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]{.underline}
>
> 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]{.underline} (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]{.underline} 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]{.underline} (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]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **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]{.underline}.
> 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]{.underline}
>
> 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]{.underline} 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]{.underline} 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]{.underline}. 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline}-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]{.underline}, 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]{.underline} 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]{.underline} 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]{.underline} [donovani]{.underline} infection, it is a
> control measure to treat them.
>
> Cutaneous leish. we treat to prevent morbidity. With [L.
> major]{.underline} 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]{.underline} [tropica]{.underline} 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]{.underline} 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]{.underline}, some by [L.
> tropica]{.underline} 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]{.underline}, but for Iraq cases, for all of
> which there is species data, all of them have been caused by [L.
> major]{.underline}, which is not to say that some haven\'t been caused
> by [L. tropica]{.underline} but to date [L. major]{.underline} 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]{.underline} which can cause visceral or cutaneous leish.
> Therefore, it potentially could be a cause either of cutaneous or
> visceral cases. [L. donovani]{.underline}, 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]{.underline} 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]{.underline}, if we have a zero here for the U.S., notice, for
> [T. cruzi]{.underline} we have 5, not counting the 2 in Canada, and we
> are quite confident that we are transfusing [T. cruzi]{.underline}
> 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]{.underline} and the fact that we have only 5
> reported [T. cruzi]{.underline} 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]{.underline}, 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]{.underline}
> and [L donovani]{.underline} 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]{.underline} 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]{.underline}
> 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]{.underline} 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]{.underline} and with [L.
> donovani]{.underline}. 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]{.underline} actually
> was somewhat more hardy than [L. tropica]{.underline} 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]{.underline}. 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]{.underline}.
>
> 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]{.underline}.
>
> 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]{.underline} 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]{.underline}, 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]{.underline}. 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]{.underline} 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]{.underline} 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]{.underline} endemic regions, the three organizations
> believe that [Leishmania]{.underline}-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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline}\--
>
> DR. NELSON: I am asking does the serologic test for Chagas cross-react
> with [Leishmania]{.underline}.
>
> 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]{.underline} 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]{.underline} 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]{.underline}
> areas.
>
> DR. SMALLWOOD: Question number three reads does the committee agree
> that a recommendation for donor deferral for travel to
> [Leishmania]{.underline} 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]{.underline} 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]{.underline}
> 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]{.underline} 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]{.underline} endemic area and the U.S.
> soldiers who are in Baghdad may not get [L. tropica]{.underline}
> 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline} 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]{.underline}\--encephalitis, meningitis and myelitis.
> Those are reportable conditions.
>
> In the large red spots are those counties that had greater than or
> equal to 100 cases of West Nile neuroinvasive disease per million
> population. In the orange or yellow spots it is about 10 to 99 cases
> per million. In the small blue spots, which you can\'t see very well,
> that is less than 10. So, this is what we saw in 2002. There was a
> tremendous number of cases in Chicago, Cleveland, Detroit, the whole
> upper Midwest. Then, at the end of the season we saw a lot more cases
> coming in South Dakota, North Dakota, Nebraska and in Kansas. We
> always thought that this was due to the fact that these are small
> populations and they were just popping up. At that time I don\'t think
> we really fully appreciated that this was a harbinger of things to
> come. That is why at the end of the 2003 talk I am going to tell you
> about the harbinger of things to come in 2004.
>
> Next slide, please. So, this is the summary slide. As I often joke,
> the only way that we know that West Nile Virus ends from one year and
> goes to the next is that the last slide of the previous year becomes
> an early slide of the next year. So, what we saw in 2002 is that we
> experienced in the western hemisphere the largest encephalitis
> epidemic ever. We had the largest West Nile Virus encephalitis
> epidemic ever anywhere in the world. This was really a breakthrough
> year.
>
> We described several new clinical syndromes and, as pointed out here,
> we identified new modes of transmission, including the 23 cases of
> West Nile Virus transfusion-associated transmission that Hira
> mentioned. We had four cases of transmission associated with organ
> transplantation; one case associated with breast feeding; and one
> intrauterine infection, as well as two occupational exposures.
>
> Next slide, please. So, let\'s get right into 2003. This has just been
> a tremendous increase in terms of the number of counties. What I am
> going to come back again and again and talk to is the fact that the
> eastern side of the map, the right side of this map hasn\'t changed
> all that much. If you go back and you look at 2002, these are the same
> counties that are involved. If you see lots of white areas out there
> in the east, these are counties that don\'t report any animal or human
> activity That is because those counties have West Nile fatigue
> syndrome\--they are tired of counting all the birds\--
>
> \[Laughter\]
>
> \--and they just don\'t have the infrastructure any longer to really
> support that activity any longer. We are just now getting the
> surveillance activity with regards to the animals that we used to get.
> But if you look at the eastern side, this is really familiar. But what
> is very impressive is what has happened in the high plain states of
> the West and then, of course, the areas in southern California and
> Arizona. Those, by the way, are late season findings in 2003. Also,
> New Mexico and Utah.
>
> Next slide, please. So, what do we have to date? To date we have a
> little over 2,600 cases of West Nile neuroinvasive disease reported.
> There is lag time and we will continue to receive reports of West Nile
> disease all the way through next April when we try to close the data
> set. In fact, yesterday we had 75 cases of West Nile illness reported
> to ArboNET. All of them were old cases though. People are going back
> and finally taking care of a lot of the backlog cases, finally getting
> time to enter them, because I think we are pretty much over the
> season.
>
> To date we have 207 deaths but, again, let me emphasize that there has
> been a great deal of lag time. Where the big increases occurred has
> been in reporting West Nile fever because of the availability of
> laboratory testing because I think a lot of the states and counties
> have seen the value of identifying all West Nile Virus infections. I
> think that those are the big reasons why we are getting a lot more
> West Nile fever reported. Human cases have been reported from over a
> thousand counties in 45 states and the District of Columbia. And, as
> Hira pointed out, this is a very long season for us. The very first
> case of West Nile fever was reported from Pennsylvania at the end of
> March. That is phenomenal. The latest case that we have had reported
> had illness onset on November 16th, also from Pennsylvania, a case of
> West Nile fever and a well documented case. So, this is a very, very
> long season.
>
> Next slide, please. This is the incidence map. Again, the large dots
> have the highest incidence. The small blue dots have the lowest
> incidence. I think it is very apparent that the western plain states
> have just seen a tremendous increase in the number of cases of
> neuroinvasive disease\--again, encephalitis, meningitis and myelitis.
> But look at the Midwest. There are still areas around the Great Lakes
> that have had the same incidence this year that they had last year.
> Look at the East. There are places that still had the same incidence
> this year that they had last year.
>
> Next slide. This is just showing the number of neuroinvasive disease
> cases that we have had reported over the five years that West Nile
> Virus has been in the United States. You can see that it increased
> from the 59 original cases in New York City in 1999 to a little over
> 2,900 cases last year, and right now we are at 2,600 cases and we are
> likely to get more. This is why we continue to say this year is every
> bit as bad as last year. It is not in the same areas. It has shifted
> areas, but it is very, very comparable. Then, of course, the far right
> column shows where the real big increase is. We are getting a lot more
> reports of West Nile fever and I think I have already identified some
> of the reasons for that.
>
> Next slide, please. This is showing just the neuroinvasive disease
> cases. I have thrown out the fever. So, our first neuroinvasive
> disease case occurred at the end of May in South Carolina and our last
> one occurred in Pennsylvania in the middle of November.
>
> This is a curve that is very similar to one that I have shown in the
> past, and it shows that there is a critical 6 to 7 weeks in the middle
> of summer during which time about three-quarters of the cases occur.
> It is a very long season but the peak is still in this very critical 6
> to 7 weeks distributed around the Labor Day holiday. In fact, the
> tallest peak there is the week before Labor Day.
>
> Next slide, please. In summary, what do we have here? We have a
> multi-state epidemic again. In fact, there are 16 states that have at
> least 50 cases of encephalitis, meningitis or myelitis. These 16
> states have reported nearly 2,200 of the cases, about 84 percent of
> all neuroinvasive disease cases that we have had reported.
>
> I am going to start educating you here to be entomologists. I don\'t
> think you are going to be \"leishmaniacs\" but you can be
> entomologists because this is a point I am going to come back to again
> at the end. If we look at these states with at least 50 cases of
> neuroinvasive disease, you can actually divide them into those states
> where we can identify the primary enzootic vector. In 10 of these 16
> states the primary enzootic vector is [Culex tarsalis]{.underline} and
> I am going to come back to that point. You can see the tremendous
> number of cases and, as blood bankers, you all know that these are the
> states that come up again, and again, and again.
>
> Then there are four states, Pennsylvania, Ohio, Iowa and New York,
> were [Culex pipiens]{.underline} is the primary enzootic vector. This
> is very, very different. [Culex pipiens]{.underline} tends to be a bit
> more of an ornithophilic mosquito than [Culex tarsalis]{.underline}.
> It has a more limited flight range. But you can see it still does
> quite a bit of damage. It can cause a pretty good rate of
> neuroinvasive disease. The thing that I should point out here though
> is that Pennsylvania, Ohio, Iowa and New York are the same states that
> had problems last year. This is now becoming a recurrent problem, and
> for New York this is its fifth year in a row that they have had an
> epidemic. In two other states that have had at least 50 cases of
> neuroinvasive disease there are other Culex species. In Louisiana it
> is [Culex quinquefasciatus]{.underline} and in Florida it is either
> [Culex quinquiefasciatus]{.underline} or [Culex
> nigripalpus]{.underline}. Again, these are the states that had
> problems last year.
>
> Next slide, please. Just to hit you over the head, as if you haven\'t
> been hit over the head hard enough already, what if we look at the
> number of neuroinvasive disease cases from Connecticut, New Jersey,
> New York and Pennsylvania from 1999 to 2003 and we combine them? Then
> we can see that those four states had 59 cases of encephalitis that
> were reported in 1999, only 19 in 2000 and, as I often joke, we
> thought they were going to go the way of ontovirus. Then in 2001, a
> very slight increase and last year they had 136 and they were
> astounded and it was making the front page. Well, this year already we
> have had 211 cases of encephalitis reported from those 5 states. The
> vast majority are from Pennsylvania but you can see that the other
> states are also reporting cases.
>
> Next slide, please. One of the things that we have seen over the past
> year and a half has been lots of cases coming out of small rural
> counties, rural counties that have populations less than 10,000. What
> this table shows is the 700 counties, 800 counties that have reported
> at least one case of West Nile neuroinvasive disease and the number of
> encephalitis, meningitis and myelitis cases that have been reported
> from those counties. Then I divided them by county population. So, in
> the first row we have 155 counties with a population less than 10,000.
> Those 166 counties have reported 299 neuroinvasive disease cases,
> which results in an incidence of about 33/100,000.
>
> You can see that the incidence of West Nile neuroinvasive disease in
> these smaller counties is much, much greater than in the larger
> cities, and this has just been a tremendous increase. I have shown you
> this same slide for 2002, and the incidence in the smaller counties is
> roughly about 20 and that all came at the end of the year last year
> when we started to see cases in Nebraska and the Dakotas. But really
> the big change this year has been the paucity of cases that have come
> out of the larger cities.
>
> Next slide, please. This is going to be the last entomology slide that
> I will show you. This is the reason. This is [Culex
> tarsalis]{.underline} and this is the reason that we have had a
> problem for the past year and a half. This is the vector of the
> irrigated lands of the arid west. It is an extremely efficient virus
> transmitter in the laboratory. It is a long distance flyer. It will
> fly miles in a day. It loves to feed on mammals; loves to feed on
> birds; loves to feed on anything it can feed on. We have shown some
> exceptionally high infection rates in 2003 including in my current
> home, Ft. Collins, Colorado, where we have seen up to 30 percent of
> the mosquitoes being infected with West Nile Virus, which is just an
> astronomic infection rate.
>
> The real concern here, of course, is that [Culex tarsalis]{.underline}
> populations are a function of the irrigation patterns of a given area.
> Irrigation patterns are relatively constant from year to year. So,
> this has a very ominous concern for us.
>
> Next slide, please. What about recent developments before I talk about
> the blood specifically? Well, what has happened over about the past 60
> weeks that we have seen local human transmission in California and
> Arizona? We have had two cases of neuroinvasive disease in southern
> California in September. We have had six in Arizona already in
> September and October. We have seen increasing animal activity in
> Arizona and California throughout November and we are seeing ongoing
> animal infections throughout the southwest. In birds, we have seen
> activity in Arizona, California, Louisiana, South Carolina and
> Oklahoma. The latest report that we have in ArboNET is from
> mid-November in Louisiana for mosquitoes, lots and lots of isolates
> out of multiple counties in southern California and throughout
> Arizona. Again, what is going to happen next year? I don\'t even have
> to show you the last slide because I know you already know what I am
> concerned about. Then, in horses and then, of course, in sentinel
> chickens. The activity has continued throughout.
>
> Next slide, please. We will just talk about blood donor surveillance,
>
> Next slide, please. Just to quickly review that in 2002 we did have
> the 23 cases of confirmed West Nile Virus transfusion-associated
> transmission. That was recently in the New England Journal, September
> 25th. At that time we estimated that there were probably about 550
> viremic donors. That is a model from Drs. Biggerstaff and Peterson
> that they developed last year and that is what the estimate was. I
> think when we are talking about the fact that we have had a comparable
> outbreak this year, I suspect that that model was a little bit low
> but, you know, it is less than a log off so that is pretty good.
>
> Next slide. Just to remind you, this is the epi curve from 2002. As I
> pointed out, three-quarter of the neuroinvasive cases in 2002 occurred
> in a six-week period distributed around Labor Day. The 16 infectious
> units that we identified in the investigation last year occurred
> during the real height of the epidemic. We thought, well, that is why
> we saw that, because there were just so many cases, there were so many
> asymptomatic viremic people out there that this is why it really poked
> its head up.
>
> Let me have the next slide, please. So, this year we did something a
> little bit different. We started two surveillance systems especially
> to track the transfusion investigations and to get together with the
> people in the blood banking industry to talk about the number of
> presumed viremic donors. We were using this as a surveillance event.
> We actually had two complementary surveillance systems. There was a
> weekly AABB conference call that included the FDA, AABB, DoD, CDC. The
> AABB reps that were on the phone represented about 90-95 centers that
> cared for about 90-95 percent of the U.S. donors. What they gave us
> was really the number of tests and results by state.
>
> Now, blood banks were reporting to the states, and most of the time
> states would report them to ArboNET. So, we were also able to get more
> information on many of those blood donors. We were able to get
> clinical follow-up as well as demographic information. So, there were
> two complementary systems.
>
> Next slide, please. These are the findings from ArboNET. To date,
> about three-quarters of the viremic donors that have been identified
> by the blood banking industry have been reported in ArboNET. As of
> yesterday, there were 742 presumptive viremic donors that had been
> reported. Seven of them had been infected as travelers but most of
> them reflect what is going on in their state and their county of
> residence.
>
> We have more complete information for 608 of these donors. The mean
> age was about 51, with a range of 15 to 83 years. Most of them were
> asymptomatic, surprisingly 81 percent. It is hard to believe when
> immunology really works out that well. Six of them actually developed
> West Nile neuroinvasive disease, which is about one percent and
> surprisingly young, about 45 years of age, although most of them
> developed meningitis so that is consistent with what we see in a lot
> of clinical cases. Then, about 16 percent of them developed West Nile
> fever. About 90 percent of the 742 come from these states and those
> are the [Culex tarsalis]{.underline} states.
>
> Next slide, please. This is a map of distribution at the end of the
> season. There are only two flavors of dots this time. The large red
> ones represent 70-20 presumptive viremic donors from a county. The
> smaller gold ones are about 1-6. That is the entire season. This just
> reinforces what we saw in the earlier map with regards to where the
> epidemic occurred. The states with the high incidence of neuroinvasive
> disease, in fact, had the most presumptive viremic donors.
>
> There are some areas\--Colorado has not mapped all of their
> presumptive viremic donors yet and we are just having technical
> problems getting the Kansas information\--well, they are having
> technical problems getting their information to us.
>
> This next map is going to run for about 45 seconds. It is going to be
> a time series and it is going to start from the middle of June and it
> is going to change on a weekly basis. It is just going to show what
> has occurred in that week. You are going to see counties lighting up.
> I think there are three flavors of dots in that one. There are large
> red ones and then smaller brown ones and then small\--I forget what
> color it is but you will see it soon enough. But I just want to
> emphasize that what you are going to see\--and I wish I could find
> some music by Gustav Holtz to put up there because you are going to
> see this little \"bup, bup, bup\" and then it is just going to hit
> you. For four weeks you are going to just experience an incredible
> number of presumptive viremic donors in this country and then it is
> going to go away. What that emphasizes is that when we make decisions,
> they have to be rapidly implemented. We have to plan these things. I
> mean, we have this problem in terms of surveillance in general because
> once this starts you have to be ready to go. We think of it in terms
> of getting our investigations going. We have to have everything ready
> to go overnight, and I think the blood banks are going to find the
> same thing.
