at the comments that the American Red Cross submitted to this committee to review, I think there are two questions.  One is not answering long-term questions that have already been answered before.  The second thing is the personal and sensitive nature.  Obviously, the abbreviated questionnaire does not address the issues of probing into sexual activity which appears to be just as sensitive, if not more offensive, to the repeat donor than answering long-term questions that may not be relevant.

     The other issue that has been shortened is medical capture.  I am a physician who takes care of a chronic care population and I see them every six months and I have to ask them questions about the intervening six months.  I can just tell you that the memory, even with respect to a specific disease like bleeding and hemophilia, is not that good and oftentimes needs to be probed by additional questions.  The question is how relevant that really is to recipient safety.  Of course, that needs to be ascertained.

     But I do believe that if the questionnaire is important to the process of maintaining your repeat donors, which I believe it is, there might need to be some tweaking here and I don't doubt that both sides are willing to make sure that that happens.

     DR. NELSON:  Mike?

     DR. BUSCH:  Just in response to one of the comments, there was no difference in the repeat reactive rates in the donors who did or didn't get the abbreviated donor history questionnaire.  The only significant difference was in the temporary deferral rates which was lower and probably related to the type of donor mix.  But what really struck me in the analysis of the Blood Systems' data was the incredible safety difference between the donors who were qualified for this versus other repeat donors and first time donors in all of these measures.

     What I think the abbreviated history will quickly be able to demonstrate is that it is resulting in more frequent donations by the safest subset of our donors.  So, I think it will translate into an overall safer donor pool by encouraging more regular donations by this safest subset.  We are actually using the fact that if you come in within this six-month time frame you get the abbreviated questionnaire as a recruitment tool.  So, I really think that the net effect of this will be a significant increase in safety.

     DR. NELSON:  Yes, I think the way the questionnaire was shortened really pretty much left the really key questions in, like the higher risk for HIV, hepatitis and stuff like that, and the things that were changed were medical history and travel history, which I think makes sense really.  I think it is probably an advance.  I am not sure that it will dramatically increase the number of repeat donors.  It might increase some.  Yes?

     DR. KLEIN:  Again, I want to point out that what we are looking at is improving the process without sacrificing safety.  I think the data that we saw from Blood Systems certainly suggests that that is the case.  I would like to see Dr. Allen's rewording of the question because there is no way you are going to get enough data to ever answer this question in the affirmative.  In my mind, it is simply not going to exist so that is really probably not a good question for us to give you advice on.

     The second point that I would like to make is that we are now talking about an abbreviated standardized form that would be approved compared to a lot of other questionnaires that aren't standardized.  They are approved but they are "mom and pop" forms that have been used over the years that really aren't very good.  So, having this equivalent to that is really no step forward.  This is probably substantially better although it will be very difficult to get those data.

     Finally just a comment on this issue of the very sensitive question.  There are data on that.  There are at least two publications, that are a decade old, showing that direct questioning is effective and really doesn't lose you very many donors, and I think that is well established and we need to move on from there.

     DR. NELSON:  Steve?

     DR. KLEINMAN:  Yes, Steve Kleinman, AABB.  I just want to follow-up on the point about data collection because I think, obviously, we saw the BSL data today and I think that if an abbreviated questionnaire is used it is obviously going to be of great interest to the people who administer it to continue to collect data, interest from a research standpoint; interest from a public policy standpoint.  So, I am sure that BSL isn't going to stop its data collections because of this meeting.  In fact, they have worked out a very good system to tabulate their data and I am sure they are going to continue to tabulate it.  If at some point they get data that indicates it is not a safe process, they are going to come back and change their policy if that is what their data shows.  It doesn't require the FDA to change the policy.  I am sure that the industry itself--and I think it is very analogous to blood testing information.  If a blood screening test is approved and it is out there and used in the field and it is not performing properly, then people switch.  And, people will switch here.  If the abbreviated donor questionnaire for some reason doesn't turn out to be effective, they will go back to the follow questionnaire.  Until they are allowed to use the abbreviated donor questionnaire how are we ever going to accumulate enough data?

     I don't think pilot programs are the answer.  Pilot programs will require much more effort on the part of blood centers.  They are logistically complicated.  They require FDA review and I think they are totally unnecessary because I think the industry can monitor what happens and share the information.  So, I think we should move on and approve it.

     DR. NELSON:  Jay?

     DR. EPSTEIN:  First of all, I both accept and endorse industry's stated interest in collecting data in an ongoing fashion even if abbreviated questionnaires are introduced.  However, the real problem is that the control group could disappear.  In other words, if everyone adopts the standardized abbreviated questionnaire, you will not longer be in a situation in which you randomize or otherwise separate users of the full-length versus users of the abbreviated and compare outcome data.  We are lucky that we have those data and are very grateful that UBS obtained it.

     But if we do not establish pilot programs the implication is that control groups may disappear.  We would then be trying to do historic controls which have many, many more confounders.  So, that is the real issue.

     Also, it is important to point out that the outcome data that we are looking at is not endpoint transfusion safety; it is not infections in recipients.  What we are looking at are things like marker rates and post-donation information reporting, frequency of donations and, of course, blood centers will continue to aggregate those data because they can't help but aggregate those data.  It is only a question of whether they will compile and report it but they have it because they have to obtain it.

     So, I am not worried about whether the data that we are talking about will cease to be generated.  The fear, if there is a fear, is that we won't have control data.

     DR. NELSON:  Matt?

     DR. KUEHNERT:  I still echo the sentiments that Harvey articulated.  You know, the way it is currently worded, it is sort of a foregone conclusion what the answer is because the questionnaire hasn't been used yet.  The data we have seen concerns, you know, abbreviated questionnaires but not that questionnaire.  So, if we are talking about whether it is our opinion that the questionnaire is going to be as effective overall, that is one thing, but about specific questions is quite another thing, particularly concerning combination questions about medical history or medications.  I would like to see data showing that they are equivalent questions.

     DR. NELSON:  I wonder if we could read the modified question?  I agree that that is a little easier to vote on and make a judgment on.  Do you want to read it again?

     DR. SMALLWOOD:  The question as proposed, the revised question as proposed, do current data support use of the AABB UDHQ abbreviated questionnaire as being as effective as the current donor screening process at eliciting important health history information in a selected repeat donor population?

     DR. NELSON:  The only current data we have seen is that from San Francisco.  It was an abbreviated questionnaire but not exactly the same one.  I think the real issue is--I guess you could interpret it one of two ways, do we have solid data, number one, and, number two, do we feel that it is likely that--and those are somewhat different questions.

     DR. CUNNINGHAM-RUNDLES:  Substitute the word "suggest."  It won't give anybody what they want but suggest the use of--sure, it does suggest it.  Other than that, we don't know.

     DR. NELSON:  Jay?

     DR. EPSTEIN:  I think that framing the term "current data" has misled people a little bit because the way we have approached it is a little bit broader than strictly comparative data in a controlled trial.  What FDA had in mind was the general corpus of knowledge which encompasses what do we know about questionnaires; what do we know about donor attention; what do we know about motivation.  In other words, we were trying to look data in a broader context than strict comparison of the abbreviated questionnaire to the long questionnaire.  So, we may have misled you.

     I have taken a stab at a revision also having heard this discussion and with your permission I would like to read it--

     DR. NELSON:  Go ahead.

     DR. EPSTEIN:  --because I think it is a little simpler:  Does current knowledge support the use of the AABB UDHQ abbreviated donor questionnaire as an alternative to the current donor screening process for appropriately selected donors?

     DR. NELSON:  Yes, I think that is better.

     DR. EPSTEIN:  If you like it, we will use a grease pen and put it up there.

     DR. NELSON:  Yes.  Are people ready to vote on that modification?  Yes, quickly.

     PARTICIPANT:  Quickly, I just wanted to answer Dr. Epstein's question about his concern that our control group will go away.  I only wish the control group would go away because that means that donors are coming in at least every six months, and that will not happen.  So, the control group will not go away.  People will come in at four months and get the abbreviated questionnaire.  Then, when they come back in eight months they will automatically have to go back to the full-length questionnaire.  So, we will have our control group still.

     DR. NELSON:  Yes, it won't be perfect because it will be a different interval and all that, but there is no perfect study.  Are we ready to dispense with this?

     MS. CIARALDI:  He is making a new slide.

     DR. NELSON:  It takes me three days to make a new slide.

     MS. CIARALDI:  While we are waiting for that, I just want to let Dr. Boyle know that in our guidance document on the self-administered questionnaires we did include as a critical control point that the donors be instructed that if they have uncertainties that they leave it blank and discuss it with the donor screening personnel.

     DR. NELSON:  So, if we vote yes on this, then there is no need to answer 1(a), 2(b), 2(c), 3, etc.

     [Laughter]

     MS. CIARALDI:  I will read it again.  Does current knowledge support the use of the AABB UDHQ abbreviated questionnaire as an alternative to the current donor screening process for appropriately selected donors?

     DR. NELSON:  Do you agree with this rephrasing?  We are ready to vote then.

     DR. SMALLWOOD: The voting on this question must be taken by a roll call vote.  Therefore, I will call the names of the members and you may reply.  Dr. Allen?

     DR. ALLEN:  Yes.

     DR. SMALLWOOD:  Dr. Cunningham-Rundles?

     DR. CUNNINGHAM-RUNDLES:  Yes.

     DR. SMALLWOOD:  Dr. Kenneth Davis?

     DR. DAVIS:  Yes.

     DR. SMALLWOOD:  Dr. DiMichele?

     DR. DIMICHELE:  I am going to say no.

     DR. SMALLWOOD:  Dr. Doppelt?

     DR. DOPPELT:  Yes.

     DR. SMALLWOOD:  Dr. Goldsmith?

     DR. GOLDSMITH:  Yes.

     DR. SMALLWOOD:  Dr. Klein?

     DR. KLEIN:  Yes.

     DR. SMALLWOOD:  Dr. Laal?

     DR. LAAL:  No.

     DR. SMALLWOOD:  Dr. Boyle?

     DR. BOYLE:  Yes.

     DR. SMALLWOOD:  Dr. Callero?

     DR. CALLERO:  Yes.

     DR. SMALLWOOD:  Dr. Harvath?

     DR. HARVATH:  Yes.

     DR. SMALLWOOD:  Dr. Kuehnert?

     DR. KUEHNERT:  Abstain.

     DR. SMALLWOOD:  Dr. Nelson?

     DR. NELSON:  Yes.

     DR. SMALLWOOD:  Ms. Knowles, how would you have voted?

     MS. KNOWLES:  I would vote yes.

     DR. SMALLWOOD:  And Dr. Strong?

     DR. STRONG:  Yes.

     DR. SMALLWOOD:  Just give me a second.  There are 13 members that are eligible to vote.  There was one abstention and two no votes and ten yes votes.  The non-voting consumer and industry representative agreed with the yes vote.  Is that clear for the record?

     MS. CIARALDI:  Thank you very much.

     DR. NELSON:  Yes, Harvey?

     DR. KLEIN:  Mr. Chairman, before we move off this issue I would like to bring something to the committee's attention.  They may not want to vote on it but maybe they want to give the sense of the committee.  That is, that every member of this committee may not realize that the full-length questionnaire, the standardized questionnaire that was prepared by the task force addressed only questions that were not part of the FDA's guidance in the past.  This, I feel, was a great defect in that process because many of the questions that were part of the FDA guidance were questions, again, that are very convoluted--that is as kindly as I can say it--probably difficult questions, not at all validated by any sense of the word.  So, I think perhaps the committee might wish to give a sense that those questions be revisited and when that standardized questionnaire is looked at again all of the questions be looked at and be restated according to perhaps the best process for doing so.

     DR. NELSON:  Yes, okay.

     DR. GOLDSMITH:  I just have a regulatory comment.  If the Agency agrees to issue a guidance regarding the use of this abbreviated questionnaire and puts this in writing, would it be appropriate to also consider a less rigorous regulatory stance on implementation?  That is, to make this, let's say a CB-30 rather than a prior approval supplement because things will be outlined fairly well?

     MS. CIARALDI:  That is certainly something that we can consider including in the guidance document.

     MS. O'CALLAGHAN:  I am Sharon, from the FDA.  I just want to clarify one thing about the questions.  The statement that you made I think is a little bit confusing.  The task force did not look at whether FDA-recommended questions were or were not appropriate but all the questions were, in fact, tested by focus groups and cognitive interview.

     DR. KLEIN:  No, I agree with that.  I think they need to look at all of the questions by the best scientific process.

     MS. O'CALLAGHAN:  I wanted to clarify that they did not look at the scientific process but the questions themselves were, in fact, all tested through the same methodology.  I want it to be clear that any previously recommended questions weren't excluded from the work that was done.

     MS. CIARALDI:  Thank you again.

     DR. NELSON:  Why don't we break for lunch and come back at 1:45?

     [Whereupon the proceedings were recessed for lunch at 1:00 p.m., to reconvene at 1:45 p.m.]

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

     DR. SMALLWOOD:  May we have your attention?  We are ready to reconvene.  While everyone is coming in, I just wanted to make a correction.  For the previous discussion we took a vote and the vote of the consumer representative was not counted but it should have been counted.  Therefore, for the result of voting on the abbreviated donor questionnaire the vote would be 11 yes votes, 2 no votes and 1 abstention.  This correction will be reflected in the minutes.

     DR. NELSON:  We are moving from donor questionnaires to parasites.  We will talk about leishmaniasis and Leishmania exposure risk in blood donation, and to introduce the topic is Dr. Robert Duncan.

Topic II: Potential Recommendations on Blood Donor

Deferral for Leishmaniasis and its Exposure

Introduction and Background

     DR. DUNCAN:  I am Dr. Robert Duncan.  I am leading this session on the issue of blood donor deferral for leishmaniasis exposure.

     I would like to start out with the next slide just to kind of give an overview of the whole session so you see how the parts fit together.  I am going to give a little, brief background but the bulk of the information about Leishmania and leishmaniasis will be given by Dr. Barbara Herwaldt, from the CDC, followed by a report by the Defense Department, Lt. Col. Ruth Sylvester, who will talk about their decision to have a donor deferral.  Impact on the blood supply will be covered by Sharyn Orton, from the Division of Blood Applications of the FDA.

     We are not going to have lunch.  I think we will just continue straight through--

     [Laughter]

     --but I wanted to put this up to bring attention to the fact that we will come back for the questions after the open public hearing.

     So, if I go to the next slide, just a little, brief information to sort of get us in the same book.  The further speakers will get us, hopefully, on the same page.  Leishmaniasis is a disease.  It is caused by infection of white blood cells, macrophage cells, with a protozoan parasite, the genus Leishmania.  There are a number of species involved and I think Barbara will probably cover some more details on that.

     A person acquires the infection primarily by the bite of an insect, a Leishmania parasite infected insect, and the distribution of the disease is largely determined by the distribution of that insect.  So, the disease is endemic to tropical and subtropical areas.  Those areas are found in the Middle East, Asia, Africa, Central and South America and that includes the Mediterranean Coast of Europe.  Another important thing to note right from the beginning is that Leishmania transmission in blood transfusions has been demonstrated.

     Let me have the next slide.  That is the disease.  Why are we bringing the issue today?  The primary reason is because a large number of potential U.S. donors are traveling currently in an endemic area.  In fact, there are reported cases of the disease in U.S. troops in Afghanistan and Iraq.  There have also been recommendations issued so there is a need to have a harmonization of policy so there is a need to develop an FDA policy on this.  That is why we are bringing the issue today.

     I am going to go into a little bit more detail of some of these with the next slide.  The question about potential U.S. donors traveling to an endemic area has to do with U.S. military actions first in Afghanistan and then in Iraq.  It didn't come up related to Afghanistan because the entire country's donors are deferred because it is a malaria endemic area so they were deferred already due to the malaria policy.

     In Iraq, the areas where leishmaniasis is endemic are not completely overlapping with malaria so there could be a need for additional deferral recommendations.  The other thing that has sort of shifted the question of risk in Iraq is the past experience from the first Gulf War.  Parasites which were traditionally thought to only cause cutaneous disease visceralized or it was described as the viscerotropic leishmaniasis and that is associated with potentially higher risk in transfusion transmission.  So, again, there is a difference in terms of risk.

     There is another point about traveling to the endemic areas, particularly to Iraq, and that is the nature of the contact.  I think I am going to make that point later but there is a difference between traveling through an endemic area and actually living outdoors, in tents.  So, there are some particular areas of a situation of the exposure that is going on in Iraq that shift the balance of risk.  Of course, as I said, there are current cases that have been detected and diagnosed.  In all cases, the diagnosis has been at the parasitological level, that it is cutaneous parasite but there is potential for visceral parasite in that area.

     Next slide.  On the issue of harmonization, I am not going to go into any great detail about the AABB and the Department of Defense policy because we probably have speakers, one definite and I assume the AABB is going to present their position, which is available written, so I am not going to go into any more detail there.

     Next slide.  But the importance of developing an FDA position--an issue with any infectious disease is can the blood be tested?  In this case, no, it cannot.  There is no approved FDA test for past exposure for Leishmania or leishmaniasis as a disease.  So, in the absence of tests, generally the blood supply is protected by deferral of potentially exposed individuals but there is no FDA policy on deferral for leishmaniasis.  So, we want to initiate the process of developing that policy, potentially leading to a guidance document and bringing the issue before you today is a step in that process.

     Lastly, in the next slide, I am just going to present the questions now in order to focus your attention as you listen to the other presentations.  So, the questions are, number one, does the committee agree that a recommendation for lifetime deferral for history of any type of leishmaniasis is appropriate?

     Number two, does the committee agree that a one-year deferral recommendation for travel to Iraq is appropriate at this time?

     Number three, does the committee agree that a recommendation for donor deferral for travel to Leishmania endemic areas other than Iraq is not appropriate at this time?

     Number four, does the committee agree that a recommendation for donor deferral for immigration for any Leishmania endemic area is not appropriate at this time?

     So, I will just recap all those in a way to help focus your memory with the words that I have underlined.  Question one is lifetime deferral for history of, you know, diagnosed disease.  Number two is one-year deferral for travel to Iraq.  Number three is no deferral for travel to other endemic areas anywhere.  Number four is no deferral for immigration from any endemic country.

     Those are the four questions.  If you have read the summary statement that was handed out, there is also a paragraph in there with some of the current thinking by the FDA that did not appear as questions.  There are some things that we are thinking about but our thinking is not clear enough to rise to the level of putting a question before the advisory committee, but I would just like to make note that we are thinking about sort of what is lacking in the medical and scientific community that would make policy on leishmaniasis easier or more implementable.

     One of them would be a better resource for geographic distribution of transmission of the disease, something like web-based documentation that could be easily available in any blood center so that a person could say I traveled to such-and-such city and that city and that area would be clearly documented as to whether there is Leishmania transmission or not.  That is one kind of idea.  It is certainly only in the thinking stage.

     The other thing is the absence of sufficiently sensitive tests.  One of the big concerns with leishmaniasis is the possibility of an asymptomatic chronic carrier.  There are not currently available tests that would detect that kind of individual.  Certainly, if we had a test like that it would alter our ability to implement policy in terms of being able to separate out the asymptomatic chronic carrier.

     With that kind of background, I would like to call Dr. Barbara Herwaldt to give us a more detailed background on the disease.

Leishmania Pathogenesis and Epidemiology

     DR. HERWALDT:  Thank you very much for inviting me here today.  I decided to reword the title of my talk to does leishmaniasis pose a substantial risk to the safety of the U.S. blood supply?

     Next slide, please.  Some of you may be wondering why we are here today, and you may not realize we are here to celebrate.  We are celebrating a 100-year anniversary of the seminal publications by Leishman and Donovan about the parasite now called Leishmania donovani which causes visceral leishmaniasis which they were studying in India.  So, celebrate today!

     If they were here today, they would probably be disappointed that there is so much we don't know about this disease, but they would be happy that we are having the first-ever BPAC meeting about leishmaniasis.

     Next slide, please.  Most of the attention of the blood bankers in the audience in the past has been on viruses and to some extent bacteria, but the time for parasites has come--

     [Laughter]

     --and the paradigm that you folks have been following for viruses may not be appropriate for the world that I am going to take you to.

     Next slide, please.  You are not in Kansas anymore--

     [Laughter]

     --we are going to a different world, the world of parasites, and it is a mysterious world, sometimes a scary world but it is a very important world to visit, to know about so that when you return to Kansas you can introduce rational policies.

     Next slide, please.  Now, when we think about parasites and the major bloodborne ones--there are others that can be transmitted through this route--we think of the diseases and organisms listed here.  Chagas and babesiosis are also diseases close to my heart by I am "leishmaniac" down to the bone marrow--

     [Laughter]

     --so I am very happy to be talking about leishmaniasis today.  When we think about screening in the U.S., as you know, there is no infection or disease specific lab screening for these organisms, simply questions about some of them.

     Next slide, please.  What are the key questions that we are here to answer?  The first question is quite easy, are leishmanial parasites transmissible by blood transfusion?  Absolutely yes.  It has been documented both in humans and in animals, and I will talk more about this later.

     Question number two is the hard one.  Question number two, what is the risk in the U.S. in general and in special circumstances, such as the one we are facing now, like the arrival or the return of "many" persons from leishmaniasis-endemic areas?  I don't know the answer.  I will tell you from the start I don't know.  But here is what I do know and that is what the rest of the talk will be about.

     Next slide, please.  I first want to step back.  Whenever one is considering establishing policies for donor deferral one should start with science and that is why I am here.  I hope that the science will help drive the policy, but I also am aware that we live in the real world and the real world has other considerations, like the consistency among policies for various microbes; logistics; resources and costs like blood supply versus demand; the availability or unavailability of tests that are appropriate for mass screening of blood donors; and political sensitivities and the public's perception and a lasting negative legacy about the government's perceived mishandling of the risks and illnesses associated with the first Persian Gulf conflict, for example.

     Next slide, please.  Well, what is leishmaniasis?  Or what are the leishmaniases?  And, why is the subject so confusing?  And, why do only people like me like leishmaniasis?

     [Laughter]

     Next slide, please.  What are the complexities?  I am going to try to make these complexities simpler and less complex for you so that by the end of the talk you too will want to be a "leishmaniac."  First, most clinicians, microbiologists, scientists have never even heard of leishmaniasis and they can't even pronounce it correctly.  It is not "leishmyniasis;" it is not "lyshmaniasis."  It is leishmaniasis, named after a Scottish doctor, Sir William Leishman.

     There are multiple clinical syndromes which I will be talking about; multiple leishmanial species, greater than 20 that infect humans, some anthroponotic with humans as the primary reservoir host; some zoonotic; some can be either; some viscerotropic that infect internal organs; some primarily dermotropic; some can be either.  Of the multiple phlebotomine and sandfly species, about 30 are thought to serve as vectors for the parasites that infect humans.  Multiple ecologies--all the way from the tropics and the subtropics to places like southwestern Europe and Texas--talk about a range--jungles to deserts; rural to urban areas and this affects the control measures that are effective, appropriate and even whether any control measures can be used.  Unfortunately, we don't yet have any vaccines or prophylactics that are available.

     Now, I don't mean to imply that there isn't some specificity and it is just diversity.  In fact, in a particular area with a particular syndrome there may be one sandfly species that transmits a particular leishmanial species.  So, again specificity amidst the diversity.  Of course, there are key host factors that affect whether an infected person becomes a diseased person.

     Next slide, please.  First of all, I will start with the leishmanial syndromes.  With leishmaniasis we have the visceral and the cutaneous.  Under cutaneous, New World versus Old World.  There are some other syndromes that I am not going to talk much about.  I want you to focus on visceral versus cutaneous; New World versus Old World because those are the big distinctions.

     Next slide, please.  Let's step back to infection.  There are many more infected people than there are diseased people in most Leishmania-endemic areas.  So, the asymptomatic to symptomatic ratio can be quite high depending on how long the disease has been or the infection has been endemic in a particular area.

     Among infected persons there is a spectrum all the way to what I am going to talk about now, which is the classic kala azar syndrome.  Kala azar means black fever in Hindi.  This is a syndrome associated with fever, cachexia, usually a big spleen, much bigger than the liver, pancytopenia, infection of the reticuloendothelial system.  This disease tends to be fatal if not appropriately and expeditiously treated.  There have been major epidemics ongoing in India and Sudan and to some extent Brazil of this life-threatening disease.  I will simply briefly mention post kala azar dermal leishmaniasis to make the point that this visceral syndrome can be associated with some dermal manifestations.  I am not going to dwell on this point but people who have post kala azar dermal leishmaniasis in countries like India where humans are the primary reservoir host, these people can serve as reservoirs of the organism.

     Next slide, please.  Just like with visceral infection there is a spectrum, the same thing with cutaneous infection.  You can be infected and be totally asymptomatic but if you are diseased, which by definition you are if you have leishmaniasis which is the disease, it is not necessarily a trivial problem.  You can have multiple, big, unsightly lesions that last and last.  With some organisms, like L. major, cause of Old World leishmaniasis, the lesions may self-cure in a relatively short period, on the order of weeks to months, or may not manifest themselves as disease at all.  But, again, some organisms are associated quite commonly with chronic lesions that may last for months, if not years.  They can be facial and have cosmetic consequences.  They can be associated with nodular type transmission of the lymphatics.  Again, this is not a trivial disease.

     Next slide, please.  There are local names for this disease, and the reason I bring this up is that ultimately when one thinks about questions for blood donors if you ask do you have a history of leishmaniasis, a lot of people may never have heard that word, leishmaniasis.  But if you ask them have you had Baghdad boil or sore, or Aleppo boil, or chicleros ulcer, then they might say yes, I have.  So, that is an important point.

     Next slide, please.  I am just going to briefly mention mucosal leishmaniasis.  When one thinks about blood deferral considerations, one always thinks, okay, how bad can this disease be?  And, we have already talked about visceral leishmaniasis potentially being fatal.  With cutaneous leishmaniasis in the New World, if you are infected with standard particular species, there is a small but non-zero risk for going on years or even decades later to develop clinically evident mucosal leishmaniasis which usually begins in the nose--this person has lost his nasal septum--and can give a very morbid chronic condition.

     Next slide, please.  Well, how is leishmaniasis transmitted?  This is why we are here but this is what happens in nature.

     Next slide, please.  It is vector borne.  It is the bite of female phlebotomine sandfies.  I have already mentioned that there are many vector species and these are very small flies, much smaller than mosquitos.  They are noiseless and weak fliers.  The fact that they are weak fliers means that they are often microfoci of disease activity, and they are most active from dusk to dawn.  For example, in Iraq with the sandfly species that has been studied there by the Army, the peak time of activity is from about midnight to 3:00 a.m., which is not to say they are not out biting at other times from dusk to dawn or that they can't be disturbed when they are resting during the day, but different species have different sort of peak times of activity.  Also, even the saliva of the sandfly can be an immune modulator.  So, the sandfly is not just some little host or vector that just transmits the infection.  It is not an innocent bystander; it also is an important player in this whole scenario.

     Another public health issue when we think about transmission is whether there can be secondary transmission.  Congenital transmission has been documented.  I will be talking a lot about bloodborne transmission not just by blood transfusion and possibly organ transplantation, but there are other types of bloodborne transmission, for example needle sharing.  The IV drug users in southwestern Europe--this is a mode of transmission that has been pretty well documented.  There is a lot of HIV visceral and to some extent cutaneous leishmaniasis co-infection, co-disease in southwestern Europe and spreading to other areas of the world as well.  Also, there are laboratory accidents, which is not really secondary transmission but is another potential sort of bloodborne type route.

     Next slide, please.  Well, where is leishmaniasis endemic?  To some extent I have already alluded to this, as has Dr. Duncan.  There are 88 countries in the world that are "endemic" for leishmaniasis.  Most of them are developing countries and actually 60 or more of them--66 if I remember correctly--are in the Old World.  Leishmaniasis is notifiable in only relatively small fraction of them, and even if it were notifiable, as you know, that doesn't guarantee that cases would be detected and reported.

     Again, subtropics, tropics and places like southwestern Europe.  In the New world, all the way from northern Argentina to south central Texas.  I have also noted where it is not found.  In the Old World, for Asia it does include southwest and central Asia but not southeast Asia.  For Africa, it is especially East and North Africa but there are sporadic cases in other countries.  Again, I keep emphasizing southwestern Europe because when we think about donor deferral and travelers--I mean, think about Spain, France and Italy and all the people going to places like that.

     Next slide, please.  I am just going to show this briefly but I want you to look not just where leishmaniasis is but also where it isn't.  It is not present everywhere in the tropics.  It is not present everywhere in any particular continent.  So, it is very important to have information about where it is and where it isn't.

     Next slide, please.  How common is leishmaniasis?

     Next slide, please.  The World Health Organization estimates that there are about 350 million persons in the 88 countries who are at risk for leishmaniasis, and about 2 million new cases of disease per year, about 500,000 visceral leish. and these are usually in poor, remote areas, and more than 90 percent of the cases are in places, again, that are quite poor and remote.

     For cutaneous leish., it is a total of approximately 1.5 million.  This is obviously just hand waving.  These are gross, gross estimates.  But, notice, greater than 90 percent of the cases are thought to occur in key countries for our discussion today.  Of course, the caveat is that cases evaluated, say, in the developed world reflect travel and immigration patterns and foreign policy as well.

     Next slide, please.  What are the sources of information about the cases evaluated in the U.S., irrespective of where they were acquired?  Well, cases of leish. are not nationally notifiable to CDC.  But CDC is contacted about civilian cases and the DoD about military cases if a long series of "if's" is met.

     First of all, if clinically active; if the person seeks medical evaluation; if the clinician considers leish.; and if the clinician contacts CDC for clinical tele-consultation, diagnostic services or for the drug, sodium stibogluconate, trade name Pentostam, which we provide under an IND through FDA as sort of a pseudo-surveillance system but, again, there is a long series of "if's" here.

     Next slide, please.  What about transmission in the United States, vector-borne transmission?  I already mentioned Texas.  Cutaneous leish. caused by L. mexicana has been documented there and this number I am sure is out of date by now.  Dog cases have been reported in multiple states, not just dogs imported from other countries but dogs who acquired infection in the U.S.  We do have sandfies capable of transmitting infection in some states in the U.S.

     Bloodborne--again, I will be talking more about this later.  No documented cases acquired by blood transfusion in the U.S. but there have been some cases in dogs documented to have been transmitted by blood transfusion.

     Again, the caveat, not for transmission in the U.S. but for cases that are seen here, is the number of persons who acquired infection elsewhere and returned or moved to the U.S. is unknown.  All I can say is, and I will talk more later about other caveats, that CDC releases Pentostam 20 to 40-some times per year but not all cases meet the long series of "if's" and not all cases need to be treated and not all cases need to be treated with Pentostam.

