UNITED STATES OF AMERICA

	 DEPARTMENT OF HEALTH AND HUMAN SERVICES

	 FOOD AND DRUG ADMINISTRATION

	CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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	TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
	ADVISORY COMMITTEE

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	9th Meeting

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	Thursday,

	June 28, 2001
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		The Advisory Committee was called to order at 8:30 a.m., in the Versailles Ballrooms I and II, of the Holiday Inn-Bethesda, 8120 Wisconsin Avenue, Bethesda, Maryland by Dr. David C. Bolton, presiding.
MEMBERS PRESENT:
		DAVID BOLTON, Ph.D., Chairman
		JOHN C. BAILAR, III, M.D., Ph.D.
		ERMIAS D. BELAY, M.D.
		DONALD S. BURKE, M.D.
		DEAN O. CLIVER, Ph.D.
		STEPHEN J. DEARMOND, M.D., Ph.D.
		BRUCE M. EWENSTEIN, M.D., Ph.D.
MEMBERS PRESENT: (continued)
		LISA A. FERGUSON, D.V.M.
		PETER LURIE, M.D.
		J. JEFFREY MCCULLOUGH, M.D.
		PEDRO PICCARDO, M.D.
		SUZETTE A. PRIOLA, Ph.D.
		SHIRLEY JEAN WALKER
		ELIZABETH S. WILLIAMS, D.V.M., Ph.D.
		WILLIAM FREAS, Ph.D., Executive Secretary
GUESTS PRESENT:		
		RICHARD DAVEY, M.D.		
		DR. LOUIS KATZ, M.D.
		DR. HARVEY KLEIN, M.D.
		STEPHEN PETTEWAY, JR., M.D.
CONSULTANTS PRESENT:
		PAUL R. MCCURDY, M.D.
		KENRAD E. NELSON, M.D.
		STANLEY B. PRUSINER, M.D.

	C O N T E N T S
	PAGE
I.	Administrative Remarks by Dr. William Freas  	4
II.	Opening Remarks by David Bolton, Chairman	10
III.	Presentation by Dr. David Asher	12
IV.	Presentation by Dr. Joachim Kreysa	37
 V.	Presentation by Jean-Hugues Trouvin	59
VI.	Presentation by Christl Donnelly	71
VII.	Presentation by Antonio Giulivi	95
VIII. Presentation by Alan Williams	124
IX.	Open Public Hearing	196
XI.	Committee Discussion, Conclusions, Votes	252
XII.	Topic 2, Introduction, Charge,
	 and Questions by Dorothy Scott	402
XII.	Presentation by Robert Rohwer	361
XIII. Presentation by Henry Baron	399
XIV.	Presentation by Jeff Davies	420
XV.	Presentation by Gordon Busenbark	429
XVI.	Presentation by Christopher Healey	439
XVII. Open Public Hearing	474
XVIII. Committee Discussion, Conclusions, Vote	482
XIX.   Adjournment for Day One	507

	P R O C E E D I N G S
	(8:00 a.m.)
		DR. FREAS:  I would like to welcome everybody to this, our 9th meeting of the TSE Advisory Committee.  I am Bill Freas, the Executive Secretary for the Committee, and both days of this meeting will be entirely open to the public.
		At this time, I would like to go around to the head table and introduce those that are seated at the head table.  Would the members and guests please raise their hand when I call out their name.
		At the end of the table is Dr. Donald Burke, Director for the Center for Immunization Research, Johns Hopkins University.
		The next chair is occupied by a standing member of this committee, Dr. Elizabeth Williams, Professor, Department of Veterinary Service, University of Wyoming.
		Next is Dr. Jeffrey McCullough, a standing committee member, and he is a Professor in the Department of Laboratory Medicine and Pathology, University of Minnesota.
		The next is an empty chair, which will soon be filled by Dr. Stan Prusiner, Professor of Neurology, University of California Institute of Neuro Degenerative Diseases; and Dr. Prusiner will be a temporary voting member for this meeting today.
		The next individual is a standing committee member, Dr. Peter Lurie, a medical researcher for the Public Citizen's Health Research Group, Washington, D.C.
		And in the next chair is our consumer representative, Shirley Walker, Vice President of Health and Human Services, Dallas Urban League.
		Next is a standing committee member, Dr. Dean Cliver, Professor, School of Veterinary Medicine, University of California at Davis.
		Around the corner of the table is a new committee member, and I would like to welcome all our new committee members, the first one being Dr. Stephen DeArmond, Professor, Department of Pathology, University of California, San Francisco.
		Next is another new committee member, Dr. Suzette Priola, Investigator, Laboratory of Persistent and Viral Diseases, Rocky Mountain Laboratories.
		We will soon be joined in the empty chair by a temporary voting member for today, and he is Dr. Kenrad Nelson, and he is also Chairman of the FDA Blood Products Advisory Committee, and he is a Professor in the Department of Epidemiology, Johns Hopkins University School of Hygiene and Public Health.
		Next is the Chairman of this Committee, and he is Dr. David Bolton, head of the Laboratory of Molecular Structure and Function, New York State Institute for Basic Research.  
		Next is another new committee member, Dr. John Bailar, Professor Emeritus, Department of Health Studies, University of Chicago.
		Next is a standing committee member, Dr. Ermias Belay, a medical Epidemiologist,  Centers for Disease Control and Prevention.
		Around the corner of the table is a standing committee member, Dr. Lisa Ferguson, Senior Staff Veterinarian, U.S. Department of Agriculture.
		Next is Dr. Pedro Piccardo, Associate Professor, Indiana University Hospital; and next is a temporary voting member, Dr. Paul McCurdy, Consultant to the National Heart, Lung, and Blood Institute.
		Next is a standing committee member, Dr. Bruce Ewenstein, Clinical Director, Hematology Division, Brigham and Women's Hospital of Harvard Medical School.
		Next is a guest for today from industry, Dr. Stephen Petteway, Director of Pathogen Safety and Research, Bayer Corporation.
		Next is a guest, Dr. Richard Davey, and he is a representative from the Public Health Service Blood Safety and Availability Advisory Committee, in Washington, D.C.
		Next is an invited guest, Dr. Lou Katz, Vice President for Medical Affairs and Medical Director for the Mississippi Valley Regional Blood Center, Davenport Iowa.
		And at the end of the table is a guest, Dr. Harvey Klein, Chief, Department of Transfusion Medicine, National Institute of Health.  Welcome to everybody.  
		Dr. Pierluigi Gambetti is a new member of this committee who could not be with us today.  I would now like to read into the open public record the conflict of interest statement for this meeting.
		The following announcement is made part of the public record to preclude even the appearance of a  conflict of interest at this meeting.  Pursuant to the authority granted under the committee charter, the Director for the Center for Biologics Evaluation and Research has appointed Drs. Paul McCurdy, Kenrad Nelson, and Stanley Prusiner, as temporary voting  members for the meeting.
		Dr. Lester Crawford has been appointed as a temporary voting member for tomorrow's session.  Based on the agenda made available, it is has been determined that the agenda addresses general matters only.  
		General matters waivers have been approved by the Agency for all members of the TSEAC Advisory Committee, as well as consultants for this meeting.
		The general nature of the matters to be discussed by the committee will not have a unique and distinct effect on any members' personal or imputed financial interests.  
		In regards to FDA's invited guests, the Agency has determined that the services of these guests are essential.  The following reported interests are being made public to allow meeting participants to objectively evaluate any presentation, and/or comments made by the participants.  
		Dr. Richard Davey is employed by the  Georgetown University.  He is also a member of the PHS Blood Safety and Availability Advisory Committee.
		Dr. Christl Donnelly consulted with Oxford Biologica.  Dr. Lou Katz is employed by the Mississippi Valley Regional Blood Center.  Dr. Harvey Klein is employed by the Department of Transfusion Medicine, National Institute of Health.
		Dr. Stephen Petteway is employed by the Pharmaceutical Division of Bayer, and consults with Intersouth Investors, and is an advisor for Biologic Science Board.
		Dr. Robert Rohwer consults widely on TSE issues with both blood industry and gelatin industry, for which he receives compensation.  His laboratory research program receives support from the Gelatin Manufactures of Europe.  Dr. Rohwer is an advisor and has equity positions in several companies related to TSE.
		Dr. Michel Schoentjes is employed by SKW Gelatin and Specialties, France.  He also is the vice president of the Gelatin Manufacturers of Europe.  
Dr. Jean-Hugues Trouvin is employed by the Department of Biologics, France.
		In addition, listed on the agenda are speakers making industry presentations.  These speakers were not screened for conflict of interests because they are employed by industry, and are invited here to present industry's point of view on this topic.
		In the event that the discussions involves specific products or specific firms for which FDA's participants have a financial interest, or participants are aware of the need to exclude themselves from such involvement, then their exclusion shall be noted on the public record.
		A record of waivers are available upon written request under the Freedom of Information Act.  With respect to all meeting participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they wish to comment upon.
		Dr. Bolton, I turn the meeting over to you.
		CHAIRMAN BOLTON:  Thank you, Bill.  I won't say  much this morning in my opening remarks as we have a very full agenda.  I want to do a couple of things.  I want to welcome the new members of the committee.  
		We are very happy as I am sure the FDA are very happy that you have agreed to serve on this committee.  I consider and have for the last few years a privilege to serve as a member of the committee, and now I am doubly honored to serve as the Chairman of the Committee, although you may have to check back with me this evening to see if I am still in that mood.
		I would also like to thank the returning members of the committee for their continued service.  I think it is a very important thing that you do, and you have done it, and know how difficult it can be at times.
		We do provide an important service both for the FDA and obviously for the nation at large, in trying to help them come to an understanding of some very difficult issues, and often times with very little information, and not as much as we would like to have, but as much as is available.
		And I guess with that, I think we will move on to the first topic of the day, which is -- oh, and I have one more thing actually.  I want to thank also the former members of the committee who are now serving as consultants, and in particular, Stan Prusiner, my former mentor.
		And I have the gavel, and so I have an opportunity now to overrule.
		DR. PRUSINER:  Couldn't we read something into the record.
		CHAIRMAN BOLTON:  And that is another thing.  Those who are returning members of the committee recall our usual set-up with the microphones that have switches on them.  
		I think that these may be live all the time.  So just be aware that you may have a live microphone sitting in front of you.
		DR. FREAS:  Could I just comment on that?  The microphone is turned down right now.  So if you start talking, the microphone may not be very loud.  But please don't put down this microphone, and try to pick up a microphone next to you.  
		Keep talking and the gentleman at the sound board will then turn up the volume.  But, please, your microphone should be working.  Just pause a little bit until the volume has been turned up.
		CHAIRMAN BOLTON:  Okay.  Well, the first topic for this morning is topic one, the suitability of blood donors who have lived or traveled in various countries based on recent information concerning new-variant Creutzfeldt-Jakob disease, and bovine spongiform encephalopathy.
		And our first presentation will be the introduction, charge, and questions by Dr. David Asher of the FDA.
		DR. ASHER:  Thank you, David.  Good morning.  Today we are asking the committee to review for the third time the issue of blood donors potentially exposed to the BSE agent, and hence having some probability, presumably very small, of incubating Creutzfeldt-Jakob disease.  
		There is a theoretical risk that their blood might serve as a vehicle to transmit the effects to recipients.  The FDA has already recommended a limited deferral policy for some potentially exposed donors, and the committee previously advised a modest extension of that policy.
		Much less is known about variant Creutzfeldt-Jakob disease in other forms.  As you may recall, unlike sporadic vCJD and variance CJD, the abnormal protease-resistant prion protein accumulates to substantial levels of lumpohoid tissues, and of course some lymphoid cells normally enter blood.
		That raised a concern early on that the relatively reassuring epidemiological evidence suggesting that blood was unlikely to be an important vector for other forms of CJD might not be predictive for variance CJD. 
		Then came reports last year that BSE had been transmitted by blood of experimentally infected mice, and finding that not uncommon in other rodent TSC models; and then by transfusion from an experimentally infected sheep, a unique isolated and preliminary finding, but one that is troubling nonetheless.
		Now there is concern not only about donors exposed to BSE in the U.K., where cases of variant CJD continue to rise to 104 at my last count, but also about people who ate U.K. beef products in continental European countries.
		The three French patients with variant CJD had no history of travel to the U.K.  France may have imported at least five percent of its supply of beef products from the U.K. during some years of the epidemic.  So there were ample opportunities for exposure there.	
		Other European countries also imported U.K. beef.  There is also concern about the spread of BSE into other national cattle herds because U.K. meat-and-bone meal was exported to many countries, and possibly used in cattle feed.
		In just the last year, four new European countries have recognized BSE in native cattle.  So BSE may have spread more widely in European cattle than previously thought.
		Now there is in addition to the risk from U.K. beef an additional risk to humans from indigenous BSE in cattle of continental Europe.  Regarding variant CJD itself, there is both bad news and good news.  
		Rates of variant CJD have continued to rise in the U.K., although fortunately not in France.  Two other cases have been reliably diagnosed outside the U.K. and France, but both were in long-time U.K. residents.
		Attempts to transmit TSE to mice and monkeys from blood of patients with variant CJD have apparently been negative, but the total volume of blood tested has been small.
		A number of recipients are said to remain well after receiving blood products from donors who later went on to get variant CJD, but they have been observed for only a few years.  We may hear more about that in this afternoon's session.