>
> So, go ahead and start that next one. It should start right up. So,
> the gold ones are just one case per week. The brown ones are 2 to 3;
> the red are 4 to 6. This is per week; this is not cumulative. And, now
> you are experiencing the real height of the epidemic. Now it is going
> to peter off. That was it. By the way, this is only for the 608 for
> which we have more information. That is not the 1,000 that have been
> identified by the blood bankers and I should have pointed that out. At
> the end of the year we will be able to get that done because we are
> going to be getting all of that information as well.
>
> So, if I may have the next slide, please. So, let\'s look at this a
> little differently. Here is the epi curve that I showed you
> previously. Where do the presumptive viremic donors occur in
> relationship to this epi curve?
>
> Next slide. They are way outside. They are starting at the beginning
> of the investigation. This is only for the 608 for which we have more
> information. The first infectious donation was collected on June 19th.
> The latest one that we have in ArboNET is on 10/23 and I can guarantee
> you that there are other ones out there.
>
> Next slide, please. We also have investigations. To date we have been
> involved in 21 investigations. We investigate people who have received
> blood products in the four weeks before their West Nile Virus illness
> onset, or who received blood products from viremic donors who were
> identified in individual donation testing and look-back was done by
> industry. To date, six of those donors are definitely not a case. In
> fact, some of them don\'t have West Nile viral illness. Those cases
> are closed. We have the two confirmed cases that have been reported in
> MMWR. One of those was identified through an industry look-back, as
> Hira described earlier, and one of them was identified through the
> public health department investigating an illness in their transfusion
> recipient. We have four highly suspect cases that I think are going to
> become probable cases. We just received these samples. We are testing
> them in our lab. We are not going to put them as confirmed until they
> are tested in our lab. One of them is on an IDT look-back; three of
> them have been found in public health department investigations. One
> is inconclusive and eight are just too early to call yet.
>
> Next slide, please. In summary, what has happened in 2003? Well, we
> just experienced our second consecutive national epidemic and it is
> quite comparable to 2002. The epidemic has shifted into the western
> plains. It has increased in more rural counties. [Culex
> tarsalis]{.underline} has emerged as a preeminent vector of West Nile
> Virus in 2002 and 2003. The key thing is that it is associated with
> irrigation which is relatively constant every year, and it is
> extremely difficult to control because of the rural nature of their
> breeding sites.
>
> Human encephalitis activity has persisted in the rest of the United
> States besides the high plains. Northeastern states have had their
> fifth year of epidemic. And, there are ten states that had
> encephalitis cases in 2001 that had cases in 2002, that had cases in
> 2003\--completely unprecedented for a flavivirus.
>
> Next slide. With regards to the blood donors, and you will hear about
> this as we move along, there have been greater than 1,000 presumptive
> viremic donors that were identified and we estimate, depending on
> whose estimate you want to use, that is 1.3, 1.5 potentially
> infectious products that were never circulated.
>
> Your presumptive viremic donors occur in areas where there is lots of
> neuroinvasive disease and I think that is what that map does show.
> There are tremendous advances in screening this year. But I think with
> the investigations we have shown that the risk of
> transfusion-associated transmission is still not zero.
>
> Something that I pointed out at the AABB meetings and did not show
> here is that these West Nile Virus illnesses\--the presumptive viremic
> donors precede human West Nile Virus illnesses in about 40 percent of
> the counties. Actually, that number is going to go up but we are
> waiting to complete a lot of our data sets. That may allow
> intervention so that really underscores my last slide here, that is,
> viremic donors are an exceptionally valuable piece of surveillance and
> I want to thank all you blood banking people for doing that.
>
> Next slide. What is going to happen in 2004? The real question is are
> we going to have another national epidemic and I think we are. These
> are the reasons why I think we are: We have never experienced a
> back-to-back flavivirus epidemic in the United States, 2002-2003 was
> the first.
>
> We have seen persistent human transmission that is equal, if not
> greater than it has been in previous years in the northeast. We have
> seen persistent animal activity in many, many states. We have seen
> simultaneous epidemics going on in parts of the country that have
> very, very different weather patterns. We have seen it in urban
> settings, rural settings. Wherever it occurs, West Nile Virus has
> managed to cause a lot of disease.
>
> In areas where there is both West Nile Virus and St. Louis
> encephalitis irus, West Nile Virus comes up earlier, causes more cases
> and it lasts longer. I have shown you the prolonged transmission
> season and then, of course, the many potential bridging species, the
> increasing role of [Culex tarsalis]{.underline} in our irrigated
> western lands and, of course, the many amplifying bird species.
>
> So, I think next year we have to look at those areas that showed up at
> the end of 2003. What we are talking about is Arizona, New Mexico,
> southern California, potentially the central valley where we are
> thinking about these problems. But I want to emphasize that I think we
> are going to continue to have problems in the high plain states as
> well.
>
> Next slide. I just want to thank everybody, ArboNET, the people who
> work for me in ArboNET, all the cooperators in the states, AABB, the
> blood banks, HRSA and the FDA and thank you for your attention,.
>
> DR. NELSON: Thanks, Tony. Questions or comments? Yes, Jim?
>
> DR. ALLEN: The amplifying avian species do not die from this
> infection?
>
> DR. MARFIN: It is actually a mix. When we look at the crows, which was
> the most impressive thing that we saw when it very first came in,
> crows get infected. They get very high viremia and they die very, very
> quickly. They will die probably within 48 hours of infection. That is
> not actually your best amplifying host because they are just too
> short-lived. We have another group, the small song birds, house
> finches, house sparrows, that can achieve high viremia and stay
> viremic for 8-12 days. Those are good birds to be feeding on.
>
> What I think you are getting at is if humans don\'t play any role in
> the cycle how is this ever going to burn out? What you are thinking of
> is, well, what happens when the birds are protected and they have
> antibody? That will be the thing that will change that. The
> difficulty, of course, is that these are the small song birds. How
> LONG does a house sparrow last? Two to three years and then they are
> rapidly replaced with immature birds. These are not birds that live
> for 80 years.
>
> DR. NELSON: Steve?
>
> DR. KLEINMAN: Tony, in the slide that you showed about the
> relationship between presumptive viremia in donors and clinical cases,
> you indicated that in about 40 percent of the counties there was a
> viremic donor prior to a viremic case, but I would have suspected that
> would be more. I know the data set is incomplete but assuming that
> that is somewhat correct, then you have to show the other kind of
> things\--how many counties that didn\'t have viremic donors didn\'t
> get clinical cases in an expected time frame and, similarly, how many
> counties had their first clinical case before the viremic donor, if
> you are thinking about this as a predictive tool. Perhaps you haven\'t
> had a chance to look at that yet in your data set but I think that
> would be important.
>
> DR. MARFIN: I think I showed a very, very early slide of that at AABB
> and, actually, the positive predictive value was very, very good which
> is nice because that complements our bird surveillance where the
> positive predictive value is not very good. It is very sensitive but
> it is not very specific. What happened is that the presumptive viremic
> donors gave us the specificity. I think it is going to be some
> combination of that that we are going to use. But that took me a long
> time to do the last time and until I get a complete data set I am not
> going to do it again.
>
> DR. KLEINMAN: So, I guess the follow-up question is do we have any
> tool to predict where we are going to have the presumptive viremic
> donor before he actually turns up?
>
> DR. MARFIN: That is the important one. I am telling you that
> presumptive viremic donors are very highly predictive of ill people
> that are presumably infected by mosquitoes, and your question is a
> very, very important one. That is, then does animal transmission
> predict the occurrence of presumptive viremic donors because then we
> say, \"ah, look at that.\" Then we would turn off testing and it all
> goes away and it comes back to West Nile fatigue. The states are
> simply having a very, very difficult time keeping up with animal
> surveillance. Here we have this gift. We have never had an early
> warning system in any of our arboviral epidemics, ever, but it is time
> consuming. It is expensive and a lot of states have started to pull
> out of that. At our West Nile meetings next month we are going to try
> to fire them all up again but I am not sure that is going to happen.
> By the way, as soon as we get our data sets complete on birds and all
> of those things, we will answer that question specifically.
>
> DR. NELSON: What about horses? You know, people don\'t own crows and
> dead crows are everywhere but if somebody\'s horse dies they would
> probably know about it. My sense is that they may have a higher rate
> of clinical illness than humans. Is that right?
>
> DR. MARFIN: They have a higher mortality rate.
>
> DR. NELSON: Could they be a sentinel animal for humans because they
> are outside, etc.?
>
> DR. MARFIN: I think that we have always thought that during the first
> two years. I think people are very, very disappointed in horses. When
> you looked in New York and Connecticut horses were very, very poor.
> They came in at the very, very end of the season, long after the
> epidemic had occurred. Why is that? Well, these things ultimately all
> tie together. [Culex pipiens]{.underline}, which doesn\'t like to feed
> on mammals all that much, is the predominant enzootic vector at that
> time. So, all of a sudden it makes sense. Now we move into the high
> plains states where [Culex tarsalis]{.underline} loves to feed on
> horses and, in fact, we have seen a tremendous number of horse cases.
>
> Now, what has happened, of course, is we have several other
> determinants or dynamics going on. One, the vaccination. We have a
> vaccination program that is out there. Not only may it protect a horse
> from infection but it certainly makes interpreting their serologic
> results very, very difficult. Two, USDA has dropped out of testing of
> horses for free. There is now a fee for that. So, we have lost some of
> that as well. In fact, we have seen somewhat of a decrease in the
> number of horses that have been reported to us. Again, as soon as our
> data sets are complete we will go back and ask that question, is it
> still a valuable tool. It is a very valuable tool because it means
> that there is now an infected mammal-biting mosquito that is in your
> area and that increases our risk as well.
>
> DR. NELSON: Mike?
>
> DR. STRONG: In the past you have given us a lot of bird data. You
> didn\'t have as much bird data this time. What was the earliest bird
> case in 2003? Also, there were some counties that had bird cases and
> animal cases in 2002 that were completely negative in 2003. What is
> your explanation for that?
>
> DR. MARFIN: Our first bird cases were coming up in January in Florida
> and Louisiana. In fact, that is a point that I have made in the past.
> West Nile Virus, in terms of thinking of ongoing transmission whether
> it is through animals or humans, is a year-round disease. The horse
> cases are earlier. Sentinel chickens, I think it was in late February
> or early March when there was a tremendous number of seroconverting
> chickens at that time, meaning that transmission was ongoing. So, it
> is a year-round disease there.
>
> Your second question, a lot of that has to do with the fact that
> counties just are not collecting birds anymore. They do not use birds
> anymore; they are not testing birds; not collecting birds.
>
> DR. STRONG: More specifically, we did have a few cases in Washington
> State and I know there was a concerted effort up there.
>
> DR. MARFIN: Yes, I can\'t explain that, except for the fact that it
> just did not become established in a good over-wintering mosquito
> species and, therefore, just was not there, what happens with West
> Nile Virus is it over-winters in the adult mosquito and that is how we
> see rapid emergence in the spring. If I showed you all the maps we
> have going all the way back, for instance, in 2002 and 2001 the very
> last county was Erie County, Pennsylvania. That was the furthest west
> that we had been. Well, where was one of the earliest counties we had
> in the following year? Eerie County, Pennsylvania. These mosquitoes
> over-winter in the infected state so they rapidly emerge. With regards
> to Washington and Oregon, I would just say they probably have not had
> a good over-wintering species.
>
> DR. STRONG: Also as a follow-up, we now have it in California and I
> know there have been positive mosquito pools in the very south of
> California to a pretty large extent. Are you going to help us with the
> bird fly-aways as to where the migrations are going to take place?
>
> DR. MARFIN: Yes, that has been an ongoing argument and it is one of
> those things where you sit around, drinking brandy and smoking cigars,
> to discuss because you can ever prove those things. But with regards
> to your comments about animal events in southern California, you know,
> they have picked up birds in Long Beach, San Juan, San Diego and that
> is somewhat of a surprise to us. We have never seen that kind of
> arbovirus activity on the coastal areas of California in the past and
> now we are starting to see it.
>
> DR. EPSTEIN: Tony, is there any evidence that mosquito control was of
> benefit in 2003, particularly in the non-plain states which aren\'t
> irrigating?
>
> DR. MARFIN: Yes, that is an ongoing discussion point as well for
> arbovirologists. It has been a leap of faith. In the past we have
> never had a good animal warning system and by the time good mosquito
> control has occurred, it is usually after the peak of the human
> epidemic. Now that we have animals, we have said we can start that
> control earlier and, therefore, prevent the epidemics. We have not
> prevented the epidemics but a lot of the problem is the counties
> aren\'t acting on animals. You could drop a hundred infected crows at
> the foot of the board of county supervisors and they are not going to
> act on that. There are many counties that won\'t act on one case of
> human encephalitis even though you know there are at least 150 other
> people that are infected out there and you don\'t know the risk
> factors for progression. It is very, very expensive. Now, I do think
> that in 2003 there is going to be a relatively good study that comes
> out of Larimore County, my home county, Ft. Collins, because it
> happened in our back yard and we were able to get out and do that. The
> results of that should be out in about the next six to eight weeks.
>
> DR. DIMICHELE: I was just wondering if you could say something about
> the two cases of transfusion-transmitted disease. Was that before the
> surveillance system was put into place?
>
> DR. MARFIN: I am sorry, I assumed everyone saw that in MMWR. I should
> have had that as a handout. In fact, essentially all of the screening
> was in place on July 1st. There were a few late states, and both of
> these cases occurred after that time. In fact, I will let Sue and Mike
> talk about the industry look-backs using individual donation testing
> of minipool negative tests. One of them came through that but the
> other one had been in a minipool, was found to be negative and,
> therefore, it was released. It was only identified because this person
> was a transfusion recipient identified through the public health
> department. I am sorry, I assumed everyone was aware of that already.
>
> DR. KLEINMAN: One more question about the epidemiology, Tony. Are
> there any data about West Nile in either Mexico or the Caribbean?
>
> DR. MARFIN: We have a Caribbean case from 2001. The person never
> traveled. It has to have been acquired there. There are some good,
> strong suspect cases from other areas in the Caribbean and we have
> good suggestions that horse infections are occurring south of the
> border within about 100 miles of the U.S.-Mexican border as well as
> down in the Yucatan. So, the virus is there as best as we can tell
> although we have never made an isolate. This is all on serology.
>
> This gets back to that problem of flaviviruses. There is so much
> cross-reactivity that you want to have an isolate before you start
> going around and advertising that, in fact, it is truly there. So, we
> continue to look but, yes, it probably is going on in southern Mexico.
>
> DR. KLEINMAN: And based on mosquito breeding patterns, would you
> expect that to be year-round in those locations, if it does exist?
>
> DR. MARFIN: Not knowing what the vector is, which mosquito vector it
> is, it would be hard to speculate but I think that would be fair to
> say. I mean, we are seeing it down in southern Arizona, down in
> Tucson. They have a very, very late season for animal findings. So, I
> think that would be fair to say.
>
> DR. STRONG: You mentioned West Nile fatigue syndrome among the testing
> labs in the states. Can you give us some idea of how bad that is, and
> are the states going to continue to test throughout the wintertime?
>
> DR. MARFIN: States in the southeast do continue to test during the
> wintertime. Florida tests through the wintertime, Louisiana, Harris
> County, Texas which is where Houston is, do test through the
> wintertime but that is because they have a long experience with
> arboviruses. This didn\'t just come along with West Nile Virus\--gosh,
> this is a good idea to monitor our environment to look for the virus.
> So, they have always done it year round. In the north most of the
> states have already stopped. In places like Maryland, because they
> wanted to put their resources elsewhere, they stopped testing after
> one positive bird in a zip code and then they would test no further
> birds in that zip code. So, they had to come up with a strategy to
> prioritize their funds and their testing.
>
> DR. KUEHNERT: I assumed you were talking about testing birds but the
> question is whether clinicians are going to test in patients. They
> probably won\'t because they think West Nile doesn\'t happen in the
> wintertime. But the blood donor data may actually prove otherwise.
> Just looking how wide that so-called calendar year is becoming, I am
> wondering if there is compelling data to suggest that it won\'t be
> happening year round.
>
> DR. MARFIN: It is always nice to have full-year data that is collected
> equally in all of those months to say, oh, look at that, it does not,
> in fact, occur. I think one of the biggest reasons that we know about
> some of these cases this year is because of the availability of
> testing in private laboratories. So, physicians may see an
> encephalitis and many of them will probably just order the same panel
> that they would have ordered in July. It is just automatic and it just
> runs right down the thing.
>
> DR. KUEHNERT: It is in a standard panel.
>
> DR. STRONG: I don\'t believe we have had a positive blood donor since
> the first week of November.
>
> DR. NELSON: Sue will tell us. Sue, are you ready?
>
> **Updates on WNV Testing Under IND and Plans for 2004**
>
> **Red Cross**
>
> DR. STRAMER: If I could have presentation number one, please? I am not
> going to help us catch up on time so get that thought out of your
> heads, but I will go as quickly as possible.
>
> Next, please. Many of these slides I showed before and I included them
> again as background and update of where we are. So, we began testing
> at the Red Cross on June 23rd for one of our regions, Southwest, based
> on animal and bird reports. We implemented system-wide on June 29th.
