ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
>
> This transcript has not been edited or corrected, but appears as
> received from the commercial transcribing service. Accordingly the
> Food and Drug Administration makes no representation as to its
> accuracy
>
> BLOOD PRODUCTS ADVISORY COMMITTEE
>
> 74th MEETING
>
> Thursday, September 12, 2002
>
> 8:00 a.m.
>
> Hilton Silver Spring Hotel
>
> 8727 Colesville Road
>
> Silver Spring, Maryland
>
> PARTICIPANTS
>
> Kenrad E. Nelson, M.D., Chair
>
> Linda A. Smallwood, Ph.D., Executive Secretary
>
> Members
>
> James R. Allen, M.D.
>
> Charlotte Cunningham-Rundles, M.D., Ph.D.
>
> Kenneth Davis, Jr., M.D.
>
> Samuel H. Doppelt, M.D.
>
> Michael G. Fitzpatrick, Ph.D.
>
> Harvey G. Klein, M.D.
>
> Raymond S. Koff, M.D.
>
> Suman Laal, Ph.D.
>
> Judy F. Lew, M.D.
>
> Daniel L. McGee, Ph.D.
>
> Terry V. Rice
>
> Paul J. Schmidt, M.D.
>
> Sherri O. Stuver, Sc.D.
>
> Consumer Representative
>
> Robert J. Fallat, M.D.
>
> Non-Voting Industry Representative
>
> Toby L. Simon, M.D.
>
> Temporary Voting Member
>
> Liana Harvath, Ph.D.
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> Welcome, Statement of Conflict of Interest 5
>
> Announcements 8
>
> **Committee Updates**
>
> Meeting Summary: PHS Advisory Committee on Blood Safety and
> Availability Meeting Held on September 5, 2002
>
> Virginia Wanamaker 10
>
> Summary of Workshop on Pathogen Inactivation,
>
> August 7-8, 2002
>
> Jaroslav Vostal, M.D., Ph.D. 23
>
> West Nile Virus and Blood Safety
>
> Anthony Marfin, M.D. 33
>
> Jesse Goodman, M.D. 69
>
> **Self-Administration of the Uniform Donor History**
>
> **Questionnaire: First-Time Donors**
>
> Background and Introduction:
>
> Alan Williams, Ph.D. 94
>
> Presentation:
>
> John Boyle, Ph.D. 105
>
> Presentation:
>
> Victoria Virvos, M.Ed 147
>
> Open Public Hearing
>
> Mary Townsend, M.D., AABB 174
>
> Peter Page, M.D., American Red Cross 186
>
> Celso Bianco, M.D., America\'s
>
> Blood Centers 206
>
> Paul D. Cumming, Ph.D., Talisman Limited 210
>
> Committee Discussion and Recommendations 221
>
> **Update on Testing for Chagas Disease**
>
> **(Informational)**
>
> Introduction:
>
> Robert Duncan, Ph.D. 251
>
> Latest Trends in Transfusion-Transmitted
>
> Chagas Disease:
>
> David Leiby, Ph.D. 254
>
> Regulatory Pathway for Donor Screening:
>
> Robert Duncan, Ph.D. 277
>
> [C O N T E N T S]{.underline} (CONTINUED)
>
> Open Public Hearing
>
> David Persing, M.D., Corixa 295
>
> Kay Gregory, AABB 296
>
> **Window Period HIV Cases and Current Estimates**
>
> **of Residual Risk (Informational)**
>
> Introduction and Background:
>
> Indira Hewlett, Ph.D. 297
>
> Case Report\--Florida Blood Services:
>
> German Leparc, M.D. 304
>
> Viral Dynamics in Early Seroconversion:
>
> Michael Busch, M.D. 311
>
> Open Public Hearing
>
> Wm. Andrew Heaton, M.D., Chiron 331
>
> Dr. James Gallarda, Roche 342
>
> Sherrol McDonough, Ph.D., Gen-Probe 350
>
> Ronald O. Gilcher, M.D., 354
>
> Oklahoma Blood Institute
>
> Susan Stramer, Ph.D., American Red Cross 361
>
> Paul Holland, Blood Source 369
>
> Celso Bianco, M.D., America\'s
>
> Blood Centers 375
>
> Kay Gregory, AABB 380
>
> Adjournement 383
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Welcome, Statement of Conflict of Interest**
>
> DR. SMALLWOOD: Good morning. Welcome to the 74th meeting of the Blood
> Products Advisory Committee.
>
> I am Linda Smallwood, the Executive Secretary of the committee. At
> this time, I will read the Conflict of Interest Statement that applies
> to this meeting.
>
> The following announcement is made part of the public record to
> preclude the appearance of a conflict of interest at this meeting.
> Pursuant to the authority granted under the Committee Charter, the
> Director of FDA\'s Center for Biologics Evaluation and Research has
> appointed Dr. Liana Harvath as a temporary voting member.
>
> Based on the agenda, it has been determined that there are no products
> being approved at this meeting. The committee participants have been
> screened for their financial interests. To determine if any conflicts
> of interest existed, the agency reviewed the agenda and all relevant
> financial interests reported by the meeting participants.
>
> The Food and Drug Administration has prepared general matters waivers
> for the special government employees participating in this meeting who
> require a waiver under Title 18, United States Code 208.
>
> Because general topics impact on so many entities, it is not prudent
> to recite all potential conflicts of interest as they apply to each
> member. FDA acknowledges that there may be potential conflicts of
> interest, but because of the general nature of the discussion before
> the committee, these potential conflicts are mitigated.
>
> We would like to note for the record that Dr. Toby Simon is
> participating in this meeting as an Industry Representative acting on
> behalf of regulated industry.
>
> With regard to FDA\'s invited guests, the agency has determined that
> the services of these guests are essential. There are interests which
> are being made public to allow meeting participants to objectively
> evaluate any presentation and/or comments made by the participants.
>
> For the discussions on the Window Period HIV Cases and Current
> Estimates of Residual Risk, Dr. Michael Busch is the Scientific
> Director, Blood Centers of the Pacific. He has grants, receives
> speaker fees and is an advisor for firms that would be affected by the
> discussion.
>
> Dr. German Leparc is employed as the Chief Medical Officer for Florida
> Blood Services. In addition, listed on the agenda are speakers making
> industry presentations. These speakers are employed by industry and
> thus have interest in their employer and other regulated firms.
>
> 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 conflict 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.
>
> At this time, I would ask if there any additional declarations to be
> made from any meeting participants.
>
> Hearing none, I would like at this time to introduce to you the
> members of the Blood Products Advisory Committee.
>
> Members, when I call your name, if you would please raise your hand.
>
> Dr. Kenrad Nelson, Chairman. Dr. Stuver. Dr. Allen. Dr. Harvath. Dr.
> Lew. Dr. Doppelt. Dr. Klein. Dr. Fitzpatrick. Dr. Fallat. Dr. Simon.
> Mr. Rice. Dr. Laal. Dr. McGee. Dr. Koff. Dr. Schmidt.
>
> **Announcements**
>
> DR. SMALLWOOD: Before we proceed with the formal meeting, we have two
> retiring members leaving the committee at this time, and I would like
> to ask Dr. Jay Epstein, the Director of the Office of Blood Research
> Review, to come forward and to make the presentations to Mr. Terry
> Rice and Dr. Toby Simon. If you would come forward, please.
>
> DR. EPSTEIN: It is my sad pleasure and privilege to be awarding
> plaques in recognition of the years of good service that have been
> given to us both by Mr. Rice and Dr. Simon as members of the Blood
> Products Advisory Committee.
>
> We know that it takes substantial effort on the part of the members to
> read the voluminous packets that we send you on very short notice and
> to deliberate long and hard on the many difficult questions that we
> bring before the committee.
>
> I just want to express the thanks of the Food and Drug Administration
> to each of you for the work that you have done these last couple of
> years, and we do hope that you will agree to say on as special
> government employees, so that we can also tap your expertise ad hoc
> from time to time.
>
> Thank you very much.
>
> \[Applause.\]
>
> DR. EPSTEIN: These are also letters of appreciation.
>
> DR. SMALLWOOD: I would just like to remind everyone that this is a
> one-day meeting of the Blood Products Advisory Committee. We have a
> very full agenda today and we will try to adhere to our time range as
> best as we can. We would ask that when it is time for your
> presentation to be made, that you be prepared, and if you have a
> presentation for which you will need assistance with our audio-visual
> group, would you please let them know.
>
> At this time, I would like to turn over the proceedings of the meeting
> to the Chairman, Dr. Kenrad Nelson.
>
> DR. NELSON: Thank you, Dr. Smallwood.
>
> The first part of the agenda is a series of summaries of workshops and
> of other evolving issues. First, on the agenda, is Virginia Wanamaker
> summarizing the Advisory Committee on Blood Safety and Availability
> meeting that was held about a week ago.
>
> **Summary of PHS Advisory Committee on Blood Safety**
>
> **and Availability Meeting, 9-5-02**
>
> **Virginia Wanamaker**
>
> MS. WANAMAKER: Good morning. I am pleased to be here this morning to
> tell you a little bit about the Advisory Committee on Blood Safety and
> Availability that met last Thursday, September 5th, and the topic of
> our meeting was how can government and industry work together to
> assure the availability of blood and blood products.
>
> There were actually two issues at the meeting, the first being the CMS
> proposed rule on new payments for outpatient services, and the other
> was the blood supply.
>
> So, right away, fairly shortly after the meeting started early in the
> morning, the committee proceeded with two recommendations. One of the
> recommendations was for HHS to direct CMS to establish 2003 Medicare
> hospital outpatient prospective payment system payment rates for blood
> and blood components, transfusion services, and the transfusion
> laboratory procedures based on the current year acquisition and actual
> total cost rather than hospital outpatient claims from previous years.
>
> Then, there was another recommendation relatively similar, but this
> one addressed payment for plasma-derived therapies and their
> recombinant analogs and that they be based on current year acquisition
> and total actual cost of providing such products and services both
> within hospitals and non-patient settings to include physicians\'
> offices to assure patient access to care.
>
> From that, we moved on to looking at the blood supply. There were
> actually two components of this. One was monitoring of the blood
> supply, and the other was to look at the question how much is enough.
> We also, at the end of the day, had a brief updating on the West Nile
> virus, but I believe that is on your program and I will just merely
> mention that and move on.
>
> In the Monitoring Section, we heard from about five monitoring systems
> that are currently in process.
>
> The first was the Department of Health and Human Services monitoring
> system, which is a sentinel site blood monitoring project. This
> project has 26 hospitals and 3 community sites. It collects
> quantitative data.
>
> From this project report, it appears that the overall supply,
> especially from these sentinel sites, is adequate, however, there are
> a few of these sentinel sites that have chronic issues or chronic
> shortage problems.
>
> The next was FDA\'s TransNet. It is not yet fully functional, but it
> is a web-based plan with daily entry. It has various markers of
> shortage. There will be a daily\--once the web site is up\--there will
> be a daily map displaying areas, and it will highlight the areas with
> shortages. This is a qualitative system with no quantitative data.
>
> Next, we heard from ABC, America\'s Blood Centers. My understanding of
> their system is that it is a two-phase system. The first phase
> monitors the day\'s supply. The second phase will show members areas
> of access, however, to date, they have mostly had shortage issues, and
> that is mostly what they are displaying.
>
> Then, we had a presentation from the National Blood Data Resource
> Center. There were about four points from their presentation, that
> total collections information 2001 were over 50 million units; more
> surgeries were affected by shortages in 2001 than in 1999.
>
> The collections and inventory total so far this year are unchanged in
> comparison with last year prior to September 11. By the year 2020,
> there will be 12 million people added to the age group that are at
> risk for transfusion. NBDRC believes that long-term quantitative
> monitoring is an essential part of the blood monitoring system.
>
> We also heard from the American Red Cross. They manage inventory
> across 36 regions. They consider a two-day supply to be critical
> inventory, and they did fall to this level at the end of last month.
> They do consider a seven-day supply to be optimal.
>
> We had a small session on forecasting, which actually was an overview
> of the monitoring programs. The speaker or the presenter favored
> quantitative programs or the need for quantitative programs. He
> actually liked the sentinel site, and he did state that a shotgun
> effect, if you have a lot of different monitoring systems, and they
> approach monitoring in various ways, that they give you a comparable
> end result, then, they are doing a good job.
>
> We also heard from the Department of Defense on strategic reserves,
> that there are problems with frozen reserves, and a liquid reserve on
> a national basis would be advantageous to all.
>
> There was a suggestion that there would be four to six sites
> throughout the U.S. located near large international airports or large
> military bases.
>
> Then, we moved to session of how much is enough. We heard from Puget
> Sound Blood Center, which says that about two-thirds of the blood they
> collect is used in the Seattle metropolitan region, the other
> one-third goes to surrounding counties, and they can export small
> amounts.
>
> We heard from Georgetown University Hospital on the hospital
> perspective. The point here was stressed that appropriate usage is a
> very important issue, and that their oversight is driven by
> educational programs and that blood utilization reviews play into
> this. The speaker did point out that platelets can sometimes be an
> issue.
>
> Then, we heard from the New York Blood Center, who says they continue
> to struggle with the aftermath of 9/11. They have lost some of their
> blood drives due to loss of offices or companies that participated in
> these blood drives. They continue to struggle with the CJD deferral,
> the summer slump, and self-deferral of some donors.
>
> We heard from the Oklahoma Blood Center, which said that really blood
> serves two purposes. One of the purposes that we don\'t really speak
> to are addressed quite often, but is very significant and very
> important, is the availability of the blood.
>
> Even though blood is not used, it is still an insurance policy that
> allows for a procedure to occur. Quite often a unit of blood may never
> be used, but it may have been cross-matched three or four times, so it
> has indeed served a purpose because it was available for those medical
> procedures to go forward.
>
> The presenter did tell us that their blood center supplies 89
> hospitals with 11,000 units. They have in excess a 17-day supply with
> their liquid, and they are moving to having a frozen supply that will
> allow them to have a 23-day supply.
>
> We heard from the Mississippi Valley Regional Blood Center, which says
> they are able to supply their hospitals with a 5-day supply, keep a
> 10- to 12-day supply in their center, and export up to 50 percent of
> the red blood cells they produce.
>
> After that, we move to Recommendations. These, of course, are
> paraphrased. One of the recommendations was that the Department should
> support initiatives to improve management of blood inventories\--I am
> sorry, I skipped the first one\--that DHS should promote increased
> public awareness of the ongoing need for routine blood donations by
> healthy persons, and this could be done through periodic public
> service announcements, visible blood donations by top officials, and
> paid advertising campaigns, also by funding of demonstration projects,
> supporting specific initiatives to encourage routine donations by
> young persons and minorities, and play a leading role in increasing
> participation of federal employees in donating blood.
>
> Another recommendation was that DHS should maintain and/or increase
> funded support for blood supply monitoring. Some of the ways to do
> this would be long-term trends in blood collection and use or some of
> things that should be done, should be addressed.
>
> Data on daily national distributed blood inventories, indicators of
> blood shortages and excesses, predictive models to identify trigger
> points for coordinated national donation campaigns, and coordination
> of government and non-government initiatives.
>
> There was another recommendation that has not yet been voted on, but I
> will go ahead and mention it to you, that DHS should support
> initiatives to improve management of blood inventories. This would
> include defining the roles of liquid into frozen reserves and by
> integration of supply forecasting into intervention strategies, and
> also strategies to facilitate movement of blood from areas of surplus
> to areas of shortage.
>
> I failed to mention earlier, under the \"how much is enough,\" that we
> also had a presentation from American Red Cross, and they did mention
> that they monitor some 36 sites and that on occasion, it has fallen to
> a two-day supply.
>
> Actually, that is my presentation for today. I notice that many of the
> speakers are in the audience, so I would like to take this opportunity
> to apologize if I misquoted or missed the point of your presentation,
> but I thank you very much for his opportunity, and I hope I did
> highlight the main points of the meeting.
>
> DR. NELSON: Thank you.
>
> Any question or comments? Toby.
>
> DR. SIMON: When these discussions are held, for the most part people
> tend to forget that in the late 1980s, there was a program called the
> National Blood Resource Education Program that was funded by the
> National Heart, Lung, and Blood Institute. It was designed to use the
> same techniques that the institute had used for awareness on
> cholesterol and high blood pressure, for awareness on blood donation.
> They created a huge advertising campaign. There were ads in airport
> billboards, and other such things, and it was largely regarded as a
> failure.
>
> So, I think if we are going to move forward or if there are
> recommendations to move forward, I would suggest that people look back
> at that program and try to diagnose the problems it had before
> investing in a similar program in the future.
>
> DR. KLEIN: I just wanted to comment that there was one other
> presentation that you didn\'t review. After the major blood
> organizations reported surprising shortages, especially over the past
> two months and especially in terms of O-positive blood, and the New
> York Blood Center told us that they were transfusing increasing
> amounts of O-positive to O-negative patients because they didn\'t have
> sufficient supplies of O-negative blood.
>
> The American Hospital Association gave us what I thought was a very
> startling page of data, which included the fact that of their 5,000
> transfusing members, some 57 percent had delayed surgery during the
> past year because of unavailability of blood, and that in urban areas,
> 77 percent of their membership had delayed surgery because of lack of
> blood for transfusion. I found that startling.
>
> DR. ALLEN: A question for any member of the blood banking community
> that might have an answer. My guess is that most people, when they
> donate, do so with a certain sense of civic responsibility and under
> the assumption that their blood probably is going to be used in the
> geographic area. The Puget Sound Blood Center was mentioned, the
> majority is within the Seattle area of surrounding counties, and I
> suspect that that is what most donors would expect.
>
> Is there a reaction on the part of donors if they understand, if they
> are in an area where there is excess red cells being collected, that
> it may be sent anywhere around the country? Does that tend to defer
> people from coming in to donate, and is that an issue that needs to be
> addressed as we look at the supply and distribution of blood?
>
> DR. SIMON: The general rule over the years is if you educate donors
> about that, they are agreeable to having their blood used for anyone
> who is in need. So, as long as people have been educated
> appropriately, this does not seem to be a serious issue.
>
> DR. FITZPATRICK: We heard an excellent report from Iowa at the meeting
> on a community blood center that produces an excess and exports, and
> the community is very supportive of that. I think there is proven
> community blood centers that are able to do that.
>
> DR. EPSTEIN: I think that we have not really looked strategically at
> what I would call large system issues, and I think one of the points
> that came across I mean clearly in a disaster, it is obvious that
> there is enough blood out there, in other words, there are enough
> qualified donors if you can bring them in.
>
> It has been said by many people that the crux of the matter is
> investing in recruitment efforts, but then that has a collateral
> effect on raising the cost of blood, and then we have, on the other
> side, problems with reimbursing any additive costs of blood, and I
> think that we haven\'t really looked at the economic issues that
> affect the whole issue of trying to bring in donors and that it is
> sort of an unspoken part of the problem.
>
> DR. NELSON: The cost of blood has really increased quite a bit
> recently. It was interesting that there was a mention of the
> reimbursement for that. I don\'t know if that is a continuing problem,
> but the cost has certainly increased, yes.
>
> DR. SCHMIDT: One often forgotten point in relation to what Jim Allen
> and the other statement is that local blood centers are not really
> operated by their CEOs who see this big picture, and if they are
> operated by their boards of directors, who are local citizens who are
> charged with having enough blood locally, but also cutting down the
> expenses or looking for other sources of income over expenses, and
> shipping blood out to a place like New York and supplying hospitals
> can bring income to those blood centers, so policies are made by those
> people and we generally just talk to the CEOs who, when they go home,
> they may hear a different story from their board of directors.
>
> DR. FITZPATRICK: Just to follow up on Jay\'s comment, while we know
> that there are plenty of donors available and that we can collect the
> blood after a tragedy or a disaster, the key element is that we have
> to have it available, on the shelf, at the right place, at the right
> time to meet the needs of the disaster, and 24 to 48 to 72 hours later
> is not the solution to the problem. The solution is having it
> available at the time we need it.
>
> DR. NELSON: The second item, if there are no more comments, is the
> summary of a workshop, an important workshop on pathogen inactivation.
> This was held in August at NIH.
>
> Dr. Vostal.
>
> DR. SMALLWOOD: While Dr. Vostal is coming, I would just like to
> apologize to the speakers. We are having some obvious technical
> difficulties. I am told that this LCD is not accepting the signal from
> the laptop, so we are trying to secure another one, hopefully, very
> shortly.
>
> **Summary of Workshop on Pathogen Inactivation**
>
> **August 7-8, 2002**
>
> **Jaroslav Vostal, M.D., Ph.D.**
>
> DR. VOSTAL: Thank you. Thank you for this opportunity to share with
> you the summary of a workshop we had in August. The title of the
> workshop was Safety and Efficacy of Methods for Reducing Pathogens in
> Cellular Blood Products.
>
> The objectives of the workshop were to review the different approaches
> to evaluating efficacy of pathogen reduction methods in cellular blood
> products, to establish the appropriate methodology for testing
> efficacy, to obtain consensus on what is the minimum level of efficacy
> required, to discuss appropriate evaluation of toxicity of the
> methods, and that is toxicity to the cellular product, as well as to
> toxicity to the recipient of the treated cellular products, and
> finally, to summarize the risks and benefits of using the
> pathogen-reduced cellular products in clinical situations.
>
> The outline of the workshop. The workshop was presented over two days.
> On the first day, we had an overview of the pathogens found in
> cellular transfusion products and the risk of transfusion-transmitted
> diseases from these pathogens and the ones we focused on were
> bacteria, viruses, and parasites.
>
> We then had an overview of the molecular mechanisms of pathogen
> reduction systems. Then, we had a discussion on the evaluation of
> efficacy for the methods against each class of the pathogens, and this
> was followed by a panel discussion.
>
> The first day ended with a presentation from the manufacturers, and
> they presented their own data on their individual systems.
>
> On the second day, we focused on toxicity. We started off with
> evaluation of toxicity to the cellular products, and we focused on
> platelets and red cells, and each session was followed by a panel
> discussion.
>
> We then moved on to an overview of toxicity and carcinogenicity
> evaluations for biologic products as is usually done by FDA, ad this
> was also followed by a panel discussion. Then, we had two talks on
> risk-benefit analysis, and this was followed by a public comment
> period.
>
> So, to get into the actual summary, for the transfusion-transmitted
> pathogens, it was pointed out that bacteria posed the highest risk,
> and the risk of a serious adverse reaction is probably somewhere
> between 1 per 10,000 to 1 per 100,000 platelet transfusions.
>
> For viruses, the transfusion-transmitted risk is a lot lower. It
> ranges somewhere between 1 per 1 million transfusions to 1 per 5
> million transfusions when these products are screened by NAT testing.
>
> Of interest was that the window period viral load can be very high, up
> to 10^8^, 10^10^, and 10^12^ particles/ml for HAV and B19 viruses, and
> also interesting was that low levels of virus maybe at 10^2^
> genomes/ml can transmit disease.
>
> For parasites, it was noted that these are emerging diseases that we
> should be concerned about. An example is Chagas disease, which there
> is 1 in 25,000 donor seropositive for Chagas disease, and 63 percent
> of these are parasitemic.
>
> We then moved on to a discussion of the mechanisms or overview of the
> mechanisms of pathogen reductions, and it was pointed out that all
> methods involve addition of a chemical to a cell product that
> interacts with nucleic acids to kill the pathogens. All are therefore
> potentially mutagenic and carcinogenic. They also bind proteins and
> lipids, which may lead to unexpected toxicity to the product itself or
> to the recipient of those products.
>
> They do reduce the titer of extracellular or intracellular envelope
> viruses, however, their activity against non-envelope viruses is less
> defined. They can increase the titers of bacteria and parasites in
> blood, however, they are not effective against spores or endotoxin.
>
> The next session was a presentation or several presentations followed
> by discussions on the efficacy against viral agents. It is difficult
> to capture the discussion in a summary like this, but I will just try
> to point out some of the statements that were made.
>
> It was agreed that treatment will not eliminate current testing. The
> treatments may have potential to inactivate new and emerging pathogens
> not detected by testing, and they should have capability of 6 to 10
> log reduction in the viral load based on the window period loads.
>
> Again, it was pointed out that low levels of viral load can transmit
> infectivity, therefore, it would be good that the methodology would
> have excess pathogen kill.
>
> There was a discussion about a need for standard methodology for
> testing efficacy, for example, to define log reduction per ml of
> product, for the total bag of product.
>
> Then, we moved on to a session with bacterial pathogens, and some of
> the points made in that discussion was that contaminants are most
> often skin organisms, but donors with occult bacteremia contribute
> significantly.
>
> Both gram positive and gram negatives are associated with fatalities.
> Gram negatives produce endotoxin and do not require extended storage
> to reach toxic levels. Therefore, to eliminate these, the treatment
> needs to be pre-storage.
>
> In terms of what bacteria should be used to establish efficacy, it was
> suggested that a limited list of bacteria is sufficient. The list
> should include the most commonly found organisms.
>
> Finally, the clinical isolates of the bacteria should be used to model
> real life conditions.
>
> We then moved on to discussions of toxicity to the cellular product,
> and I am going to summarize the discussion that went on for both
> platelets and red cells.
>
> This evaluation is usually done in three parts. The first phase is in
> vitro studies, and it was pointed out that in vitro studies have
> limited predictive value for in vivo performance, and they should
> serve as a screening method for identifying gross damage to different
> aspects of cellular function.
>
> In Phase II, these are small clinical studies. These are usually done
> with radiolabeling and reinfusion of controlled and treated cells.
> Recovery and survival and circulation post-infusion are the readouts
> of these experiments.
>
> There was a discussion on the necessity for establishment of uniform
> control and for platelets, this was considered to be fresh platelets,
> and a discussion on the minimal acceptable values for recovery and
> survival of these products.
>
> In Phase III clinical studies, these will be large clinical studies
> that look at the function and some of the functional endpoints of
> these products should be bleeding for platelets and oxygen delivery
> for red cells.
>
> These kind of studies should also follow kinetic endpoints, such as
> transfusion response and frequency of transfusions.
>
> We then moved on to a discussion on evaluation of toxicity to the
> recipient of these products, and this was a presentation to
> demonstrate how FDA reviews toxicity in general and to get advice on
> whether this is appropriate for pathogen-reduced products.
>
> So, we covered general toxicity studies for biologic products, and
> these are usual animal models in small clinical trials. We talked
> about genotoxicity studies, which are aimed at identifying gene
> mutations and chromosomal aberrations, and usually, this required two
> in vitro studies and one in vivo study.
>
> Carcinogenicity studies usually require a long-term carcinogenicity
> study in rodents, usually up to two years. We are moving towards using
> transgenic animals, which shorten that period down to six months. CDER
> guidances are available for design interpretation of these studies.
>
> These products will likely be transfused to pregnant women, so
> reproductive toxicity is also an issue, and reproductive toxicity is
> studied in three phases. The initial phase evaluates toxicity to
> fertility, in general, reproductive performance.
>
> This is followed by the second phase is a teratological study in
> rodents and non-rodents, and this will be followed by perinatal and
> postnatal toxicity in rodents, a unique toxicity that may be
> associated with these products with the generation of immunogenicity,
> so we had a presentation that dealt with how to evaluate this.
>
> This is actually a difficult problem for not only these cells, but for
> other products. We found out that immunologic response to novel entity
> is not dose dependent and response could be to the original compound,
> metabolites, treated cells, or treated plasma proteins.
>
> Animal models for immunogenicity may not be relevant to humans, and it
> was pointed out that this may be a low frequency event, it might not
> be detected in preclinical or clinical studies, and that postmarket
> surveillance would most likely be the way to attract these problems.
>
> Another unique toxicity that may be associated with these products is
> toxicity to the health care workers. These individuals will be
> handling high concentration of the chemical compounds and may be
> actually the highest risk population when these methods go into
> clinical use, and safeguards need to be in place for their protection.
>
> So, then, we moved on to the final portion of the workshop, which was
> a risk-benefit analysis, and we had two talks. I think the main point
> was that the blood supply is very safe, as it is today, that bacterial
> contamination is the highest infectious risk, but there are other
> risks, such as medical errors, that are even 10- to 100-fold higher
> risk category.
>
> The chemical treatment of blood decreases effectiveness of the
> transfused product and adds toxicity to the recipient that is not
> clearly defined. Pathogen reduction may be appropriate for certain
> patients, and the use pathogen-reduced products should be a medical
> decision, not a regulatory decision.
>
> Finally, the cost of implementing universal pathogen reduction should
> be weighed against other approaches, such as bacterial detection.
>
> So, that concluded our workshop. I would be happy to answer any
> questions.
>
> DR. NELSON: Questions? Toby.
>
> DR. SIMON: This may be a question you can\'t answer, but can you give
> any further guidance timewise as to when we might expect to see such
> technologies be approved and come into use?
>
> DR. VOSTAL: It is difficult to say because there are problems on the
> company side, as well as on the regulatory side, in terms of review,
> so I would say we are still maybe five years away from routine use.
>
> DR. FITZPATRICK: Based on the meeting, do you see the need to revise
> or change any of the guidance documents that are currently used by
> industry to develop the path for submission of applications for these
> products?
>
> DR. VOSTAL: I am sorry, I didn\'t catch the first part.
>
> DR. FITZPATRICK: Based on the meeting, do you see the need for FDA to
> revise or put out different information regarding any guidance
> documents that industry uses to submit applications for approval of
> these products?
>
> DR. VOSTAL: I think that is a good suggestion. We have certainly
> covered a lot of area in terms of how to evaluate platelets and red
> cells, so we have a platelet testing guidance we would like to update
> with that information. We would also like to put together a red cell
> guidance to have a similar type of thing.
>
> Of course, we do not yet have a guidance for pathogen reduction, and
> that will be very helpful to have for other companies to follow, so
> based on what was presented at the workshop, we will try to put
> something like that together.
>
> DR. NELSON: Thank you.
>
> Next, our two speakers are going to review an emerging issue, mainly
> West Nile virus and blood safety.
>
> First, is Dr. Marfin from the Division of Vector- Borne Infectious
> Diseases from CDC.
>
> Dr. Marfin.
>
> **West Nile Virus and Blood Safety**
>
> **Anthony Marfin, M.D.**
>
> DR. MARFIN: Good morning. I apologize to people. I see a lot of
> familiar faces. This is very similar to the talk that I gave last
> week, but I promise you there is going to be updates of numbers, and I
> promise you that there is even some new maps in there.
>
> \[Slide.\]
>
> Here is the order of topics. I will just say a few things briefly
> about the virus. Then, I am going to talk about the viremia infection,
> the antibody response. I am an epidemiologist, so you know that I am
> going to talk about the epidemiology because that is what has really
> predominated our time in Fort Collins anyway.
>
> With regards to the epidemiology, I am going to emphasize the
> geographic spread over the years since 1999 with special emphasis on
> the 2002 epidemic, which we are probably in about the middle of. Then,
> I am going to talk about a special case that we have been
> investigating with regards to confirmed West Nile virus infection that
> occurred in organ transplant recipients.
>
> \[Slide.\]
>
> West Nile virus is a flavivirus. Flavivirus is a big family, but there
> are only a few human pathogens. Most of the human pathogens are, in
> fact, arthropod-borne other than hepatitis C.
>
> Specifically, with regard to West Nile virus, it is related to yellow
> fever and dengue, and these are classic human pathogens. They can
> achieve high viremia and I should emphasize here that they have never
> been associated with a transfusion-related case of illness.
>
> West Nile virus is only distantly related to hepatitis C. West Nile is
> part of the Japanese encephalitis serocomplex, and there has been a
> similar virus, an almost identical virus, that has been in the United
> States since 1933, when there was an outbreak of about 2,500 cases in
> St. Louis, St. Louis County, and the surrounding areas.
>
> Almost all the members of this serocomplex, there is eight members in
> the serocomplex, and all of them are primarily bird viruses. They make
> birds sick, that is what they do. Human beings, horses, we are not an
> amplifying host that we know of. We have never served as a reservoir
> for any of these eight in the Japanese encephalitis serocomplex. We
> are merely incidental hosts.
>
> Despite that, the West Nile virus since its introduction in 1999 into
> New York City has caused quite a stir, and I am going to show you why.
>
> \[Slide.\]
>
> Just a little about the infection. I want to emphasize this because
> this is the part that has somewhat been lost over the past few weeks,
> and that is, essentially all infections in the United States are due
> to mosquito bites.
>
> Over the years, there have been infections that have occurred in the
> lab either due to percutaneous injury or inhalation, but I want to
> emphasize that when I get to the numbers, that almost all of those are
> due to mosquito bites.
>
> With regards to the incubation, illness onset usually occurs about two
> to six days after infection. Again, these are measured in settings
> where the infections are due to mosquito bites. There may be some
> variation if we identify new modes of transmission.
>
> The bite will occur. You get local viral replication. You get more
> replication in the regional lymph nodes, and this has been studied
> extensively in animal systems.
>
> There is supposed to be a primary viremia in which the virus will
> spread from the regional lymph nodes to seed and replicate in the
> liver and spleen. This has not been demonstrated in humans, it has
> been seen in animal systems.
>
> Then, there is a secondary viremia that leads to invasion of the
> central nervous system, and it can result in febrile headache, which
> we call West Nile fever specifically. It can result in aseptic
> meningitis or it can result in encephalitis.
>
> An important part when speaking last week and this week to people that
> are interested in transfusion is that the second viremia lasts five to
> six days, and this has been shown primarily in studies from the 1950s
> in Israel, as well as some experimental evidence from human beings
> also done in the fifties in cancer patients where the West Nile virus
> is being used as a therapeutic agent.
>
> One of the problems when you look at these studies, especially the
> ones in Israel in the mid-fifties, are that this peak viremia occurs
> the day before illness onset, and that is not helpful to people who
> are wanting to have clues as to whether somebody is infected with West
> Nile virus.
>
> \[Slide.\]
>
> We have been involved in some recent West Nile fever studies in
> Louisiana this year, and we have screened approximately 250 people who
> presented to a health care facility with headache, fever, and no other
> identifiable source of infection.
>
> In those people, we have collected an initial serum sample, measured
> it for IgM to West Nile virus, but in addition, we have used NAT to
> see if there is any West Nile virus in there, and they are currently
> being set up for culture.
>
> We have had the opportunity to identify three seroconverting people,
> people who had no evidence of West Nile virus infection on their
> initial testing, and then two weeks later, have IgM antibody to West
> Nile virus.
>
> In fact, some of these people progressed to encephalitis, which is a
> relatively new finding. We have always assumed that people declared
> themselves. When you get infected and then you go on to illness, you
> are either in encephalitis, meningitis, or febrile headache.
>
> In fact, we have measured people that go from the febrile headache to
> the encephalitis, but one of the things we haven\'t been able to do is
> we haven\'t been able to measure any viremia in these seroconverting
> people.
>
> They initially present to us. There is no IgM in their blood, and when
> we put them through our TaqMan testing, we are not able to demonstrate
> the presence of any sequence due to the West Nile virus.
>
> In fact, isolating virus in the United States since 1999 has been very
> difficult. We only have one documented human isolate.
>
> This was from a person who had very low levels of immunoglobulin and,
> in fact, NIH and the State of Maryland were able to make several
> isolates from this gentleman, and it is my understanding that he
> recently died despite treatment with intravenous immunoglobulin that
> was sent to the NIH center from Israel, and the Israeli population and
> immunoglobulins from Israel tend to have a higher concentration of
> antibody to West Nile virus.
>
> So, I am going to come back to this last point, and that is, that in
> the fifties, when you go back and you look at these studies,
> especially the Israeli studies, that, in fact, humans develop a very
> low concentration of virus, about 10^3^ or 10^4^ virus per ml.
>
> Our primary method of diagnosis for West Nile virus over the
> years\--and it is kind of old hat for a lot of people who want to use
> Taq polymerase\--is serology.
>
> When I came to the Division of Vector-Borne Infectious Diseases, we
> still had to learn about complement fixation and hemoagglutinin
> inhibition, and I am glad to say those are gone, but now we rely
> primarily on looking at viral-specific IgM and IgG, but I am just
> going to summarize it by saying that with regard to the flavivirus,
> this can be a problem.
>
> Despite those problems, about 95 percent of people will develop West
> Nile virus IgM antibody by the eighth day of illness, and something
> that we have seen at least empirically, and we are going to have to
> look at it a little more closely, is that as the IgM titers go up, the
> viremia rapidly drops.
>
> \[Slide.\]
>
> I actually did this on the plane two days ago, so you will pardon
> those curves, but what we are able to see in the green line is that
> the viremia is peaking just before the illness onset. Illness onset is
> shown by that dotted white line.
>
> By the first or second day of illness, that IgM is coming up rapidly.
> In fact, it is almost the rule given the sensitivity of our serology
> testing now, that when people come in with illness, that we are
> already able to demonstrate that they have IgM to West Nile virus, so
> that goes up rapidly.
>
> It peaks at about day 14 to day 21, and then it starts to decrease.
> What we have seen, at least in our New York City cohort, is that about
> two-thirds or three-fourths of those people are still going to have
> IgM antibody in their blood a year to two years later. That makes a
> little bit of a problem in terms of attributing last year\'s infection
> to this year\'s presentation of encephalitis.
>
> Then, with regards to the IgG and neutralizing antibody, which is
> primarily IgG, this usually starts to rise about the fourth to sixth
> day, and then it peaks about day 21, and then it lasts for a lifetime,
> and is supposedly protective for the rest of their life.
>
> \[Slide.\]
>
> Here are many diagnostic methods. There has been much discussion that
> there are no rapid diagnostic tests for West Nile virus. In fact,
> there are rapid tests. The truth of the matter, though, is that they
> are not ready for the use in large-volume industry, such as the
> transfusion industry.
>
> We do have West Nile virus antigen detection. This is primarily used
> for insect pools, and we are now going to start using them in terms of
> testing animal tissues, and it is simply a dipstick, we also have an
> ELISA, and it detects about 10 plaque-forming units per 100 lambda.
>
> We have amplification testing. We have both traditional RT-PCR and
> then we use TaqMan PCR, and for people that are not familiar with that
> real-time PCR, it involves the science of both Taq, as well as a probe
> that is chopped away, and then has a fluorescent signal when the
> components become liberated from that probe.
>
> With TaqMan, we are able to identify virus if it is present in this
> concentration as low as a 10th of plaque-forming unit per 100 lambda,
> which is about equivalent to 50 copies per ml.
>
> In addition, of course we still do virus isolation, which is not
> rapid, but for West Nile, it is rapid compared to some of the other
> ones that we have. The virus that we have in this country will come up
> positive in cell culture in about five to six days.
>
> Most of the other flaviviruses with which we work are up to two weeks,
> and sometimes will not grow at all. They are very, very temperamental.
> This virus does not seem to be. We also have immunohistochemistry in
> which we use both polyclonal and monoclonal antibodies to demonstrate
> the present of antigen in affected issue, and then, of course, the
> serology.
>
> Our classic serologies are IgM capture ELISA, IgG ELISA, and then the
> plaque reduction neutralization assay.
>
> \[Slide.\]
>
> With regard to the epidemiology, then, we know that the human
> infection rate correlates well with the mosquito infection rate in the
> Culex, BC\'s Culex, the urban Culex mosquito, the northern house
> mosquito, the southern house mosquito drives this epidemic. Although
> they are primarily bird vectors, they can develop such an infection
> rate that they can also bite horses, humans, and other mammals, and
> that is when we get into an epidemic situation as we have this year.
>
> From studies especially in Bucharest, in 1996, we know that infection
> rates are roughly equal across age groups. We also know that because
> of the work that we have done with regards to St. Louis encephalitis
> especially in Pine Bluff in 1991.
>
> We know that illness, and this is meningoencephalitis, primarily
> affects people who are 65 years and older. We have looked at infection
> rates in this country. We have done four serosurveys, and these things
> are exhausting, so we try to stay away from them, but there was one
> done in the Hot Zone of Queens in 1991, and it was demonstrated that
> 2.6 percent of the population had evidence of recent West Nile virus
> infection.
>
> I should point out that the survey area was extremely gerrymandered to
> look at the maximum seroprevalence rate that could be achieved. That
> is not a seroprevalence rate for the entire borough of Queens.
>
> In 2000, we had serosurveys in Staten Island, Suffolk County, and in
> the southern part of\--well, in Greenwich and Stamford townships. You
> can see that we had less than half a percent Staten Island, we had 0.1
> percent in Suffolk County, which is on Long Island, and in Stamford,
> we were unable to demonstrate anyone that had a recent West Nile virus
> infection.
>
> As I pointed out to the people last week, I was part of all three of
> these serosurveys. I literally walked the neighborhoods and birds are
> falling out of the trees. I mean there is an epizootic of undescribed
> proportion going on. There is crows that are dancing in the middle of
> the street everywhere.
>
> These two were hot zones at least from an epizootic standpoint. In
> that year, though, there were only 10 human cases reported from Staten
> Island. There were no human illnesses reported in Suffolk County and
> then in Connecticut site.
>
> \[Slide.\]
>
> This is part of the problem when we talk about West Nile virus. Very
> few people\--and that is the very top of this triangle\--very few
> people develop what we call meningoencephalitis, and this has been
> show repeatedly. It has been shown in Bucharest in 1996. It was shown
> in Volvograd in 2000. We have shown it here in the United States since
> 1999. The Israelis have had a similar problem over the year since
> 1998, have also shown that only a few people that are infected develop
> illness.
>
> In fact, what we find is that ratio is about 1 to 150. For every 150
> infections, you will get about one case of West Nile
> meningoencephalitis. For every 150 infections, you will get about 20
> to 30 cases of what we call West Nile fever - fever, headache,
> myalgias, flulike symptoms. All the rest of the people are going to be
> asymptomatic.
>
> They are going to have good antibody response. To the best of our
> knowledge, their viremia is the same as the top. In fact, the only
> difference is that you see that there are host factors that can
> account for this progression to West Nile meningoencephalitis. One of
> the ones that you will see discussed often is age.
>
> So, when we are talking about the top of the triangle, we are talking
> about primarily older people. When we are talking about the bottom of
> the triangle, asymptomatic infections, these are primarily younger
> people.
>
> \[Slide.\]
>
> Let me talk a little bit about the epizootic.
>
> \[Slide.\]
>
> In 1999, infected birds were reported in 28 counties. This is when the
> virus is first introduced into the country.
>
> \[Slide.\]
>
> In 2000, 136 counties reported infected birds. These are birds that
> people picked up and actually demonstrated the presence of virus.
>
> \[Slide.\]
>
> In 2001, there were 328 countries. You are seeing a theme here as it
> is moving centripetally.
>
> \[Slide.\]
>
> Let\'s talk about the components that led to this year.
>
> \[Slide.\]
>
> In 1999, human infections\--this is meningoencephalitis\--human
> illness, meningoencephalitis, was reported from six counties.
>
> \[Slide.\]
>
> In 2000, we now are talking about 10 counties, but it has really not
> moved out of the New York City metropolitan area.
>
> \[Slide.\]
>
> This is the growth year here. In fact, 39 counties reported human
> infections, but you can still see this primarily along the eastern
> seaboard. It is maybe spreading a little to the west, down in the
> south.