		Concern about the potential infectivity of blood from persons incubating variant CJD prompted FDA's current precautionary policy announced in 1999 for implementation by April of last year.
		That policy recommends deferral of donors residented in the U.K. for any cumulative six months from the presumed start of the BSE epidemic in 1980, to the full implementation there of a series of measures to prevent human exposure to the BSE agent implemented by the end of 1996.
		Since there is no early diagnostic test to identify donors who will get variant CJD, and no validated screening test to identify blood bearing the infectious agent, the deferral of donors offers the only practical way to reduce the theoretical risk.
		The current policy was predicted to remove almost 87 percent of total risk expressed as donor days in the U.K., while deferring 2.2 percent of donors, which is a substantial number.
		No appreciable loss of donors was observed after implementation, and no methods for monitoring donor losses are not well developed.  
		This committee reviewed the situation on January 18th of this year, and offered the FDA seven pieces of advice summarized in this slide, taking some liberties in the interest of clarity.  
		First, continue to defer donors who spent any cumulative six months in the U.K. from 1980 through 1996.  Defer for 10 years residence in France from 1980 through the present, but recommend no blanket deferral for other European countries.
		By the narrowest of margins, the committee did advise deferring donors who spent 10 years in Portugal, or the Republic of Ireland, from 1980 to the present.  
		The committee also advised not adding up the total time donors have spent in different BSE countries to determine deferral, and not treating exposure to U.K. beef on U.S. military bases as being equivalent to exposure in the U.K., although some deferral policy not further specified for donors exposed to U.K. beef on Department of Defense bases was advised.	
		The FDA acknowledges the concerns that the committee expressed in January, agreeing that the risk of transmission of variant CJD is theoretical, and that the potential loss of blood donors from increased deferrals is substantial.  
		The FDA also understands the reluctance of the committee to lump together under one deferral policy all 30 countries, that in addition to the U.K., are under the current U.S.D.A. BSE list.
		However, the FDA has not been convinced that existing information is adequate to justify recommending a stratified risk-based policy for deferral of donors potentially exposed to the BSE agent in France, Portugal, and Ireland, while accepting the risk of exposure in other continental European countries.	
		The vast majority of BSE cases is more than 180,000 have been diagnosed in the U.K.  Britain reported 1,352 cases for the year 2000, and 177 through the end of April of this year.
		Although Ireland and Portugal indeed have the next highest numbers, 613 and 568 cases to date, according to OIE figures earlier this month, BSE cases in Switzerland were also substantial, exceeding the number reported from France.
		The numbers of BSE cases in cattle borne in Germany and Spain to date seem more modest, 75 and 46.  But it is troubling that all of those cases were found just within the past 10 months, and one additional country, the Czech Republic, confirmed its first case of BSE only two weeks ago.
		Considering the uncertainties surrounding the prevalence of BSE in Europe, the FDA staff doubt the ability of available risk assessments to provide reliable estimates of potential human exposure to BSE agent in various countries.  Drs. Kreysa, and Trouvin, and Donnelly may elaborate on the situation later in the morning.
		So it is difficult for the FDA to be confident that a bright line can be drawn distinguishing the risks of human exposures to the BSE agent in France, Ireland, and Portugal from risks elsewhere in Europe.  
		There seems to be consensus among stakeholders that until the potential infectivity of blood from persons incubating variant CJD is better understood, and we all hope that it will eventually prove not infectious, deferral of those donors with the greatest probability of past exposure to the BSE agent is prudent.
		Most of us also agree that it will not be feasible to defer all donors who spent any time in a BSE country, but that the risk can be greatly reduced, but not completely eliminated by a donor deferral policy.
		Furthermore, everyone is committed to providing an adequate supply of safe blood to all persons who need it.  But the potential loss of blood donors that might result from additional deferrals to be considered today are very large.  Two of them are probably without precedent.
		It is clear that any substantial loss of additional blood donors, if not compensated by greatly increased efforts to recruit suitable new donors and retain them, would inevitably cause shortages and almost certainly hurt some people needing blood products to sustain life and health, an unacceptable outcome.
		Unfortunately, the uncertain state of knowledge about BSE and variant CJD does not yet allow us to develop a policy that is strictly science-based, and as I think we will learn during our open public hearing today, there is no consensus among stakeholders either about the probable magnitude of the BSE risk, or the additional deferrals that blood programs can safety tolerate.
		With those things in mind, we ask the committee to review four options for additional deferrals; a slightly modified version of the policy they advised in January; an aggressive policy recently proposed by the American Red Cross; a compromise option developed by the FDA; or any other program that committee members or representatives of blood programs or others may propose.
		The FDA intends to use the committee's advice to develop a revision of the current guidance for industry to be published as a proposal for comment, a proposed revision, so that everyone concerned will have another chance to provide additional information, identify problems, and suggest solutions to the FDA.
		And I might add here that we are prepared to receive additional comments at any time after today's meeting before the issuance of the proposed guidance.
		We anticipate that after analysis of comments a final guidance we will then issue for implementation within six months of issuance.  We also encourage well-planned and monitored pilot studies, using deferral options that exceed FDA policies.  
By the way, additional background information is available through the CBER website.         
		Helping us today are several expert speakers.  Dr. Joachim Kreysa led the European commission's scientific steering committe's group that developed the geographic BSE risk analysis, a qualitative assessment of the risk and possible prevalence of BSE in countries responding to a request for information. 
		Professor Jean-Hugues Trouvin, of the French Blood Services, will provide another view of the situation concerning BSE in blood from the European medical perspective; and Christl Donnelly will present the results of epidemiological models to assess risk of human infection with the BSE agent in several countries, perhaps providing a paradine for assessments of risks in other places.
		Dr. Tony Giulivi from the Canadian Blood Services will share the results of important risk assessments performed in Ottawa, and we have also asked Tony to consider the effects on public health that might be expected should shortages of various magnitudes occur.
		Then FDA's Alan Williams will describe a model that he developed to estimate reductions in risk offered by various deferral options, as well as losses of donors that might be expected based on a survey that he coordinated.  He will also expand on the advantages an disadvantages of each option.
		It is especially important to remember that predicted donor losses would not be borne uniformly across the USA.  Losses will be more severe in the metropolitan areas of the East and West Coast, and especially in the New York City area.
		Several speakers in the open public hearing will undoubtedly address that problem.  The committee will then be asked to discuss the options, and then finally to vote on them.
		In your discussions, we ask members to consider reductions in risk and donor losses predicted from the model, because that provides a useful way in which to compare options.  
		Dr. Williams will describe the model fully, but it may be useful now to list some of its underlying assumptions.  The risk of human infection is assumed to be proportional to the duration of exposure and to the fraction of consumed beef likely to have been contaminated.
		And food chain protections are assumed to be substantially effective in reducing exposure so long as they are faithfully implemented.  The risk is taken to have been greatest in the U.K.  
		The Department of Defense risk is taken to have had a maximum of 35 percent U.K. risk, and risk in France, 5 percent, and risk in the rest of Europe extrapolating from Switzerland, 1.5 percent of U.K. risk.
		Now to summarize features of the options briefly.  Option 1, based on the committee's advice of January, proposes to defer donors who spent six months or more in the U.K. from the beginning of 1980 through the end of 1996, which is FDA's current policy.
		Or six months or more on a DoD base from 1980 through 1996, or open through 1990 on bases north of the Alps; rr 10 years or more in France or Portugal, or Ireland, from 1980 to the present.  This option is estimated from the model to yield a total reduction in exposure risk of 82 percent at a cost of 2.2 percent of current dollars.  
		The American Red Cross proposal, Option 2, is to defer donors who spent any period of three months or more in the U.K. from 1980 to the present, or six months or more in the rest of Europe in the same years, as well as any recipient of blood transfusion in the U.K. from 1980 onwards.  
		Reduction in total donor BSE exposure risk is estimated by the model to be about 92 percent, and donor loss from 7.8 to 9.1 percent.  The range of results from survey donors who reported travel to both the U.K. and other European countries, Alan can explain that later.  
		The FDA's compromise proposal, Option 3, would defer donors resident for any period of three months or more in the U.K. from 1980 through 1996, or for six months or more on a Department of Defense base from 1980 through 1996, or only through 1990 on those bases north of the Alps.
		Or for five years or more in the rest of Europe from 1980 through the present, as well as any recipient of a blood transfusion in the U.K. from 1980 until the present.
		The reduction in total donor BSE exposure risk is estimated to be about 91 percent, and donor loss from 4.6 to 5.3 percent, which is still a one-time loss of donors that would be unprecedented I am told in the history of U.S. blood banking.
		Of course, if the American Red Cross implements its proposed policy, the national donor loss would be greater than indicated both for options one, and for this option depending on the number of blood programs that elected to follow the American Red Cross.  In that case the risk reduction would also be significantly greater under Option One.
		Here now are the questions that the committee will be asked.  The first three are accompanied by a review of the summaries of the relevant options to it to assist you.  
		We will ask the committee to vote on the FDA proposal first by answering question one.  Do committee members concur with the FDA proposal, and that is Option 3 that we just summarized, to defer additional blood and plasma donors based on their potential exposure to the agent of BSE.
		If the committee does not endorse the FDA proposal, we will ask you next to answer Question 2.  If they do not agree with the option proposed by the FDA, do committee members advise the FDA to recommend a blood and plasma donor deferral policy recently proposed by the American Red Cross, and that is Option 2.
		If the committee also declines to accept the American Red Cross proposal, then in Question 3, we will ask them to consider the option based on the committee's earlier advice in January of this year.
		If they do not agree with the previous options, do TSC advisory committee members advise the FDA to recommend a blood and plasma donor deferral policy based on advice by the committee on January 18th, 2001, and that is Option 1.
		Then if none of the three options has been endorsed, then in Question 4, we will ask the committee to suggest or accept some other option.  
		Finally, after the committee has voted on the options, in Question 5, we will ask them to comment on steps that should be taken to monitor and ensure adequate national and regional supplies of blood, blood components, and plasma derivatives, if additional donors are deferred based on possible exposures to the BSE agent.
		We look forward to having an informative session this morning, and I thank you very much.
		CHAIRMAN BOLTON:  Thank you, David.  We are running a little ahead of schedule actually, and so at this point in time, I would just like to ask any of the committee members if they have any questions for David on these proposals.  Yes?
		DR. LURIE:  David, my question is that it is not my recollection that previous guidances that have ensued from our committee suggestions have resulted or have been produced in a notice and comment period, and so forth, and so on.  Am I correct about this?
		My concern is that -- I mean, there have been now three at least advisory committee meetings on this, with the industries being given ample opportunity for input, including again today.  So I am wondering if this is an unusual procedure at all.
		DR. ASHER:  I can't comment on whether it is absolutely unusual.  The last version of the guidance for blood donors potentially at increased risk of CJD was issued as a draft guidance I believe in the summer of 1999, and only in final form in November.  So that there was an opportunity for comment.
		As I recall, the gelatin guidance in 1997 was issued without opportunity for notice and comment, although there was an active, though public, discussion at a TSC advisory committee meeting.
		DR. PRUSINER:  David, I wonder if it wouldn't be useful for you to review the FDA's position and why it chose 1996 as that cutoff, because when we had these discussions originally, it may be my failed memory, but I never remembered a cutoff date.
		You all talked about beginning this in 1980 and looked at that very carefully, and then these epidemiologic studies were done every six months to look at donor loss.  But I would like to hear from you why the FDA then decided that 1996 was the cutoff date.
		DR. ASHER:  The decision was made in response to information provided by the U.K. about when there had been full implementation of the food chain protections, and those are removal of specified risk materials over a 30 month slaughter scheme, and the prohibition of advanced meat recovery.  
		I wasn't part of the discussions that chose that date, and perhaps Dr. Epstein, who was, would want to comment further on the considerations that went in to selecting the end of 1996 for the cutoff.
		DR. EPSTEIN:  That issue was a part of the discussion, and you have already given the answer.  The concept was that the food chain protections had been sufficient by that time, and we did hear an estimate for the number of infected animals that could potentially enter the food chain subsequent to that date.  
		It was felt to be less than one per annum, and so it was on that basis that we made that decision, but it was a discussed issue back in 1998-1999.
		DR. PRUSINER:  It was or was not?
		DR. EPSTEIN:  It was discussed.  
		DR. PRUSINER:  So my memory is failing.
		DR. EPSTEIN:  However, with respect to deferral for exposure in Europe, we have asked the committee both in June of 2000 and January of 2001 whether there should be such a deferral, and we basically proposed a 10 year exposure period leading to deferral, and in that case we did not put a limit on it because we felt that we did not have knowledge when food chain safeguards throughout Europe were adequate, if indeed they are at all.
		DR. ASHER:  You may notice the deferral for injection of bovine insulin from the U.K. was also not part of the discussion.  The agency does have discretion to go beyond the committee discussion.
		DR. PRUSINER:  I'm not challenging that.  I was just asking.
		DR. ASHER:  And those are my understanding for why that happened.  By the way, if anyone feels that the cutoff date is '96 is not appropriate, this would be a useful venue in which to discuss it.
		DR. PRUSINER:  I just think that is very important, David, that as the Chair for you to bring that up, and that we discuss this issue of 1996 later.
		CHAIRMAN BOLTON:  Steve, you had a comment or a question?