     Next slide, please.  For risk assessment we need to include--remember that map?--not just the country where the person went but the area of the country and the fact that there are microfoci of disease activity and where humans are the reservoir host of infection, where those infected people are and whether our people are having contact with those people.  Then, there is the force of infection in a particular place, in a particular season, and this takes into account numbers of sandfies, and the species, and numbers of infected sandfies, etc., etc.  Then activities, the type of activity, the timing of the activity, the duration, the sleeping conditions, use of personal protective measures.  But in theory all it would take is one bite from an infected sandfly and one parasite to become infected.  In practice, obviously, it probably would usually be more than that but, in theory, one parasite from one bite would be enough.

     Next slide, please.  With our pseudo-surveillance system, with our Pentostam releases, if we look at our data from 1991 to 2001 for releases of Pentostam, 366, and divide the pie by the syndrome, three-quarters of our cases are cases of New World cutaneous leishmaniasis.  As more and more of the reservists and people who were in the operations currently ongoing in southwest and south central Asia start coming back and are being treated by the civilian community rather than the military community, this slice of the pie, of course, might increase.

     Next slide, please.  Within New World, even though that is not the issue today I want to make the point that, again, it is not that one size fits all or all countries are equal.  Within the New World cases, 276 that received Pentostam during this period, Costa Rica was far and away over-represented.  Well, why?  Lots of tourists go there.  And why do they go there?  They go there to get leishmaniasis--

     [Laughter]

     --they go there to go to where leishmaniasis is hanging out.  I mean, what do you do when you are in Costa Rica?  So, again, there are certain countries that are going to be at higher risk than others.

     Next slide, please.  The next question is how is leishmaniasis diagnosed and is it easily diagnosed?  The answer is no.  Obviously, one would like to actually see the parasite.  That is one of the fun things about being a parasitologist, actually to see the parasite.  These are one-celled organisms, intracellular parasites though but with the processing you may see some extracellular organisms and, obviously, to get from cell to cell the organism is extracellular for a time.  The tissue form is the amastigote, without a flagellum, where the promastigote is what is found in the sandfly in culture.  The magic word is kinetoplast.  We want to see within the amastigote not just the nucleus but also this extranuclear bottle-like structure or rod-like structure, mitochondrial-like structure that actually contains DNA in mini and maxi circles.  This is something that is taken advantage of by the molecular biologists.

     Next slide, please.  Well, what is the gold standard for diagnosis of leish.?  We don't have one.

     Next slide, please.  How do we diagnose leish.?  Again, we want to see the parasite.  We want to see the organism to know that the person is actively infected.  I am not going to go through the details here but I want to point out--because in later slides I am going to be talking about PCR and how that has been used to document infection in asymptomatic persons--that PCR is an investigational tool, and there are a lot of techniques that different people use, and they may not have evaluated them well; they may not have optimized them for blood versus skin versus whatever.  So, keep that in mind when I talk about the PCR data.

     Again, we keep getting back to the gold standard because for something like L. major it can be pretty easy to find the parasite but for a lot of the syndromes and species we deal with it can be very difficult to find the parasite and that is where this gold standard issue comes into play.

     The next two types of diagnosis relate to a person's reaction to the parasite, either by production of antibody or through a delayed type hypersensitivity reaction.  Again, I am not going to go through the details here but I just wanted to give you a sense that, unfortunately for example for serologic, for cutaneous leish., although people are working on more sensitive techniques, right now we don't have very sensitive serologic methods for cutaneous leish.

     Also, there is the issue of active disease from infection.  There is no skin test that is licensed in the U.S.  When I talk later about the issue of sterile cure, there is the issue of skin test positivity going to negativity and we don't know if that reflects a lack of boosting, or reflects sterile cure, or what.  But the bottom line for you to remember is it is not easy to diagnose leish. and we don't have a gold standard and we certainly don't have something available for mass screening of blood donors.

     Next slide, please.  What about treatment?  You want some good news, right?  Is it easily, effectively and affordably treated with commonly available drugs?  Sorry, no.  No, no, no.

     Next slide, please.  Why treat?  Again, I have mentioned that with visceral leish. it is to prevent death.  And, if humans are the reservoir host as they are, for example, in India with Leishmania donovani infection, it is a control measure to treat them.

     Cutaneous leish. we treat to prevent morbidity.  With L. major you may have relatively rapid self-healing, maybe over several weeks to months but, as I mentioned, with some other species it can be quite chronic and you may want to accelerate the rate of healing of these lesions and also the local dissemination such as lymphadenopathy, but also keep in mind the cosmetic, social and psychologic consequences of having a big lesion, for example, on your face or a big scar on your face if you weren't appropriately treated.

     So, again, we are trying to prevent morbidity, prevent relapse, prevent some of the possible late sequelae and, for certain organisms like Leishmania tropica for which humans are the primary reservoir host, it can be a control measure.

     Next slide, please.  I am not going to try to make "leishmaniacs" out of you so I am not going to talk about treatment in detail, but I just want to mention for the parenteral therapies, look at the stuff in italics--FDA IND, off-label--this is the only drug that the FDA approved for treating leish. in the U.S. and it is for visceral leish. only.

     Off-label, not available anywhere in the world at the moment.  Investigational and for pentavalent antimonial, which is what we provide through CDC, it is several weeks to a month or so of a daily IV infusion.  So, this is not a walk in the park.

     Next slide, please.  There are various oral and other therapies that are appropriate for certain situations.  Again, I don't want you to be extrapolating to all the syndromes and species.  Miltefosine is looking highly effective.  It is an oral therapy for treatment of visceral leishmaniasis in India.  It is being studied now for cutaneous leishmaniasis.  There are various other drugs, just a grab bag of all sorts of drugs, almost any drug you mention or someone claims is useful for leish. and it is very difficult to look at the literature and try to remain sane.  So, I would encourage you not to read the treatment literature.

     There are various local and topical therapies that are actually being discussed now in terms of whether any of them might be useful for treating the large numbers of folks with cutaneous leish. in southwest and central Asia.

     Next slide, please.  With that in mind, I want to briefly tell you about leish. and the first Persian Gulf conflict and the second one.  First of all, surprise, surprise, for Operations Desert Storm and Shield 12 were reported, and I emphasize reported--we don't know how many occurred--cases of an unusual syndrome, viscerotropic leish. caused by L. tropica which we usually associate with dermotropic leish., meaning cutaneous infection.  So, that is why it was surprise, surprise, that it actually visceralized to the internal organs.  Most of the people that become infected in Saudi Arabia--some had been in Iraq but, you know, whether that is relevant or not we don't know.

     Given that there weren't good screening tests, as I mentioned before, there was the whole question of, you know, Gulf War syndrome and what proportion of the cases could have been attributable to leishmaniasis and there were the possible implications for blood safety.  So, there was all this hoopla and concern.

     But no surprise, there were cases of cutaneous leish. reported and some were caused by L. major, some by L. tropica and for some the species was not identified.  Again, this is just what was recognized and reported in over 500,000, 600,000 troops.

     Next slide, please.  In the current conflict, pick a number.  Everybody has a different number to use here but the number of cases of cutaneous leish. is rising every day.  I think there are 180-some people who are being evaluated.  The official number yesterday of parasitologically confirmed cases was 127 but 140-plus is probably pretty accurate.  But, again, every day it is going to be a different number because these people are in the pipeline and being evaluated as we speak.  Almost all the cases were acquired in Iraq.  Some might have been acquired in some border camps near Iraq, in Kuwait, very few in Afghanistan and U.S. troops, for the most part, weren't Kabul.  Except for the Afghanistan cases, of which there are very few, one of those was caused by L. tropica, but for Iraq cases, for all of which there is species data, all of them have been caused by L. major, which is not to say that some haven't been caused by L. tropica but to date L. major has been the cause.  Sandfies that have been collected by the Army have been found in this area of Iraq to be infected with L. infantum which can cause visceral or cutaneous leish.  Therefore, it potentially could be a cause either of cutaneous or visceral cases.  L. donovani, a related organism, is thought to be present in Iraq as well.

     Next slide, please.  Now to the heart of the issue, bloodborne leish. and how many cases, first of all, have been reported?

     Next slide.  I am fudging a lot here because I don't read French and Portuguese and Chinese and Hindi.  There is a lot of literature that is about leish. that may have hidden away some bloodborne cases and then also, just in general, sometimes there are papers that have sort of some paragraph in them, something about maybe a case being bloodborne.  So, I am hedging and saying less than 15 and maybe 10-11 potential bloodborne cases.  The reason I say potential is that few of the investigations were optimal.  Very few implicated a donor, for example.  But one was fatal so we have to keep that in mind.  The blood products were known, whether whole blood or packed red cells, and often the blood product wasn't even reported in the scientific publication.  Again, no U.S. reported cases but there have been cases from various European countries as well as elsewhere.

     All of the recipients developed visceral leishmaniasis but one of the donors who had skin lesions and lymphadenopathy and a sterile puncture, for whatever it is worth, did not demonstrate any evidence of visceral dissemination.  So, there is at least a theoretical possibility that this person had just cutaneous leish.  He had been to Spain, and L, infantum is there and can cause visceral leish.  As I said, all the recipients developed visceral leish.  Most of the recipients were quite young. The incubation period is relatively long and the year of occurrence of these cases has ranged quite widely.

     Next slide, please.  I am just going to briefly compare the various bloodborne parasites.  Those on the committee can look at this table later in more detail.  But what I want to emphasize when I have my epidemiologist's hat on instead of my clinician's hat on is that the issue of occurrence and reporting are very different.  Again, if you look at this column, the number of reported blood transfusion cases in the world, parentheses in the U.S., and compare leish. and T. cruzi, if we have a zero here for the U.S., notice, for T. cruzi we have 5, not counting the 2 in Canada, and we are quite confident that we are transfusing T. cruzi with more regularity than we are detecting it.  All of these patients were immunocompromised.

     So, my point is don't put too much stock in this zero given what we know about T. cruzi and the fact that we have only 5 reported T. cruzi bloodborne cases in the U.S.

     Next slide, please.  How many cases have been missed?  In endemic areas, of course, they could easily just be attributed to vector-borne transmission and in the U.S., in an ICU or whatever, if you have someone who is very sick are you going to think, oh, their infection is because they got a blood transfusion?  Is their infection because they developed leishmaniasis?  Again, if it is visceral and it is manifested by fever and drops in their counts, well, a lot of people getting blood have fever and drops in their counts.

     Also, how many of you have papers that are, like, five years since you have finished the data and you haven't published them yet?  I mean, this is in the Western world.  Think about the situation of a lot of people maybe having documented cases--in fact, I have documented cases of Babesia and T. cruzi, blood transfusion cases, and I haven't had time to publish yet.  So, again, be very aware of the fact that what is in the literature may not reflect reality.

     Next slide, please.  So, there is the tip of the "blood bag berg" phenomenon of what we may be looking it.  We don't know how big this berg is and we don't know if our ship is just about ready to crash into it, but all we know is that this is what we are seeing and we are worried about this, and we have very little knowledge about what is under the sea.

     Next slide, please.  It can happen but what is the risk?

     Next slide, please.  What factors influence the risk?

     Next slide, please.  We think about the prevalence of asymptomatically infected donors.  We think about the leish. species.  And this is key, and we don't know about the kinetics, about the frequency, the duration and level of parasitemia in white cells and also maybe extracellularly.

     What about the survival and infectivity under blood banking conditions?  This has been well documented for L, tropica and L donovani and they do survive and they are infectious for animals after being held under blood banking conditions.  Also the transfused blood products are important as are the recipients and the likelihood that they are going to survive.

     Next slide, please.  I just want to briefly get back to detection because that is such an important issue.  Remember when I talked about PCR?  If we are trying to detect the parasite in whole blood, buffy coat or plasma--plasma if we have some extracellular organisms--first of all you just want to do a blood smear or look at a buffy coat.  As most of you know, in clinical labs most slides are reviewed by machine, not manually.  Then, there are all these other issues that affect, we think, the likelihood that you would find it on blood smear.  Then, there are the various methods besides blood smear for looking for parasites.  I am going to be talking more later about the molecular techniques and culture but, again, keep in mind that a number of these techniques are investigational.

     Next slide, please.  You are wondering are there any studies in blood donors and the answer is yes.  In southern France a study was done of asymptomatic blood donors, 565 of them, and 76 or 13 percent were seropositive; 16 were either PCR and/or culture positive.  Again, those of you who have the handout can look at the details later.  These are the various permutations and combinations of PCR and culture positivity.

     I will throw in a little caveat, these cultures didn't turn positive until one to six months after they were inoculated which raises some question.  We usually don't hold cultures longer than a month.  But, if taken at face value, three percent of their asymptomatic donors were PCR and/or culture positive.  They took their culture-positive people, nine, and they retested them several months later and one was culture-positive again.

     Next slide, please.  For the same study but reported in two different papers, six of the nine culture-positive donors were first tested before the transmission season had begun.  So, the authors concluded that they thought the donors had probably been infected for at least a year.  They were able to infect Syrian hamsters with blood from these culture-positive donors.  So, that is an important point.  The authors concluded that L. infantum circulates intermittently and at low density in the blood of healthy seropositive persons.  Again, keep in mind that southern France is a leish. endemic area.

     Next slide, please.  The Brazilians have also looked at bloodborne leish. and found that multiply transfused hemodialysis patients were more likely to be seropositive than other blood donors, 37 percent versus 9 percent; 24 percent of a small number of seropositive healthy donors had PCR-positive blood.  And, they were able to transmit organisms in their hamster model by blood transfusion.

     Also, a study has been published out of Greece where they looked at a couple of thousand donors and found that there was a relatively low rate.  I actually have the numbers here but not on a slide.  Let me just see if I can find them quickly because I think it is relevant.  Out of 2,000 donors they detected 33 cases with parasites in the peripheral blood, leukocytes.  That was 1.65 percent.  This was confirmed by PCR.  One of the PCR positive cases was negative by flow cytometry.  The folks in Greece have proceeded to leukoreduce all of the blood that they transfuse.

     DR. NELSON:  Doctor, we are getting further and further behind.  Could you sort of abbreviate or summarize?

     DR. HERWALDT:  Yes.

     Next slide, please.  So, when we think about the species that can be in the blood, it is no surprise that the organisms associated with visceral leish. can be.  It is a surprise that some of the organisms associated with cutaneous leish. can be.  Again, L. major is not always benign.  It can be associated with some severe disease.

     Next slide, please.  So, the issue is can someone who is infected be cured?  Is sterile cure ever achieved?  Is it commonly achieved?  Is parasitemia always a potential risk, and does the magnitude of the risk vary by these factors?

     Next slide.  I am not going to go through all the permutations, but the issue is there are all these permutations of exposure, being asymptomatically infected, developing leish. early, developing leish. only years or decades later, being treated or self-healing, and we don't know whether all these people are still infected and how often it gets into the bloodstream.

     Next slide.  So, we are starting with all the persons in the U.S. who have ever been in leish. endemic areas and we are wondering how many people are up here.

     Next slide.  There is currently no reliable way to assess cure and most "leishmaniacs" think sterile cure is unlikely and/or uncommon for the reasons I have talked about already.

     Next slide, please.  In conclusion, the infection and the disease--we have simplicity amidst complexity.  We have recurring themes of being able to activate decades after latency; the possibility of at least intermittent long-term parasitemia; the transmissibility by blood transfusion but we don't know the level of risk, and the fact that visceral leish. can be fatal and even bloodborne leish. can be fatal.  Cutaneous leish. can be chronic and morbid.  No gold standard for diagnosis; no tests for mass screening; no great treatment and the treatment probably doesn't result in sterile cure; and the need for better understanding of the persistence and bioavailability of these parasites.

     Next slide.  So, what should be done?

     Next slide, please.  The ideal world of having a zero risk blood supply.

     Next slide.  The achievable real world of intervention measures that decrease risk.

     Next slide.  The issue of this inverse relationship that we are all aware of.

     Next slide.  This is my last slide, the importance of doing research, taking advantage of the opportunity that is at hand to assess risk and understand epidemiology and biology of leishmanial species.  We are going to have more conflicts in this area of the world and we need now to take advantage of these cases of cutaneous leish. and appropriate controls to look at the issue of parasitemia pre-treatment and in asymptomatic controls and determine whether it is a real issue for these parasites as well as others.  Thank you very much.

     DR. NELSON:  Thank you.  I have one question.  How effective is leukoreduction?  Has that been studied?

     DR. HERWALDT:  In Greece they looked at leukoreduction.  The issue, of course, with leukoreduction is that you reduce the white cells by several logs.  They thought it was effective.  It does decrease, of course, the number of organisms but it hasn't really been studied in a systematic way.

     DR. NELSON:  It could be studied in animals, I would think.

     DR. HERWALDT:  Yes.

     DR. NELSON:  I think that might be a priority since an increasing amount of the U.S. blood supply is leukoreduced.

     DR. HERWALDT:  Yes.  In fact, we were talking about that issue at lunchtime, about leukoreduction.

     DR. KLEIN:  First let me say how happy I am for you that leishmaniasis is now becoming a big problem in the United States--

     [Laughter]

     DR. HERWALDT:  I have job security, yes.

     DR. KLEIN:  I gather from your comments that it is not sexually transmitted, or is that not so?

     DR. HERWALDT:  I wish you hadn't asked.  There was one case published several decades ago where a woman became infected from her sexual--we think--her sexual activity with her husband who had visceral leishmaniasis but remitted and relapsed.  But it is this one case report and we generally don't make much of it in the sense that we don't have precautions.  We don't tell people, you know, not to have sex, to wear condoms, or whatever.  It is just one case report and it is a very complex situation.  The husband's history of visceral leish. was very complex.

     DR. NELSON:  The same with perinatal.  I guess trypanosomiasis is one of the major risks now in Latin America.  Is that also the issue with leishmaniasis?

     DR. HERWALDT:  Leishmaniasis has been documented to be congenitally transmitted.  Very few cases have been reported, in contrast to T. cruzi but, again, in terms of really studying it in a systematic way, it hasn't been done but it can be transmitted by the placenta.

     DR. ALLEN:  Just following up on the question about leukoreduction, it would seem to me that if you are going to study that issue, associated issues would be risk of transmission perhaps from platelets or plasma as opposed to anything with red cells in it.  That is why I think that laboratory studies with hamsters might be the way to answer the question.

     DR. HERWALDT:  Right, there are various animal models that can be used for various species.

     DR. NELSON:  Jay?

     DR. EPSTEIN:  Could you comment on the data on survival in stored blood components?  We do know that white cells fall apart during storage and it would seem that an organism that has an obligate residency in the white cell might not survive a lysed white cell.  So, do the data actually show a fall-off or is it actually stable and they don't mind the white cell being lysed?

     DR. HERWALDT:  I have the paper here.  It was a paper done by the folks at Walter Reed with L. tropica and with L. donovani.  They did look at various points in time and there was some drop-off.  I don't remember the exact figures but they were able to demonstrate survival.  L. donovani actually was somewhat more hardy than L. tropica but they did demonstrate survival for quite long periods.  I could show you the actual data and, again, infectivity for animals so not just survival but infectivity.

     DR. NAKHASI:  To follow-up, I think it was up to 25 days or 30 days that they could show survival in storage conditions.

     DR. HERWALDT:  Yes, but to be able to survive for a rather prolonged period.

     DR. NAKHASI:  Barbara, I just wanted to add a little bit here.  I think it should be important for the committee to remember that all the cases of transfusion that you mentioned, less than 50 or approximately 50, were all visceral?

     DR. HERWALDT:  Well, there was that one donor who had skin lesions and lymphadenopathy.

     DR. NAKHASI:  Because I think that is very important.  There are cases of cutaneous leishmaniasis, cases where transmission has occurred.

     DR. HERWALDT:  That one donor, correct.

     DR. NAKHASI:  Also, I think emphasis has to be on the time, the time a person gets infected and the time when the disease appears.  For us, for donor deferral that is a very important question, which will be heard later on.  Distinction should be made between the cutaneous form and the visceral form because the durations--you know, the appearance of the disease is different between these two cases.

     DR. HERWALDT:  Do you mean the incubation period?

     DR. NAKHASI:  Yes.  By the time you see the infection versus the sore development in the cutaneous form versus the infection, lymphadenopathy, spleen and, you know, liver disease.

     DR. HERWALDT:  Right, it can be weeks to months and, in fact, even over a year in some patients with cutaneous but typically weeks to months and for visceral it is typically on the order of months.  But, again, you can have asymptomatic parasitemia before that point.

     DR. NAKHASI:  Yes, thank you.

     DR. NELSON:  Maybe we can move on.

     DR. GOLDSMITH:  You showed one slide where there was distribution of infectious organisms into cellular components but not in plasma components in, I think, rodents.  Is there any more information about that in terms of what would happen in a plasma fractionation situation with the separation of the liquid part of plasma from the cellular components?  Do you know where infectious particles whether segregate?

     DR. HERWALDT:  Are you talking to me?

     DR. GOLDSMITH:  Yes, I am.

     DR. HERWALDT:  Which slide are you referring to?

     DR. GOLDSMITH:  The one you showed!

     DR. HERWALDT:  I mentioned the fact that you can see sometimes some extracellular organisms.  So, theoretically, they could be in plasma.  Is that what you are referring to?

     DR. GOLDSMITH:  I just was wondering if you knew if separation into plasma versus cellular components would distribute the infectious parasites into the cellular components.

     DR. HERWALDT:  Well, most of the parasites would go into the buffy coat because most of them would be intracellular.  But, because there could be some extracellular organisms, there is a theoretical possibility that some would be in the plasma.

     DR. KLEIN:  I presume those would be filtered out though during the fractionation and post-fractionation process.

     DR. NAKHASI:  And also inactivated during further manufacture.

     DR. NELSON:  Let's move on if we can.  Thank you very much, Dr. Herwaldt.  It is very interesting, comprehensive.  Lt. Col. Sylvester is going to talk about the military policy.

Department of Defense Leishmaniasis Donor

Deferral Policy

     LT. COL. SYLVESTER:  Good afternoon.  I am not a "leishmaniac," I am a blood banker so we will bring it down a little bit here.

     This is really all I have on Leishmania.  We don't really need to go through this; we have seen it all.

     Next slide.  This is also the studies she was talking about recently.  They are able to survive up to 25 days in blood products under standard conditions.  She talked about transfusion-transmitted cases; the relatively long asymptomatic period and then the chronic nature of the disease.

     Next slide, please.  In August, the Department of Defense recognized that we are seeing an increase in the number of cases of leishmaniasis in OIF, Operation Iraqi Freedom.  At that time, it was nine cases.  As with everything, it came in on Friday afternoon at four o'clock.

     [Laughter]

     At the last count, she said it was 140.  When I got the last count at the end of last week it was 115 and it is going to continue to grow because we have not reached six months past peak period yet.  So, the cases continue to grow but, as she said, the majority are L. major.

     The environment in central Iraq has proved very favorable to sandfly reproduction.  The swamp and marsh areas were drained by the Iraqi regime, which created a cracked earth syndrome which made it ideal for the sandfies to get down into the cracks in the earth and it makes it very difficult to eradicate the sandfies.  Our troops are living in those areas.

     The field preventive medicine people were trapping thousands of sandflies in unbaited traps in our encampments.  They were doing PCR on those sandflies that were trapped and 1/50, or 2 percent, of the sandflies were coming up positive by PCR for Leishmania.

     Then, there was a large rodent reservoir, the rodent cutaneous and the dog reservoir.  They were killing tens of dogs every day in and around our camps.  All of that led to a large number of individuals who were reporting in for treatment.  We had soldiers who were reporting in with hundreds of bites per individual.  As she said earlier, we are talking about one bite will do it and these people were coming in with them all down their arms and their legs.

     The typical season in Iraq is April and May through October/November, with a peak in September and October.  We started seeing cases much earlier than this.

     Next slide, please.  I will remind you of the images you saw on the march to Baghdad that were being transmitted by the embedded media that we had.  These people were sleeping next to their tanks and next to their vehicles in the dirt.  When they went forward they did not have their bed nets.  They did not have very much in the way of tenting or any kind of hard structure.  The living conditions there were very, very difficult and they continue to be very difficult today, and I think that has contributed to the large number of cases that we are seeing.

     Back two slides, please.  The other thing we were seeing was the large number of cases.  What you will see in the first slide here at the top is by year, the number of cases that we have reported within DoD to the Washington Army Institute of Research where we send all of our cases for treatment.  So, this has been the number of cases by year, starting in 1989 when they started tracking this data all the way to 2003, and all of a sudden you see the huge spike that we had in 2003.

     By country, the vast majority now are in Iraq.  As we look at these data, a large number were in Panama.  These people were all in jungle training and were deferred for the malaria.

     Next slide.  So, in the Armed Services Blood Program Office we believed that we had an increased risk of leishmaniasis in our troops and we believed that there was a risk to the blood supply, as was shown in the fact that there is a long asymptomatic period and it survives in the blood.  So, we felt that we had to do something.

     Next slide.  So, we issued a policy.  The first thing in that policy is that we maintain deferral.  We have been deferring all people who have been diagnosed with cases of leishmaniasis ever since Desert Storm, and we continue to maintain that deferral today for diagnosis.

     The next question we had to decide was what are we going to do with Iraq.  We felt we needed to defer and then it became do we defer for areas of Iraq or do we do it for the whole country?

     When you look at the map here of Iraq, down in the red areas here in the Al Basrah Province, as well as the whole northern mountainous region, up here, that is all malarial endemic.  All of the troops that either went through here, and everybody going in on the march to Baghdad, by the way, went through Al Basrah.  That is the way they came in through Kuwait, and the 101st that was defending came in through here, in the northern region.  So, a large number of our forces went through the malaria endemic areas.  Unfortunately for us, unlike Afghanistan--and she was talking about this, this is where we were first starting to see leishmaniasis cases and we also have found positive traps here, in Baghdad, and up in the mountainous regions to the north.

     So, the question was how do we try to do area deferral?  We would be deferring down here for malaria, up here for malaria, here for leish., here for leish., here for leish., and it got to the point that it was impractical to try to do area deferral.

     Please return to the previous slide.  So, we chose just to do a blanket deferral for all individuals who were in Iraq.  The living conditions are poor and we intend to maintain that deferral until the living conditions improve and we see a drop-off in the number of cases of leish., as we saw following Desert Storm, and you saw that in a previous slide.

     For the other countries in southwest Asia, in Afghanistan there were two cases.  Both of those were in 2002; none in 2003 so far.  Afghanistan--for our deferral the entire country is considered malaria endemic.  So, all of our troops that we had in there were deferred for malaria anyway so we were not concerned about leishmaniasis.  As far as we were concerned, we had it covered.

     There was one case from Kuwait but in the report that we got this individual was way up by the Iraqi border and most likely contracted that in Iraq and we have seen no other cases from Kuwait since then.

     Then we looked back at our Desert Storm experience.  Yes, we had those initial 30-something cases.  I think it was 7 or 12 of the visceral, 20 cutaneous.  But once the living conditions there improved and we got those people into harder structures and we got them out of the tents, out of the sand, then those cases of leishmaniasis dropped off.  And, we expect the same thing probably will happen here, at least we hope will happen here.  In the meantime, we decided to go ahead and put a deferral in place.

     The last question we had to answer was how long to defer for.  The asymptomatic period can be days; it can be months.  Most of the time they are diagnosed in a period of six months.  When we consulted--we consulted with a lot of people.  We consulted with the armed forces epidemiological board, the armed forces medical community.  We consulted with WHO.  We consulted with Dr. Nakhasi at the FDA.  We felt that a 12-month deferral would be a reasonable deferral since most of the cases would be showing symptoms by the six-month period.  In fact, that is what we are seeing today with all of our troops that have reported so far.  So, we chose to defer for 12 months.

     Next slide, please.  The other question that was asked is what is the donor impact?  The reality is that anybody who is there is going to be lost as a donor.  We estimated that at the time to be 250,000 people.  Just because I have deferred 250,000 people does not mean I have lost 250,000 units of blood because not everyone is going to donate.

     We went through a model where we said we have a population at risk of 250,000.  We did not know what the active duty component versus the reserve component mix was.  The reserve component is not a large donor pool for me in DoD.  The majority of those people donate to the civilian sector.  Anyway, we didn't look at that.  We took the whole mix of 250,000 and we estimated we were probably going to lose two-thirds to the malarial prophylaxis.  So, we took them out of the pack because we are not losing those due to the leishmaniasis.  We figured out that 166,000 roughly would be deferred to malaria and in DoD we see only about a 20 percent deferral rate.  That is about all the people that we can penetrate to donate.  So, we assume that those that are left are 84,000 or 20 percent of them.  So, we are looking roughly at 16,800 typical donations we would have gotten out of those people coming out of Iraq assuming the same donation rate.  Then, we see about a 15 percent deferral rate for all the other reasons.  So, we applied that also.  Once we have taken all of those calculations out, we estimated we were going to lose about 14,000, a little over 14,000 donations out of this deferral due strictly to leishmaniasis.

     The mitigation strategy that we put in place, we launched a marketing campaign that targeted the eligible donors.  We are trying to target our training populations because those people are not deployed yet so they haven't had the opportunity to be exposed to malaria, to be exposed to Leishmania and any other disease that is out there.  Then, the other was the marketing to tell people not to donate.  We have also included it in the material for returning troops.  It tells them they aren't eligible to donate, as well as if you develop any signs and symptoms you should seek treatment.  That is all I have.

     DR. NELSON:  Thank you very much.  How has this affected the blood availability for the troops in Iraq, or is blood shipped from outside for their use?

     LT. COL. SYLVESTER:  All routine red blood cells that are provided not only to Iraq but to all of our contingency operations are collected here, in the Continental United States.  They are fully tested.  They are licensed products and we ship those overseas.  The only products that are collected in theater for us is whole blood and that is the need of platelets because we don't have the ability to get platelets into theater.

     DR. NELSON:  So, you would need to accept platelets from donors that otherwise might be deferred, but it might be a small amount.

     LT. COL. SYLVESTER:  In theater?

     DR. NELSON:  Yes.

     LT. COL. SYLVESTER:  In theater they are being collected from the troops that are deployed there.  It is whole blood, yes, sir.

     DR. KUEHNERT:  I had to step outside so I may have missed this.  You had a slide on the cases by year and by country and I saw the second most frequent country was Panama.  I wondered if that was distributed evenly over the years that you looked at or whether there was a spike, and if you could comment otherwise on that.

     LT. COL. SYLVESTER:  Yes, when this data was provided my by Col. Aaronson from the Walter Reed Army Institute of Research over there, we plotted this data out and it was evenly distributed between '89 and I think '95 might be when we pulled all our troops out of Panama.  They used to have a general training course down there and it was pretty much even reporting in Panama among those years.

     DR. KUEHNERT:  I don't know the denominator so is the rate similar when you compare Iraq to Panama?

     LT. COL. SYLVESTER:  I can't answer that.  I have not looked at the denominator so I don't know.

     DR. NELSON:  Thank you very much.

     LT. COL. SYLVESTER:  Thank you.

     DR. NELSON:  Sharyn Orton is going to talk about the impact on the U.S. blood supply.