> However, based on the data that we started to receive from two of our
> regions, Central Plains, which collects from Kansas, and Midwest
> region, which collects in Nebraska, we did the following actions:
>
> Initially we did a 28-day inventory test or inventory rotation
> performed from our first positive pool result which occurred on these
> two dates in these two regions, and we went back and did a 28-day test
> when testing had not been implemented yet. So, we went back to June
> 11th in Nebraska and went back to June 16 in Kansas and did single
> unit testing for these days. Those are the days prior to the
> implementation of minipool tests. Now, we did not find any true
> positives. We did find some false reactives but no confirmed
> positives. So, we used that as data to indicate that we started
> testing at the right time, that is, no cases were missed.
>
> Then, because of the increasing number of cases in these two states,
> we went to individual donation prospective screening and we did that
> for over a month in both of the two regions. Then, again, because of
> increasing numbers of cases, we did a frozen transfusable market
> withdrawal in these two regions, covering the period of time in which
> we were not doing individual unit testing but we had minipool
> positives.
>
> Next, please. To date, or to the end of November, we have screened
> over 2.9 million donations and had 797 NAT reactives. Of those 797,
> 413 we classified as hot cases. Using the Gen-Probe test in pools of
> 16 when we see a signal to cut-off ratio of greater than or equal to
> 25, we call that presumptive. So, this hot category includes all these
> hot cases that would have confirmed and any other cases that had lower
> S/COs but also confirmed. The number of confirmed cases we have are
> 409 out of 409 tested. These other 4 cases are still pending. Cases
> that didn\'t confirm or are still pending but are unlikely to confirm
> include 384 and to date we have confirmatory negative results for 377
> of 377 tested.
>
> Based on the time period from the beginning of testing to our
> conclusion of testing, we had a system-wide prevalence of 1 in 5,700.
> Our two highest states, including all the minipool testing we did and
> individual document testing that we did that you will hear in my
> second presentation, this was our prevalence in Nebraska and Kansas.
> So, 0.57 percent and 0.41 percent from the first to the last confirmed
> case. So, this is actually greater, at least in Nebraska, than 1 in
> 200. The reason\--we had 2 fail or repeat tests were 2.5 percent at
> the individual donation level or the individual sample level\--very,
> very low. These rates are very good and actually better than we see
> with HIV-HCV combined test that is licensed.
>
> Two ways of looking at what our initial reactive rate is\--this is
> during the time that we also had positives so this is the total
> initial reactive rate\--ranged from a pool reactive rate of 0.8
> percent to the time that we did individual donation testing at a 1.14
> percent. So, it is somewhere around 1.0 percent.
>
> During the last period of time, the last month, we haven\'t seen any
> more confirmed positives and the number of donors that we have lost
> that have been pool reactive and then individual donation reactive, or
> one could consider that as a repeat reactive rate\--we have only been
> losing about 1 in 25,000 donors, which is much better than when we
> started the test. So, the false positivity of the tests is greatly
> decreased; the specificity greatly improved by some parameters that we
> put into place.
>
> Next, please. This shows you West Nile false positives relative to
> HIV-HCV. I always show this slide too because it gives us a good
> comparison of what we are seeing with West Nile in comparison to all
> the NAT testing we have been doing with HIV-HCV by year. So, this
> gives you the percentage of false reactives due to pools. Here is the
> number of lost donors, about 1 in 40,000. So, for HIV-HCV the
> specificity has been excellent. Although West Nile is improving, this
> is our percentage that don\'t resolve and for a total, as I showed you
> about 1.0 percent, but if we just look at those that do not resolve it
> is about 0.6 percent. Then, the number of lost donors coming from
> reactive pools isn\'t as good as HIV-HCV but it has been getting
> better.
>
> Next, please. Our criteria for confirmatory include 4 different
> classifications. We collect our samples in a plasma preparation tube.
> They are shipped from the NAT lab to our confirmatory lab, National
> Genetics Institute. If the sample is positive by PCR that is in a
> parent tube, either by a qualitative or quantitative test, it is
> considered a confirmed positive. The qualitative test has 95 percent
> sensitivity at 5 copies/ml; quantitative at 100 copies/ml. Through
> this presentation and my next presentation when I use 50 copies/ml it
> means that it was quant negative but qual positive.
>
> We also get an alternate sample which is the index plasma unit or
> index retention type, and if that is positive by PCR or repeat TMA we
> also consider the sample confirmed positive. If it is the alternate
> sample which we test for IgM the sample again is considered confirmed
> positive. If the donor seroconverts within 28 days of a West Nile
> Virus reactive donation, we also consider that a confirmed positive
> but we have only had two of this last category so those have been
> rare, one of which I think was a carryover from the previous year that
> I will talk about.
>
> Next, please. You have seen this slide before. This just shows you the
> epidemic curve of the 2002 update. As we have seen from Tony\'s
> presentation, the 2003 has been a little bit more spread.
>
> Next, please. This shows our 2003 data and this gives you all
> donations that were reactive. Here, in eggplant or aubergine depending
> on what your preference is for color, are false positives and in
> lavender are confirmed positives. You can see in the trailing weeks
> here a false-positive rate of about 1 in 25,000. So, we are still
> picking up a couple of false positives. Our last confirmed positive
> from South Carolina occurred on November 14th.
>
> Next, please. These are the same data in a line graph.
>
> Next, please. I should have said on the previous slides when we
> implemented different strategies to deal with false positives, also
> when we started single unit testing but I will get back to that in a
> third slide. I have shown this before but this gives you data for two
> different Red Cross national testing laboratories and our
> false-positive rates were kind horrendous. So, what we did is an
> experiment with increased spin time and that is the way we have been
> managing our false positivity to this date. Now we are spinning at
> 32,000 rpm which is the maximum rating for the rotor, and from the
> data collected by Gen-Probe, the sites that do run at 32,000 are
> getting the best specificity. So, that is my message to anyone who
> isn\'t spinning fast and for a pretty long time.
>
> Next, please. This is the signal to cut-off ratios of what we call our
> hot cases including the confirmed positives. Most of the signal to
> cut-off ratios that are greater than 25\--here most are greater than
> 35 but we do still see some confirmed positives coming out of pools or
> individual tests that have low signal to cut-off ratios.
>
> Next. This is the inverse showing those that do not confirm positive
> and, as with any test, most of the false positives run right around
> the assay cut-off. We have had some that have had high signal to
> cut-off ratios that have not confirmed.
>
> Next, please. This complements the slide that Tony showed, focusing on
> Nebraska and Kansas. Interestingly about Kansas, and we have had a
> couple of battles with them, they only report cases to ArboNET if they
> have confirmed meningeal encephalitis out of a CSF sample. There is
> going to be some under-reporting here relative to Nebraska but the red
> points here show you the number of counties that have had confirmed
> positive blood donors. Here, on my left, your right, are the states
> with our five highest numbers. So, between Nebraska and Kansas of our
> 409 confirmed positives, 200 cases or 50 percent of what we have seen
> at Red Cross have come from those two states alone. Our last cases,
> two occurred in Georgia in the first week of November and our last,
> and only case in the fair State of South Carolina occurred on November
> 14th.
>
> Next, please. This shows you Nebraska. The numbers on the boxes here
> show you the number of cases per county, 15 in Douglas County in Omaha
> which should be no surprise, but 15 here, in Holt County which sits on
> the Platte River, is quite a high number considering the population,
> which I don\'t know for that county but I assume it is quite low. Here
> you can see 11 for Jason County, Buffalo. So, initially when we
> started to see cases in Nebraska they were in counties that lie
> adjacent to the Platte River, which I was rafting on in June of this
> year.
>
> Next, please. This is Kansas, basically the same scheme here, with the
> number of cases per county in a little box.
>
> Next, please. This shows only the confirmed positive cases by criteria
> of confirmed positivity. Remember, I showed you four. So, here are the
> first cases that we saw. Here is one case in California, our first
> confirmed positive case but it actually was a case that had IgM at
> index and I believe that probably was a carryover from the previous
> year.
>
> Moving on forward, what is in blue here are those that were confirmed
> by NAT only. In green were NAT, IgM, TMA and/or PCR reactivity at
> index. This is IgM only at index. These 2 were the 2 that were
> confirmed by seroconversion. What you see here is an increase as the
> season progressed in the number of donors that contained IgM as well
> as being flagged by minipool or individual donation NAT.
>
> Here is the point where we started single donation testing for the two
> regions and you can see that this curve started to increase prior to
> our switch to ID-NAT. About half of our cases for Kansas and
> Nebraska\--I don\'t know if I said this already\--came from minipool
> screening and the other half came from individual donation testing.
>
> Next, please. This is the viral load of our positives. The median is
> only 970, so not a lot of virus for these samples, with the mean being
> 26,000. This is not a normally distributed population so this is
> really the only relevant number. If you focus on the low level of
> positives, the 89 here, 82 of those were IgM positive and then out of
> these there were 36 that were IgM positive. So, of the 409 total
> confirmed positives we had 120 of those being IgM positive but they
> were all with relatively low viral loads, as you would expect.
>
> Next, please. I have shown this before. This is the correlation of the
> quantitation that we do with NGI and CDC and there is good
> relationship. So, the NGI test that we use correlates quite well
> standard CDC TaqMan assay.
>
> Next, please. A question was asked by BPAC last time, the Isabelle
> BPAC, about donor demographics so we tried to put some together that
> we collected for each of our donors. Here are 409 confirmed positive
> versus the 377 confirmed negative.
>
> Firstly, what you have here are the number of components made from
> those donations. Assuming all of these would have been infectious and
> each component would have been infectious, from our screening we would
> have prevented 823 components from being released and potentially
> infecting recipients.
>
> If we look at gender distribution of the cases versus the controls,
> and our false positives act as our controls, gender is a little bit
> higher with more males confirmed positive, and we saw that for 2002
> that I will show later as well. I don\'t know how significant this is
> but we saw more males confirm than didn\'t confirm.
>
> Distribution of donations is representative of what we see in a normal
> donor population and the mean age of the positives isn\'t any
> different than the mean age of the false positives.
>
> Next, please. Based on symptoms\--you know, we are asking donors at
> the time we are calling them back in with the West Nile Virus reactive
> screening test, have you had symptoms? If someone asks me if I had
> headache, I would say yes because I have a headache every single day.
> Painful eyes? Yes, I have painful eyes right now as a matter of fact
> and probably you do too.
>
> \[Laughter\]
>
> Anyway, if you look at headache, in 66 percent of our cases\--firstly
> I should say that 81 percent of the donors said they had at least one
> symptom. We broke out these symptoms individually and then put in
> these other symptoms, and there were a zillion of them, nausea,
> vomiting, diarrhea, etc., and we grouped those as \"other\" symptoms.
> What stands out here are headache, new rash and 62 percent of the
> donors reported symptoms after the day of donation.
>
> Next, please. In contrast, here are our controls. So, even our control
> population said they had one of these and 35 percent said they had at
> least one of these symptoms. About 60 percent had a headache, just
> like we all do. Many fewer had rash. So, rash stood out on the
> previous slide and 63 percent, I believe, was the number on the
> previous slide who reported symptoms after day of donation; here only
> 43 percent did. So, those are the things that stand out.
>
> Next, please. Now I want to end with our follow-up studies. Of the 797
> NAT reactives that we have had, 66.5 percent or 530 have participated
> in follow-up, which is an amazingly high number. It included 68
> percent or 279 of our 409 confirmed positives. Of the confirmed
> positives, 261 or 94 percent seroconverted in a mean time of 20 days,
> with a range of 2-77 days. Of those that have seroconverted, 94
> demonstrated NAT reactivity either by TMA or PCR on follow-up. Of
> those 94, 24 or 25 percent had repeat NAT reactivity by these two
> tests on multiple follow-up samples, so not just on one follow-up but
> repeatedly had NAT reactivity. Of those 24, 14 or almost 60 percent
> demonstrated intermittent NAT reactivity by one or both tests. The NAT
> reactivity maintained in these 24 donors had a mean time of 18 days,
> with a range of 6 to the longest person exhibiting intermittent
> viremia for 59 days. I will show you a couple of profiles.
>
> Next, please. Just to show you the testing on each donation, index
> PPT, as I mentioned, is tested by the test of record, TMA. Then we
> send it to NGI for PCR. We retrieve a plasma co-component. It is
> tested by TMA. We repeat the NGI PCR test. We run IgM and we do
> follow-up TMA, PCR and IgM.
>
> One donor of interest here went from 1,300 copies/ml and then four
> days later went to 150,000 copies/ml. So, we were able to calculate
> about a 14-hour doubling time, which is pretty fast and kind of
> HCV-like.
>
> Next, please. I have shown this slide before using that donor that
> went from 1,300 to 150,000, I plotted him over the four days and then
> plotted all the other index donors at day zero, the index time, along
> a curve that I fit between these two lines, and then plotted their
> subsequent follow-up samples whether they were NAT reactive of IgM
> reactive. Here you can see the 18 days I have been talking about in
> repeat sampling and these donors maintained NAT reactivity.
>
> Next, please. This just gives more of the data. I haven\'t updated
> this yet with our most recent data but this is what I showed at the
> last BPAC.
>
> Next, please. The 18 days actually compares favorably with about 12
> days of IgM reactivity that we got out of our 2002 studies looking at
> various categories of donors. This is the number of donors fitting the
> various categories of decreasing NAT reactivity over time, increasing
> IgM reactivity over time, and just giving you the relative days of
> each of these categories. So, we had about a 7-8 day period of viremia
> only, followed by 12 days of IgM in the presence of virus.
>
> Next, please. These are just some profiles to show you what some of
> these donors look like. This is the index. It will always be plotted
> on the Y axis here. These are the TMA signal to cut-off ratios,
> followed by the IgM results. You have initial testing and then
> duplicate retests and we plotted both.
>
> Here, this donor came back and was NAT reactive but was not yet IgM
> seroreactive and still had virus. The subsequent sample that was TMA
> negative still had virus by NGI\'s qualitative test.
>
> Next, please. This is another donor showing a similar pattern where
> virus was maintained on the first follow-up sample. IgM was reactive
> but low and we still had PCR detectability for a couple more
> follow-ups.
>
> Next, please. Here you see the opposite where PCR was negative after
> IgM was produced, but here you see a nice spike of TMA reactivity
> showing intermittent viremia. Probably all of these represent the same
> thing, low level of virus at the cut-off and it is just a crap shoot
> whether you pick one up by one test versus the other.
>
> Next, please. Here is one where you see both. You see the spike but
> you see PCR and TMA being reactive.
>
> Next, please. This is my favorite one. With this one you see NAT
> reactivity at first follow-up. NAT reactivity decreases. Two bleeds
> are negative but, coincidentally, so is the IgM. So, in this gentleman
> we actually see a trough between RNA detectability disappearing and
> then IgM kicking in.
>
> Next, please. The last one shows you IgM produced earlier, prior to
> the decline of virus but, again, still a period of intermittent
> viremia.
>
> Next, my last slide. So, I just want to end with our plans for 2004.
> We have not stopped testing. We will continue West Nile Virus NAT in
> pools of 16 using the Gen-Probe test in 2004.
>
> The issue with us and IDT testing this year is it came on relatively
> fast. Kansas and Nebraska had these huge numbers. So, even when we
> decided to do IDT testing it took us two to three weeks to get the
> resources ready to do it so we were missing a big chunk of the
> epidemic. What we are doing now is preparing three NTLs for individual
> testing depending on where the need should be. We have reasons for
> selecting these sites, two of which will be in a Tigris clinical study
> so we will have instruments there validated, and we will again add St.
> Louis because of the issue in the central plains area.
>
> So, depending on where cases occur and the trigger that will develop,
> we will develop and refine\--this is the trigger that we used this
> year, prevalence of greater than 1,000 and 4 confirmed positives. From
> the prevalence data that I will show you I will explain that for every
> 4 pools reactive we would have released an individual donation that
> likely would have been infectious. So, we had a ratio of 4:1 from our
> earlier prevalence studies and that is where this 4 came from. So,
> when we see these two parameters we could convert a specific region
> from pooling to IDT. But our plan is really dependent on the
> availability of automation from our vendor\--that is a plug for our
> vendor, but we need these instruments and these 3 NTLs, which I think
> we will accomplish. Thank you. See, that wasn\'t so bad!
>
> DR. NELSON: Questions? Yes?
>
> DR. STRONG: I was interested in your S/CO numbers. You have some lower
> S/COs in your follow-ups on your donors so it seems surprising\--of
> your 377 false positives at least some of those might have been true
> positives. Do you know why that was happening?
>
> DR. STRAMER: Why they had a higher signal to cut-off ratios?
>
> DR. STRONG: Why below the 25 signal to cut-off ratios in your false
> positive group, none of those confirmed, whereas you had lower signal
> to cut-off ratios in follow-up samples.
>
> DR. STRAMER: I don\'t think S/CO is 100 percent predictive. Certainly
> there is a tendency for higher S/COs to be more predictive of true
> positivity but, you know, maybe because of technical error in running
> the assay, you know, we had some differing S/COs, contamination or
> what-not but it is not 100 percent relationship.
>
> DR. STRONG: Then, in terms of your copy number results, have you run
> confidence intervals to know how accurate copy numbers are from NGI?
>
> DR. STRAMER: Well, I showed you the correlation with CDC for each of
> the intervals. I have the confidence intervals, I just haven\'t
> presented them.