		DR. DE ARMOND:  So when I look at your tables here, particularly this table of kind of comparing risks and the effect on blood donor loss, the only other issue that I don't understand and would like to see some data on, or some calculation on, is the risk of deaths due to the decrease in the blood supply.
		We are talking about a theoretical risk in terms of BSE to variant CJD, to humans receiving blood supplies.  But we don't understand, or at least I don't understand what a decrease of 5 percent, 8 percent, 9 percent, would mean in terms of real deaths.
		DR. ASHER:  Yes.  Tony Giulivi is going to be presenting a graphic prediction of what various -- of what donor losses of various magnitudes would mean for public health, and it answers exactly that question.
		And of course there is going to be a full discussion of the model by Alan Williams later in the morning.
		CHAIRMAN BOLTON:  Dr. Cliver.
		DR. CLIVER:  What I am disappointed not to have seen is any broader trace of where British beef and British beef bone meal went during the suspect period.  What we are seeing now is a kind of ethnocentric focus on Europe, and we don't know how much of those products went to Asia and Africa.
		Over half of the world's population lives on those continents, and the idea that my visiting in Europe puts me at risk, but perhaps eating some things on another continent doesn't put me at risk, I would like to see some documentation to that. 
		DR. ASHER:  Well, unfortunately, the documentation concerning the export of meat and bone meal from the U.K. is limited.  U.K. customs and Excise has, I believe, published a list of exports.  
		The problem is that they don't match very well with the country's own records of imports, and there has apparently been a lot of -- for instance, there was importing of a certain amount of British beef and bone meal into the United States that apparently doesn't match our customs records for import.
		So I don't pretend to be an expert on either topic.  The Ministry of Agriculture, Fisheries, and Foods was quick to point out the reliability of their own records is really questionable.  
		So it is complicated by inaccurate records in the U.K., or incomplete records in the U.K., and accurate records or incomplete records in the importing country, and the probability that there was a considerable amount of untraced transhipment from one country to another.
		But I think that your concern is very well taken.  We are all concerned about the possibility that BSE was exported to many countries around the world. 
		At the moment, the FDA has found the only realistic way in the absence of independent sources of information that we can function in a practical sense is by relying on the U.S. Department of Agriculture's determination of which countries are at high risk of having BSE in their cattle.
		And you will hear more about that from Dr. Kreysa from the European Commission's independent and thorough efforts to determine the risk in the various countries.  
		Those efforts are also limited by the fact that the countries self-report and not every country has sent a dossier in to the scientific steering committee.  
		CHAIRMAN BOLTON:  Thank you, David.  One more?
		DR. FERGUSON:  Actually, let me add just a bit to David's response to the last question.  I am speaking for USDA and then also two hopefully quick questions just for clarity's sake.  
		The Department is in the process of trying to obtain information to allow us to assess the risk of countries, especially in Asia, based on all the recent concerns.  
		We just recently started that process, and as David said, that is obviously dependent on those countries reporting to us.  But we have started that process, and so hopefully we will have some more of that information available to us here in the next few months.  
		Two questions for clarity's sake.  How are you defining European country?  Is that the same as ours?  Is it the USDA list?  And then also what is the distinction in the DoD bases, and why the difference between those bases north of the Alps?
		DR. ASHER:  First, the European countries on the list, we were intentionally vague about Europe because frankly we anticipate that the USDA will perhaps soon expand the -- that the line that the USDA has drawn in Europe at the moment is at the border of the former Soviet Union, which has a history of -- at least according to British Customs and Excise records, a history of importing meat and bone meal from the U.K.
		Now, where that meat and bone meal went inside the former Soviet Union, we do not know.  But we anticipate that additional European countries not currently on the USDA BSE list will in all probability be appearing on that list before too long.  Am I correct in that assumption?
		As much as possible, we would like to rely on the USDA list, but the actual issuing of interim guidance, in which the interim regulation in which the USDA promulgates its list, it lags somewhat behind the appreciation of risk.  The other question was?
		DR. FERGUSON:  The distinction on the DoD based north of the Alps and the time frame.
		DR. ASHER:  Colonel Fitzpatrick is here today.  The program purchasing U.K. beef for European military bases north of the Alps stopped in 1990, and continued in bases south of the Alps, and there is a list of what constitutes a base north and south of the Alps.	
		It continued until 1996 south of the Alps.  And, of course, 35 percent is thought to have been the maximum percentage of U.K. beef that was purchased for any base, on many bases, and presumably the amount of beef purchased from the U.K. was less than that.
		CHAIRMAN BOLTON:  Okay.  So I would like to just remind the committee how we are going to deal with this.  Once we get to the public comment and our discussions, we will actually be voting on these proposals sort of out of order.
		We will first discuss and vote on the FDA plan, and then the American Red Cross plan, and then finally the committee's recommendation from January 2001.
		And so if you are uncomfortable with some part or disagree with some part of each of those proposals, you can always vote no on each of them, and if we vote no on all of them, then the fourth item is do we have a new recommendation that we would like to consider.
		So as you listen to the proposals this morning, keep those in mind.  This is a lot of information to juggle about in one's brain, and we are looking at competing risks.
		I think as Dr. DeArmond pointed out, a real risk of a shortage in the blood supply, versus some theoretical risk of transmission of new variant CJD are numbers that we don't really know much about.
		So having said that, we will move on to our first informational presentation, and that is the -- sorry.
		DR. BURKE:  Will there be an opportunity for the Red Cross to present their position, and is the FDA or someone going to present for them, and do we know what their positions are, and whether or not they accept the FDA's estimates, and the rationale for their proposed policy change?
		CHAIRMAN BOLTON:  Yes, I believe that they are on the open public hearing today as presenters.  And we certainly -- I hope to provide adequate time for discussion of all of these various points of view. 		The problem that we may run into is that I would also like to keep this session intact if at all possible, and that may mean that we would push lunch back beyond the 12:45 time at this point.
		But if it gets to the point that we are not able to wrap up discussion, we may have to break for lunch first, and then come back and continue the discussion and vote.  So keep that in mind also.
Okay.  So any more questions?  
		(No audible response.)
		CHAIRMAN BOLTON:  Good.  Oh, I would like to remind everybody on the committee, too, that it may be helpful for the transcriber if you give your name before -- oh, it is not necessary?  Very good.  
		All right.  Our first presentation this morning is by Joachim Kreysa.  It is the geographic BSE risk assessment conducted for the European Commission.  Dr. Kreysa.
		DR. KREYSA:  Chairman, Ladies and Gentlemen, first of all, thank you very much for this opportunity to speak to you on this geographic BSE risk assessment, which has been carried out over the last three years by the scientific steering committee.
		I am one of the two secretaries of this committee and have been monitoring this event since the beginning.	
		I will speak about the method and the results, but following a request from Dr. Asher, I will also speak a little bit about risk management, and the BSE risk management issues or measures which have been talked about in Europe, which will also clarify a little bit the changes in the possible risk for humans over time in the European Union.
		The staffing point of this is obviously the BSE transmission to humans, and that is the reason why everybody is so concerned about it.  Up to now the mechanisms are not fully understood as far as I gather from the discussions of our committee.
		The most likely of this is the exposure via food, and finally you run the risk of exposure of man to the agent is dependent upon manufacturers, but first of all on the risks that the agent enters the food chain and came into the human plate.
		The BSE assessment is an attempt to estimate the risks in a given country or region the lines could be incubating BSE.  At the moment, there are in fact no cases already recognized.  
		So GBR is not very essential anymore when you want to assess the prevalence in a country that you know already that BSE is there, but it is useful to see if there is a risk of BSE in a country which has not yet found its first case.
		The GBR is not an assessment of the human exposures.  It is based, however, on the currently available knowledge about the BSE agent, its transmission, the pathogenesis of the disease, and the possibility to control its propagation.
		It is on the other hand also flexible enough to take account of new information of the uncertainties that still exist, which means that the method is so simple and crude that we can easily adapt it, but that we also only provide qualitative science.
		If we go into the question of the knowledge, the first question which is always raised is the question of the origin of BSE.  There are many hypotheses, such as spontaneous occurrence, which was never proven; or the effective scrapie moved into bovines, which up to now has not been experimentally shown.
		But it is nevertheless one of the most favorite hypotheses.  For the purposes of GBR, the EC  simply assumes that BSE exists somehow and we don't know exactly yet how in the U.K. 
		It was distributed from the U.K. and later on from other countries which developed the BSE in their own national health via the export of feedstuffs and of infected cattle.  Apparently, there are also other products which could have exported it, but these are the most important ones.  
		The next element is to have an idea on the transmission system for BSE, and it is very clear that horizontal transmission seems simply not to happen, and the transmission from cattle to cattle has not been discovered.
		The question of vertical transmission is also an open one, and it has been stated, but it has not been shown finally, and particularly the biological mechanism is not understood.
		Then we have the clear transmission root of the oral transmission via feed, which in fact is the one that seems to be non-disputed.  And then we have discussions on the transmission via semen, embryos, or also other third routes, but not of these has yet really shown a remarkable effect.  So for the GBR, in fact, we are only on the oral route.
		The next big aspect which as already been mentioned this morning is the question of what happens with the BSE once it is in a country, and if the transmission route is feed, there must be a recycling from the live animal back to the live animal via the feed chain.
		And in fact that is the basic thought of the BSE model.  With BSE infected cattle in a country, these cattle are going to be processed at a certain point in time, which means that infected BSE, or infected BSE infective materials are rendered into feed.	
		And domestic MBM infected cattle, and cattle are exposed, and the vicious circle is closed.  So a question which has to be addressed is this vicious circle existing or not in a country.  Fortunately, this feed back loop can be controlled.
		And now the first one which is always the first element or control point of ordinary services is surveillance, and to a certain extent, culling.  Culling means the slaughtering of cattle which are perceived to be at risk of incubating BSE because of the link to an index case.
		The next element or control point would be to exclude SRMs.  SRMs are these famous specified risk materials which according to the SSC would contain something like 95 or 98 percent of infectivity in a material BSE case.
		Excluding these obviously reduces the amount of infectivity entering, and rendering, and therefore reduces the risk in their system.  The same is not the same, also quite interesting, is the age at slaughter. 		Because of the long incubation period and the ideas that we have about the development and the building up of infectivity in the bodies of the cattle, the other animals are generally at much later risk, even older animals, simply because even if they are infected at birth, or close to birth, they will have had not enough time to build up a lot of infectivity.
		Very often they will have even have reached the brain and the spiral cord measurable radius.  The rendering process and the feeding and feed controls are obviously also very important steps.
		Rendering processes can reduce if properly applied the infectivity of the material by a factor of about three logs.  So by a factor of a thousand.  The SSC insists, however, to make clear that they cannot sterilize.  
		So if a lot of infectivity enters rendering the upcoming MBM is not to be regarded as safe.  This has been shown by countries who rely too much on this one control.  
		The feeding is obviously one of the cull or key factors to control.  If you can avoid cattle with receiving MBM, or contaminated MBM to be very precise, ruminant MBM, you would break the cycle, and the vicious circle would not work.  
		The problem there is the control of the cross-contamination.  The European experience shows that whenever you are feeding it to other animals, you have a risk of cross-contamination, and this is difficult to control.
		However, to start the whole thing rolling, you need an initial source of BSE, and according to the GBR model, this is imports on the one hand, and it is the import of MBM, which would lead to exposure of cattle to the BSE agent.
		Apparently measures which are controlling the fate of the imported MBM in the country can manage this does make sense.  Then we have the import of cattle, which would increase the number of BSE infected cattle in the country.  
		Again, surveillance of these imported cattle could manage that risk; and we have seen in our GBR exercise examples of those countries who control the import of MBM, and in particular of cattle, so that they have imports, but these cattle did not reach internal impact routes.
		So the GBR exercise, on the basis of this model and these thoughts, simply tries to answer two main questions.  First, is the risk to the BSE agent important, and this is difficult enough.  
		We have just heard about the problematics with the U.K. export figures to compare the disease import figures, and what we do is we have very intensive discussions with the country of these figures, and we try to verify this by all means, even by going back to the importing and exporting countries, requesting a very detailed research on that.
		The second question is, yes, what would have happened on the one hand if BSE was recycled and probably amplified, or was it eliminated?  And this obviously depends on the internal system.  
		The recite of this is in the Geographic BSE Risk, which is a qualitative indicator of the likelihood that one or more cattle are present in a country or region while being infected with the BSE agent clinically or pre-clinically.
		The SSC defines four levels which are I guess readily well known.  Number One says that it is highly unlikely that the BSE agent is present.  The second one is that it is unlikely, but it cannot be excluded, that the BSE agent is present.
		Third, it is likely that the BSE agent is present or confirmed at the lower level; and this lower level simply means that a lower arbitrary level was taken of less than a hundred cases per million adult cattle confirmed in the last 12 months.
		This is just in line with the OIE, the international standards setting organization, and then we have finally the last two, and we have only two countries that come from the higher level, and that means more than a hundred cases per million of adult cattle.
		When the SSC produced these four levels, it had in mind the ultimate objective, which is the contribution to the managing of the risk for humans.  So these levels should give risk managers a kind of orientation of what should be done.
		And under this perspective, level one would means nothing is needed to be done.  Secondly, the second level would be that some precautions should be taken, and this can vary depending on the specific situation of the country.