Impact of Leishmaniasis Donor Deferral Policy

on the Blood Supply

     DR. ORTON:  Of course, they give me the worst topic.  I have good news and I have bad news.  The good news is I have nine slides.  The bad news is the committee has a set of slides that, if you actually look at them, should make no sense to you.  They are completely wrong.  Earlier today they did hand out a correct copy of the slides.

     Dr. Duncan asked me to take a look at what would be the estimated impact on the blood supply of donor deferral for travel to or immigration from areas endemic for leishmaniasis that are not currently covered by the malaria travel deferral.  As was noted, leishmaniasis is very geographically centered in some places.  So, what I had to really look at was just countries in general.

     Next slide, please.  Next.  This is a list of countries that Rob asked me to take a look at.  There are 20.  I want you to particularly note the ones that have stars, Portugal, Italy, Spain, France, Greece, Israel and Taiwan, which will play a part in travel.

     Next slide, please.  Trying to get a handle on the data, I used U.S. census data to take a look at some of the immigration patterns.  I used 2001/2002 Office of Travel and Tourism Industries data.  This is data that is based on airlines and their travel patterns.  It is voluntary data collection.  So, data on many countries was either not available or the numbers were so small that, in fact, they are not included in the travel portion of what we are looking at.

     For the percent of individuals who donate annually, the NCHS Healthy People 2020 initiative in 2001 did ask individuals how many reported donating in the previous year.  So, I have an updated figure for that.  For ease, I used the AABB website, which is 2001 data, stating that there are 8 million donors, 15 million donations per year and this comes out to about 1.875 donations per donor.  I do want to stress, however, that 2001 did include the 9/11 donations and, in fact, the data I have from last year looks like the numbers are a little bit smaller than that.

     Next slide, please.  For travel, the data that I have is on the seven countries that previously had stars.  In 2002, approximately a little over 6 million people traveled to those countries.  Using the Healthy People 2020 survey where 6 percent of people indicated that they had donated in the previous year, this comes out to about 362,000 potential donors.  That translates to about 4.5 percent of the U.S. blood supply.  So if, in fact, you were to defer for travel it could be as high as 4.5 percent.

     Next slide, please.  Using the immigration data from the Census Bureau, there was data for 20 countries.  About 176,000 immigrated and this includes last place of residence or country of birth or living here but changing to a permanent residence.  I used one percent just as an arbitrary figure.  I assumed that these individuals were not as likely to donate.  I could be wrong; it could be 6 percent but I used the one percent and this comes to 1,762 donors or 0.02 percent of the blood supply.  So, this would be a small number.

     Next slide, please.  I also included what they call non-immigrants, not for pleasure.  This includes individuals who are living here because of work although they are not residents nor do they intend to become residents, and exchange students are a part of that population.  There was data from 19 countries which included 621,000 individuals.  Again, I used one percent potential donors, which came to 6,200 donors or approximately 0.08 percent of the blood supply.

     Next slide, please.  So, the total potential impact could be as high as 4.6 percent.  In fact, I just want to stress this figure could be higher if the actual number of donors is less than the 8 million that we had in 2001 or the actual number of donations is less than the 15 million, because that is the denominator that I used, or the actual number of individuals traveling is higher because, as I noted, the travel tourism industry website is only volunteer reporting only by airlines so that number could be substantially smaller.

     Next slide, please.  In conclusion, FDA believes that in the absence of evidence of an ongoing transfusion transmission of Leishmania, the risk/benefit of implementing this extensive a donor deferral needs to be thoroughly investigated.  Thank you.

     DR. NELSON:  Thank you.  Donna?

     DR. DIMICHELE:  Sharyn, do you have any information on what countries such as Spain, Italy, Portugal and France have done with their own donor deferral programs, given the higher incidence--

     DR. ORTON:  No, I don't have any information.

Open Public Hearing

     DR. NELSON:  Thank you.  Dr. Duncan, are we back to the questions?  Wait a minute, first we have the open public hearing before we go to the questions.  Do I have to read that thing again?  I read it.  People were here this morning.  I will abbreviate the reading.

     DR. NAKHASI:  Dr. Nelson, could I have a minute, please?  I just want a clarification of what was said earlier.

     DR. NELSON:  Sure, go ahead.

     DR. NAKHASI:  The countries which Sharyn showed, which are 19 or 20, they are the countries which do not overlap with the malaria countries.

     DR. NELSON:  Yes, I think we understand that.

     DR. NAKHASI:  The asterisks were mostly the European countries.

     DR. NELSON:  Right.  Let's go to the open public hearing.  Again, you should be encouraged to state your affiliation and any financial or other affiliation.  The first one who wanted to speak was Celso Bianco.  Is he here?  No?  Steve Kleinman.

     DR. KLEINMAN:  Good afternoon.  I am Dr. Steven Kleinman and I am Chair of the AABB Transfusion-Transmitted Diseases Committee, and this statement is a joint statement on behalf of the American Association of Blood Banks, America's Blood Centers and the American Red Cross.

     On behalf of those organizations, we appreciate the opportunity to address the Blood Products Advisory Committee on Leishmania.  As of October 30th, due to the risk of transfusion-transmitted leishmaniasis, the AABB adopted a policy of deferring prospective donors for 12 months after their last date of departure from Iraq.  The deferral includes armed services personnel as well as any civilians, contractors or other individuals who have visited the country.  This policy is similar to that recently adopted by the Armed Services Blood Program.

     We believe that this deferral is an appropriate precaution because of the high risk of Leishmania transmission via sandfly bites to U.S. personnel in Iraq.  As recently reported in the MMWR and updated just a few minutes ago, a large number of U.S. military personnel stationed in Iraq have been diagnosed with cutaneous leishmaniasis.  Although some forms of leishmaniasis have been transmitted by transfusion, we believe that purely cutaneous forms should not be transmitted by this route.  It is of note, however, that some cases of leishmaniasis diagnosed in personnel serving in the Persian Gulf War over a decade ago showed both a cutaneous and visceral component, and that was nicely summarized by the previous speaker.

     It is possible, therefore, that current Leishmania cases acquired in Iraq could, in fact, have a visceral phase.  It is, therefore, warranted to adopt the current deferral criteria until further studies are performed on the current cases.

     Because the risks for exposure appear much higher for U.S. personnel visiting Iraq than for U.S. citizens visiting other Leishmania endemic regions, the three organizations believe that Leishmania-based deferral should not be extended to other countries outside Iraq.  Since no cases of transfusion-transmitted leishmaniasis have ever been diagnosed in the United States, it seems clear that travel to or immigration from other parts of the world poses a very minimal or, more likely, only a theoretical risk of such transmission.  As Dr. Sylvester has just noted, the Armed Services Blood Program Office has provided figures indicating that the potential donor loss for implementing the current deferral for Leishmania could be up to 14,280 persons or about 5 percent of the total of the approximately 250,000 military personnel who have been deployed to Iraq.

She went through the basis of those estimates.

     I will skip the next sentence and go on.  Extending the impact of the donor deferral to other Leishmania endemic regions, which include other parts of the Middle East as well as parts of the Mediterranean Coast, Asia, Africa, Central America and South America, has not been measured and is not warranted at this time.  Undoubtedly, a broadening of the deferral policy to other geographic areas would have an increased impact on blood availability.  We just heard one estimate to suggest it might be up to 4.6 percent of donations.

     The AABB, ABC and Red Cross encourage further monitoring of the epidemiology of the infection in Iraq as well as further studies to determine if the current cases exhibit a bloodborne, i.e., a visceral phase.  Based on the results of these studies it may be possible to discontinue such deferrals, as was done by the AABB several years after a similar deferral was introduced following Operation Desert Storm.  Thank you for your attention.

     DR. NELSON:  Thank you, Dr. Kleinman.  Next was Mr. Kirt Love.  Is he here?

     MR. LOVE:  My name is Kirt Love, with the Desert Storm Battle Registry.  For Gulf War Service Group I am tracking medical information, medical records and military records related to the first Gulf War.  I am also an advocate on the second Gulf War.

     First slide.  I will make one observation while I am waiting for the slide.  I have heard some mocking and some commentary today concerning leishmaniasis and I am sure the individuals commenting probably are not close friends or know individuals with, say, visceral leishmaniasis.  Well, I do know people with visceral leishmaniasis and, especially when it hasn't been treated after the first year, it is a death sentence.  It is a slow, miserable, horrible daily existence.  I won't joke at any given point concerning that and I would appreciate at any given point today that people try to curb any comments concerning that.

     Mr. and Mrs Brown, whom I am presenting on behalf of, are positive for visceral leishmaniasis.  Mr. Brown brought it back from Iraq and transmitted it to his wife, and this is still an ongoing debate with the military and other veterans that I am working with.  So, I am coming at this from the standpoint as a veteran living out here, outside the system, trying to make what is happening recognized.

     Third slide.  Go ahead to the next one.  The CDC presentation actually covered most of what I was going to end up covering at this point.  I am thrilled with the presentation being as thorough as it was.  However, all it does now is make me repeat myself on a couple of elements.  However, I will stipulate, starting with this slide, that our organization met with the Pentagon Deployment Health Support Directorate before the deployment into Iraq.  Our key concerns, and there were 17 categories, and one of them was leishmaniasis because of how badly it was tracked from the first Gulf War, and our concerns about the blood supply and exposure after the fact because once it becomes visceral and the person is having to live with it long-term, that is what we want to avoid.  The cutaneous, we understand it is treatable and we are not overly concerned about the cutaneous but the visceral side of this is what we are concerned about.

     Next slide.  So, when we addressed the committee at the Deployment Health Support Directorate concerning leishmaniasis or visceral leishmaniasis, the Director at that time, Mike Kilpatrick, told us during the conversation that they understood that the PCR techniques at that time were still not conclusive.  They have not been improved in the 12 years since our deployment and we were concerned that in the field--what we are worried about the most is the diagnosis.

     Next slide.  We understood that the problem in the field, even though the Army Surgeon General has specified that they should look for it--that the procedure that was going to be done in Iraq is visual observation.  They are going to be looking for cutaneous scars.  They are not going to be looking--you can't find visceral by looking for it.  This is not something that a field medic can find.  There have to be specific laboratory procedures, which they are not doing.  So, our concern is that these troops in the theater are going to be coming down with a variety of strains.

     We know that there are up to 17 different strains or variations of leishmaniasis.  Our concern is that the visceral will go undetected, much like it did during the first Gulf War, and we are going to have the problem with these troops coming back home with visceral leishmaniasis entering into the blood base and these individuals, they will not be familiar with it.  These soldiers coming home, E-4 and below, won't have a clue as to what it is.  They may be living with it for several years before they even become aware of symptoms.  Our concern is that, again, they will be transmitting before something can be done.

     Next slide.  We are aware that there is a visceral leishmaniasis outbreak in Iraq currently, even though it is on a small scale.  Our concern is if it is there at all, it is there.  So, we don't really want the stats played down.  This is just a quote from UNICEF.  There are several other articles and there are other countries that are also monitoring it at this time.  So, even though the numbers may be small, the numbers are there.  We are aware of the cutaneous.  We are tracking the cutaneous but, again, our key concern is the lesser known visceral.

     Next slide.  Public Law 105-85 has stipulated they wanted to track this in pre- and post-deployment of troops going into Iraq.  It was stipulated that they would take surveys and draw blood samples from these people.  In the most recent GAO report we found out that they have been a little lax on the troops going in.  At least 25 percent had not filled out the surveys and a higher percentages had not given blood samples going in or coming back.

     Next slide.  Our key problem with this one is if the blood samples do not enter the HIV blood vault there is no cryogenic storage.  Should that veteran leave the military and they do not get a screening before they leave and it is not diagnosed while on active duty, therefore, they are not attributed to developing leishmaniasis on active duty.  Therefore, it is not tracked by the military.  So, our concern is these people will be medically discharged before they are diagnosed and they won't be given the opportunity.

     Next slide.  We have covered the ELISA/PCR and how the tests are not reliable.  We understand that it is not 100 percent effective in tracking visceral leishmaniasis.  Usually, when you have PCR you also have a culture, or if you have a culture you have a PCR.  With the PCR test a lot of times it is done in triplicate just to verify the procedure but it is still not 100 effective and there are literally 100 different studies with 100 different conclusions on this one.

     Next slide.  We just want to reiterate one fact.  Visceral disease is incurable if untreated, especially in the short duration.  We want to reiterate that this is very serious and we want it to be taken very seriously.

     Next slide.  The medicines are very expensive.  Pentostam is in short supply.  Once you go beyond a certain point they are not going to even help you.  So, this becomes a very expensive and drawn out procedure, and one of them is a form of chemotherapy treatment in the way that it is used.  The other one is mixed with a lipid fat, the way that it is delivered.  These are also painful procedures, as well as living with it is painful.

     Next slide.  Again, we are discussing issues of incubation over a period of time.  We are aware of one case at Walter Reed that 47 years after a cutaneous scar had healed it reinfected or manifested itself  So, we are not even sure of the total amount of time of incubation concerning visceral leishmaniasis.

     Next slide.  In summary, we are concerned that DoD will not do a proper job tracking visceral because the problem in theater is diagnosis.  We don't believe that the diagnosis procedures are 100 percent or conclusive, or they are not able to pin down the specific species.  So, we feel that there are going to be troops that are going to go through and they are going to miss the diagnosis on them.

     Next slide.  In conclusion, our recommendation--we are hoping that the FDA will impose a permanent ban on all blood products, especially plasma or any other type of blood products from soldiers serving in Iraq or in Afghanistan.  In the Afghanistan case, we had 200,000 cases of cutaneous in Kabul alone.  So, we know that there is a leishmaniasis outbreak in Afghanistan as well as in Iraq.  It is in the population but we know that eventually it is also spreading to the troops.  We just want that the benefit of the doubt be given that visceral is out there and that we are not going to dismiss it because the numbers are small.  Because it is such a horrible condition, we hope that the committee will take it very seriously.  Since there is no diagnosis procedure for it that is 100 percent effective, we don't think it is worth the risk in order to introduce this into the general population.  That concludes my presentation.

     DR. NELSON:  Thank you very much, Mr. Love.  Questions?

     MR. LOVE:  I apologize to the committee and the room for my presentation but I have an abscessed tooth and I am kind of fading in and out on this one.

     DR. NELSON:  Your presentation was very valuable. Thank you.

     MR. LOVE:  Thank you for your time.

     DR. NELSON:  Ms. Venus Hammack.

     MS. HAMMACK:  Good day, committee.  I am with the Persian Gulf Era Veterans of Massachusetts.  My name is Venus Hammack.  I am here because members of this non-profit veterans organization are aware and have met and interacted with individuals who have contracted leishmaniasis during their tour of service in the Middle East.

     Next slide.  We are concerned because of lack of knowledge, probably communication issues.  I, myself, tried to donate blood a year post deployment.  I was not adequately informed that I was banned from donation.  The blood collection center was ready to accept my blood.  The only reason that it was not collected at that time was because of a screening hematocrit that held me ineligible.

     But what I am shocked to find out today, as much as DoD has told you and their Armed Forces Blood Donation Program that they are not collecting it, that they are having a ban.  That is true.  But I am meeting individuals who have returned from Iraq and from Afghanistan who are unaware that there is a ban.  Some of them from the first Gulf War have told me several times, because they are currently having other undiagnosed problems but have yet managed to pass the screening that is currently in place, that they have given blood.  These people have fallen through the protection that the armed forces has, which is why we come today to speak.

     Next slide.  What I said before is that this danger is real.  It is coming into our system.  Our problem is the impact of this particular parasite.

     Next slide.  Because this tiny fly--we expect to get so many bites and it doesn't raise red flags.  Unfortunately, the strength and the gung-ho attitude of the military personnel makes them ignore it even more.  As you heard from other speakers today, the screening mechanisms, most of which don't directly address leishmaniasis, the returning soldier doesn't even address whether they might have encountered fly bites or if this fly bite was enough to disturb them.

     Next slide.  Something else that alarms us is that even from the past Gulf War, and statistics are coming out today, DoD's discussion is mainly on cutaneous and doesn't address the visceral.  I am sure it is there in classified information but on the nightly news or in general communication those troops are missing this information.

     Next slide.  We are threatened because there is no adequate screening process, because tools like PCR analysis are still investigative, that even what material does slip through the donor process has a greater chance of infecting the total American pool.  We are insecure in the science that exists today.

     Next slide.  Our immune systems--American soldiers specifically, unless they are from a Middle Eastern background and we have a larger population than ever that are non-citizens that are getting their status by joining the military, has increased that number more.  I think because of that genotype in the military pool who are not aware, who are now coming into the American blood donation pool, it will increase the chances of contamination.

     Next slide.  Therefore, since science yet has not caught up with the activity of this parasite, with even the treatment of its virulence, we would wish to protect the American blood pool at least for this time because we can't count on the Department of Defense to adequately notify the American blood bank system of this threat, and because this is something that goes not only from the parent but through the child, to consider this ban.  Thank you very much.

     DR. NELSON:  Thank you, Ms. Hammack.  Any questions or comments?

     [No response]

     DR. NELSON:  Thank you very much.

     MS. HAMMACK:  Thank you.

     DR. NELSON:  Dr. Duncan, could you show us the questions again?

FDA Current Thinking, Questions for the Committee

Committee Discussion and Recommendations

     DR. DUNCAN:  What I intend to do here is go through the questions, starting with question one.  I have already read through the questions as a whole.  I will first just give a very brief summary of the FDA thinking and just rely on the committee to ask questions where you need more clarification.

     So, the first question is does the committee agree that a recommendation for lifetime deferral for history of any type of leishmaniasis is appropriate?

     We think the answer should be yes because there is evidence that Leishmania can be transmitted by blood transfusion.  There is strong evidence that infection remains at a chronic low level after recovery with occasional parasitemia.  The cutaneous as well as visceral leishmaniasis should qualify the individual for deferral.  Even though there is some evidence that the cutaneous presents less danger, it is the practicality of implementation and some possibility of blood transmission of the cutaneous parasite that has been mentioned already, and the uncertain potential for viscerotropic disease.

     In this question, and as we go through the other questions, it is the same thing.  In all cases we are trying to balance risk and impact.  Our feeling in this case is that the impact will be fairly small.  The number of diagnosed cases that will be coming to donate blood in the United States is a very small number of people.  So, that risk, however large or small it might be, can just be removed without having the severe impact.  So, that is our thinking on question number one.

     I am just going to stop here and have the committee's vote on number one before we move to number two.  That is my idea.

     DR. GOLDSMITH:  I just want to ask my question again.  Do we know anything about the separation of the parasite into plasma versus the cellular components and, therefore, should you have a lifetime deferral as a plasma donor, source plasma?  Is that appropriate?  Is there any information about this?

     DR. DUNCAN:  I mean, I could come up with a logical argument from what I know.  You know, hard and fast data is not that easy to point to but the mere fact that leukoreduction is thought to virtually reduce the risk of transfusion transmission to zero would suggest that plasma is not a major source of danger.

     DR. NELSON:  You know, when you talk about the numbers of donors that would be affected by this, I can't see the rationale for allowing plasma donors or anybody if there is any risk.  Hira?

     DR. NAKHASI: Dr. Nelson, I just wanted to clarify a little bit more.  With regard to plasma, I think there are several issues as I mentioned earlier.  One is the freezing time and the parasite will not survive that.  Second is the leukoreduction so it will be gone through that.  Third is the processing after solid detergent and other things.  So, I think the risk with that is very, very minimal.

     DR. NELSON:  I guess this might add another question to our donor, right?  Have you ever had leishmaniasis?

     DR. DIMICHELE:  I was just going to ask the same question again.  Does anybody at the FDA know what the blood deferral policies are in countries like France, Spain and Portugal where this is much more endemic, and what impact it has had on the blood supply?

     DR. NAKHASI:  As far as I know from the literature, I think especially the cases which were presented early on in southern France where asymptomatic cases are much, much higher, what they did in those studies, in looking at the number of cases or looking at the transmission for a period of time, they found out the risk was much, much lower and they really have no deferral policy in that country.

     DR. DUNCAN:  We have talked to blood bankers in Brazil and it is a fairly similar thing.  The whole country is endemic and they don't have a deferral policy certainly for exposure, nor do they have deferral for--no, I can't say that but they haven't seen transfusion transmission so they are not making it part of their deferral policy as far as I know.

     DR. NAKHASI:  It is important to remember that even after having this disease for so many years, and it is not just a Johnny-come-lately disease, we have not seen any of these cases in the United States--so far, zero cases.  Again, as Barbara mentioned, it depends upon how hard you look at it.  Eventually, you know, you may find some but so far with what has been seen there are no transfusion-transmitted cases.

     With regard to Brazil, which Dr. Duncan was mentioning, we had a chat with the people in one of the groups there and they have interesting observations.  First of all, the number of donations is much smaller.  Second, they told us that they do the clinical evaluation before the person is asked a question.  That way, it reduces the impact quite a bit passing through these people.

     DR. NELSON:  Were they deferred donors who had a history of clinically diagnosed--

     DR. NAKHASI:  Yes, these were diagnosed cases.

     DR. NELSON:  And that donor would be deferred for life?

     DR. NAKHASI:  Yes, because it is a chronic phase.  That is right.

     DR. NELSON:  They also screen for Chagas serologically.  Is there a cross-reaction?

     DR. NAKHASI:  They screen for Chagas and, therefore, that takes care of it, but then there are places where Chagas and Leishmania--

     DR. NELSON:  I am asking does the serologic test for Chagas cross-react with Leishmania.

     DR. NAKHASI:  I don't know what they do.  I can't answer that question.  Maybe Dr. Celso Bianco knows more about it.

     DR. BIANCO:  Celso Bianco.  There is some cross-reaction but it is not a perfect overlap.

     DR. NELSON:  And there are half a dozen different Chagas screening tests that are used, as I understand it.

     DR. BIANCO:  But it was selected for the ability to screen for Chagas--

     DR. NELSON:  Yes, I understand that.

     DR. BIANCO:  So, it is accidental, the cross-reactivity.

     DR. NELSON:  Right, right.  Dr. Page?

     DR. PAGE:  In response to Dr. DiMichele's question, I spoke with the head of the Israeli blood program a couple of months ago.  They accept for whole blood donation individuals with cutaneous leishmaniasis as long as they have no more than five skin lesions, they are not infected and they are starting to resolve.

     MS. HAMILTON:  I am Jan Hamilton, with COB Plasma Services.  I have no conflict to declare.  I would like to point out that there is precedent for making a distinction between whole blood donation and normal source blood donation with regard to Chagas disease or babesiosis and malaria.  There may be some benefit in not including a question on leishmaniasis for normal source plasma donors given the complexity of questions being asked, and there may not be a benefit in return.

     DR. NELSON:  I think there are some limitations on what blood banks or blood collection facilities in endemic areas might do and what we might do in the U.S.  An example is the core antibody test for hepatitis which is not used in areas where hepatitis is very endemic and, yet, it probably does have some effect on decreasing the risk of hepatitis B transmission.  So, it still is, I believe, possibly applicable in the U.S., or at least there is a different risk/benefit.

     DR. EPSTEIN:  I just wanted to comment that it was our intent to bring these questions forward in relation to whole blood donation.  FDA will reflect on whether we need to address the source plasma donor but that is why you didn't hear data on clearance or inactivation of Leishmania parasites in fractionation.

     DR. NELSON:  Okay.  Well, that helps.  You are right, there was no data presented on inactivation so we are really talking about whole blood.

     DR. DUNCAN:  So, the deferral for whole blood donation could be added to the question.

     DR. NELSON:  Are we ready to vote?

     DR. DUNCAN:  So, if you could just read it and insert "whole blood donation" after "deferral."

     DR. SMALLWOOD:  The question is does the committee agree that a recommendation for lifetime deferral for whole blood donation for history of any type of leishmaniasis is appropriate?  Are you read to vote?

     DR. NELSON:  Right.

     DR. SMALLWOOD:  We will take a roll call vote.  If there are no abstentions or no votes it could be unanimous.  Dr. Allen?

     DR. ALLEN:  Yes.

     DR. SMALLWOOD:  Dr. Cunningham-Rundles?

     DR. CUNNINGHAM-RUNDLES:  Yes.

     DR. SMALLWOOD:  Dr. Davis?

     DR. DAVIS:  Yes.

     DR. SMALLWOOD:  Dr. DiMichele?

     DR. DIMICHELE:  Yes.

     DR. SMALLWOOD:  Dr. Doppelt?

     DR. DOPPELT:  Yes.

     DR. SMALLWOOD:  Dr. Goldsmith?

     DR. GOLDSMITH:  Yes.

     DR. SMALLWOOD:  Dr. Klein?

     DR. KLEIN:  Yes.

     DR. SMALLWOOD:  Dr. Laal?

     DR. LAAL:  Yes.

     DR. SMALLWOOD:  Dr. Boyle?  I am sorry, he has gone.  Dr. Callero?  He has gone.  Dr. Harvath?

     DR. HARVATH:  Yes.

     DR. SMALLWOOD:  Ms. Knowles?

     MS. KNOWLES:  Yes.

     DR. SMALLWOOD:  Dr. Kuehnert?

     DR. KUEHNERT:  Yes.

     DR. SMALLWOOD:  Dr. Nelson?

     DR. NELSON:  Yes.

     DR. SMALLWOOD:  It is unanimous, yes.

     DR. DUNCAN:  If we could go to the next slide--somebody is waving his hand.

     DR. SMALLWOOD:  I am sorry, please excuse me.  The non-voting industry rep?

     DR. STRONG:  The conflicted non-voting industry rep votes yes.

     DR. SMALLWOOD:  Thank you.

     DR. DUNCAN:  So, now we are ready?  Question number two, does the committee agree that a one-year deferral for whole blood donation recommendation for travel to Iraq is appropriate at this time?

     The FDA's thinking is that it could be appropriate for all the reasons that have been stated: the large number of potential U.S. donors, pointing here, again, to this specific incidence of the travelers, especially the troops, that are exposed to environmental conditions that are favorable for transmission, and also on the point of how long should the deferral be.  The one-year is adequate for disease symptoms to arise in most cases and that once the disease symptoms arose they would need permanent deferral or, without any disease symptoms, the symptom-free traveler could reenter the blood donor pool.

     DR. NELSON:  Do you want to vote on this?

     DR. DUNCAN:  Oh, and one other point I was going to say about the one year is that it also makes it harmonious with the malaria deferral, which is also a one-year deferral.

     DR. NELSON:  Yes, Jim?

     DR. ALLEN:  Is this also for whole blood?

     DR. DUNCAN:  Yes, I inserted the whole blood.

     DR. ALLEN:  And the second question is, as I listened to the presentation, it seemed to me that perhaps there is a distinction in risk of exposure to our troops compared to business travelers and diplomatic personnel who may be living in hotels and perhaps never being exposed.  I don't know whether it is worth making that kind of a distinction or not.  It is obviously perhaps more difficult than not.

     DR. NELSON:  I think it would be tough.

     DR. DUNCAN:  We have thought through and discussed those issues.  It is probably true that people living in a hotel would not be presenting the same risk but it is a matter of implementation.  It would just be simpler to defer all travelers to Iraq, not trying to distinguish, you know, how many days were you there?  Where were you?  Again, weighing that against the impact because it isn't that many people, it would be more satisfactory to just have a uniform ban for travel.

     DR. SMALLWOOD:  Question two reads does the committee agree that a one-year deferral recommendation for travel to Iraq is appropriate at this time for whole blood donors?

     Roll call for question number two, Dr. Allen?

     DR. ALLEN:  Yes.

     DR. SMALLWOOD:  Dr. Cunningham-Rundles?

     DR. CUNNINGHAM-RUNDLES:  Yes.

     DR. SMALLWOOD:  Dr. Davis?

     DR. DAVIS:  Yes.

     DR. SMALLWOOD:  Dr. DiMichele?

     DR. DIMICHELE:  Yes, and I would like to add that I would hope that the Department of Defense does take its veterans' concerns very seriously.

     DR. SMALLWOOD:  Dr. Doppelt?

     DR. DOPPELT:  Yes.

     DR. SMALLWOOD:  Dr. Goldsmith?

     DR. GOLDSMITH:  Yes.

     DR. SMALLWOOD:  Dr. Klein?

     DR. KLEIN:  Yes, and I am assuming that whole blood donors includes plateletpheresis donors as well.  With that stipulation, I would say yes.

     DR. SMALLWOOD:  Dr. Laal?

     DR. LAAL:  Yes.

     DR. SMALLWOOD:  Dr. Harvath?

     DR. HARVATH:  Yes.

     DR. SMALLWOOD:  Ms. Knowles?

     MS. KNOWLES:  Yes.

     DR. SMALLWOOD:  Dr. Kuehnert?

     DR. KUEHNERT:  Yes.

     DR. SMALLWOOD:  Dr. Nelson?

     DR. NELSON:  Yes.

     DR. SMALLWOOD:  And our non-voting industry representative, how would you vote?

     DR. STRONG:  Thank you, yes.

     DR. SMALLWOOD:  Again we have a unanimous vote of yes.

     DR. DUNCAN:  So, if we could go to question number three, this is just sort of the flip side of question number two but we want to get it on record.  Does the committee agree that a recommendation for donor deferral for travel to Leishmania endemic areas, other than Iraq, is not appropriate at this time?

     Here, again, it is all a matter of balancing the impact of the blood supply against the risk as far as we can estimate the risk.  There are no other endemic areas where there is a large influx of U.S. travelers exposed to the same kind of environmental conditions that are being seen in Iraq today.  Even though I think Dr. Herwaldt presented it in its right context, it still is a fact that there have been no documented U.S. transfusion-transmitted cases.  And, the great difficulty there would be in implementing any kind of deferral policy that could be focused on a small number of the most high risk donors.  It is just not technically feasible and, as Sharyn Orton presented, the large impact of deferral to travel to all Leishmania areas.

     DR. SMALLWOOD:  Question number three reads does the committee agree that a recommendation for donor deferral for travel to Leishmania endemic areas, other than Iraq is appropriate at this time for whole blood donors?

     Roll call, Dr. Allen?

     DR. ALLEN:  Yes.

     DR. SMALLWOOD:  Dr. Cunningham-Rundles?

     DR. CUNNINGHAM-RUNDLES:  Yes.

     DR. SMALLWOOD:  Dr. Davis?

     DR. DAVIS:  Yes.

     DR. SMALLWOOD:  Dr. DiMichele?

     DR. DIMICHELE:  Yes.

     DR. SMALLWOOD:  Dr. Doppelt?

     DR. DOPPELT:  Yes.

     DR. SMALLWOOD:  Dr. Goldsmith?

     DR. GOLDSMITH:  Yes.

     DR. SMALLWOOD:  Dr. Klein?

     DR. KLEIN:  Yes.

     DR. SMALLWOOD:  Dr. Laal?

     DR. LAAL:  Yes.

     DR. SMALLWOOD:  Dr. Harvath?