>
> DR. STRONG: On the headache question, with 60 percent of donors having
> headaches what was the time frame? Was it the week before and the week
> after? Presumably you didn\'t have a headache on the day of donation.
>
> DR. STRAMER: It is what we used last year in the 2002 studies and what
> the standardized CDC vehicle was this year, and I can\'t remember
> whether it was one week or two weeks. Tony, do you remember? One week?
> So, it was one week before and one week after.
>
> DR. NELSON: Jay?
>
> DR. EPSTEIN: Sue, as you know, FDA recommended that donors be tested
> if they had fever with headache within the week before donation. In
> your data, did that combination of symptoms have any positive
> predictive value above control?
>
> DR. STRAMER: I haven\'t looked at the data that way.
>
> DR. EPSTEIN: It would be nice to know before 2004.
>
> DR. STRAMER: Yes, we can stratify the data a number of different ways.
>
> DR. NELSON: I didn\'t see fever on your list. Was it there?
>
> DR. STRAMER: Fever should have been there. You should have the
> handout. Dr. Smallwood was supposed to hand them out.
>
> DR. KUEHNERT: You had a slide on the duration of NAT positivity and
> the outlier looked like it was 39 days, and I wondered how far out you
> tested people, particularly that person, to see where the viremia
> stopped especially since, as you said, it can be intermittent.
>
> DR. STRAMER: Yes, that person was one of the donors whose profile I
> showed you and that one was out to 50 days.
>
> DR. KUEHNERT: So, they were tested out to 50 days. Was everyone
> tested\--
>
> DR. STRAMER: Well, as long as they participate I review all cases
> before they are closed, and we try to get multiple bleeds negative by
> both TMA and PCR before a case is closed with full IgM seroconversion.
> So, we did multiple bleeds following any intermittent\--we usually
> follow a donor, if we can, for two months. That is the short answer.
>
> DR. NELSON: Maybe we can move on. Gen-Probe, Jeff Linnen.
>
> **Gen-Probe**
>
> DR. LINNEN: Let me give an update on the West Nile Virus assay. This
> is a collaboration between Gen-Probe and Chiron. In the handouts it
> actually has tomorrow\'s date but I was optimistic and changed it back
> to today. So, it says December 11th.
>
> Next slide, please. I am going to cover three topics. I am going to
> give a brief update on the clinical performance of the assay, focusing
> mostly on the non-ARC data; also give some information on work that we
> have been doing recently showing the feasibility of running this assay
> on a completely automated system, Tigris; and also talk about some
> future options for this assay.
>
> Next slide. This is just a little bit of a review. As I think most of
> you know, this assay uses the same instrument platform as our licensed
> HIV-HCV assay. What a number of you may not realize is that we
> consider this really a high throughput system because we can test 182
> results in about 5 to 6 hours, and that is with one operator. If you
> consider 16 donations, that is nearly 3,000 results in 5 to 6 hours.
>
> Down below I just show the instrumentation both for pooling. The
> middle picture shows the target capture system and then, finally, the
> full luminometer for reading the results.
>
> Next slide, please. This is a little bit more review. Our live testing
> under IND started June 19th and most sites started testing by July
> 1st. The testing is being done at 24 sites. The first confirmed
> positive in our non-ARC database occurred at the end of June.
>
> Now, to review the confirmatory testing for the test when it is run
> outside the ARC organization, we are doing the confirmatory NAT assay
> at our reference lab, and that is a kinetic PCR assay that was
> developed by Chiron. The IgM testing is done at Focus Labs in Orange
> County, California. Early on during the season we started doing
> additional confirmatory testing with our alternate TMA assay and I
> think Mike Busch will present some data on that later.
>
> Next slide, please. Here are really the most important numbers. With
> the Procleix West Nile Virus assay we have screened approximately 5.1
> million donations and this data is as of the end of November. Out of
> those 5.1 million donations we have confirmed 824 positive donations.
> So, this is data from all of the testing sites including the American
> Red Cross sites.
>
> Outside of the American Red Cross sites the ranges go from zero
> percent, and it is not too surprising where\--central California and,
> surprisingly, we haven\'t detected West Nile in any blood donors yet,
> and also in Hawaii, as you would expect, although the number of
> donations there is pretty small but we are not anticipating seeing
> very many.
>
> Now, the data from Colorado again goes through the end of November.
> So, that confirmed reactive rate is probably lower if we limit the
> time span because they haven\'t seen confirmed positive results for
> some time now. So, that is 0.18 percent in Denver, Colorado. Of
> course, for a number of confirmatory results the final numbers are
> still pending.
>
> Next slide. This slide shows how we define the results at Gen-Probe.
> You see in the second row how we define confirmed and that is, of
> course, identified in the TMA screening. Then, upon retesting it can
> be either reactive or non-reactive but it must be positive either in
> the IgM test or in the alt NAT, or we must demonstrate seroconversion
> with a follow-up donation.
>
> These next two categories are really when the results are pending. In
> one case we identify it as initially reactive where the other testing
> is unavailable and, in the second case, repeat reactive with the IgM
> testing in the alt NAT unavailable. The next one is very similar. We
> call it a probable true positive where the TMA screen is reactive, the
> retest is reactive and, of course, it is very convincing if these
> results came out of a 16 donation pool but the IgM and the alt NAT may
> be non-reactive. A probable false positive then is a reactive
> screening result but not reactive results for all the other testing.
>
> Next slide. Now I will show some of the data outside of the ARC
> results. This includes screening 2.2 million donations and that
> involved nearly 300,000 reactions, meaning those 300,000 reactions are
> the individual donor tests or the pooled tests.
>
> As you can see, we have 415 confirmed results. I want to add that this
> also includes an additional 10 that were identified using the alt TMA
> assay run at Gen-Probe. Seven fall in the category of initially
> reactive with the rest of the results pending. We have 20 that are
> repeat reactive. We have 59 that fall in the probable true positive
> category, and we have a total of 868 probable false positives.
>
> If you look at the specificity in terms of the denominator using the
> individual reactions, specificity is 99.7 percent through the end of
> November. If you look at it in terms of the total number of donations,
> the specificity looks very good, 99.96 and, as Sue pointed out, there
> have been some changes made during the course of the testing so we are
> kind of stuck with some of the numbers that we obtained early on in
> the season and, actually, we expect to see much better numbers next
> year in terms of specificity.
>
> Next slide. What I want to show here is some data about the IgM
> positive index donations. Again, this is the non-ARC data. We have
> seen a total of 70 IgM positives. Of those 70, 64 percent were repeat
> reactive in TMA. I just wanted to point out also that it might be of
> some interest that 65 percent of those 70 IgM reactives were IgG
> positive. Now, 36 percent of those 70 were positive with the PCR assay
> that is run at the reference lab. A much smaller number were tested
> with the alt TMA at Gen-Probe and 80 percent of those were TMA
> reactive. So, this is about 17 percent of the total confirmed viremic
> donations so that is 70 out of 415. Of the IgM reactives, 58.5 percent
> were identified in 16 donation pool testing and about 40 percent were
> identified in individual donor testing.
>
> Next slide, please. What I want to move onto now is what at least part
> of the group has started to focus on, that is, putting this assay on a
> completely automated system. So, this shows a picture of the system.
> There are a few points that I want to make here. This is a fully
> automated system for sample handling and assay processing. It has even
> higher throughput than our current system, about 1,000 tests in 14
> hours. We have a reagent dispense verification for the addition of key
> reagents.
>
> Next slide. This is actually a pretty small study. This is something
> that was presented at AABB. I just want to show you that we have
> determined the analytical sensitivity of the West Nile Virus on this
> automated system. As you can see, it is fairly similar to what we see
> in the manual assay. This is only based on 8 replicates of each level.
> We are able to detect 100 percent down at 30 copies and 88 percent at
> 10 copies.
>
> Next slide. This shows additional data that we have generated just at
> 30 copies and 10 copies. You can see here that at 30 copies we
> detected 235 out of 235 replicates, 100 percent. Ten copies were at
> about 78 percent. This is really with very little optimization on the
> instrument. So, what we are going to be doing in the next couple of
> months is looking at the parameters very closely and trying to get
> better sensitivity at the lower end and I think it won\'t be too
> difficult to make some improvements.
>
> With the next slide I would like to show you some of the specificity
> data that we have generated very recently. This is using mostly fresh
> samples. We have really been focusing on specificity. As you can see
> here, the results are very good. We have tested over 1,100 samples and
> you can see it is a combination of fresh PPTs, 230; fresh EDTAs,
> almost 700; and then some frozen EDTA tubes, a little bit over 200.
> So, overall we haven\'t seen any false reactives and we have made some
> minor changes to the formulation to get this type of performance.
>
> Next slide, please. I would just like to finish by making a couple of
> comments. Gen-Probe and Chiron are prepared to support testing in
> smaller pools, 8 in 4 donations, or targeted individual donor testing.
> It will really be up to the customers but we are committed to support
> additional testing.
>
> The other thing is, as I showed, I think we have shown feasibility on
> Tigris and I think we can continue to work and so we are evaluating
> the possibility of making this available for the next mosquito season.
> Thank you.
>
> DR. NELSON: Thank you very much. Yes, Jim?
>
> DR. ALLEN: In your pool testing if you got an initial reactive on NAT,
> do you repeat the test on the full pool or do you immediately go to
> the individual testing?
>
> DR. LINNEN: The pool is broken out into the 16 individual donations.
> The pool is never retested.
>
> DR. NELSON: If the individual donations are all negative, then the
> pool is called a false positive?
>
> DR. LINNEN: Right. I should point out that is not the case with
> individual donor testing. If there is a repeat test, that is the end
> of the line for that unit.
>
> DR. STRONG: Just to comment, I think it is an important point that you
> made concerning the tweaking of the test because these tests were put
> together in a pretty short period of time and implemented nationwide
> by June. Obviously, there is work to be done during the process, as
> Sue talked about changing the spin speeds. So, both sensitivity and
> specificity I think have room for improvement probably on both sides
> and, hopefully, in the next season will be even better.
>
> DR. NELSON: Thank you. Jim Gallarda, from Roche.
>
> **Roche**
>
> DR. GALLARDA: I would like to kind of give a summary of what we found
> out this year in the last frantic six months of 2003. First slide,
> please.
>
> This is kind of a little overview of the time line. Actually, in late
> September we had a meeting to talk about this. We submitted our IND in
> April. We went live in June. The first bag positive was on June 26th
> and now we have screened about 2 million samples in both Canada and
> the U.S., and we have over 100 confirmed positive units.
>
> Next slide. I will go over three aspects of our non-clinical
> performance studies, looking at analytical sensitivity with available
> panels; sensitivity in high risk populations from 2004; and then some
> other JEV related members.
>
> Next slide. This is a one-slide summary of the panels that we have had
> made available to us where there was some assigned titer. We started
> out with BBI lineage one. Although we did not calculate a 95 percent
> limit of detection with this particular lineage, in a blind panel that
> Mike Busch provided us we were able to detect the sample that was
> titered at 30 copies/ml as an individual sample. We did not detect
> that sample when we diluted it 6-fold. Then, there was another member
> at 100 copies/ml that we detected neat as well as diluted 6-fold. So,
> that corresponds roughly with the one point estimate of about 17
> copies/ml.
>
> We also did a limit of detection study on lineage two. The titer was
> assigned by BBI of the stock material. In that study we had about a 7
> copy/ml sensitivity. We have been using Bioclinical Partners lineage
> one for a lot of our operative validation studies, as well as our gold
> standard for development. I believe that titer is assigned by the New
> York State Department of Health. We got a 95 percent limit of
> detection around 15 copies/ml.
>
> John Saldanha provided recently a Health Canada panel which he will
> report on in the next few minutes. We anticipated in a collaborative
> study, and we were surprised, but the results point out in limited
> reps that we were detecting that at 250 copies/ml, and that is a 95
> percent hit rate. So, we don\'t understand the reason for that but
> those are the data that we reported on.
>
> I think one thing that John has been a proponent of, which I think is
> a good idea, is that we need to have a standardized panel, whether we
> call them copies or detectable units or whatever that we use as a
> basis for bench-marking and especially for lot release once we have
> licensure.
>
> Next slide. Now, in two studies looking at the 2002 mosquito season we
> got a panel from Sue Stramer, 384 blinded samples, and tested that
> both undiluted and in pools of 6.
>
> Next slide. So, we detected 12 samples. The Focus IgG and IgM as well
> as Abbott IgM was done. NGI did the titering. We detected 12 samples
> undiluted and we detected 10 of those samples when we diluted them
> 10-fold. Those two samples that were missed in 6-fold dilutions were
> both IgM positive. I will come back to these particular samples in a
> moment. In summary, 372 samples were negative; 12 positive neat and
> 10-12 detected as minipool.
>
> Next slide. We also worked looking at a select number of samples from
> ABC recall from plasma components last year. We got these from Mike
> Busch. We had 1,469 units that we tested again in a similar fashion
> undiluted and in dilutions of 6.
>
> Next slide. In this particular study we found there was one
> sample\--IL-8 was the one positive sample that we detected. We
> detected that undiluted. When we diluted 6-fold we did not detect it.
> It was an assigned titer of 440 copies/ml. We were kind of surprised
> not to detect that in a 6-fold dilution especially because, as I had
> said earlier, the following samples were the BBI lineage one members
> that were also included in that panel and, as I said, we had detected
> the 100 copy/ml sample 6-fold diluted. In summary, we detected the one
> positive sample as well as the expected number of controls that were
> in the population.
>
> Next slide. We have also extended our testing of JEV serocomplex
> members. So, in addition to lineage one and two isolates, we have
> detected St. Louis encephalitis, and we have just recently constructed
> armored RNA constructs for the Kunjin variant of West Nile, as well as
> the Japanese encephalitis virus and we detect those. We are developing
> a quantitative assay for these constructs so we can get a sense of the
> limit of detection.
>
> Next slide. I would like to move into looking at a summary of our
> clinical performance studies, looking at both minipool and single unit
> aspects of this last season.
>
> Next slide. This slide basically covers from the start of the clinical
> trial, which was around the July 1 time frame, until the first week of
> December. This is U.S. data only. We tested about 1.4 million samples.
> We had 100 positive pools in that population and 19 of those pools did
> not resolve as positive to the individual level and 81 of them did. In
> addition, we had select areas doing some single unit testing as well
> as end-of-run single unit testing. The second to the last column shows
> we had 89 positive individuals during this time period. The 19
> positive pools that did not resolve corresponds to a frequency of a
> false-positive pool that doesn\'t resolve to an individual in 1 in
> 12,000 pools or 1 in 74,000 donors.
>
> Next slide. This is a summary statistics histogram of 72 of the
> samples that we did quantitation on, and the point here is that West
> Nile is a low titer virus. This is not a normal population so
> statisticians don\'t like us to use the mean so the median for this
> population is around 20,000 copies/ml. It ranged from 200 up to
> three-quarters of a million copies. We did have one sample that is not
> included here that was below detectable limits.
>
> Next slide. We did limited testing in the month of September at 3
> sites. This blood center with targeted collection centers in Nebraska
> and South Dakota tested 3,000 samples. We found 6 individual NAT
> positives in that group for a prevalence of 1 in 500. Gulf Coast
> tested 2,300, 2,400 samples and did not find any. Community Blood
> Services in the Saskatchewan area screened 2,200 samples and found 2
> individual NAT positives. Both of those John Saldanha, I believe,
> reported at the last BPAC were IgM positive. I will come back to these
> 2 Calgary samples in a moment.
>
> Next slide. If we look at the 8 samples that were identified in
> minipool testing, we tested them in minipools to see if they would be
> reliably detected, as well as to do a titer on them. So, it was
> puzzling to see for a sample, like the top row, the Nebraska 16034
> titer at 100 copies/ml. If we diluted that 6-fold we were able to get
> 10 out of 10 hits in a diluted sample. Then, for other samples that
> had higher titers we were not seeing a corresponding hit rate so we
> don\'t understand why this is. It could be either because there are
> errors in titration and especially at the lower levels there is easily
> a plus/minus 0.25 or 0.3 log of uncertainty above and below in nominal
> assignment, or that there was some stability issue.
>
> Next slide, please. As Mike had said earlier, I think that in our rush
> to go ahead and try to get this out by mosquito season both
> manufacturers did a remarkable job to get this out. But I think the
> thing we are realizing now is that we are not done with this. We kind
> of like the iceberg diagram that Tony has shown on West Nile
> distribution of disease. We also have on the development side a
> similar issue, and that is, we have just taken care of the top part
> and now we have the bottom part to close out for licensure.
>
> So, we are continuing to optimize and assess both the sensitivity and
> the specificity of the assay. I would just like to go through some
> data with you that we will use to look at whether or not we can make
> improvements in this area.
>
> Next slide. What this shows on the X axis is cycles for TaqMan and
> then the fluorescence output, a normalized fluorescence output on the
> Y axis. This shows 12 negative samples across this growth curve. Right
> now, for the 2003 season we are using what would be equivalent to a
> 1.2 relative fluorescence index for the cut-off.