		And level three would mean that precaution measures must be taken, because there is a real risk that BSE infected cattle exist in the country, and therefore infectivity could end up in the domestic line of the food chain.
		And in the mind of the SSC, for example, SRM in feed ban should be there, and there should be good rendering in the country, and an active surveillance and cohort culling should be in place to really estimate as good as possible the risk.
		And then level four apparently everything must be taken that can be conceived to reduce the risk of human exposure to the agent, and in our view this is successfully done in the U.K., where the human exposures might be very low.
		The current GBR assessment situation is that we have 46 countries done, and 40 member states, and 32 subcountries, and 20 more are in the process, and we will adopt another batch of three tomorrow.  That's why I have to leave you already at lunchtime today.
		The 32 non-EU countries are listed on this slide.  You don't have it in your handout, but you will get a copy.  I added this to make it a little bit more clearer.  
		What you have is the next slide, which is the broad map as it looks from the GBR perspective for the moment.  What is apparent is that level three and four is concentrated to Europe.  It is the European Union and Eastern Europe.
		What is clear is that all these countries have received a lot of imports, and a really big amount of MBM, but also cattle, and most of them have also rather unstable systems, and that means that they would have recycled and probably amplified the agent when it entered.
		The point which one should nevertheless make is that the level of risk is much lower than apparently the U.K., and that all the incident figures that we have so far in the European Union, even on the basis of the massive MBM screening testing that is going on, shows that the order of magnitude is much, much lower than it was in the U.K. in the biggest period.
		The same is also for the Eastern European countries.  If we look at the time frame of the exports, most of the exports happened in fact in the '90s, and mostly from other BSE infected countries, and the U.K.
		And this indicates that in fact the Eastern European countries are very much at the beginning of the BSE epidemic, if an epidemic ever develops.  But they are there.  If I can go back once more.
		The GBR two level, you find in the yellow spread to North America, and then spread to the different continents.  The common feature of these countries is that they have some imports of 
meat-and-bone-meal, or use the customary meals, and flaws and pellets made from meat and offal, and grease, not fit for human consumption.
		So looking into these customs figures, we recognize that these countries have received some and also live cattle, but to a large extent, they have been able to manage the risk of these imports.
		However, most of them have unstable systems, and can therefore not be put into category one.  In category one then, you find a lot of countries which have very unstable systems.  
		The reason why they are there is in fact that they have negligible imports, or they have been able to demonstrate that those -- that the number of cattle, for example, entering into their system was negligibly small.
		Now, we have finished with that, and now we can go to the next slide.  So if you try to estimate the impact, and what does that mean for humans, we should try to estimate the development of the prevalence.ce.
		And as I said, the GBR is not really providing you with qualitative data on this.  What it does is that it provides a qualitative estimate of the internal challenge of the imports, and then the qualitative estimate of the stability over time, which means the ability of recycling or not.
		And then also the qualitative estimate of what we call the internal challenge, which is a kind of other way of saying prevalence.  We avoided using the word prevalence because it is implying too much a quantitative thing.  
		So an internal challenge simply means the building up of a pool of infectivity of a domestic heard.  It does not provide quantitative estimates of the prevalence, because this would really depend on the quantitative estimates of external challenges to population dynamics, and the relations.
		And in effect why we tried this at the beginning, and then the method was developed, and we recognized that the effort would be much-to-much to do this for a large number of countries.
		And, two, the data quality is very difficult to reach a level that it makes sense to the developed figures.
		As we look at the human exposure risk that the SSC has developed, it provides also an opinion on that.  We have a number of factors coming.  It is the prevalence of BSE in the live cattle population and the GBR gives you a kind of qualitative idea of that.
		Then the prevalence of BSE in the slaughtered cattle.  The problem there is that this can be quite different from the prevalence in the live population of cattle.  So you have to look into the measures taken at that level, and also the normal customs.
		The age at slaughter is important because of the pathogenesis, which I already mentioned, and the slaughter methods, pithing, is supposed to create a kind of cross-contamination or contamination of the other tissues with SRM, and in particular with brain tissues.
		And the use of SRM is an essential key factor, because more than 90 percent of the infectivity is concentrated in those tissues, or at least that is what we are learning.  Then the question of the ability of certain processing conditions to reduce infectivity, and that is on your agenda, and you are discussing gelatin, and some new processes there also.
		But at least those processes which apparently have a capacity of reducing infectivity by about five logs.  And I see that I have to stop, and so the next point anyway is that the imports and exports of food products also influences risk.
		And just keep this in mind as you talk about this geographical aspect, because the flows of food products are very, very complex.  I will skip the next slide.
		And this is taken from the human exposure according to the SSC just to show you a little bit of the complexity of the passways between the cows and the human consumers, and the central role of SRM.
		Again, I am sorry for the time.  We have to skip the next one, and so if you would just go through it very quickly.  Okay.  The European Union BSE risk management was shown by a greater improvement. 
		At the beginning, it focused on certain elements.  So, first import and then vis-a-vis the U.K., and then in '90 the material had to be rendered correctly.  But now since 2000 all materials are finally rendered.
		In '94, the first mammalian MBM ban was put in place, which is now a total feed ban, and in 2000 finally there is an SRM ban at the EU level.  There was something on country level.
		And in 2001, a complete surveillance is now in place of all cattle over 30 months, and of risk to populations.  To continue, this is just some details.  Again, you don't have a copy of it in your handout.  You will receive that later.
		You just see that in '88 and '89 that there matters of staffing to do, and focusing on the import question, and in '94, the feed bin, and in '97, heat treatment was required for all materials, which took some time to implement until June 2000.
		And since 2000, there is a European-wide SRM ban.  On the next slide, SRM being the most important action that you take to put human -- national SRM ban as they came in place, and more or less in line when the countries had their first cases.
		You will see that Italy and Spain in '96, only from imported cattle, but not from the domestic cattle; while France and Ireland did a lot in '96 in this field.
		In 2000 now we have an European-wide SRM ban which also acts in countries which don't have BSE, and this is the underlying ones.  And so I am finished, and I would just like to remind you that you can find all the opinions of the Scientific Steering Committee on the internet at their address, and all of this is in much more detail, and you will find a detailed report for each country.  Thank you very much.
		CHAIRMAN BOLTON:  Thank you, Dr. Kreysa.  We have just a few minutes for questions.  Does anybody have a question?  Quite a few.  Dr. Belay.
		DR. BELAY:  It is my understanding that Category 4 countries include the United Kingdom and Portugal; and that Category 3 includes most other European countries, including France and the Republic of Ireland.
		 Now, my question is do you consider countries under the Category 3 to be homogeneous in terms of their BSE risk; and if not, did you try to look at the different countries by different subcategories if you will? 
		And where would the Republic of Ireland and France specifically would lie in terms of the BSE risk within Category 3?  I am interested in the Republic of Ireland and France because this committee specifically looked at these countries during our last meeting.	
		DR. KREYSA:  Well, you are referring back to a discussion which was very intense that we had at the Scientific Steering Committee level in '98 or '99, because obviously this definition of the categories was very, very difficult.
		It is very clear that it should be understood that all these four categories apparently lump together quite some different situations in terms of risk.
		But the same is true for Category 2 and for Category 3 definitely.  The SSC has not really tried to differentiate these different risk levels in much more detail.  
		The problematic with surveillance data is very clearly shown now with the upcoming recites from the intensive massive TSE screening recites, which show that the previous purely passive surveillance was not really able to give a correct picture of the situation.
		So it is very difficult to quantify within Category 3 the different level of the risk of the different countries because also we don't or we cannot go back in time and prove that level of risk during that period.  So for that reason, it was not even tried to really put the countries into different sublevels.                                           
		DR. NELSON:  I have a question.  The question I had was relating the temporality of the risk.  In other words, that would relate to the numbers of BSE cattle were identified, and if the risk increased very recently, there would have to be time for the disease to incubate and be shown up in surveillance and the same with humans.
		And the concern that I have is that when the problem occurred in the U.K. was there a large export of risk materials to other countries or can we assume that the risk was fairly stable in the group of three countries over time and didn't vary that much?
		DR. KREYSA:  Well, I think the question of what happened in the U.K. when BSE appeared is difficult to answer, and a little bit tricky.  However, the statistics show that the U.K. changed from a import of MGM to an export in a period of time.
		And as they continued to export mammalian MBM until '96, apparently very keenly not to be used for ruminants, and I think that this was even clearly stated in the export permits.
		But what happened in the receiving countries was totally a question of the controls in the countries.  Since '96, and I think it was March  '96, there is an export prohibition from the U.K. of mammalian MBM.
		The only MBM exported after that period was poultry, and unfortunately it is included in the same customs categories.  So this was one of the problematics that you have looking into those figures.
		CHAIRMAN BOLTON:  One more question.
		DR. EWENSTEIN:  Yes.  I think we were trying at the last meeting to distinguish between sort of the indigenous risk that might grow up through the cattle from the imported risk directly, say, from the U.K. beef.
		And I think that is where France seemed to be a unique situation, or if not unique, then at least quantitatively different, and so maybe you could comment on that difference of risk.
		And now we are talking to the human population that we could assign to the importation of material directly for human consumption, rather than the risk that would then have to sort of grow up through the food chain.
		DR. KREYSA:  Well, I think that I have to agree with you that the importation of products for dietary consumption is a very important element, and as I mentioned, this is complicating the BSE human exposure risk.
		But it is also an element that we have ignored for practical reasons of GBR, because for example if half-carcasses were exported from the U.K. in the late '80s to France, they contained spinal cords, or at least until '99. 
		And this means that for some time that quite risky material could have been exported for human consumption from those countries.  The same thing obviously is with meat products. 
		Meat products contain the same as mechanically recovered meat.  Mechanically recovered meat was made or is made in some countries by using bones from skulls and the vertebra column with or without including the brain and spinal column.
		And it is mixed into a lot of meat products in various more quantities, and these are traded worldwide.  So, this is in fact also a source which one has to take into account when looking into the human exposure risk.  
		CHAIRMAN BOLTON:  I would just like to follow up on that exact question.  Do you know when mechanically recovered meat was banned from items for human consumption in the U.K., France, and/or the EU at large?
		DR. KREYSA:  Well, I cannot tell you the dates because I did not look that up.  I happen to come across the information that in the U.K. that skull and spiral cord was excluded from mechanically recovered meat in '96.
		But other countries continued to produce and use it for quite some time.  It is now banned.  It is not anymore.
		CHAIRMAN BOLTON:  Was that EU ban within the last year or so; is that correct?  Do you know that perhaps?
		DR. KREYSA:   I think it was.  In fact, the EU ban on the vertebrae column from use in mechanically recovered meat was last year.
		DR. FERGUSON:  Yes.  And I think that was included in the October 2000 SRM ban.  
		DR. KREYSA:  Some countries had included it before, and that is problematic.  You have the two different levels which is actually quite complicated, and I didn't look into these in detail.  But I could provide you with this information if you want.
		CHAIRMAN BOLTON:  Yes.  I guess the point that I would like to make is that during -- and especially in the U.K. during the peak of the BSE epidemic, mechanically recovered meat was still being incorporated or at least could have been incorporated into food for human consumption.
		That clearly presents the greatest risk of exposure of human to BSE.
		DR. LURIE:  I noticed that at one point that you had on the general slide describing the appropriate levels of precautions that countries at levels one, two, three, and four should be taking.
		And I am wondering that even though they were general, if you have any countries that in your mind stick out as being at that particular level, but not taking in a general way the corresponding precautionary actions.
		DR. KREYSA:  Well, if you want to minimize the risk that the BSE gets into the chain, you have different intervention points as shown in this GBR model.
		And the simple logic is the higher the risk, the more interventions that you should do, and the message from the experience in Europe is very simple.  It is not enough to try to control the vicious circle in one place.
		You should -- and you probably have to -- act on all possible control points.  It is kind of a hazard approach that one should have, and because of this very complex system, it is very difficult to have a hundred percent efficiency of the measures.  That is the sad experience which you have to make.
		CHAIRMAN BOLTON:  Okay.  I am afraid at this point that we must move on.  Thank you, Dr. Kreysa, again.  Our next presentation is by Professor Jean-Hugues Trouvin.  It is VCJD and blood risk assessment, an EU policy position.  Professor Trouvin.
		PROFESSOR TROUVIN:  Okay.  Thank you, Chairman.  It is a pleasure for me to be here to present the new points of view on the geographics of the VCJD and blood products.
		And for that, I would like to briefly present the EU analysis, and the situation in the European Member States, and before touching on the exclusion criteria, and segregation and sanitization issues.
		However, before entering the topic of my presentation, I would like to continue on the presentation made by Dr. Kreysa, and insist on a few  points on the BSE situation within the European countries.  And particularly on the interdiction of animal BSE testing.
		Thanks to these tests and based on the most recent figures, it is possible to have an estimate of the global incidence of the BSE.  In the EU, incidents calculated for three categories of animals, and these figures lead you to conclude that currently there is no even BSE activity in the EU.
		Another point to consider is the introduction of the U.K. cases of BSE reported in Europe since 1998 to March of this year.  It is important to mention that cases reported on this slide include those which have been found by testing where the animals are apparently healthy.
		From these figures, it is clear that, first, most of the cases have occurred in the U.K., but this is already well known; and, second, that the European countries as such should not be considered as one single entity.