>
> You will see one county down in Louisiana, Jefferson County, in which
> there was one case reported, but as you will see in the later map,
> this was a harbinger of sorts.
>
> \[Slide.\]
>
> So, these are the human cases from 1999 through 2001. In 1999, despite
> intensive investigation, only 62 cases. In 2000, we are bringing on
> almost every state east of the Mississippi to find cases. Only 21
> cases identified. Last year, there were 66 cases from 10 states in 39
> counties.
>
> I will take the opportunity now to show that, in fact, the illness
> onset date is very long for this disease or for this epidemic. The
> earliest onset in 2001 was the middle of July, but the latest was just
> before Christmas, and that is not unusual.
>
> We have cases from Massachusetts in late November, so it is not just
> the addition of the southern states.
>
> \[Slide.\]
>
> Again, a summary of any activity in the United States, and we will go
> right to 2001. Last year, there were 28 states or 358 counties in 28
> states, and you can see that samples were collected from the beginning
> of April all the way until the day after Christmas.
>
> \[Slide.\]
>
> So, where are we now?
>
> \[Slide.\]
>
> This is as of yesterday, so this is the update from last week. There
> are now 42 states and the District of Columbia that report any West
> Nile virus activity in animals. There are now 30 states and the
> District that are reporting human West Nile virus illness. This is
> fever or meningoencephalitis. Now, we are up to 1,201 human illnesses
> that were reported. This includes 46 deaths. Approximately, 60 to 70
> percent of that 1,200 are due to West Nile virus.
>
> If you use that 150 to 1 multiplier, we are talking, in these 42
> states and the District, we are talking about 100,000 to maybe 130,000
> total infections. Those are not illnesses, those are infections. As I
> pointed out, about 80 percent of these infections are going to be
> completely asymptomatic.
>
> So, in terms of illness, it is relatively rare. When you start doing
> the multiplication by 150, numbers add up, but when you put it over 42
> states, it is still not all that frequent. We are not talking about
> influenza here.
>
> \[Slide.\]
>
> Here are the maps and here are the birds as of two days ago. You can
> see that the birds are predominantly being reported from the north
> central states. You can see several red areas especially up in Cook
> County there in Illinois, Harris County down in Texas, that is where
> Houston is, where they have hundreds of positive birds that they have
> been picking up.
>
> \[Slide.\]
>
> This is the map for horses, somewhat of a different area. Again, the
> red areas are the areas where the most horses have been reported, and
> you can see this is northern central, but a little further to the
> west. In fact, many of these counties don\'t have any positive birds
> at all, as you can see when you compare this to the map before.
>
> The first illness is a horse. Now, why is this important? Mosquitoes
> that bite horses also bite humans. They are mammalophilic as opposed
> to ornithophilic. People that live in these counties are at risk.
> There are not a lot of people that live in these counties, though,
> these are relatively low density except for my county right there in
> Colorado.
>
> \[Slide.\]
>
> These are the human cases. You can see that the human cases have
> spread way out of the New York City metropolitan area. In fact, when
> you look at the southeast, where in 2001, that is where a lot of our
> activity was, we have really shifted. We are now in the Mississippi
> River delta.
>
> The hot areas right now are, in fact, Houston, Texas, New Orleans,
> Jackson, Mississippi, Memphis, St. Louis, Chicago, Detroit, and
> Cleveland, right up the Mississippi River Valley. In fact, that is
> roughly the way that they were reported to us, ascending northwards
> along the Mississippi River Valley.
>
> By the way, this map here looks a whole lot like 1975, St. Louis
> encephalitis outbreak, and we are predicting that that is the kind of
> year that we are going to have this year.
>
> \[Slide.\]
>
> So, what are the problems? We have widespread and spreading activity.
> We have focal hot spots. It is not continuous. Again, this is not
> influenza. Activity can persist in a given area. Something I didn\'t
> mention earlier is that Suffolk County has had West Nile virus
> infections in humans reported four years in a row. That is something
> we haven\'t experienced a lot with St. Louis encephalitis for the most
> part. It is a relatively low human infection rate when you put that
> 100,000 over 41 states.
>
> Other problems are the peak viremia occur prior to the illness, 80
> percent of infected people are asymptomatic. Most of the symptomatic
> people are older and a lot of the are ill and not necessarily in your
> donor population.
>
> The most important one, like almost all the other viruses in the JE
> complex, they cause unpredictable, sporadic, and epidemic infection
> patterns, so that is a real problem.
>
> \[Slide.\]
>
> Let me just say something about the West Nile virus infections in the
> organ transplant recipients, which has pulled my division into making
> presentations at meetings like this. We don\'t do a lot of blood
> transmissible agent stuff.
>
> \[Slide.\]
>
> In late July of 2002, an eventual organ donor was in a motor vehicle
> crash. This person was a resident of the southeastern United States
> and from an area of moderate enzootic activity and low human activity.
>
> During the first 24 hours, there were valiant attempts to save this
> person, and that was surgery and massive transfusions. The person then
> survived another 18 hours until they harvested her organs and during
> that 18 hours, they were preparing the person for organ donation.
>
> There were five tissues that were collected. The two kidneys, the
> liver, and the heart did eventually go to four recipients. In late
> August, three of these four recipients had developed West Nile virus
> encephalitis. This is confirmed, there is no question that they
> developed infection, and one of those people died.
>
> Just recently, the fourth recipient was confirmed to have West Nile
> virus fever, and that is recent confirmation, in fact, they all
> developed illness approximately the same time.
>
> \[Slide.\]
>
> Two of the four cases had outdoor exposure after transplant. They went
> home. They went home to areas where there were mosquitoes biting. They
> went home to areas where there was enzootic activity. They went home
> to places where there might have been a human case. So, they have some
> outdoor exposure.
>
> They were residents of the southeast United States, but these two
> people did not receive any transfusions before their illness. The
> other two people had no outdoor exposure, they never went home after
> their transplant. They, too, were residents, so if they were to have
> received their infection at home, they would have had to have been
> done quite a bit before their hospitalization, but they are residents
> of enzootic counties, and they received lots of transfusions.
>
> \[Slide.\]
>
> What we tried to do very early on, then, is look at our organ donor to
> determine if this person had West Nile virus infection prior to the
> crash, and this is an exhaustive search by the Georgia and Florida
> state health departments, as well as CDC. All we came up with was 75
> lambda of early serum. This is serum that was collected prior to the
> first transfusion.
>
> We were unable to demonstrate any antibody to West Nile virus in
> there. Our TaqMan was negative, and the culture, I put \"culture
> pending,\" I am not sure that we had enough to culture, and if we did,
> I am not sure what it is going to mean.
>
> Since that time, by the way, about two ago we identified a new vial of
> serum that had been collected by police in terms of the investigation
> of the crash, and those have been sent to Fort Collins, so hopefully,
> this slide will change in the coming weeks.
>
> We then identified some late\--it says serum, but it is actually
> plasma from the organ donor\--and again, no antibody to West Nile, but
> now we had a very low level, but repeatable positive TaqMan for West
> Nile virus. This one, the culture is pending and it is still growing
> or it is not growing anything, but it is still incubating.
>
> \[Slide.\]
>
> You have to ask yourself, well, what about the transfusions. Here, the
> organ donor comes in, they are healthy, they are in a motor vehicle
> crash. There is no evidence that an encephalitis presentation
> contributed to that crash. In fact, they received blood products from
> 63 unique donors. Those 63 donors actually produced about 142
> co-components, and here is the breakdown.
>
> I don\'t have to tell you how massive the investigation is. There are
> 63 organ donors or blood donors for the organ donor that are going to
> be approached. There is 35 recipients of the co-components. There is
> 27 of these units, however, being returned from the fractionator, but
> 2 have already been pooled by a fractionator. The other ones have been
> expired, broken, discarded, or simply not distributed.
>
> \[Slide.\]
>
> So, where are we in terms of the investigation? American Red Cross has
> been invaluable in terms of their contribution. They have located the
> segments from donation that we are currently testing in Fort Collins.
> They have identified and retrieved in-date co-components that we are
> testing in Fort Collins.
>
> They are identifying the consignees that transfused the recipients of
> co-components. They are going to be identifying, and, in fact, they
> have already started identifying and contacting the donors, the blood
> donors to the organ donor, so that we can obtain more information, as
> well as test them for IgM to West Nile virus.
>
> They are assisting the state health departments, CDC, in terms of
> identifying the consignees, to do the same thing with recipients of
> potentially infect co-components. They, too, will be tested for West
> Nile virus IgM.
>
> \[Slide.\]
>
> So, the ongoing investigation then, what are we trying to do? We are
> trying to estimate the infection date of the organ donor. That is why
> we continue to look for tissues and liquid from the organ donor,
> because we are trying to figure out when this person was infected. So,
> we are continuing to test other tissue and blood.
>
> We are currently doing TaqMan PCR of the segments from the original
> blood donors, as well as any recovered products. Then, of course, as I
> mentioned in the last slide, we are going to be determining if the
> donors were recently West Nile virus infected, and that will be by
> doing serology for IgM, and then the same with the recipients.
>
> \[Slide.\]
>
> This is my second to last slide. I apologize for going over.
>
> This organ transplant very likely resulted\--I added \"very likely\"
> because that is the way CDC is, we are a conservative group. I would
> like to say that organ transplant resulted in these four West Nile
> virus illnesses in terms of the organ recipients.
>
> I don\'t think that that is going to be an arguable point. It is very
> unlikely that these four people were infected by mosquitoes and all
> came down with this illness, but we still have some more work to do to
> completely nail that down.
>
> I want to emphasize that mosquito bites are still the principal means
> of acquiring infection in endemic and epidemic zones in this country,
> but that transfusion, when you look at this case, you have to consider
> it. We have to go out and we have to ask ourselves whether the
> transfusions were the source of infection to the organ donor
> especially when you look at some of these results.
>
> But I think it is also fair to say that to date, there has been no
> case of West Nile virus infection that has been shown to be
> transfusion, and it still in there because that\'s the same thing I
> said week.
>
> Next and last slide.
>
> \[Slide.\]
>
> We are involved in other investigations. In fact, yesterday, we were
> on a conference call with the state health departments, all 48 of the
> contiguous states, and we are soliciting more case reports from the
> state health departments, and what we are doing is looking for
> probable or confirmed cases of West Nile meningoencephalitis in
> persons who received blood products in the four weeks prior to their
> illness onset.
>
> To date, we have been involved in investigations in Georgia, the one
> that I just described, as well as Mississippi, North Dakota, and
> Louisiana. So, right now we have about six ongoing investigations.
>
> That is it. Do you want me to take questions or wait until Dr. Goodman
> is done?
>
> DR. NELSON: Any questions? Harvey.
>
> DR. KLEIN: Could I ask you if those handful of lab infections that you
> reported, were they from concentrated virus or were they from human
> specimens?
>
> DR. MARFIN: It is a mix. In terms of the inhalation, it was from
> concentrated virus. In terms of the percutaneous injury, it could be
> working with infected tissue directly taken at necropsy, or it could
> also be concentrated virus, as well.
>
> DR. KOFF: I think you said we are halfway through the current
> epidemic. Can you give us some sense of what you would envision the
> total number of cases, and is this based on last year\'s experience?
>
> DR. MARFIN: We can\'t base this year on any year\'s experience with
> West Nile. What we are looking to is the 1975 outbreak of St. Louis
> encephalitis in which a large number of the cases occurred in the last
> week of August and the first two weeks of September, and it primarily
> affected the Midwest.
>
> The states at that time that were affected were Ohio, Illinois,
> Indiana, and those are the big three states. We are kind of seeing the
> same situation again this year. We are seeing Cleveland, we are seeing
> Chicago, we are seeing St. Louis, a very, very similar pattern. So, we
> are waiting for later reports meaning the September reports from these
> areas. In addition, there is always a lag with regards to surveillance
> data.
>
> DR. SCHMIDT: I would like to see in the record something I consider a
> correction. In the transfusion literature, in the recent report from
> the CDC, it states that another flavivirus, dengue, was transmitted by
> transplantation in Puerto Rico in sort of a background information.
>
> Well, that was 1995. Granted, the dengue laboratory for the CDC is in
> Puerto Rico, but at that time, I was the Director of Clinical Service
> for the American Red Cross in Puerto Rico, which supplied this
> particular hospital with all of its transfusion services and arranged
> through the Miami Red Cross to back up the bone marrow transplant.
>
> The case was two sisters. The timing was right that after the
> transplant, both developed dengue, however, just before the
> transplant, both sisters\' young children were at home, they shared a
> bedroom, and we heard about the urban Culex, well, there certainly are
> a lot of urban Culex in San Juan while I was there, and I remember
> specifically the admonition from the Health Department to be aware of
> the bedroom closet because that is where they were.
>
> So, I think the evidence for this dengue transmission by
> transplantation was circumstantial, and the significance only is that
> now it\'s in the transfusion literature as a fact.
>
> DR. NELSON: I think it may be very difficult to separate this out to
> exclude mosquito transmission even in somebody who has been
> transfused, but even if you have a couple of donors positive, that
> still doesn\'t prove that it was transfusion, so it is a difficult
> problem, I think.
>
> DR. MARFIN: I think you are correct. I think that what we would be
> looking for would be either demonstration of virus in the segment
> going into the organ donor in this case or you are identifying
> IgM-positive donors, and then you have potentially as many as three
> co-recipients\--that is a situation we haven\'t identified\--and then
> showing that they are all IgM-positive, as well. The likelihood of
> that would be low, but it is circumstantial.
>
> With regards to the dengue, I have spoken about this with my division
> director Duane Gubler, who has been looking for evidence of a
> transfusion excluded from transplantation, evidence of dengue like for
> 30 years, and he brought up that case, but I had to point out to him
> that there is transplantation involved there, so it is not as
> straightforward as we would like, but your point is very well taken.
>
> It is very difficult to show for dengue and yellow fever, not
> necessarily because it doesn\'t happen, but because the infection rate
> in the population is so high, how do you ever attribute it to the
> transfusion as exposed to exposure.
>
> DR. NELSON: But these organ transplants are pretty convincing at this
> point.
>
> DR. FALLAT: Could you amplify a little bit more about the parallels of
> this epidemic with the St. Louis epidemic to give us some at least
> speculation about what the future holds?
>
> DR. MARFIN: I can tell you that in 1974 through 1976, there were
> probably about 2,500 cases reported over that three-year time period,
> maybe a little more, but \'75 was the big year, and the infection
> rates were, as I mentioned, highest in Illinois, Indiana, and Ohio.
> Those were the big three. A lot of cases were in Chicago. They came
> actually late in the year.
>
> With regards to more about that, I mean it was very much like West
> Nile virus. It is predominantly older people who had West Nile virus
> meningoencephalitis. During that time, there were no cases of
> transfusion-associated St. Louis encephalitis reported.
>
> Did we have the technology to identify it, did we have the
> surveillance to identify it? Probably not. Do we have the capacity to
> go back and look at some of those things? It\'s a question that we are
> contemplating, but I don\'t think that we have any of the material
> left.
>
> DR. FALLAT: I was thinking more in terms of what has happened since
> 1975 with regard to the St. Louis virus, and would you speculate that
> the same thing is going to occur with the West Nile virus.
>
> DR. MARFIN: Oh, I am sorry. In fact, 1975 was a banner year and most
> of the country responded by intensifying the control of their urban
> Culex, and there were huge programs put into the control of urban
> Culex.
>
> As things will happen when diseases don\'t show up for a number of
> years, those funds for the control of urban Culex begin to dwindle,
> and, in fact, as we have come into this year and last year, that is
> what we have seen. We have seen large urban areas that used to have
> good mosquito control operations, they longer have those, they are not
> longer there.
>
> Has that contributed to the outbreak of West Nile virus now? There
> will be some people that would suggest that. Since 1975, there have
> been some outbreaks. In 1989, in Mesa County, Colorado, in Grand
> Junction, there was an outbreak. In 1991, in Pine Bluff, Arkansas,
> there was an outbreak. Last year in Northeast Louisiana, there were 72
> cases of St. Louis encephalitis in Northeast Louisiana.
>
> So, it is still out there, and you can see that the pattern is
> somewhat different. It is hitting, burning, hitting, burning, hitting,
> burning, and you are not seeing the persistence as we are in some of
> these areas, and you are seeing very focal outbreaks. There is no
> large tracts of area that are involved in the epidemic as they were in
> 1975.
>
> Why is that? I think that it is probably because this virus is coming
> into equilibrium with its mosquito vectors, it is coming into
> equilibrium with its amplifying hosts, and whether it gives us a St.
> Louis encephalitis-like pattern or whether it is going to forge its
> own pattern is simply not known, and we don\'t enough data yet.
>
> DR. LEW: Although it sounds like your CDC is asking for people to
> think of cases of people who get illnesses after four weeks, number
> one is why was four weeks chosen. I would assume that those who got
> the virus potentially from transplant had disease soon after, but if
> you could also elaborate on that, when did they have to start their
> illness.
>
> Also, I guess if the illness does come within four weeks\--is that
> what you are saying?
>
> DR. MARFIN: Within four weeks of transfusion, yes.
>
> DR. LEW: But what data is that based on?
>
> DR. MARFIN: Oh, the data. It is going back and looking at the organ
> transplants. Some of these people had illness onset as long as 19 days
> after the organ transplantation. I would have to go back and look at
> my line listing, but that is why there is always a consideration, did
> they get infected while they were out of the hospital during those 19
> days.
>
> But, in fact, if you look at them, they tend to be a little bit
> longer. I think, like you, a lot of us would have said these people
> have no intact immune system, why do we not have onset of illness by
> the second day or the third day, and, in fact, that was not seen. It
> would appear to be a little bit longer although I think one of the
> cases was within about four or five days.
>
> When you go back and you look at the 1957 data in which people with
> terminal cancer were given West Nile virus experimentally, you do see
> people who had viremia the very next day after they were injected
> intradermally with West Nile virus. In fact, those would be the higher
> levels of viremia that we have seen, but, in fact, illness came on, on
> the second or third day.
>
> So, that is a little bit of a difference here. These are organ
> transplants. Why is there that delay, and we do not know why, but that
> is why are we pushing out those dates. We now know that some people
> can become ill as long as 17 to 19 days out after infection.
>
> DR. LEW: One last question. Is that the only prospective study that
> you are reaching out to do, to look at possible transmission of West
> Nile?
>
> DR. MARFIN: I am sorry. Which study?
>
> DR. LEW: Well, it sounds like CDC is asking people to consider this
> and then refer it to you guys, but is there any other prospective
> study, or maybe the blood banks know, to try to take a look at that
> issue?
>
> DR. MARFIN: We do have a surveillance system in this country that is
> one of the CDC\'s few real-time surveillance system. It is called
> Arbonet, and Arbonet collects cases within days of their
> identification, and we are adding a new component to that, to
> specifically inquire of states and ill persons about transfusions, so
> those will also result in the potential identification of new cases.
>
> DR. LAAL: What is the Israeli experience with the West Nile virus to
> blood transfusions?
>
> DR. MARFIN: I am sorry, I don\'t know, but it is one of the things
> that is on our list of things to do. Last year they had hundreds of
> cases in Israel, as well as the year before. They have a very similar
> age structure to ours, they have a very similar medical system, but it
> is something that we are going to reach out and find out what their
> experience is.
>
> DR. FITZPATRICK: I am sorry, I might have missed it on one of your
> slides, but have you been able to get tissue samples from the organs
> and test any tissue samples from the organs that were transplanted?
>
> DR. MARFIN: The organs that were transplanted, yes. Some services will
> set up a routine biopsy as part of their postoperative care. Some will
> only do it when there is evidence of rejection. We have looked at, at
> least one of the kidneys, and we were unable to demonstrate any viral
> antigen in that kidney.
>
> Thank you.
>
> DR. NELSON: Dr. Goodman from FDA.
>
> **Jesse Goodman, M.D.**
>
> DR. GOODMAN: Good morning. Similar to Tony, I have to apologize for
> those who heard my presentation at the PHS Advisory Committee last
> week, but similar to him, I can say it is updated and I hope you find
> it interesting.
>
> I was going to say that it is not quite as dramatic, but perhaps in
> our case we have the regulators falling from the trees right now, at
> least that is how we feel late at night when we are working on this.
>
> \[Slide.\]
>
> Here is some background. Basically, the world of thinking about West
> Nile virus in blood changed on 9-4. Before that time, we were all
> concerned about the biological plausibility for transfusion
> transmission to occur, and this was based on the known transient
> viremia in West Nile virus patients, as Tony showed you, believed to
> be on the order of just days to perhaps a couple of weeks, the fact
> that most patients with infection are asymptomatic and therefore would
> certainly be at risk of being in a donor pool.
>
> The risk, though, was viewed as likely to be quite low. Why is that?
> Well, there is certainly on chronic carrier state known, and again, as
> Tony reported, some fairly extensive and systematic and also
> diagnostic studies from CDC reported pretty low yield of PCR in
> cultures in patients with West Nile disease. That would certainly
> suggest that once infected, you don\'t have prolonged viremia, even as
> detectable by a sensitive PCR assay.
>
> There have been no cases reported in prior years or in endemic
> countries. I didn\'t get the details of the question about Israel, but
> FDA did make at least an informal query to Israel, and the Israeli
> blood folks could not tell us about any cases of transfusion
> transmitted disease there.
>
> One point I would like to make about that is that, you know, just like
> the healthy public exposed to West Nile, it is possible that there
> could be transmission through transfusion and that many or most
> transfusion recipients would not have disease, but we need to bear
> that in mind, that the absence of evidence in other countries that
> this was not transmitted, the absence of evidence of transmission is,
> of course, not proof that transmission did not occur.
>
> CDC recently published some risk modeling based on the 1999 New York
> epidemic and an assumed six-day viremia and 100 percent transmission
> rate, and came up with an estimate that something like 1 to 2 in
> 10,000 individuals during an epidemic could conceivably be viremic at
> one time when they were in a donor pool.
>
> That is a useful estimate, but it is based on a number of assumptions
> and another epidemic.
>
> With plasma derivatives, we do know that closely related flaviviruses,
> which have been used in most of the inactivation schemes, these
> include enveloped viruses, such as BVDV, hepatitis C, et cetera, are
> very inactivated, but this situation is being looked at carefully I
> know by the plasma industry. Even though we are confident of this, it
> may be that other studies will be done.
>
> So, based on the above, FDA, working together with CDC and NIH, did
> issue the alert 8-17 about this possibility, trying to raise awareness
> and particularly in endemic areas or epidemic transmission areas be
> sure to be very vigilant about donor exclusion criteria, such as fever
> and prodromal symptoms.
>
> \[Slide.\]
>
> What about after 9-4? Well, that is the day when based on confirmation
> of diagnosis in multiple organ recipients and evidence that the donor
> may have been infected, we concluded there was a high likelihood that
> transmission has occurred via transplantation, as CDC just presented.
>
> As mentioned, the possible sources still remain natural mosquito-borne
> exposure or the multiple transfusions which this donor received. Given
> the number of multiple transfusions, a very high number, we are quite
> concerned that that could be a source in this case although there
> obviously are alternative explanations.
>
> So, there has been a heightened level of attention and concern. At
> present, though, there is still no proven transmission by transfusion,
> there is an increased suspicion with additional recent reports and
> some suggestive PCR results, which Tony didn\'t go into, but I believe
> are mentioned in an NMWR that is out or forthcoming.
>
> But this is a very incomplete investigation and ongoing at this point,
> and cultures, follow-up serology of these individuals is pending. In
> some of those instances, results are negative, as well.
>
> I think it is important to recognize and some of the questioning in
> this room before with Tony raised this, that the results of these
> particular few case investigations may, in fact, not be definitive.
> They may be or they may not, because individuals in areas with
> exposure to blood from potentially viremic donors have so far also had
> high potential for naturally acquired infection.
>
> So, follow-up serologies and PCR on any PCR-positive donors may be
> helpful in sorting this out, also, co-recipient tracking. Certainly,
> if one saw, as in the organ transplant case, a high number or
> co-recipients of products also developing disease in a similar time
> frame, this would be highly suggestive, so we want to be vigilant to
> that, and hopefully, CDC\'s increased awareness in reporting
> mechanisms could bring that to attention.
>
> In addition, if there were cases where there was long-term
> hospitalization prior to onset without mosquitoes flying around
> hospitals and having worked in many hospitals in the United States, I
> would say that mosquitoes do fly around hospitals, sometimes even bats
> and squirrels fly around hospitals, but this would seem helpful and
> unlikely.
>
> Another thing would, and it is hidden by the button, but an
> out-of-area case. I mean I think if we had an instance where blood
> from a highly epidemic area was routed to an individual who had been
> in an area with no ongoing transmission, and that individual developed
> disease, that would be the kind of thing that would make us all feel
> pretty strongly that this was likely going on.
>
> I think still getting back to the original point, it is biologically
> plausible, and I think I would be somewhat startled if this never
> occurred. The question is how often may this occur, is it a problem,
> and what would we need to do about it.
>
> \[Slide.\]
>
> So, what has been the public health response so far? You heard much of
> this from Tony. There has been a very close working relationship, very
> positive, between FDA, CDC, the States, the blood collectors in
> industry, and in the case of the organ transplant, HRSA, who regulates
> that area.
>
> You heard about the continued investigation. There has been withdrawal
> of all in-date products as soon as CDC and FDA were notified of these
> cases. There has been a lot of work, such as this, with you, but also
> with the blood community, the media, consumers, to share information,
> and I think this can be challenging because sometimes information can
> be difficult, especially complex information like this can be
> difficult to communicate effectively.
>
> On the other hand, I think the fact that we are sharing information
> helps increase trust and confidence and understanding.
>
> Also, this stimulates reporting that we want to do. It gives us the
> opportunity to try to do balanced-risk communication that keeps in
> mind the risk and benefits of transfusion and transplantation.
>
> I think we need to continually give the message that there is
> uncertainty of the current knowledge base regarding risk, and this is
> rapidly evolving. Tony and our other colleagues at CDC, I mean we are
> being spun like a yo-yo by lab results and reports coming left and
> right, and we need to keep equilibrium and a careful look at those,
> and things may change in a matter of hours, days, weeks, or they may
> not.
>
> It is still a very important point, and Jim Hughes of CDC made this,
> and I am sure Tony would agree, that the risk of West Nile virus from
> a mosquito bite right now is the big public health problem in this
> country. Of course, we are concerned about the safety of the blood
> supply, we are very serious about this, but that is another
> perspective.
>
> \[Slide.\]
>
> So, what is needed? Well, I think one of the questions that I heard
> before raised the question of how are we going to figure this out.
>
> I think to some degree these cases may help, particularly if we have
> some definitive ones, such as I suggested, but we do need to define
> the problem and rapidly deploy a research agenda, that retrospective
> studies are generally case reports and investigations, such as you
> have heard described, and others that may occur.
>
> But also there is a potential to use some of the banked studies from
> some of the transfusion study groups and a group of people involved
> with that, and the FDA and CDC had a phone conversation yesterday
> about trying to mobilize such a study with one of the banked groups
> that may have sites in epidemic areas.
>
> There is a need for prospective studies, we think, and a real
> important question particularly raised by some of the most recent
> testing data is that you saw the risk estimate from the original CDC
> study of Dr. Peterson based on the New York epidemic. It really
> predicted a very, very low incidence of viremia at a specific time in
> a donor population.
>
> I think we need to be sure that we are not, based on some of what we
> are seeing and our level of concern, that there isn\'t something
> completely different and unexpected going on, and so we are trying to
> work with various partners to mobilize a pretty rapid study during
> this season while transmission is still going on of the incidence of
> viremia in donors in an epidemic setting.
>
> An early study may not be a definitive one, but it may give us a
> better idea of the scope, if any, of the problem. This should include
> emerging hot spots and also we think controlled populations where
> there is no disease transmission particularly given issues that come
> up about PCR methodologies.
>
> Seroprevalence in frequently transfused individuals could be another
> study, studies to evaluate duration of viremia, et cetera, potentially
> needed laboratory research on the nature of the pathogen itself, its
> inactivation by various measures and conditions.
>
> \[Slide.\]
>
> Well, if we are identifying a significant problem, right now we don\'t
> know the seriousness or extent of it. As I said, we really believe we
> need to take this very seriously, and we want to prepare and move on
> these studies and on other things as if there were a problem. We can
> always then, if there is not one, at least have been ready, and if
> there is one, be ready as quickly as possible.
>
> So, it further intervention is needed, the basic arms of such an
> intervention could include the traditional donor screening and
> deferrals, and we have been asked questions at press conferences about
> could you exclude everybody with mosquito bites, et cetera.
>
> Obviously, this would not be a particularly sensitive or specific
> intervention. We suspect that lots of people who maybe do not recall
> mosquito bites could be infected, and certainly the vast majority of
> people we know from the epidemiology, everyone in these areas is
> bitten by mosquitoes, yet, you saw seroprevalence data of 2 percent in
> some of these outbreak situations.
>
> So, it wouldn\'t be effective and given current problems we heard
> about earlier today with supply, it could harm a lot more people than
> it could potentially even help even if this were a true threat in the
> blood supply.
>
> It is possible that one could hone this if our CDC and State
> colleagues could identify sort of hyperepidemic areas, and if those
> seem to be the places where this risk were occurring, it is possible
> that one could try to, as a temporary measure, remove donors from
> those areas if this were an emergency and the risk was identified and
> present and threatening lives.
>
> If that occurred, there would be supply implications, as well, but I
> think again we would have to understand that we were dealing with a
> potential public health emergency. So, this is just something to look
> at.
>
> Again, I would like to say none of this is FDA or CDC policy or
> recommendations. We are still in the early stages of an investigation
> to determine what is going on, but we are concerned.
>
> You heard earlier from Jaro that there was a recent workshop. There is
> a lot of very innovative work going on in industry about pathogen
> inactivation. This is an area where there may be targeted products or
> targeted recipients or targeted areas that could potentially evidence
> a favorable risk-benefit ratio for considering those kinds of
> interventions under the right circumstances.
>
> So, it is just something that we all need to recognize that although
> currently unlicensed, it is a potential part of our armamentarium.
>
> \[Slide.\]
>
> Well, a lot of questions raised about testing of donor blood if it
> were needed, and if it were needed, we would have to ask who needs it,
> should this be general screening of all blood versus should it be
> possibly targeted screening if we can identify high-risk transfusion
> recipients, or at-risk areas in terms of the donor pool, or defined
> time periods which we heard are rapidly expanding.
>
> Antibody testing appears to be unlikely to identify most early
> asymptomatic donors with viremia, but whether, for instance,
> hypersensitive IgM assays might detect some, we just don\'t know that
> at this point.
>
> It would appear that direct detection is\--it is funny, this reminded
> me when I have been thinking about it, it is also the reverse of the
> HIV situation where the window period is where most transmission is
> going on, and there sort of is no other period, so our focus here is
> really on a window period\--direct detection therefore would be most
> likely of potential value.
>
> Of course, there is nucleic acid amplification, as Tony has described,
> this can be quite sensitive, although we need to say that the levels
> of virus in blood appear quite low and one questionable issue is
> whether this would be sensitive enough to do on pooled specimens, such
> as done with NAT for HIV and hep-C. Antigen detection methods have
> been developed, but are significantly less sensitive.
>
> These assays have really been deployed and developed in research and
> clinical lab settings. They have not been applied to samples where you
> would expect the overwhelming majority of samples to be negative and
> from healthy donors, and so their performance in that setting is
> unknown at this time.
>
> So, there are challenges in terms of transferring research and
> academic and public health lab technology to an industry blood banking
> setting, the issue of validation and use for donor screening in low
> prevalence populations. These things can\'t be underemphasized.
>
> There is many things that are wonderful in one center or one lab, that
> when the rubber meets the road, there are bumps, but on the much more
> positive side, and I have tried to say that I think if we have a
> problem here, you know, this country and our industries and our
> scientists have the capability to respond to this.
>
> It may not be overnight, but there are facilitating factors, one of
> which is all the industry, blood bank, and FDA experience with
> existing NAT testing. Those platforms are out there, the testing
> centers are out there, et cetera.
>
> Another is that some of these diagnostic technologies currently in
> use, I think would be promising for adaptation into that, and that
> might speed availability again at least in targeted areas potentially
> under IND, et cetera, again, if this were needed.
>
> \[Slide.\]
>
> In finishing, the investigation continues. I think we should not
> underestimate the level of alert and level of concern we all have.
> Even though the risk has been believed to be quite low, I think we
> need to be sure that we work hard to be sure of that and to define it.
>
> We do need to better define that risk, as I said, and strategies
> potentially to mitigate it. There has been really close interagency
> collaboration and the blood industry has been extremely cooperative.
>
> There has been good communication and information sharing with
> multiple parties and again I think that there has been a balanced yet
> flexible perspective on the level of risk, but it is a real challenge
> to keep doing this with rapidly evolving, almost on a daily basis, and
> an uncertain situation, and sometimes scientists and public health
> people and regulators, we just have to I think be candid and share the
> information and try to explain the complexities of it, but, you know,
> that is life.
>
> FDA, we are certainly considering the need to move towards guidance
> for industry, and I think we are going to be planning to move in that
> direction rapidly, but again, given the changing target here, we want
> to be able to adapt to that in terms of what the guidance is.
>
> For now, we have been involved with CDC and others in communication
> with industry that has encountered these cases or questions related to
> West Nile, to try to be helpful and consistent in those
> communications, and we welcome that.
>
> If there is a potential need for a donor screening test, and I would
> say there certainly is a potential need at this point, we feel it is
> important to be as ahead of the curve as possible and encourage and
> facilitate technology development and transfer.
>
> I would say that is probably true given what has gone on this year
> with the expansion of this epidemic. This may not go away, and that
> even if we don\'t have a big blood problem this year, we should at
> least have the things in place, so that if one were to develop, we
> could deal with it.
>
> To that end, we are planning and working with both the blood community
> and the medical diagnostic device industry to try to bring people
> together to begin to move forward on these issues there.
>
> That is really about it. In terms of the BPAC, we welcome discussion
> here, we welcome input, and I know that FDA and CDC will continue to
> seek that input.
>
> Thank you very much.
>
> DR. NELSON: Thank you.
>
> Yes, Judy.
>
> DR. LEW: Could you help put this, or maybe CDC, as well, in
> perspective in terms of we heard that maybe 100,000 people have been
> infected, how does this compare to St. Louis eastern equine, western
> equine?
>
> I mean these are diseases we expect to see during the summer, so if it
> is truly epidemic of West Nile, I mean in comparison to the other
> encephalitides, which we normally would test for if we saw
> encephalitis.
>
> DR. GOODMAN: Maybe Tony can answer, but this is an epidemic in this
> country at this point, and there are less cases of these other
> diseases right now.
>
> Do you want to comment?
>
> DR. MARFIN: Just to reiterate what Jesse said, if we looked at last
> year, we are talking about potentially 900 to 1,000 total infected
> people for the entire year, so this is out of proportion to previous
> years.
>
> Theoretically, it should be about the same as St. Louis encephalitis,
> in fact, the ratio is about the same. It is about 1, in that case, it
> is a little higher, 200 to 300, and the patterns, the viremias, all of
> the things are almost identical. It is almost the same virus. With
> regards to eastern, in fact, it does have a higher attack rate, so it
> would be a relatively small number.
>
> The fact of the matter is, though, that we are not seeing most of
> those. We have not seen western equine encephalitis in this country
> for many years. Every year, there are 100 to 150 cases of La Cross
> encephalitis, but that primarily affects younger people, 9-year-olds,
> 10-year-olds, that are not donating.
>
> So, in terms of arboviruses, this is a brand-new phenomenon given what
> has been going on with the others for the past few years.
>
> DR. LEW: I recognize for West Nile, since it is new to this country,
> this is truly an epidemic, but just in terms of perspective, we are
> talking about we are worried about West Nile in our blood system,
> whatever, but St. Louis has been around and every year it infects so
> many people.
>
> So, comparatively, is it just meeting what St. Louis has always been
> at its baseline, not epidemic, or is this really much more than even
> St. Louis at this time. Do you see where I am going with this?
>
> DR. MARFIN: Well, I can say that we have had epidemics in the past 25
> years of St. Louis encephalitis. Last year, there were 72 cases in one
> city in Louisiana. There were no other cases in the country or one or
> two.
>
> That is the pattern that they have established. It is very focal. It
> is periodic. The last one before last year was 1991, so we haven\'t
> had an outbreak of St. Louis encephalitis, a focal outbreak, in 10
> years. So, it is very, very spotty.
>
> I don\'t know whether West Nile virus is going to become like that. I
> just know that this year we have a lot more cases than we would have
> anticipated.
>
> DR. GOODMAN: I think a legitimate comment and maybe where you were
> coming from is there are probably other viral diseases that cause
> transient viremia and offer the theoretical possibility of
> transmission in blood, and we just need to keep this in perspective
> with other risks and other infections.
>
> But we are dealing here with this striking transplant case and with
> some reports of at least cases potentially associated with, but not
> clearly due to, transfusion. So, I think we do have to keep that in
> perspective, that is different, and obviously, there is much more
> influenza, and influenza can be in your blood for a short time.
>
> We are not aware of horrendous problems with influenza such as this,
> but again, how robust are our studies and monitoring systems to detect
> that. So, in a way we have a challenge here. I mean it is a modeling
> for many things. It is a model for dealing with a new potential threat
> to blood, but it is a model also to keep that in perspective and try
> to respond to it responsibly and with changing and grossly deficient
> knowledge.
>
> DR. NELSON: I think this epidemic sort of illustrates that there are
> many different agents that come and go, and this year West Nile is
> very important. It would be good if there were sort of an ongoing pre-
> and post-transfusion serum bank linked to donors that we could look at
> risks, and there were in the past, the TTV study, the FACT study, et
> cetera.
>
> As far as I am aware, there is no ongoing large, I mean NIH has some
> follow-up, but in terms of a comprehensive database that we could go
> look at a new risk, I don\'t think there is one. It is often hard to
> make a case that, well, something is going to happen and we need to
> know it. It is always retrospectively, after it happens, and then you
> can\'t get the data that you really need.
>
> During the FACT study, we studied several different agents
> sequentially, not what we started with, but it is has always been
> difficult to get that funding, but it would be good if we had a
> donor-linked pre- and post-transfusion that we could look at, because
> with most infections being asymptomatic, both in the donor and the
> recipient, you are really looking at a really small iceberg when you
> are looking at clinical events retrospectively.
>
> DR. GOODMAN: Right, and I think some of the repositories\--again, Jay
> and many of you at the table know much more about this than I do\--but
> some of the repositories like REDS, RADAR, et cetera, are potential
> resources for looking at this.
>
> DR. HARVATH: Ken, I would like to say that the NHLBI REDS study has
> the RADAR repository, and I think Mike Busch would like to describe
> what the discussions have recently been about utilizing that.
>
> DR. BUSCH: Yes, the RADAR repository is being put down by REDS. It is
> actually a collaboratively supported study with CDC. There are five
> large blood centers, main REDS centers, plus two CDC-supported sites
> that are currently freezing down donation samples pre-transfusion, and
> then follow-up samples from recipients. I think the total goal is
> about 10,000 recipients, about 50- to 100,000 units that went into
> those recipients plus additional donations that didn\'t go into the
> recipients are being frozen down in parallel.
>
> These include some of the hot spots. Detroit is one, and, in fact,
> will likely include Detroit in an initial study of West Nile
> prevalence. There is also a study at NIH that is called the TRIP
> study, that Harvey Alter is conducting. It is kind of interleaved with
> the RADAR, it has got more frequent recipient sampling.
>
> In this particular epidemic, it is turning out are the sites where we
> are recruiting these donors and recipients at the hot bed of the
> epidemic, and so we are realizing that we need to supplement what we
> are going to do with RADAR with some unlinked and then downstream
> linked studies in some of the other hot zone regions.
>
> MR. RICE: Just a clarification. With respect to an identified donor
> that went into a manufactured pool, the current way that that is being
> handled is a withdrawal situation of in-dated product as opposed to a
> recall, and has there been any established like effectiveness check as
> follow-up since you are taking the product out of circulation as a
> result of an identified donor post-manufacture, is that the way that
> it is currently being handled as opposed to a more formal situation in
> a recall sense?
>
> DR. GOODMAN: I will let Jay comment, but in the absence of guidance,
> which as I said we are working towards, that is the way it is being
> handled, but FDA has been involved very directly in each of these
> cases with the blood organizations.
>
> Jay, any comment on that?
>
> DR. EPSTEIN: Yes. We have not been recommending withdrawal of pooled
> products, in other words, there have been no plasma derivatives
> withdrawals.
>
> At the present time, however, it is also the case that we have not
> been told of a product that contained a unit made from a donor who
> potentially may have transmitted to a component recipient, but our
> current perspective is that we have reviewed all of the validation
> data for virus inactivation of the plasma derivatives. In all cases,
> representative viruses in the Flavivirus family were studied, so we
> believe that the products will remove or inactivate, and the
> processing will remove or inactivate this flavivirus.
>
> We have a dialogue ongoing with the fractionators to talk about
> additional studies with the West Nile virus, but bear in mind that
> these products have been made safe for hepatitis C and that all of
> that was done with marker virus studies since you can\'t grow
> hepatitis C in vitro.
>
> So, we do think that the safety profile is very good, and we are not
> at this point in time asking for derivative withdrawals. What we have
> bee doing case by case is discussing with the blood centers retrieving
> any in-date components from the donors when the donors are under
> investigation for the possibility of having transmitted through
> components to a recipient.
>
> DR. GOODMAN: And we are asking for retrieval of any plasma that has
> gone to fractionators, as well.
>
> DR. EPSTEIN: Right.
>
> MR. RICE: So, you are retrieving the components, but not the
> derivative products.
>
> DR. EPSTEIN: That is correct.
>
> MR. RICE: Okay.
>
> DR. NELSON: Other comments?
>
> Thanks, Dr. Goodman.
>
> DR. GOODMAN: Thank you.
>
> DR. NELSON: The next item is a discussion of Self-Administration of
> the Uniform Donor History Questionnaire for First-Time Donors.
>
> Dr. Alan Williams.
>
> It has been suggested that maybe since there are several
> presentations, we are a bit behind, maybe we should take a break and
> do it afterwards, and then up until the lunch hour, we will discuss
> the whole issue rather than have one or two presentations and then a
> break.
>
> DR. WILLIAMS: It sounds fine particularly since those aren\'t my
> slides.
>
> \[Laughter.\]
>
> DR. NELSON: We will come back at 10:30, please.
>
> \[Break.\]
>
> DR. NELSON: Dr. Williams.
>
> **Self-Administration of the Uniform Donor**
>
> **History Questionnaire: First-Time Donors**
>
> **Background and Introduction**
>
> **Alan Williams, Ph.D.**
>
> DR. WILLIAMS: Again, good morning. I would like to start off with just
> a brief administrative announcement before getting to the topic.
>
> As many of you know, blood establishment registration, which is for
> blood and plasma collection establishments and all FDA-registered
> laboratories, is required annually near the end of the year.