     DR. HARVATH:  Yes.

     DR. SMALLWOOD:  Ms. Knowles?

     MS. KNOWLES:  Yes.

     DR. SMALLWOOD:  Dr. Kuehnert?

     DR. KUEHNERT:  Yes, but I would add that an assessment resource is necessary.

     DR. SMALLWOOD:  What resource?

     DR. KUEHNERT:  What was talked about before, a base resource or some other resource to be able to evaluate risk is necessary in the future.

     DR. SMALLWOOD:  Dr. Nelson?

     DR. NELSON:  Yes.

     DR. SMALLWOOD:  And Dr. Strong, how would you have voted?

     DR. STRONG:  Yes.

     DR. SMALLWOOD:  The vote for question three is unanimous, with the condition stated by Dr. Kuehnert.

     DR. DUNCAN:  We can move to the next slide for question four.  Does the committee agree that a recommendation for donor deferral for immigration from any Leishmania endemic area is not appropriate at this time for whole blood donors?

     Again, the FDA thinking on this has to do with balancing impact versus risk, with our assessment of risk being low and that the impact would be high and the size of the impact here since, as was shown, the number of immigrants is certainly lower than travelers.  It just leads to complexity.  You know, when did you immigrate?  Did you immigrate last year, next year, in the future?  There is a lot of complexity that would be involved with any kind of deferral for immigration.  We are also including that Iraqi immigrants are not deferred.  It is only the travelers who are currently arriving in Iraq and returning that would be deferred.

     DR. NELSON:  Dr. Smallwood?

     DR. SMALLWOOD:  Does the committee agree that a recommendation for donor deferral for immigration from any Leishmania endemic area is not appropriate at this time for whole blood donors?

     Roll call for question number four, Dr. Allen?

     DR. ALLEN:  I am going to abstain.  I need to consider this.  I know that there is certainly an overlap with malarious areas.  You know, I have a little difficulty in terms of our asking travelers to Iraq for one year to defer and I am going to have to abstain temporarily.

     DR. CUNNINGHAM-RUNDLES:  I am not ready to vote either.  Let's discuss this more.

     DR. NELSON:  Comment?

     DR. SMALLWOOD:  Voting is being deferred at this time.

     DR. NELSON:  Did you have a comment?

     DR. CUNNINGHAM-RUNDLES:  I just think we probably want to discuss that a little bit more.  Right?  I don't think I quite get the gist of this one yet.

     DR. KUEHNERT:  I think part of the issue might have been your comment on the justification.  I mean, it is not so much the complexity because there are lots of questions that are complex, as we discussed today, but that we think the risk is low from what we know, and there are a lot of caveats to that and that is why I made the condition before on the previous question, that we really do need to have an assessment resource like we have for malaria because right now it is sort of a black box.  We just don't know.  But from what we know, which is very little, what is being said here is that deferral isn't appropriate.  Is that what you said?

     DR. DUNCAN:  Yes, the only reason I brought up the word complexity is in trying to articulate the balance of risk and impact because the impact of deferring immigrants would be relatively less than the impact of deferring travelers but it poses other problems.

     DR. NELSON:  And also the question talks about any endemic area.  So, it is not limited to Iraq and I think even the conditions of exposure of an Iraqi citizen might be quite different than of a soldier sleeping out in the sand.  Yes, Harvey?

     DR. KLEIN:  I wanted to point out that we currently don't exclude immigrants from endemic areas for this disorder.  There is no reason to anticipate that we would have more than we do now.  That includes South America, Central America, even immigrants from Texas.

     [Laughter]

     It includes a lot of people and I think the issue is that the risk clearly, from what we do know, is virtually zero.  Nothing is zero but it is close to zero.  And, I think the issue with the visitors to Iraq is that it is easier to exclude all of them than to try to find out whether they lived in tents.  That is simply a logistic thing.  But extending that to immigrants from anywhere that might be endemic for this disease I think would be overkill.

     DR. ALLEN:  First all, when we talk about immigrants, presumably that is somebody who is going to the country on a relatively permanent basis as opposed to somebody who comes here for a number of years on a student visa or for other reasons.  You know, if they want to walk into our blood donor centers if they meet the other criteria they are acceptable as donors.  We don't require citizenship or anything like that.  I have no idea how many people who have come to this country, for whatever length of time, donate within the first 12 months after they come.  That is a totally unanswered question.

     I guess, given all of that and the statement by Dr. Klein, this in fact would just agree with what is currently being done.  Why is it even necessary for the committee to vote on it?  I agree the risk is probably extremely low.  I am not sure that, as a committee, we necessarily need to make a statement on it therefore.

     DR. DUNCAN:  Well, the reason FDA is asking for a statement on this question is because there is a potential risk and we don't want to be on record as having taken no action or not having considered it.  So, we just want to be on record as having considered it and deciding that it was not appropriate at this time.

     DR. CUNNINGHAM-RUNDLES:  But doesn't it seem just a tiny bit paradoxic, two and four?  On the one hand, with two you can travel there for two weeks but you can't live there for ten years and come here?

     DR. DUNCAN:  It is the other way around.  You can't travel there for two weeks but you can live there.

     DR. CUNNINGHAM-RUNDLES:  You can live there but you can come here and give blood; perfectly fine.  So, doesn't that seem a little paradoxic to you?

     DR. NAKHASI:  Exactly.  The travel is only Iraq and also, you know, we are talking about immigration from all the countries.  As Dr. Klein mentioned earlier, we haven't seen any cases so far.  So, thinking now that there will be all of a sudden an increased risk, you know, in our mind doesn't make sense.

     So, I think there are a couple of other issues that one needs to think about.  One is that just by having a war in Iraq and the living conditions that the army personnel are subjected to is not exactly what is happening in the rest of the world.  So, I think that is why we would like to make clear that people have been coming so far and we have not seen an increased risk.  So, we would like to be on record.

     DR. NELSON:  Yes, actually, we are dealing with a population that is having an epidemic, which is the U.S. military.  With the first one we excluded donors for life if they had had clinical leishmaniasis.  So, I think it makes sense in some ways.  I can see the difficulty of trying to exclude donors who had lived in any area where leishmaniasis was endemic.

     DR. CUNNINGHAM-RUNDLES:  Well, I was just thinking of the special situation with Iraq in this question because it doesn't state one way or the other.  It is one thing to live in Portugal.  It is perhaps another to live in Iraq.  I don't know.

     DR. NELSON:  Well, I don't know either.  Here the question is in an Leishmania endemic area.  Please go to the microphone because this is being recorded.

     DR. HERWALDT:  I think people are assuming that the risk is higher for the soldiers than for people living in Iraq and I think that is potentially an erroneous assumption.  In fact, for example, Baghdad is historically an L. tropica endemic area and the U.S. soldiers who are in Baghdad may not get L. tropica because, again, humans are the reservoir hosts and they are not being exposed closely to the endemic population.  There are lots of cases now being documented of cutaneous lesion/visceral leish. in Iraqi civilians.  So, one could have this question to make a distinction between Iraq and other immigrants, but then on the previous question dealing with travel to Iraq it makes it sound like this deferral will be in perpetuity and I don't know that it necessarily would be.  So, I think one could make it clear that at this point travelers to Iraq are going to be deferred for a year but that may not be appropriate in the future.

     DR. NELSON:  But the problem I see with this is that visceral leishmaniasis is endemic in Tbilisi, Georgia and, you know, it seems to me that it is going to be very, very difficult to rationally implement who is at risk and who isn't based not on their illness but which country they came from or lived in.  Yet, the other part of the thing we voted on deals with an epidemic situation.  Currently it is clear; there have been 140 cases, or whatever.

     DR. KLEIN:  If I could get Dr. Herwaldt back to the microphone for just a second, the question that I would ask you is whether you see any difference now for people who are immigrants from Iraq than for people who are immigrants from Iraq five years ago.  Because I think that is probably the issue.  We have been accepting them all along.  If their conditions have changed now so they are more likely to be a danger, I think that is one thing.  If they haven't, then they and immigrants from all other endemic areas in the world have been acceptable and there hasn't been any issue.

     DR. HERWALDT:  The Ministry of Health in Iraq is reporting increased numbers of cases of cutaneous lesions and visceral leish.  One of the questions deals with the validity of the diagnosis and whether all the cases truly are cases of leish. but they also are reporting increased numbers of cases.

     DR. KLEIN:  So, is that a firm maybe?

     DR. HERWALDT:  Well, the reason I am hedging a bit is that I am privy to some data that have not been made public, but the Ministry of Health is reporting increased numbers of cutaneous cases.

     DR. KLEIN:  I hope that you will be able to perhaps make those data available to the FDA.

     DR. DUNCAN:  On the FDA's part, we have seen data on the epidemiology in Iraq and, you know, I would state the case a little differently from what Dr. Herwaldt stated.  The number of cases has been going up and down over the last five to ten years.  So, the question I had to ask in looking at the data is, is there evidence that the number of cases has increased in parallel with U.S. actions in that country and that is not clear.

     But the other point, as long as I have the mike is that I would like to focus the question that is being discussed which is would deferral for immigrants from Iraq be appropriate?  I don't think anybody is really proposing deferring immigrants from all the rest of the world but just should we make the policy consistent, you know, travel to Iraq as well as immigration from Iraq?

     The problem with that is this, for malaria there is deferral of three years for either immigration or living for a substantial period of time in a malaria area.  Leishmaniasis is a different disease.  A three-year deferral would not effectively protect the blood supply from an asymptomatic donor.  If you haven't presented with symptoms in one year, probably you are not going to present with symptoms in three, four, five years but you may still have some risk of carrying the parasites.  So, the only appropriate immigration deferral that we could come up with would be permanent deferral.  And, I think to impose permanent deferral now would be very inconsistent with immigrants who came from Iraq last year and the year before because I would say again that I don't see a consistent pattern that there is suddenly a higher risk of leishmaniasis among Iraqi citizens.

     DR. NELSON:  Or from Iran.  I mean, the risk must be similar.

     DR. KLEINMAN:  I was just thinking of a practical problem in the blood collection situation, and that is if you ask the question have you traveled to Iraq in the last year? and someone says, "oh, I'm an exchange student from Iraq.  I came seven months ago but I'm an Iraqi citizen," I am sure with better relations with Iraq we will get some Iraqis in this country.  So, how does the blood screener handle that?  Is that travel to Iraq?  It is certainly being in Iraq in the last year and we have just heard that any U.S. civilian that goes to Iraq even for a day is deferred.  So, I wouldn't know how to handle that at the blood collection site because there is an inconsistency there.  I mean, the person traveled to Iraq, they started in Iraq.  So, I think this is part of the semantic confusion that the committee is feeling, that there is some internal inconsistency here "within the last year."

     DR. NELSON:  So, you would propose either an Iraqi citizen or U.S. citizen who was in Iraq during the last year be deferred?

     DR. KLEINMAN:  Well, I think it makes it more consistent to apply.  As long as we are saying we can't distinguish between U.S. civilians and U.S. military personnel and the kinds of living conditions they were in, in Iraq, I would say the same holds for anybody who has been in Iraq.  So, yes, "have you been in Iraq within the last year?"

     DR. NELSON:  Yes, the only inconsistency is that for malaria we try to define areas that are endemic; for leishmaniasis we are not.  An Iranian citizen is probably at as great a risk.

     DR. KLEINMAN:  If you want to look at it that way, I am sure we can find many more inconsistencies in what we do if you want to look across all the parasitic diseases but I was just focusing on the smaller problem.

     DR. NELSON:  Right.  Jay?

     DR. EPSTEIN:  I think for purposes of getting a vote or further discussion on question four, FDA will take under advisement several points that we have heard.  The first is that the deferral for exposure in Iraq is likely to be a temporary policy considering current conditions.  The second is that we see no reason long-term to distinguish immigration from Iraq versus immigration from any other country that has endemic Leishmania species.  However, the third point is that in the current interim situation, where there already is a voluntary deferral policy and may be an FDA policy on deferral of persons who have been exposed in Iraq, it would minimize disruptions and minimize complexity if that also applied to immigrants from Iraq.  But that would only be the case during whatever period of time we are deferring people who were in Iraq for the last year.

     So, I think with those understandings, the FDA will consider those points in developing any further policy.  I would submit that it would be helpful to us if the committee would consider question four, recognizing as an aside that FDA may address the special circumstance in Iraq.  What we are really trying to ask here is should we be extending deferral policies to endemic areas in general, and there may be a short period of time where Iraq is a special case.

     DR. NELSON:  Do you want us to vote on that or are you happy with a discussion.

     DR. EPSTEIN:  Well, I think it is important to vote.

     DR. NELSON:  Okay.  So, the question now becomes that from any endemic areas is the key.  The previous vote we took on deferral for Iraq applies to not only U.S. citizens but Iraqi citizens or German citizens, or whatever, that were in Iraq during this time.

     DR. EPSTEIN:  I am not trying to change the previous vote, just to say if you would like this reworded, recognizing that an interim policy may apply solely to Iraq, does the committee otherwise agree that a recommendation for deferral from any Leishmania endemic area is not appropriate at this time?

     DR. ALLEN:  I appreciate Jay's clarification and the only thing is that what will show up in the official record is the actual wording that is there and I would be happy to vote on this if we added the words "from any Leishmania endemic area other than Iraq is not appropriate at this time."

     DR. NELSON:  Okay.

     DR. EPSTEIN:  My suggestion was recognizing that an interim policy may apply specifically to Iraq.  So, are you specifically rejecting that?

     DR. ALLEN:  I am sorry, you are proposing an actual wording change?  Read that again.

     DR. EPSTEIN:  Recognizing that an interim policy may be appropriate for Iraq, does the committee otherwise agree?

     DR. ALLEN:  If those words are added, I will accept that clarification.  Thank you.

     DR. DOPPELT:  May or will?  Because if it is "may" I don't know.  If it is "will" then it is consistent with vote number two, but if it is "may" then, as pointed out, the way it is written is relatively inconsistent with the vote on number two.

     DR. EPSTEIN:  Well, we don't actually make FDA policy here.  We only receive recommendations.  So, I can't commit to "will" but what I have informed you is that we understood the discussion and we will take it under advisement when we make actual policy.

     DR. DOPPELT:  I understand that but why not just add the modification that was already suggested, just excluding Iraq in this statement?

     DR. DUNCAN:  So, the final suggestion is to just add the words "other than Iraq" at the end of the sentence.

     DR. NELSON:  Okay.

     DR. SMALLWOOD:  I think I have it.  Question number four, does the committee agree that a recommendation for donor deferral for immigration from any Leishmania endemic area is not appropriate at this time of whole blood donors other than Iraq?  No, that is not right--other than Iraq for whole blood donors.

     DR. NELSON:  From any Leishmania endemic area other than Iraq is not appropriate at this time for whole blood donors.

     DR. SMALLWOOD:  Corrected--

     PARTICIPANT:  Is there still time for a comment?

     DR. NELSON:  I think I would like to move this forward.  We still have several hours here so unless it is really--

     PARTICIPANT:  Well, I think it is singularly important.

     DR. NELSON:  Okay, go ahead.

     PARTICIPANT:  I think what we are debating about here is the wording of question two.  If question two was properly worded to say "have been in Iraq during the past 12 months" then this question would not create the problem it is creating.  I think the rewording is going to create more difficulty--

     DR. NELSON:  No, I don't think so.  This question is are we adding other endemic countries to the exclusion.  Go ahead, Dr. Smallwood.

     DR. SMALLWOOD:  Let me try.  Reworded question number four is does the committee agree that a recommendation for donor deferral for immigration from any Leishmania endemic area, other than Iraq, is not appropriate at this time for whole blood donation?

     We are voting for the revised number four question.  Dr. Allen?

     DR. ALLEN:  Yes.

     DR. SMALLWOOD:  Dr. Cunningham-Rundles?

     DR. CUNNINGHAM-RUNDLES:  Yes.

     DR. SMALLWOOD:  Dr. Davis?

     DR. DAVIS:  Yes.

     DR. SMALLWOOD:  Dr. DiMichele?

     DR. DIMICHELE:  Yes.

     DR. SMALLWOOD:  Dr. Doppelt?

     DR. DOPPELT:  Yes.

     DR. SMALLWOOD:  Dr. Goldsmith?

     DR. GOLDSMITH:  Yes.

     DR. SMALLWOOD:  Dr. Klein?

     DR. KLEIN:  Yes.

     DR. SMALLWOOD:  Dr. Laal?

     DR. LAAL:  Yes.

     DR. SMALLWOOD:  Dr. Harvath?

     DR. HARVATH:  Yes.

     DR. SMALLWOOD:  Ms. Knowles?

     MS. KNOWLES:  Yes.

     DR. SMALLWOOD:  Dr. Kuehnert?

     DR. KUEHNERT:  Yes, but with the same qualifications that I had for question three about risk assessment, need for risk assessment.

     DR. SMALLWOOD:  Dr. Nelson?

     DR. NELSON:  Yes.

     DR. SMALLWOOD:  And Dr. Strong, how would you have voted?

     DR. STRONG:  Yes.

     DR. SMALLWOOD:  The vote on the revised question number four is unanimous, yes.

     DR. NELSON:  Maybe while we are warming up for West Nile we could take a break for a couple of minutes.  Ten minutes.

     [Brief recess]

     DR. SMALLWOOD:  We are on the last topic so we can see the light at the end of the tunnel, the last topic for today.  Dr. Nelson, you are in charge.

     DR. NELSON:  Right.  We are now back to viruses and a topic that is more familiar.  Dr. Nakhasi?

Topic III: Update on West Nile Virus Epidemic

and Donor Testing in 2003

Introduction and Background

     DR. NAKHASI:  I am ready as long as everybody else is ready.  I just want to tell everybody to sit back, relax and I hope you guys have your sleeping bags with you tonight.  Hopefully, we will be trying to see how far we can go with this session.

     But without any kidding, I think we should start this session and the purpose of the session is to really give you a year-end roundup, basically what our progress has been with the West Nile testing.  So, this is the topic and you will hear from various groups so let me start with this thing.

     Next slide, please.  The issue which we will be discussing today is basically an update on epidemiology, including reports of transfusion-transmitted cases of 2003.  Dr. Tony Marfin will talk about that.  Then we will have an update on West Nile minipool NAT testing under IND which was started this year, in the middle of June and by July 1st most of the blood supply was being tested under the minipool NAT IND.

     You will also hear from those people who have designed these and also the future plan for 2004.  We will also hear the status reports with respect to prospective and retrospective testing using ID-NAT and individual donation NAT, and I will tell you why we did that.  Then also, relative clinical sensitivity of West Nile tests among different test manufacturers and infectivity studies for the West Nile positive samples to make sure what is the minimum level of virus which could be infectious, and we will hear from Dr. Hewlett about those studies, what is happening or the planning of those studies--nothing has happened yet but the planning of those studies.

     Next slide, please.  I just want to give you briefly a status report of the 2002 epidemic versus 2003.  I know Dr. Tony Marfin will go to into detail and clarify some of the misunderstandings which people may have had over the last one year.

     I think in 2002 we had around 4,156 cases, human cases, of which 284 were deaths and out of which around 2,941 cases were West Nile meningitis encephalitis.  Forty-four states, including D.C., were endemic for West Nile.

     The average risk--but, mind you, in 2002 there was no testing going on but the average calculated risk was 0.4 per 10,000 donations nationwide, and in some areas where the epidemic was much higher it went up to around 11 per 10,000 donations, for example in the State of Michigan.  And, you will hear what is happening this year.

     During the last epidemic, the samples which were collected, even though the testing went up to June, 2003 it doesn't mean that the cases were up to June, 2003--you know, there were 61 possible transfusion-transmitted related cases, out of which 23 were confirmed; 19 were not transfusion related and 19 were inconclusive because of incomplete donor follow-up.  There were 6 deaths but West Nile could not be established as the cause in most of these cases.

     Next slide, please.  With comparison to that, during 2003 the human cases so far are 8,694 and 206 deaths.  Again, the rate of West Nile meningitis and encephalitis was around 30 percent.  There was also 66 percent of West Nile fever because this year the fever was also scored.

     The difference I think we need to emphasize, which I think Dr. Marfin will emphasize further, is that the reporting this year was much more precise and reported early on, whereas last year the cases were reported later on and it was not complete.  So, I think you will see that there is a discrepancy in the cases.  That doesn't mean the epidemic was much higher this year as compared to last year.  However, if you look at this thing, the death rate was 206 and still going up.  When you compare it to 284 maybe in that respect it is still the same.

     Again, 44 states including Washington, D.C. were endemic for West Nile--you know, maybe Tony will update if some of these states have changed since last we talked.  There were some putative West Nile transfusion-related cases which are being analyzed at this time and Dr. Marfin will talk more about those cases.  The confirmation is done through NAT and IgM reactivity.  So far, this year in CDC's September 18th MMWR two confirmed cases of West Nile transmission through transfusion have been reported as compared to last year's 23.

     Next slide, please.  I think this slide has been seen.  I don't want to blabber because of the time constrictions.  We did several things, including presenting throughout the year at the BPAC committee meetings our progress report for what is happening with the West Nile epidemic and testing, and also we issued two guidances and, as I heard last time, there were three IND approvals.  We are participating weekly, biweekly and now triweekly with the blood bank committee task force, which includes CDC and NIH, and basically monitor the epidemiology and West Nile testing and how it is going on.  It has been very, very fruitful for us to decide how things can be changed as we go along.

     Next slide, please.  With regard to FDA's activities, we still are in the process of panel development and also isolating and characterizing the different strains from these different samples from both 2002 and 2003 epidemics, and also following up with infectivity studies.  There is nothing to report at this time.  Those studies are still ongoing and, hopefully, next time we meet we will talk more about those studies.

     Next slide, please.  The two isolates from which we are making the panels are from the New York '99 and human isolate from 2002.  This New York '99, as I mentioned previously, is a flamingo strain passed through tissue culture vero cells and those are the various studies being performed on that, while infectivity determinations are in a concentration.  Finally, specifications are being established through the collaborative studies, that is, you know, how much is the wild concentration even though we have spiked and depending on the ranges between 1000-5 copies/ml.

     Next slide, please.  Again, you have seen this slide previously.  This was done in-house, and it shows you that there are differences between the copy number and the plaque forming unit and one plaque forming unit could be approximately 500 copies/ml.

     Next slide, please.  You have also seen this previously.  It is to show you that when we heat inactivate when we make these panels there is a slight reduction in the number of copies/ml even though the plaque forming infectivity is gone probably.

     Next slide, please.  With regard to the testing, where are we now?  As I said earlier, starting on July 1st, 2003 when the country started being tested using minipool NAT under IND, as far as we know around 5 to 6 million donations have been screened and approximately 1,000 units have been interdicted.  So, I think that has been a tremendously remarkable job because otherwise these cases would have been transfused into people compared to last year, 2002, when we did not have any testing available.  In a nutshell about all this testing, we have removed more than 75 percent of the infected donations entering the blood supply.  Why is it 75 percent?  I will talk to you about that.

     Next slide, please.  This is the model from Dr. Mike Busch's chart which you saw last time with minipool NAT testing sensitivity and ID-NAT is the chart here that shows you that curve between 6 and 7 days takes care of about 75 percent.  There are cases where we will have before and after increase in viremia and there will be ID-NAT plus/minus minipool negative, antibody negative and the second stage will be ID-NAT positive, minipool negative or IgM negative.  Then the other side of the curve is the stage 4 which will be the ID-NAT positive, minipool negative IgM positive, and then stage 5 where mostly there are plus/minus negative or positive with ID-NAT but they are both IgM and IgG positive.

     Next slide, please.  Therefore, from this what we concluded is that there could be some potential for transmission even through minipool NAT testing and minipool NAT negative.  There could be some of these units which have low level viremia.  Because of that, in certain areas, which you heard last time also, there were certain areas, like Colorado, Kansas and Nebraska, where the incidence of minipool NAT reactivity was much higher, sometimes 1 in 250.  There, the blood banker establishments instituted ID-NAT testing to further lower the risk.  Also, where the ID-NAT was started early on, the voluntary withdrawal of frozen transfusible in high incidence areas was initiated before the ID-NAT was initiated.

     Next slide, please.  So, the purpose of instituting ID-NAT in those areas is to understand the residual risk because, as I said, there is some risk even with the minipool NAT negative samples as I showed you with the curve before and after that.  You will hear more from Dr. Mike Busch's presentation and Dr. Susan Stramer's presentation about those studies.  There were several studies done.  There were some retrospective studies done in last year's samples, 2002, and also this year's samples, 2003, retrospective and also prospective studies when ID-NAT was done prospectively.

     Basically, the other purpose was to really identify those samples and to test whether they are infectious.  The question is even though they may be minipool ID-NAT positive or IgM negative, are they really infectious?  Those studies are being planned in animal models such as non-human primates.  Also, to find out at the lower end of the sensitivity of these tests, are the clinical sensitivity studies which you will hear from Dr. Mike Busch's presentation.

     Next slide, please.  You will hear also about progress made in 2003 and I just want to focus your attention here also on next year's testing, things to be considered.  Because there were some discussions on whether we should have this testing year around because the epidemic may be waning off during the winter months, or should we stop and start?

     But what I think we need to keep in mind is that there are several caveats to that, which I think will come out through the discussions both from Tony's presentation and some other people's presentations, the epidemic has been expanding over the last few years.  You know, earlier we thought the epidemic was between maybe last summer or middle of summer to late fall, or something like that but last year cases were found as early as March and as late as December also.

     Also, new geographical regions are being identified.  Last year, in the 2002 epidemic there were certain areas which were hot but in 2003 other areas became hot.  Also, we need to keep in mind what the outcome is of this 2003 testing because I think that would be a very good measure to at least find out what was the yield during the 2003 testing.  Again, you will hear from Tony Marfin about these new mosquito species establishing infections.  So, I think there are a lot of complicated issues, not only infection but also how these new species of mosquitoes are better replicators for this virus as compared to the previous known mosquito species.

     Also, we need to keep in mind travel because, you know, people are coming from warmer areas, southern areas.  If there is still some background infection going to traveling to north or some place and they donate there, what will happen in those cases.

     We will also need to consider again what we would gain by doing an ID-NAT versus a minipool NAT.  I think those are the discussions you will hear from the presentations of both Mike Busch and Susan Stramer's presentation.

     With that, I think I will invite Dr. Tony Marfin to present to you the epidemiology studies of 2003.  Thank you.

Update on Epidemiology Including Reports of

Transfusion-Transmitted Cases

     DR. MARFIN:  Good evening and thank you for inviting me back.  I am sorry that I wasn't able to make it here last time with the hurricane, and everything.

     I am going to talk about four things today.  I am going to remind people of what happened in the epidemic of 2002 and discuss what has happened in the epidemic of 2003.  I am going to then talk about some of the implications with regards to the blood supply, and then I am going to try to give you an overview of what I think is going to happen in 2004.

     If I could have the next slide, please?  As you know, usually I start out with lots of pictures of birds, and horses, and cycles and things like that.  Barbara stole my iceberg slide so I can't show that!  But I am just going to give you two slides reviewing what is important to know about West Nile Virus with regards to the blood supply.

     The very first thing that we all have to remember is that West Nile Virus is transmitted primarily in a cycle that involves birds and ornithophilic mosquitoes.  Ornithophilic means that these are mosquitoes that like to feed on birds.  Humans and mammals are only dead-end hosts.  This cycle will always go on, regardless of whether there is ever a human infection.  It is always going to be there.  I think we are all committed to that now.  Human risk does occur when the threshold infection rate in ornithophilic mosquitoes is elevated, and it also occurs when the infection rate in bridge mosquitoes is also elevated.  Bridging mosquitoes are those mosquitoes that will feed equally on birds and on mammals.  There are several that we have identified through the years, and I have mentioned those before.

     The other important thing to remember is that humans have a very short, low-level viremia and that it is somewhat surprising that it has been so much of a problem to the blood supply.

     With regards to clinical expression, about one percent of all infections result in West Nile neuroinvasive disease that includes encephalitis, meningitis and myelitis, and I will abbreviate that as WNND for the remainder of the talk.  About 20 percent of infections result in West Nile fever and in 80 percent of infections the people will remain asymptomatic.  We presume that they have the same viral and antibody kinetics.  This is actually a good time to point out that these are all based on studies from the '50s, the '60s, the '70s, all the way up through about 2001, and we are finding out a whole lot now from what the blood banking people are finding out and I suspect a lot of this is going to change in the coming years so I will have to change all my slides, but I will take the next one now.

     Among ill people, we have to remember that virus isolation in nucleic amplification testing and immunohistochemistry are not very useful.  To compound that problem, we have to realize that serology is not very straightforward, and that has to do with cross-reactivity with other flaviviruses and the fact that we believe, at least in the most symptomatic people, that the West Nile specific IgM antibody is relatively long-lived.

     We also have to remember that essentially all ill persons have West Nile specific antibody present at the time of onset and no significant viremia.  Then, what I hope to really convey to you today is that West Nile Virus, at least in the past three years, has just had tremendously explosive epidemics.  There is very, very little warning from the time of the first animal events to the first human infections.  Having discussed this with Mike Busch in the airport yesterday in Denver, I think that he will be showing some of the same message with regards to viremic donors.

     Next slide, please.  Let's get right to the 2002 epidemic and this is just to remind you what happened.  Here is the map showing the involved counties.  The red counties are those counties that have human cases and animal activity.

     Next slide, please. This was a breakthrough year for West Nile Virus because there were close to 3,000 cases of West Nile neuroinvasive disease that occurred at that time that resulted in about 284 deaths.  In 2002 we had almost 1,200 cases of West Nile fever reported.  We estimated in 2002 that there were about 300,000 to 500,000 infections.  That is not illnesses; that is infections, going back and remembering that 80 percent of all people that get infected do not develop any symptoms whatsoever.

     There were human cases reported from 740 counties in 39 states and the District of Columbia and, as I said, they are shown here in red and the period of transmission went on from the middle of May to about the middle of December and made for a very, very long season for everyone.

     Next slide, please.  This is an incidence map.  The larger red dots are those counties that have an incidence of greater than or equal to 100 cases of neuroinvasive disease.  I always deal in neuroinvasive disease.  I very rarely speak about fever because different jurisdictions report fever in different ways.  So this is somewhat the lingua franca--encephalitis, meningitis and myelitis.  Those are reportable conditions.

     In the large red spots are those counties that had greater than or equal to 100 cases of West Nile neuroinvasive disease per million population.  In the orange or yellow spots it is about 10 to 99 cases per million.  In the small blue spots, which you can't see very well, that is less than 10.  So, this is what we saw in 2002.  There was a tremendous number of cases in Chicago, Cleveland, Detroit, the whole upper Midwest.  Then, at the end of the season we saw a lot more cases coming in South Dakota, North Dakota, Nebraska and in Kansas.  We always thought that this was due to the fact that these are small populations and they were just popping up.  At that time I don't think we really fully appreciated that this was a harbinger of things to come.  That is why at the end of the 2003 talk I am going to tell you about the harbinger of things to come in 2004.