		Moving on to the VCJD question and blood products, and before discussing exclusion types and other strategies, I would like briefly to summarize the main conclusions so far reached by the EU experience.
		The conclusions are the results of numerous meetings which have been held at regular intervals in Europe.  I have put at the end of this presentation a few slides -- but I will not choose them, of course.  Those you have in your handout documents, but to summarize the main dates and documents issued on this question.
		Based on all the opinions expressed so far, the risk analysis can be summarized in a few words.  First, the situation is different for the sporadic agent and the new variant, of course.
		For sporadic, it is possible now to conclude that the risk is remote to absurd in the transmission of sporadic CJD by blood.  As such, only exclusion criteria for certain donors should apply, and even it is known that there is no need to recall batches of medical products in case of a donor is found in post-donation to be at risk of CJD.
		In contrast, for the variant CJD agent, there are still many things unknown, and particularly whether or not it is present in blood of the CJD patients.
		In addition, it is an emerging agent in the epidemiological data are not sufficient to have a clear view as we have got for the sporadic agent.
As such, it is clear that there is a need for adopting precautionary measures.
		I would also like to remind the committee that there is a difference in the risk evaluations for plasma-derived medicinal products, which are the products which are discussing today, and the bovine blood products for transfusion.  
		Indeed, although it is two types of products obtained from the same mechanism, i.e., blood, for plasma derivatives, the manufacturing process has a number of steps that have been now investigated in the ability to remove the TSC agent if present.	
		And it is available now to compute that tests which are routinely used in the manufacture of these products are produced to remove the agent.  Along these steps, to mention the ethanol fractionation, the precipitation steps, or even the leucodepletion.
		And these contract with the bovine blood products from which in their preparation there are no steps identified as either to remove the agent if present in the initial donation.
		It is worth noting that at the moment the value of the leucodepletion goes for sedative component and for plasma is still under execution, even if some could consider that at the present time as a precautionary measure there is no reason for not using this product.  This is what is done in France, and in the U.K. at the moment.
		This slide is also to remind you that the products which are derived from plasma can be used either as active ingredients, such as coagulation or immunoglobulin, but can also be used as excipients, and particularly albumin in a wide range of medicinal products, such as vaccines.
		And finally there are also used sometimes as a reagent in the production of biology and biotech products, such as recombinant protein.  This is to say that in the biological plasma derived products.  
		Based on this risk analysis, it is possible to summarize, briefly now, the approach taken in the EU to minimize the potential risk of VCJD transmission by transmitted additives.
		First, to mention the U.K. decision to stop using the U.K. plasma for the manufacture of plasma derivatives.  I can tell you that in France they did not go the same way, and maintain the use of the French plasma for fractionation.
		Many Member States have also introduced or are introducing an exclusion criteria for donors whose spent time -- 6 months or 12 months -- in the U.K.  And as far as leucodepletion is concerned, both the U.K. and France are already commencing this, as have other Member States, after discussing the value of these measures.
		And other measures that I would like to mention is the precautionary measure to recall batches in case a donor subsequently gives lots of VCJD, and as you can imagine, France would be at the moment the first EU Member State to actually apply this measure one way or another.
		And finally all the measures and recommendations are essentially aimed at diminishing the side of the population exposed to blood and blood products.  
		Briefly, there are other measures which can be mentioned as having been adopted by some EU Member States and this potentially to mention the exclusion of donors with neurosurgery, but also permanent deferral for donors who have previously been transfused to remit the diminution of the potential agent.
		Now, going to the question of exclusion criteria, I would like first to remind you of the risk factors so far identified.  The main risk factors seems to be the residence, time, and time spent in the U.K. as clearly indicated by the hundred of cases reported in the U.K.
		However, we have also to take into consideration the risk factor for a donor of being exposed to the BSE indeed only count three, even without traveling to the U.K.
		There are three cases in France, and it is clearly traced the endogenous risk, which is essentially depending upon two factors.  First, the BSE incidents within the country, as well as the delivery of imported BSE infected material from the U.K. in 1990-1996. 
		This is to say clearly that EU countries have a different level of risk, and that we have a wide spectrum, starting from the most risk situation within the U.K., and ending very lightly with Finland, for example.
		Again, we are still of the notion that Europe should not be considered as one entity.  As an example, in France, it has been exclamated that the risk is 1/20th of the risk exposure in the U.K.
		And we estimate the potential date of two figures.  The importation rate of future MBM and entering the food chain in France in the period at risk, and the three percent related figures in VCJD cases in France compared to the U.K.
		And these two figures are very close, and we see certainly incidents.  However, these two figures are a clear and good indication of the BSE exposure risk in France are endogenous or imported.
		As such, France should be considered as the worst European case after the U.K., and it is very unlikely that any of the other EU Member States will ever catch up with the U.K. or French situation.
		And with discussing the scientific basis for deciding exclusion criteria, I would now like to discuss the possible frequency of further exclusion measures are settled.
		First, we have to consider for plasma derivatives that this is a global market situation.  Indeed, for U.S. plasma first, as you know, commercial producers are working on a global scale using both U.S. and EU plasma.	
		And even if the destination of the resident products are different, this is a global market.  It is also important to mention that since 1998, when the U.K. decided to stop fractionation of their plasma, they have been using U.S. plasma in such a quantity that when in France, they attempted to find potential sources of plasma outside France and the EU.
It has been impossible and the plasma market was already reserved.
		Now, in the European picture, we have almost the same picture.  Indeed, the commercial producers are using plasma collected essentially in Germany, Austria, and Sweden.
		And as the plasma is delivered, the plasma is collected usually by the National Red Cross organization, and sales to produce plasma derivative medicinal products which are used domestically, but also certain diseased products enter the global worldwide market.
		And I think with those elements in mind, it is very easy now to see the foreseeable frequency of new stringent exclusion criteria which could be taken at the U.S. level.
		There will be first a further loss of U.S. donors, and then the diminution in plasma availability.  And an increased demand for U.S. plasma and for the finished product because of a passage of recent induced by the exclusion decision.
		And there could even be the case where commercial producers could decide to no longer use the EU plasma anymore.  This is to say that the consequences of an exclusion measure of not only to be considered at the U.S. level, but also under a worldwide scale.
		Another alternative or proposed measure could be the segregation of manufacturing line.  At the moment, the situation is that commercial producers are making use of the same manufacturing line to fractionate U.S. and/or EU plasma at least in the EU manufacturing sites.
		However, it should be acknowledged that in these manufacturing facilities the EU plasma has the same exclusion criteria as the U.S. plasma at the moment.  
		However, what would occur if the EU plasma, due to new exclusion criteria applicable for the U.S. plasma is no longer or can no longer co-exist with the U.S. plasma on the same manufacturing line.
		The imposed segregation line will impact on plasma availability and it will take a substantial period of time to establish a separate line, and eventually even to close facilities for implementing this segregation.
		There will be the question of what to do with batches produced and eventually to evolve the segregation issue, and producers may even decide not to use the EU plasma, and we are back to the situation forcing segregation.
		And finally, but not too forget it, the segregation creates a loss of flexibility to move to alternative facilities.  The last point just before concluding deals with the sanitation procedure, which has to be envisaged as an alternative to line segregation.
		However, depending on the type of sanitation procedure to be put in place, this could also impact on the time scale of correction, and therefore diminution of the global and world production capacities.
		All these elements have to be taken into consideration before making any decision.  The respective value of each individual measure has to be technically evaluated.
		In conclusion, I would first like to stress again that for blood or blood products that a local policy will have local impacts for plasma derivatives, and it is clear that the impacts of any  proposed intervention have to be initiated globally in a worldwide approach.
		And with the exclusion of donors who spent time in Europe, the impact on the blood supply is largely dependent on the option chosen.  As long as the option maintain both the EU and U.S. plasma are the same or very similarly level of requirements, the global impact on plasma supply would be affordable.
		With regards to segregation, just to remind that segregation would take considerable time to put in place.  The U.K. experience which has been reported in front of this committee two years ago should be considered in this respect.
		The improvement of sanitation procedures may be seen as a possible alternative to line segregation, and should be technically investigated.  And finally, as a general comment, Chairman, I would like to stress the need to balance any precautionary measure against the real risk of supply shortage in plasma products.  Thank you.
		CHAIRMAN BOLTON:  Thank you, Professor Trouvin.  Do we have questions from the committee?  
		DR. EWENSTEIN:  You seem to be making the same case that we made last time to look at France differently than perhaps the rest of Europe.  How does that translate into your own recommendations for French donors versus the rest of Europe?
		PROFESSOR TROUVIN:  If you -- the French case as apart from the rest of Europe -- at the 
moment, and maybe as we knew, and maybe you knew that in Europe the French plasma is essentially used for fractionation and for internal and domestic use in France.  
		There is very few plasma used in the European plasma collections, and the derivatives that are derived from the French plasma.  So this means that it is a very internal market for France.  
		So even if there is a further exclusion criteria for those donors who spent time in France, and restriction for French donors, the impact on the global availability would be very little. 
		CHAIRMAN BOLTON:  Okay.  Thank you, Professor Trouvin.  Our next presentation will be by Dr. Christl Donnelly, and it is the mathematical  modeling of potential human BSE exposures in various BSE countries.  Dr. Donnelly.
		DR. DONNELLY:  Thank you for inviting me back.  I first spoke to this committee -- well, the one other time, two years ago when the consideration was focused on the U.K.
		And I pointed out that in some ways I had the easiest job of anybody advising you, because there was a great deal of data on BSE and the U.K.  We knew very precisely what was going on.  
		But you had to consider what was going on. First, the potential risk of variant CJD infection from food, and then furthermore what that might pose as a blood risk.
		When we moved to BSE in Europe, as you will see in the course of this presentation, things are very different.  There is the BSE you see and the BSE you don't.  The BSE you see comes in two forms; traditionally reported clinical cases, and these reporting varied through and from country to country.
		It has been the case of every BSE epidemic that has been -- every country's BSE epidemic that has been analyzed in detail -- Great Britain, Northern Ireland, France, Portugal, Switzerland, all of those countries that have had substantial BSE epidemics, when you actually look at the data in detail, the ages of animals infected, you can find evidence that cases were under-reported to begin with.
		Now the difficulty in switching from analyzing those countries to countries where you only have a couple of cases is impossible to prove just looking at the fact that you have had two cases in the country, and whether you have excellent surveillance, and have picked up the only two cases that have happened.
		Or whether you have poor surveillance, and you have only picked up two out of "N" and where "N" 
could conceivably be quite large.  But more recently and starting at the beginning of this year, there has been the requirement across the EU, not for Britain, and as I will explain later, but for other countries across the EU, to test using a test for animals slaughtered for consumption over 30 months of age.
		And this provides primarily not consumer protection, although it was misinterpreted initially, because the test won't necessarily pick up all infected animals.  
		But it gives from the point of view of risk assessment an objective additional piece of information where we can actually then distinguish between those countries that have surveillance, and where they are picking up everything and are just low cases.
		Or where they might not be picking up the cases.  So we can compare these two.  But it is important to realize the risk to humans comes from BSE you don't see.  
		Those animals that are picked up as reported confirmed cases are not then eaten by anyone.  Also, those animals that are tested over 30 months that are tested and come out positive aren't eaten.
		So it is the other infected animals that weren't picked up and either of these methods that were consumed and therefore pose risk to humans from direct transmission from BSE.
		The ratio of infected -- of original infections to clinical cases, even with a completely reported situation, is about 5 to 1.  And that is because the incubation period of BSE is so long, about five years on average, compared to the average life span of cattle.
		And most of those animals will be slaughtered early in the incubation period, but still it means that in the UK we estimated on the order of three-quarters of a million infected animals were eaten over the course of the epidemic, compared to the 178,000 clinical cases that have been reported so far.
 		What I was originally going to concentrate on in this talk was on that calculation analyses that the technique originally designed for the analysis of age data that our group developed in 1996 for the analysis of the U.K. BSE epidemic.  
		Since it was used to analyzed data in Portugal, and you can see here that it was originally analyzed in 1998, and we were able to estimate using various assumptions under-reporting what the infections were through time.
		You see the infection incident on the top graph on the right by birth cohort, which shows that it was variable.  The blue is, if I assume no under-reporting, and all cases were reported fully. 
		The red is if I allow for under-reporting,  because the age profile of the cases that you see gives you some indication of what reporting patterns were through time.  And that leaves at the bottom as you can see projections of future cases.  Next slide, please.
		More recently in France, I published an analysis last December looking at the epidemic in France, and there was particular concern because the year 2000 had the highest number of cases so far.  
		Now, what you see in the epidemic in the U.K., both in Great Britain and in Northern Ireland separately, is that these epidemics peaked in terms of the number of cases back in the early '90s, and the case numbers are going down reassuringly.
		The problem is that when you look at other countries, you find in some cases that case numbers are still going up.  But the difficult balance is what you want to know is what the pattern of clinical cases was, because that gives you some idea of what the pattern of exposure was.
		But what you see is reported clinical cases.  So you could have reporting going up, and clinical cases going down, and it still looks like the risk is going up.  
		But now because of this additional information we have across Europe, where it was actually looked beyond the clinical case data, and look at the actual testing data.  
		This shows the estimates allowing for reporting and under-reporting in this graph on the right.  In the red, it shows my estimates if I allow for under-reporting; and in the light blue, if I don't allow for under-reporting.  