>
> We would just like to provide a heads-up that it is FDA\'s intent this
> year to offer an electronic version of this registration form. This
> form is actually going to mimic the paper form and will be available
> with last year\'s data and can simply be modified electronically and
> resubmitted.
>
> The detailed information about this and the instructions for
> completion will be sent to all registrants at the time of renewal, and
> acknowledgment of receipt of the form will still be done manually just
> to ensure that everyone knows that the material has been received. So,
> just an indication of FDA\'s intent in this direction.
>
> \[Slide.\]
>
> The major topic for discussion is a follow-up to previous discussions
> regarding the revised Uniform Donor History Questionnaire which has
> been under active study by an interagency task force coordinated by
> the American Association of Blood Banks, and the decision point for
> today really concerns whether components of the questionnaire should
> be self-administered versus administered by oral interview or
> equivalent means.
>
> \[Slide.\]
>
> I would like to start of the discussion just by establishing a little
> bit of context as far as regulatory oversight of the mode of
> administration of the donor screening process as opposed to the
> content of the screening process.
>
> Prior to the early 1990s, there was really no regulatory position on
> donor screening methodology and industry practices tended to be mixed,
> varying between self-administration of certain portions of the
> questionnaire to actual interview administration of the whole or
> portions of the questionnaire.
>
> That changed in early 1992 with an FDA memorandum recommending direct
> oral administration of the AIDS-related high-risk questions, and this
> was on the heels of a published study by Donna Mayo, et al., in
> Transfusion, showing that, in fact, this method was more effective at
> eliciting high-risk behaviors from the donor population.
>
> In 1998, based on submitted data, which to my knowledge have not been
> published, some blood centers applied and have been approved for a
> fully self-administered questionnaire, and that includes the higher
> risk questions. This is not true of the entire industry, it is limited
> to a subset of current blood establishments.
>
> In January of 2002, final guidance was issued with respect to the
> travel deferrals for protection against variant CJD and BSE exposure.
> This guidance recommends oral questions about European travel and
> residents for first-time donors.
>
> The reason for this change was specific to the nature of the questions
> and the complexity of the information that was being gathered. From
> the earlier guidance relating to UK travel, there was recognized a
> marked increase of biologic product deviation reports to FDA related
> to post-donation information.
>
> In Fiscal Year 01, 76-plus percent of the deviation reports were
> related to post-donation information or PDI, and close to 90 percent
> of the PDIs were due to false negative screening tests, that is, the
> donor was apparently aware of the information at the time of donation
> and it wasn\'t reported as part of the screen.
>
> Interestingly, about 45 percent of those PDIs were related to either
> United Kingdom or malaria travel questioning, and these data are
> available on the FDA web site.
>
> In April of 2002, pertinent to today\'s discussion, FDA issued its
> current thinking on self-administration of the donor questionnaire in
> draft guidance, and I will go over some elements of this guidance
> document because they impact on the revised Uniform Donor History
> Questionnaire and its future mode of implementation.
>
> Some key aspects of this guidance document were recommendation for
> oral interview of first-time donors, and the intent of the guidance
> was to apply this to the newer, more complex travel questions, as well
> as questions that use more complex medical or scientific terminology,
> such as Chagas disease, babesiosis, xenotransplantation, and terms
> like that, as well as the high-risk questions.
>
> This guidance actually removes the recommendation in the earlier memo
> for oral risk interview for the high-risk questions and repeat donors,
> and the intent, although this is discussable based on the
> considerations being given to the parameters today, that previous
> approvals for oral questioning with respect to other aspects of the
> questionnaires will stand. In the absence of data showing any sort of
> safety problem, FDA doesn\'t currently feel that mode of
> administrations that are currently approved should be altered.
>
> \[Slide.\]
>
> A little more specific history with respect to the discussions of this
> committee particularly at the last meeting, we gave a little
> background of certain aspects of the donor qualification process that
> we didn\'t want to spend time reviewing today, that is, the importance
> of having an accurate donor qualification process not only to remove
> risk for agents such as HIV and hepatitis C where there are tests
> available, but equally, if not more importantly, to have the ability
> to remove potentially harmful donors in situations where a test does
> not exist. So, accuracy is very important.
>
> Secondly, we reviewed the stages of donor qualification. This runs the
> gamut from pre-donation education of the donor and self-deferral at
> that point, to screening and self-deferral at the time of the donation
> process, to recognition after the donation fact and reporting by
> post-donation reports.
>
> We reviewed the donor screening process, evidence of successes,
> namely, that first-time donors and repeat donors have considerably
> lower levels of risk in evidence compared to the general population,
> and some of the areas where sensitivity of the process appears to be
> flawed, for instance, those donors who are found to have a
> transmissible infection at the time of screening frequently have risks
> that should have prevented their donation.
>
> Survey research shows that a certain proportion of uninfected donors
> also carry risk.
>
> I think I would also attribute the post-donation information data as
> representing a failure of that donor to recognize that that
> information should have been brought forward at the time of the
> screening process.
>
> Unfortunately, most of these data cannot be stratified in terms of
> whether the donation screening process was done by a
> self-administration process or by an oral interview. The data for the
> most part simply aren\'t available to do that stratification, and that
> is one of the problems.
>
> Back to the last slide.
>
> \[Slide.\]
>
> At the last meeting, there was a very elegant presentation of the
> revised Uniform Donor History Questionnaire by Dr. Joy Friday and
> discussion and review of that revision, and BPAC voted unanimously
> that the final FDA-approved version of the UDHQ is suitable to screen
> donors of allogeneic whole blood and blood components for transfusion.
>
> The task that remains is to integrate this revised questionnaire with
> FDA\'s current thinking represented in the draft guidance, and that is
> the charge for today.
>
> The draft guidance was made available in April of 2002 and comments
> were due and received by June 21st of this year.
>
> \[Slide.\]
>
> Looking specifically at some of the elements, 12 comments to the
> docket were received with respect to the draft guidance. The most
> frequently commented element was the self-administration aspect for
> new donors with the exception of the audio-assisted computer
> self-administration.
>
> Eight comments referred to this. There was also a split. Some of the
> comments argued that, in fact, for even the risk questions, that the
> evidence didn\'t support use of oral questioning for high-risk
> questions, and some of them reflected some confusion about the intent
> of the guidance and whether or not we were potentially recommending
> that blood centers currently using self-administration for medical
> portions of the questionnaire would have to go back and change their
> current procedures.
>
> We also included in the guidance that new or modified questions should
> be highlighted in some way, so that repeat donors, who have seen the
> bank of questions before, would have some way of recognizing that a
> question was new and being aware of that, because I think some prior
> data indicate that in the scanning of the questionnaire, sometimes
> each individual question isn\'t looked at in tremendous detail for
> repeat donors who may have donated many times before.
>
> The current thinking reflected in the guidance removes the
> recommendation for oral administration of the high-risk behavior
> questions for repeat donors. This had six comments largely supportive
> of that position.
>
> FDA recommended that there be secondary measures to assure donor
> understanding. FDA didn\'t say specifically what these measures should
> be. Potentially, they could run the gamut from asking a donor at the
> end of the process whether they understood the questions, which is
> commonly in place now, to other means to assess understanding and
> comprehension, readability of the questions.
>
> Also included were adequate instruction of staff and of the donors,
> assistance as needed with the process, and quality assurance of the
> process through internal SOPs, and special provisions for audio and
> visual administration of the questionnaire and particularly for audio
> computer-assisted technology, which has become popular in the larger
> general population in high-risk surveys, and the literature tends to
> be very supportive that this is an elegant way to obtain at-risk
> information.
>
> \[Slide.\]
>
> To tackle today\'s topic, our first speaker will be Dr. John Boyle
> from Schulman, Ronca, and Bucuvalas. The title of his talk is
> Administering the Blood Donor Screening Questionnaire: Issues Related
> to Sensitive Information. I must say John has put together a very
> extensive review of the current literature and look forward to his
> presentation.
>
> The next talk is entitled Beyond Literacy: Collecting Accurate Medical
> Information. This is a review of the literacy aspects of the
> discussion, and again, I think also a very excellent collection of
> current knowledge about literacy factors. The presenter is Vickie
> Virvos, who is an educator with Enlightening Enterprises in Richmond.
>
> Finally, I will return with questions for the committee and I will
> give a little preview of the questions now.
>
> \[Slide.\]
>
> 1\. Does the committee agree that audio-CASI procedures, that is,
> audio computer-assisted self-interview, that these procedures are as
> accurate as direct oral questioning for eliciting blood donor
> medical/behavioral histories? Yes or No.
>
> 2\. Does the committee believe that for first-time donors,
> self-administration procedures other than audio-CASI are as accurate
> as direct oral questioning for the entire donor questionnaire? Yes or
> No.
>
> 3\. If not, for procedures other than audio-CASI, are the following
> portions of the donor questionnaire appropriate for
> self-administration to first-time donors?
>
> Specifically, we have highlighted the routine medical questions,
> which, in fact, are frequently self-administered in blood centers
> today.
>
> The next component is HIV/AIDS high risk questions, yes or no, and the
> complex medical or travel, and I would include in there those with
> complicated scientific or medical terminology.
>
> We look forward to your deliberations and thank you.
>
> DR. NELSON: Thanks very much.
>
> Dr. John Boyle, who is a former valuable member of BPAC, will review
> the literature.
>
> **Presentation**
>
> **John Boyle, Ph.D.**
>
> DR. BOYLE: Thank you. It is great to be here again. Alan and the FDA
> did an extensive search for people who had served on BPAC of
> professional survey researchers that served on the Uniform Donor
> History Questionnaire and who lived or actually had an office within
> three blocks of this facility, and my name just rose right to the top
> of the list.
>
> While we are waiting, what I was asked to do was to address the issue
> of sensitive information in interview settings and specifically, some
> of the issues here, what about self-administered, what about
> interviewer-administered, what about audio-CASI, what do we know, what
> does the literature know or tell us about the likelihood of getting a
> better report of sensitive information as in the HIV/AIDS risk
> behavior sections.
>
> \[Slide.\]
>
> What we did was do a review of the methodological journals in survey
> research for articles on the reliability of survey measures by mode of
> interview.
>
> Secondly, we did a review using Medline for articles on validity and
> reliability in health surveys. We took in references in articles from
> either source. We added transfusion and other areas in this
> literature.
>
> We reviewed over 50 articles. Although that list is probably not
> exhaustive of everything in this, it will provide you a broad overview
> of what the literature has available.
>
> I believe for those members of the committee, we provided an annotated
> listing of 20-plus articles, so if you had a chance to read them on
> the plane or would like to read them later, you can go back to the
> source documents.
>
> \[Slide.\]
>
> The first thing that I really want to impress upon the committee,
> because I think it is something, if you are not survey research, you
> are not necessarily that well aware of it, an interview is not a test.
>
> The donor screening interview is a key element in the protection of
> blood safety, but interview data does not have the fixed properties of
> a biologic test, such as specificity and sensitivity.
>
> Interview data is subject to a variety of observational errors. That
> means non-sampling errors.
>
> Finally, there are multiple sources of observational errors that may
> vary with the content and context of the interview. While this is true
> in survey research, it should be true in other interviewing settings,
> such as the donor interview.
>
> \[Slide.\]
>
> How much does what somebody tells you in an interview vary from what
> you think you know about reality? If you compare what we did in a
> reverse records check of people who reported themselves as victims of
> crimes, to what they would say subsequently in a survey, you can see
> that the agreement rate is anything from 48 percent to 90 percent.
>
> So, in the case of burglary, a uniform donor screening of burglary,
> about 90 percent will tell you that that indeed has happened in the
> past 12 months. If you should ask about rape, however, it will be
> about two-thirds, and assault, 48 percent.
>
> So, you do not have\--and don\'t take these rates as being true of
> everything, just take these rates as indicative that people, for a
> variety of reasons, do not reply to an interview in a way that it
> matches what other measures of truth necessarily are.
>
> \[Slide.\]
>
> We are not talking about rape or physical assault in these things.
> Let\'s talk about things we are. We had the opportunity to do a
> test/retest of a national sample of this happens to be men, they
> happen to be in their 50s to 60s, and we asked them whether their
> doctor had ever told them they had had hepatitis.
>
> Six months later, we went back to the same sample and repeated the
> same question. It was embedded in a larger health survey. Now, the
> tools block this down here a little bit, but the reporting consistency
> is 97.3 percent. So, if you are interested in psychometrics, that is
> really great.
>
> On the other hand, about 1 out of 5 persons who positively reported
> that they had hepatitis, and answered the follow-up questions, when
> was it first diagnosed and what kinds of hepatitis do not report that
> consistently at two points in time.
>
> So, you have some sense on at least the hepatitis question, and this
> is a telephone interview with experienced monitored interviews in the
> midst of a health survey, not affected by setting and other issues,
> presumably very private, you had this kind of issue about whether or
> not it gets reported. So, the question is why.
>
> \[Slide.\]
>
> There are whole sources of error in AIDS behavior research, and it is
> true of all research. Some come from the respondent, like recall,
> ability to comprehend, motivation, threat or approval of the
> particular question.
>
> Some come from the instrument, the terminology, the question
> structure, the order effects. Some from the mode, channel capacities,
> length and pace, privacy, interviewer behaviors as it relates to the
> mode, and finally, some from the interviewer, the personal
> characteristics and how that interacts with the respondent, the
> ability or willingness of the interviewer to follow rules, and
> finally, training and control.
>
> I am supposed to be talking about mode here because we are talking
> about several different modes, but the bottom line is mode interacts
> with respondent, with instrument, and interviewer, so there is a lot
> of stuff going on here. When you change mode, you have to be aware of
> how these other things contribute to the error measurement.
>
> \[Slide.\]
>
> I will skip this one. This is just technical, it is how mode works.
>
> \[Slide.\]
>
> Very quickly, the two principal concerns about mode in observational
> error. The bottom one, effects on disclosure, the biggest concern is
> that there is underreporting of sensitive information and how that
> relates to mode.
>
> The second area is the effect of mode on respondent comprehension -
> understanding, attention and recall, reporting accuracy.
>
> In terms of the issues before this committee, the biggest issue will
> be does an interviewer\'s presence asking questions, possibly in an
> open setting, is that going to contribute to an underreporting of
> sensitive behavior because of issues related to privacy.
>
> On the other hand, will an interviewer, interacting with respondent,
> give them better understanding, greater attention and better reporting
> accuracy in those settings. Those are effectively the two big
> questions.
>
> \[Slide.\]
>
> In terms of the comprehension, what we know is respondents may not
> understand a word, but are unwilling to show ignorance. They may try
> to simplify a difficult question, they may try to answer what they
> think is the spirit of the question rather than the exact words.
>
> They may overlook parts of a question. They may have response
> categories that don\'t fit their experience, but maybe they are not
> willing to ask how to do it.
>
> The question order may affect the way they answer questions, and
> questionnaire burden may cause respondent to answer without thinking.
>
> \[Slide.\]
>
> Let\'s talk about some of the things that might be on a donor history
> questionnaire. There was a study done\-- this is qualitative\--by NCHS
> some years ago where they asked, tell me if you have heard of the term
> and definitely know what it is, you have heard of the term and are
> pretty sure you know what it is, or you have never heard of the term
> and you are not sure what it is.
>
> The important issue is probably not that diverticulitis is not
> recognized by about half of the people in this particular study, but
> terms like hepatitis are not recognized and they don\'t feel familiar,
> they are not sure what it is, for 1 out of 5, and if you stick the old
> \"or jaundice\" on it, it doesn\'t really improve things, because 1
> out of 5 don\'t really know what jaundice is.
>
> Even in areas like anemia, you have got 10 percent. Fortunately,
> syphilis and diabetes are pretty well recognized. But the familiarity
> of terms is an issue.
>
> \[Slide.\]
>
> A real life example in a survey that I monitored where somebody tried
> to get at sexual preferences, and the question was: \"Are you
> bisexual?\" And the answer was, \"Yes, my husband is the only man in
> my life.\"
>
> Now, let me point out in terms of our issues, on a self-administered
> questionnaire, the person would have checked \"bisexual.\" One of the
> advantages of the interviewer-administered questionnaire is the
> opportunity, whether it is right or wrong we have to discuss, but the
> opportunity of interviewer to interact, to potentially correct or at
> least make notes of this type of issue.
>
> Now, you are going to say to me, John, we don\'t use words like
> bisexual in our instrument. You know, we use things like
> xenotransplantation, because we all know it is all about a warrior
> princess.
>
> But moving on to simpler terms.
>
> \[Slide.\]
>
> Let\'s take really simple terms. Let\'s talk about the word
> \"weekday.\" This was tested. What is meant when I say weekday, we are
> open weekdays 9:00 to 5:00? Half said it is Monday through Friday.
> Another third said it is every day of the week. Then, 12 percent
> weren\'t sure, and the other people picked sort of more bizarre
> choices, but the bottom line is even a term like weekday, if we don\'t
> test it, we assume everybody understands it, has the source for error.
>
> \[Slide.\]
>
> Part of the issue why follow-up is good, this is very complex, but let
> me simply say we used to ask in transportation studies, \"While
> driving this vehicle, how often do you wear your shoulder belt - all
> the time, most of the time, some of the time, or rarely?\" And then
> someday, because the data did not match observational studies, we
> asked, \"When was the last time you didn\'t wear the belt?\"
>
> Of the people who say they wear the belt all the time, that is your
> first column there, what you see is 4 percent of them say they didn\'t
> wear it today, and another 6 percent said not within the past week.
> So, 10 percent who wear it all the time didn\'t wear it at sometime
> during the past week.
>
> Now, the nice thing is you get a nice metric up here. Today, 4
> percent, 32, 64, 75. It is not that people are stupid, it is not that
> people are lying to you. It is simply the fact that people are
> answering in their own metric and how they understand the question.
>
> If you put these two pieces together, how often do you usually wear,
> and when was the last time you didn\'t wear the belt, and I take all
> the time and take all those people who didn\'t wear it within the past
> 12 months out, and we created a variable called all the time minus, it
> actually matches observational data, but you have to take those steps
> to be able to get something approaching reality.
>
> \[Slide.\]
>
> We will skip the irritable bowel question, but part of the issue is if
> your response categories are yes or no, you get a different answer
> than if you ask frequency, so it is important if you are trying to get
> at certain issues.
>
> \[Slide.\]
>
> In terms of the communication of response, what you have to ask
> yourself is the question embarrassing to the respondent, is the
> response sensitive or threatening, how private is the interview
> setting, how confidential is the response, and does the purpose of the
> question justify any embarrassment or threat to the respondent.
>
> Now, why do we have to do that?
>
> \[Slide.\]
>
> What you see is even two decades ago, the public felt that
> institutions in our society were asking unnecessarily personal
> information, and when asked do they limit their questions to what they
> really need to know or do they ask for too much personal information,
> we are not surprised when we see that credit bureaus ask too much, but
> 24 percent of the public say hospitals ask too much unnecessary
> information, and 11 percent say their private doctors do.
>
> \[Slide.\]
>
> Moreover, what we find is that the public is not very convinced about
> the confidentiality of this information. When asked whether the Census
> Bureau protects the privacy of their personal data, the good news is
> 14 percent of the public are very confident that it does. The bad news
> is, is that almost half say not at all or not too confident about
> that, and that is the Census Bureau, who ranks relatively high.
>
> \[Slide.\]
>
> And how does this impact? We don\'t know how it impacts upon
> reporting, but we do know that it impact very markedly on willingness
> to participate, which presumably will translate, so concern about
> privacy, low to high, willingness to participate in the census, low to
> high, impacts dramatically.
>
> If we say that that is likely to translate also into issues of
> accuracy of reporting and full disclosure, then, we may have a
> problem.
>
> \[Slide.\]
>
> So, then, how embarrassing are these questions, we ask. Going back to
> some stuff from NCHS, we asked people how they rated how embarrassing
> certain conditions where, and it was from definitely embarrassing at
> 1.0, somewhat embarrassing 2.0, and not at all embarrassing at 3.0.
>
> Looking at the means, everybody agrees anemia and hay fever are not
> very embarrassing to report. On the other hand, syphilis is really not
> a good thing to report. But if you look at something like hemorrhoids,
> cirrhosis, but let\'s also look at hepatitis, and, of course, some of
> these people don\'t understand what hepatitis is, but nonetheless, the
> bottom line is that many of the things you would like to know about,
> people recognize as embarrassing conditions, hence, they will be
> subject to sensitivity issues.
>
> \[Slide.\]
>
> Let\'s skip this one. Move on.
>
> \[Slide.\]
>
> Now, from some data. In the National Fertility Survey, they had some
> data on doing the questions about the number, well, actually, various
> sex questions, self-administered versus interviewer-administered.
>
> What we are looking at is the number of sex partners in the past year.
> It was 1.7 self-administered, it was 1.4 interviewer-administered.
> Number of sex partners in the past five years, 3.9 versus 2.8.
>
> Condom use in the past 30 days, 46.7 percent self-administered, 35
> percent interviewer-administered. Since these were women, this was the
> condom use of their partner.
>
> If you look at the odds ratio what you really is across all of these,
> they vary in terms of the absolute rates, that self-administered gives
> a higher rate than interviewer-administered, which suggests if you
> believe that more reporting of a sensitive behavior is better
> reporting, then, it suggests that self-administered gets higher
> reports.
>
> \[Slide.\]
>
> Looking at another study, this is a study that deals with what was
> always viewed for some years as very sensitive, and this has to do
> with questions that are race related. Attitudes about
> African-Americans.
>
> Would not vote for a political candidate who is African-American. Ten
> percent face to face, 22 percent self-administered by mail.
>
> Would not want a close relative or family member to marry. There is
> really no difference here.
>
> Favor equal opportunity in education and training for
> African-Americans, 30 percent to 22.
>
> Favor spending more money on preschool and early education for
> African-Americans, 60 to 39.
>
> Strongly oppose special preferences in hiring and promotion for
> minorities, 30 to 38 percent.
>
> So, there is difference on these questions, not all of them, but many,
> always in the direction of the self-administered getting a higher
> report of what would be viewed as less socially acceptable behaviors.
>
> \[Slide.\]
>
> One of the things that we have been asked to address is the issue of
> face to face versus audio-CASI. For those of you who have heard this
> blow by you several times and don\'t know what audio-CASI is,
> basically, it\'s computer-assisted self-administered, which means the
> questionnaire is on your computer, and you are given the computer, and
> you are answering all the questions on the computer, but so that
> people don\'t really know the questions you are answering, you have
> got headphones on and you are listening to the question and only the
> answers go onto the screen, so people don\'t see what it is you are
> responding to. That is audio-CASI.
>
> \[Slide.\]
>
> We asked in a survey about mental health symptoms.
>
> \[Slide.\]
>
> First, we asked the questions in person or with one sample we did it
> in person. What we found was major depressive episodes in the past
> year, 7 percent. Generalized anxiety, 1.6. Panic attacks, 2.0, and
> agoraphobia, 1.6.
>
> Let\'s compare it to what you get with the same type of sample
> audio-CASI.
>
> \[Slide.\]
>
> Fifteen percent, 6 percent, 4 percent, and 2 percent. The bottom line
> is that you have got a 2 to 1, you have got almost a 3 to 1, you have
> got a 2 to 1, and here no difference, but in each of the cases, what
> you find is higher reporting of sensitive symptoms or symptoms of
> sensitive conditions by audio-CASI rather than in person.
>
> \[Slide.\]
>
> Why do we get higher prevalence of sensitive items in
> self-administered questionnaires regardless of whether or not they are
> paper and pencil or they are audio-CASI?
>
> The sources are interviewer-induced error. This involves the
> interaction between the interviewer and the respondents. The
> interviewer contributed error, this is where the interviewer actually
> makes the error, and the privacy of the response, which is the
> interaction between the question, the interviewer, the setting, and
> the respondent.
>
> \[Slide.\]
>
> Once again, how would an interviewer per se affect a response? We saw
> differences between self-administered and interviewers in terms of the
> race questions. Let\'s look at some race questions. These are a little
> bit older.
>
> \[Slide.\]
>
> White respondents asked by white interviewers if they would mind if a
> relative married a Negro. Obviously, by our language, we are about 25
> years old. But 25 percent would not mind.
>
> Believe Negro and white students should go to the same school, 56
> percent.
>
> Would not mind if Negro of the same class moved into the block, 66
> percent.
>
> Finally, they should play together freely, 84 percent.
>
> \[Slide.\]
>
> If the white interviewer is responding to a black interviewer, what
> you see here is a higher rating in all of these, most dramatically on
> the issue if a relative would marry, it goes from 26 to 72 percent,
> which basically means that the characteristics of the interviewer is
> interacting with the respondent and the question and affecting
> response. You have got an error term floating around out there.
>
> \[Slide.\]
>
> In addition to the interviewer who because of his gender, because
> gender impacts, his socioeconomic status, age, the way they dress,
> their race, all of this can impact upon a respondent and their answers
> without the interviewer ever intending to do anything.
>
> Now, let\'s talk about when we get to the issue of how the interviewer
> actually behaves. Studies have been done monitoring telephone
> interviews, and telephone interviewers know they are being monitored,
> which looked at exactly how interviewers follow rules, who do they
> deliver the question, do they read it exactly as written.
>
> Fifty-six percent closed, 51 percent restricted open and open-ended
> questions, only 30 percent read it exactly as written. Minor changes.
> Major changes 7, 4, 8, and they didn\'t even read it, 1, 1, and 16.
>
> Interviewers, even when they are being monitored, may not follow
> rules.
>
> \[Slide.\]
>
> In another study that was done where they actually observed
> interviewers in role-playing exercises, mock interviews, the same
> thing. Did they read it exactly as written? Experienced interviewers,
> 67 percent. New interviewers, 66.9. New interviewers at the end of
> training. 66.4. In other words, it is really not an issue of training,
> it is really not an issue of experience, interviewers don\'t always do
> what they are told even when they are being observed.
>
> \[Slide.\]
>
> But the interviewer gives you the opportunity to probe responses. The
> good news is about 80 percent probed properly when observed, and under
> observation, about 1 out of 5 couldn\'t do the probes properly.
>
> \[Slide.\]
>
> Let us go back to another issue in terms of paper, audio-CASI, and
> this is from the National Survey of Adolescent Males, and this is
> where a lot of the audio-CASI data comes from.
>
> They were asked about any male to male sex ever, 1.5 percent paper
> self-administered, 5.5 percent audio-CASI. Needless to say, very
> significant odds ratio.
>
> Male to male anal sex ever, 1 percent, 2 percent. It is not
> significant. So, a lot of what is happening here is stuff other than
> male to male anal sex.
>
> Sex with a prostitute, 0.7, 2.5 percent. Very significant.
>
> Street drugs with a needle, 1.4, 5.2.
>
> Shared needle ever, 0.1 to 1.1.
>
> Needless to say, on many HIV risk factors, it is fairly clear that
> self-administered does not give the same level reporting as another
> form of self-administered, audio-CASI. However, let me put a caveat
> here.
>
> The biggest difference here occurs among adolescents. Once you move to
> the older group, the difference between paper self-administered and
> audio-CASI drops dramatically, in many cases becomes nonsignificant.
>
> \[Slide.\]
>
> Another thing that is being used is telephone-CASI compared to a
> telephone interviewer, and respondents were asked how they preferred
> it in terms of protecting their privacy. Forty-nine percent said
> telephone-CASI was better, 11 percent telephone interviewers, 40
> percent were indifferent. Getting honest answers, respondents, 73
> percent said the telephone-CASI was better than the telephone
> interviewers at getting honest answers.
>
> Asking sensitive topics, 66 percent thought telephone-CASI was better
> compared to 23 percent. However there is a tradeoff here. Easier to
> use, 30 percent said the telephone-CASI was easier to use, 59 percent
> said the telephone interviewer was.
>
> Easiest to change answers, 1 percent to 61 percent.
>
> So, like everything, there are tradeoffs here in terms of what you are
> getting. One form is viewed as more private, the other one is viewed
> as easier to use and easier to change.
>
> \[Slide.\]
>
> Why is the prevalence of sensitive items usually higher in audio-CASI
> than self-administered?
>
> Audio-CASI guarantees by its technology greater privacy of questions.
> You are listening. Nobody can see what the question is. In terms of
> the self-administered questionnaire, I don\'t know from the literature
> whether we are sitting in a group filling these out, whether we are
> sitting in private cubicles where the people are coming around, you
> don\'t know.
>
> The audio-CASI guarantees that. It guarantees greater privacy of
> responses. You are putting this in. Nobody can see or hear what you
> are doing. It is not setting dependent. You can do this in a crowded
> area and people listening and so on, whereas, the paper is going to
> depend upon exactly the setting.
>
> Also, there is no data on this, but novelty may be a factor and
> legitimacy may be a factor, that is, it is complicated, it\'s
> expensive, maybe that means it is more important.
>
> \[Slide.\]
>
> How does this stuff affect the donation process, because there is a
> small literature on this. This is a case of at-risk potential donors
> who left the donation process as a function of the health history and
> reason for leaving.
>
> Current health history only, currently health history plus behavioral
> questions, and current health history plus comprehension questions.
>
> What this shows, there is no differences in the rates, the base rates
> all about the same, no differences in the potential deferred for
> medical, very little for not specified, and most of it comes in from
> the AIDS risk, and it comes in from current health history plus
> behavioral questions.
>
> However, what this doesn\'t tell you is whether or not these
> behavioral questions, if they have been added in a self-administered
> rather than a non-donor administered form, would have had the same
> effect. In most research we do, the more questions we ask about a
> sensitive behavior, the higher rate we get.
>
> So, it is inconclusive, but interesting.
>
> \[Slide.\]
>
> In another study, we looked at the HIV deferral rate for 100,000
> donations before and after direct oral questions were implemented at
> four blood centers in 1990 to 1991. You can see the rate per 100,000
> before the DOQ and note that it varies dramatically from a low of 67
> to a high of 477, after DOQ, where it varies from a low of 253 to a
> high of 555.
>
> The odds ratio is such that in two cases, it is not significant and in
> two cases it is significant. Now, the interesting fact here is
> introducing direct oral questioning affects the likelihood of deferral
> in two out of four facilities. What is interesting among other things
> is the two that it does, it brings the rate up more in the range of
> those before, so I am not convinced that I am not dealing with
> something like a demonstration effect, a Hawthorne effect where by
> introducing the things, you are changing something in someplace rather
> than others, but the authors concluded you can\'t say that adding
> direct donor questions necessarily increases the reporting of
> deferrable conditions. It does in some places, in other places it
> doesn\'t, and we don\'t know why.
>
> \[Slide.\]
>
> Looking in the same study at the actual cases of HIV seropositive
> donations per 100,000 before and after, the bottom line is that in
> none of these cases is it significant.
>
> \[Slide.\]
>
> In another study, there was a study of direct questions versus
> indirect questions in terms of deferrals of 6 to 8 blood centers, and
> what you found basically is this is all donors logged in, all
> deferrals, and then the rate of deferral based on customary HIV
> screening, there is basically no difference between these, positive
> answers to oral HIV risk, which was not done here.
>
> What you see is a higher rate in direct questions than it was
> indirect, refusal to give answers to additional questions, which would
> get you deferred, no difference between direct and oral, but if you
> add these together, if you add additional questions, you get a higher
> rate of deferral. Unfortunately, it doesn\'t tell you whether or not
> if you added these questions in a self-administered versus an oral,
> you would get these differences.
>
> \[Slide.\]
>
> So, to finally add up, we asked in one of the studies, we asked donor
> reaction to the additional oral questions, and this is both indirect
> and direct, but let\'s just look at direct.
>
> Were they easy to understand? Yes, 90 percent said yes. Was the
> privacy good to excellent? 82 percent said yes. Obviously, 1 out of 5
> said it wasn\'t.
>
> Would it stop high risk donors? Only 17 percent said it would, would
> or might stop them. Well, 79 percent said it will or might.
>
> Did it cause embarrassment? Seven percent who went through the direct
> questioning said yes, it caused them embarrassment. And would it stop
> them from donating? Very few said it would, but 1 to 2 percent said
> that it would.
>
> So, bottom line, from the standpoint of the donors going through the
> oral questioning, what they tell us is 7 percent say\--I am sorry,
> starting up here\--1 to 2 percent they would not donate again as a
> result, 7 percent said it caused embarrassment. About 80 percent
> thought it would stop high risk donations, 20 percent did not think it
> would. Almost 20 percent said the privacy in which they did it was not
> good or excellent, and almost everybody said it was easy to
> understand.
>
> \[Slide.\]
>
> What about the staff reaction? Same questions basically. Let\'s just
> talk about direct. Did they understand? Ninety-seven percent of staff
> said yes, they understood. Was the privacy adequate? Well, they tended
> to agree, 80 percent said it was adequate, 20 percent said it wasn\'t
> adequate.
>
> Would it screen out high risk? Staff was more likely to think it will
> screen out, but only 64 percent thought it would.
>
> Are donors honest? Eighty-four percent said they were. Twenty-seven
> percent of the staff said donors minded the questions, and 24 percent
> of the staff thought that this would decrease returns.
>
> \[Slide.\]
>
> Probably more of concern if we moved to oral questioning on total
> basis, based upon this survey, only 81 percent of the staff said the
> donors understand the need to ask these questions. Only 83 percent,
> after extensive training, said the training for the staff was
> adequate.
>
> The one you should be most concerned about is only 78 percent of the
> staff who administered it said they were comfortable asking the
> questions. If people are not comfortable asking the questions, don\'t
> expect the answers to be the ones that you are trying to get.
>
> \[Slide.\]
>
> Finally, the issues that should be addressed from these donation
> studies. Findings suggest that additional questions identify
> additional at-risk donors. The question is how many questions can you
> ask.
>
> It is not clear that removal of these donors reduces HIV
> seroprevalence in the donation at least from one study.
>
> There are serious issues of training adequacy for donors, the
> interviewing role may not be comfortable, and privacy may not be
> adequate for direct questions.
>
> \[Slide.\]
>
> From the literature, there is no consensus on the best method to
> collect sensitive information. The limitations of the data is there is
> a limited number of studies, most are opportunistic, comparison is
> always between one or two modes.
>
> There is limited control over interactions between mode, interviewer,
> respondent, instrument, and setting, and there are different results
> for subgroups, which I have not gone into here - older versus younger,
> race related. All of these produce different results in terms of
> modes.
>
> \[Slide.\]
>
> Finally, I am forced to answer the question about what is at least the
> direction of the findings. Self-administered questionnaires tend to
> result in higher reported levels of sexual activity, drug use and
> depression, which is only one of a series of mental health behaviors,
> than interviewer administered questions.
>
> Increased privacy in interview settings, like audio-CASI, will
> increase reporting rates of sensitive behaviors, but audio-CASI is not
> so much a technology as a technology that helps achieve a goal, and
> that is privacy.
>
> Finally, perceived confidentiality of survey will affect reporting
> rates of sensitive behaviors. If people understand why it is necessary
> and are assured and believe that the data is treated confidentially,
> they will report more honestly.
>
> My conclusion basically is\--if somebody asked me to vote, and they
> don\'t because I am no longer here\--is the data basically says that
> interviewer administered questionnaires, unless you really control the
> setting, introduces errors that are likely to reduce the correct and
> accurate reporting of sensitive behaviors compared to
> self-administered under appropriate circumstances.
>
> This does not say that the interviewer or donor historian cannot
> achieve in concert with the process a higher rate. The respondent has
> to be assured of why this is being done, they have to be convinced
> that it is valuable, they have to be convinced that it is confidential
> and will be used in the right way. They have to be able to answer
> questions.
>
> All of these things can be part of the process in a very valuable role
> for the interviewer or donor historian in the process, however, the
> literature, at least my conclusion is, basically says if you have to
> choose between the two, the interviewer administered way introduces
> more error in a field setting than it can contribute in terms of
> improving understand and comprehension.
>
> Thank you.
>
> DR. NELSON: Thank you.
>
> Questions? Dr. Allen.
>
> DR. ALLEN: In the blood donor setting, there is a complex set of
> interactions going on in that there may be social pressure to donate,
> there may be altruistic reasons for donating, and so on, as opposed to
> just a person who is agreeing to participate in a survey to collect
> information.
>
> Do you have any sense in that kind of a setting where there may be
> other reasons for wanting to move through the process and donate, why
> a person may give less accurate information on one methodology or
> another in terms of collecting the information?
>
> DR. BOYLE: The reason that I started with sort of the general survey
> research information and then brought in the limited number of studies
> we do have from the blood setting is I found the results remarkably
> similar.
>
> We don\'t have the kind of extensive study to know the differences in
> terms of whether or not the people who are less likely to respond
> honestly don\'t even come in. We do know from other settings we don\'t
> allow interviewers who know respondents in a community to be part of
> the setting because we know that affects it. So, in a small community,
> if everybody knows each other, then that setting is likely to make
> issues of privacy and accuracy of reporting more of a problem.
>
> But what you are seeing up here is the literature is limited because
> most people do not fund methodological studies, and in addition to
> that, the complexity of the dimensions are such that we are working by
> analogy.
>
> I think the analogy from the data that we were seeing from the blood
> centers makes it similar to what we see in other setting, but in most
> other settings, we do it by telephone or by mail or in other ways
> where it is almost by definition a more private setting than in a
> bustling blood collection center.
>
> DR. ALLEN: Second question, and that is with the complexity of the
> medical and social information that is being collected. I most often
> donate either where there is at least in part a self-administered
> questionnaire or it is totally interviewer administered, and I, over a
> period of years, actually more than a decade, have been concerned that
> the interviewers tend to present information so quickly, even though
> it is being read, the questions are fairly complex, they are multiple
> part, there are lots of medical terms and what I will call medical
> jargon in there.
>
> I am a physician. I find it hard to listen and understand everything
> even though I have been donating for 30-some years.
>
> Is there evidence that the audio-CASI or even self-administered
> questionnaires can elicit the information accurately, is that a better
> way of doing it perhaps given the complexity and the precision that is
> required here?
>
> DR. BOYLE: There is two very different questions. One is the whole
> issue of attention to the questionnaire and the way that it is done.
> When we monitor telephone interviewers, what you see happen in terms
> of quality control is when they start the first interviews, up to
> maybe 40 interviews, you see a constant improvement in quality control
> and reading the questions correctly, and so on, and after you get to
> about 50 interviews, it starts dropping off partly because they are
> familiar with it, they are not listening as much, they think they knew
> it all, and they are worried about production rates, so they start
> moving it along. They are not as interested, they are bored, and so
> on.
>
> From the standpoint of the respondent, the respondent who is hearing
> this for the first time or the second maybe, is more likely to spend
> more attention, in my impression, than an interviewer who has done it
> over and over and over again, from doing something on the order of 400
> telephone interview surveys a year, you hear the respondents being
> much more thoughtful in terms of the responses than interviewers who
> have heard it all.
>
> So, I would expect, don\'t know, but would expect that that would
> translate into the type of setting that you are talking about, as
> well, unless you have extraordinary monitoring of those health
> interviewers.
>
> DR. SCHMIDT: In your study of this literature, I wonder if anybody has
> used this technique where they are listening to the questions by
> earphones and they are looking at the computer monitor which says yes
> or no, but the computer monitor also gives them a picture.
>
> So, if you are talking about jaundice, you see what it is they are
> saying, and we used to talk about sex questions and using stick
> figures, but the opportunity to amplify the question with a picture
> exists.
>
> Has that been used in studies?
>
> DR. BOYLE: I think there will be some people commenting later on
> perhaps about that. The literature is new enough and the techniques
> are new enough that I certainly don\'t have a lot to report to you on
> that, but certainly it is an obvious application and a way to improve
> understanding through that methodology.
>
> DR. DOPPELT: I was going to ask a related question. The conclusion you
> came to seem to be based mostly on the differences in response for
> questions to which the person has an answer, they just may not feel
> comfortable giving the answer, and the question is comparing the
> interviewer versus the self-administered, when the person doesn\'t
> understand the question like the jaundice or, you know, at least with
> an interviewer, you have a chance to say, well, you know, jaundice
> means you are yellow or something.
>
> DR. BOYLE: One of the issues that is probably true I think across the
> board, at least in the survey research industry, is that we insist
> that the interviewers read only what is on the screen. That may
> involve follow-up probes, and so on, but when the interviewer is
> supposed to explain to somebody what something is, they are as likely
> to make an error in that description by making it too broad or too
> narrow or leave something out that you really don\'t know necessarily
> what is going on.
>
> From the data you saw about interviewer following rules, even under
> observation, you worry about that. Clearly, if you have interviewers
> or technology that can flip you to an explanation about what is or
> what are the symptoms or whatever, you can improve the knowledge and
> comprehension of the respondent, but unless you have people who are
> knowledgeable enough and controlled enough to give the same and
> correct answers each time, you do not want to have somebody who is
> paid, I don\'t know, 12, 14 dollars an hour giving explanations about
> what hepatitis is or other things to a respondent if you want an
> accurate response. That would be my general response.
>
> When we move to the technology, whether it is CADI or CAPI OR CASI, we
> are basically, you know, under hepatitis, you put you are not sure,
> and then it brings up data on here is a description of a person, here
> is a description of symptoms, and these things have all been
> standardized, so that people who are experts agree that these are good
> probes, you are much further down the line.
>
> But I would prefer a technology that provides that in a standardized
> fashion than watching interviewers. I have listened to over 50 hours
> of well-trained field interviewers doing surveys when they knew that
> it was being taped, and they say things like \"Now about your drug
> use, oh, no, I can tell you are a nice person, you wouldn\'t answer
> yes to any of these questions,\" this is a Census supervisor.
>
> So, my concern is if you can control the interviewer and the
> interviewer setting, they have an opportunity to be value-added, but
> they have to be very good, very well trained, and very controlled, or
> they simply introduce sort of uncontrolled error.
>
> Yes.
>
> DR. LEW: I wanted to comment, though, on the single study or the
> larger study looking at blood donors, and I was impressed with that
> study, that I don\'t know if it is really powered to give you the
> answers, because if you notice, at the one center that has the most
> donors, it was highly significant that there was an increase, in fact,
> the two centers that had lots of donors, it was very significant that
> if you were giving the oral questions, people were more likely to
> admit to them than in the written.
>
> I think I would like to distinguish between a written questionnaire
> versus the audio-CASI, which is very new and has a lot of potential.
>
> Also, I was impressed that even though the other two smaller donor
> centers didn\'t statistically have significance, all of them showed at
> least a trend I would say that, you know, face-to-face interviewing
> got more answers that would suggest a donor should not donate.
>
> Now, their bottom line was maybe the questions aren\'t good, and if
> you can comment on that. Again, I am very impressed that at least in
> those centers, if you ask face to face, it does make a difference to
> be able to exclude people who might be at risk.
>
> DR. BOYLE: Oh, I believe that some of the contributors to that
> research or at least the organizations may even be present here may be
> able to provide more detail on that than I can.
>
> DR. WILLIAMS: John, one mechanism that has potential application in
> the blood donor setting is computer-assisted self-interview without
> the audio component. There may not be data to directly correlate, but
> would you equate that closer to a paper questionnaire or would it
> carry many of the potential benefits of the audio-CASI?