>
> Next slide. What I have here are two samples, positive samples. As
> soon as you start to see a growth curve, depending on the titer, you
> will have an inflection at a certain point and that inflection is what
> was referred to as a CT value. Or, if it is a low titer sample it will
> have a delayed CT. It will start to kick out at a higher cycle number
> and it will have a different slope.
>
> The Nebraska sample is an extremely low titer sample that we were
> unable to detect in our screening operation. So, we are looking at
> this and saying, well, shall we look at changing the cut-off to detect
> samples like Nebraska?
>
> Next slide. Here I have shown several samples. The ARC samples are the
> 12 that were identified out of the 384. These are the growth curves
> that those 12 display. Ten of those were detected both neat and as
> dilutions. Two of them were detected neat but not detected in pools of
> 6 or diluted 6-fold. So, you can see the two black lines that are kind
> of a lower slope. Those are the 2 samples that had a lower titer,
> which were positive only by ID-NAT. Of course, the Nebraska sample
> growth curve is that. Then, the 2 Canadian Blood Service samples which
> were extremely low titer, which were IgM positive, are shown on this
> graph as well. So, the question is what would happen if we lowered the
> cut-off? Could we reliably detect these?
>
> Next slide. What we have done just recently is to look at 190,000 data
> points and ask what is the essential tendency of this negative
> population relative to a cut-off? The mean of this population was 1.08
> and the standard deviation was 0.016. So, that puts our cut-off 7.5
> standard deviations away from the mean of the population. That is in
> part, we believe, responsible for the observation of the specificity
> of the test on initial pools and repeatability. The cut-off of 7.5
> corresponds nicely to the observed false-positive rate of 1 in 74,000
> samples or a 99.992 percent specificity.
>
> So, we will continue this assessment of the data but before next
> mosquito season it is quite likely that we will change our cut-off,
> and we certainly believe we will be able to detect some of these other
> samples that were not detected in the early part of 2003.
>
> Next slide. I am going to finish up with a non-epidemiological view of
> what happened relative to interdicting units for West Nile in the
> cases that were reported to CDC, human cases of West Nile.
>
> Next slide. What we wanted to find out is was there general agreement
> between the ability to interdict units per donor population and the
> reported cases of human disease to ArboNET. So, what I did was to
> query some of my colleagues in the blood testing area to find out what
> would be a reasonable rule of thumb to assign what percent of the
> donor population donates blood.
>
> We had several states that had yield cases throughout the year. We are
> assuming that the eligible donor population in this case is 18 and
> older because there is U.S. Census data on that population although
> that age can be different from state to state. We are assuming that in
> general 5 percent of the eligible population donates. Just to pick a
> number, I said Roche is testing half of those. That might be true;
> that might not be true but it is just to get an estimation of the
> number of donors to establish the frequency of interdicted West Nile
> units per assumed donor population, and then just compare that to the
> CDC reported human cases for each of the states that we had a yield
> case identified for, and to plot state by state interdicted units to
> reported cases.
>
> Next slide. This is simply a stacked ranking of states that had high
> frequency of West Nile interdicted units to low frequency. On the Y
> axis is simply 1 per given number of population, so 1 in 50,000 or 1
> in 250,000 for an interdicted unit. That is seen with the red
> diamonds. Then to compare this to the CDC reported cases, and these
> were for total cases so I didn\'t break it out with meningeal
> encephalitis versus fever; it was just the total number.
>
> In general, what you see is that for the states like South Dakota and
> Nebraska there is pretty close agreement, within a 2-fold range or
> thereabouts of the CDC reported cases and the number of interdicted
> units per population. But it looks like it really starts to change for
> states that were, you know, the epicenter of the epidemic early on. I
> don\'t know if this is significant. This is simply an exploratory
> plot, as I call it, so it has no statistical validity nor would I
> claim that but it would be interesting to see, if this is true, if
> there really is a difference, why would that be. It could be something
> about the dynamics of the bird population, their immune status or the
> immune status of humans, you know, in the earlier states that were the
> focus of the epidemic in \'99 and 2000. Anyway, this is curious at
> best. But the reason we did this is just to see are we detecting
> roughly what we would expect to detect.
>
> Next slide. Our future activities\--obviously, we will continue the
> IND and an important aspect will be to prepare for the 2004 mosquito
> season for targeted ID-NAT; to finalize the device specifications
> reagents and to close out and establish the performance attributes of
> the finalized device, both from a clinical performance perspective and
> non-clinical perspective. Thank you.
>
> DR. NELSON: Thanks. Steve?
>
> DR. KLEINMAN: Jim, one question about the issue of apparent different
> analytical sensitivity depending upon what standard you use, do we
> know that these standards\--have the lineages been sequenced and are
> they exactly the same? Do we know that?
>
> DR. GALLARDA: I don\'t know the answer, Steve. I think one thing that
> would be very good if we are going to establish a standard or a panel
> of standards then, obviously, it would be important to do as much
> characterization of that standard as possible. Right now, clearly with
> three different suppliers or sources of standards there is a wide
> difference in titers and certainly in characterization. So, I don\'t
> know the answer but that will be important to find out.
>
> DR. STRONG: Sort of a related question to the one I asked Sue on the
> copy number accuracy, have you looked at what the confidence intervals
> are for the copy number of reports?
>
> DR. GALLARDA: That is a very good question. We did kind of a quasi
> blind study where we sent out a blinded panel to a lab that does
> quantitation with replicates and asked were they getting the same
> titer. In fact, the answer is no. There is a level of uncertainty in
> titer assignment for any laboratory with a quantitative assay. From
> our experience with the monitor assays quantitation can easily be
> plus/minus 0.3 logs above and below a mean. So, you have a 0.6 log
> spread that there is going to be with most quantitative assays.
>
> DR. NELSON: Hira?
>
> DR. NAKHASI: Jim, thank you very much for a nice presentation. I have
> a couple of questions. You said that out of 100 positive pools 81
> resolved and 19 did not. The question is, is it because the virus
> level was low and did you confirm these by any other method, and what
> was the IgM status of those and, finally, were any of those cases
> transfused cases?
>
> DR. GALLARDA: None of those 19 were transfusion-transmitted cases. We
> do IgM on all of them. If we get an amplified product we do DNA
> sequencing on the amplified DNA. We do alternate primer pairs for
> looking at whether they are true positives or not. So, on the basis of
> a set of confirmatory assays, we conclude those 19 are not
> reproducible.
>
> DR. NAKHASI: I think I agree with you, as Mike also pointed out, that
> tweaking of these tests may really help more in the sensitivity of
> that.
>
> DR. GALLARDA: Yes.
>
> **Status Reports**
>
> **Prospective and Retrospective Testing Using ID-NAT**
>
> **and Update on Relative Sensitivity Study for**
>
> **WNV NAT Testing**
>
> DR. BUSCH: I am going to cover this fairly quickly and won\'t take the
> full 25 minutes. I want to quickly summarize the Blood Systems\'
> experience both with routine testing and with various studies, quickly
> reviewing the yield of our minipool screening program using the
> Gen-Probe platform; address the issues of the viral load and the IgM
> profiles of the minipool yield cases; and then talk about the final
> findings from our retrospective ID-NAT study; and then talk about our
> experience applying perspective ID-NAT and contrasting the kinds of
> infected units of viremic donations that were found early in the
> epidemic to retrospective testing compared to the turn-on of
> prospective testing in September; then summarize the results of the
> study that was initiated kind of at the request of the FDA and the
> industry to compile a panel of low viremic samples and assess the
> performance of pretty much all of the NAT assays that are out there
> under development or being used; compare the specificity of minipool
> ID-NAT to give you a sense of what the hit rate would be on our donor
> pool were we to convert to ID-NAT with the current assays; then,
> finally, just to touch on some ongoing and planned studies.
>
> Next slide. This is a familiar curve, basically the overall Blood
> Systems Laboratory both reactive rate and total number of reactive
> units. You can see that we peaked in the early August time frame at 1
> in about 1,100 donations confirmed positive and overall confirmation
> of 212 positive units.
>
> Next slide. If we focus exclusively on the units that were screened,
> which was the vast majority, through minipools we identified 200
> reactive donations. Of those, 176 were repeat reactive. If a donation
> coming through minipool was repeat reactive, all but one of these was
> confirmed positive based on additional testing of index and follow-up.
> We did have 24 samples from minipool where the individual sample was
> reactive but then could not be repeated on an immediate retest of that
> sample. We did find 8 confirmed positives out of this. The majority of
> these though were confirmed negative.
>
> Next slide. This is sort of that model just emphasizing here that for
> these 133 yield units, the true positives, full volume units were
> available so it allowed us to do extended additional testing and a
> similar median viral load of about 2,800\--and I will show these
> distributions. Coming out of the minipool NAT screening, 8 percent of
> the minipool yield samples had IgM detected.
>
> Next slide. This shows the distribution of the viral loads ranging
> from 0-10, 10-100, 100-1,000, 1,000-10,000, etc. You can see that
> samples detected through minipool had a distribution that had sort of
> a median in the range of 1,000-10,000. We probably aren\'t seeing all
> the low viremics because these samples had to have enough virus in
> order to score positive in the 16 dilution minipool context.
>
> What we have done down here is to sort the IgM reactives versus the
> IgM negatives. You can see that the samples that have IgM have much,
> much lower viral loads. So, these are, as the model sort of predicts,
> the tail end of the viremic curve. As IgM kicks in those units tend to
> have unquantifiable or very low viral loads.
>
> Next slide. What concerned us was both the data from Sue from last
> year showing low level viremia, and the fact that in our minipool
> screening we were seeing donations that had low level viremia and this
> really marked clustering of our yield cases in Texas and the Dakotas.
> This precipitated us conducting initially the retrospective ID-NAT
> project.
>
> Next slide. What this study involved, in the early to late August time
> frame, is that we retrieved samples that were from high yield regions.
> These units at that point had been released based on negative
> minipools so, as expeditiously as possible, we conducted retrospective
> single sample testing on donations that were drawn from July 15th,
> which was the first date of a positive minipool in the high yield
> regions, through August 13th when we stopped the retrospective
> testing\--we actually stopped the retrospective testing at the very
> end of August but we had tested through August 13th and at that point
> we converted all of our ID testing to prospective screening. If we had
> a reactive individual sample we worked them up, immediately retrieving
> any non-transfused products for extended additional testing and donor
> follow-up, with collaboration with CDC, to determine whether these
> transfusions infected people.
>
> Next slide. So, out of 11,240 donations that had been originally
> screened as negative by minipool and were then retested by ID-NAT, 43
> were reactive. Very much unlike the minipool testing, the majority of
> the initial reactives coming from minipool were non-reactive on second
> test and most of these proved to be false positives. There were 10
> though that were repeat reactive and all of these 10 proved to be
> infected donors and 8 of them confirmed through follow-up and 2 had
> corroborating viremia\--the donors did not participate in follow-up
> but there was corroborating viremia and demonstrable viral load by
> several other assays.
>
> Importantly, with the ID-NAT of these reactives that were initial
> reactives and couldn\'t be repeated on the very same test, 6 of these
> actually proved to be infected donors based on IgM status in
> follow-up.
>
> Next slide. So, what I have done here is to distribute the samples
> from the retrospective study according to sort of the staging that was
> outlined earlier. So, during that period we identified from those
> 11,000-plus donations 52 minipool NAT yield donations. In further
> testing we found 6 units that were negative on minipool but were
> detected by ID-NAT that had no antibody; 6 that had IgM only and 3
> that had IgM, IgG.
>
> Next slide. One of these units which was from the front end, i.e., no
> antibody, did infect a patient. I am not going to go through this but
> this was a Texas transmission case where the initial donation was
> given here. The retrospective retest that found the donation to be
> reactive was on the 14th and the implicated unit was actually
> transfused on the 5th of August. After the investigation which was
> triggered from this, the patient was subsequently determined to have
> developed meningeal encephalitis that hadn\'t bee diagnosed as West
> Nile related.
>
> Next slide. That case made everyone, obviously, very concerned. That
> was sort of the first confirmed transmission and that is what led us
> to raise the issue and then convert to ID prospective. I just want to
> show this, which is similar to what I showed last time but a little
> more simple, just basically taking the relative number of units during
> this stage of the early epidemic that were detected by minipool NAT
> and the average length of time that that window is thought to last,
> and then looking at the units that were detected as ID-NAT positive,
> minipool negative without antibody that we think are probably
> infectious\--several cases now have been proven to be infectious\--as
> well as the units that were found that did have antibody that we
> suspect are probably neutralized.
>
> Using these ratios, you can estimate at this stage of the early
> epidemic the relative lengths of these periods and the proportion of
> units that may be being missed, and this is kind of the 10 percent
> potential breakthrough of infectious units, and maybe as many as 25
> percent if you include these units that have antibody.
>
> Next slide. So, we then converted to prospective ID-NAT in the Dakota
> area. These are the results of units when we went to prospective
> ID-NAT. A small number of these were also derived from end-of-run
> testing. What you can see here is that of samples that were screened
> prospectively by ID-NAT, 4 of them were repeated and all 4 of those
> were confirmed; 47 initial reactives didn\'t repeat and the majority
> of those were negative but, again, we are finding a rate of low
> viremics that are real.
>
> Next slide. This is the same plot, and I will show them side by side
> in a minute, with respect to our prospective screening. The profile
> has shifted dramatically. So, during this period, based on dilution to
> 16, only 3 of the 15 samples that were found to be yield cases diluted
> out and remained positive at 1:16. There were none in this front end
> that were antibody negative; 3 were IgM positive and a much larger
> number, 9, were IgM and IgG positive. We started the prospective
> testing on September 3rd. The last positive true viremic was found on
> the 17th. Then we had another 10 days of testing with zero yield
> before we then turned back to minipool testing in those regions.
>
> Next slide. So, side by side just to contrast, and I think this is
> quite important, when we did the retrospective testing, which was
> testing back to the very first detection of minipool positivity, then
> we found these front-end viremic units with no antibody as well as an
> equal number that had IgM and only and a small number that had IgM and
> IgG. By the time we turned on prospective ID-NAT the profile had
> completely shifted and we only had a couple of minipool yield cases,
> and all of these low viremics had antibody. In fact, of the 12 that we
> picked up as low viremics, 11 of them were reactive on only one of the
> reps. So, when we repeated it we couldn\'t even repeat the reactivity
> and, yet, they were truly infected.
>
> So, this is just evidence that there are a lot of low level viremic
> donations in the later stages of the epidemic in a region because in
> the presence of antibody the viremia is suppressed to such low levels
> that it is erratically detected even by individual donation NAT.
>
> Next slide. I just wanted to mention that there was earlier
> evidence\--and this was alluded to by Jim and I think I presented this
> last time\--of this low level viremia in the setting of antibody so in
> a study that we had done, a related study where we tested about 1,500
> units under code by both Roche and Gen-Probe, as well as serology, as
> Jim mentioned, there was 1 viremic donation but we had 7 samples that
> were IgM, IgG reactive and 1 that was IgM only. Those samples that
> were negative by single testing by both TMA and PCR were tested in
> replicates of 10 at Gen-Probe and we found 2 additional viremic
> samples that had been missed. So, relative to the 1 pickup, there were
> 2 that had viremia that was missed by ID-NAT but could be detected if
> we did reps in 2 of 10 and 7 of 10 cases. Both of those samples,
> importantly, had neutralization. It was work that showed that they had
> high level neutralizing activity.
>
> This slide just further shows that. This looks complicated but
> basically what I want to point out is that both of these low viremic
> units, and in fact all of the units that had IgG as well as IgM, had
> high level West Nile specific neutralizing activity. So this, in the
> absence of any demonstrated transmissions to date of units that have
> IgM, IgG in particular, makes me believe that those low viremic
> donations that have that antibody are likely uninfectious; they are
> probably neutralized viremia.
>
> Next slide. This is from Kendra Ford and Ron Giltrid, OBI. From our
> work I would have suggested that we could probably monitor minipool
> yield and as soon as you get some minipool yield, kind of as Sue
> alluded to and we did this past year. If you turn on ID-NAT at that
> point you will probably catch most of these low viremic donations.
>
> The one center that has had extensive screening by ID-NAT exclusively
> is Oklahoma Blood Institute. When they get reactives that prove to be
> real they can subject them to dilutions and see whether they would
> have been detected in the antibody profile. This is basically 2-week
> intervals of their experience. They did have a modest epidemic in
> Oklahoma. What you are seeing here is that in the minipool yields they
> had approximately 1 case every 2 weeks within this time frame. But in
> that first period they started right off the bat with 3 samples that
> were viremic and antibody negative and could not be detected on
> dilution to minipool.
>
> So, this sort of argues that the idea of tracking your minipool rates
> and turning on ID-NAT only after you see them in the minipool might
> not be very successful at interdicting particularly these early low
> viremic antibody negative units.
>
> Next slide. Moving on, I am not going to go into detail on the
> structure of this panel but I talked about it before. We developed a
> panel of 25 samples that represented very low viremic samples from
> these early stages that we have described. It also included an
> analytic sensitivity panel using the Soldano standard that John will
> describe in a bit. Basically we took the proposed 1,000 copy
> concentration and, using proven negative plasma, we diluted that down
> to 100, 30, 10, 3 and 1 copy/ml. Each of the companies got 30 ml of
> each of the samples and we have ample volumes to allow validation
> downstream of test improvements.