		And you can see that you get varied different estimates.  As I said, allowing for under-reporting substantially improves the fit.  You can find significant, very significant statistical evidence of under-reporting through time.  
		This, combined with more recently -- earlier this year an analysis of the Republic of Ireland of what got a lot of press interest was the conclusion that because of the 30 month ban in Britain, and I think this is the key thing that was chosen, that 1996 was chosen as the cutoff for Britain in the ban that was selected two years ago, is because in 1996, a whole lot of things happened with the identification of variant CJD.
		Two very critical things happened; stopping the animal epidemic, in terms of primary infections in huge clampdowns and additional regulations on feed, and including monitoring of feed.
		And there are various enforcement documents that you can find on the web that show testing that goes on in various speed lots to look for both on material or mammal material in any bovine feed.
		And also the most direct thing to prevent additional human exposure was this ban on animals over 30 months being slaughtered for consumption.  And that has been in force from 1996 and continues to be.
		This did not take place throughout Europe. It was only in the U.K., and as a result, with the increasing numbers that we are seeing in France and Ireland, you could actually find that in the year 2000 there were more late stage infected animals, those animals within 12 months of clinical onset.
		And which have been found in various tests to be potentially the most infectious to mice in tests, and that there were more slaughtered for consumption in France and in Ireland than in the U.K.
		I would argue that this is not the key relevance to you, because you are worried about the main bulk of infections, and even these were with relatively small numbers.
		The reason that the U.K. number by comparison is so small is because of the 30 month age ban.  But compared to the 750,000 infested animals consumed over the course of the British epidemic, what is going on in terms of these relatively small distinctions is not key.
		The key thing is in looking at the overall course of the BSE cases in the BSE epidemic, what that means in terms of variant CJD risk.  You see here in purple the things that we have information on, the BSE cases and the variant CJD cases, and in between are all of those boxes for things that we don't know very well.
		How infection was transmitted, and how infectious it is, and what the human incubation period  is.  And we found by our analyses in the U.K. that there is a wide range of scenarios that are consistent with the BSE cases and exposure that we have seen, and the number of variant CJD cases, which is roughly about a hundred right now in the U.K.
		So this could range in terms of future epidemic size from very small epidemics and we would see relatively few additional cases if the incubation period is relatively small, to considerably more cases, over a hundred-thousand, even in the 40 percent of people that have a specific genotype.
		It is the one that has been shown to be susceptible.  We don't know yet about the 60 percent of other people, and whether they are less susceptible or simply have longer incubation periods.  
		The difficulty is, of course, that not only do you have all that uncertainty, but you are adding the additional uncertainty of when we have done those analyses we have assumed that all infections come from feed, or from food, to humans.
		And that in terms of order of magnitude, the right thing to do for this sort of assessment now. But since there is the possibility of blood borne infections, that adds another layer of uncertainty, and means that you are really dealing with something where you don't have epidemiological data.
		Even over the course of the whole epidemic, if we look back on this in 20 years time, we won't actually know which people for the most part, we won't know for the most part which people were infected by blood and which from food.
		So I think the key thing that I am going to focus on then is this European testing program.  There are limitations though.  I don't actually know the ages of animals that were tested specifically, and the ages of those that were positive.
		There will be age facts both in terms of animals born at a particular time might be more likely to be infected, and also the fact that this sort of testing is almost certainly picking up only very late stage infections, which means that even if they were testing animals under 30 months, they would probably pick up few of those animals that are infected.  
So there is that caveat.
		But within those limitations I think we can see some very interesting results.  This shows -- and I will show you graphically the conclusion of this, and so don't worry about all the specific numbers.
		These are European countries, EU countries, not including the U.K., and this requirement of testing of all animals over 30 months slaughtered for consumption doesn't apply to the U.K. because those animals slaughtered over 30 months aren't for consumption.
		So I am just comparing these countries, and also because Switzerland is not in the EU, and it does not have comparable data, and so it is not shown here.
		This shows the results, which show that there were 76 infections found in the nearly 1.8 million healthy adult animals that were tested across the EU.  But it is interesting to look at where these actual animals are found.
		I will mention Portugal specifically a bit later, which has found no infections, but does have 37 results pending, which I am not exactly sure what that means.  Next slide, please.
		I think it is important to look at the variable amount of testing effort before we actually look at it, because if you are doing less testing, then you are less likely to find positives.  So you should take that into account.
		And you see that it varies actually quite a bit, and Sweden had no tests at all.  But you find that Germany has had a huge number of tests.  This is healthy tested cattle per million adult cattle in population.
		And so it should be comparable across countries.  It should be independent of actual size. You see that Portugal surprisingly for a country that has relatively such a high risk is doing relatively little testing.
		But other countries are doing considerable amounts of testing, and these results have come through.  Next slide, please.
		Presenting the results here in two ways, showing the difference in ordering.  Here I have shown the prevalence expressed in positive per 10,000 healthy animals tested, in terms of the estimated prevalence.
		And you see that Spain is the highest, 22 positive tests out of the animals that were tested, and that drops off, and you see that positives were found in Italy, Belgium, France, Germany, The Netherlands, and the Republic of Ireland.  
		I then have shown you for those countries that have found zero infections, and in each case the 95 percent confidence interval, which we statisticians like.  And that shows you that if you found no cases, how certain are you of what the prevalence is.  
		And you see like in cases in Finland, and Portugal, and Greece, and Luxembourg, the testing numbers are so low that you could have still a very wide range of possible incident levels.
		So then in the next slide, we will look at the possible potential risk for prevalence, and you see that it is still possible that the four countries -- Finland, Portugal, Greece, and Luxembourg -- could have potentially higher prevalence than Spain, because their testing is such that they can't rule that out. 
		But I think that you need to keep these two things in mind.  How much testing has gone on, and what prevalence has actually been found.  But I think one of the key results from here is that you can see by looking at this that Spain has significantly more positive tests coming out than France does.
		And Portugal still has or is in the range of that confidence interval, and I showed 32, 26, and 12, and that is the upper limit of the confidence intervals for the countries of Finland, Portugal, and Greece.  So they really are hugely variable.  Next slide, please.
		Then you think, okay, let's compare what has been found in terms of the testing results with what had been reported in clinical cases.  And what I have done is shown you the reported clinical cases that were confirmed before 2001.
		Because it has been pointed out that France had more cases in 2000 than in previous years, and Portugal's big leap in case numbers was in 1998 and so on.  But you are finding that some countries are now reporting clinical cases that hardly had ever had them before, Spain being one of those.
		In the past, Spain had two cases that were showing up in the end of 2000, and there are now reports of clinical cases in Spain, as well as the 22 positives that were shown up through testing.
		So I think one of the lessons from this is doing testing of asymptomatic animals can have a good effect on your reporting levels of clinical cases.  But what it does show is that there is not a good concordance between the relative prevalences found in terms of testing, and not found in clinical cases.  
		So I think it would be very difficult for you to actually pin all your hopes on looking at relative risks in terms of just those reported clinical cases, because it is a difficult balance between what cases occur and what are actually reported.  Next slide, please.
		And finally I have shown you still the same reported incidents, in terms of the number of cases, but compared to the reported clinical cases per millions of adult cattle, because I think it is important when you are actually looking at this to take into account that two BSE cases in a country with a much larger cattle population does per State pose a lower risk, or per unit of MBM.
		And again you see that Portugal as being the highest, and I think that's why it was put in this top category with the U.K., and to put these numbers in perspective though if you were looking at reported clinical cases per million adult cattle in the U.K., that would be on the order of 18,000.
		So these are still considerably lower risks, and I should point out that I sort of categorize things in terms of the color of relatively high, medium, and lower risks.  
		These were purely -- I was just trying to give you distinctions looking at them.  I am not in any means categorizing them on the basis of what you might want to do in terms of precautions, but just showing you to compare.
		And the other one that I should point out is Italy, which had no clinical cases reported before 2001, has the second highest prevalence in adult healthy cattle tested.  So it has been extremely difficult in comparing those two things.  And the next slide, please.
		If you were looking in 1996, only those three countries -- Portugal, the Republic of Ireland, and France -- had had clinical cases by then.  So things are changing all the time, but I think it is this testing that doesn't help you realize in non-EU countries.
		But I think that the testing program that has gone on in the EU will show increasingly more information that you can actually use, and that you don't rely on countries reporting systems and the debate that surrounds that.  Next slide.
		And the way to learn more about this is that the British epidemic is described in what was the Ministry of Agriculture for Fisheries and Food, and what we now call DAFRA, which has a website.
		And there is information on worldwide BSE from the International Organization for Animal Health, and there is access to this EU cattle testing data also on the web through the U.K. Food Standards Agency, and through the EU.  Next slide, please.
		And there is additional publications, and I am happy to send people by E-mail a list of more publications, and finally I should thank my colleagues that have worked on this with me over the past 5 years.  Thank you.
		CHAIRMAN BOLTON:  Thank you, Dr. Donnelly.  Questions?  A few maybe, or perhaps none.
		DR. DE ARMOND:  I have just some simple questions.  Can the clinical diagnosis of BSE be confused with any other disorders?  Are we really certain of those numbers?
		DR. DONNELLY:  Oh, I think there are quite a few -- well, it is difficult for me to answer that.  It has varied over time in the U.K.  In the U.K., there is quite a few animals that are put forward by vets and farmers that when tested histologically are found ont to have BSE. 
		So certainly even in the U.K., where vets should be relatively familiar with it.  But people are encouraged and actually get greater compensation for animals that are slaughtered and found BSE negative, and even for the BSE suspects themselves, they are paid to encourage reporting.
		It is probably better maybe for one of the vets to comment on that, on the histologically background, but there certainly are those epidemiological evidence that it is difficult.
		But that is sort of distinguishing what you have identified as suspect.  Actually, what we are worrying about here is just not realizing that you should call the vet in at all.  
		And certainly from the video that I have seen, if you allow an animal to go to late stage disease, I think that any farmer should see that something has gone wrong with it.  
		And it could be that milk yield goes down, because the animal is not milking well, and so it gets sent to slaughter before it is actually realized that something is more fundamentally wrong, and it is difficult to rule that out.
		DR. DE ARMOND:  The other question has to do with testing of normal animals without clinical disease, and what kind of testing was that, and that is in a lot of animals, close to a million animals.
		DR. DONNELLY:  Yes.
		DR. DE ARMOND:  So, how was that done?
		DR. DONNELLY:  The so-called rapid test.  I am not actually aware of the -- and some other people would be in a better position to discuss that, but my understanding is that it is a test where you really only pick up late stage animals.  
		But the difficulty is that these people aren't aware of how early in the incubation period it will pick them up.  
		CHAIRMAN BOLTON:  Dr. Cliver and then Dr. Piccardo.
		DR. CLIVER:  The signal to noise ratio about BSE tracking in the U.K. has been perturbed by the foot-and-mouth disease outbreak, and along the way we see some concerns about FMD animals that were put down, and then buried somewhere there was ground water intrusion and so on.
		I am wondering if anything is being done in the U.K. to try and get a handle on how stable and transmissible BSE prions may be via ground water or surface water, or alternate routes of transmission than the ones that we are already considering?
		DR. DONNELLY:  There is.  The only cattle that have been buried as a result of foot-and-mouth disposal have been animals under 30 months of age, and the TSEAC group in the U.K. spent a lot of time considering whether to allow that.
		But the scale of the foot and mouth slaughtering and disposal problem was such that that choice was made.  There were details and sort of environmental assessments of the areas that were chosen, and I believe that is being studied.
		But it would be best for this group to contact TSEAC directly on what the actual details are that are going on.  In terms of actual surveillance of BSE, I don't think the foot-and-mouth epidemic will have any long term consequences on that, because as well as delaying that from getting on to the farms, it was actually delaying animals getting slaughtered, and in terms of routine slaughtering as well.
		So I doubt that that will actually affect the clinical cases that we see reported.  
		CHAIRMAN BOLTON:  Dr.Piccardo.
		DR. PICCARDO:  Will governments in the European Union provide compensation for reporting or is there a discrepancy among different governments?
		DR. DONNELLY:  My understanding is that all European countries would provide compensation for BSE cases.  It also is the case that outside the U.K. the whole herd is slaughtered.  
		Oh, it has been changed, but this has historically been the case, that the whole herd was slaughtered, which would have positive benefits from a human health point of view; that if you got a clustering of cases, that would ostensibly reduce the number of infections of animals that might slaughtered while infected out of that heard.
		But it does mean that there have actually been cases prosecuted in the Republic of Ireland, and I don't know of elsewhere, but where people were actually trying to import a BSE infected animal into their herd so that they could get out of farming.
		But I think that for the most part that the whole herd slaughter policy could be seen as a possible disincentive to report a single case if you wanted to continue to farm.
		DR. PICCARDO:  I am suspicious about the situation in Portugal, because it shows that the amount of clinical cases reported and the amount or the discrepancy between the number of clinical cases and false-positive cases.
		DR. DONNELLY:  Yes, I was quite surprised as well that they had zero positive tests, but one of the things that you do see is that they have done a lot less testing than you would expect compared to other countries, and they are the only country that lists pending results.
		So if in the worst case scenario all those 37 were positive, they would be at the top of the list in terms of prevalence.  I did look back though at previous months to see what the pending results were, and there have been pending results throughout the case, but you would certainly want to see how those are getting resolve.