>
> DR. BOYLE: It has many advantages over the paper questionnaire in
> terms of comprehension because you have the opportunity to have the
> follow-up screens where you can ask the question have you traveled
> outside of the United States in the past whatever years.
>
> If yes, then, it takes you to the continents. If yes, it takes you to
> the countries where you are much more likely to get an accurate answer
> to your question than the question that says have you been to the
> British Isles including Wales, the Isle of Mann, and so on, on a
> questionnaire.
>
> The opportunities of CAPI to get more accurate answers, I mean I think
> are demonstrable even without data. It allows you to answer, to get
> more specific questions, to provide information, yet not expand the
> interview link by any notable amount.
>
> In terms of privacy issues, you do not have the same level of privacy
> as audio-CASI where you are hearing the questions and nobody can see
> on the screen what the question is. So, I think in terms of privacy,
> it is probably comparable to a self administered because whether you
> are sitting at a computer screen or you are sitting there with your
> questionnaire in front of you, depending upon the setting where you
> are cheek by jowl together or you are sitting by yourself, that tells
> you what the privacy is.
>
> You probably will generate some novelty effects. It will also increase
> the sense of the legitimacy, which is equated with the level of effort
> you make to get these answers, but the big advantage of CAPI is it
> would allow you to ask better questions and get better answers than
> you can do in any self-administered, any paper and pencil format.
>
> DR. FITZPATRICK: Based on the lack of any difference in serological
> testing at those sites, do you think we need to do something to study
> the effectiveness or see if the oral questions are actually
> accomplishing anything?
>
> DR. BOYLE: Well, that is a very good question. I mean when in point of
> fact you get higher rates of deferral, but you don\'t get higher
> seroprevalence, the question is whether or not the additional
> deferrals you are getting are reducing risk.
>
> It is one study. I would hate to hang my whole hat on it, but it is
> the obvious question you ask at the end of the day there.
>
> DR. LEW: If I could just comment on that, because I also thought about
> that. I don\'t think the study was designed adequately to even address
> that question, because if you look at it, they took historical data,
> and we know that the trend is going down, et cetera, they could have
> done a better job to really address that question.
>
> DR. FITZPATRICK: My question was do you think it is worthwhile, is
> that enough evidence to promulgate more research into that area
> though.
>
> DR. BOYLE: Well, let\'s put it like this. When I was on the committee,
> I promulgated research for everything, but particularly as it relates
> to the donor screening questionnaire, because you are doing, you know
> millions of them a year, it is a burden on the respondent, it is a
> burden on the facility, it impacts upon presumably donation, so it
> better have a good response in terms of risk.
>
> At the same time, it covers issues that may not be picked up by other
> forms of testing. So, in terms of the amount of money that is being
> spent now, spending a fraction to improve the quality of the risk
> protection afforded by the process would seem to be a very valuable
> and very important and very significant thing to do, and then I
> wouldn\'t have to stand up here and sort of say I have got an apple
> here and a melon here and an orange here, so I conclude we could
> actually have some critical tests.
>
> DR. SCHMIDT: I would think that some of these studies benefit from
> being repeated after the American public is exposed to donor voting
> techniques, computer assisted, because in my day to day life I almost
> never run into a situation where I have to answer computer assisted
> questions, so for many donors coming in, blood donors, this would be
> pretty unique, but I think in a couple of years they will be more used
> to it except in Florida, of course.
>
> DR. NELSON: The next presentation, Victoria Virvos is going to talk
> about the literacy issues.
>
> **Presentation**
>
> **Victoria Virvos**
>
> MS. VIRVOS: Good morning.
>
> \[Slide.\]
>
> Let me start off just by saying I want to give you just a little bit
> about my background only because I come from a very different
> perspective of everyone pretty much in this room. I am a educator 24
> years, I am a bright person, but in this environment, which is out of
> my realm, I feel very illiterate. I think this is a real good issue
> because as we look around and as we think about this whole piece, and
> it goes way beyond literacy, the bottom line is this.
>
> We are talking a very complex question that has lots of different
> pieces to it, and we are trying to boil it down and say yes or no, and
> I am saying that from the start because when I was first asked to come
> and present, one of the first things I did was I went and I called
> some of my friends who are reading experts, and I was trying to get
> information about literacy.
>
> I want you to know I spent so much time talking to people who are very
> bright and well versed in their area, and they could not give me a
> specific answer. So, as we look at this information, what I want you
> to understand is this. The bottom line is at the end, I will tell you
> in my professional opinion the answer to the question that is being
> asked, but I will also tell you that it\'s a very complex issue.
>
> So, having said that, if we would please start with the
> transparencies, the first one on the considerations.
>
> \[Slide.\]
>
> There are some issues here as you look at answering the question of
> whether or not first-time donors should be allowed to actually do a
> self-administered questionnaire.
>
> I am not going to go over all of these, but I want you to understand,
> if any of you are interested, you find me and I will talk at great
> length, but in order to put this in a context and do it within a
> relatively reasonable amount of time, I tried to really limit this,
> but when you are talking about that, one of the first things we need
> to do is look at what is the definition of literacy, because I will
> tell you my definition of literacy was very different from what the
> current definition of literacy is.
>
> The second thing is when you look at the literacy, and we will go over
> this, but then there are different levels or scales of literacy, so I
> am suggesting that you can look, and the information that I will share
> with you, what you need to understand is that depending on what scale
> you are in, can change depending on the environment, and so on and so
> forth.
>
> So, again, all of this is to say we are taking complex information,
> trying to make is very simplistic.
>
> You now have also an area of functional literacy, and again, it is
> connected, but it is a different component.
>
> You have health literacy, and this is an issue I think really that for
> me personally, I really want you to think about this because if you
> take people, such as yourselves, who are embedded in this, this is
> your life, your health literacy is going to be very different from
> mine.
>
> If you take the general public who is going to be the type of person
> who is donating blood, you need to understand they may not be at the
> same level of health literacy as some of you are, not because they are
> stupid people, but because they have other lives.
>
> I will also tell you I would invite any one of you\--and this is not
> meant to be unkind, it is meant to be very honest\--come into my world
> and see whether or not you would have the same level of literacy if
> you were talking to me as an educator.
>
> So, when I looked at this, I was looking really from the point of view
> of people, not necessarily those of you who are just immersed in this
> whole health issue.
>
> You have got readability issues, and I think you mentioned, and it has
> major implications, now again, I am not suggesting one or another
> thing, but I am saying that the whole readability issue, you could
> give me a lot of what has been discussed on paper, and I can read it,
> and not necessarily make any sense out of it.
>
> But then you have got characteristics of adult learners, and again,
> this is an issue I think for some of you that you are missing the
> boat, and the reason is this. Adult learners\--and what I looked at
> specifically was information as it relates to adults\--and I think the
> point of all of this is what looks good, makes sense on paper in this
> scientific environment, is very different when you take it into the
> real world and you deal with adults.
>
> So, having said that, let\'s just quickly start with the whole
> literacy issue.
>
> \[Slide.\]
>
> If you look at the top, personally, this was my interpretation of
> literacy. If you look at the second one, this is the current
> definition. When they took that current definition, because it is way
> beyond just being able to read and make sense out of something that is
> written, because you are going to have information presented in lots
> of different ways.
>
> \[Slide.\]
>
> The study that was done and this whole data that I am giving you is
> the most comprehensive, up-to-date, and I am saying that because it is
> also onboard for 2002 to actually be updated, so what I am giving you
> is recognized in terms of literacy to be the most up-to-date.
>
> What this organization and the whole literacy survey, what they did
> was they created three literacy scales.
>
> \[Slide.\]
>
> These are the three scales that will affect whether or not someone is
> at a certain level of literacy, and if you will just take a moment and
> read over those.
>
> The bottom line is literacy, it is not just being able to read
> something and make sense.
>
> \[Slide.\]
>
> These are five levels. What NALS did was they looked at and they said
> bottom line is you don\'t have just literate or illiterate people.
> Wouldn\'t that be nice if we could do that, but literally, it is a
> continuum. Again, I mean this sincerely. If you look at me in
> different areas of my life, sometimes I will be at one level, another
> time I will be at a different level depending on the environment and
> what is expected of me.
>
> Now, again, I am saying, and being very honest with you, if I go
> somewhere and there is a computer, I don\'t care what level you want
> to call it, I am illiterate, and I say this upfront because does it
> not make sense to some of you that again we are not all on the same
> level, and it has nothing to do with my degree or my level of
> intelligence.
>
> A lot of it has to do with the environment meaning if I am in an
> environment with auto mechanics, I am going to be at a different
> level. Again, if you come into my world of education, if I looked and
> if I was talking to every one of you just one on one, and I said
> something like you need to know about me, something you need to know
> is that I do have a learning disability and truly, I actually have ADD
> as a result of, too, and I have problems at times trying to focus.
>
> See, I can talk and talk and talk. You could look at it on paper, but
> it is going to affect whether or not you understand if your background
> is not educational in nature. In this environment, if I stopped in the
> middle of this, and if I said does everyone understand or do you have
> any questions, and if you are sitting next to someone in this room
> that you deem to be important, crucial to your career or whatever
> else, I will guarantee the majority of you in this room may not have
> any idea of what I just said, but ain\'t going to raise your hand
> because you don\'t want to appear to be stupid.
>
> So, I can go into a blood donation center, which I did last week as a
> matter of fact, and I was asking the people in this center about the
> whole idea of the self-administered and what they thought, and so on,
> and so forth, and I asked this one lady, I said do you believe that is
> a good idea, and she said yes.
>
> I said, well, tell me how do you know if people, what if I am doing
> this writing, answering, and I don\'t understand. She said, well, you
> can ask someone. I said what if I don\'t know what to ask, and she
> just looked at me and she said I never thought about that.
>
> Now, again, I am giving you a broad overview, but if you look at the
> different levels, Level 1, 21-23 percent of American adults scored in
> this level. Now, again, I need to be upfront with you. That doesn\'t
> tell you one thing, I mean it really and truly does not tell you a
> lot, and I also don\'t want you to make some assumptions based on
> that, because\--if you will go to the next slide, please\--
>
> \[Slide.\]
>
> See, Level 3 from literacy experts is considered functional literacy,
> and what that means if you are trying to be successful in today\'s
> labor market, you need to be at at least Level 3, but I go back to
> what you need to know is going to change depending on your occupation
> and your environment.
>
> My father would have been in Level 1. My father was one of the
> brightest men I knew, but my father came over from Greece, and his
> English was very limited. So, you see where a lot of people who will
> fall into the first category may be people in this country who do not
> have English as their primary language.
>
> \[Slide.\]
>
> This is another way that you can look at this. Personally, I found it
> a little too simplistic, but I just wanted to again put it in here
> because I thought it might be helpful for some of you.
>
> \[Slide.\]
>
> The issue of readability. Now, again, remember that literacy is really
> big. Let\'s now look at readability, because this, to me, if you do
> chose to go towards the whole idea of a self-administered inventory
> questionnaire, you are going to have to really think about the
> readability issue.
>
> \[Slide.\]
>
> These are some current formulas that are used, and I am not here to
> tell you which is right or which is wrong or if one is better than the
> other, but I am going to tell you that what I found fascinating is
> that the results will vary depending on which formula you use.
>
> So, my question to you will be if you choose to do this, which formula
> are you going to use and how are you going to make that decision,
> because what might make sense to me as an educator may not make sense
> to the general public.
>
> If you look, one of the formulas will return a score two to three
> grades lower than other formulas, so again it depends. There is a lot
> of variability when you look at the different types of formulas that
> you are even going to use.
>
> \[Slide.\]
>
> To me, this, I believe, is even more critical, and if you will look
> over that, you can have a readability formula on some literature and
> come up with one, if you will, grade level. You can take the same
> literature, change the length of the sentence, some of the words that
> you use, take out some of the abbreviations, maybe look at how it is
> formatted, possibly put some pictures in there, look at the writing
> style of the author, and get a completely different readability grade
> level.
>
> \[Slide.\]
>
> Most formulas really look at two factors, and that is the number of
> syllables and the number of words in a sentence, but what I wanted you
> to see with the slide before, there are too many variables.
>
> If you again look at just the number of syllables and the number of
> words in the sentence, I believe, if you will go to the next slide,
> wonderful example, that this might make no sense at all, but if you do
> a readability formula, depending on which one that you use, it will
> come out with the grade level because of the number of syllables and
> so on, and it makes no sense.
>
> \[Slide.\]
>
> I know this is simplistic sounding, but I want you to understand, in
> essence, that is what I feel like sometimes is being asked, it is say
> too complex in the real world.
>
> \[Slide.\]
>
> If you look at the second statement, that the reading level, the
> readability piece, it predicts, if you look at it more for prediction,
> most of them look at how people will answer, getting 50 percent
> correct answers on a comprehension test.
>
> What that means in English is this. If I have something that is scored
> at a ninth grade level, what it means is if you have reasonable
> reading ability, you should be able, when you read something at a
> ninth grade level, if you are a ninth grader, to answer 50 percent of
> the questions on comprehension correctly.
>
> Now, again, I go back to if I am going to be getting blood, I don\'t
> like that.
>
> \[Slide.\]
>
> These are some things that again I want you to think about as you make
> some decisions. The first is adults typically, if you look at all of
> the adults across the country, typically will read at an eighth grade
> level. That is if you take everyone together, add them up, and so on,
> that many adults read at least one to two grade levels below their
> last school grade completed.
>
> So, you can\'t look at someone who has finished high school and assume
> they would be on a grade 12. There was some fascinating information on
> the whole idea of health. Again, I am saying this because of recently
> having quite a bit of experience with my mother who was in the
> hospital and talking to physicians, reading material, being competent
> in my world, but in a health environment not being able to make a
> great deal of sense.
>
> What I have found through some of the readings that I have done is
> that for a lot of people in this country, when it is health related,
> the literacy level is a lot lower than most people realize.
>
> Again this is not meant to be unkind, it is meant to be honest. Many
> physician in the room and in this country, they might say something,
> it makes great sense to them, but if the consumer does not understand,
> what you are going to find is comprehension goes down. Again, it is
> not because they are stupid people, it is because they don\'t
> understand what is being said.
>
> So, what was recommended really is that information be written at a
> fifth grade or lower reading level. Now, that sounds to me really low,
> but I will also tell you, if your ultimate goal is for people to be
> able to comprehend what it is that they are reading, you need to look
> at the people to whom the information is directed.
>
> The reading ability of a person does not always match his or her
> educational level. That is why I am not really spending time talking
> about the blood donors that you currently have because to me this goes
> way beyond that, and what their academic level is may not necessarily
> have anything to do with the understanding of questionnaires.
>
> As a general rule, it is better to write a document that is below the
> reading skill level of the intended audience. Again, this goes back to
> if you want people to be able to give you accurate, honest
> information.
>
> \[Slide.\]
>
> This bottom line in conclusion. If you were to ask him for my
> professional opinion should self-administration of the donor history
> questionnaire for first-time donors be allowed, I would say you will
> make whatever decision you choose. I personally believe it is not
> right, and it is not right for a variety of reasons.
>
> I would also ask you to really think about that if you are doing this
> self-administration, if you choose to do that, I would make sure that
> you look at how it is written, I would make sure that you look at what
> words are being used, I would make sure that you look at what happens
> from the moment people walk into the environment, because I will tell
> you, and again it goes back to just working with people, that if you
> want first-time donors to be repeat donors, I believe really and truly
> that you need to have the human interaction one on one.
>
> Does that mean that that is perfect? I am not suggesting it does mean
> that, but I am going to tell you, and it has been fascinating for me
> just to look at some of the reactions because again, keep in mind my
> background is behavior, I can\'t turn it off, but it is amazing to me
> where sometimes there is information that people are giving facially,
> I mean it is very blatant, and other people will miss it.
>
> If you want some people behind this whole idea about having human
> interaction, Daniel Goldman, you are familiar with him I am sure, who
> has written a lot of books on the whole emotional intelligence, one of
> the things that comes out loud and clear in a lot of his books is if
> you take two people with the same skill level, the ones who are more
> successful in this life are the people who have people skills, and I
> think we are forgetting that in this whole quest.
>
> Again, it is to be scientific, but you can\'t remove the human piece
> out of this because you are dealing with people. The other thing I
> want you to really think about is Eric Jensen, who has spent a great
> deal of time looking not just at the brain research, but with learners
> and people, he has got a lot of information that pretty much says that
> people let you know what state. You will have learner states. They
> will let you know what state they are in, in very blatant terms.
>
> As a teacher, when I am giving information, I will tell you I might
> ask people do you understand. They can nod their heads, but they are
> nonverbally giving me very different information.
>
> It was fascinating, last week, when I was in a blood donation
> location, that will remain nameless, someone passed out, literally
> fainted, and I asked one of the people, I said could you not tell that
> this person was having some problems, I mean because someone does not
> raise their hand and say excuse me, the fact of the matter is if we
> look at if we expect people to give us all of this information, you
> see where we are going to lose sight of information people are giving
> us that might be more non-verbal.
>
> I go back to\--again, if any of you are interested, I will be more
> than happy to talk to you about this, but when you look at some of the
> research on adult learners, one of the things that you will find that
> is loud and clear in the literature\--again, this is pretty much how I
> make my living\--is that for most people who are adults, when they are
> successful on the job, it is even more difficult for them to ask for
> help. If I go off of my job into a donation environment, and I am in
> an environment and I am looking at this information, and I believe I
> am supposed to know everything, it is very uncomfortable for me to
> raise my hand or go ask someone for some help.
>
> So, does it make sense that if you need help, you should ask for it,
> yes, but in the real world, I go back to that is questionable. So, all
> I am going to ask for those of you in this room who are in a
> decisionmaking position, just keep in mind that we want to do what is
> right, but we also want to understand that when you are looking at
> donors, particularly your first-time donors, and if you want to make
> them ultimately become repeat donors, we need to realize that we
> can\'t become elitist and have expectations that everyone is on the
> same playing ground in terms of the knowledge of health issues.
>
> Thank you.
>
> DR. NELSON: Thanks.
>
> Questions?
>
> DR. DOPPELT: We have in our packet this donor questionnaire. Have you
> read this?
>
> MS. VIRVOS: Yes, sir, I have.
>
> DR. DOPPELT: At what grade level do you think this is?
>
> MS. VIRVOS: I have no clue. I will also tell you this, I was\--
>
> DR. DOPPELT: I mean you talk about sentence length, and so forth. I
> mean they are not very long. They are all pretty short.
>
> MS. VIRVOS: That is relatively new. If you remember the one prior to
> that, was so convoluted. But to answer your question, I am not sure,
> and the reason I am not sure is because even if you had little words,
> you need to understand that because some of the medical terms, I mean
> you have got so many medical terms there that even if you had single
> syllable words, it is going to impact.
>
> So, to answer, I don\'t know the answer. I don\'t know the answer, and
> I don\'t know that there is truly a reading formula that will be able
> to get at not just the number of syllables and the length of the
> sentences, but also tie into the whole comprehension piece.
>
> To me, that is something you need to really think about is I might be
> able to read something, have it in my hand, I may not be able to
> comprehend enough to give a correct answer.
>
> DR. EPSTEIN: Could I ask you to focus specifically on the question of
> audio-CASI, because we made a distinction in our draft guidance
> between a presumed equivalence of audio-CASI to a face-to-face
> interview versus other forms of self-administered questionnaire, and I
> am concerned that in your general conclusion that a
> self-administration, a general questionnaire to first-time donors is
> not appropriate, you haven\'t focused on whether there is any useful
> distinction to be made for audio-CASI versus other formats.
>
> I think that that is very important for the committee because it is
> sort of the focal point of the questions that the members will be
> asked.
>
> MS. VIRVOS: I understand. I will acknowledge that, and the reason I
> did not focus on that was because I was asked specifically to talk
> about the self-administration of the donor questionnaire and I am not
> that familiar with that other piece.
>
> DR. EPSTEIN: So, if I could sort of focus this point, the opinions
> that you have provided would be largely applicable to a person reading
> the questionnaire.
>
> MS. VIRVOS: No. Let me say this. Because you can take the computer
> piece, in essence, it is going to be some of the same information,
> because it\'s on a computer, because I have headphones on, and I am
> hearing the words does not help me comprehend any better.
>
> So, if you are looking at reading it or having headphones and having
> the information on a screen, and we are still going over the same
> words, and I can\'t understand it in print, then, even if I hear it,
> the comprehension personally I think will still be\--
>
> DR. EPSTEIN: Well, let me press that point. Are you suggesting to us
> that the professional literature indicates that auditory literacy is
> different or not different from written literacy? You are suggesting
> that there is no difference.
>
> MS. VIRVOS: No, I am not suggesting that. What I am saying is we are
> looking beyond. You can read it, you can hear it, you can see it, but
> if I don\'t understand it, it doesn\'t matter. It is the same thing in
> a one-on-one interview. If you talk to me and even if I am able to
> look at the information in front of me, if I cannot comprehend the
> information because I do not understand the words, you see, to me what
> you are looking at, you are looking at apples and oranges.
>
> I want to look at more of the comprehension piece. If I am sitting in
> front of a computer or if I am doing a self-administered\--again, this
> is where I might disagree with some of you\--I will tell you this. If
> I am watching you and if you show me on your face you do not
> understand, then, I would stop. Whether or not I am supposed to, I
> know I would stop and say you look like you have a question, but if I
> am in a room by myself and I am doing this, no one is going to be able
> to even pick up on that.
>
> DR. EPSTEIN: Again, just to try to clarify matters, you might argue
> that there may be no ultimate difference in comprehension, but it is
> conceivable that there might be differences in honesty of reporting.
>
> In other words, your argument would tend toward a conclusion that the
> use of computers or computer-plus audio may not alter comprehension,
> but one could still potentially have a useful difference in accuracy
> or honesty of responses unrelated to comprehension in other words.
>
> MS. VIRVOS: But how can I be accurate in my response if I don\'t
> understand?
>
> DR. EPSTEIN: No. I am saying that the percent of respondents who
> comprehend might not be different, but among the subset who do
> comprehend, there might be differences in accuracy of reporting based
> on the medium.
>
> DR. NELSON: You are saying that you won\'t be able to detect
> non-comprehension as well in a self-administered questionnaire as you
> would with a personal interview, isn\'t that right?
>
> MS. VIRVOS: That is one of the things I am saying.
>
> DR. NELSON: Isn\'t that what you are saying?
>
> MS. VIRVOS: Yes, sir. The other issue is this. Again, please
> understand I don\'t come from your background, so I could probably say
> it in a more eloquent way and have you understand better, but I
> can\'t, this is me, but I will tell you that when you have
> face-to-face human interaction, my experience has been that people are
> more honest when they feel a connection to the person.
>
> DR. NELSON: Well, I think there are two issues. One is honesty and the
> other is comprehension, and I think, as I understand it, you may be
> focusing on the comprehension issue, Dr. Boyle was focusing on the
> honesty issue related to privacy and the fact that the human
> interaction has a down side as well as an up side.
>
> MS. VIRVOS: Yes.
>
> DR. NELSON: And the down side is if it is your next-door neighbor, you
> may not be as honest if it were the computer even though the computer
> could probably be linked to 10 million people, people think it is more
> private.
>
> MS. VIRVOS: I go back to what I really do believe is this. I believe
> that there is not a simple answer to this, that it doesn\'t matter
> which method you choose, there are going to up and down sides to
> everything that you choose.
>
> DR. NELSON: Well, the endpoint is validity, in other words, can we get
> valid answers to the questions we are asking, and there is
> multi-components that I think we have to weigh.
>
> Another thing, as I understand it, the committee is being asked is
> should the whole questionnaire be self-administered in some form or
> another or should it be part self-administered and part direct
> questions, and when you come to travel to various places, it changes
> commonly, I can see that that is a problem.
>
> DR. FITZPATRICK: Just as an educator, one of the things that isn\'t
> evident from the literature today or the discussion today, but we have
> talked about a little bit in the past, what difference do you think it
> would make, or do you think it would make a difference, for those
> places that provide the donor some sort of education about the
> questions prior to giving them the questionnaire, and there are sites
> that provide a videotaped explanation of the importance of questions
> and what some of them mean, and then provide them the questionnaire,
> there are some places that stand before a group and do the same thing,
> and then provide them the questionnaire for self-administration?
>
> I know you probably didn\'t evaluate that, but do you think that could
> make a difference?
>
> MS. VIRVOS: My first response would be yes. My second response would
> be depending on, because it goes back to the comprehension piece, that
> the video, whatever other literature is going to be supplemental,
> needs to be at a level that I can understand.
>
> Again, so, yes, I am saying that could help, but I am also suggesting
> to you it is not that simple. It is taking complex medical information
> and trying to put it into a level where people can comprehend even if
> they don\'t have a health background.
>
> DR. ALLEN: I want to thank you for your presentation and the
> information. I think it is very helpful for us because it does provide
> a totally different perspective. I commend you also for going to a
> blood collection center and doing direct observation.
>
> Did you get a chance to observe any questioning of donors in the
> process, or have you yourself donated blood and gone through that?
>
> MS. VIRVOS: I have donated blood, I have gone through that. I also,
> because I had traveled last year, I had to wait a year to donate
> blood, so I was asked some of those questions one on one.
>
> I will tell you that\--again, this is my honest response\--if I had
> not been so involved with the focus groups when we were trying to look
> at the questions and rewrite them, so that more people could
> understand them, based on the explanation that I got from the person
> who was helping me, I don\'t know that I would have been as successful
> in answering them, but I will also tell you, having said that, if I
> had had the opportunity to read without even a human being around, and
> asked, you know, go to someone if I needed help, I will tell you what
> I would have done, is I would have probably very sweetly, because my
> mama taught me to do that, I would have smiled, and when that person
> turned his or her back, I would have left the center, not to return,
> because people don\'t like feeling incompetent, and it had nothing to
> do with the individuals in the room. I am saying it has to do if I am
> successful on my job, when you put me in another environment, and I am
> not successful, what a lot of us will do is we will try not to go back
> into that environment.
>
> Personally, I want to make it so that the blood donation process is
> open to all people, because I think really and truly as we look at
> some of the people coming up through schools today, we have got a lot
> of people who are doing more traveling and they are not just going to
> normal places, and so I personally believe your pool is going to be
> smaller and smaller and smaller.
>
> That is why to me\--again, I do realize we are looking at first-time
> donors, and that is really what I tried to focus on, but in the back
> of my mind, what I also want to do is I want to make those first-time
> donors be repeat donors.
>
> DR. NELSON: Other questions?
>
> If there is no other discussion, there were three groups that wanted
> to make comments at the open public hearing.
>
> First is America\'s Blood Centers. Mary Townsend.
>
> **Open Public Hearing**
>
> DR. TOWNSEND: Thank you. I did want to clarify I am speaking for the
> AABB Task Force, not for ABC.
>
> I want to refer you to the written comments that you have in your
> packet. I don\'t want to take your time to tell you who AABB is
> because you know who we are. The members of the AABB
> Interorganizational Task Force to redesign the Uniform Donor History
> Questionnaire, which is a mouthful, the members are listed in there.
>
> I just want to mention that we had membership from many blood
> organizations, as well as from the government agencies, from the
> military, survey design experts, a statistician, and an ethicist.
>
> As you know from the presentation to this advisory committee three
> months ago, the Task Force have completed an extensive process to
> redesign and simplify their donor questionnaire. We appreciate the
> unanimous endorsement that you gave us three months ago.
>
> The Task Force members unanimously support the use of
> self-administered questionnaires, or SAQs. The concept of the
> self-administered format was the fundamental principle underlying the
> Task Force\'s redesign effort. The Task Force requests that all donors
> be permitted to self-administer the questionnaire.
>
> There is a considerable body of survey design literature that supports
> the use of SAQs over face-to-face interviews. First, to address the
> concerns about SAQs in first-time donor use, a study by Mayo that is
> referenced showed that, in general, first-time and occasional donors
> were actually more likely than frequent donors to pay attention to
> self-administered questions.
>
> Furthermore, a precedent for allowing donor self-administration of a
> questionnaire has already been established in 1998 when the American
> Red Cross received FDA approval for such an approach, and you will be
> hearing from the Red Cross in a moment about their experience.
>
> In other non-Red Cross blood centers, it is common practice for both
> first-time and repeat donors to self-administer all the questions on
> the questionnaire except for the HIV high-risk questions. This
> practice has been in place many years, and there is no evidence that
> by now prohibiting self-administration of the questionnaire by
> first-time donors, an improved donor qualification process would
> result.
>
> Indeed, the primary, if not the sole, reason that donors are not
> permitted to self-administer the high-risk questions is that FDA
> currently prohibits this practice. At the time these questions were
> first introduced, it may have been prudent to require that staff
> administer these questions, but there is no evidence that this is
> still a valid concept.
>
> A CDC-sponsored interview study of HIV-positive blood donors at major
> blood centers throughout the United States between 1988 and 1998
> showed that among 425 HIV-positive first-time donors interviewed,
> approximately 20 percent expressed privacy concern as one reason that
> they did not self-defer even though they knew that they should.
>
> Outside of the blood donor screening area, there has been considerable
> evidence of this response anonymity effect that was described by John
> Boyle in which respondents are reluctant to admit to an interviewer
> that they have engaged in illegal or embarrassing activities.
>
> Examples also cited include studies by Aquilino demonstrating greater
> likelihood to discuss a history of depression and admit to illegal use
> of drugs and alcohol in self-administered questionnaires compared to
> other modalities, and Tourangeau showing a significantly increased
> likelihood to report a number of sexual partners, sexually transmitted
> diseases, and condom use in SAQs as opposed to face-to-face
> interviews. In fact, Tourangeau concluded that increasing the privacy
> of data collection via self-administration is the approach most widely
> believe to improve accuracy of answers to sensitive questions.
>
> It is particularly relevant to this discussion to note that the
> cognitive interviews performed for the Task Force by Paul Beatty and
> his colleagues at the National Center for Health Statistics assumed a
> self-administered survey, and they were done using participants who
> had never donated blood, that is your equivalent of the first-time
> donor.
>
> So, when we talk about taking this donor questionnaire into the real
> world, it was done, the studies have been done by the committee, by
> the Task Force. These studies offer reassurance that a SAQ would be
> effective in a blood donor screening milieu.
>
> A final argument against use for SAQ is that the interview process
> itself, as Dr. Boyle has already shown, may serve as a vehicle for
> introducing errors into data collection. Interviewers may inject such
> errors by reading questions too quickly, which we have all heard
> about, or with little discussion, thereby resulting in failure to
> trigger an appropriate or accurate response.
>
> Vocal inflections can also have the same effect. This can be avoided
> by having individuals read the questions themselves, an approach that
> has been shown to improve response and focus inaccuracy. Even
> well-trained interviewers can start to anticipate responses to
> questions that have little response variation and may introduce
> unintended variables into question administration. The SAQs appear to
> reduce the unintended effects of interviewer on the answers to the
> questions.
>
> Finally, we would like to address FDA\'s concerns about donor
> literacy. Data from the REDS study show that the vast majority of
> donors have a high school education or greater, whatever that means,
> and literacy therefore should not be an issue for many donors.
>
> I want to remind that you donor screening does not occur in a vacuum.
> The Task Force realizes that donor screening is a process including
> donor education, questionnaires, and interaction with the donors after
> this questionnaire is completed.
>
> Even if a donor has literacy problems or reading problems for that
> matter, and those of us who are getting older understand that, the FDA
> is aware that the donor receives careful attention through the
> donation process. Simply observation alone can determine that someone
> is inattentive and does not appear to be reading the questions.
>
> In such situations, the staff will intervene and administer questions
> if necessary. The User Brochure developed by the Task Force emphasizes
> that blood center staff should invite inquiries from donors and be
> available in the event that the donor is having problems.
>
> The Task Force also took a common sense approach of embedding quality
> assurance tools within the new questionnaire to demonstrate donor
> attentiveness and understanding by designing the new questionnaire to
> detect when somebody is just, quote \"checking\" the boxes.
>
> It is worth noting that FDA representatives to the Task Force were
> involved in the very rigorous discussions that led to the Task Force
> taking these additional measures. The Task Force does not endorse oral
> administration of the questionnaire for all first-time donors in the
> unlikely event that an isolated donor may be illiterate. The means to
> determine if someone is having difficulty reading the questions
> already exist in current screening practice and, further, has been
> built into the new questionnaires.
>
> Again, I want to remind the committee that this does not occur in a
> vacuum. We are not talking about handing a person a donor screening
> implement, having them fill it out, turn it back, and say okay, let\'s
> go.
>
> If the User Brochure instructs the screener to interact with the donor
> upon completion of that instrument. For example, on the travel
> question, if a donor checks yes, they have traveled out of the United
> States, then, the donor screener sits down and discussed the travel
> pattern and history with the screener.
>
> I want to remind you that these are capture questions and they are
> aimed at capturing activity that then will be elicited and discussed
> by the screener. I also want to remind you that the Task Force, in
> designing this new questionnaire, has already a great deal of time and
> effort to already address sentence length, word choice, use of
> abbreviations, the layout of the document, formatting of the document,
> and overall organization of the content.
>
> I want to remind you that we are talking about the new questionnaire,
> not the old, complicated, complex one.
>
> Blood centers around the United States are still awaiting FDA\'s
> response to the questionnaire redesign proposal that was submitted to
> FDA in March. The Task Force would like to assist the FDA review
> process in any way possible, and would not like to see the process
> further delayed by any possible impasse over the issue of donor
> literacy.
>
> As an alternative to the very prescriptive requirement to orally
> administer the questionnaire, to detect a very small number who may
> have a literacy or reading problem, the Task Force would like to offer
> several suggestions.
>
> One is that FDA recommend that blood centers develop a mechanism for
> determining if first-time donors have literacy or other reading
> problems. Another approach utilized in the plasma industry is simply
> to ask donors to read aloud selected items from the educational
> material or the questionnaires to demonstrate literacy.
>
> We would emphasize that we would like to have as much flexibility as
> possible for the blood centers.
>
> In closing, the Task Force would again like to emphasize its firm
> conviction, based on survey design literature and expertise, and the
> evaluation project of the National Center for Health Statistics, that
> the blood donor questionnaires should be self-administered by all
> donors.
>
> Thank you for your time.
>
> DR. NELSON: Thank you.
>
> Comments or questions?
>
> DR. LEW: Just a quick one. You mentioned the CDC study that 20 percent
> of people who were HIV-positive who donated said there were privacy
> concerns, but what we don\'t know is how many people, because they
> were confronted with questions face-to-face, as we saw with the other
> studies, they actually admitted that they did, and then they deferred.
>
> DR. TOWNSEND: And I don\'t believe that was addressed in that study.
>
> DR. LEW: That\'s right, so it could be that many more people, because
> of the face-to-face, actually said no, I have this risk, I am not
> going to donate. Also, you didn\'t give the other 80 percent of why
> people continued to donate, was it comprehension?
>
> DR. TOWNSEND: To be honest with you, I don\'t have that study. That
> data was provided to us, I believe by Mary Chamberland, who is not
> here.
>
> DR. FITZPATRICK: Are we to infer from your comments that since you
> submitted it to FDA in March, there has been no dialogue between you
> and FDA?
>
> DR. TOWNSEND: Not that I know of. Kay? That is correct.
>
> DR. FITZPATRICK: Second, in the studies and the activity that was done
> in developing the Uniform Donor History Questionnaire, were there
> instances when you provided the questionnaire to a group, and then
> repeated it at some later date with that same group to determine the
> validity and honesty of the answers and the questions?
>
> DR. TOWNSEND: No.
>
> DR. FALLAT: I think it the questionnaire that you were using is the
> one that we have in front of us?
>
> DR. TOWNSEND: Yes, that is the new questionnaire.
>
> DR. FALLAT: Is that the one that you were using?
>
> DR. TOWNSEND: Right.
>
> DR. FALLAT: It seems to me curious that there is no column that says
> \"don\'t understand\" or \"not sure.\" Has that ever been considered,
> and wouldn\'t that be an important column to add to respond to the
> understanding or illiteracy question.
>
> DR. TOWNSEND: No, actually, that is covered in the User Brochure. As I
> said, this is not done in a vacuum. Donors will be handed this
> questionnaire and will be instructed what to do, and one of the
> instructions is if you are not sure about an answer, leave it blank,
> and they can also mark on it.
>
> At the end, the donor sits down with the screener and they go over
> this questionnaire together if there are any questions. So, these are
> capture questions simply to see where the screener needs to put the
> emphasis, which we believe is a better use of screener time, talking
> one-on-one with the donor about where their issues are, where their
> questions are, and the rest of the stuff that is easily understood
> could be answered.
>
> DR. FALLAT: Do you have any data on the number of people or the number
> of questions and the kinds of questions that were left blank then?
>
> DR. TOWNSEND: No, the testing of this was not done on the whole
> instrument. The testing of these questions was done question by
> question in donor interviews, looking at the content of the question
> itself.
>
> The Task Force had limited funds and our emphasis was on developing
> better questions, and the studies were done in developing better
> questions. Although we would have liked to have taken the whole
> questionnaire at the end and tested it as a whole, we were unable to
> do that. Kay, am I correct? Yes.
>
> DR. NELSON: The next is Dr. Peter Page from the American Red Cross.
>
> DR. PAGE: Thank you. The American Red Cross is a member of the
> American Association of Blood Banks and supports the statement that
> they just made. They and others earlier this morning referred to some
> data the Red Cross has collected in the past and presented to the FDA,
> which I will now review with you on the SAHH or Self-Administered
> Health History.
>
> \[Slide.\]
>
> I will first describe the process. It provides standard written
> informational materials. We have a brochure that we call What You Must
> Know Before Donating Blood, which relates risk behavior in relation to
> blood safety. The donors later sign that they have read and understood
> that brochure.
>
> Each presenting donor is provided instructions for completing the
> Self-Administered Health History in a confidential setting.
>
> The donor completes the questions on what we call the Blood Donation
> Record, and then the health historian, the Red Cross staff person
> assesses the donor\'s comprehension by asking four questions orally.
>
> \[Slide.\]
>
> The health historian reviews the Blood Donation Record for any \"yes\"
> responses to questions. They review it for legibility and they review
> it for completeness to ensure that all questions have an answer.
>
> The health historian then reviews with the donor orally and documents
> information for any and all \"yes\" responses, and it is the health
> historian, the staff person, that then determines the donor
> eligibility.
>
> \[Slide.\]
>
> The procedure for verifying donor comprehension. After the donor has
> completed the form and answered all the questions, the health
> historian asks each donor four things. He asks the donor: Do you have
> any questions? Do you understand all of the questions on the form?
> Would you like someone to go over the questions you answered with you?
> Do you feel that your form was completed in a confidential manner?
>
> If there are any \"no\" responses, then the staff will perform a
> staff-administered health history for that presenting donor.
>
> \[Slide.\]
>
> We compared Self-Administered Health History with Direct Oral
> Questioning or DOQ. This was a study in which we had four parts. We
> assessed donor call back, otherwise also known as post-donation
> information, exemplified by a donor developing a fever a day or two
> after the donation and calling back to make sure we are aware of that,
> something that was referred to in an earlier presentation today on
> another subject.
>
> We also assessed donor deferral rates for the high-risk questions in
> self-administered versus direct oral questioning. We looked at the
> confirmed positive viral marker rates, and then there was a survey of
> donor and staff regarding satisfaction.
>
> The next slide describes the sequence and the size of the study.
>
> \[Slide.\]
>
> There were nine study regions of Red Cross\'s 36 blood regions around
> the country, and there were 5 control regions that were selected for a
> similar urban-rural mix.
>
> The study began in January of 1996 and both the study and the control
> group for six months used Direct Oral Questioning, so we have
> comparison of the study regions and the control regions doing the same
> things at the same time in the beginning.
>
> Then, the study region, nine of them, for a year used
> Self-Administered Health History for over 2 million donations, and
> then the control regions stayed with Direct Oral Questioning for
> 800,000 donations.
>
> So, we have the Self-Administered Health History data, which we can
> compare historically to the same regions earlier, and we can also
> compare it to, at the same time, the other control regions. Both
> comparisons were done.
>
> The next slide shows the conclusions.
>
> \[Slide.\]
>
> The donor call back rate or post-donation information was
> statistically significantly greater with the Self-Administered Health
> History, but not a large difference.
>
> The deferral on high-risk questions had a statistically significant
> increase overall and depending on whether you looked at the other
> regions at the same time or the same regions historically, it was a 42
> to 57 percent increase in deferrals for high-risk questions or people
> who didn\'t donate and we don\'t have a test result on.
>
> We looked at the infectious disease marker rates and for HIV and
> hepatitis B surface antigen, there was no difference and no change.
>
> For hepatitis C and syphilis, there was an increase, however,
> historically from the early part to the latter part, but the same
> increase was observed in the control regions.
>
> For HTLV, in three of the nine study regions, there was an increase,
> and the same increase was not observed in control regions. The
> increase was small.
>
> We concluded that Self-Administered Health History is comparable to
> Direct Oral Questioning.
>
> \[Slide.\]
>
> The donor and staff satisfaction surveys showed the donor processing
> time decreased an average of 4 minutes and up to 8 minutes, an issue
> that has been a complaint from many donors that it takes so long to
> donate.
>
> There was a sense that particularly the older donors were less
> embarrassed, and the staff felt that donor comprehension was good.
> Some staff members felt that donors would be more honest in not having
> to verbalize some sensitive information. This is based upon surveys of
> staff and donors.
>
> \[Slide.\]
>
> This slide is a copy of a letter we received from the FDA in 1998.
>
> \[Slide.\]
>
> This slide summarizes the key points that the FDA has accepted this
> data and accepts us including Self-Administered Health Histories as an
> alternative to direct oral questioning in our procedures.
>
> \[Slide.\]
>
> My last slide just states that since that approval, we have screened
> over 5 million first-time donations using this process.
>
> Thank you.
>
> DR. NELSON: Do you have any sense of the issue raised by the previous
> speaker about the proportion where there were real significant
> comprehension problems with the questionnaire when you went to the
> self-administered from the oral?
>
> DR. PAGE: I don\'t have with me, and don\'t know if we have, data
> about the number of times the donors answers \"yes\" to one of the
> four questions trying to determine whether they understood it or not,
> and I don\'t have data as to how many questions are left unanswered in
> self-administered to bring to the person, but that is data that we
> could prospectively collect.
>
> DR. SIMON: I may have missed it, but this includes now the high-risk
> questions or does not?
>
> DR. PAGE: Yes, all questions.
>
> DR. SIMON: All questions.
>
> DR. PAGE: The only questions necessarily asked are the ones do you
> have any questions, do you understand the questions, do you want
> somebody else to go over it with you, and do you feel it was done in a
> confidential manner.
>
> DR. STUVER: Do you have any sense of if there were any differences
> between the two methodologies with respect to whether they were
> first-time donor or repeat donor?
>
> DR. PAGE: No. This study was done to study the acceptability or a
> similarity of direct oral and self-administered, and this study did
> not provide out first-time from repeat. This was done six to seven
> years ago.
>
> DR. NELSON: Twenty, 30 percent of donors are first-time?
>
> DR. PAGE: That\'s correct, about 20 percent in general were
> first-time, or 20 percent of donations are from first-time donors.
