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 iden