     Next slide, please.  So, this is the summary slide.  As I often joke, the only way that we know that West Nile Virus ends from one year and goes to the next is that the last slide of the previous year becomes an early slide of the next year.  So, what we saw in 2002 is that we experienced in the western hemisphere the largest encephalitis epidemic ever.  We had the largest West Nile Virus encephalitis epidemic ever anywhere in the world.  This was really a breakthrough year.

     We described several new clinical syndromes and, as pointed out here, we identified new modes of transmission, including the 23 cases of West Nile Virus transfusion-associated transmission that Hira mentioned.  We had four cases of transmission associated with organ transplantation; one case associated with breast feeding; and one intrauterine infection, as well as two occupational exposures.

     Next slide, please.  So, let's get right into 2003.  This has just been a tremendous increase in terms of the number of counties.  What I am going to come back again and again and talk to is the fact that the eastern side of the map, the right side of this map hasn't changed all that much.  If you go back and you look at 2002, these are the same counties that are involved.  If you see lots of white areas out there in the east, these are counties that don't report any animal or human activity  That is because those counties have West Nile fatigue syndrome--they are tired of counting all the birds--

     [Laughter]

     --and they just don't have the infrastructure any longer to really support that activity any longer.  We are just now getting the surveillance activity with regards to the animals that we used to get.  But if you look at the eastern side, this is really familiar.  But what is very impressive is what has happened in the high plain states of the West and then, of course, the areas in southern California and Arizona.  Those, by the way, are late season findings in 2003.  Also, New Mexico and Utah.

     Next slide, please.  So, what do we have to date?  To date we have a little over 2,600 cases of West Nile neuroinvasive disease reported.  There is lag time and we will continue to receive reports of West Nile disease all the way through next April when we try to close the data set.  In fact, yesterday we had 75 cases of West Nile illness reported to ArboNET.  All of them were old cases though.  People are going back and finally taking care of a lot of the backlog cases, finally getting time to enter them, because I think we are pretty much over the season.

     To date we have 207 deaths but, again, let me emphasize that there has been a great deal of lag time.  Where the big increases occurred has been in reporting West Nile fever because of the availability of laboratory testing because I think a lot of the states and counties have seen the value of identifying all West Nile Virus infections.  I think that those are the big reasons why we are getting a lot more West Nile fever reported.  Human cases have been reported from over a thousand counties in 45 states and the District of Columbia.  And, as Hira pointed out, this is a very long season for us.  The very first case of West Nile fever was reported from Pennsylvania at the end of March.  That is phenomenal.  The latest case that we have had reported had illness onset on November 16th, also from Pennsylvania, a case of West Nile fever and a well documented case.  So, this is a very, very long season.

     Next slide, please.  This is the incidence map.  Again, the large dots have the highest incidence.  The small blue dots have the lowest incidence.  I think it is very apparent that the western plain states have just seen a tremendous increase in the number of cases of neuroinvasive disease--again, encephalitis, meningitis and myelitis.  But look at the Midwest.  There are still areas around the Great Lakes that have had the same incidence this year that they had last year.  Look at the East.  There are places that still had the same incidence this year that they had last year.

     Next slide.  This is just showing the number of neuroinvasive disease cases that we have had reported over the five years that West Nile Virus has been in the United States.  You can see that it increased from the 59 original cases in New York City in 1999 to a little over 2,900 cases last year, and right now we are at 2,600 cases and we are likely to get more.  This is why we continue to say this year is every bit as bad as last year.  It is not in the same areas.  It has shifted areas, but it is very, very comparable.  Then, of course, the far right column shows where the real big increase is.  We are getting a lot more reports of West Nile fever and I think I have already identified some of the reasons for that.

     Next slide, please. This is showing just the neuroinvasive disease cases.  I have thrown out the fever.  So, our first neuroinvasive disease case occurred at the end of May in South Carolina and our last one occurred in Pennsylvania in the middle of November.

     This is a curve that is very similar to one that I have shown in the past, and it shows that there is a critical 6 to 7 weeks in the middle of summer during which time about three-quarters of the cases occur.  It is a very long season but the peak is still in this very critical 6 to 7 weeks distributed around the Labor Day holiday.  In fact, the tallest peak there is the week before Labor Day.

     Next slide, please.  In summary, what do we have here?  We have a multi-state epidemic again.  In fact, there are 16 states that have at least 50 cases of encephalitis, meningitis or myelitis.  These 16 states have reported nearly 2,200 of the cases, about 84 percent of all neuroinvasive disease cases that we have had reported.

     I am going to start educating you here to be entomologists.  I don't think you are going to be "leishmaniacs" but you can be entomologists because this is a point I am going to come back to again at the end.  If we look at these states with at least 50 cases of neuroinvasive disease, you can actually divide them into those states where we can identify the primary enzootic vector.  In 10 of these 16 states the primary enzootic vector is Culex tarsalis and I am going to come back to that point.  You can see the tremendous number of cases and, as blood bankers, you all know that these are the states that come up again, and again, and again.

     Then there are four states, Pennsylvania, Ohio, Iowa and New York, were Culex pipiens is the primary enzootic vector.  This is very, very different.  Culex pipiens tends to be a bit more of an ornithophilic mosquito than Culex tarsalis.  It has a more limited flight range.  But you can see it still does quite a bit of damage.  It can cause a pretty good rate of neuroinvasive disease.  The thing that I should point out here though is that Pennsylvania, Ohio, Iowa and New York are the same states that had problems last year.  This is now becoming a recurrent problem, and for New York this is its fifth year in a row that they have had an epidemic.  In two other states that have had at least 50 cases of neuroinvasive disease there are other Culex species.  In Louisiana it is Culex quinquefasciatus and in Florida it is either Culex quinquiefasciatus or Culex nigripalpus.  Again, these are the states that had problems last year.

     Next slide, please.  Just to hit you over the head, as if you haven't been hit over the head hard enough already, what if we look at the number of neuroinvasive disease cases from Connecticut, New Jersey, New York and Pennsylvania from 1999 to 2003 and we combine them?  Then we can see that those four states had 59 cases of encephalitis that were reported in 1999, only 19 in 2000 and, as I often joke, we thought they were going to go the way of ontovirus.  Then in 2001, a very slight increase and last year they had 136 and they were astounded and it was making the front page.  Well, this year already we have had 211 cases of encephalitis reported from those 5 states.  The vast majority are from Pennsylvania but you can see that the other states are also reporting cases.

     Next slide, please.  One of the things that we have seen over the past year and a half has been lots of cases coming out of small rural counties, rural counties that have populations less than 10,000.  What this table shows is the 700 counties, 800 counties that have reported at least one case of West Nile neuroinvasive disease and the number of encephalitis, meningitis and myelitis cases that have been reported from those counties.  Then I divided them by county population.  So, in the first row we have 155 counties with a population less than 10,000.  Those 166 counties have reported 299 neuroinvasive disease cases, which results in an incidence of about 33/100,000.

     You can see that the incidence of West Nile neuroinvasive disease in these smaller counties is much, much greater than in the larger cities, and this has just been a tremendous increase.  I have shown you this same slide for 2002, and the incidence in the smaller counties is roughly about 20 and that all came at the end of the year last year when we started to see cases in Nebraska and the Dakotas.  But really the big change this year has been the paucity of cases that have come out of the larger cities.

     Next slide, please.  This is going to be the last entomology slide that I will show you.  This is the reason.  This is Culex tarsalis and this is the reason that we have had a problem for the past year and a half.  This is the vector of the irrigated lands of the arid west.  It is an extremely efficient virus transmitter in the laboratory.  It is a long distance flyer.  It will fly miles in a day.  It loves to feed on mammals; loves to feed on birds; loves to feed on anything it can feed on.  We have shown some exceptionally high infection rates in 2003 including in my current home, Ft. Collins, Colorado, where we have seen up to 30 percent of the mosquitoes being infected with West Nile Virus, which is just an astronomic infection rate.

     The real concern here, of course, is that Culex tarsalis populations are a function of the irrigation patterns of a given area.  Irrigation patterns are relatively constant from year to year.  So, this has a very ominous concern for us.

     Next slide, please.  What about recent developments before I talk about the blood specifically?  Well, what has happened over about the past 60 weeks that we have seen local human transmission in California and Arizona?  We have had two cases of neuroinvasive disease in southern California in September.  We have had six in Arizona already in September and October.  We have seen increasing animal activity in Arizona and California throughout November and we are seeing ongoing animal infections throughout the southwest.  In birds, we have seen activity in Arizona, California, Louisiana, South Carolina and Oklahoma.  The latest report that we have in ArboNET is from mid-November in Louisiana for mosquitoes, lots and lots of isolates out of multiple counties in southern California and throughout Arizona.  Again, what is going to happen next year?  I don't even have to show you the last slide because I know you already know what I am concerned about.  Then, in horses and then, of course, in sentinel chickens.  The activity has continued throughout.

     Next slide, please.  We will just talk about blood donor surveillance,

     Next slide, please.  Just to quickly review that in 2002 we did have the 23 cases of confirmed West Nile Virus transfusion-associated transmission.  That was recently in the New England Journal, September 25th.  At that time we estimated that there were probably about 550 viremic donors.  That is a model from Drs. Biggerstaff and Peterson that they developed last year and that is what the estimate was.  I think when we are talking about the fact that we have had a comparable outbreak this year, I suspect that that model was a little bit low but, you know, it is less than a log off so that is pretty good.

     Next slide.  Just to remind you, this is the epi curve from 2002.  As I pointed out, three-quarter of the neuroinvasive cases in 2002 occurred in a six-week period distributed around Labor Day.  The 16 infectious units that we identified in the investigation last year occurred during the real height of the epidemic.  We thought, well, that is why we saw that, because there were just so many cases, there were so many asymptomatic viremic people out there that this is why it really poked its head up.

     Let me have the next slide, please.  So, this year we did something a little bit different.  We started two surveillance systems especially to track the transfusion investigations and to get together with the people in the blood banking industry to talk about the number of presumed viremic donors.  We were using this as a surveillance event.  We actually had two complementary surveillance systems.  There was a weekly AABB conference call that included the FDA, AABB, DoD, CDC.  The AABB reps that were on the phone represented about 90-95 centers that cared for about 90-95 percent of the U.S. donors.  What they gave us was really the number of tests and results by state.

     Now, blood banks were reporting to the states, and most of the time states would report them to ArboNET.  So, we were also able to get more information on many of those blood donors.  We were able to get clinical follow-up as well as demographic information.  So, there were two complementary systems.

     Next slide, please.  These are the findings from ArboNET.  To date, about three-quarters of the viremic donors that have been identified by the blood banking industry have been reported in ArboNET.  As of yesterday, there were 742 presumptive viremic donors that had been reported.  Seven of them had been infected as travelers but most of them reflect what is going on in their state and their county of residence.

     We have more complete information for 608 of these donors.  The mean age was about 51, with a range of 15 to 83 years.  Most of them were asymptomatic, surprisingly 81 percent.  It is hard to believe when immunology really works out that well.  Six of them actually developed West Nile neuroinvasive disease, which is about one percent and surprisingly young, about 45 years of age, although most of them developed meningitis so that is consistent with what we see in a lot of clinical cases.  Then, about 16 percent of them developed West Nile fever.  About 90 percent of the 742 come from these states and those are the Culex tarsalis states.

     Next slide, please.  This is a map of distribution at the end of the season.  There are only two flavors of dots this time.  The large red ones represent 70-20 presumptive viremic donors from a county.  The smaller gold ones are about 1-6.  That is the entire season.  This just reinforces what we saw in the earlier map with regards to where the epidemic occurred.  The states with the high incidence of neuroinvasive disease, in fact, had the most presumptive viremic donors.

     There are some areas--Colorado has not mapped all of their presumptive viremic donors yet and we are just having technical problems getting the Kansas information--well, they are having technical problems getting their information to us.

     This next map is going to run for about 45 seconds.  It is going to be a time series and it is going to start from the middle of June and it is going to change on a weekly basis.  It is just going to show what has occurred in that week.  You are going to see counties lighting up.  I think there are three flavors of dots in that one.  There are large red ones and then smaller brown ones and then small--I forget what color it is but you will see it soon enough.  But I just want to emphasize that what you are going to see--and I wish I could find some music by Gustav Holtz to put up there because you are going to see this little "bup, bup, bup" and then it is just going to hit you.  For four weeks you are going to just experience an incredible number of presumptive viremic donors in this country and then it is going to go away.  What that emphasizes is that when we make decisions, they have to be rapidly implemented.  We have to plan these things.  I mean, we have this problem in terms of surveillance in general because once this starts you have to be ready to go.  We think of it in terms of getting our investigations going.  We have to have everything ready to go overnight, and I think the blood banks are going to find the same thing.

     So, go ahead and start that next one.  It should start right up.  So, the gold ones are just one case per week.  The brown ones are 2 to 3; the red are 4 to 6.  This is per week; this is not cumulative.  And, now you are experiencing the real height of the epidemic.  Now it is going to peter off.  That was it.  By the way, this is only for the 608 for which we have more information.  That is not the 1,000 that have been identified by the blood bankers and I should have pointed that out.  At the end of the year we will be able to get that done because we are going to be getting all of that information as well.

     So, if I may have the next slide, please.  So, let's look at this a little differently.  Here is the epi curve that I showed you previously.  Where do the presumptive viremic donors occur in relationship to this epi curve?

     Next slide.  They are way outside.  They are starting at the beginning of the investigation.  This is only for the 608 for which we have more information.  The first infectious donation was collected on June 19th.  The latest one that we have in ArboNET is on 10/23 and I can guarantee you that there are other ones out there.

     Next slide, please.  We also have investigations.  To date we have been involved in 21 investigations.  We investigate people who have received blood products in the four weeks before their West Nile Virus illness onset, or who received blood products from viremic donors who were identified in individual donation testing and look-back was done by industry.  To date, six of those donors are definitely not a case.  In fact, some of them don't have West Nile viral illness.  Those cases are closed.  We have the two confirmed cases that have been reported in MMWR.  One of those was identified through an industry look-back, as Hira described earlier, and one of them was identified through the public health department investigating an illness in their transfusion recipient.  We have four highly suspect cases that I think are going to become probable cases.  We just received these samples.  We are testing them in our lab.  We are not going to put them as confirmed until they are tested in our lab.  One of them is on an IDT look-back; three of them have been found in public health department investigations.  One is inconclusive and eight are just too early to call yet.

     Next slide, please.  In summary, what has happened in 2003?  Well, we just experienced our second consecutive national epidemic and it is quite comparable to 2002.  The epidemic has shifted into the western plains.  It has increased in more rural counties.  Culex tarsalis has emerged as a preeminent vector of West Nile Virus in 2002 and 2003.  The key thing is that it is associated with irrigation which is relatively constant every year, and it is extremely difficult to control because of the rural nature of their breeding sites.

     Human encephalitis activity has persisted in the rest of the United States besides the high plains.  Northeastern states have had their fifth year of epidemic.  And, there are ten states that had encephalitis cases in 2001 that had cases in 2002, that had cases in 2003--completely unprecedented for a flavivirus.

     Next slide.  With regards to the blood donors, and you will hear about this as we move along, there have been greater than 1,000 presumptive viremic donors that were identified and we estimate, depending on whose estimate you want to use, that is 1.3, 1.5 potentially infectious products that were never circulated.

     Your presumptive viremic donors occur in areas where there is lots of neuroinvasive disease and I think that is what that map does show.  There are tremendous advances in screening this year.  But I think with the investigations we have shown that the risk of transfusion-associated transmission is still not zero.

     Something that I pointed out at the AABB meetings and did not show here is that these West Nile Virus illnesses--the presumptive viremic donors precede human West Nile Virus illnesses in about 40 percent of the counties.  Actually, that number is going to go up but we are waiting to complete a lot of our data sets.  That may allow intervention so that really underscores my last slide here, that is, viremic donors are an exceptionally valuable piece of surveillance and I want to thank all you blood banking people for doing that.

     Next slide.  What is going to happen in 2004?  The real question is are we going to have another national epidemic and I think we are.  These are the reasons why I think we are:  We have never experienced a back-to-back flavivirus epidemic in the United States, 2002-2003 was the first.

     We have seen persistent human transmission that is equal, if not greater than it has been in previous years in the northeast.  We have seen persistent animal activity in many, many states.  We have seen simultaneous epidemics going on in parts of the country that have very, very different weather patterns.  We have seen it in urban settings, rural settings.  Wherever it occurs, West Nile Virus has managed to cause a lot of disease.

     In areas where there is both West Nile Virus and St. Louis encephalitis irus, West Nile Virus comes up earlier, causes more cases and it lasts longer.  I have shown you the prolonged transmission season and then, of course, the many potential bridging species, the increasing role of Culex tarsalis in our irrigated western lands and, of course, the many amplifying bird species.

     So, I think next year we have to look at those areas that showed up at the end of 2003.  What we are talking about is Arizona, New Mexico, southern California, potentially the central valley where we are thinking about these problems.  But I want to emphasize that I think we are going to continue to have problems in the high plain states as well.

     Next slide.  I just want to thank everybody, ArboNET, the people who work for me in ArboNET, all the cooperators in the states, AABB, the blood banks, HRSA and the FDA and thank you for your attention,.

     DR. NELSON:  Thanks, Tony.  Questions or comments?  Yes, Jim?

     DR. ALLEN:  The amplifying avian species do not die from this infection?

     DR. MARFIN:  It is actually a mix.  When we look at the crows, which was the most impressive thing that we saw when it very first came in, crows get infected.  They get very high viremia and they die very, very quickly.  They will die probably within 48 hours of infection.  That is not actually your best amplifying host because they are just too short-lived.  We have another group, the small song birds, house finches, house sparrows, that can achieve high viremia and stay viremic for 8-12 days.  Those are good birds to be feeding on.

     What I think you are getting at is if humans don't play any role in the cycle how is this ever going to burn out?  What you are thinking of is, well, what happens when the birds are protected and they have antibody?  That will be the thing that will change that.  The difficulty, of course, is that these are the small song birds.  How LONG does a house sparrow last?  Two to three years and then they are rapidly replaced with immature birds.  These are not birds that live for 80 years.

     DR. NELSON:  Steve?

     DR. KLEINMAN:  Tony, in the slide that you showed about the relationship between presumptive viremia in donors and clinical cases, you indicated that in about 40 percent of the counties there was a viremic donor prior to a viremic case, but I would have suspected that would be more.  I know the data set is incomplete but assuming that that is somewhat correct, then you have to show the other kind of things--how many counties that didn't have viremic donors didn't get clinical cases in an expected time frame and, similarly, how many counties had their first clinical case before the viremic donor, if you are thinking about this as a predictive tool.  Perhaps you haven't had a chance to look at that yet in your data set but I think that would be important.

     DR. MARFIN:  I think I showed a very, very early slide of that at AABB and, actually, the positive predictive value was very, very good which is nice because that complements our bird surveillance where the positive predictive value is not very good.  It is very sensitive but it is not very specific.  What happened is that the presumptive viremic donors gave us the specificity.  I think it is going to be some combination of that that we are going to use.  But that took me a long time to do the last time and until I get a complete data set I am not going to do it again.

     DR. KLEINMAN:  So, I guess the follow-up question is do we have any tool to predict where we are going to have the presumptive viremic donor before he actually turns up?

     DR. MARFIN:  That is the important one.  I am telling you that presumptive viremic donors are very highly predictive of ill people that are presumably infected by mosquitoes, and your question is a very, very important one.  That is, then does animal transmission predict the occurrence of presumptive viremic donors because then we say, "ah, look at that."  Then we would turn off testing and it all goes away and it comes back to West Nile fatigue.  The states are simply having a very, very difficult time keeping up with animal surveillance.  Here we have this gift.  We have never had an early warning system in any of our arboviral epidemics, ever, but it is time consuming.  It is expensive and a lot of states have started to pull out of that.  At our West Nile meetings next month we are going to try to fire them all up again but I am not sure that is going to happen.  By the way, as soon as we get our data sets complete on birds and all of those things, we will answer that question specifically.

     DR. NELSON:  What about horses?  You know, people don't own crows and dead crows are everywhere but if somebody's horse dies they would probably know about it.  My sense is that they may have a higher rate of clinical illness than humans.  Is that right?

     DR. MARFIN:  They have a higher mortality rate.

     DR. NELSON:  Could they be a sentinel animal for humans because they are outside, etc.?

     DR. MARFIN:  I think that we have always thought that during the first two years.  I think people are very, very disappointed in horses.  When you looked in New York and Connecticut horses were very, very poor.  They came in at the very, very end of the season, long after the epidemic had occurred.  Why is that?  Well, these things ultimately all tie together.  Culex pipiens, which doesn't like to feed on mammals all that much, is the predominant enzootic vector at that time.  So, all of a sudden it makes sense.  Now we move into the high plains states where Culex tarsalis loves to feed on horses and, in fact, we have seen a tremendous number of horse cases.

     Now, what has happened, of course, is we have several other determinants or dynamics going on.  One, the vaccination.  We have a vaccination program that is out there.  Not only may it protect a horse from infection but it certainly makes interpreting their serologic results very, very difficult.  Two, USDA has dropped out of testing of horses for free.  There is now a fee for that.  So, we have lost some of that as well.  In fact, we have seen somewhat of a decrease in the number of horses that have been reported to us.  Again, as soon as our data sets are complete we will go back and ask that question, is it still a valuable tool.  It is a very valuable tool because it means that there is now an infected mammal-biting mosquito that is in your area and that increases our risk as well.

     DR. NELSON:  Mike?

     DR. STRONG:  In the past you have given us a lot of bird data.  You didn't have as much bird data this time.  What was the earliest bird case in 2003?  Also, there were some counties that had bird cases and animal cases in 2002 that were completely negative in 2003.  What is your explanation for that?

     DR. MARFIN:  Our first bird cases were coming up in January in Florida and Louisiana.  In fact, that is a point that I have made in the past.  West Nile Virus, in terms of thinking of ongoing transmission whether it is through animals or humans, is a year-round disease.  The horse cases are earlier.  Sentinel chickens, I think it was in late February or early March when there was a tremendous number of seroconverting chickens at that time, meaning that transmission was ongoing.  So, it is a year-round disease there.

     Your second question, a lot of that has to do with the fact that counties just are not collecting birds anymore.  They do not use birds anymore; they are not testing birds; not collecting birds.

     DR. STRONG:  More specifically, we did have a few cases in Washington State and I know there was a concerted effort up there.

     DR. MARFIN:  Yes, I can't explain that, except for the fact that it just did not become established in a good over-wintering mosquito species and, therefore, just was not there, what happens with West Nile Virus is it over-winters in the adult mosquito and that is how we see rapid emergence in the spring.  If I showed you all the maps we have going all the way back, for instance, in 2002 and 2001 the very last county was Erie County, Pennsylvania.  That was the furthest west that we had been.  Well, where was one of the earliest counties we had in the following year?  Eerie County, Pennsylvania.  These mosquitoes over-winter in the infected state so they rapidly emerge.  With regards to Washington and Oregon, I would just say they probably have not had a good over-wintering species.

     DR. STRONG:  Also as a follow-up, we now have it in California and I know there have been positive mosquito pools in the very south of California to a pretty large extent.  Are you going to help us with the bird fly-aways as to where the migrations are going to take place?

     DR. MARFIN:  Yes, that has been an ongoing argument and it is one of those things where you sit around, drinking brandy and smoking cigars, to discuss because you can ever prove those things.  But with regards to your comments about animal events in southern California, you know, they have picked up birds in Long Beach, San Juan, San Diego and that is somewhat of a surprise to us.  We have never seen that kind of arbovirus activity on the coastal areas of California in the past and now we are starting to see it.

     DR. EPSTEIN:  Tony, is there any evidence that mosquito control was of benefit in 2003, particularly in the non-plain states which aren't irrigating?

     DR. MARFIN:  Yes, that is an ongoing discussion point as well for arbovirologists.  It has been a leap of faith.  In the past we have never had a good animal warning system and by the time good mosquito control has occurred, it is usually after the peak of the human epidemic.  Now that we have animals, we have said we can start that control earlier and, therefore, prevent the epidemics.  We have not prevented the epidemics but a lot of the problem is the counties aren't acting on animals.  You could drop a hundred infected crows at the foot of the board of county supervisors and they are not going to act on that.  There are many counties that won't act on one case of human encephalitis even though you know there are at least 150 other people that are infected out there and you don't know the risk factors for progression.  It is very, very expensive.  Now, I do think that in 2003 there is going to be a relatively good study that comes out of Larimore County, my home county, Ft. Collins, because it happened in our back yard and we were able to get out and do that.  The results of that should be out in about the next six to eight weeks.

     DR. DIMICHELE:  I was just wondering if you could say something about the two cases of transfusion-transmitted disease.  Was that before the surveillance system was put into place?

     DR. MARFIN:  I am sorry, I assumed everyone saw that in MMWR.  I should have had that as a handout.  In fact, essentially all of the screening was in place on July 1st.  There were a few late states, and both of these cases occurred after that time.  In fact, I will let Sue and Mike talk about the industry look-backs using individual donation testing of minipool negative tests.  One of them came through that but the other one had been in a minipool, was found to be negative and, therefore, it was released.  It was only identified because this person was a transfusion recipient identified through the public health department.  I am sorry, I assumed everyone was aware of that already.

     DR. KLEINMAN:  One more question about the epidemiology, Tony.  Are there any data about West Nile in either Mexico or the Caribbean?

     DR. MARFIN:  We have a Caribbean case from 2001.  The person never traveled.  It has to have been acquired there.  There are some good, strong suspect cases from other areas in the Caribbean and we have good suggestions that horse infections are occurring south of the border within about 100 miles of the U.S.-Mexican border as well as down in the Yucatan.  So, the virus is there as best as we can tell although we have never made an isolate.  This is all on serology.

     This gets back to that problem of flaviviruses.  There is so much cross-reactivity that you want to have an isolate before you start going around and advertising that, in fact, it is truly there.  So, we continue to look but, yes, it probably is going on in southern Mexico.

     DR. KLEINMAN:  And based on mosquito breeding patterns, would you expect that to be year-round in those locations, if it does exist?

     DR. MARFIN:  Not knowing what the vector is, which mosquito vector it is, it would be hard to speculate but I think that would be fair to say.  I mean, we are seeing it down in southern Arizona, down in Tucson.  They have a very, very late season for animal findings.  So, I think that would be fair to say.

     DR. STRONG:  You mentioned West Nile fatigue syndrome among the testing labs in the states.  Can you give us some idea of how bad that is, and are the states going to continue to test throughout the wintertime?

     DR. MARFIN:  States in the southeast do continue to test during the wintertime.  Florida tests through the wintertime, Louisiana, Harris County, Texas which is where Houston is, do test through the wintertime but that is because they have a long experience with arboviruses.  This didn't just come along with West Nile Virus--gosh, this is a good idea to monitor our environment to look for the virus.  So, they have always done it year round.  In the north most of the states have already stopped.  In places like Maryland, because they wanted to put their resources elsewhere, they stopped testing after one positive bird in a zip code and then they would test no further birds in that zip code.  So, they had to come up with a strategy to prioritize their funds and their testing.

     DR. KUEHNERT:  I assumed you were talking about testing birds but the question is whether clinicians are going to test in patients.  They probably won't because they think West Nile doesn't happen in the wintertime.  But the blood donor data may actually prove otherwise.  Just looking how wide that so-called calendar year is becoming, I am wondering if there is compelling data to suggest that it won't be happening year round.

     DR. MARFIN:  It is always nice to have full-year data that is collected equally in all of those months to say, oh, look at that, it does not, in fact, occur.  I think one of the biggest reasons that we know about some of these cases this year is because of the availability of testing in private laboratories.  So, physicians may see an encephalitis and many of them will probably just order the same panel that they would have ordered in July.  It is just automatic and it just runs right down the thing.

     DR. KUEHNERT:  It is in a standard panel.

     DR. STRONG:  I don't believe we have had a positive blood donor since the first week of November.

     DR. NELSON:  Sue will tell us.  Sue, are you ready?

Updates on WNV Testing Under IND and Plans for 2004

Red Cross

     DR. STRAMER:  If I could have presentation number one, please?  I am not going to help us catch up on time so get that thought out of your heads, but I will go as quickly as possible.

     Next, please.  Many of these slides I showed before and I included them again as background and update of where we are.  So, we began testing at the Red Cross on June 23rd for one of our regions, Southwest, based on animal and bird reports.  We implemented system-wide on June 29th.  However, based on the data that we started to receive from two of our regions, Central Plains, which collects from Kansas, and Midwest region, which collects in Nebraska, we did the following actions:

     Initially we did a 28-day inventory test or inventory rotation performed from our first positive pool result which occurred on these two dates in these two regions, and we went back and did a 28-day test when testing had not been implemented yet.  So, we went back to June 11th in Nebraska and went back to June 16 in Kansas and did single unit testing for these days.  Those are the days prior to the implementation of minipool tests.  Now, we did not find any true positives.  We did find some false reactives but no confirmed positives.  So, we used that as data to indicate that we started testing at the right time, that is, no cases were missed.

     Then, because of the increasing number of cases in these two states, we went to individual donation prospective screening and we did that for over a month in both of the two regions.  Then, again, because of increasing numbers of cases, we did a frozen transfusable market withdrawal in these two regions, covering the period of time in which we were not doing individual unit testing but we had minipool positives.

     Next, please.  To date, or to the end of November, we have screened over 2.9 million donations and had 797 NAT reactives.  Of those 797, 413 we classified as hot cases.  Using the Gen-Probe test in pools of 16 when we see a signal to cut-off ratio of greater than or equal to 25, we call that presumptive.  So, this hot category includes all these hot cases that would have confirmed and any other cases that had lower S/COs but also confirmed.  The number of confirmed cases we have are 409 out of 409 tested.  These other 4 cases are still pending.  Cases that didn't confirm or are still pending but are unlikely to confirm include 384 and to date we have confirmatory negative results for 377 of 377 tested. 

     Based on the time period from the beginning of testing to our conclusion of testing, we had a system-wide prevalence of 1 in 5,700.  Our two highest states, including all the minipool testing we did and individual document testing that we did that you will hear in my second presentation, this was our prevalence in Nebraska and Kansas.  So, 0.57 percent and 0.41 percent from the first to the last confirmed case.  So, this is actually greater, at least in Nebraska, than 1 in 200.  The reason--we had 2 fail or repeat tests were 2.5 percent at the individual donation level or the individual sample level--very, very low.  These rates are very good and actually better than we see with HIV-HCV combined test that is licensed.

     Two ways of looking at what our initial reactive rate is--this is during the time that we also had positives so this is the total initial reactive rate--ranged from a pool reactive rate of 0.8 percent to the time that we did individual donation testing at a 1.14 percent.  So, it is somewhere around 1.0 percent.