>
> DR. NELSON: So, you would probably have several hundred thousand.
>
> DR. PAGE: Five million since then. Oh, but in the study\--
>
> DR. NELSON: In the study.
>
> DR. PAGE: In the study, it would have been several hundred thousand,
> yes.
>
> DR. KOFF: Peter, can you mention what the four questions that were
> asked that were used to judge comprehension?
>
> DR. PAGE: They are: one, do you have any questions; two, do you
> understand all of the questions on the form; three, would you like
> someone to go over the questions you answered with you; and, four, do
> you feel that your form was completed in a confidential manner.
>
> DR. KOFF: Those really don\'t sound to me like they are really getting
> to the question of comprehension. They are getting to perception maybe
> of comprehension, but have there been any studies using SAHH actually
> trying to get a handle on how much comprehension actually occurred?
> Have you done anything in that direction?
>
> DR. PAGE: Not that I am aware of specifically, but this is not a field
> that I have been close to over the years.
>
> DR. LEW: That is something I wanted to ask myself. I am just amazed
> that we are now jumping into this, 5 million people already using
> this, and yet, there is some important questions about comprehension
> and validity of using the self-administered test, but we are jumping
> into it without any prospective studies, I mean studies to actually
> look at it and make the decision if this is the right thing to do.
>
> I am also impressed with one of the slides that was shown. A fifth of
> all people, 20 percent don\'t know what hepatitis means. If you look
> at the new questionnaire, you know, have you ever had it, et cetera,
> and the way this is set up, your system, you only kind of pursue those
> questions where people answer yes.
>
> Many people, when they see a word they don\'t understand, oh, no, I
> didn\'t have that disease, and they are just going to check off
> \"no.\" It is hard to believe that we are doing this to millions and
> millions of people without stronger testing to make sure it is the
> right thing to do.
>
> DR. PAGE: We do ask them if they have any questions, but if\--
>
> DR. LEW: I would like to ask the people who do these studies that have
> these questionnaires, with a box saying \"I don\'t understand,
> actually make people more honest, because if you don\'t have that
> option, and you have to say \"yes\" or \"no,\" well, no one wants to
> look dumb, and they may say \"no,\" but if they said \"don\'t
> understand it,\" and it\'s a standard question, they feel comfortable
> saying \"I don\'t understand.\"
>
> DR. PAGE: I think the intent is to permit them to leave the question
> unanswered until they interact with a staff person, who can then
> handle it verbally with them.
>
> DR. LEW: Most people would like to complete a test, that\'s my guess.
>
> DR. NELSON: There are actually some data from the REDS study, which
> follows up donors who have markers, and how often has the issue been
> comprehension as opposed to socially desirable responding.
>
> DR. SIMON: I would just like to try to put in context, following on
> the last comments, actually, the interview given by an interviewer has
> not been validated or studied to any greater extent than the
> self-administered.
>
> This has simply not been an area that has received attention or study
> until really the Task Force, as far as I know, well, there was some
> other work done by Donna Mayo, and there have been sputterings of
> efforts over the years, but I think a lot of the attention is being
> focused now is because this is the first time that we have really
> looked at it. Maybe Harvey has on that same point.
>
> DR. KLEIN: It is a point that I think has been made, but perhaps this
> committee needs to have reemphasized, and that is to the best of my
> knowledge, none of the questions on any of the donor questionnaires
> ever used has ever been validated.
>
> Yet, we collected 15.1 million units of whole blood and components
> last year, so we have what is clearly a non-validated system in place.
>
> Many of the questions vary dramatically from center to center. This is
> no standardization. To be brutally frank, some of the questions on
> risk behavior and geographical exclusion that have been accepted
> verbatim as given by the FDA are literally incomprehensible.
>
> I have a high school degree and I was reasonably high up in my high
> school class, and when I donate blood, I have to read them several
> times. So, I think sort of like the HTLV-3 assay, that was
> anti-HTLV-3, that was licensed in 1985, it is not the same assay that
> we are using today.
>
> I hope that we will clearly see this as a starting point and start to
> validate this kind of questionnaire, but looking at what we are
> currently using, I don\'t think we should be in any way satisfied that
> we are stepping off of a very comfortable and a very useful
> questionnaire into an abyss. We are not. This is clearly a step in the
> right direction whether it is applied as a self-administered or as one
> that is administered by a screening nurse.
>
> DR. FITZPATRICK: I was just curious, in the light of you seeing very
> little significance and difference in serological testing between
> groups or PCR testing I am assuming since some of this was done after
> NAT, but seeing an increase in 42 to 56 percent of your deferrals, why
> would you choose to increase your deferrals over what you were seeing
> as benefits?
>
> DR. PAGE: Those deferrals were the high-risk deferrals, and we don\'t
> have a sample on them to know what their viral positive marker rate
> is, but I would say that if there is any question about their
> suitability or answering \"yes\" to a question, it would have been
> best not to have collected, which is what happened when there was
> self-administered health history.
>
> Am I understanding your question?
>
> DR. FITZPATRICK: Well, a large number were repeat donors, though, that
> would have been self-deferring for the first time even though they had
> donated previously.
>
> DR. PAGE: Presumably. I don\'t know the proportion that were
> first-time versus repeat in that group.
>
> DR. FITZPATRICK: So, you would have available the data to look at to
> see if you were\--
>
> DR. NELSON: I doubt very much that the data would answer this question
> just because the proportion with markers is small enough, and the
> denominator is so large, and the number of diffused is deferred.
> Additional deferrals is probably a fairly small number of the total.
>
> DR. PAGE: The number deferred for those high-risk questions is a
> relatively small proportion of the overall deferrals. I don\'t have it
> at hand, but that\'s available.
>
> DR. NELSON: I don\'t think the data are going to be adequate, but it
> would be interesting if you, in fact, could measure markers in that
> group without taking a unit. That is I think difficult for you to do.
>
> DR. PAGE: A possibility is to the fingerstick and put a drop on the
> filter paper, which can then be analyzed for some of those markers. It
> has been considered, but I don\'t believe done.
>
> DR. NELSON: Well, they separately do a hematocrit, so there is a
> fingerstick part of it, before the unit is taken.
>
> DR. PAGE: It could be done, and ELISA testing can be done on such
> blood on filter paper.
>
> DR. LEW: If I could just add a comment that I guess on the study that
> you showed, that was based on that study, that you could use that
> questionnaire, I guess I have concerns are those populations truly
> comparable between the controls and the test group, because if you
> look at it, it looked to me that the controls only donated twice over
> that time period. There were I think 400,000 and then 800,000
> donations, and then the actual test group, there was only 500,000, but
> they donated two million times.
>
> There were some differences in HTLV-3. Again, I just don\'t know the
> data, so I don\'t know if those are truly comparable in that study.
>
> DR. PAGE: You are astute to notice that there is not the same ratio of
> sample sizes in the study and the control group, and that was related
> to not every study started on January 1st, and not every study stopped
> on June 1st, but they were all done during that period of time.
>
> One might have done it for three months, another one might have done
> it for five months.
>
> DR. LEW: And then the other last thing is that I agree that we don\'t
> have a validated system with the oral. It is just that we are calling
> this the standard because it has been used forever, and I think a good
> point is brought up. We need to start validating these tests.
>
> My concern is we are just jumping from one unvalidated to another
> unvalidated, and I don\'t think that is the way to go. I think we
> really should encourage the appropriate tests to be done to validate
> the actual questionnaire.
>
> DR. EPSTEIN: I just wanted to add a few historical notes, because I
> sense the general frustration why hasn\'t this field moved faster.
> Just a few perspectives, first, that the FDA twice funded studies on
> the use of direct oral questions for high-risk screening. This was a
> study done by the American Institute for Research. It is the Donna
> Mayo study that was published.
>
> It was FDA dollars that funded it, and at that point in time, which
> was early 1990s, around 1990 or so, the issue was introduced in
> questions for heterosexual risk, and questions that had been
> studied\--I draw a little bit shy using the word validated, but at
> least studied\--were then proposed in FDA guidance.
>
> Now, FDA never said that the questions had to be adopted verbatim.
> Indeed, in all FDA guidances, we say that alternative validated
> methods are acceptable, but I think what everybody realizes is that
> validating questions is a very expensive proposition, and so there
> hasn\'t been a lot of that done.
>
> Later in time, toward the end of the \'90s, we became very concerned
> about supply issues, particularly in the wake of introducing the
> deferrals for classic CJD and then vCJD, and so with the increased
> concern on supply, one of our initiatives, again government led, was
> to try to remove barriers to safe donation, and one of the elements of
> that initiative was the recognition that we deferred a lot of donors
> because of questionnaires without knowing that these were validated
> deferrals.
>
> But once again, it was recognized that true outcome measures, which is
> what you are talking about, were difficult to obtain, that you would
> like to be able to show differences in marker rates between donors who
> did and did not defer, and ultimately, you would like to know about
> impacts on residual risk because, after all, even if you had
> differences in marker rates, you remove the marker positives, it is
> the marker false negatives that you are worried about.
>
> But once again, those are very expensive propositions. Short of that,
> the FDA solicited an industry-led initiative on the Uniform Donor
> History Questionnaire, and we have been highly cooperative with that
> initiative, but it has been focused more at sort of the normative
> level of, you know, do donors comprehend.
>
> We think that that is a step forward although we all recognize that it
> is short of any ultimate validation in terms of safety outcomes.
>
> So, this is where we are. I guess I am trying to say all this to sort
> of disabuse the notion that the problem has been that the FDA has been
> ignoring this. We recognize that use of questionnaires has come into
> play, you know, dating back to the 1950s without formal validation.
>
> We can only be where we are, and I think that these are steps forward,
> and I would note also that the NHLBI did fund the first development of
> the computer-assisted interview and that implementation of it was
> studied in a second study with America\'s Institute for Research,
> which was the second Donna Mayo paper cited.
>
> So, you know, we have been trying to be proactive, but there simply
> have been limitations which are technological. I mean these are
> difficult methodologies and economic. These are costly studies and
> sources of funding have not materialized.
>
> DR. ALLEN: Just a comment and one quick question. I think this
> historical perspective is important and, Jay, I appreciate what you
> just said. Certainly early in the AIDS epidemic, there were regular
> conference calls involving the blood collection centers, the FDA, the
> CDC, and others, and as it became apparent that questions were not
> doing the adequate job of having people self-defer who should, the
> questions were changed.
>
> The most obvious one in 1985 was the change from asking people or
> telling people if they were homosexual, they should not donate without
> asking the question directly to using the concept of behavior, men who
> have sex with men.
>
> I think there is still a lot of refinement in some of those questions
> now that has got to be looked at very carefully. I mean in particular
> asking people have any of your partners ever had that. I suspect most
> people have no idea.
>
> I am not sure that the blood-collection centers\--certainly the FDA
> has done some work in the past. CDC has done a little bit. The NIH has
> some done. This may be an area where we need to put out a very strong
> call for additional resources.
>
> Putting this advisory committee together on safety and adequacy has
> some recognition of the level of the problem, but I am not sure this
> translated into appropriate resources, and that probably is something
> that ought to be addressed at some point.
>
> My question really is with regard to the comprehension, the general
> comprehension questions. I assume that if somebody indicates that they
> have got a question or didn\'t understand something fully, there are
> notations made on the donor collection form.
>
> Do you have any idea about the frequency with which that was done or
> what the type of response was?
>
> DR. PAGE: You are correct that in the Remarks sections of the blood
> donation record, it is noted if there were any questions of that
> nature, and the answers may be changed. I don\'t know the frequency,
> but we can retrospectively review for that.
>
> DR. NELSON: Thank you.
>
> Celso, did you want to\--I erroneously attributed Mary Townsend to
> American\'s Blood Center.
>
> DR. BIANCO: It was not your error, it was maybe our error.
>
> I am Celso Bianco. I am with America\'s Blood Centers. That is an
> association of 75 blood centers. They are community based and collect
> about half of the U.S. blood supply.
>
> We were active participants in the AABB Task Force and donor history.
> We support entirely the conclusions of the Task Force including the
> self-administered questionnaire. I would like to reemphasize what has
> been said by many here. This is new. That is, even with limited
> funding, limited resources, we are able at least to address issues of
> comprehension, to address questions that are so complex, so crazy,
> that really lead to a lot of confusion on the part of the donors.
>
> I would like also to remind the committee the words of Dr. Boyle, that
> the questionnaire is not a test and that no matter how perfect we try
> to be with the questionnaire, we are not going to get 100 percent
> sensitivity and 100 percent specificity or 99 percent specificity that
> we get with our tests.
>
> It is one of the layers of safety that we have, and with sufficient
> information, we can address and actually improve, as Dr. Epstein
> presented, the deferral rates for inappropriate reasons.
>
> One final point that I want to make very quickly, I want to give Dr.
> Williams a slightly different interpretation about post-donation
> information. Post-donation information, all donors are offered the
> opportunity to call the blood center back and say, oh, I realize that
> a question that I answered to this morning or yesterday or two days
> ago was not the correct answer. I told you that I had not been in a
> malarial area in the past year, but actually, I went home, I looked at
> my passport, and it was 10 months ago, and the blood center will
> attempt to retrieve these units or most often, because of the short
> time, is able to retrieve those units, but will report to FDA as
> post-donation information, and this goes to the deviation reports for
> which Dr. Williams indicated that the most frequent or among the most
> frequent issues are travel questions.
>
> Second, are at risk behavior questions. I consider that a success of
> the current lousy medical history that we have. These people went home
> thinking about those questions. They asked their girlfriend or their
> boyfriend, they went to look at a passport, they checked their travel
> history, and they realized that they said something that was not
> accurate, and they went to the trouble of picking up a telephone and
> calling the blood center to say, look, what I told you is not correct.
>
> Donors are very concerned. They don\'t want to hurt patients, they
> want to help patients, and most often when we get inaccurate
> information, obviously, there are all the behavior issues that were
> raised here, but particularly travel questions, they are not
> embarrassing questions, they relate very much to lack of information,
> confusion about dates, the temporal relationship of things, the
> confusion that in the way we currently ask the questions, that we will
> ask something that happened last week, three months ago, a year ago,
> all mixed up, and then we ask even a question is you had sex with
> another man since 1977, when most of us cannot, at least the older
> ones like me, cannot remember what we were doing in 1977.
>
> The actual question that we should be asking is behavior in the past
> three, four weeks.
>
> So, just to finalize, I want to emphasize that our enthusiasm for the
> new proposed Donor History Questionnaire, the improvement that this
> represent for the life of blood donors and for the life of blood
> centers, and hope that this whole discussion will stimulate more
> funding and more studies for a true validated questionnaire.
>
> Thank you.
>
> DR. NELSON: Thank you.
>
> MS. CIARALDI: Dr. Nelson, my name is Judy Ciaraldi. I am from the FDA.
> I wanted to give an update on the review of the new questionnaire that
> was part of your handout, the proposed questionnaire from AABB.
>
> There was a comment that we hadn\'t communicated our findings yet. The
> evaluation of AABB\'s proposed questionnaire was discussed at the last
> BPAC, the June BPAC, and we discussed what our preliminary findings
> were from nine out of the 10 reviewers, four of which were BPAC
> members.
>
> We also mentioned that we were going to review this with an internal
> group and come out with a written response to the Task Force. We have
> just finished that review, and we are now preparing our response.
>
> Thank you.
>
> DR. NELSON: Thank you.
>
> There is one other person, Paul Cumming wanted to testify or make a
> statement. Is he here? I wonder if you would be as brief as possible
> because we have to then discuss the questions that were posed to us,
> particularly if areas have been covered by other speakers.
>
> DR. CUMMING: I will do my best. I have very hard to get the
> presentation down to 10 minutes or less. I have taken out a lot of the
> pretty graphics unfortunately.
>
> \[Slide.\]
>
> What we have provided was a summary of the literature on alternative
> methods of donor interviewing, which we provided to the committee in
> advance. By \"we,\" I mean myself and Louis M. Katz, a physician from
> the Mississippi Valley Regional Blood Center.
>
> \[Slide.\]
>
> It needs to be noted upfront that Talisman, the company I am with,
> produces the Quality Donor System or QDS, an audio-video touch screen
> computer-assisted self-interviewing system or AVT-CASI as opposed to
> A-CASI which you have heard about.
>
> \[Slide.\]
>
> We undertook the task of looking through the literature because when
> we read the AABB\'s Streamlining Task Force and the CBER draft
> guidance materials, we noted a distinct lag or aging to the literature
> on computers and what they were doing.
>
> I forgot to mention we are partially supported by the National Heart,
> Lung, and Blood Institute with grants. For those of you who are
> familiar with the grant process, that means we have to submit what we
> propose to do and the credentials of our people in advance and get the
> pass-through peer review before we can even do anything, and then we
> publish everything we can.
>
> This was also what was referred to earlier as a priority of the
> Department of Health and Human Services and their Five Point Plan,
> which is on the blood safety and availability web site.
>
> The literature that we reviewed, we went online, did easy stuff
> basically, shows that audio-CASI technologies to be superior to paper
> and face-to-face interviewing with regard to literacy, truthfulness on
> socially and legally sensitive questions, clarity, donor satisfaction,
> and likelihood of return, as well as error reduction.
>
> \[Slide.\]
>
> Literacy arises as an issue because printed and electronic
> questionnaires presume donor literacy and illiteracy is a large and
> often hidden problem in the U.S. According to the Census, at least 21
> million people speak English less than very well.
>
> \[Slide.\]
>
> Health illiteracy has become something which has been increasingly
> recognized. The American Medical Association has a page on their web
> site which, among other things, notes that nearly half of all
> Americans may struggle with understanding basic health care
> information.
>
> Sixty-seven percent, two-thirds of patients with read difficulties are
> successful in hiding it from their wives.
>
> \[Slide.\]
>
> This is literature or points from the American Medical Association web
> site, and I was just noting one of theirs being how much the problem
> is hidden from even spouses.
>
> \[Slide.\]
>
> If two out of three health illiterates hide the deficiency from
> spouses, how do blood center staff detect it? Further, doesn\'t it
> make more sense to use technology to prevent or minimize reading
> problems?
>
> \[Slide.\]
>
> On blood donor illiteracy, there is no direct data. There is a study,
> however, of health literacy among 1,000 Baltimore residents by a
> gentleman named Al-Tayyib, who is a member of the Turner Group, some
> of the data which was shown before.
>
> It showed that 18 percent of subjects with some college or a two-year
> degree were reading at the levels of eighth grade or below. This
> \"some college\" group is sometimes cited as typical of blood donors.
>
> The group went on to point out that this provides important evidence
> of the potential benefits of audio-assisted self-interviewing
> technologies.
>
> An update to that, the AABB presentation listed a study by Wu of
> 900,000 first-time donors. That study set out that 64 percent of them
> had less than a college education and 12 percent had less than high
> school education.
>
> \[Slide.\]
>
> This if more of I believe of what Dr. Boyle presented with some
> slightly different questions. We took the group that was most like
> those blood donors, paper questionnaire versus audio and versus
> adjusted odd ratio where the multiple of the first column divided into
> the second. You can see that for this group of questions.
>
> These are what Turner was looking at, was the provision of sensitive
> information that you get multiplier rates of reporting at 3 to 17
> times as great with audio-CASI as you do with paper questionnaires.
>
> Also, note the bottom line there, I don\'t know if many of you can see
> it, in our judgment, 18 of the 49 questions currently on the AABB
> Uniform Donor History Questionnaire are questions that are judged
> sensitive.
>
> \[Slide.\]
>
> The authors of a related group, Cooley, as a senior author on that,
> set out the advantages of audio-touch screen-CASI as distinct from
> audio-CASI. Most of those, in fact, are audio-CASI advantages. The
> touch screen advantages aren\'t only in two areas. The audio
> eliminates the need for the questions that are a requirement for
> literacy, the second bullet here.
>
> The touch screen advantages relate to donor satisfaction and clean
> data files, and I don\'t think we want to go into clean data files
> right now, but I will answer any questions you want on that later.
>
> \[Slide.\]
>
> One of the things when I was talking about donor preference or user
> preference, users have a high preference. They found that users prefer
> the small sample, 108 STD clinic patients. Users preferred the
> A-T-CASI by a factor of 2 to 1 over keypad audio-CASI or interviewers.
>
> Specifically, on privacy, they preferred it by a factor of 2 to 1, as
> well, and that was privacy of A-T-CASI versus A-CASI.
>
> \[Slide.\]
>
> We have, as I said, this QDS system, which is more appropriately
> referred to as Audio Video Touchscreen-CASI. We try not to make a
> commercial out of this, but we have the only data that is available on
> the technology.
>
> It is headphone audio, touch screens, touch screens because no
> training is required. Everyone knows how to use their finger. It
> doesn\'t require you to miss a key ion a keyboard, for example.
>
> It has on-screen text, AABB questions. It is tied into a staff review
> mode with flags for any question that is inappropriately answered, as
> well as electronic databases.
>
> \[Slide.\]
>
> The Mississippi Valley Regional Blood Center, adaptation of this
> technology. It has also been used in pilot tests at the Hoxworth Blood
> Center, which was published in the December issue of Transfusion last
> year.
>
> It has been implemented at Mississippi Valley for a year now. It is at
> all nine of their fixed sites. We have utilized it in over 30,000
> donor interviews. It is a product of 10 years of research and
> development.
>
> \[Slide.\]
>
> This is a picture of a staff member doing an on-screen registration as
> opposed to a keyboard registration, which is the most common, to
> illustrate that as an option. Staff do not use headphones normally,
> those are for donors, but in the next screens that follow, there was
> no place to put headphones to emphasize the audio privacy.
>
> \[Slide.\]
>
> This is a standard format slide. There are 49 questions. They have the
> same format. The only thing that changes is the wording under the
> question, and the picture, which is selected to highlight some part of
> the question.
>
> It took, by the way, a committee at Hoxworth three months to agree on
> what were socially appropriate pictures. Also, for purposes of
> bloodmobiles, the privacy feature is you can touch the center of the
> text area, and the text and the picture disappear, so that no one can
> know what response is being made, what question is being responded to.
>
> \[Slide.\]
>
> This is an example of a gay picture, to try and get at that behavior.
>
> \[Slide.\]
>
> This is IV drug use, to draw attention to that.
>
> \[Slide.\]
>
> This is to draw attention to Europe for vCJD questions.
>
> \[Slide.\]
>
> This is a staff review screen. This note, the information goes
> directly from the donor\'s fingers to the review screen with nothing
> in between, no typos, no transposition errors. The computer highlights
> those questions that need review.
>
> Those with green checkmarks need no review. Those with the yellow
> triangle are required to be reviewed before they can go on. Those with
> the yellow triangle plus a stop sign that you can see there were
> aberrant, were reviewed, reviewed aberrant, but not fatal. That is,
> they did not prevent the donor from donating.
>
> The fatal or donor deferred is a big X that goes on that array. All of
> the questions highlighted in blue or the yellow triangle have to be
> reviewed before they can go on.
>
> \[Slide.\]
>
> This is an on-screen printout. It only occurs after the staff member
> has selected the print of accept or defer the donor, which you can see
> down there in the lower left side. At that time, the computer checks
> to make sure that all of the logic is consistent and all of the
> questions complete before it can be printed.
>
> Then, it must be signed by the donor. We can see here how legible it
> is by comparison. You don\'t have any problems with that with this
> technology. It is not dissimilar from a paper self-administered
> questionnaire except that it is all typewritten when it is done.
>
> \[Slide.\]
>
> The system was pilot tested at Hoxworth, as I said, various
> performance measures that we have used on the system, refusal to use
> it at all being perhaps the biggest one. We get almost no refusals. We
> have quit keeping track of it.
>
> At the Mississippi Valley, we did 1,500 donor satisfaction surveys,
> which include privacy, clarify, truthfulness, time satisfaction,
> understanding, likelihood of donation again, which is a big one for
> us, and all of them are multiple factors of preference for the system,
> the audio video touch screen system versus face-to-face nurse
> interviews. Nothing less than a factor of 4.
>
> \[Slide.\]
>
> On the staff, we looked at that, much small sample sizes, however,
> staff prefer the system to their own staff interviews by a factor of
> 3. They see it as faster for staff, donors more honest, answers more
> accurate, answers more confidential, fewer staff errors, and
> personally, much more satisfying to use than doing a face-to-face
> interview.
>
> Also, Mississippi Valley has looked at three other areas - errors and
> omissions, and it has reduced those by at least 60 percent. Looked at
> time of donation. It increased the donor\'s time by 4 minutes and
> decreased staff time by 5 minutes.
>
> \[Slide.\]
>
> Significance.
>
> \[Slide.\]
>
> Our conclusions. Donor interviewing should include a verbal or audio
> component, and that new, unfamiliar questions in particular must be
> posed in one of these two modes. Also, the medical-scientific
> literature supports stronger guidance from CBER, encouraging the use
> of technologies that enhance understanding and honesty, for example,
> audio video touchscreen-CASI technology.
>
> There is more information our web site. Any details of any these
> studies you want are there.
>
> Thank you for your time.
>
> DR. NELSON: Thank you.
>
> Questions? Comments? That was a very good presentation. It was very
> clear.
>
> DR. ALLEN: How easy is it to integrate this system into the
> multiplicity of existing blood bank computer systems?
>
> DR. CUMMING: We are working on that right now. It should not be
> difficult. It was designed to be integrated with paper. That is what
> most blood bankers wanted, but not in real time. That is, a batch kind
> of integration should not be a problem except we have to go to FDA and
> do a 510(k) to do that.
>
> **Committee Discussion and Recommendations**
>
> DR. NELSON: Dr. Williams, do you want to give us the questions again
> that you need our input on?
>
> DR. WILLIAMS: Question 1. Does the committee agree that audio-CASI
> procedures are as accurate as direct oral questioning for eliciting
> blood donor medical/behavioral histories? Yes or No.
>
> DR. SCHMIDT: Since we didn\'t hear anything about the added use of
> illustrations or pictures until the very end, I am wondering if the
> question could be modified to say audio-CASI with illustrations or
> something. That is number one. Number two, since nothing ever gets
> validated including our responses, to be willing to change this
> question to instead of \"are as accurate,\" \"may be as accurate.\" I
> think you will get more from us that way by not nailing us down.
>
> DR. KLEIN: Actually, I wanted to modify that a little bit, too, Paul,
> to say that the available data don\'t indicate that they are any less
> accurate than, because I don\'t think we saw data that could convince
> us that they are as accurate or not as accurate, but certainly what we
> saw and what we heard don\'t suggest that they are less accurate than
> what we are currently using.
>
> DR. SCHMIDT: I accept.
>
> DR. NELSON: Actually, we have been doing a study in Baltimore of
> injection drug users or largely, the literacy rate would be lower than
> hopefully the blood donor population, and we found that these people
> have been interviewed every six months dating back to 1989, and we
> recently introduced the audio-CASI system, and we found some changes.
> We saw repeated declines in reports of injection risk behavior with
> some declines in incidence of new infections, but the declines in risk
> behaviors far outstripped what we found in the incidence.
>
> When we went to the CASI, there was an increase in reported risk
> behavior, and also the drug users, they were happier. They thought
> this was a neat system. Now, it may be just that once you have been
> interviewed 12 times with the same questionnaire or a modification
> thereof, it becomes sort of boring and not very interesting, and this
> was the novelty of it, but it did work better.
>
> The other thing we found was that sexual behavior was actually
> probably overreported by our male subjects on the interview. It was
> challenging were they still with it kind of, and when it went to the
> audio-CASI, the sexual behavior reports declined, and that sort of fit
> with what we found with STD reports over time.
>
> So, I think that at least\--now, these aren\'t blood donors,
> hopefully\--but it did seem to work in this population that wasn\'t
> terribly literate. Now, they didn\'t have the same sort of pressures.
> In fact, you had to use drugs to be in the study and you got money to
> come for your interview and blood drawing, so there were different
> incentives here than they would be if it were a blood donor.
>
> I think in a variety of populations, this technology may be an
> improvement over interviews by thousands of different people maybe
> using a not so standard interview and not administering it the same
> way.
>
> DR. EPSTEIN: I would like to follow up on Paul Schmidt\'s comment.
> Paul, I take your implicit endorsement of the visually enhanced system
> over audio-CASI per Sergeant, but I would rather see the question
> voted as written. The reason is that we refer to audit-CASI in our
> current guidance document, and if you were to, for argument\'s sake,
> vote in favor of the visually enhanced audio-CASI, we would left in a
> quandary what exactly you thought about it if it wasn\'t video
> enhanced, which is where we now are with the Red Cross system.
>
> If you feel strongly enough that audio-CASI is not enough, then vote
> no, and you can comment on what you would consider sufficient, but I
> think we are going to end up with a muddy situation if we edit that
> question.
>
> DR. NELSON: Good clarification.
>
> Are we then ready to vote on this issue?
>
> DR. SMALLWOOD: Voting will be taken by roll call.
>
> Dr. Allen?
>
> DR. ALLEN: The question, as modified, and with the understanding that
> we still need a lot of work, yes.
>
> DR. NELSON: Just the may be as opposed to are, is that the
> modification?
>
> DR. ALLEN: Yes. I preferred the no less accurate than, but I think
> what we haven\'t done, my personal feeling is I have got a little
> hangup with the term \"accurate\" since there haven\'t been any direct
> comparisons.
>
> I am not sure that I really understand accuracy. Does the CASI method
> seem to defer donors with at least the same or higher degree of
> frequency? Yes. It is probably getting more accurate information, but
> the materials that were passed out, and I read the presentations I
> have heard, I don\'t have anything to do a direct, you know, I don\'t
> have a gold standard for what the answer should be from any of the
> people responding in the questionnaires.
>
> DR. NELSON: I guess we know that, but the FDA is asking us a judgment
> call based on what is available.
>
> DR. SIMON: I was going to see if this wording would work for both
> parties if we say the procedures are comparable to and get away from
> this word accurate that seems to be hanging up.
>
> DR. NELSON: Do we want to take a vote on that?
>
> DR. EPSTEIN: Okay. We accept that. Does the committee agree that the
> audio-CASI procedures are comparable to direct oral questioning for
> eliciting blood donor medical behavior.
>
> DR. NELSON: That is an improvement.
>
> DR. ALLEN: Yes.
>
> DR. SMALLWOOD: For clarity, let me read the question as it has been
> modified.
>
> Does the committee agree that audio-CASI procedures are comparable to
> direct oral questioning for eliciting blood donor medical/behavioral
> histories?
>
> Dr. Allen.
>
> DR. ALLEN: Yes.
>
> DR. SMALLWOOD: Dr. Cunningham-Rundles?
>
> DR. CUNNINGHAM-RUNDLES: Yes.
>
> DR. SMALLWOOD: Dr. Davis.
>
> DR. DAVIS: Yes.
>
> DR. SMALLWOOD: Dr. Doppelt.
>
> DR. DOPPELT: Yes.
>
> DR. SMALLWOOD: Dr. Fitzpatrick.
>
> DR. FITZPATRICK: Yes.
>
> DR. SMALLWOOD: Dr. Klein.
>
> DR. KLEIN: Yes.
>
> DR. SMALLWOOD: Dr. Koff.
>
> DR. KOFF: Yes.
>
> DR. SMALLWOOD: Dr. Laal.
>
> DR. LAAL: Yes.
>
> DR. SMALLWOOD: Dr. Lew.
>
> DR. LEW: Yes.
>
> DR. SMALLWOOD: Dr. McGee.
>
> DR. McGEE: Yes.
>
> DR. SMALLWOOD: Mr. Rice.
>
> MR. RICE: Yes.
>
> DR. SMALLWOOD: Dr. Schmidt.
>
> DR. SCHMIDT: Yes.
>
> DR. SMALLWOOD: Dr. Stuver.
>
> DR. STUVER: Yes.
>
> DR. SMALLWOOD: Dr. Fallat.
>
> DR. FALLAT: Yes.
>
> DR. SMALLWOOD: Dr. Harvath.
>
> DR. HARVATH: Yes.
>
> DR. SMALLWOOD: Dr. Nelson.
>
> DR. NELSON: Yes.
>
> DR. SMALLWOOD: Dr. Simon, how would you have voted?
>
> DR. SIMON: Yes.
>
> DR. SMALLWOOD: There was a unanimous yes for Question No. 1, and the
> industry representative agreed with the yes votes.
>
> DR. WILLIAMS: Question 2. Does the committee believe that for
> first-time donors self-administration procedures other than audio-CASI
> are as accurate as direct oral questioning for the entire donor
> questionnaire?
>
> DR. SIMON: Shall we change this one to comparable, too, also?
>
> DR. NELSON: Yes, change it to comparable.
>
> DR. WILLIAMS: That works.
>
> DR. NELSON: So, now you are talking about a paper theoretically, the
> standard donor questionnaire filled out not using CASI, but
> self-administered essentially, right?
>
> DR. WILLIAMS: It would include paper and I guess, by implication,
> would also include a non-audio-CASI, would include a video
> administration of the questions as currently worded.
>
> DR. SCHMIDT: Was comparable accepted or not accepted?
>
> DR. NELSON: Yes.
>
> DR. WILLIAMS: Yes.
>
> DR. FALLAT: Another comment. It was clear from the presentations that
> even the self-administered questionnaire involved additional
> interaction, and I think that should made clear that we are not
> approving just a self-administered questionnaire, but the
> self-administered questionnaire with the appropriate additional
> interactions.
>
> DR. NELSON: Yes, you referred to it one time as secondary, what was
> it, secondary contact, or something? In other words, you don\'t just
> hand them a piece of paper and collect it, but follow-up questions,
> whether or not they are ones that should be standardized like the Red
> Cross four questions or whether there should be something else, but
> some contact with regard to the\--
>
> DR. WILLIAMS: As I mentioned, the current draft guidance that it out
> there asks that within the blood center SOP there be an effort to
> assess comprehension of the questions to be defined within the SOP and
> asking did you understand is one way to approach that.
>
> DR. NELSON: So that would remain as recommended as mandated or
> something.
>
> DR. WILLIAMS: That is the current thinking.
>
> DR. LEW: Can I just get clarification that the data that the Red Cross
> showed us did not really look at first-time donors, I mean separately,
> that it was just kind of all lumped together looking like the controls
> looked like those that got the self-administered questionnaire looked
> the same, but again, they didn\'t take first-time donors to really
> look at that issue very carefully.
>
> DR. WILLIAMS: That is correct.
>
> DR. NELSON: The obvious reason why this may be a separate question is
> the donor who has been in many times and may be familiar with the
> questionnaire, and I think the committee had previously sanctioned
> this for repeat donors, so now we are moving into the issue of the
> first time somebody shows up.
>
> Toby.
>
> DR. SIMON: I thought that Dr. Boyle\'s presentation to some extent
> addressed this in that the first-time donor might be even more likely
> to find embarrassment or concern and appreciate the more private
> setting.
>
> I guess from the presentations that were made, I thought in some ways
> the literacy presentation took us a little bit aside from some of the
> major concepts, because I think the concern that people don\'t
> understand the words would be the same for self-administered or one
> that is being given verbally.
>
> The advantage, obviously, the verbal interview is that a highly
> skillful interviewer like we would think of, some of us who are
> physicians trained in internal medicine, who are schooled in the arts
> of taking history, recognize that there is ability to elicit
> information, but here we have an interview being given 13, 14 million
> times a year in the United States, and from the presentation of Dr.
> Boyle, that I gleaned from that, is that even under circumstances of
> well-trained interviewers in a systematic way, it is a very difficult
> to eliminate the interviewer effect on the results, and therefore it
> would appear that particularly with potentially embarrassing
> information, that the self-administration would be at least comparable
> even for the first-time donor in eliciting the kind of information
> that we want in terms of behavior.
>
> So, I obviously am speaking in favor of the proposal. It is something
> apparently FDA has already allowed, I guess, the Red Cross to do, and
> it is something that has been tested by the Task Force, and it would
> seem that given that we are in the status where the interview that is
> given orally has not been completely validated, but from the
> information that we have, it would appear that self-administration is
> comparable.
>
> DR. SCHMIDT: I would like to point out the word \"comparable\"
> doesn\'t mean a thing here. It comes from \"to compare,\" saying we
> are able to compare it as either better, worse, or the same. It is not
> assisting you at all, Jay, to say something is comparable.
>
> DR. NELSON: Maybe equivalent is a better word?
>
> DR. FALLAT: I would agree with Dr. Lew that we really don\'t have data
> on first-time users, and I think it is very difficult to make a strong
> statement with regard to first-time users.
>
> DR. NELSON: Right. I think what we are being asked is without any
> validation studies, does it seem like we can get the information, the
> same information by the self-administered.
>
> DR. FALLAT: Suggesting we use the term \"seems like it\'s.\"
>
> \[Laughter.\]
>
> DR. ALLEN: I think that is important. My initial response, if I am
> looking at it strictly from a scientific perspective, the answer is I
> haven\'t seen the data, and I was going to vote abstain, and then I
> reread the question and it says, \"Do the committee members believe,\"
> well, my gut feeling is that probably a self-administered
> questionnaire other than audio-CASI could be as good, may be better
> under some circumstances than some of the interview questions, because
> I have had some donor interviews where I don\'t think anybody was
> paying attention to my facial response, my body language, or anything
> else. All they wanted to do was to get through the questionnaire as
> rapidly as possible.
>
> I don\'t think that those are effective methodologies either. So, if
> the answer is in the absence of evidence, do we think that the
> self-administered questionnaire can be administered at least as
> successfully as a reasonably good interview, I will be willing to vote
> yes on that one.
>
> DR. FITZPATRICK: I think, Alan, in the first draft, the draft required
> oral questioning of first-time donors in the first draft guidance.
>
> DR. WILLIAMS: The draft guidance that the current draft, yes. It
> recommends oral questioning, and the intent of that recommendation,
> although there appeared to be some confusion, was for the high risk
> questions and the complex travel, and high level terminology
> questions.
>
> DR. FITZPATRICK: So, making a leap here, if the committee responds yes
> to that, it provides FDA some basis for changing that recommendation
> for oral questioning of first-time donors.
>
> DR. WILLIAMS: That\'s correct.
>
> DR. FITZPATRICK: And that is kind of really what you are trying to get
> at here?
>
> DR. WILLIAMS: That\'s correct.
>
> DR. FITZPATRICK: In the comments that you received to the draft
> guidance, since we weren\'t provided those, how many comments
> addressed oral questioning of first-time donors?
>
> DR. WILLIAMS: Eight of the 12 addressed administration to first-time
> donors.
>
> DR. FITZPATRICK: And what was the gist of those comments?
>
> DR. WILLIAMS: I believe virtually all eight made the point that they
> didn\'t feel that the data supported a recommendation that there be
> oral administration to first-time donors, and as I mentioned earlier,
> 2 of the 8 had some confusion about whether we were referring to the
> more difficult questions or to the entire questionnaire, and raised
> the issue as to whether, in fact, we were changing stance and those
> centers that had been approved for self-administered questionnaire
> would not need to redo their SOPs and have those reevaluated. The
> latter is not the case.
>
> DR. FITZPATRICK: So, with the lack of data, we are being asked to just
> say do we believe that self-administering, which occurs in some
> centers now of medical history questions, and evidently by the Red
> Cross of over 5 million donors, is at least as good as direct oral
> questioning and CASI.
>
> DR. WILLIAMS: Right. Two points, keeping in mind number one, that
> approvals for that process were based on submitted data, and number
> two, you asked what would the changes be.
>
> One would be the draft guidance. Two would be a change in the earlier
> memorandum requiring oral questioning for the high-risk donors
> applicable to centers that have not submitted data to support a change
> to the self-administration.
>
> DR. HARVATH: Alan, I would like to ask one question, and this is
> procedural. In your opinion or in your experience in reviewing such
> data, does FDA, have they received sufficient data on this specific
> question, because in my opinion, this could be a very interesting
> research question in certain settings.
>
> I think in view of what you have heard of the data presented by Paul
> Cumming, what I would like to ask of FDA is if the answer to this
> question is yes, would FDA then still require or require data from
> individual centers to support such an approach, or would there not
> then be the need for any further data submission?
>
> DR. WILLIAMS: Well, number one, I am not sure I am allowed to have an
> opinion, but I think were the committee to vote yes on this question,
> it would certainly be considered very seriously in the agency\'s
> deliberations, and we would still independently review the extant
> literature and make an internal decision, but obviously, this is our
> advisory committee and we would weigh it very heavily.
>
> DR. HARVATH: Has the committee seen all of the available data to help
> us specifically address this question?
>
> DR. WILLIAMS: To the best of our knowledge, yes, there are data coming
> from many different aspects that are not directly comparing oral
> versus self-administered in a blood donor setting comparing first-time
> versus repeat donors. Those studies just don\'t exist currently, and
> as Dr. Boyle referred to, you are sort of making assumptions applying
> studies that don\'t quite meet the correct target to apply that to a
> blood donor situation.
>
> A blood donor interview is not a survey, it is a social interaction to
> determine eligibility for health activity that a donor usually very
> much wants to be successful at, so I think it\'s a different
> situation. There are a lot of complications that aren\'t captured in
> any single study.
>
> But to answer your question, we would review all of the extant
> literature in addition to the committee\'s recommendation.
>
> DR. NELSON: Can we vote on this? I wonder if we could\--as accurate
> as, or as inaccurate as, whatever, the equivalent, that we use \"other
> than audio-CASI are equivalent to direct oral questioning?\"
>
> DR. KLEIN: I still like the term \"comparable\" since equivalent means
> something different.
>
> DR. NELSON: I think the issue Paul was making was they may be
> comparable, but much worse or much better, and I was using
> \"equivalent\" to mean equally good or bad.
>
> DR. KLEIN: I don\'t think we have seen any data to tell us that they
> are equivalent. I think the data that we have seen does not suggest or
> indicate that a self-administered questionnaire is worse and that data
> that Dr. Boyle presented from other areas where sensitive information
> is gotten by questionnaire suggests perhaps that from a privacy
> standpoint, self-administration has some advantages.
>
> DR. NELSON: Well, if we change it to comparable, does that help the
> FDA?
>
> DR. FITZPATRICK: Paul brought up a good point, but how about \"at
> least as effective as\"?
>
> DR. NELSON: Well, that is why I said \"equivalent.\"
>
> DR. FITZPATRICK: Which doesn\'t really say a whole lot either.
>
> DR. WILLIAMS: And he has to be careful, the semantics aren\'t as
> important as the gold standard that you are talking about.
>
> DR. CUNNINGHAM-RUNDLES: What is the verb of that sentence going to be?
> I am going for \"may be.\"
>
> DR. KLEIN: We can\'t design the question. The question is coming from
> the FDA. They have got to tell us what the question is. They have
> heard the discussion.
>
> DR. NELSON: I think the issue here is in the first question, we said
> that CASI is equivalent or whatever, comparable to oral questions.
> Here, we are talking about first-time donors and we are talking about
> another self-administered questionnaire other than the CASI, so there
> are two differences in this question, first-time donors and another
> form of self-administered question, right?
>
> DR. WILLIAMS: Correct.
>
> DR. DOPPELT: When you say it\'s non-audio-CASI, but it is some written
> self-administered, is it this form or are we speaking about a form in
> general?