>
> Next slide. This was tested under code at Gen-Probe with 10
> replicates. Every company was asked to run 10 replicates. The
> screening manufacturers ran the assay, both neat and at their
> dilutions. Gen-Probe also ran an intermediate dilution to see whether
> that would enhance the detection of these low viremics, Roche 1:6, and
> then 4 different other confirmatory assays that are either widely used
> or now developed.
>
> Next slide. This is the analytic sensitivity data. Again, based on the
> Soldano standard and the hit rate on the 10 replicates of each of
> those different dilution levels you can derive curves which then allow
> you to calculate these 50 and 95 percent detection limits. Basically,
> the neat assays, summarized here as A through G, had 50 percent
> detection limits, ranging from lows of about 1 to 3 to a high of 29.
> By minipool analysis the 50 percent hit rates ranged from 13 to 300.
>
> Next slide. What I am going to show is three slides and then a
> combination of the data from all three. Basically, what I did was to
> group the data into the samples that had no antibody. These are all
> very low viremic clinical donations that were identified mostly
> through Gen-Probe screening so there could be some selection bias as a
> result of that. We had 6-7 samples that were antibody negative, low
> viremic. The reason for the 6 versus 7 is we had gained access to the
> Nebraska transmitting donation at the last minute. So, for the
> screening manufacturers we were able to substitute that very important
> infectious donation into the panel, whereas the confirmatory assays
> got an extra negative control. Again, all of these are 10 reps. These
> basically represent the percentage of 60-70 determinations that were
> reactive by these different assays that were either run neat or in the
> context of minipools.
>
> What you can see here is that most of the assays run neat picked up
> 80, 90 percent of these, with one outlier picking up 40 percent. On
> pooled analysis you see that the pick up rates are lower.
>
> Next slide. We are looking at the 4 units that had IgM. Here the pick
> up rate was lower, around 60 percent. Again, we are seeing consistent
> rank order performance of the tests, and the rank order performance of
> the assays based on these clinical samples is also consistent with the
> analytic sensitivity data. Here we are only seeing 10-20 percent pick
> up or none of them picked up with the dilutions.
>
> Next slide. Then we get to the samples that have both IgM and IgG so
> these are further along in seroconversion. There is viremia present in
> these samples but it is at a much lower level. So, we see the neat
> assays only pick up about 50 percent of the time, at best and, again,
> low percentage pick up by minipool.
>
> Next slide. Just to make the same point, on the same axis you can see
> that these IgM negatives tend to have higher viral load and,
> therefore, 90 percent detection neat. As the antibody kicks in the
> viral load distribution of these samples is lower and, therefore, the
> ability of these tests to pick them up is reduced.
>
> Next slide. Just one important point, the question of whether an
> intermediate pool size would be useful. We do have data looking now at
> the 1:16 versus going to a dilution of 1:4 relative to the neat
> detection of one manufacturer. The point I want to make here is that
> in the antibody negative units, by going from 1:16 to 1:4 we pick up
> about half of the units that could be detected were we to go all the
> way to neat. So, this is a very nice linear line, whereas in the
> samples that have antibody going to an intermediate dilution has a
> very limited increased pick up rate relative to what would be detected
> neat. That, again, is probably because these samples that have
> antibody have much lower viral load distribution. So, in terms of
> going to an intermediate pool size, it would buy us something but
> certainly not close to all the pickup and particularly will not be
> successful at picking up the seroreactive low viremic units.
>
> Next slide. Just a couple of last points, specificity has been alluded
> to but in our system when you take the minipool NAT algorithm you gain
> very high specificity. We had 9 per 100,000 false positives. But that
> is partly because you are taking it through a pool and it would have
> to be false positive both in the pool and in the individual sample.
> But if you test individually you get a much higher false-positive
> rate. In our studies of ID-NAT it runs around 0.25 percent. Similarly,
> if we look at our end result pool rate it is the same, around 0.2
> percent. This might not seem like that high a problematic rate but,
> because of the low viremia, we have to throw away blood that is
> initial reactive and defer the donor. As we saw, a fair number of
> these low viremic donations are initial reactive, non-repeatable and,
> yet, they are real. So, we have to operate as if initial reactivity is
> real.
>
> The next slide just shows that if we take those false-positive rates
> that we have observed with the Gen-Probe system, either minipool or
> individual donation, and we apply that to 13 million units per year,
> converting from minipool to ID-NAT annually all year round would lead
> to over 30,000 or about 30,000 discarded donations and at least
> temporarily deferred donors.
>
> Next slide. In terms of critical issues, clearly further understanding
> of the infectivity of these stages is very important, both in terms of
> animal studies that you will hear about as well as the opportunity to
> do additional retrospective look-back investigations.
>
> We need to better understand the durations of these viremia stages in
> different periods of the epidemic, because these various modeled
> estimates are critically determined by when in the epidemic you look
> for the relative frequencies of these units. But I think the other
> approach to get these estimates, as Sue described, is that by
> following these donors we will be able to better define the duration
> of low viremia in the setting of IgM or IgG and neutralizing activity.
>
> The question of a smaller pool size is still open although the data, I
> think, doesn\'t suggest that we will gain a lot of incremental pickup
> by going to intermediate pools. More work needs to be done.
>
> Improved sensitivity and specificity and, finally, evaluate factors
> which might predict the severity of the epidemic so we could convert
> potentially to ID-NAT in these focal regions.
>
> The next and final slide is just mentioning a working group that has
> formed with CDC and Brian Custer, and we are really looking very
> critically\--I don\'t have time to go into this\--but at all of the
> different screening options and, based on empiric data, the
> probability of infections and looking at options in terms of time
> period of testing, focal testing, various strategies and using a
> formal sort of cost effectiveness modeling strategy to try to gain
> some sort of objective evidence as to which of these strategies might
> be appropriate for next year. Thank you.
>
> DR. NELSON: Thanks, Mike, for some impressive data. Sue?
>
> **Prospective and Retrospective Testing Using ID-NAT**
>
> DR. STRAMER: I apologize, I have a lot of slides so I will go through
> this as quickly and as painlessly as possible.
>
> Next, please. What I hope to cover is a review of what we did for the
> 2002 year, including investigation of the CDC cases and then
> preclinical prevalence studies that we did firstly with CDC and then
> with Gen-Probe, and our 2003 clinical experience in two epidemic
> regions.
>
> Next, please. This just gives you the 2002 epidemic curve again but
> this is the subset of samples from which we investigated for the first
> panel that I am going to show.
>
> Next, please. As published by Pealer, there were 23 confirmed cases.
> What I am going to focus on are the 16 implicated donors that were all
> viremic and all IgM negative, and the investigations to identify those
> 16 donors.
>
> Next, please. What we did in 61 cases that were investigated from
> which those confirmed positive 16 donors came, the Red Cross
> investigated 32 of those. So, we obtained plasma co-components from
> the same donation where there was a West Nile Virus positive
> recipient. As Jim Gallarda mentioned, we had a panel of 383 frozen
> plasma. CDC had done extensive evaluations of not only the plasma but
> red cell segments and follow-up from implicated donors to prove
> transfusion transmission. Of the 16 donors involved, there were 11
> plasma co-components that were fished out, if you will, from these 32
> case investigations. The 383 plasma were tested by the CDC TaqMan
> assay followed up by CDC IgM ELISA. Initially we did a standard test
> but any one that showed IgM positivity on follow-up was exposed to a
> more sensitive test for virus at CDC.
>
> Next. Just to go through this slide quickly, CDC detected all 11. Of
> those 11, 8 have follow-up available and all seroconverted upon
> follow-up.
>
> Next. When Gen-Probe tested those 383 samples, there were 15 IRs but 3
> were IR only; 12 repeated and all 12 of those did turn out to be true
> positives. In this case, 9 of the 12 from follow-up samples that were
> available did demonstrate seroconversion. So, all 383 samples were
> tested by all available West Nile Virus NAT and IgM assays.
>
> Next. This just shows the CDC data. Here you see PFU/ml and the two
> highest PFU/ml were the 2 cases where the donor symptoms occurred at
> or just 1 day following donation. So, high viral load correlates to
> time of symptoms, at least in this study. Those were also positive in
> red cell segments but here red cell segments were much less efficient
> in detecting virus than the frozen plasma. This represents either
> duplicate or triplicate testing neat, 1:8 or 1:16 by the Gen-Probe
> assay and all 11 of the transfusion-transmitted cases were detected by
> all dilutions on this assay.
>
> We had one other sample here that was detected by Gen-Probe that had
> IgM equivalence or elevated IgM but wasn\'t quite positive at index
> that did show seroconversion in the donor. This was a particular donor
> who was a call-back donor, who was part of the investigation but whose
> products weren\'t associated with transfusion transmission, but the
> donor himself had diagnosed West Nile Virus. That is why it is in a
> different color, but it is an interesting sample because it is a more
> challenging sample.
>
> Next, please. These are the S/COs by the Gen-Probe assay showing
> robustness in all the different dilution factors except for this
> sample which was somewhat troubling but did have low level IgM.
>
> Next, please. This slide summarizes the results of all assays. NGI\'s
> test detected a 13th sample. This sample is also in yellow because it
> was not involved in transfusion transmission. It was from a pheresis
> donor whose prior donation, not this one, was involved in transfusion
> transmission. NGI reliably detected it by their qualitative assay, not
> by quantitation, but it was negative by all other assays.
>
> Gen-Probe\'s data are here. These are the Roche data and Roche picked
> up almost everything that Gen-Probe did with the exception of one
> sample here that was the lowest viral load sample involved in
> transfusion transmission, 480 copies/ml at NGI. Jim also mentioned
> that it had low level IgM detected by the Abbott assay but not by the
> CDC assay.
>
> Next, please. These are the results of all the IgM testing we did.
> This was the transfusion-transmission case that showed no IgM at CDC
> but reactivity at Abbott and then reactivity at Focus. These are the
> other IgM positives that were both viremic and IgM at the same time.
> Then, there were 3 other IgM positives detected in the study that were
> positive at CDC and Abbott but negative by the Focus assay. So, there
> was some variability observed.
>
> Next, please. To summarize that study, we found 13 positive samples
> and all NAT assays performed comparably on those 13 positives. Two
> samples were consistently not detected in dilutions but they were IgM
> equivalent or positive and neither was involved in 2002 transfusion
> transmission cases. All 11 samples involved in the 2002 cases were
> detected at their operational dilutions with the exception of one
> sample using one manufacturer\'s test. Here I list the number of
> positives detected by each manufacturer, a high of 12 to a low of 11,
> so they are all relatively comparable, and only one difference in the
> operational dilution of the two tests in use.
>
> Next, please. In IgM assays we saw more variability in the positives.
> Abbott nailed all 6, with variable results from the other
> manufacturers.
>
> Next, please. Talking about the repository studies we have done, at
> the end of 2002 from the time period of the beginning of September
> through the middle of October we collected 89,000 samples from 6 West
> Nile Virus high risk regions identified by CDC. Samples were saved for
> West Nile Virus study with IRB approval and waiver of consent, and we
> saved the samples with basic demographic info.
>
> Next. These are the regions that we selected, again, based on
> projections from Lyle Petersen. We also added our Mississippi-Alabama
> region just as a control and, because we collected these samples late
> in the year, we wanted to see a southern region that had the epidemic
> earlier in the year and how they would perform in the same study.
>
> Next, please. From the CDC portion of the study, what we did was we
> picked the highest epidemic regions and those were Cleveland and
> Detroit, and we only did the first 3 weeks of samples which totaled
> 7,915. As part of the protocol, we took any sample that was positive
> by TaqMan, equivocal or had what I call an elevated negative, and I
> will explain what those are, and they were further tested by
> Gen-Probe\'s assay in 1:2, 1:16 dilutions and were tested by Abbott\'s
> IgM assay. We did dilutions here before we went to neat testing just
> to conserve sample volume so if something was negative in dilutions we
> could go back and test it neat. The CDC criteria for positivity was
> less than or equal to 37 cycles using two primer pairs and duplicate
> testing qualified a sample as positive. Anything less than that but
> having some positive reactivity was deemed equivocal, and if a
> positive occurred over a longer cycle time, I called that an elevated
> negative.
>
> Next, please. We had 173 classified as positive, equivalent or
> elevated negative by the CDC test for which Gen-Probe testing and IgM
> testing was done. Four samples were reactive at CDC of these 173. All
> 4 of those were reactive at dilutions by Gen-Probe and all were IgM
> negative. So, these were the high titer type samples we detect by
> minipool testing. There were 4 additional reactives by Gen-Probe and 2
> were detected at both dilutions, 2 at only the 1:2 dilution and 3 of
> them were IgM positive. So, out of these 4 additional reactives we had
> 1 that really fit this top category that would be detected by minipool
> NAT and was IgM negative. The point estimate on prevalence for the
> study was 1 per 1,000. An important point here is that 6 of the 8 of
> the RNA positives were detected by pool testing, or 75 percent. Two
> were not.
>
> Next, please. This is a summary of those data. Here are the 2 that
> were not detected by pool testing, or 25 percent out of the small N.
> But for those that were detected by pools here are the signal to
> cut-off ratios at 1:2 and 1:16\--so, pretty high signals in duplicate
> testing; CDC cycle numbers to positivity; all IgM negative; and these
> are the viral loads and as we go to decreased viral loads, the lowest
> viral loads here are those that were IgM positive and that were not
> detected in pools.
>
> Next, please. Again, the point estimate was one for the study and the
> differences between the two regions.
>
> Next, please. Those samples, except for the 173 that were already
> tested by Gen-Probe were returned to the main repository and then we
> did the larger study with Gen-Probe looking at all of the regions over
> a longer period of time to determine the efficacy of pooling, that is,
> 1:16 dilutions, and determine viral loads. It was part of the
> Gen-Probe IND to validate their assay. I will show data for IgM
> seroconversion and donors in this study and for recipient tracing
> which is ongoing.
>
> Next, please. We did the testing in 2 NTLs; trained 16 staff;
> developed documents; used investigational software, etc.\--the usual
> validation stuff.
>
> Next slide, please. Our confirmatory testing\--all initial reactives
> for ease in the protocol were batched and then tested at the end by an
> IgM and IgG assay, a research assay from Abbott. We did dilutions,
> again starting with dilutions because we can always go back to the
> neat sample if the dilutions are noon-reactive. If one dilution was
> reactive but not the other dilution, we could do intermediate
> dilutions. All samples went to NGI for quant.
>
> Next. Out of the grand total when we put 173 samples back into the
> pool, we tested by the Gen-Probe assay 48,620 samples individually. We
> had 90 initial reactives; 46 confirmed positive or only 47 percent.
> This was before we knew about centrifugation and I was going nuts
> trying to figure out what in the world was going on but, anyway, now
> it is a beautiful world. Of these 40, 6 confirmed positive.
>
> They split into 4 categories and I am going to refer to these 4
> categories a lot so we will go through them, and 16 were high titer,
> 16 out of 46 and that is only 35 percent which were detected pooled,
> antibody negative, and they had titers of 210-42,000 copies/ml. Then
> we had 10 samples that could be detected at 1:2 dilution, variably at
> 1:8 dilution. If we are talking about reducing pool size, according to
> this study the only pool size that looks efficacious is 1:2. They were
> IgM positive with low to mid-level signal to noise ratios and IgG
> plus/minus with lower copy numbers, less than 100-500 copies/ml. Then
> we had 13 low titer samples that couldn\'t be quantitated and were
> detected neat only, but they were reproducibly detected neat. They had
> high levels of antibody, IgM and IgG. Then we had 7 very low titer
> samples, like Mike just talked about, IR only but they were IgM with
> very high titers and IgG positives, and I mentioned the 50 false
> positives.
>
> Next, please. This is the slide I showed previously showing the
> 16\--in my previous talk stratifying the 10 that were detected in
> pools of 16\--the 16 that were detected in pools of 16\--I am talking
> too fast\--the 10 that were detected at lower pool sizes and had
> increasing amounts of antibody and then 13 that were detected neat
> only and 7 that were IR only and increasing amounts of IgM, as
> indicated in red plus/minus signs. Then, this is the relative duration
> based on the number of positives we got, again, assuming a 1-2 day
> ramp up time; 6.5 days from the literature of the \'50s that peak
> viral loads will be detected by minipool, corresponding to the earlier
> literature gives us a total viremic time of 7.5 to 8.5 days, and then
> an additional 12 days where RNA coexists with IgM.
>
> Next. Of these 16 positives we had in pools of 16, these are the 4
> samples that gave us some trouble and that I was most concerned about
> and gave us the 4:1 ratio that I referenced as far as our trigger for
> West Nile individual unit testing. These were detected neat, in pools
> of 2, variable by increasing dilutions so not reliably in pools of 16.
> They had either very low level IgM, and 5 is the cut-off by S to N.
> So, low level IgM, either low level IgG, and this is an S/CO of 2, or
> no IgG and still a quantifiable virus, so low antibody but enough
> virus to cause concern.
>
> Next, please. If you put all the data together by time, this gives us
> the prevalence over the weeks of the study. Like the CDC study, we had
> a summary of about 1 per 1,000. This is just the various categories
> and I won\'t bore you with details.