     During the last period of time, the last month, we haven't seen any more confirmed positives and the number of donors that we have lost that have been pool reactive and then individual donation reactive, or one could consider that as a repeat reactive rate--we have only been losing about 1 in 25,000 donors, which is much better than when we started the test.  So, the false positivity of the tests is greatly decreased; the specificity greatly improved by some parameters that we put into place.

     Next, please.  This shows you West Nile false positives relative to HIV-HCV.  I always show this slide too because it gives us a good comparison of what we are seeing with West Nile in comparison to all the NAT testing we have been doing with HIV-HCV by year.  So, this gives you the percentage of false reactives due to pools.  Here is the number of lost donors, about 1 in 40,000.  So, for HIV-HCV the specificity has been excellent.  Although West Nile is improving, this is our percentage that don't resolve and for a total, as I showed you about 1.0 percent, but if we just look at those that do not resolve it is about 0.6 percent.  Then, the number of lost donors coming from reactive pools isn't as good as HIV-HCV but it has been getting better.

     Next, please.  Our criteria for confirmatory include 4 different classifications.  We collect our samples in a plasma preparation tube.  They are shipped from the NAT lab to our confirmatory lab, National Genetics Institute.  If the sample is positive by PCR that is in a parent tube, either by a qualitative or quantitative test, it is considered a confirmed positive.  The qualitative test has 95 percent sensitivity at 5 copies/ml; quantitative at 100 copies/ml.  Through this presentation and my next presentation when I use 50 copies/ml it means that it was quant negative but qual positive.

     We also get an alternate sample which is the index plasma unit or index retention type, and if that is positive by PCR or repeat TMA we also consider the sample confirmed positive.  If it is the alternate sample which we test for IgM the sample again is considered confirmed positive.  If the donor seroconverts within 28 days of a West Nile Virus reactive donation, we also consider that a confirmed positive but we have only had two of this last category so those have been rare, one of which I think was a carryover from the previous year that I will talk about.

     Next, please.  You have seen this slide before.  This just shows you the epidemic curve of the 2002 update.  As we have seen from Tony's presentation, the 2003 has been a little bit more spread.

     Next, please.  This shows our 2003 data and this gives you all donations that were reactive.  Here, in eggplant or aubergine depending on what your preference is for color, are false positives and in lavender are confirmed positives.  You can see in the trailing weeks here a false-positive rate of about 1 in 25,000.  So, we are still picking up a couple of false positives.  Our last confirmed positive from South Carolina occurred on November 14th.

     Next, please.  These are the same data in a line graph.

     Next, please.  I should have said on the previous slides when we implemented different strategies to deal with false positives, also when we started single unit testing but I will get back to that in a third slide.  I have shown this before but this gives you data for two different Red Cross national testing laboratories and our false-positive rates were kind horrendous.  So, what we did is an experiment with increased spin time and that is the way we have been managing our false positivity to this date.  Now we are spinning at 32,000 rpm which is the maximum rating for the rotor, and from the data collected by Gen-Probe, the sites that do run at 32,000 are getting the best specificity.  So, that is my message to anyone who isn't spinning fast and for a pretty long time.

     Next, please.  This is the signal to cut-off ratios of what we call our hot cases including the confirmed positives.  Most of the signal to cut-off ratios that are greater than 25--here most are greater than 35 but we do still see some confirmed positives coming out of pools or individual tests that have low signal to cut-off ratios.

     Next.  This is the inverse showing those that do not confirm positive and, as with any test, most of the false positives run right around the assay cut-off.  We have had some that have had high signal to cut-off ratios that have not confirmed.

     Next, please.  This complements the slide that Tony showed, focusing on Nebraska and Kansas.  Interestingly about Kansas, and we have had a couple of battles with them, they only report cases to ArboNET if they have confirmed meningeal encephalitis out of a CSF sample.  There is going to be some under-reporting here relative to Nebraska but the red points here show you the number of counties that have had confirmed positive blood donors.  Here, on my left, your right, are the states with our five highest numbers.  So, between Nebraska and Kansas of our 409 confirmed positives, 200 cases or 50 percent of what we have seen at Red Cross have come from those two states alone.  Our last cases, two occurred in Georgia in the first week of November and our last, and only case in the fair State of South Carolina occurred on November 14th.

     Next, please.  This shows you Nebraska.  The numbers on the boxes here show you the number of cases per county, 15 in Douglas County in Omaha which should be no surprise, but 15 here, in Holt County which sits on the Platte River, is quite a high number considering the population, which I don't know for that county but I assume it is quite low.  Here you can see 11 for Jason County, Buffalo.  So, initially when we started to see cases in Nebraska they were in counties that lie adjacent to the Platte River, which I was rafting on in June of this year.

     Next, please.  This is Kansas, basically the same scheme here, with the number of cases per county in a little box.

     Next, please.  This shows only the confirmed positive cases by criteria of confirmed positivity.  Remember, I showed you four.  So, here are the first cases that we saw.  Here is one case in California, our first confirmed positive case but it actually was a case that had IgM at index and I believe that probably was a carryover from the previous year.

     Moving on forward, what is in blue here are those that were confirmed by NAT only.  In green were NAT, IgM, TMA and/or PCR reactivity at index.  This is IgM only at index.  These 2 were the 2 that were confirmed by seroconversion.  What you see here is an increase as the season progressed in the number of donors that contained IgM as well as being flagged by minipool or individual donation NAT.

     Here is the point where we started single donation testing for the two regions and you can see that this curve started to increase prior to our switch to ID-NAT.  About half of our cases for Kansas and Nebraska--I don't know if I said this already--came from minipool screening and the other half came from individual donation testing.

     Next, please.  This is the viral load of our positives.  The median is only 970, so not a lot of virus for these samples, with the mean being 26,000.  This is not a normally distributed population so this is really the only relevant number.  If you focus on the low level of positives, the 89 here, 82 of those were IgM positive and then out of these there were 36 that were IgM positive.  So, of the 409 total confirmed positives we had 120 of those being IgM positive but they were all with relatively low viral loads, as you would expect.

     Next, please.  I have shown this before.  This is the correlation of the quantitation that we do with NGI and CDC and there is good relationship.  So, the NGI test that we use correlates quite well standard CDC TaqMan assay.

     Next, please.  A question was asked by BPAC last time, the Isabelle BPAC, about donor demographics so we tried to put some together that we collected for each of our donors.  Here are 409 confirmed positive versus the 377 confirmed negative.

     Firstly, what you have here are the number of components made from those donations.  Assuming all of these would have been infectious and each component would have been infectious, from our screening we would have prevented 823 components from being released and potentially infecting recipients.

     If we look at gender distribution of the cases versus the controls, and our false positives act as our controls, gender is a little bit higher with more males confirmed positive, and we saw that for 2002 that I will show later as well.  I don't know how significant this is but we saw more males confirm than didn't confirm.

     Distribution of donations is representative of what we see in a normal donor population and the mean age of the positives isn't any different than the mean age of the false positives.

     Next, please.  Based on symptoms--you know, we are asking donors at the time we are calling them back in with the West Nile Virus reactive screening test, have you had symptoms?  If someone asks me if I had headache, I would say yes because I have a headache every single day.  Painful eyes?  Yes, I have painful eyes right now as a matter of fact and probably you do too.

     [Laughter]

     Anyway, if you look at headache, in 66 percent of our cases--firstly I should say that 81 percent of the donors said they had at least one symptom.  We broke out these symptoms individually and then put in these other symptoms, and there were a zillion of them, nausea, vomiting, diarrhea, etc., and we grouped those as "other" symptoms.  What stands out here are headache, new rash and 62 percent of the donors reported symptoms after the day of donation.

     Next, please.  In contrast, here are our controls.  So, even our control population said they had one of these and 35 percent said they had at least one of these symptoms.  About 60 percent had a headache, just like we all do.  Many fewer had rash.  So, rash stood out on the previous slide and 63 percent, I believe, was the number on the previous slide who reported symptoms after day of donation; here only 43 percent did.  So, those are the things that stand out.

     Next, please.  Now I want to end with our follow-up studies.  Of the 797 NAT reactives that we have had, 66.5 percent or 530 have participated in follow-up, which is an amazingly high number.  It included 68 percent or 279 of our 409 confirmed positives.  Of the confirmed positives, 261 or 94 percent seroconverted in a mean time of 20 days, with a range of 2-77 days.  Of those that have seroconverted, 94 demonstrated NAT reactivity either by TMA or PCR on follow-up.  Of those 94, 24 or 25 percent had repeat NAT reactivity by these two tests on multiple follow-up samples, so not just on one follow-up but repeatedly had NAT reactivity.  Of those 24, 14 or almost 60 percent demonstrated intermittent NAT reactivity by one or both tests.  The NAT reactivity maintained in these 24 donors had a mean time of 18 days, with a range of 6 to the longest person exhibiting intermittent viremia for 59 days.  I will show you a couple of profiles.

     Next, please.  Just to show you the testing on each donation, index PPT, as I mentioned, is tested by the test of record, TMA.  Then we send it to NGI for PCR.  We retrieve a plasma co-component.  It is tested by TMA.  We repeat the NGI PCR test.  We run IgM and we do follow-up TMA, PCR and IgM.

     One donor of interest here went from 1,300 copies/ml and then four days later went to 150,000 copies/ml.  So, we were able to calculate about a 14-hour doubling time, which is pretty fast and kind of HCV-like.

     Next, please.  I have shown this slide before using that donor that went from 1,300 to 150,000, I plotted him over the four days and then plotted all the other index donors at day zero, the index time, along a curve that I fit between these two lines, and then plotted their subsequent follow-up samples whether they were NAT reactive of IgM reactive.  Here you can see the 18 days I have been talking about in repeat sampling and these donors maintained NAT reactivity.

     Next, please.  This just gives more of the data.  I haven't updated this yet with our most recent data but this is what I showed at the last BPAC.

     Next, please.  The 18 days actually compares favorably with about 12 days of IgM reactivity that we got out of our 2002 studies looking at various categories of donors.  This is the number of donors fitting the various categories of decreasing NAT reactivity over time, increasing IgM reactivity over time, and just giving you the relative days of each of these categories.  So, we had about a 7-8 day period of viremia only, followed by 12 days of IgM in the presence of virus.

     Next, please.  These are just some profiles to show you what some of these donors look like.  This is the index.  It will always be plotted on the Y axis here.  These are the TMA signal to cut-off ratios, followed by the IgM results.  You have initial testing and then duplicate retests and we plotted both.

     Here, this donor came back and was NAT reactive but was not yet IgM seroreactive and still had virus.  The subsequent sample that was TMA negative still had virus by NGI's qualitative test.

     Next, please.  This is another donor showing a similar pattern where virus was maintained on the first follow-up sample.  IgM was reactive but low and we still had PCR detectability for a couple more follow-ups.

     Next, please.  Here you see the opposite where PCR was negative after IgM was produced, but here you see a nice spike of TMA reactivity showing intermittent viremia.  Probably all of these represent the same thing, low level of virus at the cut-off and it is just a crap shoot whether you pick one up by one test versus the other.

     Next, please.  Here is one where you see both.  You see the spike but you see PCR and TMA being reactive.

     Next, please.  This is my favorite one.  With this one you see NAT reactivity at first follow-up.  NAT reactivity decreases.  Two bleeds are negative but, coincidentally, so is the IgM.  So, in this gentleman we actually see a trough between RNA detectability disappearing and then IgM kicking in.

     Next, please.  The last one shows you IgM produced earlier, prior to the decline of virus but, again, still a period of intermittent viremia.

     Next, my last slide.  So, I just want to end with our plans for 2004.  We have not stopped testing.  We will continue West Nile Virus NAT in pools of 16 using the Gen-Probe test in 2004.

     The issue with us and IDT testing this year is it came on relatively fast.  Kansas and Nebraska had these huge numbers.  So, even when we decided to do IDT testing it took us two to three weeks to get the resources ready to do it so we were missing a big chunk of the epidemic.  What we are doing now is preparing three NTLs for individual testing depending on where the need should be.  We have reasons for selecting these sites, two of which will be in a Tigris clinical study so we will have instruments there validated, and we will again add St. Louis because of the issue in the central plains area.

     So, depending on where cases occur and the trigger that will develop, we will develop and refine--this is the trigger that we used this year, prevalence of greater than 1,000 and 4 confirmed positives.  From the prevalence data that I will show you I will explain that for every 4 pools reactive we would have released an individual donation that likely would have been infectious.  So, we had a ratio of 4:1 from our earlier prevalence studies and that is where this 4 came from.  So, when we see these two parameters we could convert a specific region from pooling to IDT.  But our plan is really dependent on the availability of automation from our vendor--that is a plug for our vendor, but we need these instruments and these 3 NTLs, which I think we will accomplish.  Thank you.  See, that wasn't so bad!

     DR. NELSON:  Questions?  Yes?

     DR. STRONG:  I was interested in your S/CO numbers.  You have some lower S/COs in your follow-ups on your donors so it seems surprising--of your 377 false positives at least some of those might have been true positives.  Do you know why that was happening?

     DR. STRAMER:  Why they had a higher signal to cut-off ratios?

     DR. STRONG:  Why below the 25 signal to cut-off ratios in your false positive group, none of those confirmed, whereas you had lower signal to cut-off ratios in follow-up samples.

     DR. STRAMER:  I don't think S/CO is 100 percent predictive.  Certainly there is a tendency for higher S/COs to be more predictive of true positivity but, you know, maybe because of technical error in running the assay, you know, we had some differing S/COs, contamination or what-not but it is not 100 percent relationship.

     DR. STRONG:  Then, in terms of your copy number results, have you run confidence intervals to know how accurate copy numbers are from NGI?

     DR. STRAMER:  Well, I showed you the correlation with CDC for each of the intervals.  I have the confidence intervals, I just haven't presented them.

     DR. STRONG:  On the headache question, with 60 percent of donors having headaches what was the time frame?  Was it the week before and the week after?  Presumably you didn't have a headache on the day of donation.

     DR. STRAMER:  It is what we used last year in the 2002 studies and what the standardized CDC vehicle was this year, and I can't remember whether it was one week or two weeks.  Tony, do you remember?  One week?  So, it was one week before and one week after.

     DR. NELSON:  Jay?

     DR. EPSTEIN:  Sue, as you know, FDA recommended that donors be tested if they had fever with headache within the week before donation.  In your data, did that combination of symptoms have any positive predictive value above control?

     DR. STRAMER:  I haven't looked at the data that way.

     DR. EPSTEIN:  It would be nice to know before 2004.

     DR. STRAMER:  Yes, we can stratify the data a number of different ways.

     DR. NELSON:  I didn't see fever on your list.  Was it there?

     DR. STRAMER:  Fever should have been there.  You should have the handout.  Dr. Smallwood was supposed to hand them out.

     DR. KUEHNERT:  You had a slide on the duration of NAT positivity and the outlier looked like it was 39 days, and I wondered how far out you tested people, particularly that person, to see where the viremia stopped especially since, as you said, it can be intermittent.

     DR. STRAMER:  Yes, that person was one of the donors whose profile I showed you and that one was out to 50 days.

     DR. KUEHNERT:  So, they were tested out to 50 days.  Was everyone tested--

     DR. STRAMER:  Well, as long as they participate I review all cases before they are closed, and we try to get multiple bleeds negative by both TMA and PCR before a case is closed with full IgM seroconversion.  So, we did multiple bleeds following any intermittent--we usually follow a donor, if we can, for two months.  That is the short answer.

     DR. NELSON:  Maybe we can move on.  Gen-Probe, Jeff Linnen.

Gen-Probe

     DR. LINNEN:   Let me give an update on the West Nile Virus assay.  This is a collaboration between Gen-Probe and Chiron.  In the handouts it actually has tomorrow's date but I was optimistic and changed it back to today.  So, it says December 11th.

     Next slide, please.  I am going to cover three topics.  I am going to give a brief update on the clinical performance of the assay, focusing mostly on the non-ARC data; also give some information on work that we have been doing recently showing the feasibility of running this assay on a completely automated system, Tigris; and also talk about some future options for this assay.

     Next slide.  This is just a little bit of a review.  As I think most of you know, this assay uses the same instrument platform as our licensed HIV-HCV assay.  What a number of you may not realize is that we consider this really a high throughput system because we can test 182 results in about 5 to 6 hours, and that is with one operator.  If you consider 16 donations, that is nearly 3,000 results in 5 to 6 hours.

     Down below I just show the instrumentation both for pooling.  The middle picture shows the target capture system and then, finally, the full luminometer for reading the results.

     Next slide, please.  This is a little bit more review.  Our live testing under IND started June 19th and most sites started testing by July 1st.  The testing is being done at 24 sites.  The first confirmed positive in our non-ARC database occurred at the end of June.

     Now, to review the confirmatory testing for the test when it is run outside the ARC organization, we are doing the confirmatory NAT assay at our reference lab, and that is a kinetic PCR assay that was developed by Chiron.  The IgM testing is done at Focus Labs in Orange County, California.  Early on during the season we started doing additional confirmatory testing with our alternate TMA assay and I think Mike Busch will present some data on that later.

     Next slide, please.  Here are really the most important numbers.  With the Procleix West Nile Virus assay we have screened approximately 5.1 million donations and this data is as of the end of November.  Out of those 5.1 million donations we have confirmed 824 positive donations.  So, this is data from all of the testing sites including the American Red Cross sites.

     Outside of the American Red Cross sites the ranges go from zero percent, and it is not too surprising where--central California and, surprisingly, we haven't detected West Nile in any blood donors yet, and also in Hawaii, as you would expect, although the number of donations there is pretty small but we are not anticipating seeing very many.

     Now, the data from Colorado again goes through the end of November.  So, that confirmed reactive rate is probably lower if we limit the time span because they haven't seen confirmed positive results for some time now.  So, that is 0.18 percent in Denver, Colorado.  Of course, for a number of confirmatory results the final numbers are still pending.

     Next slide.  This slide shows how we define the results at Gen-Probe.  You see in the second row how we define confirmed and that is, of course, identified in the TMA screening.  Then, upon retesting it can be either reactive or non-reactive but it must be positive either in the IgM test or in the alt NAT, or we must demonstrate seroconversion with a follow-up donation.

     These next two categories are really when the results are pending.  In one case we identify it as initially reactive where the other testing is unavailable and, in the second case, repeat reactive with the IgM testing in the alt NAT unavailable.  The next one is very similar.  We call it a probable true positive where the TMA screen is reactive, the retest is reactive and, of course, it is very convincing if these results came out of a 16 donation pool but the IgM and the alt NAT may be non-reactive.  A probable false positive then is a reactive screening result but not reactive results for all the other testing.

     Next slide.  Now I will show some of the data outside of the ARC results.  This includes screening 2.2 million donations and that involved nearly 300,000 reactions, meaning those 300,000 reactions are the individual donor tests or the pooled tests.

     As you can see, we have 415 confirmed results.  I want to add that this also includes an additional 10 that were identified using the alt TMA assay run at Gen-Probe.  Seven fall in the category of initially reactive with the rest of the results pending.  We have 20 that are repeat reactive.  We have 59 that fall in the probable true positive category, and we have a total of 868 probable false positives.

     If you look at the specificity in terms of the denominator using the individual reactions, specificity is 99.7 percent through the end of November.  If you look at it in terms of the total number of donations, the specificity looks very good, 99.96 and, as Sue pointed out, there have been some changes made during the course of the testing so we are kind of stuck with some of the numbers that we obtained early on in the season and, actually, we expect to see much better numbers next year in terms of specificity.

     Next slide.  What I want to show here is some data about the IgM positive index donations.  Again, this is the non-ARC data.  We have seen a total of 70 IgM positives.  Of those 70, 64 percent were repeat reactive in TMA.  I just wanted to point out also that it might be of some interest that 65 percent of those 70 IgM reactives were IgG positive.  Now, 36 percent of those 70 were positive with the PCR assay that is run at the reference lab.  A much smaller number were tested with the alt TMA at Gen-Probe and 80 percent of those were TMA reactive.  So, this is about 17 percent of the total confirmed viremic donations so that is 70 out of 415.  Of the IgM reactives, 58.5 percent were identified in 16 donation pool testing and about 40 percent were identified in individual donor testing.

     Next slide, please.  What I want to move onto now is what at least part of the group has started to focus on, that is, putting this assay on a completely automated system.  So, this shows a picture of the system.  There are a few points that I want to make here.  This is a fully automated system for sample handling and assay processing.  It has even higher throughput than our current system, about 1,000 tests in 14 hours.  We have a reagent dispense verification for the addition of key reagents.

     Next slide.  This is actually a pretty small study.  This is something that was presented at AABB.  I just want to show you that we have determined the analytical sensitivity of the West Nile Virus on this automated system.  As you can see, it is fairly similar to what we see in the manual assay.  This is only based on 8 replicates of each level.  We are able to detect 100 percent down at 30 copies and 88 percent at 10 copies.

     Next slide.  This shows additional data that we have generated just at 30 copies and 10 copies.  You can see here that at 30 copies we detected 235 out of 235 replicates, 100 percent.  Ten copies were at about 78 percent.  This is really with very little optimization on the instrument.  So, what we are going to be doing in the next couple of months is looking at the parameters very closely and trying to get better sensitivity at the lower end and I think it won't be too difficult to make some improvements.

     With the next slide I would like to show you some of the specificity data that we have generated very recently.  This is using mostly fresh samples.  We have really been focusing on specificity.  As you can see here, the results are very good.  We have tested over 1,100 samples and you can see it is a combination of fresh PPTs, 230; fresh EDTAs, almost 700; and then some frozen EDTA tubes, a little bit over 200.  So, overall we haven't seen any false reactives and we have made some minor changes to the formulation to get this type of performance.

     Next slide, please.  I would just like to finish by making a couple of comments.  Gen-Probe and Chiron are prepared to support testing in smaller pools, 8 in 4 donations, or targeted individual donor testing.  It will really be up to the customers but we are committed to support additional testing.

     The other thing is, as I showed, I think we have shown feasibility on Tigris and I think we can continue to work and so we are evaluating the possibility of making this available for the next mosquito season.  Thank you.

     DR. NELSON:  Thank you very much. Yes, Jim?

     DR. ALLEN:  In your pool testing if you got an initial reactive on NAT, do you repeat the test on the full pool or do you immediately go to the individual testing?

     DR. LINNEN:  The pool is broken out into the 16 individual donations.  The pool is never retested.

     DR. NELSON:  If the individual donations are all negative, then the pool is called a false positive?

     DR. LINNEN:  Right.  I should point out that is not the case with individual donor testing.  If there is a repeat test, that is the end of the line for that unit.

     DR. STRONG:  Just to comment, I think it is an important point that you made concerning the tweaking of the test because these tests were put together in a pretty short period of time and implemented nationwide by June.  Obviously, there is work to be done during the process, as Sue talked about changing the spin speeds.  So, both sensitivity and specificity I think have room for improvement probably on both sides and, hopefully, in the next season will be even better.

     DR. NELSON:  Thank you.  Jim Gallarda, from Roche.

Roche

     DR. GALLARDA:  I would like to kind of give a summary of what we found out this year in the last frantic six months of 2003.  First slide, please.

     This is kind of a little overview of the time line.  Actually, in late September we had a meeting to talk about this.  We submitted our IND in April.  We went live in June.  The first bag positive was on June 26th and now we have screened about 2 million samples in both Canada and the U.S., and we have over 100 confirmed positive units.

     Next slide.  I will go over three aspects of our non-clinical performance studies, looking at analytical sensitivity with available panels; sensitivity in high risk populations from 2004; and then some other JEV related members.

     Next slide.  This is a one-slide summary of the panels that we have had made available to us where there was some assigned titer.  We started out with BBI lineage one.  Although we did not calculate a 95 percent limit of detection with this particular lineage, in a blind panel that Mike Busch provided us we were able to detect the sample that was titered at 30 copies/ml as an individual sample.  We did not detect that sample when we diluted it 6-fold.  Then, there was another member at 100 copies/ml that we detected neat as well as diluted 6-fold.  So, that corresponds roughly with the one point estimate of about 17 copies/ml.

     We also did a limit of detection study on lineage two.  The titer was assigned by BBI of the stock material.  In that study we had about a 7 copy/ml sensitivity.  We have been using Bioclinical Partners lineage one for a lot of our operative validation studies, as well as our gold standard for development.  I believe that titer is assigned by the New York State Department of Health.  We got a 95 percent limit of detection around 15 copies/ml.

     John Saldanha provided recently a Health Canada panel which he will report on in the next few minutes.  We anticipated in a collaborative study, and we were surprised, but the results point out in limited reps that we were detecting that at 250 copies/ml, and that is a 95 percent hit rate.  So, we don't understand the reason for that but those are the data that we reported on.

     I think one thing that John has been a proponent of, which I think is a good idea, is that we need to have a standardized panel, whether we call them copies or detectable units or whatever that we use as a basis for bench-marking and especially for lot release once we have licensure.

     Next slide.  Now, in two studies looking at the 2002 mosquito season we got a panel from Sue Stramer, 384 blinded samples, and tested that both undiluted and in pools of 6.

     Next slide.  So, we detected 12 samples.  The Focus IgG and IgM as well as Abbott IgM was done.  NGI did the titering.  We detected 12 samples undiluted and we detected 10 of those samples when we diluted them 10-fold.  Those two samples that were missed in 6-fold dilutions were both IgM positive.  I will come back to these particular samples in a moment.  In summary, 372 samples were negative; 12 positive neat and 10-12 detected as minipool.

     Next slide.  We also worked looking at a select number of samples from ABC recall from plasma components last year.  We got these from Mike Busch.  We had 1,469 units that we tested again in a similar fashion undiluted and in dilutions of 6.

     Next slide.  In this particular study we found there was one sample--IL-8 was the one positive sample that we detected.  We detected that undiluted.  When we diluted 6-fold we did not detect it.  It was an assigned titer of 440 copies/ml.  We were kind of surprised not to detect that in a 6-fold dilution especially because, as I had said earlier, the following samples were the BBI lineage one members that were also included in that panel and, as I said, we had detected the 100 copy/ml sample 6-fold diluted.  In summary, we detected the one positive sample as well as the expected number of controls that were in the population.

     Next slide.  We have also extended our testing of JEV serocomplex members.  So, in addition to lineage one and two isolates, we have detected St. Louis encephalitis, and we have just recently constructed armored RNA constructs for the Kunjin variant of West Nile, as well as the Japanese encephalitis virus and we detect those.  We are developing a quantitative assay for these constructs so we can get a sense of the limit of detection.

     Next slide.  I would like to move into looking at a summary of our clinical performance studies, looking at both minipool and single unit aspects of this last season.

     Next slide.  This slide basically covers from the start of the clinical trial, which was around the July 1 time frame, until the first week of December.  This is U.S. data only.  We tested about 1.4 million samples.  We had 100 positive pools in that population and 19 of those pools did not resolve as positive to the individual level and 81 of them did.  In addition, we had select areas doing some single unit testing as well as end-of-run single unit testing.  The second to the last column shows we had 89 positive individuals during this time period.  The 19 positive pools that did not resolve corresponds to a frequency of a false-positive pool that doesn't resolve to an individual in 1 in 12,000 pools or 1 in 74,000 donors.

     Next slide.  This is a summary statistics histogram of 72 of the samples that we did quantitation on, and the point here is that West Nile is a low titer virus.  This is not a normal population so statisticians don't like us to use the mean so the median for this population is around 20,000 copies/ml.  It ranged from 200 up to three-quarters of a million copies.  We did have one sample that is not included here that was below detectable limits.

     Next slide.  We did limited testing in the month of September at 3 sites.  This blood center with targeted collection centers in Nebraska and South Dakota tested 3,000 samples.  We found 6 individual NAT positives in that group for a prevalence of 1 in 500.  Gulf Coast tested 2,300, 2,400 samples and did not find any.  Community Blood Services in the Saskatchewan area screened 2,200 samples and found 2 individual NAT positives.  Both of those John Saldanha, I believe, reported at the last BPAC were IgM positive.  I will come back to these 2 Calgary samples in a moment.

     Next slide.  If we look at the 8 samples that were identified in minipool testing, we tested them in minipools to see if they would be reliably detected, as well as to do a titer on them.  So, it was puzzling to see for a sample, like the top row, the Nebraska 16034 titer at 100 copies/ml.  If we diluted that 6-fold we were able to get 10 out of 10 hits in a diluted sample.  Then, for other samples that had higher titers we were not seeing a corresponding hit rate so we don't understand why this is.  It could be either because there are errors in titration and especially at the lower levels there is easily a plus/minus 0.25 or 0.3 log of uncertainty above and below in nominal assignment, or that there was some stability issue.

     Next slide, please.  As Mike had said earlier, I think that in our rush to go ahead and try to get this out by mosquito season both manufacturers did a remarkable job to get this out.  But I think the thing we are realizing now is that we are not done with this.  We kind of like the iceberg diagram that Tony has shown on West Nile distribution of disease.  We also have on the development side a similar issue, and that is, we have just taken care of the top part and now we have the bottom part to close out for licensure.

     So, we are continuing to optimize and assess both the sensitivity and the specificity of the assay.  I would just like to go through some data with you that we will use to look at whether or not we can make improvements in this area.

     Next slide.  What this shows on the X axis is cycles for TaqMan and then the fluorescence output, a normalized fluorescence output on the Y axis.  This shows 12 negative samples across this growth curve.  Right now, for the 2003 season we are using what would be equivalent to a 1.2 relative fluorescence index for the cut-off.

     Next slide.  What I have here are two samples, positive samples.  As soon as you start to see a growth curve, depending on the titer, you will have an inflection at a certain point and that inflection is what was referred to as a CT value.  Or, if it is a low titer sample it will have a delayed CT.  It will start to kick out at a higher cycle number and it will have a different slope.

     The Nebraska sample is an extremely low titer sample that we were unable to detect in our screening operation.  So, we are looking at this and saying, well, shall we look at changing the cut-off to detect samples like Nebraska?

     Next slide.  Here I have shown several samples.  The ARC samples are the 12 that were identified out of the 384.  These are the growth curves that those 12 display.  Ten of those were detected both neat and as dilutions.  Two of them were detected neat but not detected in pools of 6 or diluted 6-fold.  So, you can see the two black lines that are kind of a lower slope.  Those are the 2 samples that had a lower titer, which were positive only by ID-NAT.  Of course, the Nebraska sample growth curve is that.  Then, the 2 Canadian Blood Service samples which were extremely low titer, which were IgM positive, are shown on this graph as well.  So, the question is what would happen if we lowered the cut-off?  Could we reliably detect these?

     Next slide.  What we have done just recently is to look at 190,000 data points and ask what is the essential tendency of this negative population relative to a cut-off?  The mean of this population was 1.08 and the standard deviation was 0.016.  So, that puts our cut-off 7.5 standard deviations away from the mean of the population.  That is in part, we believe, responsible for the observation of the specificity of the test on initial pools and repeatability.  The cut-off of 7.5 corresponds nicely to the observed false-positive rate of 1 in 74,000 samples or a 99.992 percent specificity.