>
> DR. WILLIAMS: The intent is to move forward with a standardized
> questionnaire, which is reflected by the revised Uniform Donor History
> Questionnaire, which you have.
>
> DR. NELSON: But this form might also be modified in the future to add
> other things to sort of embellish the jaundice, you know, I mean the
> earlier form had I think jaundice or yellow, I mean it had some other
> descriptors other than just jaundice, and I think the same thing is
> true for CJ disease.
>
> DR. WILLIAMS: That is correct, but I think the comment goes to content
> and due to funding and other reasons, one can\'t basically beat the
> content issues to death. I think the Task Force, at the last meeting,
> described the process that was used to determine what wording was
> optimal based both on focus groups and one-on-one interviews and
> arrived at the wording that is in the questionnaire, so I think
> basically, the wording that is there except for consideration of new
> questions that might be necessary, should be the wording that is
> considered.
>
> DR. DOPPELT: I just wanted to point out, you are sort of voting on two
> concepts here. One is the concept of the written exam being
> comparable, equal, whatever you want to describe it, and the other is
> over time, as the questions may change, you are dealing with a
> different product.
>
> DR. NELSON: Well, I don\'t think we are worried about the over time,
> we are worried about the first-time donors as being different from
> people who have been questioned before with a similar questionnaire,
> and we are worried about the method of arriving at the answers either,
> interviewer or questionnaire.
>
> The donor questionnaire will change over time, there is no doubt about
> it, but we can\'t anticipate that.
>
> DR. EPSTEIN: Paul said he would like FDA to state the question for the
> committee. I think that the question revised to ask, \"Does the
> committee believe that for first-time donors self-administration
> procedures other than audio-CASI are comparable to direct oral
> questioning for the entire donor questionnaire?\"
>
> There are many nuances and we could debate the language a lot, but I
> think most people understand what we are saying when we ask that. What
> we are saying is would you be just as satisfied if people are handed a
> piece of paper to self-administer the questionnaire versus audio-CASI
> or direct face-to-face, because you answered in Question 1 you would
> accept audio-CASI as the equivalent, so what we are choosing between
> here is face-to-face or audio-CASI deemed as comparable versus
> something else, which for the most part is a written self-administered
> questionnaire.
>
> So, what we are saying is that okay, in general, we think audio-CASI
> and direct oral questioning are equally acceptable. Do we think that
> for the first-time donor we should be more scrupulous about just a
> written questionnaire? That is the intent of the question.
>
> Again, if anyone is confused, I would be happy to try to clarify it
> further, but that is what we are trying to get at, because we are
> saying other than audio-CASI, and what is the common practice other
> than audio-CASI is to hand people a written questionnaire.
>
> DR. FALLAT: Would you be willing to use \"may be?\"
>
> DR. EPSTEIN: Yes, I would be willing to do that.
>
> DR. LEW: Can I just ask, all the stuff that we reviewed, was there
> ever one study that showed in blood donors that face-to-face was not
> as good?
>
> DR. SIMON: I think Dr. Boyle had such studies, didn\'t he?
>
> DR. LEW: No.
>
> DR. WILLIAMS: Not in the blood donor setting.
>
> DR. EPSTEIN: I just want to make one comment about \"may be.\" I would
> be willing to make that change because I think that there is a general
> sense that committee members are more comfortable with that change,
> however, it then begs the question of whether FDA is going to want
> additional data, because if you say \"may be,\" it implies that
> sometimes it is enough and sometimes it is not enough, so it leaves us
> in a quandary of, well, when do we decide it is not enough, and that
> is sort of the problem that we have right now is deciding that it\'s
> not enough, but again I think at some level it would be helpful with
> that change to have the question voted if it\'s too confounding
> otherwise.
>
> DR. NELSON: I sort of partly come down with Dr. Boyle in that I have
> donated several times, and I can say that sometimes the person doing
> the interview has worked there for a week or two, and has to do all
> kinds of different things in addition to take the interview.
>
> I am not sure, I mean the written instrument is more standardized, and
> if it is accompanied with some sort of contact about the questionnaire
> after it has been done, I think it probably is an improvement, but
> it\'s hard to know that over 13 million donations. That is what we are
> being asked to determine.
>
> DR. ALLEN: Which is exactly why, I guess I would like to ask Jay, what
> is the right answer if we want to encourage the FDA to look at this
> question very carefully. I think it\'s an important question that
> needs to be studied, and I am willing to be\--I think there is
> sufficient data although it is certainly not definitive to suggest
> that the FDA should allow a variety of different options at the
> present time while some definitive studies are underway, perhaps as
> part of definitive studies, but I really would like to encourage
> additional evaluation, careful evaluation of this question. I think it
> is a very important question.
>
> DR. EPSTEIN: Well, if we revise the question, that audio-CASI may be
> comparable to direct oral questioning, on your proposal you would vote
> yes and then you would make the comment you just made, which I think
> we have heard anyway.
>
> I think in the interest of moving to voting, I would accept the
> revised question, that then audio-CASI may be comparable to direct
> oral questioning. I would be happy to read it in its entirety again.
>
> MR. RICE: The question already has the word \"believe,\" it is not
> asking us that we know, but we believe that it\'s comparable. So, I
> think the word \"believe\" kind of alleviates the fact that we are not
> necessarily making a fact.
>
> DR. EPSTEIN: But again I think the nuance here is if we change it to
> \"may be comparable,\" and you vote yes, you are saying sometimes it
> might be and sometimes it might not be, so you are sort of leaving the
> FDA with the difficulty of figuring out when it is acceptable and when
> it isn\'t, whereas, we are trying to make a policy here for the U.S.
> blood system.
>
> As I said before, it leaves the FDA in a more difficult position, but
> if the committee is not able to vote the question of whether
> procedures other than audio-CASI are comparable, so be it. I mean if
> you can\'t vote that question, let\'s pose a question you think you
> can vote.
>
> DR. LEW: If I can just ask, because Terry brought out the idea of
> believe, I think the problem is that it is one thing to say if you
> believe someone is guilty of a crime and it\'s just I believe, but you
> know there is consequences to saying I believe, then, I think we are
> all strict on ourselves.
>
> I like the change of \"may be\" because I think we could feel more
> honest in saying what we truly believe.
>
> DR. NELSON: So, what is the question now we are voting on?
>
> DR. SMALLWOOD: The question as modified: Does the committee believe
> that for first-time donors self-administration procedures other than
> audio-CASI may be comparable to direct oral questioning for the entire
> donor questionnaire?
>
> Voting by roll call.
>
> Dr. Allen.
>
> DR. ALLEN: Yes, and it\'s an issue that needs additional study.
>
> DR. SMALLWOOD: Dr. Cunningham-Rundles.
>
> DR. CUNNINGHAM-RUNDLES: Yes.
>
> DR. SMALLWOOD: Dr. Davis.
>
> DR. DAVIS: Yes.
>
> DR. SMALLWOOD: Dr. Doppelt.
>
> DR. DOPPELT: Yes.
>
> DR. SMALLWOOD: Dr. Fitzpatrick.
>
> DR. FITZPATRICK: Yes, and I support Dr. Allen\'s comment.
>
> DR. SMALLWOOD: Dr. Klein.
>
> DR. KLEIN: Yes.
>
> DR. SMALLWOOD: Dr. Koff.
>
> DR. KOFF: Yes.
>
> DR. SMALLWOOD: Dr. Laal.
>
> DR. LAAL: Yes.
>
> DR. SMALLWOOD: Dr. Lew.
>
> DR. LEW: Yes, and I support Dr. Allen\'s comment.
>
> DR. SMALLWOOD: Dr. McGee.
>
> DR. McGEE: Yes.
>
> DR. SMALLWOOD: Mr. Rice.
>
> MR. RICE: Yes.
>
> DR. SMALLWOOD: Dr. Schmidt.
>
> DR. SCHMIDT: Yes.
>
> DR. SMALLWOOD: Dr. Stuver.
>
> DR. STUVER: Yes.
>
> DR. SMALLWOOD: Dr. Fallat.
>
> DR. FALLAT: Yes.
>
> DR. SMALLWOOD: Dr. Harvath.
>
> DR. HARVATH: Yes.
>
> DR. SMALLWOOD: Dr. Nelson.
>
> DR. NELSON: Yes.
>
> DR. SMALLWOOD: Dr. Simon, your opinion?
>
> DR. SIMON: Yes.
>
> DR. SMALLWOOD: There was a unanimous yes vote to Question No. 2. The
> industry representative agreed with the yes vote. Just for the record,
> there are 16 members eligible to vote.
>
> DR. NELSON: Let\'s see if we can get lunch, and if we could get back
> around 2:30, 2:35, because we have got two issues to discuss this
> afternoon.
>
> DR. WILLIAMS: Our thanks to the presenters and to the committee. It
> was a difficult discussion.
>
> \[Whereupon, at 1:50 a.m., the proceedings were recessed, to be
> resumed at 2:30 p.m.\]
>
> AFTERNOON PROCEEDINGS
>
> \[2:15 p.m.\]
>
> DR. NELSON: We are a little over an hour and a half behind. In the
> past, the way we have dealt with that is continued to meet until about
> 9 o\'clock at night or something like that. Obviously, we can\'t do
> that today because it\'s a one-day meeting, but what we are going to
> do is we will have the presentations on the Chagas disease and then
> there were some people that wanted to comment on Chagas and others
> that wanted to comment on the testing who had come here specifically
> for that.
>
> In the possibility that we won\'t finish everything by 5 o\'clock, we
> will accept, during the open public hearing, comments on either one,
> but we hope you will be brief enough that we can get through the whole
> program, and we might be able to finish by close to 5:00 at any rate.
>
> The first discussant on Chagas disease, Update on Testing for Chagas
> disease, the Latest Trends in Transfusion-Transmitted Chagas, David
> Leiby.
>
> DR. DUNCAN: Dr. Nelson, I am Dr. Robert Duncan from the Center for
> Biologics, Division of Emergent Transfusion Transmitted Diseases, and
> I just wanted to say a few words about why we are bring this
> informational session, and then Dr. Leiby\'s presentation.
>
> DR. NELSON: Okay.
>
> **Introduction**
>
> **Robert Duncan, Ph.D.**
>
> DR. DUNCAN: Recently, it was brought to our attention that there is
> little activity among manufacturers working to develop a marketable
> blood screening device to test for Chagas, and it is our intention
> that this presentation might help to provide some stimulus for
> manufacturers.
>
> I would like to give just a little bit of background to illustrate why
> we think it is important at this time.
>
> \[Slide.\]
>
> This is just some of the background about the current state of Chagas
> disease in this country. David Leiby\'s presentation will go into
> these points in detail, but there is just a couple of things that I
> wanted to highlight.
>
> Clearly, it is a disease that is affecting a lot of people in this
> hemisphere. It has been recognized as a problem for blood transfusion
> in the endemic areas. There are six cases of transfusion transmissions
> have been documented, and there are three cases of solid organ
> transplant transmission.
>
> The seroprevalence in the U.S. population has a low range, which
> mainly has to do with the proportion of immigrants from South and
> Central America, but increasing rates of immigration raises the
> concern about the potential for increased transmission, and it is this
> concern that has been coming to our attention.
>
> \[Slide.\]
>
> At the present time, there is no serological screening of donors
> recommended due to the low prevalence and to the fact that there is
> not a suitable test. Questions of sensitivity and specificity and
> availability are all still on the table, and the blood supply is,
> however, being protected with the donor questionnaire, and we have had
> a lot of discussion about the donor questionnaire, so we know the
> importance of that and also the successful rate of that.
>
> At the present time, there are Chagas tests that have been licensed
> for use in diagnostics, but not for blood donor screening. Those are
> enzyme immunoassays and radioimmune precipitation assays.
>
> Some of the questions of suitability also have to do with having a
> complete testing system that could be effective in the blood donor
> screening setting.
>
> \[Slide.\]
>
> I want to just retrace a little bit of the history of the question of
> the Chagas test vis-a-vis CBER and the Blood Products Advisory
> Committee.
>
> In 1989, the advisory committee recommended donor screening for Chagas
> provided there were a suitable test. We came back in 1995 with a
> question about the tests that were available at that time, and posed
> the questions are the available tests appropriate for donor screening.
>
> The response of the committee was three was voted yes, zero people
> voted no, and 10 abstained. So, clearly, there was no consensus on the
> committee for use of the tests that were available at that time.
>
> Part of the problem was that multiple tests were presented at the same
> time with slightly different technologies, but also there was a
> problem of CBER not coming forward with a clear set of standards for
> what would be an approvable test for blood donor screening.
>
> In the 1995 BPAC, there was also the request that there be a serious
> approach to the question of what are the implications of a false
> positive rate in a universal donor screening setting, in other words,
> would be generating more false positives than true positives
> potentially. So, that is also an important issue.
>
> With this kind of background, to understand why we are bringing the
> information forward at this time, I would like David Leiby to come up
> and make his presentation regarding the current seroprevalence and
> transmission of Chagas.
>
> **Latest Trends in Transfusion-Transmitted**
>
> **Chagas Disease**
>
> **David Leiby, Ph.D.**
>
> DR. LEIBY: I was asked by Hira Nakashi to come here and at least
> provide an update on the latest trends in transfusion-transmitted
> Chagas disease.
>
> \[Slide.\]
>
> The first slide actually gives you some characteristics on Chagas.
> First of all, it is a protozoan parasitic disease caused by a
> flagellated parasite called Trypanosoma cruzi.
>
> It is a parasite that is endemic to the Americas only in Mexico,
> Central America, and South America, although rarely it actually occurs
> in the United States. Some of you may not know that, as well. There
> are at least four or five autogenous cases reported in the U.S., one
> about a year and a half ago in the State of Tennessee, so the bugs
> themselves and the parasites are here in the United States.
>
> \[Slide.\]
>
> This is very important. It causes a chronic, asymptomatic, and
> untreatable infection. So, when one thinks about blood donors, we are
> talking about individuals that are infected for life, so their whole
> life they are blood donors, they may transmit the infection.
>
> They are asymptomatic , so when they present as blood donors, you do
> not know that they may be infected. Lastly, there is no suitable
> treatments for Chagas disease, so this is an infection that is, as I
> said, life-long, asymptomatic, and untreatable, and in 20 or 30
> percent of the individuals with chronic infections, they develop a
> rather debilitating disease that can lead to death.
>
> Transmission is by four primary methods - vectorial, and I will show
> you the bug in a second, congenital transmission, which has some
> relevance to blood banking, organ transplant seems to be the popular
> way to transmit diseases these days, and I will mention that, as well,
> and, of course the one we are most concerned about today is blood
> transfusion.
>
> \[Slide.\]
>
> This is a picture of the reduviid bug, which is the one that commonly
> transmits Chagas disease in the natural form, vectorial transmission,
> and it is not transmission by the mouth part, it is transmission by
> the back end.
>
> The parasite is found in the infective stage, or the trypomastigote is
> found in the feces of the bug, so during the course of a blood meal on
> an individual, the bug fills with blood, defecates, and then the feces
> containing the infective stage is either rubbed into the bite wound
> or, in the case of this young girl, into the eye or into any other
> mucosal surface.
>
> This is a reaction, a chagoma. It doesn\'t happen all the time, but it
> is a swelling at the site where the parasite enters the host. The
> ultimate location where the parasite lodges is in the cardiac tissue,
> and that is where it has its most significant pathological occurrence.
>
> It is there that it can sit quietly for 20 or 30 years. Individuals do
> not know they have the disease, and then later on, in their fifties,
> they may die suddenly, a sudden death, and may have congestive heart
> failure or several other problems that can lead to their demise.
>
> \[Slide.\]
>
> Well, why, if I said, if it is primarily a disease of Latin America,
> why are we so concerned here in the United States? Well, quite
> obviously, it has to do with immigration and later with demographics.
>
> Over the past 20 or 30 years, there have been millions of individual
> who have immigrated to the U.S from Mexico, Central America, and South
> America, largely for socioeconomic issues. This is just some data that
> came out of the 2000 census, and these are only individuals who report
> their country of birth as being in Mexico, Central America, South
> America, and there was over 12 million at that time. This certainly
> does not include illegal aliens, which also donate blood, so this
> number is considerably larger.
>
> In fact, if you look at the most recent census data, and you look at
> the Hispanic population, you can see there is a 60 percent increase
> from 1990 to 2000, to some 35 million. I am not here to tell you that
> all 35 million are potentially at risk, but what it tells you is that
> the Latino population continues to increase because more individuals
> are immigrating.
>
> This brings up the issue of congenital transmission, which is the
> transmission from the mother to the unborn child. We have seen several
> cases in some of our studies, and I will mention those later. So, we
> have to be concerned as far as Chagas disease in this country, not
> only about the first generation of immigrants, but also the children
> and perhaps even the children\'s children.
>
> \[Slide.\]
>
> This is from a case we described in 2001, and the similarities of this
> and the recent case in West Nile are somewhat striking. In this case,
> there is no blood transfusion, I don\'t think we know that yet about
> West Nile either, but this is a case in 2001 in which there was Chagas
> disease after organ transplantation.
>
> There was a single donor, single cadaver donor in which multiple
> organs were removed and placed into three recipients. There was a
> kidney and pancreas in one, a liver in another patient, and the last
> recipient received a kidney.
>
> This first individual, the kidney-pancreas came up positive on a blood
> smear. This is the actual blood smear. To see four parasites in a
> single blood smear is rather phenomenal.
>
> This individual died of acute Chagasic myocarditis, so from one
> recipient, we see three individuals being infected. Part of the story
> that I don\'t think is included is that when they looked at this
> cadaver donor, they also considered taking the heart, but upon looking
> at the heart, they noticed that there was a lot of pathology
> associated with the heart, so they did not transplant the heart
> fortunately. So, from a single case, we see three.
>
> \[Slide.\]
>
> In the United States, as Robert mentioned, there have been six
> transfusion cases, transfusion-transmitted cases since 1987. There are
> a couple of things that I want to point out. First of all, if you look
> at the donor, in this case Mexican, Bolivian, Paraguayan, Chilean,
> German/ Paraguayan, who is a young child born in Germany, migrated to
> Paraguay with his parents, they are mennonites, when he was very
> young. But five of the six that we know of, the donors came from
> endemic countries.
>
> The other thing to notice is that these individuals who were infected
> by transfusion are not people who live in Miami, Houston, or Southern
> California. Some live in New York City and, quite surprisingly, there
> is two from Manitoba. So, it is a disease that affects individuals not
> only in the southern part of the United States, but in all regions.
>
> I am not going to stand here and tell you that if you live in Los
> Angeles, you have the same risk as someone in Minneapolis, but the
> point is that there are probably positive individuals anywhere in this
> country and Canada. You just may take longer to find them in the more
> northern climates.
>
> \[Slide.\]
>
> The question always comes up when I talk about Chagas, and this is a
> question that is actually very fair, is why are there so few
> transfusion cases. I am going to show you data on seroprevalence that
> shows it occurs quite frequently. So, why don\'t we see more than six
> transfusion cases?
>
> What I would like to propose and tell you is that those reported cases
> are, in fact, the sentinels. Those are the ones we pick up and the
> ones we know about, but, in fact, there is many more cases that go on.
>
> Those six cases in all those individuals, they are fairly severely
> immunosuppressed. They actually had fulminant disease and it made it
> very easy to identify that they, in fact, had Chagas disease, and as I
> said, it was easily detected and diagnosed.
>
> So, what is really probably happening is that there is many cases that
> are missed. We have immunocompetent individuals. As I said, this
> infection is asymptomatic, we would not recognize it.
>
> They are often misdiagnosed. The acute infection is rather\--the
> symptoms are flu-like, probably easily missed even if they did have
> the infection. So, lastly, they are not recognized. So I would say
> that while there are cases which are very clear, there are many which
> we probably miss. This poses the risk that perhaps 20 or 30 years down
> the road, when these individuals develop cardiac complications, that
> is when we will know that they have been infected by blood
> transfusion.
>
> \[Slide.\]
>
> Just to show you that we really miss these individuals, this is a
> study I actually did our chairman, and we looked at cardiac surgery
> patients, and we were curious about looking at transfusion issues, but
> what came out of this was something I think in some ways is more
> important.
>
> This comes from the fax repository, which is a pair repository of
> cardiac surgery patients that have a preoperative sample and a
> postoperative sample. So, in this repository are over 11,000 multiply
> transfused patients that we tested by EIA. We found out of that that 6
> of them, or 0.05 percent, are actually confirmed as seropositive. That
> was postoperatively.
>
> Then, you have to go back and check the pre-op sample to see if they
> got the infection from the blood transfusions they received during
> surgery. Well, we found right off the bat that 4 had preoperative
> samples, which means they didn\'t get it from transfusion, they had it
> before they had surgery.
>
> Now, two preoperative samples were not available for us to test,
> however, those two individuals had both received heart transplants,
> and the tissues, the excised tissues from these hearts are still
> available and maintained in blocks, and when we did PCR on those, we
> found that both the hearts were also positive by PCR. So, all six of
> these individuals had Chagas before their surgery.
>
> Five of the six individuals were also Hispanic, and if one looks at
> the demographics in this repository, we find that 2.7 percent, let\'s
> say 3 percent for today\'s purposes, 3 percent of Hispanic patients in
> this repository were seropositive for Chagas disease.
>
> What was most interesting is when you looked at the medical records of
> these individuals, individuals that were Hispanic, individuals that
> had congestive heart failure, arrhythmias, other symptoms of Chagas,
> not once were they tested for Chagas, so by and large, the medical
> community is not recognizing this, they are, in fact, missing it.
>
> \[Slide.\]
>
> Some of our data from our studies that were recently published, I
> believe in Transfusion in May, in our studies in Los Angeles and
> Miami, there is Red Cross Studies, in Los Angeles, they included over
> 1.1 million donors, in Miami it was 181,000.
>
> Donors at the blood centers were asked a very simple question: Were
> you born in or have you spent more than six months in Mexico, Central
> America, or South America?
>
> When we asked that question, in Los Angeles, 7.1 percent of
> individuals responded yes, while in Miami, it was 14 percent. Some
> individuals many years ago, I don\'t think people are proposing this
> anymore, suggested that perhaps we could just ask that question, and
> based on that question, defer blood donors. Well, I don\'t think any
> blood center in this country would be willing to defer 7 to 14 percent
> of their blood donors.
>
> If you follow through with this testing through the EIA, and then by
> RIPA testing, which was the confirmatory assay we did, in Los Angeles,
> about 1 in 7,500 donors are positive, are seropositive for Chagas; in
> Miami, it was about 1 in 9,000. That is overall donors.
>
> \[Slide.\]
>
> What became very interesting is when you take that Los Angeles data
> and you look at it year by year, this is 1967, \'97, and \'98 is kind
> of covered here, this is percent donors positive. Those are hard
> numbers to work with, let\'s work with these numbers on top of the
> bars.
>
> In 1996, in Los Angeles, 1 in 9,900 donors were positive for Chagas.
> In 1997, 1 in 7,200 donors were positive. Finally, in 1998, 1 in 5,400
> donors were positive. That is a very high significant difference each
> year increase.
>
> So, what does that increase mean, what is really going on?
>
> \[Slide.\]
>
> First of all, let me tell you that in this study, all EIA-positive
> donors are deferred regardless of their RIPA test result. So, if they
> were EIA repeat reactive RIPA-negative, they were still deferred. So,
> we are pulling out any donor who is either positive or even repeat
> reactive, so we are not counting the same donors over and over, we are
> actually pulling out of the pool, so there is actually fewer positives
> available.
>
> There is a significant increase in rate each year, but what is more
> important, and these are directly related, there is a significant
> increase in at-risk donors each year, so as there is more at-risk
> donors, there is a greater likelihood of finding positive individuals.
>
> What we found was going on in Los Angeles was, in fact, there was an
> advanced minority recruitment efforts specifically targeting the
> Hispanic population, and this was really the gist of the paper we
> published in May, that as we begin our donor demographics, as we begin
> to change who we are recruiting for blood donation as per that earlier
> census data, that shows you the great increase in Hispanic population,
> we are going to encounter more individuals who are seropositive for
> Chagas.
>
> \[Slide.\]
>
> At the same time, from that same study, we also looked at different
> donation characteristics by the type of donation, allogeneic,
> apheresis, and directed. As you can see, by and large, most of the
> donations were allogeneic, 991,000, 93,000 were apheresis, and we had
> 18,000 directed.
>
> If you looked at the number of positives, for Chagas, we see that it
> was 138 allogeneic, 1 apheresis, and 8 directed. If you look at the
> rates, they became rather startling, 1 in 7,200 for allogenic, 1 in
> 93,000 for apheresis, 1 in 2,400 for directed donors.
>
> This then goes back to the same thing I said before, it goes back to
> the at-risk population, and those are the people who responded yes to
> our question, 7.5 percent for allogeneic, only 2.6 percent of the
> apheresis donors were at risk, but 10.2 percent of the directed donors
> were at risk, and there is a relationship between higher levels of
> directed donation among Hispanic populations which helps to explain
> this rather high rate.
>
> \[Slide.\]
>
> The other thing I am often asked about is why in our lookback
> investigations, we found zero out of 19 transmitting infection, so I
> will use a baseball analogy since they didn\'t go out on strike.
>
> Why are we 0 for 19? Not a very good percentage. I want to say a
> couple things you have to keep in mind. First of all, transmission by
> blood transfusion does occur. It occurs in this country, it occurs
> throughout Latin America. Chagas is tested for in all the countries of
> the Americas with the exception of Canada and the United States. In
> fact, transmission in South America is reported to be anywhere between
> 13 and 49 percent, so why don\'t we see it here more often?
>
> Well, some have proposed maybe these donors are only
> antibody-positive, they are not parasitemic. Well, in some studies we
> have done at the CDC, and presently writing up for publication, we
> observed that 33 of 52 percent seropositive donors were, in fact,
> parasitemic by PCR, so not only are we transfusing blood that is
> antibody-positive, in over the half the times they also have
> parasites.
>
> But what is interesting, though, is when you test these donors, we
> find that the parasitemia is, in fact, intermittent. Not every time
> you sample them can you demonstrate by PCR that they are positive.
> Part of that is due to the intermittent nature of the parasitemia in
> the human host, it is also issues about sample size, how big a sample
> you take in testing, as well.
>
> The other thing I want to point out is which products, of these 19
> individuals, what products were involved? Well, 11 were red cells, 3
> were fresh frozen plasma, 2 were cryoprecipitate, and 3 are platelets.
> This is where we think the answer to this issue is.
>
> \[Slide.\]
>
> We think that perhaps that platelets are the ones or the component
> that may play the greatest role, at least for Chagas. We base that on
> at least 5 to 6 reported transfusion cases in U.S. and Canada involved
> platelets. We don\'t know about the other ones, so we can\'t say 6 out
> of 6, but we know five to six were.
>
> Platelet recipients in general are more likely to be
> immunocompromised. It gets back to that statement I made earlier about
> the sentinel cases. Also, T. cruzi, because of its buoyant density
> more likely may separate out with the platelets during whole blood
> centrifugation.
>
> We have done some studies, and these are ongoing at the Red Cross and
> the home lab on survival in blood components. If we look a whole unit
> of blood inoculated with T. cruzi, it survives up to three weeks, and
> there have been some Brazilian studies I think which show it goes much
> longer in certain kinds of blood.
>
> In platelets, we are able to demonstrate viability up to four days,
> the product only is on the shelf for five, so that is mostly the whole
> product shelf life. Red cells appears to be only four days, plasma, I
> think the freezing process probably kills them.
>
> So, we think the platelets, based on the data up here, and also their
> survival, may, in fact, be the component most likely involved, and
> because our lookback only really had three platelet units out of the
> 19, we probably haven\'t just looked at enough, so we think that it
> probably is going on a much greater rate than perhaps we think.
>
> \[Slide.\]
>
> So, what about nationwide risk, how big of a problem is this? Well, if
> we say there is 13.2 million donations per year in the country, and
> that includes all the blood centers, each donor gives about 1.6 times
> a year, so if we divide that number, we get 8.25 million donors in the
> U.S. per year.
>
> Now, based on some surveys we did, we think about 2.5 percent of all
> the donors in this country are at risk, so that leaves us with 206,000
> at-risk donors, and when these donors are tested by some type of
> antibody test, and confirmed by RIPA, we find that 1 out of every 625
> of those are found to be confirmed seropositive donors, so we feel
> there is about 330 seropositive donors in the U.S.
>
> Now, again, if each one of those donates 1.6 times per year, probably
> about 528 seropositive donations per year in this country. Now, if
> each donated product has been made into about 1.17 components, we feel
> that there is probably about 618 potentially infectious components per
> year, and these are all estimates, and all these other numbers here
> are estimates, too, but it does show you there is a significant number
> of components out there.
>
> \[Slide.\]
>
> What about interventions, what can we do? Well, we have looked at
> question strategies, as I said, we looked at questioning strategies
> and published them through case-controlled studies, and these were
> designed to identify at-risk donors for deferral or perhaps for
> testing.
>
> What we found, by and large, that these lack sensitivity. Most of the
> questions had to do with birth or time spent in the country, some
> donors were uncomfortable answering the question because they thought
> we were getting at immigration issues, and the other problem with
> these questions is that they don\'t deal with the issue of congenital
> transmission.
>
> What about blood screening? Well, I guess the reason why we are really
> here is that there is a lack of licensed tests. A couple of strategies
> we could talk about for blood screening, and I am going to point this
> out right upfront, that I really don\'t feel there is any value, added
> value in NAT screening for Chagas disease.
>
> These are individuals who were infected perhaps 20, 30 years ago in
> their endemic countries, they have very high antibody titers, so we
> are not dealing with a recent ongoing active infection in the United
> States, we are dealing with something that occurred a long time ago.
> So, from the standpoint of Chagas, some type of antibody screening is
> probably sufficient.
>
> What we would probably suggest is that universal screening may be the
> most beneficial way to go. Screening in certain locations in this
> country, geographical locations in the South, would likely miss those
> infections. We already demonstrated transmissions that occur in New
> York City, Manitoba, or anywhere else.
>
> Some have suggested that since this is a chronic infection something
> people picked up 20 or 30 years ago, not actively transmitted in this
> country, why not just test people one time. One time they test, and if
> they are negative, they can continue to donate blood.
>
> We have looked at that issue and in some ways that becomes even more
> complicated. It gets to be a very difficult issue for tracking who to
> test, who not to test, and our feeling was there are probably more
> errors trying to track the donors in that format than just to screen
> universally.
>
> So, we talked about one-time testing, but we decided that was
> logistically difficult and probably not cost effective, as I just
> explained, and then universal screening is what we think would
> probably be the easiest and most effective way to go.
>
> \[Slide.\]
>
> So, to summarize this, we know that seropositive donors are found
> nationwide, but levels vary based on the at-risk population, so
> certainly places like Los Angeles are going to have more than, let\'s
> say, Minneapolis or Portland, Maine, but if you look hard enough, you
> can find them in most parts of this country.
>
> There are no reliable risk factors, as I have said. Infections, keep
> in mind, are asymptomatic, chronic, and untreatable, and most
> importantly, they are congenitally transmitted.
>
> Infectious donors are demonstrable, we do see transfusion cases, and
> likely universal screening is perhaps the best route to go.
>
> Lastly, this is going to be an ongoing blood safety issue largely
> because of continuing immigration, and also because of the second and
> third generation, so it is not an issue that is going to go away.
>
> Thank you.
>
> DR. NELSON: Thank you.
>
> Questions? Yes.
>
> DR. LAAL: I just wanted to be sure I understood this correctly. You
> said that 20 to 30 percent of the people who get infected go on to
> develop disease, am I right?
>
> DR. LEIBY: When individuals are infected, they go through an acute
> phase and then they enter what is called indeterminant phase, and that
> is what most of the blood donors we see are in.
>
> In the indeterminant phase, they generally have high antibody titers
> and intermittent parasitemia, 20 to 30 percent of those individuals go
> on to develop clinical manifestations whether it be cardiac or in some
> cases, depending on the organism, some intestinal complications.
>
> DR. LAAL: But the organism does continue to survive in those 70
> percent?
>
> DR. LEIBY: Oh, absolutely, it is not an infection that clears. If you
> are infected, you are infected for life.
>
> DR. ALLEN: Is there any screening being done in any of the Central or
> South American blood collection centers?
>
> DR. LEIBY: Yes, there is screening throughout Latin America. I think
> they are in the process of implementing screening in parts of Mexico,
> it is done in most of Central America, certainly all throughout South
> America, the blood is screened, yes.
>
> DR. ALLEN: The same basic tests being proposed here in terms of EIA
> with RIPA confirmation?
>
> DR. LEIBY: Tests will vary throughout all those countries. In some
> parts of South America, for instance, they may do two tests, even
> three tests, and then depending on how many are positive, they will
> determine whether or not they are positive. I mean there is a variety
> of tests used throughout these countries, some are better than others.
>
> DR. NELSON: I tried to get some information on this by calling Dr.
> Cruz at PAHO, and what he told me was that PAHO did some surveys of
> blood banks, which have been published and the latest data is from the
> year 2000, and Chagas is tested, as you say, in all Latin American
> countries.
>
> In about six countries, all donors are tested including Brazil,
> Argentina, Paraguay, et cetera, I can\'t remember all of them, but
> there are a number of countries where only some donors are tested, and
> there is some where its testing is much less common, and that includes
> Mexico.
>
> He said that in the year 2000, there some something over a million
> donors that were not tested for Chagas, there were about 65,000 donors
> that were not tested for hepatitis C, and there were about 5,000
> donors that were not tested for HIV in all of Latin America, and they
> have a foundation blood safety grant.
>
> But when you come down to which test is used and how does it perform,
> apparently, it varies all over the lot, and some of them use tests
> that are licensed for diagnosis in this country, Abbott, Gall, and I
> forget the third one, but there are others, Organon, there are a
> number of others that are available, not licensed in this country,
> available only in Latin America, and there are some tests that are
> essentially home brews.
>
> So, they are testing, and they recognize the importance of the
> problem, but in terms of the QC and how it is done, it is quite
> variable, but nonetheless, most blood bankers transfusion services in
> Latin America are highly sensitized to the importance of this problem
> and trying to do something about it.
>
> DR. LEIBY: I think in many respects, it gets to the socioeconomic
> issues, where they can test. It might be the big cities as opposed to
> the rural Central American countries.
>
> DR. NELSON: That was a very good summary.
>
> **Regulatory Pathway for Donor Screening**
>
> **Robert Duncan, Ph.D.**
>
> \[Slide.\]
>
> DR. DUNCAN: Again, speaking the point of view from the FDA, we are not
> bringing any question in this informational session. The FDA probably
> won\'t bring a question about Chagas testing before the advisory
> committee until we feel there is a test that is suitable for blood
> screening.
>
> But towards development of a suitable test, we would like to present
> our current thinking on what the regulatory pathway would be for a
> Chagas blood screening device, and also what the standards for that
> suitable test might be.
>
> So, the first point is that as a blood screening device, a Chagas test
> kit would be regulated under the Food, Drug, and Cosmetic, and the
> Public Health Service Acts. So, therefore, as it is regulated under
> those laws and those regulations, testing would be done with an
> investigational New Drug Application, and then marketing would require
> a biological license application.
>
> Another point that we want to make at this stage is that any BLA
> submission for a device to screen for Chagas disease should include
> the characterization of a confirmatory test. One kind of test would be
> required that could be used to screen a lot of different samples, but
> then a more rigorous test to confirm any positive samples would need
> to be characterized as part of the test.
>
> \[Slide.\]
>
> An IND submission for testing with a Chagas screening device that has
> the potential to contribute new scientific information leading to
> development of a licensed test is encouraged.
>
> There is an issue about whether to do testing under IND simply as a
> means to ensure that blood products don\'t have Chagas disease being
> transmitted. Our point here is that we want a licensed test and that
> the intention of an IND is for development of a licensed test.
>
> So, any IND submission has to at least contribute new scientific
> information that could lead to a licensed test, and any new sponsors
> that would like to submit an IND, we are asking you to come forward
> and write a draft proposal, discuss the IND with us prior to
> submission of the IND, so that the process can go quickly and more
> smoothly.
>
> \[Slide.\]
>
> I am going to talk a little bit about our current thinking on
> standards for approval of a Chagas blood screening test. This is our
> current thinking. Ultimately, we will likely be publishing a guidance
> document and on the way towards writing that guidance document, we
> would probably sponsor a workshop inviting manufacturers and blood
> bank organizations, FDA, and other interested parties, to gather
> together accumulated wisdom before writing that document.
>
> In reviewing the minutes from the 1995 Blood Products Advisory
> Committee meeting where Chagas was discussed, one of the major
> questions that members of the advisory committee had at that time was
> what are the standards, what are the standards for approval of the
> test, how can we decide what is a suitable test, you need to tell us
> what the standards need to be.
>
> In the intervening years, we have gotten some accumulated wisdom from
> licensure and review of a number of blood screening tests for HIV and
> HIV diagnostics, and the numbers that I am going to present today are
> sort of the distilling of that experience.
>
> I am going to talk in several specific areas, chemistry,
> manufacturing, and controls of both crude lysates and well
> characterized antigens, clinical sensitivity, clinical specificity,
> analytical specificity, analytical sensitivity, reproducibility, and
> instrument and software.
>
> \[Slide.\]
>
> First of all, for chemistry, manufacturing, and controls, devices
> utilizing crude lysates, crude parasite lysates would have to have
> manufacturing controls to assure lot-to-lot consistency of antigen
> composition.
>
> The kinds of things that we are recommending to achieve that kind of
> lot-to-lot reproducibility would be to generate a standard reference
> panel of sera that have varying degrees of reactivity, so that the
> product is tested both near the cutoff, as well as strong positives.
>
> There should be something like a Western blot, an immunoassay to
> characterize individual antigens and that the reference panel of sera
> should show consistent representation of the immunodominant antigens
> in the parasite.
>
> Lastly, endpoint titration curves from testing of the final product
> should have slopes and midpoints that fall within acceptable limits.
> It has been shown in this kind of immunological assay that these
> features, the endpoint, as well as the slope, give an assessment of
> the quality, as well as the quantity, of the antigen present in that
> lysate mixture.
>
> \[Slide.\]
>
> I am pointing to a draft Points to Consider guidance document that is
> available from FDA. It was used related to HIV testing, but it is also
> an antigen preparation process, and there are a lot of QC procedures
> that are talked about in this guidance document that would be
> applicable to an antigen preparation for a Chagas lysate.
>
> \[Slide.\]
>
> Next, the more well characterized antigens. A number of manufacturers
> are moving towards recombinant protein and peptide antigens in a test
> kit. We would expect to see lot-to-lot consistency by amino acid
> analysis, peptide sequence, and there is a guidance document for
> biological in vitro diagnostic products that I would refer you to that
> is on the CBER web site.
>
> \[Slide.\]
>
> So, now on the question of clinical sensitivity, any products should
> be tested with at least 100 sera from clinically diagnosed
> parasitologically positive patients. These are all presumed positives,
> so that any sera testing negative should be submitted to a
> confirmatory test, and our recommendation for the confirmatory test is
> the radioimmuno- precipitation assay. It has been characterized by the
> American Red Cross in David Leiby\'s lab, Dr. Kirkoff has developed it
> initially. It was used by Abbott in some of the testing of their
> product. So, it is a complex and technologically difficult assay, but
> it is extremely reliable and has the highest specificity, and it has
> been reproduced in multiple laboratories, so we feel that it is the
> best confirmatory test at this point.
>
> The next step in terms of showing clinical sensitivity would be to do
> a prospective study with at least 500 samples in an endemic area, and
> we are suggesting that the prevalence in that area should be greater
> than 5 percent, the idea being that the product should be usable to
> test a range of samples that could be either positive or negative, but
> where a substantial number of positives will be found.
>
> In that prospective study, each sample should also be tested by a
> reference test, and in this case, our recommendation is the
> immunofluorescence assay, which has been well characterized by the
> CDC, be used as a reference test.
>
> After these 500 samples are tested by the new test, as well as the
> reference test, then any positives, positive on either test, would be
> subject to a confirmatory test, again recommending the RIPA. This will
> be able to address the question of sensitivity of the test.
>
> \[Slide.\]
>
> Another very important point for a test to be used in a universal
> screening setting would be specificity. The device should be tested in
> the end user setting meaning in the blood collection setting, in the
> U.S. population. There should be at least three geographically
> separated sites with sufficient numbers for statistical power at each
> site, and 5,000 samples overall has been satisfactory in some of the
> other studies.
>
> At least three lots of the device need to be tested in this large
> study. No reference test is required, in other words, every single
> sample does not have to be subjected to a second test, but positive
> samples are confirmed with the RIPA test.
>
> \[Slide.\]
>
> A couple points that are more in terms of the analytical quality of
> the assay itself. Analytical sensitivity, each lot of the device
> should be tested with a dilution series of a known positive sera to
> determine the limit of detection. That is more or less the same point
> I made earlier about the endpoint titration.
>
> Then, the other recommendation here is that seroconversion panels, if
> available, should be used to test the device at the point of
> seroconversion when there might be limiting quantities of the
> antibody.
>
> \[Slide.\]
>
> Analytical specificity comes in terms of potential cross-reactivity.
> Well, there is two issues, cross-reactivity and interference. In
> cross-reactivity, the device should be tested with a panel of sera
> from patients with potentially cross-reactive infection, and some of
> the infections that have been identified, visceral leishmaniasis is
> known to cross-react with lysate samples of Chagas antigens, but
> malaria, schistosomiasis, syphilis are others that have been suggested
> to look for cross-reactivity.
>
> It is known that influenza vaccinees soon after vaccination can
> cross-react with the Chagas test. Serum samples with autoimmune
> disease would also be potential cross-reactors.
>
> On the question of interference, a Chagas-positive serum should be
> spiked into potentially interfering sera, and the final anti-Chagas
> antibody titer should be very close to the cutoff. I have listed some
> of the examples that have been looked at for other products for
> interference with the assay - hemolyzed sera, microbially contaminated
> sera with various anticoagulants, comparing fresh or frozen serum,
> bilirubin, high triglycerides or hypergammaglobulinemia.
>
> These kinds of tests should be done one time in the preclinical phase
> of development of the product. This cross-reactivity could be included
> as a lot release comparison on each lot of the device.
>
> \[Slide.\]
>
> Then, we have the question of reproducibility and proficiency. So, as
> part of the IND and the BLA, a panel of at least five sera, comprised
> of both positive, negative, and weakly reactive sera should be tested
> in at least three sites with different operators with at least three
> lots of a device.
>
> Each study site which is going to be used should demonstrate
> proficiency with this panel before screening donors. So, the idea
> here, part of the device is to develop this panel of sera which could
> be used for proficiency testing in an ongoing way.
>
> \[Slide.\]
>
> So, a lot of the kinds of devices that manufacturers are talking about
> could be run in an automated setting, and this is to remind you that
> instruments and software used for screening blood are medical devices
> and must be developed and manufactured in accordance with the quality
> system regulation, which is Regulation No. 820 there.
>
> There is a Center for Devices and Radiological Health guidance
> document called General Principles of Software Validation which may be
> used to assist in the software-related design control issues.