>
> Next, please. This shows across regions, with the highest region being
> Chicago at 1.7 per 1,000, Detroit at 1.36, and then Cleveland at 1.17.
>
> Next, please. Now if you put the data that we got for the two
> prevalence studies together with the data that was published by
> Petersen and Biggerstaff, basically all the data fall in nicely. We
> are a little higher for Chicago, a little bit lower for Cleveland.
> Most of them fell within the 95 percent confidence intervals of the
> predicted so we observed what was predicted.
>
> Next, please. This is a little bit easier to see for data over time
> for the three regions that we had the most data for. In the first week
> in September we had the most positives. Then it decreased over time by
> region, plateau-ing out over the last three weeks of September.
>
> Next, please. This is the distribution or the demographics of the
> samples evaluated in the study. This is the total population, the
> distribution of males to females, confirmed positives. We had, but no
> different than the total population, more males than females but,
> similarly, this is the same shift I showed previously that in false
> positives we had a few more females than males, which was opposite to
> our confirmed positives. And there is the number of zip codes that
> were represented.
>
> Next, please. From the look-back studies we have 46 confirmed positive
> donations made into 115 components, 71 for transfusion, but 9
> recipients so far that we have received hospital information for. Just
> quickly, 9 no symptoms were reported. These are the product
> components. We have follow-up pending for 4 living recipients; 4
> recipients have died. These 8 samples fall into the categories of
> either being a pool of 16 reactive, pool of 2 or 8 reactive and then
> neat or pool of 2 reactive, so none of them are in the lowest
> categories that we talked about.
>
> The most interesting finding of the recipient look-back so far is that
> we have one symptomatic recipient who reported symptoms three days
> post transfusion. The recipient received a red cell unit. The symptoms
> were fever, headache, chills, vomiting, diarrhea. Of course, this
> doesn\'t indicate West Nile. It could be anything, including a
> bacterial contaminated unit as Roger pointed out to me last night.
> Follow-up is pending for this recipient to see if we can find IgM or
> IgG. Interestingly enough, this was from one of the highest titers,
> 6,300 copies/ml\--one of the highest titer units of the study.
>
> Next, please. For donor follow-up of the 46 confirmed positive donors,
> we have follow-up for 11 donors. Of the 11 donors with follow-up at
> about 400 days or longer, 8 or 73 percent remained IgM positive or
> equivalent. As far as symptoms, 2 of the 11 recalled symptoms. I also
> should mention that all of them were IgG positive.
>
> Next, please. In summary, we saw regional agreement between the
> observed and predicted prevalence. However, 2002 and 2003 for those
> regions did not agree. We didn\'t have high prevalence this year for
> those same regions. And, 35 percent of RNA positive samples were
> detected in a pool of 16, only 35 percent versus 75 percent of the CDC
> subset of samples where the CDC\'s sensitivity was less. So, we pulled
> more of those samples out. Of 5 recipients investigated, there is 1
> possible transfusion transmission although we really don\'t have any
> strong data as of yet. Another 4 recipients had no symptoms. Ten
> additional samples of the 46 were detected at lower dilutions; another
> 20 were detected neat or at a lower dilution. The infectivity of these
> samples just like these samples although these samples, we know, would
> be infectious\--these remain as unknown and so far in 4 of 4
> recipients investigated we haven\'t seen any symptoms. IgM persisted
> in recalled donors, 8 out of 11 or 73 percent at greater than or equal
> to 400 days, which is very consistent with the CDC published data at
> 300-400 days of 62 percent of individual retaining IgM.
>
> Next. I want to quickly go through our 2003 IDT experience at the Red
> Cross. I have talked about this information before.
>
> Next. When we turned on IDT\--this is the cumulative number of cases
> we saw in Nebraska in the middle of September while we were doing IDT,
> but the early cases here represent minipool yield.
>
> Next. This is when we turned off testing when it reached greater than
> 1 to 1,000 and the epidemic plateau\'d.
>
> Next. The same data for Kansas while we were doing minipool testing
> and the turn on to IDT at the end.
>
> Next. This is when we turned off testing. We saw a plateau at an
> approximate prevalence of 1 to 1,000 cumulatively.
>
> Next. This is the total picture of those two regions, Nebraska and
> Kansas. Nebraska is in lavender and Kansas is in eggplant. You can see
> the epidemic curves for those two regions, minipool and IDT, again,
> half of the positives coming from minipool, about half from IDT.
>
> Next, please. This is the last group of data that I will show. The
> number of IDT samples that we tested in Kansas and Nebraska total
> 30,501. Of those, 349 or just over 1 percent were reactive. We took
> the pools that were constructed at the same time as the IDT testing
> occurred but those pools went to HIV-HCV. We took those pools that
> would ordinarily be tested for West Nile and then we tested them in
> duplicate or I should say Gen-Probe kindly tested them in duplicate.
> Then we divided them by how many at their operational pool would have
> been detected in duplicate testing in pools; how many were discordant
> representing NAT consistent detection; or how many were pool
> non-reactive. If you then divide these 97 that were detected
> consistently in pools and these samples that were not consistently
> detected in pools into those that confirm by PCR and those that don\'t
> confirm by PCR, we see a total of 44 samples here, the vast majority
> being IgM positive or equivalent. These 44 samples were of greatest
> concern because they were PCR confirmed so we know that there is virus
> but they would not have been detected in a pool. That is 12 percent of
> the total.
>
> Next, please. These are the line listings for the 16 that were
> discordant in pools. Red is positive; black is negative. As viral
> loads increase, you see here that some of the samples show no IgM. So,
> from these 16 we have 4 samples that had no IgM. The rest of the
> samples did have IgM. So, one could hypothesize that these 4 samples
> probably came from the early part of the virus curve.
>
> Next, please. These are the remaining 28 samples that were pooled
> negative. Here you can see the pool S/CO results relative to the IDT
> S/CO. They are all qual reactive but quant negative. Here we have one
> sample only that was IgM negative.
>
> Next, please. In this slide we have a second sample that was IgM
> negative, all the rest being IgM reactive.
>
> Next, please. In conclusion from this study, and this is my last
> slide, we saw a 1.14 percent reactive rate for our IDT testing; 37
> percent confirmed positive by PCR for a frequency of 1 in 238. Of the
> 128 confirmed positives, 44 were inconsistently detected at a pool of
> 16; 16 were detected once or 2 times tested. Again, 75 percent of
> those were IgM positive or equivalent; 28 were detected not out of 2
> times tested, and 93 percent of those were IgM positive or equivalent.
> So, these are the lower viral load samples.
>
> The combination of these samples plus those in the same categories
> that were PCR negative are now being tested in reps of 10 individually
> at Gen-Probe to see if we missed any positives or what additional
> findings we can get.
>
> The IgM negative samples one would consider of greatest transfusion
> transmitted risk. We saw 4 of those in the category that was only
> detected once by pool testing and 2 that were not detected by pool
> testing.
>
> So, one could say the yield of RNA low titer, IgM negative,
> potentially infected units detected by IDT were 2-6 per 30,501 tested
> for a prevalence of 1 to 5,000 to 1 in 15,000 versus the control of 84
> for the same population or 1 in 363 that were detected by pools of 16.
> So, in this study if we are considering only these samples, the lower
> titer IgM negatives being potentially infectious, our yield over
> minipool was only 2-7 percent. Thank you.
>
> DR. NELSON: Thank you. John Saldanha, from Canadian Blood Services?
>
> **Follow-up Testing of Canadian Donors who Tested**
>
> **Positive for WNV RNA by Routine**
>
> **Screening/Establishment of a Reference Reagent for**
>
> **WNV NAT Assays**
>
> DR. SALDANHA: I am going to talk about two topics. One is the
> follow-up study of the Canadian blood donors. I think you will be
> relieved to know we only have 14 so this should be fairly fast.
>
> \[Laughter\]
>
> Next slide, please. We started using the Roche Taq screen for testing
> donor samples in Canada, both at Canadian Blood Services and Hema
> Quebec. Sample testing at Canadian Blood Services started in Toronto
> on the June 23 and in Calgary on July 2.
>
> Next slide, please. So far, and this should be updated, we have tested
> over 300,000 donations but this number hasn\'t changed. We still only
> picked up 14 positive donors, and 11 samples were tested in the Roche
> pools of 6 and 1 was tested individually. This was done not
> deliberately but because at the end of the run there weren\'t enough
> samples to make up a pool. As Sue and others have sort of talked
> about, we started single donor testing in the high prevalence area,
> which was Saskatchewan and we managed to pick up 2 additional samples
> in this area.
>
> Next slide, please. This slide just shows you the titers of the
> samples that we picked up. What I should say is that when a sample was
> positive the donation was sent to the head office in Ottawa and was
> tested by an in-house West Nile quantitative assay. The quantitative
> assay only picked up West Nile Virus so all these samples were West
> Nile Virus rather than one of the other flavis that the Roche assay
> picks up. They were quantitated. The last 2 donations were at the
> threshold of detection, which is why they don\'t have a titer. In
> fact, the Roche assay did very well because they were both picked up
> on single donor testing but in our hands, using the in-house assay, we
> got them positive only in 1 out of about 40 assays.
>
> Next slide, please. This is a temporal graph of the epidemic, if you
> can call it that in Canada. Most of it was centered around August. The
> peak of the viremia, which was really very low, was 4 samples. After
> the first of September we didn\'t pick up any more positives.
>
> Can I have the next one, please? This table is a bit complicated. This
> is a table of all the follow-up of the 14 donors that we had. We had
> 10 donors from Saskatchewan. The green ones were from Alberta and the
> single purple one is from Manitoba. We managed to get follow-up
> samples on these dates and they were all tested using the in-house
> assay and were quantitated. They were also looked at by the Artis
> assay in one of the provincial laboratories, and these are the titers
> again. The other provincial laboratory used an in-house assay as well.
> We looked at the IgM and the IgG using the PanBio assay, and the IgM
> was also looked at in the provincial laboratory. One of the provincial
> laboratories also did hemagglutination inhibition. We had follow-up
> samples for all the donors apart for the one from Alberta and all of
> them seroconverted so these were confirmed positives, the 13.
>
> We also did some retrospective sort of questioning about the symptoms
> and some of them had fever or chills sort of 4 days after donation,
> for example. Interestingly, one of the donors, number 16, had chills
> and fever 2 days prior to donating. This donor, with a very low titer
> picked up by single donation, had chill and fever for 2 weeks about 5
> weeks prior to donating a sample.
>
> The other thing that is interesting is that in a couple of samples,
> number 13 for example, the titer went up substantially on the
> subsequent bleed, and I think we have seen this before. There was one
> donor that had a very high level of RNA and was also IgM positive and
> I can\'t explain that.
>
> Can we have the next slide? The next three slides are just graphical
> illustrations of some of these data. We have a donor that is positive
> on day 1 with IgG equivocal and the IgM negative. After 15 days both
> IgM and IgG are positive. This does not mean that they seroconverted
> after 2 weeks. It only means that the first follow-up sample we got
> was after 15 days.
>
> The next one, please. We also had a donor where the titer dropped
> after 4 days and the IgG and the IgM were positive.
>
> Next slide, please. And, one where the titer actually went up 2 days
> later and both the IgG and the IgM are positive.
>
> Can we have the next slide? To summarize that data looking at the
> seroconversion, 13 out of the 14 donors were positive for West Nile
> Virus. One of the donors had much higher RNA levels post donation. The
> majority of the donors lost the RNA and seroconverted, and there were
> 2 donors, which Jim Gallarda also referred to, donors 18 and 19, which
> had very low levels of RNA but were both IgM and IgG positive. They
> had very high levels of IgG and IgM and, as Mike said, it is debatable
> whether these would transmit. One donor, as I said, number 17, had a
> high RNA level but was also IgM positive. We repeated this and this
> was a high IgM.
>
> On the next slide I briefly want to acknowledge the three medical
> directors in Saskatchewan, Alberta and Manitoba who were very quick
> off the mark to make the follow-up samples, because it is very
> difficult to try and get the donors back and give samples, and also
> the two provincial labs in Saskatchewan and Alberta who did all the
> IgG and IgM testing.
>
> Now I will switch to the second part of my talk if I can have the next
> slide, please. I know it is very late to talk about standardization
> and I will try and make this as painless as possible, but I think it
> was very clear from Jim Gallarda\'s talk and from some of the
> questions we had from the committee that it is very difficult to try,
> at the lower level, to get some figure on copies/ml or whatever in a
> unit. One of the exercises we did with the Health Canada lab, the
> national microbiology lab in Winnipeg, was to try and establish a
> reference material which could be used as the yardstick against which
> all the assays could be pinned. I will describe the study we did very
> briefly.
>
> May I have the next slide, please? In this study we used the New York
> \'99 West Nile Virus strain which was isolated from a crow. It was
> grown up in Vero cells and heat inactivated for 2 hours at 60 degrees.
> It was titrated for infectivity using a plaque assay and the titer was
> about 10^7^ PFU/ml. After heat inactivation we didn\'t have any
> infectivity and the RNA titer using an endpoint dilution method was
> approximately 2 times 10^9^ copies/ml. This fits in with the figure
> for copies to PFU which has been suggested by the CDC.
>
> Can I have the next slide, please? The stock virus was diluted in
> pooled human plasma which was negative for the usual markers, and it
> was diluted to approximately what we thought was about 1,000
> copies/ml. Health Canada filled up about 6,000 vials of this material
> and gave it a code number.
>
> Can I have the next slide? I won\'t go through this in detail but,
> following the usual pattern of collaborative studies, we sent out
> vials to the participants and asked them to do an endpoint dilution
> and then calculated the endpoints using a method of maximum
> likelihood. The estimates were done in NAT detectable units/ml but we
> will go into that later. Samples were sent to 18 laboratories and we
> got results back from 13. The methods included in-house assays and
> both the commercial assays that are available at the moment. We had 3
> quantitative assays and the remainder were qualitative.
>
> Can I have the next slide, please? This is really a list of
> participants. I have put this up to show you that we had both of the
> kit manufacturers in here. We had the CDC plus NGI and also the
> national testing laboratory in Canada, Health Canada plus provincial
> laboratories and one of the reference laboratories in McMaster
> University. We also had some of the plasma manufacturers like Aventis,
> Bayer and Baxter in here as well.
>
> May I have the next slide, please? This is a histogram of the results.
> These are the calculated endpoints of all the laboratories we showed
> you, calculated in what I call detectable units/ml, and I will explain
> this. There were about 100 to 1,000 detectable units, or whatever, per
> ml. There were 2 outliers. The green boxes are the quantitative assays
> and the yellow ones are the qualitative.
>
> What I find astonishing about this study was how close the results
> are. I think this is really a reflection on how well these assays were
> set up in a very short period because I have looked at assays over the
> years in similar studies for hepatitis B and hepatitis C and HIV and
> normally the spread with different laboratories is over about 2, 2.5
> logs. Ignoring the outliers, the spread is only over 1 log, which I
> think is very, very good for the assays that were set up.
>
> May I have the next slide, please? This shows you the mean titer with
> the minimum and maximum standard deviation, and the standard deviation
> in fact is very good for this sort of assay. If we exclude the 2
> outliers the mean titer is 2.5 logs, which is about 320 detectable
> units/ml and the standard deviation is pretty good for this sort of
> assay. As I think Jim said earlier on, with a NAT assay at the lower
> end you don\'t expect to get reproducibility better than 0.5 to 0.8 of
> a log. I think you are lucky if you get that. So, I think these
> results from this assay really are very good.
>
> Can we have the next slide, please? The other question that I was
> asked was how can we be sure that with heat inactivated material the
> material was homogeneous? I must admit I was slightly worried to start
> with because in my previous experience with making standards all the
> standards we made were live. They were made with virus that wasn\'t
> inactivated. So, we were very fortunate because 2 of the laboratories,
> number 2 and number 4, did replicates on each of the vials that we
> sent them. Laboratory 2 did 10 replicates on each of the vials and
> laboratory 4 did 6 replicates of the vials.
>
> We worked out the detectable units/ml and the 95 percent confidence
> interval, and my statistician tells me that really there is no
> significant difference between the different vials. So, we were fairly
> confident that the material we filled up was homogeneous.
>
> Can we have the next slide, please? In conclusion, I think what we
> have is a material which was picked up quite well by all the assays
> that used it. We can assign it a unitage, and I think this is
> something that is debatable, we can either call it around 300 or
> 1,000. People who know me know that I don\'t talk about copies; it is
> more detectable units but I think it is very late and I am not going
> to go into that argument.
>
> I think the variation estimate is very good. There was no evidence of
> vial to vial variation, and I think this is a very good material to
> answer some of the questions that the committee were asking about how
> we standardize or arrive at a figure for the quantitation of these
> samples. That is the end, thank you.
>
> DR. NELSON: Thank you. Yes?
>
> DR. STRONG: I am sorry to have to ask a question but\--
>
> \[Laughter\]
>
> \--I wonder if you know whether the addition of IgM to your standard
> has any impact on sensitivity.
>
> DR. SALDANHA: No, it shouldn\'t. It shouldn\'t if the extraction has
> been set up properly, except if you are spinning. In fact, the first
> international standard for hepatitis C virus was from a chronic
> carrier which was positive for antibodies as well and, as far as I
> know, it didn\'t make any difference. I think Mai Ying had some
> preliminary data on HCV years ago where if it is antibody positive you
> do get a difference when you spin and extract.