		Did the results that are listed as pending now, are those later going in as negatives, and you get other ones showing up as pending; or is it just an increasing class.  But that could be investigated.
		CHAIRMAN BOLTON:  Dr. Epstein. 
		DR. EPSTEIN:  You mentioned approximately three-quarters of a million infected animals may have been consumed in the U.K. in the epidemic period.  Are there comparable figures for other countries that you have been able to estimate, because what we are mostly concerned about the cumulative human risk, country by country.
		DR. DONNELLY:  Well, it is extremely difficult because of this problem of under-reporting. It is certainly the case that you could have tens of thousands of infected animals eaten in countries like Portugal, Ireland, and even France, depending on what you submit under your reporting, and Switzerland.
		But the difficulty is of course if I looked at France a year ago, and before we had actually seen the 2000 case data, I would have given you a very different picture for France.
		So I think that actually the estimates will be much better in a year's time when we have actually had more data from this testing result, because we can only say, well, when you do this in an assessment for under-reporting, you have to assume that at some point that under-reporting went up to a maximum level of, say, a hundred percent.
		And if you assumed that reporting improved up to that level this year, looking at 2000 as opposed to next year, you would get a very different picture for Spain, for example.  So it is very difficult to be precise at this moment.
		DR. DAVEY:  One more question.  Well --
		DR. BELAY:  Dr. Donnelly, there are still some BSE cases reported in the United Kingdom among cattle born after 1996, despite the fact that the control measures were rigorous after 1996.  What are those cases attributed to?
		DR. DONNELLY:  There have only been -- I think it is either 2 or 3 cases that have been born since mid-1996 that have come out as clinical cases.  One of the things that our group did -- and we were involved in two different assessments of data relating to maternal transmission of BSE.
		That is the maternal cohort study, which looked at animals to BSE infected dams and a matched animal in the same herd, and that showed an increased risk of BSE in the off-spring.
		But since that was ambiguous, it could have been genetic.  We also looked at the database and found more dam calf pairs of BSE cases than you would expect by chance in those animals that were the last born calf, and we would suggest that it was maternal transmission.
		We then looked at how many cases of BSE we would expect in animals born after 1996 due to maternal transmission alone, and found that this is in excess of what we are seeing now if you assume 10 percent maternal transmission in the last six months of the incubation period.
		That said, it is my understanding that one of these animals that is a BSE case that has been found, its mother is still alive, and is apparently not affected by BSE.
		And it also has off-spring and it has siblings that are also not affected by BSE.  So it is very difficult to figure out how this animal could potentially have been infected unless it was through a non-maternal means, because all the evidence that we found is that it is only in the very late stage of infection that is maternally infectious.
		So there is that one animal, but it is uncertain.  But so far in monitoring it, we have seen fewer cases than we would expect through maternal transmission in these animals born after the middle of '96.
		CHAIRMAN BOLTON:  Okay.  Thank you, Dr. Donnelly.  I think it is best that we move on as we are rapidly running behind schedule.  Our next presentation will be by Dr. Antonio Giulivi, and it is entitled, "BSE Exposure, Risk Reduction, and Projected Effects on Blood supply."  Dr. Giulivi.
		DR. GIULIVI:  Thank you.   Mr. Chairman, and Ladies and Gentlemen, what I will be doing is presenting a risk assessment that Canada has done, and you have to understand the way we work in Canada. 
		The department that I head up is a public health department.  We work with industry, and we work with the blood centers and so on, and we also give information and assessment, risk assessments, to the regulators, a different department in Canada, and we are completely separate.
		And we are able to interact freely with different consumers and so on, and so we usually do risk assessments and we also suggest to the regulators what we think in public health will happen.  
		This is a step that has been three years now and it has been working well.  It is experimental, and this is the way that Health Canada is working, and it is working quite well.  
		So what we did is that the regulatory people asked us to look at again the situation of all of Europe and BSE, and should there be deferrals for donors in blood for Canada for travelers that went to Europe.
		And we constantly do this every 2 to 3 months, and so it is an open book, and we just don't shut the book.  We keep on doing that.  The other thing that you will see, and which is the most important slide at the end, is the blood supply, and the amount of supply in the hostel.  
		We have seven hostels that we fund to look at what happens if the blood is not there.  The other thing is that at the end of my presentation the CBS is going to present four slides on how they got to their risk assessment and how they got to their donor assessment.  It is quite important and I would like for them to present that data.  
		So we took all of this into consideration, the past and the present, and we took into consideration when things started to happen, and when it was discovered, the theoretical risk,a nd look at the literature.  
		We have our own experiments that we are doing with Health Canada with animals and so on about transmission, and we are funding some elsewhere.  Then the story of what happens in France with the three cases, and then animal studies that may support the transmission of blood, and I can actually say may.  The next slide.
		We looked at the total cases of VCJD in the U.K. and France., and we knew at that time while we were doing this that we knew about the case already of Hong Kong.  The annual reporting of the BSE beef during this time -- and this was very hard to find -- reporting the number of cases of BSE in Europe.
		And then we predicted the BSE. because what we are looking at is -- the first question is the BSE of that country appearing in our country, is that the same risk as the U.K. that happened 10 years ago. 
		What is the magic number of how many cases you need to consider that country high.  That was the question that the regulatory asked us.  So we had to do all these analyses for every country, which I am going to go very fast through it.
		The bottom line to it is that it is our conclusion that you need at least 1 in 700 animals coming down with BSE before you can consider that country the same risk as the U.K., and that was our conclusion.
		We looked at the emergence of the BSE, and the disease probability presenting earlier, and how it develops.  You heard this before with Donnelly, and the exposure.  We looked at the bans that took place in different countries, and especially with the U.K., and then all bans that took place in different countries, which was very hard to find.
		We looked at the human exposures that may have started in the U.K., and we really took this into consideration.  This was the major risk for us, the mechanically recovered meats.  
		We looked at how the graph was going on reported cases of variant CJD, and Canada is part of the U.K. system, a European system of reporting variant CJD and CJD, and we are very active in that.
		We get a lot of information from a lot of countries, and you can see that we are predicting that this would be around 30 to 40 this year for the U.K.  So there is an increase, and that made us rethink maybe our policy for blood has to be changed because of that increase in the U.K.  The next slide.
		The information that is not available in the incubation period, and we assumed it was 20 years or better.  The minimal dose we still don't know.  The age distribution and slaughter, and the dietary habits between U.K., France, and other European countries.  Next slide.
		We looked at the probable source, which again we did the mechanical, and that's where we really pointed to, and the prevalence of the countries that it would transmit to, the animal or cow, and the food imports.  Next slide.
		Now you are going to see a lot of graphs on the prediction of the countries that we looked at, the BSE countries that will all happen the next year or the year after, and so on.  
		These are predictions that are done, and they could be off, but for us to sort of give a value to work with.  Next slide.  We looked at the categories, and we took all the information from Europe.  Next slide.
		And we looked at how the cases of BSE was appearing in certain hard to predict countries.  Next slide.  And then we looked at the annual imports of U.K. beef by the country, by certain countries, and we see some of that information through the U.K., and some through WHO, and some through contracts, and through official contracts with governments.  Next slide.
		And this is what we got.  The increase you can see keeps going down, and then the increase of all other countries, but when we predict and predict high, you will see that it doesn't go as high as a thousand per month, and that is what is important.  
		So in public health, which is my department, we said that the public health, that really what you have to look at is U.K. and France.  The other countries are going up, but they are not hitting the level of what happened in the U.K.  Next slide.  And you can see that it is going and increasing.  Next slide.
		And I am going to show you some graphs that it was hard to predict these numbers, because of the confidence intervals are all over the place, but this is what you have to deal with when you deal with these models.  
		So this is for Belgium and for France, and it was easier, because it is a tighter fit.  Next slide.  For Germany, there is a big variance there.  Next slide.  And for The Netherlands it is the same big variance.  Next slide.  
		Ireland is a tighter fit.  Next slide.  Portugal, as you heard, we really don't know what we get from their country.  It looks like a tighter fit, but we don't know about that.  Next slide.  And Switzerland is a wide variance, and the U.K. is going down, and wide.  Next slide.
		So what we did is that we said, fine, we can't look at BSE countries, and we have to look at variance CJD, and the amount of food, and that is the second one; and the third one is blood supply.
		So we have a study with seven hospitals and it has been going on for almost nine months now.  And the hospitals are major hospitals that have 2 of the 3 criteria.  
		They have a trauma center, and they have a transplant center, and they have an oncology center.  And those are the three criteria, and four is cardiovascular.  You need two out of those four to be considered to be -- for us to do the analysis about blood supply. The next slide.  
		And the last time when we did our policy and we came out with six months, and six months, and six months; U.K., six months, and France, we looked at the reduction of risk versus blood supply and loss of donors.
		And the percent of the loss of donors, and when you have a monthly stay in certain countries, you see an increase in a hockey type stick.  So for us we went to six months, because we were able to reduce the risk to about 72 percent, the global risk to 72 percent, with a reduction of about almost four percent of the donors, 3 to 4 percent.
		And that was done in step wise; two years ago it was the U.K., and last year it was France.  Next slide.
		So we asked the blood system, CBS and Hemo Quebec, and Joanne Chiavetta will present this in more detail, to do their donor questionnaire again, and to look at where they traveled, and different countries, et cetera, and look at the cumulative risk reduction.
		And she will go into all of this, but the thing to look at here is that if you go to U.K. and France, you reduce the cumulative risk all the way up to 88 and even higher, because Hemo Quebec went to one month.
		When you add other countries to it, you don't get that much of a risk reduction, and you lose a lot of donors.  Now, the next question is what does this translate to blood loss in a hospital.  Next slide.
		This is what I was talking about.  This is about 450 units per day being issued in seven hospitals; with hospital beds of 150 to 350.  In Canada, hospital bed size of a hundred comprises about 65 percent of all hospitals in Canada.  The rest are higher, and about 20 percent are about 200 beds or higher.
		About 20 to 30 percent have trauma centers and cardiac.  So we target those centers.  And we looked at daily issues, and the amount of blood that was at the blood center, and what was given to that hospital.  
		So here when I said that the percentage of loss of blood, is that a 10 percent loss or 90 percent loss of inventory and that does not translate into donor loss.  What we are able to do with questionnaires and so on and looking at the data is what happens to that blood center if it was donor loss really.
		This translated in our eyes to about 1 to 2 percent of donor loss, and this could happen because of holidays, people on vacation, and so on.  So you get these swings.  
		And this study was done after -- also after four months of our introduction of the six months deferral for France, or that had to stabilize.  The moderate effect -- and what I mean by moderate effect is blood being delivered to the hospital bed late.  
		It does not affect that much patient outcome.  Moderate effects is when you start to switch blood around in the hospital, and you divert the blood from the floors to the ICU, and divert them to the cardiac unit, et cetera, and divert them to cancer patients treatment.
		And this is when we see about a 15 percent loss of donor -- well, not of donor, but of blood supply.  This is red units.  It was very hard to do with this platelets.  So we took the easiest one and that was red units.  And this is also excluding autologous.  
		That translated to about 2 to 3 percent donor loss at that end at the blood services.  Riskier side effects is when -- and this has happened three times during that month-and-a-half study -- for about four hours that they had to cancel an important surgery.  For example, a transplant -- kidneys, liver -- and most liver.
		And they have to postpone transfusions and transplants for bone marrow.  Also, this is where in the ICU, and the information that we got back from the ICU and the trauma center, this is where they start to increase the dopamines, and start to increase fluids to compensate for blood lost.
		So they are putting -- they are adding more pharmaseuticals in delivery and treatment that could be done easier with just blood transfusions.  This never happened in Canada, because the blood services, both Hemo Quebec and CBS, really work well.
		So within the 12 hours this doesn't happen, but since the supply is very critical right now at this level, this reflects about greater than 3.5 percent to 4 percent donor loss.
		If you put a deferral, it is going to affect about a 5 percent donor loss.  I know that they have to recruit that, but there is going to be a lag.  There is going to be 12 hours or 15 hours, or 20 hours lag, for getting that blood in.
		And this is what we saw here, is this risk for 10 hours, from 6 to 10 hours in the hospital, and in the trauma center, that a patient may die, and the possibility of that patient dying.  Next slide.
		So what we did in the past because of that information, we did the deferral for U.K. and France for six months, and we had the risk reduction, and the donor loss.
		What we are saying to the regulatory people is since the EPI center is U.K., and France is the second highest risk there, that is where you should target to reduce your risk of exposure, and which is a theoretical risk; versus the true risk of blood lost.
		And Joanne will talk about this, because they really helped us out, and they did all the work on this, on the blood services.  Joanne.
		DR. CHIAVETTA:  Hello.  I'll tell you just about two surveys done most recently.  The first is -- oh, the next slide, please.  We redid our travel survey, including more information about Western Europe.  We did this in March.
		And 13,000 donors participated, and this questionnaire was handed out in the clinic the way the other studies have been done.  So basically 13,000.  So, I won't go into all of the results, but basically we found that -- well, this is really the results from the survey itself.
		So, 3.4 percent of our donors had traveled to Western Europe, and we did only include Western Europe, but I won't go into what countries we called Western Europe.
		And then 2.4 were for six months, and one year was 1.9.  Now, we also looked at -- now, we had already deferred for the U.K. for six months or more.  But in fact in my original survey we found that there were 2.5 percent of donors -- and this is more than a year or almost two years ago now, but 2.5 percent of all donors said that they had been to the U.K. in the survey.