>
> \[Slide.\]
>
> Also, to remind potential sponsors that instrument and software is
> submitted as a separate 510(k) in a biological license application.
> There is also a Center for Devices and Radiological Health guidance on
> that question, the content of premarket submissions for software
> contained in medical devices, that describe how to do a 510(k) that is
> then linked to the biological license application.
>
> There is another question that comes up in this process, which is, is
> the device of a major or a minor level of concern, and it has been
> determined that devices used for screening blood donors is a major
> level of concern, and you can refer back to the guidance to ensure the
> appropriate documentation that is required for an item that is of
> major concern.
>
> So, that is the end of my summary of the kind of standards we would
> expect to see on a blood donor screening device for Chagas.
>
> Any questions?
>
> DR. NELSON: Any questions?
>
> DR. KLEIN: Just a comment. This has been going on for a long time, and
> this morning we heard about a disease that is not known to be
> transmitted by blood, and should it be, would be probably asymptomatic
> in most individuals who would then become immune.
>
> Here we have a disease that we know in other countries is transmitted
> readily, been transmitted in the United States, and there are tests
> that are already available.
>
> It seems to me that perhaps you need at least a sense maybe of the
> committee that there is some urgency to move forward with a strategy
> to intervene at this point in time since it is I guess five years
> since it was first brought to the BPAC.
>
> DR. DUNCAN: I would respond to that in this way, that up to this
> point, the lack of a test is mostly being driven by the manufacturers.
> Now, they are looking for a signal from the FDA that if they put the
> money into developing the test, it is going to be recommended for
> screening of all blood, and we are not at that point yet, but I mean
> these two things sort of need to come forward together I think.
>
> DR. KLEIN: I understand that. I would also add that, of course, the
> disease is chronic and untreatable, and can be fatal, and if it
> cross-reacts with visceral leishmaniasis, I think most of us wouldn\'t
> care if you omitted those donors, as well.
>
> So, I think there is probably some need maybe to encourage industry to
> submit something to you that would meet those requirements and to get
> on with it.
>
> DR. NELSON: I think that is the catch-22 situation is that
> manufacturers were not clear, that if they met all these requirements,
> would FDA recommend given the fact that there are a small number of
> cases, and that is the reason for presenting it.
>
> I hope, it is worthwhile I think for BPAC to express perhaps an
> opinion that if a test were available that met these criteria, that it
> certainly would be useful in U.S. blood donors, and that is certainly
> my feeling.
>
> DR. ALLEN: I share that sense particularly since I mean the
> demographics, the changing demographics in this country are obvious,
> and blood collectors in many markets, I think are looking for ways to
> increase the number of donors from a variety of racial and ethnic,
> so-called minority communities, Hispanics certainly or Latinos among
> them. I think this would be an important step to help assure that that
> can be done safely.
>
> DR. NELSON: We were anticipating when we did this study that we would
> find some transmitted cases, and, in fact, we found cases, but these
> 11,000 patients had been exposed to close to 120,000 units of blood,
> blood or blood products, and they weren\'t all platelets obviously. In
> fact, platelets was a small part of it.
>
> But we didn\'t find it, but we certainly found that there was a
> problem there in the U.S. population, and one of the cases, one of the
> six cases had never lived in Latin America. He was from Southern
> Texas, which Mexican citizens might consider part of the U.S. at this
> point, but it is an endemic disease in parts of the United States.
>
> DR. NAKASHI: Dr. Nelson, it is our current thinking that if a good
> test comes along which fits the criteria definitely, it will be
> recommended. In fact, if you remember, when Rob said early on in his
> early studies, the early BPAC, in 1999, it was sort of suggested that
> if a suitable test if available, FDA would recommend testing, so I
> think from our side, as soon as we see a good test, we will
> definitely, that\'s our current thinking at the moment.
>
> DR. NELSON: There were a couple of people that wanted to make a
> statement about Chagas. We could open the public hearing.
>
> Dr. David Persing. Keep in mind that we have another item.
>
> **Open Public Hearing**
>
> DR. PERSING: My name is David Persing. I am Vice President of
> Molecular Biology at Corixa Corporation, which is a for-profit concern
> in Seattle, Washington. I am also the Medical Director of the
> Infectious Disease Research Institute, which is a non-profit
> organization.
>
> I am wearing my for-profit hat today. I am trained as a clinical
> pathologist specializing in test development and prior to coming to
> Corixa, I spent nearly 10 years in clinical practice at the Mayo
> Clinic developing and implementing specialized tests for human
> infectious and genetic diseases.
>
> I would like to take this opportunity to mention that Corixa in
> Seattle has developed a recombinant immunoassay for Chagas disease.
> This test is based on detection of antibody responses to four
> complementary immunodominant epitopes that were discovered by
> serologic expression cloning, by using sera from infected patients.
> These epitopes are expressed as a single recombinant protein, called
> Therapeuticf, consisting of 101 amino acids, including a 6 amino acid
> hexahistidine tag used for purification. This protein is expressed in
> an E. coli expression vector and is purified to a single band on SDS
> page gels.
>
> The TcF antigen has been licensed by three companies for diagnostic
> purposes - Biokit of Spain, BioMerieux of France, and Diamed of
> Switzerland. These licenses do not extend to blood donor screening.
>
> These companies have developed kits based on the recombinant protein.
> The performance of the BioMerieux assay was recently published in the
> Journal of Clinical Microbiology last month. The sensitivity of the
> TcF ELISA in 101 patients from Argentina and Brazil was 100 percent.
>
> This group included 27 patients with Chagasic cardiomyopathy, which
> generally harbor very low numbers of circulating T. cruzi parasites.
> The specificity of the assay was 98.9 percent of 150 healthy controls,
> none were positive, but among 39 patients with leishmaniasis, two sera
> were reactive, which could be consistent with either coinfection with
> T. cruzi or antigenic cross-reactivity.
>
> By comparison, an assay based on a whole cell sonicate of T. cruzi
> parasites was reactive in 10 of 39 leishmaniasis patients. Other
> companies and investigators have tested the TcF protein as a target
> antigen for blood screening or sera for the presence of antibodies to
> T. cruzi and reported sensitivity and specificity values at 98 to 100
> percent.
>
> In summary, we believe that the TcF recombinant antigen may well serve
> as the basis for a test with the requisite sensitivity and specificity
> for blood and organ donor testing in the U.S. As a single recombinant
> protein, it can be manufactured consistently.
>
> One of the concerns about lysate-based assays is that of specificity,
> but it also may relate to manufacturing consistency, as was pointed
> out in an earlier talk, and manufacturing consistency might be
> enhanced by virtue of making a recombinant protein.
>
> The potential contribution of false positive results due to either
> leishmaniasis or T. cruzi coinfection in patients with a diagnosis of
> leishmaniasis, is expected to be extremely low in U.S. blood donors,
> so our expectation is that specificity numbers would be higher in the
> U.S. than in areas endemic for both leishmaniasis and Chagas disease.
>
> Corixa is willing to discuss immediate licensing of its TCF technology
> to a qualified provider of commercial blood screens in the U.S. and is
> interested in participating actively in the rapid commercialization of
> this technology.
>
> Thank you.
>
> DR. NELSON: Thank you very much for that important information. So,
> the issue is that you would provide or collaborate with a firm that
> was interested in seeking the IND and meeting the licensing
> requirements.
>
> DR. PERSING: We are not a test manufacturing company, we don\'t make
> ELISA kits, we don\'t make test kits. We rather license our antigens
> and technology out to other companies interested in manufacturing.
>
> DR. NELSON: It is hopeful that there are some people in the audience
> that may work for or represent or know about companies that would be
> interested in taking this further and getting and IND and getting it
> licensed.
>
> Kay Gregory.
>
> MS. GREGORY: In the interests of time, I believe most of you have our
> written statement, so I am going to skip describing the AABB, and I
> will quickly summarize what our position basically is.
>
> We strongly support FDA\'s current efforts to encourage the
> development and implementation of an appropriate screening test for
> Chagas. We believe that the FDA priorities should be to encourage and
> sponsor research the production of highly specific screening and
> appropriate confirmatory assays, and these can be either serologic or
> nucleic acid based.
>
> Further, we believe there is a need for studies to assess the
> prevalence in donor populations, and these studies should include an
> extensive lookback component, so that prior recipients of components
> from infected donors can be studied.
>
> This will provide estimates of donor infectivity and the infectivity
> of various transfusable components under current conditions of
> collection, processing and storage of whole blood and its components.
>
> Thank you.
>
> DR. NELSON: Thanks very much.
>
> Are there any comments from the committee additional about Chagas
> disease?
>
> If not I would like to move on to the final topic, which was Window
> Period HIV Cases and Current Estimates of Residual Risk.
>
> Dr. Hewlett from FDA.
>
> **Window Period HIV Cases and Current Estimates**
>
> **of Residual Risk (Informational)**
>
> **Introduction and Background**
>
> **Indira Hewlett, Ph.D.**
>
> DR. HEWLETT: Thank you, Dr. Nelson, and good afternoon, everyone.
>
> In this session, we will be discussing issues surrounding large-scale
> implementation of individual donation NAT or ID-NAT for whole blood
> collections. This session is informational in nature, and the FDA is
> not posing any questions to the committee at this time.
>
> \[Slide.\]
>
> The specific issue for discussion today is the feasibility of future
> large-scale implementation of ID-NAT to further reduce the window
> period and transmissions from this window period of donations screened
> by pooled sample NAT.
>
> \[Slide.\]
>
> The topics that will be discussed are the recent window period HIV
> transmission cases, residual risk estimates, their significance for
> implementation of ID-NAT and current constraints of implementation of
> ID-NAT.
>
> \[Slide.\]
>
> I will be presenting some background information on the issue,
> followed by Dr. Busch, who will review one of the recent HIV
> transmissions which occurred in Texas, residual risk estimates, window
> period, et cetera, and Dr. Leparc who will report on the second
> transmission which occurred in Florida.
>
> As we all know, viral safety of blood and blood products is ensured by
> implementation of sensitive tests for the major blood-borne viruses
> and effective virus removal and inactivation methods for plasma
> derivatives.
>
> In the case of HIV, antibody screening was implemented for donor
> testing in 1985, with improved tests being subsequently implemented
> which reduce the window period to 22 days.
>
> \[Slide.\]
>
> However, a small number of transmissions continued to occur primarily
> from window period donations that were not detected by antibody tests.
>
> In a workshop held in 1994, FDA sought to explore whether nucleic acid
> testing, or NAT, would be useful in reducing these window period
> transmissions.
>
> \[Slide.\]
>
> A large amount of data was presented at this meeting, but experts felt
> that NAT was not ready for implementation at the time although its
> development was considered to be a priority.
>
> FDA recommended HIV-1 p24 antigen testing as an interim measure to
> reduce window period HIV transmissions until sensitive and automated
> NAT assays became available. Antigen testing further reduced the
> window period to 16 days, however, the low yield of antigen testing
> accelerated the development of NAT assays.
>
> \[Slide.\]
>
> Although NAT assays offer a high degree of sensitivity, they are
> complex and labor-intensive, and testing of minipools was considered
> to be a useful interim measure until fully automated and sensitive
> assays became available for testing of individual donations.
>
> Automation was deemed critical for large-scale, high-volume testing of
> individual donations necessary in the blood bank setting.
>
> \[Slide.\]
>
> In 1999, clinical studies were initiated to evaluate pooled and
> individual sample NAT for HIV-1 and HCV in whole blood donations. FDA
> permitted clinical study of this investigational technology on a large
> scale to evaluates its utility in the intended use setting.
>
> \[Slide.\]
>
> In February 2002, FDA licensed the Procleix HIV-1/HCV assay, the first
> pooled and individual sample NAT for semi-automated qualitative
> detection of HIV and HCV RNA in whole blood.
>
> The test is manufactured by Gen-Probe and distributed by Chiron
> Corporation.
>
> It is intended for use in screening indication donor samples or pools
> of plasma comprised of equal aliquots of not more than 16 donations.
>
> \[Slide.\]
>
> In clinical studies, this assay detected 7 HIV antibody-negative,
> antigen-negative cases out of 25 million donations tested at 10 pooled
> and individual donation testing sites.
>
> \[Slide.\]
>
> The clinical utility of this assay was further established by testing
> 10 seroconversion panels in comparison with antibody and antigen
> assays, HIV-1 RNA was detected 10 and 3 days earlier at 1 to 16
> dilution, and 12 and 7 days earlier, when tested undiluted.
>
> The test met the current FDA sensitivity standard of 100 copies per
> ml.
>
> \[Slide.\]
>
> Subsequent to licensure, two reports of HIV transmission involving
> three recipients were identified. The first case was at the South
> Texas Blood and Tissue Center in San Antonio and the second at Florida
> Blood Services in St. Petersburg.
>
> \[Slide.\]
>
> Dr. Busch and Dr. Leparc will review these cases in detail, but the
> next two slides present the key points of this report.
>
> In the San Antonio case, transmission to a single recipient occurred
> from a unit of red cells that tested negative by an investigational
> minipool NAT assay, p24 antigen and antibody assays.
>
> The implicated unit was tested at different dilutions by unlicensed
> and FDA licensed assay. Importantly, inconsistent detection was
> observed in diluted samples, but the undiluted samples were detected
> suggesting that ID-NAT may have detected this donation. The viral load
> was approximately 150 copies per ml in the sample, so we are looking
> at a very low viral load sample here.
>
> \[Slide.\]
>
> In the Florida case, FFP and red cells manufactured from a unit that
> tested negative by a licensed minipool NAT assay, p24 antigen and
> antibody assays, transmitted HIV to two recipients.
>
> The cases were identified by lookback. Genetic studies are underway to
> establish linkage between donor and recipient, but in this case, the
> implicated sample is not available for further testing.
>
> \[Slide.\]
>
> These cases indicate that rare event/HIV transmissions continue to
> occur even after implementation of pooled sample NAT, which reduces
> risk to 1 in approximately 2 million and the window period to 11 days.
> ID-NAT is expected to further reduce this to 1 in approximately 3
> million and the window period to 7 days. This is for HIV.
>
> \[Slide.\]
>
> Although ID-NAT is technically feasible, further refinements are
> needed for efficient nationwide implementation. Current platforms for
> ID-NAT are semi-automated and require manual specimen preparation,
> reagent addition, et cetera.
>
> \[Slide.\]
>
> Upgrades are needed to maximize efficiency for high volume use and
> these upgrades and the regulatory submissions for approval will
> require time.
>
> Automation capabilities and associated training of lab technical staff
> will be necessary to minimize error and assure component safety and
> availability.
>
> \[Slide.\]
>
> So, in conclusion, FDA strongly encourages manufacturers to expedite
> development of fully automated platform for high volume use of ID-NAT
> to further reduce the low risk of HIV transmission from window period
> donations.
>
> FDA will work with manufacturers to expedite the review process to
> ensure timely implementation of ID-NAT nationwide at some point in the
> future.
>
> Thank you.
>
> DR. NELSON: Thank you very much for that succinct and complete
> summary.
>
> Are there any questions? No.
>
> Dr. Leparc wanted to report on the Florida case.
>
> **Case Report - Florida Blood Services**
>
> **German Leparc, M.D.**
>
> DR. LEPARC: Thank you.
>
> \[Slide.\]
>
> Following is a summary of the donation data associated to the
> investigation of the recipients of a newly seroconverted volunteer
> donor on whom serologic markers for HIV were found to be positive on
> the last of five blood donations that were collected in the course of
> eight months.
>
> \[Slide.\]
>
> This is a depiction of the total donor history. In yellow you will see
> the seropositive donation that took place in May, and all products
> from that donation were discarded. In red, you will see the donation
> immediately prior to the seropositive one during the window period
> that resulted in two of the components being made available and
> eventually transfused into two recipients, red blood cells and fresh
> frozen plasma.
>
> The platelets were discarded after their expiration date, five days
> after collection.
>
> \[Slide.\]
>
> The prior three donations were part of our lookback, also an effort
> and failed to reveal any patient, recipient of this blood, who
> seroconverted as a result of the transfusions of those components.
>
> The first donation by the donor was collected exactly a year ago
> today, during the massive public outpouring that followed the tragic
> events of September 11th, 2001. Subsequent to that, a whole blood
> donation from the same individual was collected every 56 to 61 days,
> so this person became a first-time donor and a very regular donor
> after September 11.
>
> Each and every one of those donations prior to seroconversion was
> tested individually for HIV-1/2 antibodies, for p24 HIV antigen using
> FDA licensed enzyme immunoassays, as well as for the presence of HIV
> viral genome using nucleic acid testing based on
> transcription-mediated amplification using reagent in a 16-member
> meaningful configuration as specified by the test manufacturer and
> within the testing protocol established in the IND approved by FDA to
> evaluate the feasibility of nucleic acid testing for the screening of
> blood donations.
>
> Seroconversion of the donor was detected in the last blood donation in
> May of this year. All blood components, as I mentioned before, were
> appropriately quarantined and discarded.
>
> \[Slide.\]
>
> The seropositive condition of the donor, once confirmed, prompted the
> initiation of lookback procedures that led to the discovery of
> seroconversion in the recipients of blood components from the
> immediately preceding blood donation.
>
> Both the recipient of red blood cells and the recipient of fresh
> frozen plasma from the blood donation in March were found to be
> seropositive for HIV, as well as have positive HIV RNA by nucleic acid
> testing.
>
> The inner platelets from this donation again was discarded after
> reaching the five-day expiration date.
>
> \[Slide.\]
>
> As far as the prior donations, we have at least one living accessible
> recipient for each one of those, and in every case we have no evidence
> of seroconversion indicating that there was no exposure to the HIV
> virus in those prior donations.
>
> \[Slide.\]
>
> An exhaustive analysis of the testing performed on samples of the
> index donation to runs, as well as testing on all of those who
> participate in the same donor drive did not uncover any testing
> anomalies and we had the conclusion from those results that the
> donation linked to the transmission of HIV occurred during that brief
> period estimated to be somewhere between 7 to 11 days after exposure
> when the donation cannot be interdicted by the use of current testing
> methods.
>
> \[Slide.\]
>
> Review of the testing data for the seropositive donation shows that
> the seropositive was clearly positive with the ELISA test on the
> initial testing being 7 times the cutoff, as well as on the repeat
> testing.
>
> The NAT-HIV Multiplex Minipool had values of almost 22 times the
> cutoff. In the Multiplex Singlet for HIV, it was about 18 times the
> cutoff, and in the Discriminatory HIV and Singlet, about 15 times.
>
> The immunofluorescence assay gave a positive result of 2-plus negative
> control and positive, so it was not the strongest immunofluorescent
> assay, but showing that there was some degree of early seroconversion.
>
> \[Slide.\]
>
> The donor at the time was notified of the abnormal results and
> actually follow-up samples were obtained and with similar results. By
> contrast, when we reviewed the results of the testing performed in the
> donation collected during the serological window period, we found no
> evidence of either HIV antibodies with a very low optical density and
> a signal-to-cutoff ratio of 0.2, the signal-to-cutoff ratio for the
> antigen, again these are tested on in singlet, was low, at 0.1.
>
> The nucleic acid testing in the multiplex configuration in a minipool
> of 16 members, purple, showed a good internal control with over
> 173,000 relative light units. The anilide was well below the internal
> control and with a signal-cutoff ratio of 0.2, close to 0.3, so this
> was a clearly negative result.
>
> \[Slide.\]
>
> In conclusion, we could not determine the viral load on the donor at
> the time of the collection, during the window period, and this was
> because no archival samples were available. The red blood cells were
> transfused, the plasma was transfused, and the platelets were
> discarded after expiration date. As a result of that, we are looking
> at the feasibility of maintaining archival samples for future
> investigations.
>
> Our laboratory, however, tests approximately 9 percent of the
> nation\'s blood supply for nucleic acid testing, and at that volume to
> have a feasible archival and retrieval system that can allow efficient
> aliquotting and store for long term, at this point we haven\'t figured
> how to accomplish that.
>
> We had components. As opposed to the case in Texas where there was a
> remnant of fresh frozen plasma that provided plenty of material for
> study, we didn\'t have anything like that.
>
> As Dr. Hewlett mentioned, there are studies ongoing on the HIV
> genotyping for donor and recipients to establish a link. These studies
> are being done both at the CDC and FDA laboratories from samples
> obtained at different times from each one of the three parties.
>
> Lastly, we plan to perform an HIV infection dynamic staging on the
> seropositive samples that are archived from the donor. There are ways
> where you can approximately determine the time when the donor could
> have become infected prior to donation by doing some staging tests
> that Dr. Busch will describe later.
>
> So, that is a brief summary of the case that we had.
>
> DR. NELSON: Thank you very much.
>
> Neither the donor nor any of the recipients had a seroconversion
> illness of any type?
>
> DR. LEPARC: No. Actually, this was, of course, a surprise for all
> three parties. There was no indication whatsoever that infection had
> occurred.
>
> DR. SIMON: Did you find any risk factors in the donor?
>
> DR. LEPARC: Yes, and I cannot go into much details about this because,
> of course, there is litigation now in progress, and our counsel has
> advised us not to discuss this, but there was a risk factor which was
> unknown by the donor at the time.
>
> DR. NELSON: Thank you.
>
> Dr. Busch.
>
> DR. NELSON: I think this case and these cases are important because
> they certainly say something about the sensitivity of our surveillance
> and the usefulness of lookback and the whole issue. I am impressed
> that we were able to find some cases where there was still an issue
> that all of us hypothesize might not have disappeared completely.
>
> DR. SIMON: I guess in the interim, even with individual NAT based on
> what Dr. Hewlett showed, you still have a few days there, so we are
> not going to get to zero until we get to pathogen inactivation
> theoretically is my feeling.
>
> DR. NELSON: I was a little surprised given the doubling time of HIV,
> at the very low copy number, which should be a fairly small window on
> average, but maybe this patient wasn\'t average. Maybe there was
> something going on leading to this very low copy number.
>
> **Viral Dynamics in Early Seroconversion**
>
> **Michael Busch, M.D.**
>
> DR. BUSCH: I can start just talking through the slides. The first few
> slides are the summary of the case reports both from the San Antonio
> transmission case and an earlier published study that we did in
> collaboration with CDC related to a transfusion in Singapore that
> transmitted HIV from a window phase unit.
>
> The San Antonio case, the first slide is a timeline. It is very
> similar to Dr. Leparc\'s study in that a donor seroconverted to HIV
> antibody, and the prior donation from that donor had been transfused,
> and through lookback, the recipient of that donor was recalled and
> found to be infected.
>
> Fortunately, in that case, the recovered plasma had actually been
> shipped to Europe but not yet pooled, so it was able to be brought
> back to the States and studied, and it is through studies of that
> plasma, as well as follow-up samples from the donor and from the
> infect recipient that we were able to, first, confirm that this was
> the source of transmission, so extensive sequencing studies were done
> to unequivocally demonstrate that.
>
> The other thing we were able to do was to do viral load analysis and
> most importantly, dilutional studies to assess what the detectability
> of that unit would have been had it been tested singly or at
> intervening dilutions relative to the current pooled test systems.
>
> So, there is a table that demonstrates the detection. The sample was
> detected undiluted and there was detection, and as the sample was
> diluted out on both the Roche and the Gen-Probe systems both at 1 to
> 8, 1 to 16, 1 to 24, we began to lose detection a fraction of the
> replicate tests.
>
> Importantly, this original NAT was actually what is considered a home
> brew NAT, San Antonio brought up their own assay system under IND from
> FDA, but this particular donation was just given at a viral load of
> about 150 that was just detectable essentially at the pool sizes being
> used with some relative rates of detection.
>
> The other case that is described in there was published a year and a
> half ago. It was again a transfusion in Singapore, same story in that
> a donor seroconverted. They were not screening by pooled NAT at the
> time, but the prior donation plasma that was determined to have
> infected a recipient was again available and was subjected to the same
> kind of sequence proof of transmission and then characterization of
> the viral load.
>
> The same sort of story played and that the unit was detected
> consistently by both the Roche and Gen-Probe systems undiluted and was
> detected at serial pooled dilutions with relative frequencies that
> eventually, essentially became negative out at the 1 to 24 pool size.
>
> So, these are two additional examples although in these cases, the
> plasma from the implicated unit was available.
>
> That was the time course, the sequencing.
>
> \[Slide.\]
>
> This is the dilutional data on the San Antonio case, and again at 1 to
> 8, both manufacturers essentially picked it up. At 1 to 16, it was
> still picked up 3 out of 3 by one, but a portion on the other, and at
> 1 to 24, both companies missed it, about a third or a quarter of the
> time.
>
> \[Slide.\]
>
> The Singapore case, I talked through it.
>
> \[Slide.\]
>
> So, this is the dilutional work on the Singapore case. Again, the
> upper part is controls, importantly undiluted both Gen-Probe and Roche
> systems detected consistently, but as you began to dilute it out 1 to
> 8 and then 1 to 16 and 1 to 24, you see the sample is negative, so,
> just as predicted from the earlier studies, as you will see.
>
> \[Slide.\]
>
> I just want to quickly, though, run through our understanding, which
> we have had for quite a long time, of the evolution of viremia. We
> really predicted these cases would happen, and it shouldn\'t have been
> a surprise, talk a little about the sequential stages of early
> infection for both HIV, HCV, and a little bit about HBV, and then get
> into really what we would predict would be the frequency that we would
> be missing units that could be detected by individual and are being
> missed by minipool.
>
> \[Slide.\]
>
> Just HIV, the early dynamics. Many of you have seen this many times in
> this arena. Importantly, I think this so-called eclipse period
> following exposure before we can detect virus even by single unit NAT,
> there are observations when we test back samples from infected people
> of transient periods of very low level viremia during this period,
> which we don\'t know for sure, but may be infectious, as well.
>
> Then, we have this brisk ramp-up viremia followed by antibody
> conversion and stabilization, steady-state RNA.
>
> \[Slide.\]
>
> This is just one of the examples of a blip viremia for HIV, so this is
> a plasma donor who was detected by pooled NAT at day zero. That is the
> definition here. Then, as we test back, day minus 4 on back, we can
> detect by full-input, high-sensitivity studies single unit type
> testing.
>
> Immediately prior to the early consistent minipool positive, we can
> detect low level frequency viremia, which essentially is analogous to
> these transmission events that we are observing, but interestingly, if
> we look back in a number of these panels a week or so before that
> early viremia, we detect another transient phase of viremia, sort of
> primary viremia phenomenon similar to what you heard this morning
> about West Nile.
>
> Again, whether this is infectious, we don\'t know. Again, it is
> erratically detected even by the individual NAT, and we think this
> eclipse phase between here is probably not infectious, but studies are
> in process to study that further.
>
> \[Slide.\]
>
> By looking at a large number of panels, we can quantify the ramp-up
> viremia, and it is really this data that allows us to estimate the
> doubling time and project the relative window closure achieved by
> individual versus minipool NAT or intervening pool size.
>
> \[Slide.\]
>
> HCV, a similar summary graph. Again, I will show you some examples of
> really a very common phenomenon, that before ramp-up viremia, there is
> frequently a transient very low level viremia that is observed for
> weeks before this explosive ramp-up phase, and then you go through a
> very long, almost two-month plateau viremia, very high titer, readily
> detected by minipool NAT, which explains why we are seeing such a
> relatively high yield of HCV minipool NAT.
>
> \[Slide.\]
>
> This is just one example of an HCV blip viremia, so this donor, plasma
> donor was picked up at day zero by minipool NAT. They had one sample
> here that had about 100,000 copies that was initially missed by the
> large plasma pooled NAT, but what I want to emphasize is this period
> of actually several months prior to ramp-up viremia, during which we
> could detect viremia.
>
> This is four replicate, full-input TMA assays, and the portion of the
> bars that are filled here are the percentage of the four reps that
> were positive by the single sample input full sensitivity TMA, so you
> see this donor went through sort of cycles of a week of very low level
> viremia erratically detected even by individual NAT, then negative for
> a week, and then positive for a week, then negative, then positive.
>
> \[Slide.\]
>
> Just shows a series of these. This is a group of fix panels that are
> actually, as I will show you later, being transfused into chimps now,
> serial samples from these human plasma donors, but you can see here
> this blip viremia extending back from day zero in six of these cases
> with a sort of similar cyclic kind of viremia.
>
> Again, this is the proportion of four replicate individual donation
> NATs that are positive. An important point here is this strongly
> suggests that even individual donation NAT is unlikely to interdict
> all infectivity because it is only able to erratically detect the
> viremia that exists in this early eclipse phase.
>
> \[Slide.\]
>
> Just one slide. This is from some work that Fred Prince is just
> publishing where they infected chimps with very low level, exposed
> chimps to one viral particle, then 10, then 100.
>
> What you can see here is that a single viral particle actually can
> lead to\--this doesn\'t show it on this slide\--but to transient
> viremia and a low level T-cell immune response, and then as you get to
> 10, there is actually even a low-level antibody response, and then at
> 100 copies you get full infection.
>
> So, the message here is that we think these blip viremias, they are
> either an early phase of virus just smoldering in the liver and just
> beginning to get a foothold in the body, or they may represent repeat
> exposures in these high-risk people at very low doses that are unable
> to establish a full infection.
>
> \[Slide.\]
>
> These, as I indicated, in collaboration with Harvey Alter and Chris
> Murphy, these units from these pre-blips in the valleys between the
> blips and ramp-up, and then the blips are being transfused into chimps
> to try to really define when is infectivity established relative to
> the detectability of viremia either during the blips, which is very
> erratic, or if necessary, into the early ramp-up phase.
>
> So, we are really trying to do the studies that will better
> characterize infectivity versus viral load in the early phase of
> infection.
>
> \[Slide.\]
>
> Just for HCV, similar, we have got a number of these cases, 37, where
> we have good ramp-up phase viremia load data and can, from that,
> derive a doubling time estimate, and then the next slide shows just
> one example of how we can use that ramp-up phase viremia and the
> differential sensitivity of minipool versus individual NAT, which is
> about a 20-fold difference.
>
> \[Slide.\]
>
> Given the rapid ramp-up phase, a 20-fold difference in sensitivity,
> testing a sample essentially in pools of 20 versus singly with the
> same assay, only translate into about a four-day difference in the
> window period closure.
>
> This is the important sort of conversion. It allows us to project the
> yield of the new assay, single versus pool.
>
> \[Slide.\]
>
> The same thing we have for HBV, a doubling time of about two and a
> half days.
>
> \[Slide.\]
>
> This is actually a summary of the work we did with FDA, Biswas and
> colleagues looking at the performance of different antigen tests
> versus pooled sample versus single sample NAT on HBV. The important
> point here is with HBV, we actually achieve much more window closure
> with the conversion from pooled to single unit because the doubling
> time is much slower, so the ramp-up is slower, so you actually get
> about a 20 to 30-day further closure of the window by going for
> minipool to single unit.
>
> So, as we begin to get HBV, then, clearly, single unit NAT will be an
> important advance.
>
> \[Slide.\]
>
> So, how do we take this window closure data and tell you how many
> people will get infected because we are not doing individual NAT? To
> do that, we need to know the rate of new infections in the donor pool,
> and that is the incidence rate, and this is data from the REDS group
> looking at incidence rates for the main viruses.
>
> You can see actually that the incidence rates have dropped and that we
> are now looking at incidence rates of about 2 per 100,000 person years
> for HIV and about 3 for HCV, higher incidence for HBV.
>
> \[Slide.\]
>
> The incidence rate parameter is adjusted to account for higher
> incidence in first-time donors and to exclude non-transfusable units
> and then we multiply that adjusted incidence rate times the window
> period to estimate either the residual risk or the yield of going to
> individual NAT.
>
> \[Slide.\]
>
> In terms of the duration of the pre-detectable window, what we have
> done is to take the current sensitivities of the assay system, so the
> pooled NAT systems currently are detecting at about 80 copies per ml
> for HIV and 190 for HCV, the 50 percent hit rates for HBV. We are
> still using surface antigen tests, so we are picking up at around
> 2,200 copies, and then we estimate based on the doubling time how far
> back in time would these donors, these people have had a viral load of
> 1 copy per 20 ml, which is the infused volume of plasma.
>
> So, we are now using a new, more empiric dataset to estimate the
> duration, the theoretical duration of infectious viremia that would be
> present at the level, sort of worst case estimate that one copy in an
> infused volume of blood could transmit.
>
> \[Slide.\]
>
> When we do that, we take the detection limits of the current screening
> systems, the minipool NAT or HBsAg. We take the doubling time of the
> virus and from that doubling time and viral load, we can project back
> that there is about 8 to 9 days of probably infectivity for HIV and
> HCV preceding detection by the minipool NAT.
>
> \[Slide.\]
>
> Then, we can take those periods of time and multiple them times the
> incidence rate to get current risk estimates. So, this is how we kind
> of talk in terms of the risk now for HIV is in the range of 1 and 2
> million, and for HCV is in the range of 1 and 1.5 million, and we now
> have estimates with confidence bounds integrating the incidence rate
> and the window period estimate.
>
> \[Slide.\]
>
> The critical question today, though, is how much extra closure of the
> window would be achieved if we moved from minipool to individual NAT.
> As I showed you on that one graphic, and do statistical modeling of
> the data, we can estimate the window period difference by increasing
> the sensitivities of these assays 20-fold by going from an average
> pool size of 20 to single, and we estimate that really there is only
> about a three-day for HCV and about a four-day for HIV window period
> difference between the minipool and single unit.
>
> When you them multiply those window closures times the incidence rate,
> you get around 2 per 10 million, 2 to 3 per 10 million, which would be
> about 3 to 4 per year predicted donations that are missed by minipool
> NAT, that could be interdicted were we doing single unit NAT on an
> annual basis.
>
> \[Slide.\]
>
> Now, there has been discussion, and you will hear some suggestions
> that perhaps we should move the pool size from 16 to 8, or 24 to 6,
> and this is actually the same data as I showed before, but instead of
> on a logarithmic scale, it shows it on a linear scale to give you a
> better sense of why that doesn\'t get you much.
>
> This shows, for HIV, the rate of ramp-up viremia, and for HCV, and
> what you can see here is that going from an assay that has 80 to 40
> copies, so twice the sensitivity, really only gets you a very modest
> closure of the window, because you are in an exponential growth phase
> of the viral load.
>
> So, this just graphically illustrates what I will show you in the next
> slide, which is the statistical analysis of what would you get if,
> instead of testing with Gen-Probe at pools of 16, we went to Gen-Probe
> at pools of 8, or a similar analysis on the right side for Roche if
> you went from the 24-member pools to test the intermediate 6 pools, so
> let\'s just focus on the Gen-Probe because I think that is the assay
> where there is serious discussion about reducing pool size.
>
> \[Slide.\]
>
> What you can see for HIV is that by reducing pool size in half, you
> will only detect 5 per 100 million donations so it is 1 in 20 million
> units would be predicted to be detected by going from a pool size of
> 16 to 8.
>
> In contrast, if you went all the way, and you took it that additional
> 8 individuals, you would pick up an additional 15 per 20
> million\--0.14 per 10 here. The bottom line is you will only pick up 4
> by going all the way from 16 to neat.
>
> If you go from 16 to 8, you will pick up 1 of those 4, from 8 to 4,
> you will pick up a second one, from 4 to 2, a second one, so you will
> only pick up one-quarter of the yield that you would get if you went
> all the way to single unit NAT by going from 16 to 8. That is the big
> message of this analysis with confidence bound, so essentially there
> is not even a statistically significant window closure given all the
> data we have by going from 16 to 8.
>
> \[Slide.\]
>
> This slide is just to emphasize, this is the summary of the risks,
> that pre-NAT, you know, we had risks in around 1 in a million for HIV.
> Post-minipool-NAT, we are down at close to 1 in 2 million, but even
> after we go to indication NAT, because of that low level viremia that
> exists, we think the risk will remain and we will still be talking
> about risks with individual NAT of about 1 in 3 million, so don\'t
> think that by going all the way to individual NAT we will eliminate
> risk, because we won\'t. We will still have breakthrough transmissions
> and still have risk.
>
> \[Slide.\]
>
> This is just one other way that we can estimate the residual risk and
> the impact of going to individual NAT and what we realized is that we
> actually have an unbelievably accurate measure of the rate at which
> donations are being given in this early window period. That is the NAT
> yield that we are picking up.
>
> So, what we realized is if we take the NAT yield rate as observed and
> then we simply factor the NAT yield rate times the relative durations
> of the minipool-positive window and these earlier window periods,
> either the pre-minipool NAT, potentially infectious window, or the
> ID-NAT window, we can calculate out the projected risk with minipool
> NAT or the project yield of individual donation NAT, so a very simple
> calculation of taking the yield of minipool NAT and adjusting it by
> the relative lengths of these window periods allows us to derive an
> independent, but on the next slide you will see a virtually identical
> way of estimating the risk, and they come out almost identical to the
> rates that I presented earlier.
>
> So, we have picked up so far in the first three years, about 145, 145
> HCV yield cases and 10 HIV yield cases. When we take these through
> those calculations, we estimate the same risk factors of about 1 in
> 1.5 million for HCV and 1 in 1.7 million for HIV, and we also can
> predict the yield of ID-NAT going all the way to single unit would
> pick up about 1 in 5 million donations that are currently being
> missed. So, I think strong corroborating data to support the
> predictions that were based on the window period model.
>
> \[Slide.\]
>
> I just want to take a moment, I don\'t have time to go into any
> detail, but just to mention that there are a number of studies that
> demonstrate the relationship between viral load and infectivity. I
> don\'t have time to talk about it, but there is animal studies
> analogous to kind of the studies I showed you, the infection of chimps
> with serial doses of virus or the transfusion of plasma units from
> these window period donors to understand when does infectivity exist.
>
> All of these studies for certainly HBV and HCV indicate that as few as
> 10 viruses transmit 50 percent of the time to chimps, so in my
> opinion, infectivity probably exists. Certainly single unit NAT
> positives are infectious and probably exist even in the low level that
> may exist in a component undetectable by single unit NAT.
>
> \[Slide.\]
>
> Then, the human data, these kinds of cases we are talking about, the
> transmissions from these lookback studies are actually very important
> cases to study to understand that window period infectivity, so we are
> really trying to compile as many of these cases into a national effort
> to get the data and the samples that may exist from these cases to
> build a model and understand infectivity in real humans from
> transfusion of these pe-seroconversion units.
>
> \[Slide.\]
>
> This is what I did want to talk very quickly about, though, if that,
> you know, when we talk about picking up on or two additional
> infections per year, how much does that translate into really health
> care and human savings.
>
> Obviously, for each of these patients that gets infected, it is a
> tragedy, and if we could do it, we should clearly move to individual
> NAT, but just to emphasize that the number of quality life years that
> are lost by virtue of transfusion of an HIV infected unit, because of
> the age of patients, the underlying, you know, morbidity of patients
> that are transfused translates into about seven quality life years for
> HIV and 0.6, so HCV is much less clinically important than HIV from a
> health care outcome perspective.
>
> When you then ask, okay, how many cases will be prevented per year by
> minipool NAT and how many quality life years gained by going to doing
> what we are doing now in minipool NAT. We are really, with current
> minipool NAT, only gaining about 60 quality life years by doing the
> combination HIV-HCV minipool NAT.
>
> By going the next step of introducing single unit NAT, We are only
> going to buy an additional total of about 20 quality life years.
>
> The final slide I will show is this one, which just puts into context
> that as we have moved from introducing the first generation assays in
> this example HIV, we interdicted a very large number, about 1 in
> 10,000 units was infected, and those units were causing 92,000 lost
> quality life years by transfusion of those unscreened units.
>
> Introducing the first generation assay essentially saved 90,000
> quality life years of morbidity and life. In contrast, as we
> progressively move to first generation, second generation, third
> generation antibody assays, closing the window, we really have only
> picked up a few hundred quality life years with each of those
> progressive improvements in the antibody test.
>
> Then, as we bring in antigen or NAT, because there is so little
> residual risk, the incremental gain both in terms of infections
> prevented and in quality life years gained is really extremely modest,
> only about 20.
>
> I think the point here is we have made enormous progress and clearly I
> think there is agreement that we need to get to individual donation
> NAT, but I think the additional gain that we will be gaining by doing
> so is very modest relative to where we have come.
>
> Thank you.
>
> DR. NELSON: There were a number of people wanted to comment.
>
> Dr. Andrew Heaton from Chiron.
>
> **Open Public Hearing**
>
> DR. HEATON: Thank you for the opportunity to review the recent
> introduction of the Chiron Procleix NAT test and the implications for
> a potential reduction in pool size.
>
> During my presentation, I will review Chiron\'s experience in the
> introduction of NAT on a worldwide basis to highlight the implications
> as the committee considers the appropriate pool size for nucleic acid
> testing.
>
> When the Procleix assay was approved in February of 2002, this was the
> conclusion of an extraordinary rapid development cycle from the
> challenge of FDA Commissioner Kessler in 1994 through the NHLBI
> contract in 1997, to the launch of an IND in 1999 of a completely new
> technology. That was an extraordinarily rapid development cycle.
>
> As a result, although the assay was developed very quickly, Chiron and
> Gen-Probe elected to upgrade the original semi-automatic system to an
> enhanced semi-automatic system, and it was this system that was used
> to pursue regulatory approval and is now used routinely by U.S. blood
> centers.
>
> The more fully automated walkaway system for routine testing has taken
> longer to develop with the result that industry is continuing to use
> the original system.
>
> \[Slide.\]
>
> During the period of evaluation under IND, routine blood testing was
> performed in pools of 16 with the remaining samples added at the end
> of each run, but in parallel with the trial, the U.S. military
> initiated individual donor testing, and this data, combined with the
> individual samples, were used to support the claim, which is listed up
> here, which allows both pools of 16 and individual donor testing.
>
> The specificity of the assay was excellent with minimal
> pooling-induced cross-contamination and the sensitivity of both pooled
> and individual donor testing was excellent, and as expected, there was
> a small but measurable improvement in the specificity of those samples
> tested individually.
>
> \[Slide.\]
>
> Assay analytical sensitivity of 30 copies per ml easily exceeded the
> 100 copy per ml design goals on the standards of the FDA, and in pools
> of 16, the assay also meets European and FDA regulatory standards.
>
> The yield reported in the package insert is summarized in this table
> and it has been consistent with the experience of that of most other
> developed countries where similar pool sizes have been used.
>
> \[Slide.\]
>
> In France and Australia, which were two countries that rapidly adopted
> NAT testing, the assay was, and still is, used both in pools and in
> individual testings in the same system using common training systems,
> common procedures, and common applications.
>
> In Australia, the larger centers use pools of 1 and 24, and France\'s
> pool are 1 and 8, and in each system, smaller centers use individual
> donor testing. In practice, the test performance was similar within a
> blood system and the level of false positivity and invalid run rates
> were not significantly different between IDT and minipool for a given
> blood system.
>
> In Australia, there was no evidence that pooling increased initial
> reactive rates and the frequency of true test positivity was similar.
> Consequently, there appears to be no operational difference in test
> performance where individual donor testing is performed in blood
> centers with small collection volumes compared to larger centers in
> the same system.