     So, we will continue this assessment of the data but before next mosquito season it is quite likely that we will change our cut-off, and we certainly believe we will be able to detect some of these other samples that were not detected in the early part of 2003.

     Next slide.  I am going to finish up with a non-epidemiological view of what happened relative to interdicting units for West Nile in the cases that were reported to CDC, human cases of West Nile.

     Next slide.  What we wanted to find out is was there general agreement between the ability to interdict units per donor population and the reported cases of human disease to ArboNET.  So, what I did was to query some of my colleagues in the blood testing area to find out what would be a reasonable rule of thumb to assign what percent of the donor population donates blood.

     We had several states that had yield cases throughout the year.  We are assuming that the eligible donor population in this case is 18 and older because there is U.S. Census data on that population although that age can be different from state to state.  We are assuming that in general 5 percent of the eligible population donates.  Just to pick a number, I said Roche is testing half of those.  That might be true; that might not be true but it is just to get an estimation of the number of donors to establish the frequency of interdicted West Nile units per assumed donor population, and then just compare that to the CDC reported human cases for each of the states that we had a yield case identified for, and to plot state by state interdicted units to reported cases.

     Next slide.  This is simply a stacked ranking of states that had high frequency of West Nile interdicted units to low frequency.  On the Y axis is simply 1 per given number of population, so 1 in 50,000 or 1 in 250,000 for an interdicted unit.  That is seen with the red diamonds.  Then to compare this to the CDC reported cases, and these were for total cases so I didn't break it out with meningeal encephalitis versus fever; it was just the total number.

     In general, what you see is that for the states like South Dakota and Nebraska there is pretty close agreement, within a 2-fold range or thereabouts of the CDC reported cases and the number of interdicted units per population.  But it looks like it really starts to change for states that were, you know, the epicenter of the epidemic early on.  I don't know if this is significant.  This is simply an exploratory plot, as I call it, so it has no statistical validity nor would I claim that but it would be interesting to see, if this is true, if there really is a difference, why would that be.  It could be something about the dynamics of the bird population, their immune status or the immune status of humans, you know, in the earlier states that were the focus of the epidemic in '99 and 2000.  Anyway, this is curious at best.  But the reason we did this is just to see are we detecting roughly what we would expect to detect.

     Next slide.  Our future activities--obviously, we will continue the IND and an important aspect will be to prepare for the 2004 mosquito season for targeted ID-NAT; to finalize the device specifications reagents and to close out and establish the performance attributes of the finalized device, both from a clinical performance perspective and non-clinical perspective.  Thank you.

     DR. NELSON:  Thanks.  Steve?

     DR. KLEINMAN:  Jim, one question about the issue of apparent different analytical sensitivity depending upon what standard you use, do we know that these standards--have the lineages been sequenced and are they exactly the same?  Do we know that?

     DR. GALLARDA:  I don't know the answer, Steve.  I think one thing that would be very good if we are going to establish a standard or a panel of standards then, obviously, it would be important to do as much characterization of that standard as possible.  Right now, clearly with three different suppliers or sources of standards there is a wide difference in titers and certainly in characterization.  So, I don't know the answer but that will be important to find out.

     DR. STRONG:  Sort of a related question to the one I asked Sue on the copy number accuracy, have you looked at what the confidence intervals are for the copy number of reports?

     DR. GALLARDA:  That is a very good question.  We did kind of a quasi blind study where we sent out a blinded panel to a lab that does quantitation with replicates and asked were they getting the same titer.  In fact, the answer is no.  There is a level of uncertainty in titer assignment for any laboratory with a quantitative assay.  From our experience with the monitor assays quantitation can easily be plus/minus 0.3 logs above and below a mean.  So, you have a 0.6 log spread that there is going to be with most quantitative assays.

     DR. NELSON:  Hira?

     DR. NAKHASI:  Jim, thank you very much for a nice presentation.  I have a couple of questions.  You said that out of 100 positive pools 81 resolved and 19 did not.  The question is, is it because the virus level was low and did you confirm these by any other method, and what was the IgM status of those and, finally, were any of those cases transfused cases?

     DR. GALLARDA:  None of those 19 were transfusion-transmitted cases.  We do IgM on all of them.  If we get an amplified product we do DNA sequencing on the amplified DNA.  We do alternate primer pairs for looking at whether they are true positives or not.  So, on the basis of a set of confirmatory assays, we conclude those 19 are not reproducible.

     DR. NAKHASI:  I think I agree with you, as Mike also pointed out, that tweaking of these tests may really help more in the sensitivity of that.

     DR. GALLARDA:  Yes.

Status Reports

Prospective and Retrospective Testing Using ID-NAT

and Update on Relative Sensitivity Study for

WNV NAT Testing

     DR. BUSCH:  I am going to cover this fairly quickly and won't take the full 25 minutes.  I want to quickly summarize the Blood Systems' experience both with routine testing and with various studies, quickly reviewing the yield of our minipool screening program using the Gen-Probe platform; address the issues of the viral load and the IgM profiles of the minipool yield cases; and then talk about the final findings from our retrospective ID-NAT study; and then talk about our experience applying perspective ID-NAT and contrasting the kinds of infected units of viremic donations that were found early in the epidemic to retrospective testing compared to the turn-on of prospective testing in September; then summarize the results of the study that was initiated kind of at the request of the FDA and the industry to compile a panel of low viremic samples and assess the performance of pretty much all of the NAT assays that are out there under development or being used; compare the specificity of minipool ID-NAT to give you a sense of what the hit rate would be on our donor pool were we to convert to ID-NAT with the current assays; then, finally, just to touch on some ongoing and planned studies.

     Next slide.  This is a familiar curve, basically the overall Blood Systems Laboratory both reactive rate and total number of reactive units.  You can see that we peaked in the early August time frame at 1 in about 1,100 donations confirmed positive and overall confirmation of 212 positive units.

     Next slide.  If we focus exclusively on the units that were screened, which was the vast majority, through minipools we identified 200 reactive donations.  Of those, 176 were repeat reactive.  If a donation coming through minipool was repeat reactive, all but one of these was confirmed positive based on additional testing of index and follow-up.  We did have 24 samples from minipool where the individual sample was reactive but then could not be repeated on an immediate retest of that sample.  We did find 8 confirmed positives out of this.  The majority of these though were confirmed negative.

     Next slide.  This is sort of that model just emphasizing here that for these 133 yield units, the true positives, full volume units were available so it allowed us to do extended additional testing and a similar median viral load of about 2,800--and I will show these distributions.  Coming out of the minipool NAT screening, 8 percent of the minipool yield samples had IgM detected.

     Next slide.  This shows the distribution of the viral loads ranging from 0-10, 10-100, 100-1,000, 1,000-10,000, etc.  You can see that samples detected through minipool had a distribution that had sort of a median in the range of 1,000-10,000.  We probably aren't seeing all the low viremics because these samples had to have enough virus in order to score positive in the 16 dilution minipool context.

     What we have done down here is to sort the IgM reactives versus the IgM negatives.  You can see that the samples that have IgM have much, much lower viral loads.  So, these are, as the model sort of predicts, the tail end of the viremic curve.  As IgM kicks in those units tend to have unquantifiable or very low viral loads.

     Next slide.  What concerned us was both the data from Sue from last year showing low level viremia, and the fact that in our minipool screening we were seeing donations that had low level viremia and this really marked clustering of our yield cases in Texas and the Dakotas.  This precipitated us conducting initially the retrospective ID-NAT project.

     Next slide.  What this study involved, in the early to late August time frame, is that we retrieved samples that were from high yield regions.  These units at that point had been released based on negative minipools so, as expeditiously as possible, we conducted retrospective single sample testing on donations that were drawn from July 15th, which was the first date of a positive minipool in the high yield regions, through August 13th when we stopped the retrospective testing--we actually stopped the retrospective testing at the very end of August but we had tested through August 13th and at that point we converted all of our ID testing to prospective screening.  If we had a reactive individual sample we worked them up, immediately retrieving any non-transfused products for extended additional testing and donor follow-up, with collaboration with CDC, to determine whether these transfusions infected people.

     Next slide.  So, out of 11,240 donations that had been originally screened as negative by minipool and were then retested by ID-NAT, 43 were reactive.  Very much unlike the minipool testing, the majority of the initial reactives coming from minipool were non-reactive on second test and most of these proved to be false positives.  There were 10 though that were repeat reactive and all of these 10 proved to be infected donors and 8 of them confirmed through follow-up and 2 had corroborating viremia--the donors did not participate in follow-up but there was corroborating viremia and demonstrable viral load by several other assays.

     Importantly, with the ID-NAT of these reactives that were initial reactives and couldn't be repeated on the very same test, 6 of these actually proved to be infected donors based on IgM status in follow-up.

     Next slide.  So, what I have done here is to distribute the samples from the retrospective study according to sort of the staging that was outlined earlier.  So, during that period we identified from those 11,000-plus donations 52 minipool NAT yield donations.  In further testing we found 6 units that were negative on minipool but were detected by ID-NAT that had no antibody; 6 that had IgM only and 3 that had IgM, IgG.

     Next slide.  One of these units which was from the front end, i.e., no antibody, did infect a patient.  I am not going to go through this but this was a Texas transmission case where the initial donation was given here.  The retrospective retest that found the donation to be reactive was on the 14th and the implicated unit was actually transfused on the 5th of August.  After the investigation which was triggered from this, the patient was subsequently determined to have developed meningeal encephalitis that hadn't bee diagnosed as West Nile related.

     Next slide.  That case made everyone, obviously, very concerned.  That was sort of the first confirmed transmission and that is what led us to raise the issue and then convert to ID prospective.  I just want to show this, which is similar to what I showed last time but a little more simple, just basically taking the relative number of units during this stage of the early epidemic that were detected by minipool NAT and the average length of time that that window is thought to last, and then looking at the units that were detected as ID-NAT positive, minipool negative without antibody that we think are probably infectious--several cases now have been proven to be infectious--as well as the units that were found that did have antibody that we suspect are probably neutralized.

     Using these ratios, you can estimate at this stage of the early epidemic the relative lengths of these periods and the proportion of units that may be being missed, and this is kind of the 10 percent potential breakthrough of infectious units, and maybe as many as 25 percent if you include these units that have antibody.

     Next slide.  So, we then converted to prospective ID-NAT in the Dakota area.  These are the results of units when we went to prospective ID-NAT.  A small number of these were also derived from end-of-run testing.  What you can see here is that of samples that were screened prospectively by ID-NAT, 4 of them were repeated and all 4 of those were confirmed; 47 initial reactives didn't repeat and the majority of those were negative but, again, we are finding a rate of low viremics that are real.

     Next slide.  This is the same plot, and I will show them side by side in a minute, with respect to our prospective screening.  The profile has shifted dramatically.  So, during this period, based on dilution to 16, only 3 of the 15 samples that were found to be yield cases diluted out and remained positive at 1:16.  There were none in this front end that were antibody negative; 3 were IgM positive and a much larger number, 9, were IgM and IgG positive.  We started the prospective testing on September 3rd.  The last positive true viremic was found on the 17th.  Then we had another 10 days of testing with zero yield before we then turned back to minipool testing in those regions.

     Next slide.  So, side by side just to contrast, and I think this is quite important, when we did the retrospective testing, which was testing back to the very first detection of minipool positivity, then we found these front-end viremic units with no antibody as well as an equal number that had IgM and only and a small number that had IgM and IgG.  By the time we turned on prospective ID-NAT the profile had completely shifted and we only had a couple of minipool yield cases, and all of these low viremics had antibody.  In fact, of the 12 that we picked up as low viremics, 11 of them were reactive on only one of the reps.  So, when we repeated it we couldn't even repeat the reactivity and, yet, they were truly infected.

     So, this is just evidence that there are a lot of low level viremic donations in the later stages of the epidemic in a region because in the presence of antibody the viremia is suppressed to such low levels that it is erratically detected even by individual donation NAT.

     Next slide.  I just wanted to mention that there was earlier evidence--and this was alluded to by Jim and I think I presented this last time--of this low level viremia in the setting of antibody so in a study that we had done, a related study where we tested about 1,500 units under code by both Roche and Gen-Probe, as well as serology, as Jim mentioned, there was 1 viremic donation but we had 7 samples that were IgM, IgG reactive and 1 that was IgM only.  Those samples that were negative by single testing by both TMA and PCR were tested in replicates of 10 at Gen-Probe and we found 2 additional viremic samples that had been missed.  So, relative to the 1 pickup, there were 2 that had viremia that was missed by ID-NAT but could be detected if we did reps in 2 of 10 and 7 of 10 cases.  Both of those samples, importantly, had neutralization.  It was work that showed that they had high level neutralizing activity.

     This slide just further shows that.  This looks complicated but basically what I want to point out is that both of these low viremic units, and in fact all of the units that had IgG as well as IgM, had high level West Nile specific neutralizing activity.  So this, in the absence of any demonstrated transmissions to date of units that have IgM, IgG in particular, makes me believe that those low viremic donations that have that antibody are likely uninfectious; they are probably neutralized viremia.

     Next slide.  This is from Kendra Ford and Ron Giltrid, OBI.  From our work I would have suggested that we could probably monitor minipool yield and as soon as you get some minipool yield, kind of as Sue alluded to and we did this past year.  If you turn on ID-NAT at that point you will probably catch most of these low viremic donations.

     The one center that has had extensive screening by ID-NAT exclusively is Oklahoma Blood Institute.  When they get reactives that prove to be real they can subject them to dilutions and see whether they would have been detected in the antibody profile.  This is basically 2-week intervals of their experience.  They did have a modest epidemic in Oklahoma.  What you are seeing here is that in the minipool yields they had approximately 1 case every 2 weeks within this time frame.  But in that first period they started right off the bat with 3 samples that were viremic and antibody negative and could not be detected on dilution to minipool.

     So, this sort of argues that the idea of tracking your minipool rates and turning on ID-NAT only after you see them in the minipool might not be very successful at interdicting particularly these early low viremic antibody negative units.

     Next slide.  Moving on, I am not going to go into detail on the structure of this panel but I talked about it before.  We developed a panel of 25 samples that represented very low viremic samples from these early stages that we have described.  It also included an analytic sensitivity panel using the Soldano standard that John will describe in a bit.  Basically we took the proposed 1,000 copy concentration and, using proven negative plasma, we diluted that down to 100, 30, 10, 3 and 1 copy/ml.  Each of the companies got 30 ml of each of the samples and we have ample volumes to allow validation downstream of test improvements.

     Next slide.  This was tested under code at Gen-Probe with 10 replicates.  Every company was asked to run 10 replicates.  The screening manufacturers ran the assay, both neat and at their dilutions.  Gen-Probe also ran an intermediate dilution to see whether that would enhance the detection of these low viremics, Roche 1:6, and then 4 different other confirmatory assays that are either widely used or now developed.

     Next slide.  This is the analytic sensitivity data.  Again, based on the Soldano standard and the hit rate on the 10 replicates of each of those different dilution levels you can derive curves which then allow you to calculate these 50 and 95 percent detection limits.  Basically, the neat assays, summarized here as A through G, had 50 percent detection limits, ranging from lows of about 1 to 3 to a high of 29.  By minipool analysis the 50 percent hit rates ranged from 13 to 300.

     Next slide.  What I am going to show is three slides and then a combination of the data from all three.  Basically, what I did was to group the data into the samples that had no antibody.  These are all very low viremic clinical donations that were identified mostly through Gen-Probe screening so there could be some selection bias as a result of that.  We had 6-7 samples that were antibody negative, low viremic.  The reason for the 6 versus 7 is we had gained access to the Nebraska transmitting donation at the last minute.  So, for the screening manufacturers we were able to substitute that very important infectious donation into the panel, whereas the confirmatory assays got an extra negative control.  Again, all of these are 10 reps.  These basically represent the percentage of 60-70 determinations that were reactive by these different assays that were either run neat or in the context of minipools.

     What you can see here is that most of the assays run neat picked up 80, 90 percent of these, with one outlier picking up 40 percent.  On pooled analysis you see that the pick up rates are lower.

     Next slide.  We are looking at the 4 units that had IgM.  Here the pick up rate was lower, around 60 percent.  Again, we are seeing consistent rank order performance of the tests, and the rank order performance of the assays based on these clinical samples is also consistent with the analytic sensitivity data.  Here we are only seeing 10-20 percent pick up or none of them picked up with the dilutions.

     Next slide.  Then we get to the samples that have both IgM and IgG so these are further along in seroconversion.  There is viremia present in these samples but it is at a much lower level.  So, we see the neat assays only pick up about 50 percent of the time, at best and, again, low percentage pick up by minipool.

     Next slide.  Just to make the same point, on the same axis you can see that these IgM negatives tend to have higher viral load and, therefore, 90 percent detection neat.  As the antibody kicks in the viral load distribution of these samples is lower and, therefore, the ability of these tests to pick them up is reduced.

     Next slide.  Just one important point, the question of whether an intermediate pool size would be useful.  We do have data looking now at the 1:16 versus going to a dilution of 1:4 relative to the neat detection of one manufacturer.  The point I want to make here is that in the antibody negative units, by going from 1:16 to 1:4 we pick up about half of the units that could be detected were we to go all the way to neat.  So, this is a very nice linear line, whereas in the samples that have antibody going to an intermediate dilution has a very limited increased pick up rate relative to what would be detected neat.  That, again, is probably because these samples that have antibody have much lower viral load distribution.  So, in terms of going to an intermediate pool size, it would buy us something but certainly not close to all the pickup and particularly will not be successful at picking up the seroreactive low viremic units.

     Next slide.  Just a couple of last points, specificity has been alluded to but in our system when you take the minipool NAT algorithm you gain very high specificity.  We had 9 per 100,000 false positives.  But that is partly because you are taking it through a pool and it would have to be false positive both in the pool and in the individual sample.  But if you test individually you get a much higher false-positive rate.  In our studies of ID-NAT it runs around 0.25 percent.  Similarly, if we look at our end result pool rate it is the same, around 0.2 percent.  This might not seem like that high a problematic rate but, because of the low viremia, we have to throw away blood that is initial reactive and defer the donor.  As we saw, a fair number of these low viremic donations are initial reactive, non-repeatable and, yet, they are real.  So, we have to operate as if initial reactivity is real.

     The next slide just shows that if we take those false-positive rates that we have observed with the Gen-Probe system, either minipool or individual donation, and we apply that to 13 million units per year, converting from minipool to ID-NAT annually all year round would lead to over 30,000 or about 30,000 discarded donations and at least temporarily deferred donors.

     Next slide.  In terms of critical issues, clearly further understanding of the infectivity of these stages is very important, both in terms of animal studies that you will hear about as well as the opportunity to do additional retrospective look-back investigations.

     We need to better understand the durations of these viremia stages in different periods of the epidemic, because these various modeled estimates are critically determined by when in the epidemic you look for the relative frequencies of these units.  But I think the other approach to get these estimates, as Sue described, is that by following these donors we will be able to better define the duration of low viremia in the setting of IgM or IgG and neutralizing activity.

     The question of a smaller pool size is still open although the data, I think, doesn't suggest that we will gain a lot of incremental pickup by going to intermediate pools.  More work needs to be done.

     Improved sensitivity and specificity and, finally, evaluate factors which might predict the severity of the epidemic so we could convert potentially to ID-NAT in these focal regions.

     The next and final slide is just mentioning a working group that has formed with CDC and Brian Custer, and we are really looking very critically--I don't have time to go into this--but at all of the different screening options and, based on empiric data, the probability of infections and looking at options in terms of time period of testing, focal testing, various strategies and using a formal sort of cost effectiveness modeling strategy to try to gain some sort of objective evidence as to which of these strategies might be appropriate for next year.  Thank you.

     DR. NELSON:  Thanks, Mike, for some impressive data.  Sue?

Prospective and Retrospective Testing Using ID-NAT

     DR. STRAMER:  I apologize, I have a lot of slides so I will go through this as quickly and as painlessly as possible.

     Next, please.  What I hope to cover is a review of what we did for the 2002 year, including investigation of the CDC cases and then preclinical prevalence studies that we did firstly with CDC and then with Gen-Probe, and our 2003 clinical experience in two epidemic regions.

     Next, please.  This just gives you the 2002 epidemic curve again but this is the subset of samples from which we investigated for the first panel that I am going to show.

     Next, please.  As published by Pealer, there were 23 confirmed cases.  What I am going to focus on are the 16 implicated donors that were all viremic and all IgM negative, and the investigations to identify those 16 donors.

     Next, please.  What we did in 61 cases that were investigated from which those confirmed positive 16 donors came, the Red Cross investigated 32 of those.  So, we obtained plasma co-components from the same donation where there was a West Nile Virus positive recipient.  As Jim Gallarda mentioned, we had a panel of 383 frozen plasma.  CDC had done extensive evaluations of not only the plasma but red cell segments and follow-up from implicated donors to prove transfusion transmission.  Of the 16 donors involved, there were 11 plasma co-components that were fished out, if you will, from these 32 case investigations.  The 383 plasma were tested by the CDC TaqMan assay followed up by CDC IgM ELISA.  Initially we did a standard test but any one that showed IgM positivity on follow-up was exposed to a more sensitive test for virus at CDC.

     Next.  Just to go through this slide quickly, CDC detected all 11.  Of those 11, 8 have follow-up available and all seroconverted upon follow-up.

     Next.  When Gen-Probe tested those 383 samples, there were 15 IRs but 3 were IR only; 12 repeated and all 12 of those did turn out to be true positives.  In this case, 9 of the 12 from follow-up samples that were available did demonstrate seroconversion.  So, all 383 samples were tested by all available West Nile Virus NAT and IgM assays.

     Next.  This just shows the CDC data.  Here you see PFU/ml and the two highest PFU/ml were the 2 cases where the donor symptoms occurred at or just 1 day following donation.  So, high viral load correlates to time of symptoms, at least in this study.  Those were also positive in red cell segments but here red cell segments were much less efficient in detecting virus than the frozen plasma.  This represents either duplicate or triplicate testing neat, 1:8 or 1:16 by the Gen-Probe assay and all 11 of the transfusion-transmitted cases were detected by all dilutions on this assay.

     We had one other sample here that was detected by Gen-Probe that had IgM equivalence or elevated IgM but wasn't quite positive at index that did show seroconversion in the donor.  This was a particular donor who was a call-back donor, who was part of the investigation but whose products weren't associated with transfusion transmission, but the donor himself had diagnosed West Nile Virus.  That is why it is in a different color, but it is an interesting sample because it is a more challenging sample.

     Next, please.  These are the S/COs by the Gen-Probe assay showing robustness in all the different dilution factors except for this sample which was somewhat troubling but did have low level IgM.

     Next, please.  This slide summarizes the results of all assays.  NGI's test detected a 13th sample.  This sample is also in yellow because it was not involved in transfusion transmission.  It was from a pheresis donor whose prior donation, not this one, was involved in transfusion transmission.  NGI reliably detected it by their qualitative assay, not by quantitation, but it was negative by all other assays.

     Gen-Probe's data are here.  These are the Roche data and Roche picked up almost everything that Gen-Probe did with the exception of one sample here that was the lowest viral load sample involved in transfusion transmission, 480 copies/ml at NGI.  Jim also mentioned that it had low level IgM detected by the Abbott assay but not by the CDC assay.

     Next, please.  These are the results of all the IgM testing we did.  This was the transfusion-transmission case that showed no IgM at CDC but reactivity at Abbott and then reactivity at Focus.  These are the other IgM positives that were both viremic and IgM at the same time.  Then, there were 3 other IgM positives detected in the study that were positive at CDC and Abbott but negative by the Focus assay.  So, there was some variability observed.

     Next, please.  To summarize that study, we found 13 positive samples and all NAT assays performed comparably on those 13 positives.  Two samples were consistently not detected in dilutions but they were IgM equivalent or positive and neither was involved in 2002 transfusion transmission cases.  All 11 samples involved in the 2002 cases were detected at their operational dilutions with the exception of one sample using one manufacturer's test.  Here I list the number of positives detected by each manufacturer, a high of 12 to a low of 11, so they are all relatively comparable, and only one difference in the operational dilution of the two tests in use.

     Next, please.  In IgM assays we saw more variability in the positives.  Abbott nailed all 6, with variable results from the other manufacturers.

     Next, please.  Talking about the repository studies we have done, at the end of 2002 from the time period of the beginning of September through the middle of October we collected 89,000 samples from 6 West Nile Virus high risk regions identified by CDC.  Samples were saved for West Nile Virus study with IRB approval and waiver of consent, and we saved the samples with basic demographic info.

     Next.  These are the regions that we selected, again, based on projections from Lyle Petersen.  We also added our Mississippi-Alabama region just as a control and, because we collected these samples late in the year, we wanted to see a southern region that had the epidemic earlier in the year and how they would perform in the same study.

     Next, please.  From the CDC portion of the study, what we did was we picked the highest epidemic regions and those were Cleveland and Detroit, and we only did the first 3 weeks of samples which totaled 7,915.  As part of the protocol, we took any sample that was positive by TaqMan, equivocal or had what I call an elevated negative, and I will explain what those are, and they were further tested by Gen-Probe's assay in 1:2, 1:16 dilutions and were tested by Abbott's IgM assay.  We did dilutions here before we went to neat testing just to conserve sample volume so if something was negative in dilutions we could go back and test it neat.  The CDC criteria for positivity was less than or equal to 37 cycles using two primer pairs and duplicate testing qualified a sample as positive.  Anything less than that but having some positive reactivity was deemed equivocal, and if a positive occurred over a longer cycle time, I called that an elevated negative.

     Next, please.  We had 173 classified as positive, equivalent or elevated negative by the CDC test for which Gen-Probe testing and IgM testing was done.  Four samples were reactive at CDC of these 173.  All 4 of those were reactive at dilutions by Gen-Probe and all were IgM negative.  So, these were the high titer type samples we detect by minipool testing.  There were 4 additional reactives by Gen-Probe and 2 were detected at both dilutions, 2 at only the 1:2 dilution and 3 of them were IgM positive.  So, out of these 4 additional reactives we had 1 that really fit this top category that would be detected by minipool NAT and was IgM negative.  The point estimate on prevalence for the study was 1 per 1,000.  An important point here is that 6 of the 8 of the RNA positives were detected by pool testing, or 75 percent.  Two were not.

     Next, please.  This is a summary of those data.  Here are the 2 that were not detected by pool testing, or 25 percent out of the small N.  But for those that were detected by pools here are the signal to cut-off ratios at 1:2 and 1:16--so, pretty high signals in duplicate testing; CDC cycle numbers to positivity; all IgM negative; and these are the viral loads and as we go to decreased viral loads, the lowest viral loads here are those that were IgM positive and that were not detected in pools.

     Next, please.  Again, the point estimate was one for the study and the differences between the two regions.

     Next, please.  Those samples, except for the 173 that were already tested by Gen-Probe were returned to the main repository and then we did the larger study with Gen-Probe looking at all of the regions over a longer period of time to determine the efficacy of pooling, that is, 1:16 dilutions, and determine viral loads.  It was part of the Gen-Probe IND to validate their assay.  I will show data for IgM seroconversion and donors in this study and for recipient tracing which is ongoing.

     Next, please.  We did the testing in 2 NTLs; trained 16 staff; developed documents; used investigational software, etc.--the usual validation stuff.

     Next slide, please.  Our confirmatory testing--all initial reactives for ease in the protocol were batched and then tested at the end by an IgM and IgG assay, a research assay from Abbott.  We did dilutions, again starting with dilutions because we can always go back to the neat sample if the dilutions are noon-reactive.  If one dilution was reactive but not the other dilution, we could do intermediate dilutions.  All samples went to NGI for quant.

     Next.  Out of the grand total when we put 173 samples back into the pool, we tested by the Gen-Probe assay 48,620 samples individually.  We had 90 initial reactives; 46 confirmed positive or only 47 percent.  This was before we knew about centrifugation and I was going nuts trying to figure out what in the world was going on but, anyway, now it is a beautiful world.  Of these 40, 6 confirmed positive.

     They split into 4 categories and I am going to refer to these 4 categories a lot so we will go through them, and 16 were high titer, 16 out of 46 and that is only 35 percent which were detected pooled, antibody negative, and they had titers of 210-42,000 copies/ml.  Then we had 10 samples that could be detected at 1:2 dilution, variably at 1:8 dilution.  If we are talking about reducing pool size, according to this study the only pool size that looks efficacious is 1:2.  They were IgM positive with low to mid-level signal to noise ratios and IgG plus/minus with lower copy numbers, less than 100-500 copies/ml.  Then we had 13 low titer samples that couldn't be quantitated and were detected neat only, but they were reproducibly detected neat.  They had high levels of antibody, IgM and IgG.  Then we had 7 very low titer samples, like Mike just talked about, IR only but they were IgM with very high titers and IgG positives, and I mentioned the 50 false positives.

     Next, please.  This is the slide I showed previously showing the 16--in my previous talk stratifying the 10 that were detected in pools of 16--the 16 that were detected in pools of 16--I am talking too fast--the 10 that were detected at lower pool sizes and had increasing amounts of antibody and then 13 that were detected neat only and 7 that were IR only and increasing amounts of IgM, as indicated in red plus/minus signs.  Then, this is the relative duration based on the number of positives we got, again, assuming a 1-2 day ramp up time; 6.5 days from the literature of the '50s that peak viral loads will be detected by minipool, corresponding to the earlier literature gives us a total viremic time of 7.5 to 8.5 days, and then an additional 12 days where RNA coexists with IgM.

     Next.  Of these 16 positives we had in pools of 16, these are the 4 samples that gave us some trouble and that I was most concerned about and gave us the 4:1 ratio that I referenced as far as our trigger for West Nile individual unit testing.  These were detected neat, in pools of 2, variable by increasing dilutions so not reliably in pools of 16.  They had either very low level IgM, and 5 is the cut-off by S to N.  So, low level IgM, either low level IgG, and this is an S/CO of 2, or no IgG and still a quantifiable virus, so low antibody but enough virus to cause concern.

     Next, please.  If you put all the data together by time, this gives us the prevalence over the weeks of the study.  Like the CDC study, we had a summary of about 1 per 1,000.  This is just the various categories and I won't bore you with details.

     Next, please.  This shows across regions, with the highest region being Chicago at 1.7 per 1,000, Detroit at 1.36, and then Cleveland at 1.17.

     Next, please.  Now if you put the data that we got for the two prevalence studies together with the data that was published by Petersen and Biggerstaff, basically all the data fall in nicely.  We are a little higher for Chicago, a little bit lower for Cleveland.  Most of them fell within the 95 percent confidence intervals of the predicted so we observed what was predicted.

     Next, please.  This is a little bit easier to see for data over time for the three regions that we had the most data for.  In the first week in September we had the most positives.  Then it decreased over time by region, plateau-ing out over the last three weeks of September.