>
> DR. STRONG: That was really the genesis of my question because the
> spin rates in the presence of immune complexes could change the
> sensitivity.
>
> DR. SALDANHA: That is right, yes.
>
> DR. ALLEN: An epidemiological question, not a laboratory one. I know
> the majority of Canada\'s population which is within 100 miles of the
> U.S. border are cases analogous to where they were found
> geographically in the United States in 2003.
>
> DR. SALDANHA: Yes. My Canadian geography is not very good, I have only
> been there a year, but I think Saskatchewan is almost directly north
> of the Midwest where a majority of the cases were this year in the
> U.S.
>
> DR. NELSON: Thanks. Indira Hewlett is going to talk about infectivity.
>
> **Update on Infectivity Study**
>
> DR. HEWLETT: Well, I guess it is an honor to be the last speaker
> today. I am going to be relatively brief in my presentation. I am
> going to be talking about some studies that are being planned to
> address the infectivity of West Nile Virus in blood.
>
> Next slide. Just to give you a brief background, all reported cases of
> West Nile Virus transmission by blood transfusion have been known to
> occur during the acute viremic phase so NAT was considered to be the
> most appropriate strategy to interdict infectious donations. NAT on
> pooled samples that use existing licensed platforms was implemented
> under IND to expedite screening and interdict the majority of
> infectious donations.
>
> Next slide. Although the sample pool sizes are small\--they are pools
> of 6 and 16\--the impact of sample pooling on the sensitivity of West
> Nile NAT and the residual risk needs to be evaluated. We also know
> that viremia and IgM can coexist in the late acute phase, and also
> there is a lack of data on West Nile Virus transmission by acute late
> phase donations that are either NAT negative or positive and IgM
> positive.
>
> Next slide. This slide has been shown a couple of times today so I
> won\'t spend a lot of time on it but just point out that 5 stages of
> infection have been identified on the basis of results found on
> minipool and ID-NAT and IgM and IgG assays. This slide was actually
> put together by Mike Busch and very clearly illustrates that there can
> be at least 5 stages of infection in the early phase of West Nile
> disease.
>
> Next slide, please. We know that minipool NAT detects the majority of
> viremic donations. You have heard a lot about that today. And, the
> ability of minipool NAT to detect low level viremic units was
> evaluated by performing retrospective ID-NAT on samples collected last
> year. You heard about that from Sue Stramer, but the bottom line is
> that the studies identified minipool NAT negative, ID-NAT positive
> donations and, in one case, one of these donations transmitted West
> Nile Virus infection to a recipient.
>
> Next slide, please. In 2003, retrospective studies using ID-NAT were
> performed on more than 11,000 minipool NAT negative units. In this
> study 16 minipool NAT negative, ID-NAT positive cases were identified.
> Look-back identified 2 independent transmissions to 2 recipients.
> Actually, it was one case that was identified by look-back and the
> other case, as was mentioned earlier, was from a public health
> laboratory setting. Other ID-NAT studies identified additional low
> level viremic minipool NAT negative, ID-NAT positive donations.
>
> Next slide, please. What we have learned is that these donations do
> exist and they are a cause of concern, and they also raise some
> questions. Some of the questions are listed on the slide.
>
> The first one is are minipool NAT negative, ID-NAT positive units that
> contain antibodies capable of transmitting West Nile Virus by blood
> transfusion?
>
> A second and related question is what is the minimum infectious dose
> for transfusion of West Nile Virus by blood?
>
> Third, is there a non-infectious stage in the course of West Nile
> Virus infection, that is, low level viremic period that is not
> detected by ID-NAT assays, or sporadically detected by ID-NAT assays?
>
> Next slide, please. To address this question, a working group has been
> formed consisting of people from the PHS and the AABB to address
> infectivity using animal models. What we are planning to do is to use
> plasma units identified during IND studies and characterize in regard
> to reactivity in current NAT assays. To do animal studies small animal
> models, for example the mice and hamsters, have been described in the
> literature but the drawback with these models is the volume of plasma
> that can be administered since they are very small volumes and these
> volumes may not reflect the infectious dose compared to volumes
> administered during transfusion.
>
> Next slide, please. So, we are now looking at non-human primates.
> Those that have been considered are the baboon, the rhesus macaque and
> the chimpanzee. Baboons have been known to be susceptible to natural
> infection without clinical symptoms. There are a couple of papers that
> have reported seropositivity in baboons. It has been actually the
> highest of the animals that have been looked at. So, the initial plan
> is to study the baboon model using naive animals. The animals will be
> infected by IV injection of human plasma collected during the 2003
> epidemic and identified to be at various proposed stages of infection.
>
> Next slide. The units will be infused individually or combined and
> sequentially in order of increasing probability of infectiousness. The
> samples will then be collected at various time points from these
> animals and analyzed by TaqMan or TPCR virus isolation and antibody
> assays. The susceptibility of animals that do not become infected by
> these infusions will be shown by infection with a transmitting unit
> such as the case that was identified in Nebraska, which is minipool
> NAT negative, ID-NAT positive which transmitted West Nile to a
> recipient.
>
> Next slide. In summary, the residual risk of minipool NAT for West
> Nile Virus needs to be evaluated to define future strategies for West
> Nile Virus screening. Infectivity of donations that are minipool NAT
> negative and either sporadically or consistently positive by ID-NAT in
> the presence or absence of antibodies needs to be determined. What I
> am reporting today is that such studies are being planned and expected
> to be under way in the near future. Thank you.
>
> DR. NELSON: Thanks. Yes?
>
> DR. LAAL: \[Off microphone; inaudible\]i\--infect baboons?
>
> DR. HEWLETT: We don\'t know. Obviously, that is going to be one of the
> important questions. We know that they have been found to be
> seropositive in areas where humans are positive for West Nile. We also
> know that\--
>
> DR. LAAL: \[Off microphone; inaudible\].
>
> DR. HEWLETT: No, that is one of the things that would be worth doing,
> to actually look for virus in those animals. The current plan is to
> actually look at the susceptibility of the baboon to human isolates.
> In fact, what we have been talking about in this group\--I didn\'t put
> up the slide here but basically it is the people who are conducting
> the studies on ID-NAT, such as Mike Busch, Sue Stramer, Harvey Alter
> from the NIH and Chris Mortey from the San Antonio South Texas
> Foundation. What we would like to do is to use the transmitting unit
> to infect the animal to see whether the animal does become infected
> with the human isolates. So, that is a question we are going to have
> to address before we move forward.
>
> DR. NELSON: What about using horses or colts which are known to be
> capable of being infected with the West Nile Virus naturally. I don\'t
> know how much baboons cost.
>
> DR. HEWLETT: Well, that is another issue, I am sure. There are baboon
> colonies that we have access to and, you know, it is possible to move
> forward quickly with the baboon model. The horse model was talked
> about. We also talked about small models such as birds, and so on, but
> it is just very complicated working with them. So, this is what we are
> going to start with.
>
> DR. DIMICHELE: I just have a question, since the data that we have
> seen shows that these units are less infective when they have IgM
> present in them, my question is, is this human IgM protective of the
> baboon, and is that going to be a limitation of the model?
>
> DR. HEWLETT: These are all good questions and I think, you know, the
> only way we will know is to actually do the study. The primary goal is
> to look at whether such units transmit because we know that the IgM
> negative units transmit. What we don\'t know is what is the minimum
> infectious dose; what is the lowest copy number that would be
> necessary for an infection to take place. But the other big question
> is whether donations that contain antibodies would transmit. To date,
> of course, in the human setting we have not seen transmission and I
> think several speakers made reference to that, but there may have been
> very little virus in those donations, whereas, if you were to see more
> virus would they transmit? So, it may be a virus-dependent factor
> which we will need to look at.
>
> DR. RIOS: Maria Rios, from FDA. I just want to make the point that we
> don\'t know if the antibodies are protective or not because we don\'t
> have any data to support that. All that we know is that there is a
> reduction in detection of virus but the protectiveness of antibodies
> is to be discussed and addressed.
>
> DR. HEWLETT: Yes, I just wanted to mention that actually Maria has set
> up various assays on infectivity and TaqMan assays in the laboratory
> so, you know, combined with the ability to obtain these animals, and
> having the precious samples that have been generated through these IND
> studies, and having various assays available I think we will be able
> to move forward quickly.
>
> DR. NELSON: Finally, on the agenda is the open public hearing. Dr.
> Andrew Heaton, from Chiron, are you prepared?
>
> **Open Public Hearing**
>
> DR. HEATON: Well, speaking so late it certainly behooves one to be
> brief. My intent in my few comments this evening is to comment on
> Chiron\'s and Gen-Probe\'s capacity to support pool testing in the
> face of very rapid and unexpected increases in incidence; to talk to
> the time lines to introduce the changes in the face of unanticipated
> increases in incidence; to review some expanded choices that Chiron
> will be able to make available to our customers over the next year;
> and then to comment on our capacity to support test and equipment
> requirements.
>
> Next slide, please. All of you have seen slides very similar to this
> during the day. This is a Bonfils increase in incidence. I really only
> want to make one key point, and that is that you are seeing a classic
> exponential increase in the incidence from around 2 percent of the
> pools being positive at the beginning of the epidemic to about 12
> percent being positive at the peak of the epidemic. But, if you were
> running a center, the first that you would begin to get worried would
> be about week 3 and you would reach a peak at about week 6. So, you
> would have about 3 weeks to make up your mind if you decided to make
> changes in your pool size based on the evidence in front of you.
>
> Next slide, please. As a result, we modeled out some choices and some
> options. We will provide software to allow blood centers to act based
> on the evidence in front of them. The first model was to look at 16
> pool testing and then for blood centers who are at risk to switch to
> reduced pool size testing for a 3-month period. The second option was
> to continue with pool testing at 1:16 and then to switch blood centers
> to IDT for a 3-month period. The third option was to consider
> switching all blood centers to pools of 1:8 with reduced pool size for
> at risk regions. The last would be to look at individual testing for
> all centers.
>
> What we then did, we modeled out what the increase in monthly test
> consumption would be to look at our production capacity to be sure
> that we could meet the needs in the event the centers pursued this.
>
> These two options would result in approximately a 20 percent increase
> in test consumption. This option would result in a 2 times increase in
> test consumption. And, the complete conversion to IDT would result in
> approximately 8 times test consumption. Our production capacity is so
> significant that we would easily be able to meet any of these
> anticipated increases depending on whether any of the centers elected
> to pursue these options.
>
> Next slide, please. What we are planning on doing next year is making
> pooling software available that would be configurable for pools 1:4,
> 1:8 or 1:16 so the blood centers that use our system would be able to
> adjust that pool size as they see fit and as the evidence suggests to
> them that they should. This will be Part 11 compliant. We anticipate a
> CBER submission for March of this year. We will also make available on
> that track 3.0 software which will allow data management of these
> reduced pool sizes and will also be Part 11 compliant.
>
> We have planned assay production of about 4 million tests for next
> year, and our manufacturing plant has the capacity to meet 10 times
> that amount in the event that there was a need for very rapid increase
> in test production. We have the equipment available to meet any of
> those pool sizes in the event that blood centers elected to move to
> that.
>
> Next slide, please. We are also working on developing an automated
> stand-alone walk-away system. Our partner, Gen-Probe, has developed
> this system, known as the Tigris. We have, as you have heard earlier,
> established the feasibility of West Nile Virus testing on the Tigris,
> though we have not yet concluded whether we would be able to make
> enough instruments and service and support capability available to
> meet the need by next mosquito season. We have a project team working
> vigorously on that and we will be able to provide that information
> later on. We have some upgrades for our existing equipment which
> should allow improved automation and better GMP control.
>
> Next slide. In summary then, if blood centers wish to switch to pools
> of 4 or 8, we believe the conversion would require about a 6-month
> notice from the decision point to allow us to ramp up the production
> and have the software available and have it validated. In the event
> that blood centers elected to switch to individual donor testing for
> approximately 2.4 million at risk units in the West Coast centers we,
> again, could have that available around 6 months from the time of
> identification. Lastly, automated equipment upgrades\--we have
> established feasibility for the Tigris to be able to perform the test,
> though we don\'t yet know whether we could have that available by next
> mosquito season but we certainly have the equipment that will be
> available to meet a limited conversion to reduce pool size. Thank you.
>
> DR. NELSON: Thank you. Questions? Celso?
>
> DR. BIANCO: It will be a brief presentation of the ABC and HLBI REDS
> West Nile Virus study.
>
> Next slide, please. The aims of this study is for ABC members to
> monitor West Nile screening for yield rates. The main point that I am
> going to touch on today is to evaluate the false-positive rates and
> the positive predictive value of West Nile Virus screening NAT
> reactivity for different strategies, minipool NAT versus ID-NAT, which
> I think is something that we have to think about by January.
>
> Next slide. This is a map just indicating where those centers that
> reported their results are located. There are 76 member centers,
> representing more than 90 collection facilities.
>
> Next slide. The data was collected twice a month from all the centers,
> including the number of donations screened by minipool or ID-NAT; the
> number of donations that screened reactive; and now we are completing
> the data collection in terms of supplemental testing and demographics.
>
> Next slide, please. This shows very clearly the totality of the
> centers that reported on about 2.5 million donations screened with a
> peak that came up in mid-August for the entire country.
>
> Next slide. In order to compare individual donor NAT with minipool NAT
> essentially we chose data from 4 centers that I am calling A, B, C and
> D but they are real centers. Some are sitting in this room. We chose a
> center that was performing individual donor NAT in an area of low West
> Nile Virus incidence; a center performing individual donor NAT in a
> high West Nile Virus incidence area; and then the same thing for the
> minipool NAT.
>
> Next slide. The case definitions for confirmatory testing were those
> that are based on those as part of the IND studies and essentially
> required supplemental RNA data and IgM data.
>
> Next slide. What is interesting is that when we look at false-positive
> test results, if we compare centers performing ID-NAT versus minipool
> NAT the percentage of false-positive results was about 83 percent in
> those performing ID-NAT versus the centers that were performing the
> minipool NAT, something that we would expect as we increase the number
> of tests in a low prevalence or, if we increase the sensitivity of the
> assay, we would increase the number of false positives.
>
> The next slide shows the individual data for a false-positive test
> results. We have a gradual diminution of the false-positive results as
> we move from a lower incidence using ID-NAT with a false-positive rate
> of 92.9 percent to the higher minipool rate of false-positive number
> of 3.7 percent.
>
> Next one, please. But if we look at the positive predictive value,
> again the minipool NAT will have a much higher positive predictive
> value than the ID-NAT center.
>
> Next slide. This shows the 4 centers and, again, we see the curve from
> the lower ID-NAT center to the higher minipool center with an increase
> in the positive predictive value.
>
> The next slide shows a curve for a center that was using ID-NAT, and
> this is a center in an area with a higher incidence of positives.
>
> The next one is for center D that has a high incidence, using minipool
> NAT, and this is how the curves overlap.
>
> The next slide is our conclusion that ID-NAT has a poorer predictive
> value and a higher false-positive rate than minipool NAT and we should
> take this into consideration as we make our decisions for next year.
>
> The last slide shows acknowledgement of all the groups from NHLBI,
> ABC, Gen-Probe, Roche and REDS, and we want to thank the entire group
> for this mammoth effort to collect this data. Thank you.
>
> DR. NELSON: Thank you. Steve Kleinman, can you summarize the meeting
> for us?
>
> DR. KLEINMAN: I would just like to say I agree with everything that
> has been said.
>
> \[Laughter\]
>
> As far as the AABB statement, I think it is self-explanatory and if it
> could just be read into the record I don\'t think I need to deliver it
> now, if that is okay with the committee.
>
> DR. NELSON: That is fine. Are there any other closing comments? Oh,
> somebody has a comment.
>
> DR. FORD: I really tried to go all day long and not say anything
> but\--sorry. I am assuming we were one of those centers\--
>
> DR. NELSON: Can you give your name and where you are from?
>
> DR. FORD: Kendra Ford, the Oklahoma Blood Institute. We will be doing
> individual donor NAT testing. I am assuming we were one of those blood
> centers, Dr. Bianco? Yes? Which one were we? B?
>
> I do want to comment that when West Nile first came out we did have a
> significant issue with false positives, and we also dealt with
> modifying the spin times, and we also had a lot of true positives. Our
> false-positive data doesn\'t look like that now so I don\'t know that
> it is a fair\--you are automatically going to have more false
> positives with individual donor testing. If you really think about it,
> if you are going to contaminate something within the testing process
> you contaminate either the pool or the individual donor unit and it
> makes more sense that you are going to have less contamination with
> the individual donor sample versus a pool. So, I do want to make the
> comment that our testing data looks much different now as opposed to
> originally.
>
> DR. NELSON: Well, I think the other important data was that the
> predictive value related to the prevalence and, you know, that is an
> epidemiologic principle that I am glad you have confirmed for us with
> that very expensive effort.
>
> So, 12 hours from now we will convene again.
>
> \[Whereupon, at 8:00 p.m., the proceedings were recessed, to reconvene
> at 8:00 a.m., December 12, 2003.\]

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