>
> \[Slide.\]
>
> Summarized in this slide is the Chiron worldwide experience with pool
> sizes. This ranges from individual donor testing in Singapore and
> Portugal to 8 pools in much of Europe, 16 pools in the U.S.A., and 24
> sample pools in Australia and Hong Kong.
>
> \[Slide.\]
>
> Summarized in this slide is the relationship between pool size and
> donation collection volume in blood centers. Although two-thirds of
> the blood centers perform individual donor testing, 75 percent or
> approximately 75 percent of blood is actually tested in pools of 1 and
> 16 or 1 in 24 because the larger centers process such a greater
> proportion of the world\'s blood supply.
>
> Chronologically, there has recently been a trend towards reduced pool
> sizes as new systems have come up.
>
> \[Slide.\]
>
> In order to respond to the requests of industry, Chiron has modeled
> the impact of decreasing pool size. Our model includes workload
> equipment requirements and test requirements and represents a very
> conservative approach, and we believe that blood centers in practice
> would likely improve on this.
>
> As shown in the bottom left of this slide, 1 run of 100 tubes allows
> the generation of 88 results and most centers require a technician to
> pull and complete testing of 1 run since this fits well with the
> average 8-hour work day.
>
> In the case of pooling, while the assay may take approximately 6 hours
> to complete, the pooling adds an addition 2 hours. Subsequently, a
> 2-run processing protocol has been developed and technicians are now
> being trained using this workflow system. This would have the effect
> of decreasing the workload by approximately a factor of 2, and is now
> used routinely in Australia in those centers where IDT is performed.
>
> At the request of the blood bank industry, we assess both IDT and
> pools of 1 and 8 and if you look on the top line, in blood centers of
> 100,000 per year, assuming a work week and consistent sample receipt,
> the model predicts that testing the daily requirements could be
> handled in 1 run per day and pools of 1 and 16 or 1 and 8, and the
> workload would only increase to 2 runs per day or double the workload
> for individual donor testing, which of course explains why the smaller
> blood centers perform individual donor testing.
>
> In the case of large centralized laboratories, testing 1 million or
> more per year, pools of 16 would require 3 runs per day or 2 assay
> technologists, while individual donor testing would require 37 runs
> per day, dramatically increasing personnel requirements.
>
> This does not directly translate into technologist head count
> requirements, since technologists are already being trained to perform
> 2 runs in a shift and centers have begun to adjust the workflow to do
> even better than that through improved staging of the different assay
> processing steps.
>
> \[Slide.\]
>
> Using current eSAS automation for individual donor testing, a
> technician can complete 2 runs in a shift, which depending on the time
> available and the scheduling of the workflow, could as much as double
> equipment requirements.
>
> The additional workflow increases the demand, so the software control
> pipetting devices and the frequent contamination may reduce the
> equipment service life, so there are significant equipment effects.
>
> Since blood centers are under great pressure to minimize turnaround
> time, most samples are tested overnight on the third shift, which
> maximizes simultaneous throughput requirements. Consequently, although
> staggered or sequential shifts would maximize efficiency, concurrent
> assays of common practice to maintain high throughput and minimize
> turnaround times.
>
> In addition, the separate components of the test kits must be stored
> at three different temperatures, placing great demands on
> refrigeration to frozen storage, and since all NAT tests are subject
> to significant contamination risk, special cloth, unidirectional
> workflow, and custom designed facilities are essential to maintain the
> consistency of results.
>
> \[Slide.\]
>
> Consequently, based on modeling, our analysis for the conversion of
> blood centers currently converting testing in pools of 16 to pools of
> 8 would take six to nine months to complete once the decision had been
> made. This would require that all technicians convert to 2-rack
> processing and labor requirements would likely increase by as much as
> 10 to 20 percent.
>
> This could be achieved in less than six months. The key limiting
> factor is the time to rewrite the computer software that controls the
> pipetting devices, the length of the validation, and the length of the
> regulatory cycle.
>
> Although individual donor testing would require much greater increases
> in test reagent manufacture and operating equipment, the longer
> implementation cycle is principally the result of the need for
> additional space buildout of test facilities and the hiring and
> retention of additional staff.
>
> Both Chiron and Gen-Probe would need to expand customer support and
> manufacturing personnel where the customers will need to identify
> additional assay personnel who must often meet extremely demanding
> State requirements for the performance of complex laboratory testing.
>
> A limiting factor in this conversion is that of personnel since
> equipment and reagent needs could be met in a six- to nine-month, but
> the personnel and space requirements would take longer.
>
> \[Slide.\]
>
> In order to facilitate the assay performance, upgrades are planned for
> the Procleix System. These include automation of the reagent and
> addition steps which are currently handled manually.
>
> The automation, which is anticipated to be available for trial in
> approximately 12 months, would also assist in recordkeeping and
> process control. The second upgrade would automate the addition of
> target capture reagents and the subsequent wash steps, and further
> upgrades of the luminometer and software are also planned to follow
> the first two steps.
>
> For the long term, the fully automated Procleix automated system being
> developed as the TIGRIS by Gen-Probe is expected to enter clinical
> trials by the end of 2003. Consequently, there are both mid-term and
> long-term automation plans which would support the introduction of
> reduced pool sizes.
>
> \[Slide.\]
>
> In summary, I hope that I have been able to provide a review of
> worldwide testing practices using the assay. The systems achieve
> turnaround times comparable to the immuno tests. Clearly, blood center
> test volumes have influenced the pool sizes.
>
> A transition to smaller pool sizes or individual donor testing is
> clearly possible and Chiron and Gen-Prove anticipate being able to
> meet reagent and equipment demands rapidly. A limiting factor is for
> testing pools of 8 is the existing eSAS System and the time to
> rewrite, validate, and secure approval of the pooling software.
>
> In the case of individual donor testing, the limiting factor is
> identifying appropriate facilities to support the specialized
> equipment and staffing needs together with the time required to train
> the personnel.
>
> Midlife improvements to the current system are in process and walkaway
> automated system will be available by the end of the next year. This
> combination should allow the transition to reduce pool size or
> individual donor testing based on the needs of industry.
>
> The development cycle has already greatly benefited from a
> collaborative relationship between the FDA, NHLBI, Chiron, and
> Gen-Probe, and Chiron stands ready to assist the policy makers in
> their decision of the pool size of choice.
>
> Thank you.
>
> DR. NELSON: Thank you, Dr. Heaton.
>
> Next is Karen Long from Roche. Is Karen Long here?
>
> DR. GALLARDA: I am not Karen Long.
>
> DR. NELSON: You don\'t look like Karen Long. I am Jim Gallarda. I am
> Director for Blood Screening at Roche Molecular Systems, and I will be
> giving a synopsis of our assessment of the situation.
>
> \[Slide.\]
>
> I want to thank FDA for allowing us to participate in today\'s
> discussion. We have been asked to address two general areas. The first
> is what are the current constraints in doing single unit testing using
> the COBAS AmpliScreen System that Roche has developed, and secondly,
> what are our future plans for our single unit testing program.
>
> \[Slide.\]
>
> In answer to the single unit nucleic acid testing question with the
> current system, can it be done? The simple answer is yes, but it has a
> string of caveats associated with it.
>
> Our system has been designed to a three-tiered algorithm to do either
> pools of 24, which resolve through secondary pools of 6, which are
> then resolved at the tertiary level to single unit. We provided data
> in our submissions demonstrating this fact.
>
> The implementation issues associated with the current system to be
> used as single unit NAT testing are rather complex, and I have just
> listed a few of them.
>
> Mike Busch has given a very lucid explanation about the incremental
> yield that one can expect with single unit NAT, and this has to be
> viewed in the context of what are the labor resources, both
> availability of trained labor and the cost to implement single unit
> testing with the current semi-automated systems, and also it should be
> viewed in the context of the additional risk of documentation errors
> or other type of errors that are due to the increased testing demands.
>
> \[Slide.\]
>
> Dr. Hewlett mentioned earlier in her talk that in 1994, we kicked off
> to a discussion of how to capitalize on the power of NAT to interdict
> infectious units that were in the pre-seroconversion window period.
>
> Retrospectively, looking at what happened, this has been a success
> story for both programs. For the COBAS AmpliScreen system, in our
> submission, we cited that we had over 40 HCV window period cases that
> were successfully interdicted using minipools of 24, and for HIV,
> there were three window period cases that were interdicted, again
> using pools of 24, and we just learned this morning that in our
> currently IND for the HBV clinical trials, we screened for three weeks
> now, 40,000 samples, and we have identified our first window case for
> HBV.
>
> So, the good news is the current system, semi-automated, has done a
> good job.
>
> \[Slide.\]
>
> Going to a single unit discussion, the incremental yield, the fact is
> that yes, we are all I believe in agreement, let\'s head towards
> single unit testing. Having said that, Mike has shown that it will be
> an incremental yield, but there will be, in the blip area of the
> eclipse phase of the pre-seroconversion infectious time period,
> samples that are infectious, that cannot be detected even with single
> unit, so we will not have a zero risk blood supply even with single
> unit testing.
>
> \[Slide.\]
>
> The workload issues with the current system. Both systems are
> semi-automated. They require substantial manual labor, and it is our
> view that higher workload may lead to increased operator error, and I
> might say that this is not simply Roche\'s opinion. This has been
> validated with the practitioners of NAT in the country.
>
> \[Slide.\]
>
> Potential risks. A 16 to 24-fold increase in a single unit scenario
> with the current systems could create inventory shortages. We don\'t
> know, but it is a plausible scenario.
>
> \[Slide.\]
>
> There is a shortage of skilled medical technologists in general
> required for the rather complex NAT testing in the semi-automated
> systems.
>
> \[Slide.\]
>
> So, our view is that for sure with our system, we feel that it is not
> the best approach to go to single unit testing with the semi-automated
> systems. So, I would like to switch gears to the next topic, and that
> is what are we doing about this.
>
> It is our view, Roche\'s view, that we should invest heavily into a
> fully automated single unit system for the three viruses now that are
> being screened.
>
> \[Slide.\]
>
> I just want to say that we are putting out eggs into a basket, and
> that basket is to develop a sample in, results out, high throughput
> system for a multiplex detection of the three viruses that are mainly
> being screened for currently.
>
> \[Slide.\]
>
> Our strategy for a single unit system is to really rely on what we
> have already historically proven an aptitude for, and that is what I
> would call as our core competencies.
>
> \[Slide.\]
>
> We have developed a robust back-end PCR walkaway machine, the COBAS
> Amplicor Analyzer. The users in our clinical trial all agree that this
> is probably the most robust element of our system.
>
> So, we have a very excellent Swiss engineering firm that has designed
> complex instrumentation for such type of testing.
>
> \[Slide.\]
>
> We have a very promising program in Japan where the Japanese Red Cross
> has been using a system that we call the AMPLINAT system. The front
> end of that is our GT-X automated sampler extraction device, and this
> is being used to extract simultaneously all three viruses in a
> multiplex format.
>
> \[Slide.\]
>
> On the back end, we have a lot of experience developing complex TaqMan
> master-mix reagents for the simultaneous detection of the three
> viruses. So, our core competencies cover the hardware and associated
> software for complex instrumentation, and our reagent groups have
> experience in developing field-proven multiplex reactions for
> multiplex detection of the three viruses.
>
> \[Slide.\]
>
> I will just go over a couple of slides, what are the critical customer
> requirements.
>
> \[Slide.\]
>
> The first one is it has to be able to fit into their routine workflow.
> It must be the ability to have sufficient automation to reduce
> operator involvement and associated human errors, and, of course, have
> positive ID throughout the entire process.
>
> \[Slide.\]
>
> So, we have a large program with very large teams in multiple
> countries working on an automated solution for extraction and
> simultaneous amplification detection.
>
> \[Slide.\]
>
> It should be able to handle single unit testing with minimal increase
> in labor requirements, and importantly, the ability to process at
> small and large centers, the same number of donations that would be
> covered in the time period in our current 24-pool system.
>
> \[Slide.\]
>
> It will be a multiplex assay covering HIV-1, HCV, and HBV. The system
> will provide for general menu expansion. We are actually looking at
> Parvo B19, HAV, CMV, and most recently, looking at West Nile virus.
>
> Full process control both for the target analyze, as well as the
> hardware critical control processes, and, as I mentioned, positive ID.
>
> \[Slide.\]
>
> There have been some discussions about alternatives, and we view these
> as second choice alternatives to a fully automated system, but they
> are things that we are looking at. We can go to pools of 6 with the
> manual sample prep. You don\'t have a 24-fold increase in problems,
> you have a 4-fold increase in problems.
>
> Back up one slide, please.
>
> \[Slide.\]
>
> We have several systems, in Japan, as I mentioned already, and other
> diagnostic applications that are automated sample preparation devices.
> These are not currently being pursued for licensure in the U.S.,
> however, that is something that Roche conceivably could move to.
>
> \[Slide.\]
>
> So, in conclusion, we believe strongly that moving to single unit NAT
> with the current semi-automated systems may pose a greater risk than
> the benefit provided, and that single unit NAT is best accomplished by
> aggressively pursuing and devoting sufficient resources to create
> these high throughput, fully automated systems.
>
> Finally, we believe that we have got experience, tested experience in
> developing complex systems and reagents to meet the interim and
> long-term needs.
>
> Thank you very much.
>
> DR. NELSON: Thank you.
>
> The next group that wanted to speak is from Gen-Probe. Dr. Sherrol
> McDonough.
>
> DR. McDONOUGH: Hopefully, we will get the slides going in a moment.
>
> I will be continuing the discussion on the Procleix System and I am
> really going to cover two topics. The first is the manufacturing
> facility that Gen-probe has built to address the ability to
> manufacture reagents.
>
> The second will be our fully automated system, Procleix Automated
> System or TIGRIS.
>
> \[Slide.\]
>
> This is a picture of our facility in the San Diego area. It was
> commissioned for use in 1999. It was designed and built specifically
> for the production of nucleic acid testing reagents and was used to
> build conformance labs for the HIV-HCV product. It was licensed in
> February of this year, and when we look at the capacity, we believe
> that we could adjust to the market requirements whether that is a move
> to pools of 8 or movement to individual donation testing in a period
> of 6 to 7 months from the time the decision was made.
>
> \[Slide.\]
>
> Now, I would like to talk about the fully automated instrument.
>
> \[Slide.\]
>
> Some of the design features of the automated system are listed on this
> slide. First of all, primary tubes can be loaded directly. There is no
> requirement for an ultra-centrifugation step or any serious manual
> steps.
>
> 180 tubes can be loaded on the instrument at a time. The instrument
> creates a worklist by scanning those bar codes, so that is all done
> automatically.
>
> Once the sample processing begins and the first 180 tubes have been
> sampled, they can be removed from the instrument and another 180 tubes
> can be added.
>
> When you start the day, you can put out enough reagents and fluids to
> do 1,000 tests. At that point, you need to stop, remove the wastes,
> and replenish the fluids.
>
> \[Slide.\]
>
> The Procleix System is a single tube assay. That means all the steps
> from sampling processing, amplification, and detection are performed
> in the same reaction tube, so there is no need for the instrument to
> transfer from one reaction vessel to another during the entire
> process.
>
> That helps maintain specimen I.D. and also reduces a source of
> contamination within the instrument.
>
> The productivity targets for this instrument are to have time to first
> result about 3.5 hours and then 125 test results released per hour
> thereafter. We are developing multiplex tests, for example, for our
> HIV/HCV tests, that would be 250 results per hour, 125 results for HIV
> and 1 25 results for HCV.
>
> The instruments maintains full traceability through positive
> identification of the specimens, and the assay performance will be
> comparable to that seen in the already licensed system.
>
> \[Slide.\]
>
> This is a picture of the instrument. It looks big here, but it
> actually takes up much less room than the semi-automated system, so if
> a laboratory has space for the semi-automated, they will have space
> for this instrument.
>
> Specimens are loaded in the bay that is shown open on the right side
> of the instrument. Reagents are loaded on the top left. All the sample
> processing occurs in that middle part of the instrument. All of the
> assay performance steps are performed there, and the intervention is
> through the computer on the right.
>
> \[Slide.\]
>
> The development timeline for this instrument is as follows: We are to
> the point in development where we are doing evaluations with
> customers. I am happy to report that we have already performed an
> evaluation with customers for the diagnostic side. The instrument is
> being developed for both diagnostic and blood screening applications.
>
> So, the initial evaluation with customers was completed earlier this
> year, and we are in the process of setting up the evaluation with
> blood center customers, and that will take place in fourth quarter.
>
> As you already heard, the goal is to start the clinical trials on this
> instrument at the end of 2003.
>
> \[Slide.\]
>
> So, in conclusion, we have a manufacturing facility specific for
> nucleic acid testing reagents with capacity up to 100 million tests
> per year.
>
> The automated system will give results similar to the semi-automated
> system that is available now. The instrument will reduce personnel
> time and increase adherence to GMP by performing many of the steps
> that have to be done by humans now, such as worklist creation, correct
> placement of Cals and Controls, ensuring use of master-lotted
> materials, in-date materials, et cetera.
>
> Thanks for the opportunity to present.
>
> DR. NELSON: Thank you, Dr. McDonough.
>
> Dr. Gilcher from Oklahoma.
>
> DR. GILCHER: What I want to talk about briefly, very briefly, is an
> overview of nucleic acid testing at the Oklahoma Blood Institute. We
> began in April of 1999 using HCV-RNA-PCR with a minipool of 24.
>
> In November of 1999, we added then HIV-RNA-PCR at a minipool of 24. In
> March of 2000, we set up a separate HIV-HCV-RNA-TMA, that is a
> Chiron/Gen-Probe laboratory as a minipool of 16 to compare workflow of
> the minipool PCR versus the minipooled TMA, and assuming at 100,000
> donations, the PCR would be 8,333 tests. The TMA would be 6,250 tests.
>
> \[Slide.\]
>
> In running that particular study, and it was a study for workflow, our
> conclusions were that for a large laboratory, and our collections at
> that time were about 170, 175,000. We will do over 200,000 donations
> this year that will be tested by NAT.
>
> For a large lab, over 100,000 TMA-enhanced laboratory workflow as far
> as NAT testing operations.
>
> On July 1st of 2002, we then switched to single donation nucleic acid
> testing as our test of record at OBI. So we have, in a sense, done
> both the minipool PCR, the minipool TMA, and now the single donor or
> the ID TMA.
>
> \[Slide.\]
>
> There is a particular case that I want to talk about. We have not had
> any forward misses or front-end misses as we have heard about, and I
> will mention that in a moment, but we have had an interesting, what I
> call \"back end\" miss.
>
> This occurred on February the 9th of 2000. We had an EIA and Western
> blot-positive HIV donation, which was minipool PCR-negative at a 1 to
> 24. The same donation sample, that is, a frozen sample that was tested
> 21 days later, and that is important that it was the same sample, and
> it was frozen and thawed, and that is important.
>
> I thought Dr. Busch might talk about the concerns of aggregation, but
> that doesn\'t seem to be the case here, because testing that thawed
> sample by minipool PCR at 1 to 24, it was still negative. We did a 1
> to 16, it was negative, but the \"Neat\" was, in fact, PCR-positive.
>
> \[Slide.\]
>
> There are a number of objections to single donor NAT that you have
> heard about - too costly, too much space, too many technologists,
> possibility of increase human errors, lack of total automation,
> increased opportunity for contamination, increased run failure rate,
> increased delay, and inventory release. All of those were concerns
> that we had when we addressed the issue of single donor NAT.
>
> \[Slide.\]
>
> These are our reasons that we made the switch. First, was the \"Back
> end\" miss that I showed you with HIV, and by the way, there have been
> a number of those with HCV.
>
> Then, the reported HIV \"front end\" misses that you have heard about,
> the San Antonio, later the Tampa case. There is one in France. There
> is the Singapore case.
>
> Then, the third point was that we had operational challenges, and we
> felt that we could overcome those. We overcame the issue on cost,
> space, technologists, compliance, test performance, and obviously
> operational impact.
>
> When presented to our Board, they felt that for us in Oklahoma, that
> it was the right thing to do.
>
> \[Slide.\]
>
> The cost was justified by the elimination of HIV antigen, the absence
> of pool discrimination, and that is extremely important because that
> resulted in the capture of lost products, and the objection that is
> made that it will delay the release is simply not true. In fact, we
> are able to capture platelets that would have clearly been lost during
> the discrimination period, because our discrimination is a pool size
> of one, then, other cost reduction measures that were introduced at
> the blood center.
>
> To accommodate this, we built two mirror image laboratories, each with
> the potential capacity for up to 500,000 single donor tests.
>
> Now, the numbers of techs that we had to hire is important. We went
> from 4 with our minipool to 10 for the single donor NAT, and those 10,
> it is estimated can perform up to the 250,000 tests. To do 500,000,
> obviously, we would have to increase significantly.
>
> 180,000 donations then tested by the minipool would be 15,000 tests by
> PCR, whereas, the single donor TMA was 180,000 tests or 12 times as
> many tests for us as what we had been doing.
>
> \[Slide.\]
>
> No pooling steps - reduces the time to do the NAT. There is clearly a
> faster turnaround time. There is, in our opinion, less chance for
> error without the pooling. There is the same degree of manual testing
> as with the minipool. Clearly, we would like more automation.
>
> Testing time is faster by getting rid of the pooling, and this is very
> important, laboratory operations return to a single test platform, and
> Kendra Ford has accompanied me here today, the Vice President of
> Operations, who can talk more about that if you have questions
> afterward. That is an important point.
>
> \[Slide.\]
>
> This is really our learning curve that I am demonstrating here. This
> is the Chiron validity statistics. When we started out, you can see we
> have a very high invalid run rate, the purple line.
>
> That was a number of factors. One of the most important factors for us
> was an environmental factor that we had not expected. We built the two
> new laboratories that I told you about, and inadvertently, the plumber
> hooked up the drain lines to the wrong system, and we had a sump pump
> pumping backward.
>
> We had the second lab which we have not used contaminated before we
> entered the lab, and finally figured it out. So, that is included in
> that. But our invalid run rate has come down and continues to come
> down. That is a learning curve.
>
> \[Slide.\]
>
> So, lessons learned. The total space for the two labs interestingly,
> without pooling taking up that space, is only slightly larger than the
> prior space. 180,000 donations is 15,000, as I mentioned before, with
> PCR minipool versus 180,000 tests with single donor TMA or 12 times
> more tests, but with only 2.5 times as many technologists to perform
> the tests.
>
> Detraining of existing technologists to convert from PCR to TMA was
> absolutely critical in our system. It was easier to train
> technologists who had not performed NAT testing ever than to take
> techs who had done the test and detrained them, and then trained them
> on a different test.
>
> Clearly, as I said before, it is easier to operate in a single test
> environment versus a pooled test environment.
>
> So, for us at the Oklahoma Blood Institute, we are doing individual
> donor nucleic acid testing, and we are making it work.
>
> Thank you.
>
> DR. NELSON: Thank you. Comments? Did you have viral load on the one
> case that was the back end failure?
>
> DR. GILCHER: Excellent question. We don\'t, but we have sample. One
> thing that we do at the Blood Institute is we maintain two years plus
> the current year as repository samples, so we have repository samples
> on everything, and that is something that will be done.
>
> DR. NELSON: Susan Stramer, American Red Cross.
>
> DR. STRAMER: Thank you for those who are left. I don\'t even know if
> we have a quorum, if it\'s legal to have a meeting.
>
> Even so, I will read my statement. Thank you very much.
>
> I am Susan Stramer, the Executive Scientific Officer for the American
> Red Cross.
>
> The American Red Cross through its 36 regions and nine testing
> laboratories supplies approximately one-half of the nation\'s blood
> for transfusion needs. We thank the FDA and the Blood Products
> Advisory Committee for this opportunity to speak on the implementation
> of single unit NAT to reduce the remaining risk of HIV transmission
> through transfusion.
>
> I see I am clearing the room.
>
> Recognizing the potential significance of NAT for HIV and HCV, the Red
> Cross initially began exploring the implementation of NAT in 1997
> using pools of 512, in an approach similar to that used by much of the
> plasma industry.
>
> However, to achieve the needed turnaround times for the release of
> cellular components, we instead implemented the Gen-Probe test in
> March 1999, first in pools of 128, followed in 6 months by the
> transition to pools of 16.
>
> We recognize that NAT implementation represents a step-wise
> progression towards an automated technology using individual units. We
> greatly supported the industry-wide effort to implement NAT under IND
> and were pleased to participate in the studies in support of NAT
> licensure.
>
> Over the past three-plus years of NAT screening for HIV-1 and HCV, the
> Red Cross has detected 90 HCV NAT confirmed-positive,
> antibody-negative units in approximately 23 million donations screened
> for a yield of 1 in 240,000 and 5 HIV NAT confirmed-positive,
> antibody-negative units, of which only one was HIV p24 antigen
> positive for a yield of 1 in 4.6 million.
>
> Viral loads at index for the HCV yield cases ranged from 100 copies/ml
> to 190 million copies/ml; viral loads for the HIV yield cases ranged
> from 390 to 750,000 copies/ml.
>
> At an approximate sensitivity of 30 copies/ml, at 95 percent
> confidence for the Gen-Probe test, as indicated in the package insert,
> and using a pool of 16, the expected viral load reliably detected is
> estimated at 480 copies/ml.
>
> Three HCV yield cases and one HIV yield case were each detected below
> this level. We recognize that we were lucky in these four cases, and
> as experience has now demonstrated, there will be breakthrough cases
> of HIV and HCV with viral loads around or below the assay cutoff that
> we are using today, which is set by our pool size.
>
> We also recognize that when the same assays are used to test
> individual units, there will be cases where the viral levels will be
> below 30 copies/ml and perhaps below 1 copy/ml, so that the
> expectation that NAT will detect all infectious units even with single
> unit testing is likely to be in error.
>
> Recent data also indicate that the residual risk for both HIV and HCV
> following the implementation of pooled NAT is approximately 1 in 2
> million donations and that with the additional sensitivity of single
> unit NAT, the residual risk is estimated at 1 in 3 million.
>
> So, the question that is before us is: what approaches, if any, can be
> implemented during the time between our current use of pooled NAT for
> HIV and HCV using the available technology and an automated assay that
> has sufficient throughput and process control such that single unit
> NAT is feasible in high-volume laboratories.
>
> The current testing technology, although labeled as semi-automated, is
> for the most part manual with numerous manual pipetting steps for both
> sample and reagent addition and removal, along with many manual
> vortexing and incubation steps.
>
> Processes are segregated in separate laboratories for pooling,
> amplification and detection, all of which required significant
> laboratory renovation prior to the implementation of NAT.
>
> Even with all that has gone into implementing and performing NAT, this
> assay has performed equal to, or better than, any other test used in
> our system as evidenced by donor losses due to contamination of less
> than 1 in 30,000.
>
> Therefore, given the systems that are available today, pooled NAT has
> been optimized and is a success. I would also like to mention this was
> true even after the outpouring of donations after last year\'s 9/11
> tragedy when our volume doubled by 2- and 3-fold, our error rate and
> contamination rate virtually was unchanged.
>
> What can we learn from the four donors with early HIV infection that
> have been reported to have transmitted HIV to recipients of their
> donation? The first case from Singapore that was p24 antigen-negative
> has been discussed already; in dilutional studies using the frozen
> plasma unit it was shown that detection decreased as pool size
> increased.
>
> HIV detection using the Gen-Probe assay in a pool of 24 occurred in 2
> of 3 replicates tested; using pools of 16, 1 of 3 replicates were
> reactive and using pools of 8, all 3 replicates were reactive.
>
> The second case from South Texas from which a pool of 24 failed to
> detect HIV RNA by an in-house assay was also discussed. In this case,
> dilutional studies showed that using the Gen-Probe assay on the frozen
> plasma unit, 1 of the 3 replicates was reactive at a 1 and 24
> dilution, whereas all 3 replicates were reactive at a 1 to 8 and 1 to
> 16 dilution.
>
> Therefore, the Gen-Probe assay using undiluted samples, or a dilution
> of 1 to 8, was able to detect HIV RNA in all replicates tested from
> these two cases. The last two cases of failure of pooled NAT to detect
> HIV RNA did not have residual sample from which to perform these types
> of studies, that is, the case reported from South Florida that was
> negative by the Gen-Probe assay in a pool of 16 and a case reported by
> the French in which the Roche assay in a pool of 24 was negative.
>
> So, although the estimated window period reduction with each pool size
> reduction of one-half is one doubling time, or just under 1 day of an
> estimated total 4-day window period to individual unit NAT, one could
> argue that a decrease in pool size will increase the reliability of
> detection of samples having viral loads close to the current assay
> cutoff, and will likely detect additional cases where the viral loads
> are below the level that we are currently capable of detecting.
>
> However, it should be recognized that neither a decrease in pool size,
> nor addition of single unit testing will completely close the
> infectious HIV window.
>
> The paradigm of step-wise improvements in assay sensitivity leading to
> an automated platform is not new to NAT. It has occurred for every
> virus for which we perform blood donor screening. Some changes were as
> simple as a reduction in assay cutoff to achieve increased
> sensitivity.
>
> If we look to our antibody screening systems as a model, we have still
> not implemented an automated testing system with improved assay
> sensitivity and specificity and all the desired process control
> features to minimize documentation and other potential errors.
>
> For example, the PRISM system has been in development for over 15
> years and although used outside of the United States, we are still
> waiting for licensure and implementation in the U.S.
>
> Therefore, a comparable automated NAT platform may be years away;
> consequently, we must examine all that can be done within our current
> systems to achieve whatever improvements in sensitivity are possible.
>
> There are many variables that would have to be considered prior to a
> transition to a smaller pool size. Does the small increase in
> sensitivity justify the changes that would be required for this single
> modification? This would include the hiring and training of additional
> staff and additional costs for disposables not related to reagents.
>
> Additional costs for upgrades to, and validation of, the automated
> pipetting system and upgrades to our NAT laboratory management
> software including 510(k) submissions and approvals would also be
> required. Regarding reagent costs, blood centers have invested an
> unparalleled amount for this technology.
>
> There likely will be an increase in reagent price of an unknown amount
> at this time that could be mitigated by volume. Decreasing pool size
> could occur without the need for additional testing equipment or
> laboratory renovation, but the total costs are unknown at this time.
>
> In summary, data show that single donor testing could enhance our
> ability to detect window period donations. In the interim, a reduction
> in pool size may have some impact on safety by increasing the
> reliability of detection of some samples.
>
> At the present time, the Red Cross is looking into the option of
> decreasing pool size, but no decision will be made until all variables
> related to this effort have been reviewed.
>
> But if a reduction in pool size occurs, we believe that it could occur
> without compromising the quality or efficiency of testing. We will
> then have considered all that may be done within the current systems
> and available technology until automated single unit NAT is available.
>
> Thank you.
>
> DR. NELSON: Thank you.
>
> Next is Dr. Paul Holland.
>
> DR. HOLLAND: Thank you. I am Paul Holland from Blood Source, a large
> regional blood center in Sacramento, and is a regional NAT testing lab
> for our own collections in two other centers.
>
> I had sent in a few slides to make the three points I wanted to make,
> but I believe you have the handouts, and I will describe pretty
> briefly because of the time.
>
> I wanted to discuss the elements of the testing, and as Dr. Stramer
> pointed out, they are often described as semi-automated, they are very
> manual.
>
> The second point I wanted to talk about is the reliability. While
> these nucleic acid technology tests are fantastic in terms of
> sensitivity and specificity, they are no more reliable in terms of
> failure rates than our standard serologic EIA tests.
>
> I want to end up briefly with my concerns regarding reducing the pool
> size or even going to individual NATs, because of the concerns, and I
> will point out that they are real, of the staffing, of the burnout of
> that staff, and of the errors which result.
>
> As I said, a lot of the testing is already quite manual. This means a
> lot of meticulous, repetitive motion, and the single biggest problem
> we have is burnout of the staff. I recently visited Singapore where I
> was there for 10 days evaluating their system, and they are testing
> 60,000 units a year by single unit NAT, and that is their single
> biggest problem is constantly having to rotate technologists through
> to do this repetitive, highly meticulous type of work.
>
> In California, we require licensed medical technologists, not techs,
> licensed medical technologists to do laboratory tests. We are already
> in a critical shortage. We would not be able to do the kind of testing
> that would be required with single unit testing.
>
> We already have to constantly supplement the NAT lab staff where we
> run two runs a day, five days a week, and a run on each day on Sunday
> to have enough staff to complete the testing now with mini-pools.
>
> I mentioned the failure rates. The impression I think some of you have
> gotten is that a false negative is purely due to low copy number, and
> that individual NAT may pick up at least some of these, but clearly
> not all.
>
> In our evaluation from the Roche survey, in looking at failed runs,
> our false negative samples that should have been picked up in the
> pool, half of the time the level of virus was far above what should
> have been detected in the pool, but we believe due to technical error
> it was missed.
>
> I have given you some data. Anywhere from 3 to 4 percent of runs fail
> because of the positive or negative external controls fail or the
> internal control fails. Included in this failure rate is also
> equipment failure and technical failure. People are human and they are
> doing a lot of us manually.
>
> So, about 4 to 5 percent of the time, each one of our tests fails, and
> when you are doing a dozen different tests, almost every run is held
> up because either a serologic test or a NAT has failed and has to be
> repeated.
>
> This causes additional stress in a production environment and really
> would be I think magnified by single unit or even smaller pool
> testing. In essence, without further automation and without validation
> and licensure of that automation, I think it would be foolhardy, I
> think we would add to our problems, and potentially create more risk
> than the very minimal decrease in risk that might be bought without
> going to zero risk, with single unit or even smaller pool testing.
>
> Thank you.
>
> DR. NELSON: Thank you. Comments? Toby.
>
> DR. SIMON: I just wanted to make just a couple of comments, mostly I
> guess at this point to get it on the record, but I think to put things
> in context, we need to remember that the pooled NAT method was
> originally developed for plasma fractionation and it was spurred on by
> a requirement in Europe for HCV testing because of that longer window,
> and the pooled NAT made a lot of sense for plasma because of the
> inactivation procedure, the occasional unit that is missed doesn\'t
> cause a serious problem.
>
> The blood banks I think originally got in because of selling of plasma
> into Europe, and then I think everybody recognized the possible
> benefits to the patients who received transfusion, and that increased
> the momentum.
>
> I think from the beginning we realized here we were talking about a
> unit here or a unit there, and single unit NAT made a lot of sense,
> and was the ultimate goal, but couldn\'t be achieved immediately, so
> the pooled NAT was better than nothing.
>
> I think from what we have seen here, my thought would be we will
> certainly save a case here or case there, but we are making another
> one of these small incremental steps, and as I said before, until we
> really get pathogen inactivation, we are still going to occasionally
> have these cases that get through the system and tragically cause
> disease.
>
> I think people, Dr. Gilcher and others who want to lead the way in
> single unit NAT obviously can do so providing they file the
> appropriate INDs, but I don\'t think it is a time necessarily for the
> committee or FDA to try to mandate this path until we see how
> technology moves and how things progress. That would be kind of the
> sense that I would take away from what I have heard.
>
> DR. NELSON: I think that plus the review of the fact that we have had
> some still rare documented cases that pass through even with the
> pooled NAT.
>
> DR. SIMON: We knew that, though, as Dr. Gilcher pointed out, we knew
> that was going to happen.
>
> DR. NELSON: Yes, we did, but our suspicions were validated, but again
> we were able to pick up these few cases.
>
> DR. SIMON: We picked up some.
>
> DR. NELSON: Some of them, yes.
>
> DR. SIMON: We picked up some of them and not others, and that will
> continue even with the three- or four-day further closing of the
> window, there will be that occasional case, but obviously, if I were
> the recipient of that 1 in a million cases, I would be appreciative of
> the single donor NAT, but over the aggregate, it is a very small
> effect.
>
> DR. SCHMIDT: Ron Gilcher, who is certainly dedicated to stamping out
> every vestige of disease, has pointed out to us in his statement
> something mentioned earlier. He had to sell it to his board of
> directors because again we are all committed to stamping out every
> element of disease, but when you get into the local community, it is a
> question of can we still exist.
>
> Now, I know it is not the function of the FDA to talk about cost,
> however, cost relates to supply, and as I understand it, they were
> reminded recently by the Senate Appropriations Committee that maybe
> some of the idea of keeping prions out of New York might result in no
> blood for New York, so for whatever that is worth, I mean there is a
> sort of a kickback here, and although the individual patient, you
> know, it happens to a patient, it\'s 100 percent.
>
> The community that provides blood has something to say about it, as
> well.
>
> DR. NELSON: Celso Bianco from America\'s Blood Centers.
>
> DR. BIANCO: I am Celso Bianco from America\'s Blood Centers.
>
> As you know, this is an organization of 75 member centers that collect
> about half of the U.S. blood supply. You have copies of my statement,
> so I am going to skip about half of it because it would just reiterate
> the effect, all the difficulties with moving from mini-pool testing to
> individual donor testing using the current technology, semi-automated
> or semi-manual.
>
> However, I would like to read the part from the middle where we start
> discussing intermediate changes in pool size. I also would like to
> note that Dr. Gilcher, that just spoke and presented his change, is a
> member of America\'s Blood Centers and decided to implement single
> donor NAT.
>
> Besides the concerns about the movement to single donor NAT
> contamination, staff burnout, and all the issues that were raised here
> today, we are also very disturbed by the proposals to implement
> partial reductions of pool size as interim measures, simply to
> reassure the public. Those were comments that were made by the
> members.
>
> We introduced minipool testing as an intermediate step in order to
> further reduce the window. We knew from the beginning that the window
> would not be totally closed and accepted, and this was the best we
> could do considering the limitations of semi-automated technology.
>
> We also know that individual donor testing will reduce , but not close
> the window. What changed today that forces us to reconsider the
> approach we took when we introduced NAT in 1999?
>
> We used the same tests, we have essentially the same knowledge that we
> had at that time, but however, because of these few cases of
> transmissions and concerns in the press, we are reconsidering our
> thinking.
>
> A reduction of pool size by half, as some have proposed, to 8 samples
> instead of 16, or 12 samples instead of 24, according to what Dr.
> Busch just showed us, would reduce the window by less than a day.
>
> The reduction of pool size might be feasible for certain testing
> laboratories, it would not achieve the goals of individual testing.
> Furthermore, intermediate reductions of pool size are not clearly
> justifiable.
>
> Why reduce by half? Why not go to a pool size of 2 or 1? Why not
> double the sample volume whether in pools or in single donation
> testing, and thereby double the amount of potentially detectable
> nucleic acid.
>
> There is no rational limit to this kind of thinking.
>
> It is the opinion of the majority of the ABC members that any decrease
> in the window period that may result from the reduction in pool size
> or a move towards individual donor testing using current technologies
> could be neutralized by the potential increase in human error during
> the performance of manual steps. There is also an increased potential
> for delays in the release of blood that may threaten the patients\'
> lives.
>
> Furthermore, we are concerned that such intermediate and small safety
> improvements will divert assay manufacturers, and I think that this is
> the different message that I would like to emphasize from the pressure
> to develop automation and test enhancements in a timely fashion.
>
> Without that pressure, the current semi-automated technologies may
> remain as state-of-the-art for many years to come. For instance, one
> of the test manufacturers has been advocating for migration to
> individual donor testing using current technology.
>
> It will actually not support minipool testing for centers that screen
> less than 100,000 samples a year. This manufacturer, Gen-Probe/Chiron,
> received an NHLBI contract in 1995 to develop NAT for HIV and HCV, and
> an automated instrument for the TIGRIS that we just heard about.
>
> Seven years later, we heard today, and this is a change here, that the
> instrument will be in clinical trials by the end of next year. Why
> should they continue to work on this equipment if they could sell
> individual donor testing using the current semi-automated or
> semi-manual technology?
>
> Roche is one of the biggest manufacturers of assay systems in the
> world. There are European centers performing NAT for donor screening
> with automated instruments provided by Roche. Why aren\'t these
> systems available in the U.S.?
>
> The ABC members urge Gen-Probe/Chiron and Roche to continue their
> productive collaboration with the transfusion medicine community and
> apply the maximum possible efforts and resources to the final
> development and validation of automated systems for donor screening by
> NAT in the United States.
>
> You are almost there. Please, get there. We also urge FDA to
> accelerate the review, and we heard Dr. Indira Hewlett commit herself
> to that, to accelerate the review of these instruments in order to
> allow fully automated NAT screening to start as soon as possible.
>
> Thank you.
>
> DR. NELSON: Thank you.
>
> Finally, Kay Gregory from the American Association of Blood Banks.
>
> MS. GREGORY: Again, in the interests of time, I will abbreviate my
> statement, but I would like to request that both of my statements be
> reflected in the transcript in their entirety.
>
> The American Association of Blood Banks believes that the blood
> community, the Food and Drug Administration, and manufacturers should
> move with deliberate speed to bring single donor nucleic acid
> amplification testing to donor screening laboratories throughout the
> United States.
>
> The community has made significant progress in improving blood safety
> through nucleic acid testing of minipools. Now, we should continue our
> efforts by moving toward our goal of single donor testing.
>
> Although some laboratories may be in a position to implement
> additional NAT improvements now, it is important that these
> initiatives not divert resources from the ultimate goal of nationwide
> NAT performed on automated systems.
>
> Prior to the implementation of single donor NAT, it is critical that
> the following issues be addressed:
>
> Both the licensed and IND NAT assays are substantially manual
> procedures not suited to single donor testing in the majority of blood
> center labs performing NAT now.
>
> At present, these is insufficient capacity in existing laboratories to
> perform single donor NAT nationwide. The increased number of
> laboratories will require a significant commitment of support from
> manufacturers for materials, equipment, training, and maintenance.
>
> There is a known shortage of medical technologists within the health
> care industry, and hiring additional qualified staff to implement
> single donor testing will require time.
>
> We appreciate the public discussion this meeting will provoke which
> should begin to solidify a timeline for the orderly implementation of
> single donor NAT. We also urge the committee and the FDA to expand
> this discussion to enumerate the noninfectious serious hazards of
> transfusion that are responsible for significantly more transfusion
> associated morbidity and begin prioritizing the safety initiatives to
> which the entire blood banking community should be committed.
>
> Thank you.
>
> DR. NELSON: Thank you. Questions or comments?
>
> DR. SIMON: I think it was about three or four meetings ago when we
> discussed the same thing that is in the last paragraph of the AABB
> statement, which was the need for prioritization of infectious
> disease, hazards, and noninfectious disease, hazards of transfusion,
> and the need to prioritize that list and provide a recommendation to
> the FDA for what would provide the greatest impact to the blood supply
> in the country and patient safety.
>
> I think in the fact of West Nile and what we heard about Chagas, and
> now the move to single donor NAT, that maybe we should reassert that
> recommendation and ask for that at a future meeting.
>
> DR. NELSON: You are recommending we review the global issue at a
> meeting. Okay. Any other comments?
>
> I think this was a good and important afternoon. I think we have had
> substantial successes and yet things still aren\'t perfect, but I
> think this was useful.
>
> Any other final comments?
>
> \[No response.\]
>
> Thank you.
>
> \[Whereupon, at 6:15 p.m., the meeting was adjourned.\]

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