     Next, please.  This is the distribution or the demographics of the samples evaluated in the study.  This is the total population, the distribution of males to females, confirmed positives.  We had, but no different than the total population, more males than females but, similarly, this is the same shift I showed previously that in false positives we had a few more females than males, which was opposite to our confirmed positives.  And there is the number of zip codes that were represented.

     Next, please.  From the look-back studies we have 46 confirmed positive donations made into 115 components, 71 for transfusion, but 9 recipients so far that we have received hospital information for.  Just quickly, 9 no symptoms were reported.  These are the product components.  We have follow-up pending for 4 living recipients; 4 recipients have died.  These 8 samples fall into the categories of either being a pool of 16 reactive, pool of 2 or 8 reactive and then neat or pool of 2 reactive, so none of them are in the lowest categories that we talked about.

     The most interesting finding of the recipient look-back so far is that we have one symptomatic recipient who reported symptoms three days post transfusion.  The recipient received a red cell unit.  The symptoms were fever, headache, chills, vomiting, diarrhea.  Of course, this doesn't indicate West Nile.  It could be anything, including a bacterial contaminated unit as Roger pointed out to me last night.  Follow-up is pending for this recipient to see if we can find IgM or IgG.  Interestingly enough, this was from one of the highest titers, 6,300 copies/ml--one of the highest titer units of the study.

     Next, please.  For donor follow-up of the 46 confirmed positive donors, we have follow-up for 11 donors.  Of the 11 donors with follow-up at about 400 days or longer, 8 or 73 percent remained IgM positive or equivalent.  As far as symptoms, 2 of the 11 recalled symptoms.  I also should mention that all of them were IgG positive.

     Next, please.  In summary, we saw regional agreement between the observed and predicted prevalence.  However, 2002 and 2003 for those regions did not agree.  We didn't have high prevalence this year for those same regions.  And, 35 percent of RNA positive samples were detected in a pool of 16, only 35 percent versus 75 percent of the CDC subset of samples where the CDC's sensitivity was less.  So, we pulled more of those samples out.  Of 5 recipients investigated, there is 1 possible transfusion transmission although we really don't have any strong data as of yet.  Another 4 recipients had no symptoms.  Ten additional samples of the 46 were detected at lower dilutions; another 20 were detected neat or at a lower dilution.  The infectivity of these samples just like these samples although these samples, we know, would be infectious--these remain as unknown and so far in 4 of 4 recipients investigated we haven't seen any symptoms.  IgM persisted in recalled donors, 8 out of 11 or 73 percent at greater than or equal to 400 days, which is very consistent with the CDC published data at 300-400 days of 62 percent of individual retaining IgM.

     Next.  I want to quickly go through our 2003 IDT experience at the Red Cross.  I have talked about this information before.

     Next.  When we turned on IDT--this is the cumulative number of cases we saw in Nebraska in the middle of September while we were doing IDT, but the early cases here represent minipool yield.

     Next.  This is when we turned off testing when it reached greater than 1 to 1,000 and the epidemic plateau'd.

     Next.  The same data for Kansas while we were doing minipool testing and the turn on to IDT at the end.

     Next.  This is when we turned off testing.  We saw a plateau at an approximate prevalence of 1 to 1,000 cumulatively.

     Next.  This is the total picture of those two regions, Nebraska and Kansas.  Nebraska is in lavender and Kansas is in eggplant.  You can see the epidemic curves for those two regions, minipool and IDT, again, half of the positives coming from minipool, about half from IDT.

     Next, please.  This is the last group of data that I will show.  The number of IDT samples that we tested in Kansas and Nebraska total 30,501.  Of those, 349 or just over 1 percent were reactive.  We took the pools that were constructed at the same time as the IDT testing occurred but those pools went to HIV-HCV.  We took those pools that would ordinarily be tested for West Nile and then we tested them in duplicate or I should say Gen-Probe kindly tested them in duplicate.  Then we divided them by how many at their operational pool would have been detected in duplicate testing in pools; how many were discordant representing NAT consistent detection; or how many were pool non-reactive.  If you then divide these 97 that were detected consistently in pools and these samples that were not consistently detected in pools into those that confirm by PCR and those that don't confirm by PCR, we see a total of 44 samples here, the vast majority being IgM positive or equivalent.  These 44 samples were of greatest concern because they were PCR confirmed so we know that there is virus but they would not have been detected in a pool.  That is 12 percent of the total.

     Next, please.  These are the line listings for the 16 that were discordant in pools.  Red is positive; black is negative.  As viral loads increase, you see here that some of the samples show no IgM.  So, from these 16 we have 4 samples that had no IgM.  The rest of the samples did have IgM.  So, one could hypothesize that these 4 samples probably came from the early part of the virus curve.

     Next, please.  These are the remaining 28 samples that were pooled negative.  Here you can see the pool S/CO results relative to the IDT S/CO.  They are all qual reactive but quant negative.  Here we have one sample only that was IgM negative.

     Next, please.  In this slide we have a second sample that was IgM negative, all the rest being IgM reactive.

     Next, please.  In conclusion from this study, and this is my last slide, we saw a 1.14 percent reactive rate for our IDT testing; 37 percent confirmed positive by PCR for a frequency of 1 in 238.  Of the 128 confirmed positives, 44 were inconsistently detected at a pool of 16; 16 were detected once or 2 times tested.  Again, 75 percent of those were IgM positive or equivalent; 28 were detected not out of 2 times tested, and 93 percent of those were IgM positive or equivalent.  So, these are the lower viral load samples.

     The combination of these samples plus those in the same categories that were PCR negative are now being tested in reps of 10 individually at Gen-Probe to see if we missed any positives or what additional findings we can get.

     The IgM negative samples one would consider of greatest transfusion transmitted risk.  We saw 4 of those in the category that was only detected once by pool testing and 2 that were not detected by pool testing.

     So, one could say the yield of RNA low titer, IgM negative, potentially infected units detected by IDT were 2-6 per 30,501 tested for a prevalence of 1 to 5,000 to 1 in 15,000 versus the control of 84 for the same population or 1 in 363 that were detected by pools of 16.  So, in this study if we are considering only these samples, the lower titer IgM negatives being potentially infectious, our yield over minipool was only 2-7 percent.  Thank you.

     DR. NELSON:  Thank you.  John Saldanha, from Canadian Blood Services?

Follow-up Testing of Canadian Donors who Tested

Positive for WNV RNA by Routine

Screening/Establishment of a Reference Reagent for

 WNV NAT Assays

     DR. SALDANHA:  I am going to talk about two topics.  One is the follow-up study of the Canadian blood donors.  I think you will be relieved to know we only have 14 so this should be fairly fast.

     [Laughter]

     Next slide, please.  We started using the Roche Taq screen for testing donor samples in Canada, both at Canadian Blood Services and Hema Quebec.  Sample testing at Canadian Blood Services started in Toronto on the June 23 and in Calgary on July 2.

     Next slide, please.  So far, and this should be updated, we have tested over 300,000 donations but this number hasn't changed.  We still only picked up 14 positive donors, and 11 samples were tested in the Roche pools of 6 and 1 was tested individually.  This was done not deliberately but because at the end of the run there weren't enough samples to make up a pool.  As Sue and others have sort of talked about, we started single donor testing in the high prevalence area, which was Saskatchewan and we managed to pick up 2 additional samples in this area.

     Next slide, please.  This slide just shows you the titers of the samples that we picked up.  What I should say is that when a sample was positive the donation was sent to the head office in Ottawa and was tested by an in-house West Nile quantitative assay.  The quantitative assay only picked up West Nile Virus so all these samples were West Nile Virus rather than one of the other flavis that the Roche assay picks up.  They were quantitated.  The last 2 donations were at the threshold of detection, which is why they don't have a titer.  In fact, the Roche assay did very well because they were both picked up on single donor testing but in our hands, using the in-house assay, we got them positive only in 1 out of about 40 assays.

     Next slide, please.  This is a temporal graph of the epidemic, if you can call it that in Canada.  Most of it was centered around August.  The peak of the viremia, which was really very low, was 4 samples.  After the first of September we didn't pick up any more positives.

     Can I have the next one, please?  This table is a bit complicated.  This is a table of all the follow-up of the 14 donors that we had.  We had 10 donors from Saskatchewan.  The green ones were from Alberta and the single purple one is from Manitoba.  We managed to get follow-up samples on these dates and they were all tested using the in-house assay and were quantitated.  They were also looked at by the Artis assay in one of the provincial laboratories, and these are the titers again.  The other provincial laboratory used an in-house assay as well.  We looked at the IgM and the IgG using the PanBio assay, and the IgM was also looked at in the provincial laboratory.  One of the provincial laboratories also did hemagglutination inhibition.  We had follow-up samples for all the donors apart for the one from Alberta and all of them seroconverted so these were confirmed positives, the 13.

     We also did some retrospective sort of questioning about the symptoms and some of them had fever or chills sort of 4 days after donation, for example.  Interestingly, one of the donors, number 16, had chills and fever 2 days prior to donating.  This donor, with a very low titer picked up by single donation, had chill and fever for 2 weeks about 5 weeks prior to donating a sample.

     The other thing that is interesting is that in a couple of samples, number 13 for example, the titer went up substantially on the subsequent bleed, and I think we have seen this before.  There was one donor that had a very high level of RNA and was also IgM positive and I can't explain that.

     Can we have the next slide?  The next three slides are just graphical illustrations of some of these data.  We have a donor that is positive on day 1 with IgG equivocal and the IgM negative.  After 15 days both IgM and IgG are positive.  This does not mean that they seroconverted after 2 weeks.  It only means that the first follow-up sample we got was after 15 days.

     The next one, please.  We also had a donor where the titer dropped after 4 days and the IgG and the IgM were positive.

     Next slide, please.  And, one where the titer actually went up 2 days later and both the IgG and the IgM are positive.

     Can we have the next slide?  To summarize that data looking at the seroconversion, 13 out of the 14 donors were positive for West Nile Virus.  One of the donors had much higher RNA levels post donation.  The majority of the donors lost the RNA and seroconverted, and there were 2 donors, which Jim Gallarda also referred to, donors 18 and 19, which had very low levels of RNA but were both IgM and IgG positive.  They had very high levels of IgG and IgM and, as Mike said, it is debatable whether these would transmit.  One donor, as I said, number 17, had a high RNA level but was also IgM positive.  We repeated this and this was a high IgM.

     On the next slide I briefly want to acknowledge the three medical directors in Saskatchewan, Alberta and Manitoba who were very quick off the mark to make the follow-up samples, because it is very difficult to try and get the donors back and give samples, and also the two provincial labs in Saskatchewan and Alberta who did all the IgG and IgM testing.

     Now I will switch to the second part of my talk if I can have the next slide, please.  I know it is very late to talk about standardization and I will try and make this as painless as possible, but I think it was very clear from Jim Gallarda's talk and from some of the questions we had from the committee that it is very difficult to try, at the lower level, to get some figure on copies/ml or whatever in a unit.  One of the exercises we did with the Health Canada lab, the national microbiology lab in Winnipeg, was to try and establish a reference material which could be used as the yardstick against which all the assays could be pinned.  I will describe the study we did very briefly.

     May I have the next slide, please?  In this study we used the New York '99 West Nile Virus strain which was isolated from a crow.  It was grown up in Vero cells and heat inactivated for 2 hours at 60 degrees.  It was titrated for infectivity using a plaque assay and the titer was about 107 PFU/ml.  After heat inactivation we didn't have any infectivity and the RNA titer using an endpoint dilution method was approximately 2 times 109 copies/ml.  This fits in with the figure for copies to PFU which has been suggested by the CDC.

     Can I have the next slide, please?  The stock virus was diluted in pooled human plasma which was negative for the usual markers, and it was diluted to approximately what we thought was about 1,000 copies/ml.  Health Canada filled up about 6,000 vials of this material and gave it a code number.

     Can I have the next slide?  I won't go through this in detail but, following the usual pattern of collaborative studies, we sent out vials to the participants and asked them to do an endpoint dilution and then calculated the endpoints using a method of maximum likelihood.  The estimates were done in NAT detectable units/ml but we will go into that later.  Samples were sent to 18 laboratories and we got results back from 13.  The methods included in-house assays and both the commercial assays that are available at the moment.  We had 3 quantitative assays and the remainder were qualitative.

     Can I have the next slide, please?  This is really a list of participants.  I have put this up to show you that we had both of the kit manufacturers in here.  We had the CDC plus NGI and also the national testing laboratory in Canada, Health Canada plus provincial laboratories and one of the reference laboratories in McMaster University.  We also had some of the plasma manufacturers like Aventis, Bayer and Baxter in here as well.

     May I have the next slide, please?  This is a histogram of the results.  These are the calculated endpoints of all the laboratories we showed you, calculated in what I call detectable units/ml, and I will explain this.  There were about 100 to 1,000 detectable units, or whatever, per ml.  There were 2 outliers.  The green boxes are the quantitative assays and the yellow ones are the qualitative.

     What I find astonishing about this study was how close the results are.  I think this is really a reflection on how well these assays were set up in a very short period because I have looked at assays over the years in similar studies for hepatitis B and hepatitis C and HIV and normally the spread with different laboratories is over about 2, 2.5 logs.  Ignoring the outliers, the spread is only over 1 log, which I think is very, very good for the assays that were set up.

     May I have the next slide, please?  This shows you the mean titer with the minimum and maximum standard deviation, and the standard deviation in fact is very good for this sort of assay.  If we exclude the 2 outliers the mean titer is 2.5 logs, which is about 320 detectable units/ml and the standard deviation is pretty good for this sort of assay.  As I think Jim said earlier on, with a NAT assay at the lower end you don't expect to get reproducibility better than 0.5 to 0.8 of a log.  I think you are lucky if you get that.  So, I think these results from this assay really are very good.

     Can we have the next slide, please?  The other question that I was asked was how can we be sure that with heat inactivated material the material was homogeneous?  I must admit I was slightly worried to start with because in my previous experience with making standards all the standards we made were live.  They were made with virus that wasn't inactivated.  So, we were very fortunate because 2 of the laboratories, number 2 and number 4, did replicates on each of the vials that we sent them.  Laboratory 2 did 10 replicates on each of the vials and laboratory 4 did 6 replicates of the vials.

     We worked out the detectable units/ml and the 95 percent confidence interval, and my statistician tells me that really there is no significant difference between the different vials.  So, we were fairly confident that the material we filled up was homogeneous.

     Can we have the next slide, please?  In conclusion, I think what we have is a material which was picked up quite well by all the assays that used it.  We can assign it a unitage, and I think this is something that is debatable, we can either call it around 300 or 1,000.  People who know me know that I don't talk about copies; it is more detectable units but I think it is very late and I am not going to go into that argument.

     I think the variation estimate is very good.  There was no evidence of vial to vial variation, and I think this is a very good material to answer some of the questions that the committee were asking about how we standardize or arrive at a figure for the quantitation of these samples.  That is the end, thank you.

     DR. NELSON:  Thank you.  Yes?

     DR. STRONG:  I am sorry to have to ask a question but--

     [Laughter]

     --I wonder if you know whether the addition of IgM to your standard has any impact on sensitivity.

     DR. SALDANHA:  No, it shouldn't.  It shouldn't if the extraction has been set up properly, except if you are spinning.  In fact, the first international standard for hepatitis C virus was from a chronic carrier which was positive for antibodies as well and, as far as I know, it didn't make any difference.  I think Mai Ying had some preliminary data on HCV years ago where if it is antibody positive you do get a difference when you spin and extract.

     DR. STRONG:  That was really the genesis of my question because the spin rates in the presence of immune complexes could change the sensitivity.

     DR. SALDANHA:  That is right, yes.

     DR. ALLEN:  An epidemiological question, not a laboratory one.  I know the majority of Canada's population which is within 100 miles of the U.S. border are cases analogous to where they were found geographically in the United States in 2003.

     DR. SALDANHA:  Yes.  My Canadian geography is not very good, I have only been there a year, but I think Saskatchewan is almost directly north of the Midwest where a majority of the cases were this year in the U.S.

     DR. NELSON:  Thanks.  Indira Hewlett is going to talk about infectivity.

Update on Infectivity Study

     DR. HEWLETT:  Well, I guess it is an honor to be the last speaker today.  I am going to be relatively brief in my presentation.  I am going to be talking about some studies that are being planned to address the infectivity of West Nile Virus in blood.

     Next slide.  Just to give you a brief background, all reported cases of West Nile Virus transmission by blood transfusion have been known to occur during the acute viremic phase so NAT was considered to be the most appropriate strategy to interdict infectious donations.  NAT on pooled samples that use existing licensed platforms was implemented under IND to expedite screening and interdict the majority of infectious donations.

     Next slide.  Although the sample pool sizes are small--they are pools of 6 and 16--the impact of sample pooling on the sensitivity of West Nile NAT and the residual risk needs to be evaluated.  We also know that viremia and IgM can coexist in the late acute phase, and also there is a lack of data on West Nile Virus transmission by acute late phase donations that are either NAT negative or positive and IgM positive.

     Next slide.  This slide has been shown a couple of times today so I won't spend a lot of time on it but just point out that 5 stages of infection have been identified on the basis of results found on minipool and ID-NAT and IgM and IgG assays.  This slide was actually put together by Mike Busch and very clearly illustrates that there can be at least 5 stages of infection in the early phase of West Nile disease.

     Next slide, please.  We know that minipool NAT detects the majority of viremic donations.  You have heard a lot about that today.  And, the ability of minipool NAT to detect low level viremic units was evaluated by performing retrospective ID-NAT on samples collected last year.  You heard about that from Sue Stramer, but the bottom line is that the studies identified minipool NAT negative, ID-NAT positive donations and, in one case, one of these donations transmitted West Nile Virus infection to a recipient.

     Next slide, please.  In 2003, retrospective studies using ID-NAT were performed on more than 11,000 minipool NAT negative units.  In this study 16 minipool NAT negative, ID-NAT positive cases were identified.  Look-back identified 2 independent transmissions to 2 recipients.  Actually, it was one case that was identified by look-back and the other case, as was mentioned earlier, was from a public health laboratory setting.  Other ID-NAT studies identified additional low level viremic minipool NAT negative, ID-NAT positive donations.

     Next slide, please.  What we have learned is that these donations do exist and they are a cause of concern, and they also raise some questions.  Some of the questions are listed on the slide.

     The first one is are minipool NAT negative, ID-NAT positive units that contain antibodies capable of transmitting West Nile Virus by blood transfusion?

     A second and related question is what is the minimum infectious dose for transfusion of West Nile Virus by blood?

     Third, is there a non-infectious stage in the course of West Nile Virus infection, that is, low level viremic period that is not detected by ID-NAT assays, or sporadically detected by ID-NAT assays?

     Next slide, please.  To address this question, a working group has been formed consisting of people from the PHS and the AABB to address infectivity using animal models.  What we are planning to do is to use plasma units identified during IND studies and characterize in regard to reactivity in current NAT assays.  To do animal studies small animal models, for example the mice and hamsters, have been described in the literature but the drawback with these models is the volume of plasma that can be administered since they are very small volumes and these volumes may not reflect the infectious dose compared to volumes administered during transfusion.

     Next slide, please.  So, we are now looking at non-human primates.  Those that have been considered are the baboon, the rhesus macaque and the chimpanzee.  Baboons have been known to be susceptible to natural infection without clinical symptoms.  There are a couple of papers that have reported seropositivity in baboons.  It has been actually the highest of the animals that have been looked at.  So, the initial plan is to study the baboon model using naive animals.  The animals will be infected by IV injection of human plasma collected during the 2003 epidemic and identified to be at various proposed stages of infection.

     Next slide.  The units will be infused individually or combined and sequentially in order of increasing probability of infectiousness.  The samples will then be collected at various time points from these animals and analyzed by TaqMan or TPCR virus isolation and antibody assays.  The susceptibility of animals that do not become infected by these infusions will be shown by infection with a transmitting unit such as the case that was identified in Nebraska, which is minipool NAT negative, ID-NAT positive which transmitted West Nile to a recipient.

     Next slide.  In summary, the residual risk of minipool NAT for West Nile Virus needs to be evaluated to define future strategies for West Nile Virus screening.  Infectivity of donations that are minipool NAT negative and either sporadically or consistently positive by ID-NAT in the presence or absence of antibodies needs to be determined.  What I am reporting today is that such studies are being planned and expected to be under way in the near future.  Thank you.

     DR. NELSON:  Thanks.  Yes?

     DR. LAAL:  [Off microphone; inaudible]i--infect baboons?

     DR. HEWLETT:  We don't know.  Obviously, that is going to be one of the important questions.  We know that they have been found to be seropositive in areas where humans are positive for West Nile.  We also know that--

     DR. LAAL:  [Off microphone; inaudible].

     DR. HEWLETT:  No, that is one of the things that would be worth doing, to actually look for virus in those animals.  The current plan is to actually look at the susceptibility of the baboon to human isolates.  In fact, what we have been talking about in this group--I didn't put up the slide here but basically it is the people who are conducting the studies on ID-NAT, such as Mike Busch, Sue Stramer, Harvey Alter from the NIH and Chris Mortey from the San Antonio South Texas Foundation.  What we would like to do is to use the transmitting unit to infect the animal to see whether the animal does become infected with the human isolates.  So, that is a question we are going to have to address before we move forward.

     DR. NELSON:  What about using horses or colts which are known to be capable of being infected with the West Nile Virus naturally.  I don't know how much baboons cost.

     DR. HEWLETT:  Well, that is another issue, I am sure.  There are baboon colonies that we have access to and, you know, it is possible to move forward quickly with the baboon model.  The horse model was talked about.  We also talked about small models such as birds, and so on, but it is just very complicated working with them.  So, this is what we are going to start with.

     DR. DIMICHELE:  I just have a question, since the data that we have seen shows that these units are less infective when they have IgM present in them, my question is, is this human IgM protective of the baboon, and is that going to be a limitation of the model?

     DR. HEWLETT:  These are all good questions and I think, you know, the only way we will know is to actually do the study.  The primary goal is to look at whether such units transmit because we know that the IgM negative units transmit.  What we don't know is what is the minimum infectious dose; what is the lowest copy number that would be necessary for an infection to take place.  But the other big question is whether donations that contain antibodies would transmit.  To date, of course, in the human setting we have not seen transmission and I think several speakers made reference to that, but there may have been very little virus in those donations, whereas, if you were to see more virus would they transmit?  So, it may be a virus-dependent factor which we will need to look at.

     DR. RIOS:  Maria Rios, from FDA.  I just want to make the point that we don't know if the antibodies are protective or not because we don't have any data to support that.  All that we know is that there is a reduction in detection of virus but the protectiveness of antibodies is to be discussed and addressed.

     DR. HEWLETT:  Yes, I just wanted to mention that actually Maria has set up various assays on infectivity and TaqMan assays in the laboratory so, you know, combined with the ability to obtain these animals, and having the precious samples that have been generated through these IND studies, and having various assays available I think we will be able to move forward quickly.

     DR. NELSON:  Finally, on the agenda is the open public hearing.  Dr. Andrew Heaton, from Chiron, are you prepared?

Open Public Hearing

     DR. HEATON:  Well, speaking so late it certainly behooves one to be brief.  My intent in my few comments this evening is to comment on Chiron's and Gen-Probe's capacity to support pool testing in the face of very rapid and unexpected increases in incidence; to talk to the time lines to introduce the changes in the face of unanticipated increases in incidence; to review some expanded choices that Chiron will be able to make available to our customers over the next year; and then to comment on our capacity to support test and equipment requirements.

     Next slide, please.  All of you have seen slides very similar to this during the day.  This is a Bonfils increase in incidence.  I really only want to make one key point, and that is that you are seeing a classic exponential increase in the incidence from around 2 percent of the pools being positive at the beginning of the epidemic to about 12 percent being positive at the peak of the epidemic.  But, if you were running a center, the first that you would begin to get worried would be about week 3 and you would reach a peak at about week 6.  So, you would have about 3 weeks to make up your mind if you decided to make changes in your pool size based on the evidence in front of you.

     Next slide, please.  As a result, we modeled out some choices and some options.  We will provide software to allow blood centers to act based on the evidence in front of them.  The first model was to look at 16 pool testing and then for blood centers who are at risk to switch to reduced pool size testing for a 3-month period.  The second option was to continue with pool testing at 1:16 and then to switch blood centers to IDT for a 3-month period.  The third option was to consider switching all blood centers to pools of 1:8 with reduced pool size for at risk regions.  The last would be to look at individual testing for all centers.

     What we then did, we modeled out what the increase in monthly test consumption would be to look at our production capacity to be sure that we could meet the needs in the event the centers pursued this.

     These two options would result in approximately a 20 percent increase in test consumption.  This option would result in a 2 times increase in test consumption.  And, the complete conversion to IDT would result in approximately 8 times test consumption.  Our production capacity is so significant that we would easily be able to meet any of these anticipated increases depending on whether any of the centers elected to pursue these options.

     Next slide, please.  What we are planning on doing next year is making pooling software available that would be configurable for pools 1:4, 1:8 or 1:16 so the blood centers that use our system would be able to adjust that pool size as they see fit and as the evidence suggests to them that they should.  This will be Part 11 compliant.  We anticipate a CBER submission for March of this year.  We will also make available on that track 3.0 software which will allow data management of these reduced pool sizes and will also be Part 11 compliant.

     We have planned assay production of about 4 million tests for next year, and our manufacturing plant has the capacity to meet 10 times that amount in the event that there was a need for very rapid increase in test production.  We have the equipment available to meet any of those pool sizes in the event that blood centers elected to move to that.

     Next slide, please.  We are also working on developing an automated stand-alone walk-away system.  Our partner, Gen-Probe, has developed this system, known as the Tigris.  We have, as you have heard earlier, established the feasibility of West Nile Virus testing on the Tigris, though we have not yet concluded whether we would be able to make enough instruments and service and support capability available to meet the need by next mosquito season.  We have a project team working vigorously on that and we will be able to provide that information later on.  We have some upgrades for our existing equipment which should allow improved automation and better GMP control.

     Next slide.  In summary then, if blood centers wish to switch to pools of 4 or 8, we believe the conversion would require about a 6-month notice from the decision point to allow us to ramp up the production and have the software available and have it validated.  In the event that blood centers elected to switch to individual donor testing for approximately 2.4 million at risk units in the West Coast centers we, again, could have that available around 6 months from the time of identification.  Lastly, automated equipment upgrades--we have established feasibility for the Tigris to be able to perform the test, though we don't yet know whether we could have that available by next mosquito season but we certainly have the equipment that will be available to meet a limited conversion to reduce pool size.  Thank you.

     DR. NELSON:  Thank you.  Questions?  Celso?

     DR. BIANCO:  It will be a brief presentation of the ABC and HLBI REDS West Nile Virus study.

     Next slide, please.  The aims of this study is for ABC members to monitor West Nile screening for yield rates.  The main point that I am going to touch on today is to evaluate the false-positive rates and the positive predictive value of West Nile Virus screening NAT reactivity for different strategies, minipool NAT versus ID-NAT, which I think is something that we have to think about by January.

     Next slide.  This is a map just indicating where those centers that reported their results are located.  There are 76 member centers, representing more than 90 collection facilities.

     Next slide.  The data was collected twice a month from all the centers, including the number of donations screened by minipool or ID-NAT; the number of donations that screened reactive; and now we are completing the data collection in terms of supplemental testing and demographics.

     Next slide, please.  This shows very clearly the totality of the centers that reported on about 2.5 million donations screened with a peak that came up in mid-August for the entire country.

     Next slide.  In order to compare individual donor NAT with minipool NAT essentially we chose data from 4 centers that I am calling A, B, C and D but they are real centers.  Some are sitting in this room.  We chose a center that was performing individual donor NAT in an area of low West Nile Virus incidence; a center performing individual donor NAT in a high West Nile Virus incidence area; and then the same thing for the minipool NAT.

     Next slide.  The case definitions for confirmatory testing were those that are based on those as part of the IND studies and essentially required supplemental RNA data and IgM data.

     Next slide.  What is interesting is that when we look at false-positive test results, if we compare centers performing ID-NAT versus minipool NAT the percentage of false-positive results was about 83 percent in those performing ID-NAT versus the centers that were performing the minipool NAT, something that we would expect as we increase the number of tests in a low prevalence or, if we increase the sensitivity of the assay, we would increase the number of false positives.

     The next slide shows the individual data for a false-positive test results.  We have a gradual diminution of the false-positive results as we move from a lower incidence using ID-NAT with a false-positive rate of 92.9 percent to the higher minipool rate of false-positive number of 3.7 percent.

     Next one, please.  But if we look at the positive predictive value, again the minipool NAT will have a much higher positive predictive value than the ID-NAT center.

     Next slide.  This shows the 4 centers and, again, we see the curve from the lower ID-NAT center to the higher minipool center with an increase in the positive predictive value.

     The next slide shows a curve for a center that was using ID-NAT, and this is a center in an area with a higher incidence of positives.

     The next one is for center D that has a high incidence, using minipool NAT, and this is how the curves overlap.

     The next slide is our conclusion that ID-NAT has a poorer predictive value and a higher false-positive rate than minipool NAT and we should take this into consideration as we make our decisions for next year.

     The last slide shows acknowledgement of all the groups from NHLBI, ABC, Gen-Probe, Roche and REDS, and we want to thank the entire group for this mammoth effort to collect this data.  Thank you.

     DR. NELSON:  Thank you.  Steve Kleinman, can you summarize the meeting for us?

     DR. KLEINMAN:  I would just like to say I agree with everything that has been said.

     [Laughter]

     As far as the AABB statement, I think it is self-explanatory and if it could just be read into the record I don't think I need to deliver it now, if that is okay with the committee.

     DR. NELSON:  That is fine.  Are there any other closing comments?  Oh, somebody has a comment.

     DR. FORD:  I really tried to go all day long and not say anything but--sorry.  I am assuming we were one of those centers--

     DR. NELSON:  Can you give your name and where you are from?

     DR. FORD:  Kendra Ford, the Oklahoma Blood Institute.  We will be doing individual donor NAT testing.  I am assuming we were one of those blood centers, Dr. Bianco?  Yes?  Which one were we?  B?

     I do want to comment that when West Nile first came out we did have a significant issue with false positives, and we also dealt with modifying the spin times, and we also had a lot of true positives.  Our false-positive data doesn't look like that now so I don't know that it is a fair--you are automatically going to have more false positives with individual donor testing.  If you really think about it, if you are going to contaminate something within the testing process you contaminate either the pool or the individual donor unit and it makes more sense that you are going to have less contamination with the individual donor sample versus a pool.  So, I do want to make the comment that our testing data looks much different now as opposed to originally.

     DR. NELSON:  Well, I think the other important data was that the predictive value related to the prevalence and, you know, that is an epidemiologic principle that I am glad you have confirmed for us with that very expensive effort.

     So, 12 hours from now we will convene again.

     [Whereupon, at 8:00 p.m., the proceedings were recessed, to reconvene at 8:00 a.m., December 12, 2003.]

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