		But in reality we only defer about .2 percent of donors today.  Now, this is remarkably similar to Alan Williams' study in the REDS survey.  Canadian Blood Services and the study done in the U.S. results were very, very similar with regard to the proportion of donors who traveled.
		And in fact the real deferral being about one-tenth of that which was reported in the survey.  So today in Canada, we are losing about .2 percent of donors due to U.K. travel in all provinces except Quebec.
		And so in this survey, we still had people who said that they did live in the U.K. for six months or more, and they probably should not have come back, but they did.  
		So if we shorten our policy to three months in the survey data, the survey data would be 1.9 percent additional.  Of course, you have to take one-tenth of that for the reality of whether donors who actually come in.
		And if we shorten France to greater than three months, a survey result would be .7 percent.  Next slide, please.
		We then recalculated our residual -- I'm sorry, we did our risk calculations again, and we counted France as having 1/20th the exposure, and Western Europe as 1/50th exposure of the U.K.  Next slide, please.
		And this is our risk reduction.  It is a little different from Dr. Giulivi's because we didn't include Hemo Quebec, and also we had some assumptions in the model, that basically if we had six months for everywhere, and for every place, it is 66 percent of the risk removed.
		And the last one for three months and six months, 75 percent.  It is very worrying that if we reduced the U.K. to one month that we could really substantially increase or reduce the risk substantially.  Now, that also probably wouldn't be very good in terms of blood supplies.  Next, please.
		Okay.  This is my last slide.  I am going to skip topics and tell you that I mentioned that 2.5 percent of our donors in the original survey said that they had been to the U.K. for six months or more.
		In real life, only .2 percent of our donors said that they had been to the U.K. for six months or more upon deferral.  What happened to the rest?  
		Well, this is the beginning of some analysis of a large scale -- well, for Canada it is a large scale study.  We interviewed 2,500 donors, and this is preliminary results, and we wanted to find out if people self-deferred.
		So these are donors that were drawn from the donor pool, or from the records of the donor pool, who had left after the U.K. deferral was announced.  So you can there that there is close to 700 and something donors that had lapsed, and that is the 17, plus 697.
		And 17 of those donors are 2.4 percent, and 2.4 said that they had lapsed because of the U.K. deferral, and not that they hadn't come in, but that they just decided that they shouldn't be there.  
		All of them -- I don't have it on this slide, but all of them had had U.K. travel that was appropriate.  So they understood the criteria.  More of these people who said that I didn't come back because of the CJD had heard of mad cow disease, CJD, of the U.K. deferral.
		Very few of them remember getting a letter from us telling them -- not that they were deferred, because we would not have known, but telling all donors that we were going to have this deferral.
		So we do see self-deferral, and that is a danger with Western Europe in a big way, and there is more analysis on this data set, and we are going to continue this monitoring to see whether people don't show up that should be showing up, because that is a real, although unmeasured, loss of blood supply.  Thank you.
		CHAIRMAN BOLTON:  Thank you.  Are there any questions for Dr. Giulivi or --
		DR. BAILAR:  A question for either or both of the speakers.  Your figures on donor loss seem to be based on pretty solid information.  The figures on risk reduction are less so.
		You are giving those to three significant figures.  Without knowing your method of calculating at all, I wonder if you could really go beyond one figure.  Can you comment on the accuracy of those?
		DR. GIULIVI:  Yes.  My figures are global figures between Hemo Quebec and CBS.  Remember that there are two blood systems in Canada, CBS and Hemo Quebec, the Province of Quebec and the rest of Canada.
		What Joanne showed was CBS, and what we did was take those two figures, and we did our own risk assessment, and came out with that global picture equalizing for all of Canada.  That is where the health figures from Canada came from.
		DR. BAILAR:  I am not asking about an agreement between the figures, but whether these are even in the right order of magnitude.  If you say a 92.1 percent reduction in risk, how many of those numbers can we believe?
		DR. GIULIVI:  They are quite -- one of my slides had the variance.  Could you go back to one of the slides, and it showed from 87 percent to 90 percent.  It showed the intervals, okay?  So those are the 95 percentile intervals.
		DR. BAILAR:  But the 95 percent intervals are based solely on randomness?
		DR. GIULIVI:  Right.
		DR. BAILAR:  And they do not consider possible bias or other problems in the data?
		DR. GIULIVI:  That's true.  It depends on how the surveillance was done, that's right.  How the donor survey was done.  That's true, but remember that this is our third time going and doing this. 
		What we predict the first year, there would have been a loss of -- two years ago when we introduced U.K., we predicted a loss of 2.7 percent.  There was a loss of 1.4 percent, but then when the CBS went back, a lot of people self-deferred.
		So it added up between 2 and 3 points.  So we have that past history that those figures are really good figures from what we have done in the past, because remember that Canada first did U.K. in 1999 for six months.  
		So we had certain figures, and we went back to those figures to see if we were right or wrong.  We added France in 2000 and we had certain figures, and we went back through those figures, and they are predicting what we are saying.
		DR. BAILAR:  Donor loss is fine.  It is the risk reduction that I am asking you about.
		DR. GIULIVI:  Oh, the risk reduction is based on the modeling, yes, because we assume that the U.K. is a hundred percent, and France is 1/20th of that, and the rest of Europe is .2.  So that is where the risk reduction is a problem.
		But because we are saying that the biggest risk is U.K., we are taking it as a public health analysis that we are pointing to the U.K. and France, and that is how we get our risk reduction.
		DR. CHIAVETTA:  Are you asking for the algorithm?
		DR. GIULIVI:  Yes.
		DR. BAILAR:  This is not the place to go through the algorithm.
		DR. CHIAVETTA:  I know that, but I just said --
		DR. BAILAR:  I would like a summary estimate of how accurate that algorithm really is given all the problems with whether it is the right algorithm and the problems with the input data.
		DR. GIULIVI:  What I can do is send you what we have from my statisticians.  I don't have everything.  I am not a statistician, but there is accuracy to those numbers.
		DR. BAILAR:  I am willing to wait to see that.
		DR. GIULIVI:  Okay.
		CHAIRMAN BOLTON:  Maybe we could discuss this during the break and come back and present the summary of that.  Would that be all right?  Dr. Davey.
		DR. DAVEY:  Yes.  Both CBS and Hemo Quebec have been very successful, I think, and aggressive in recruiting new donors since their inception, and certainly these U.K. bans have given us some good information on that.
		Could you give us any further information on the success of your recruiting efforts, and the expense that has been entailed in doing so?
		DR. CHIAVETTA:  That is a very good point.  There has been a lot of active recruiting.  We have had marketing campaigns that have focused on younger donors and that sort of thing.
		Now, in terms of the expense, I don't have those figures, but they can be provided for you, and I can try to get that today.  But there has been active recruitment, especially with younger donors. 
		What I didn't show here is the people we lose are often long term, older donors, and there has been -- our marketing department has done a lot of work in that area.  
		I have to say to put this in perspective for your question, but donor loss and blood shortage is really not impacted significantly by CJD.  We have other risks and other issues that are far more important.
		I'm sorry, I shouldn't say more important; far more significant in terms of eating into the blood supply.  The reality is that it is .2 percent of known donors, with an upper limit of 2.5 percent of unknown donors.  But I will try to provide figures for you.
		CHAIRMAN BOLTON:  Dr. Ewenstein.
		DR. EWENSTEIN:  Yes.  I just wanted to remind everybody that we are talking about the relative risk, which I think you were trying to say, and that if the U.K. is one or 100, then everything is a fraction.  But what we don't know is the absolute risk.
		DR. GIULIVI:  Yes, and the other thing about funding -- and we could say this, is that the system in Canada is different, because it is funded by the national funding agency through the provinces.  
		What we are going to be doing here with our recommendations, and what we may move forward is three months and three months, and possibly other places.  But we are really pointing three months and three months.
		The recruitment campaign will be helped out by Health Canada also.  Health Canada will help that out, and we will send out pamphlets, and that is the agreement that we have with the blood services.
		DR. EWENSTEIN:  But what I was going to ask though is that -- well, I guess I am still unclear about why there is a lot of difference between your projected donor loss and your actual donor loss.  
Is this solely from self-selection?
		DR. GIULIVI:  Yes.
		DR. EWENSTEIN:  And in which case isn't the donor loss the same?  I mean, even though they self-deferred, as opposed to --
		DR. GIULIVI:  Yes.
		DR. CHIAVETTA:  That is an extremely good question.  I would ask Dr. Williams to remark on that as well.  Because we have the last donor study in process, I am hoping to get more information on that. 
		I will tell you another thing about trying to find out where people have gone.  Well, I don't mean where they have gone, but traveled, and where are they, and how come they are not showing up to give us nice blood.
		And that is that there was tremendous bias when we draw these samples.  We draw a random sample of lapsed donors, but about -- I would say at least a third of the so-called lapsed donors cannot be located, and that is with all kinds of -- you know, going through the process of looking for them and trying to find them.
		I think that the estimate -- I think that we are losing closer to one percent of the donors based on the survey that I have done, even though we are -- you saw that number with the very small number of lapsed donors.  
		It said 2.4 percent of people that went away for the U.K. deferrals, but I think the number is probably much higher.  It's just that when we do our sampling to try to bring people in and find them in order to ask them have they gone away for a particular reason, it is very hard to get a proper sample of the people that have gone away.  I mean, just to find them at all.
		It is a question on why there is such a difference between the in-clinic reported travel.  I have two surveys or two studies that I have done that I didn't report here, and that actually sat down with the donors in the clinic and did a travel log to see whether their survey information -- you know, the check-off survey, matches their own travel log.  
		The correlation is remarkable and I believe people in the clinic are telling the truth.  What happens when they are not in the clinic and they get contacted later, I really don't have a good answer for that.
		CHAIRMAN BOLTON:  Stan.
		DR. PRUSINER:  I'm still not clear about how you get this number of .2 percent.  Let me just try to tell you what I think.  
		DR. CHIAVETTA:  Okay.  Well, the point -- 
		DR. PRUSINER:  Let me talk, please, because I have heard you four times now talk about this, and I do not understand it.
		DR. CHIAVETTA:  Sorry.  Okay.
		DR. PRUSINER:  And I think that other people don't understand it.
		DR. CHIAVETTA:  Okay.
		DR. PRUSINER:  How is this .2 number determined?  Are these the people that you reject when you go in the clinic, and when you go through and talk to them?
		DR. CHIAVETTA:  They are the people that get deferred at the clinic, yes.
		DR. PRUSINER:  Okay.  Sot hat is what is going on here, because I really couldn't understand that.
		DR. CHIAVETTA:  Sorry.
		DR. PRUSINER:  It is still early in California, but I think that is really what was confusing to me.  So these are the actual people that you reject?
		DR. CHIAVETTA:  Exactly. 
		DR. PRUSINER:  So you predict that you have 10 times that number lost.
		DR. CHIAVETTA:  Exactly.
		DR. PRUSINER:  And a lot of these people don't show up at the clinic, and they seem to be self-deferred is what you are saying?
		DR. CHIAVETTA:  Exactly.
		DR. PRUSINER:  Okay.  Thank you.
		DR. CHIAVETTA:  Sorry.
		CHAIRMAN BOLTON:  Dr. Klein.
		DR. KLEIN:  I am very concerned about the important data on the hospital risk assessment, but I am a little worried about the sample selection there, because you have taken the large hospitals, and I think in some ways that is appropriate, at least in the United States.  And please let me finish.\
		Blood is sometimes shuttled toward the live centers and frequently not available at some of the smaller centers.  At least their inventories aren't appropriate.  So could you tell us a little bit about the sample selection?
		DR. GIULIVI:  Okay.  When we did this first study, we realized that the only way we were going to get enough data and information about donor or about affecting patient outcome was really centers that have a trauma center, and a center that has a cardiac center.
		In Canada, the smaller hospitals, which is about 60 percent, have hospitals that are a 50, and as soon as there is a problem, they get shipped right away to a major center.  That is the way that the system works. 
		So within the 12 hours, if you are in a small hospital and you have got a major problem, or if you need blood, you are shipped right away to these major hospitals.
		DR. KLEIN:  Then I wonder whether patients have been shipped because there wasn't blood?
		DR. GIULIVI:  Yes, that could have happened.  Yes, that could have happened.  Usually they are shifted because of therapies.  You know, a plasmaphereses therapy, cardiac therapies, heart attacks, et cetera.
		And because some -- and if the blood, and we are talking like hospitals way up north in certain communities where there is no blood bank, and any of those people that need blood are usually shipped to a community hospital about a hundred kilometers down country.
		DR. KLEIN:  I think this is just a critical point for us,and we have very little data on this point.
		DR. GIULIVI:  Yes.  I can look at it, but I assume that you are right, that some people were transferred from smaller hospitals to larger hospitals because of blood shortages.
		CHAIRMAN BOLTON:  Yes, a question?
		DR. WILLIAMS:  Yes.  Alan Williams, FDA.  Unfortunately, I don't have hard data with respect to the donor deferral issue, but I can add a couple of thoughts, I think.
		First of all, there is self-deferral.  There was a lot of media attention to the original U.K. deferrals, and so that aspect has been discussed.  Another aspect -- and I know that this was done universally in Canada, and at some centers in the United States, is that blood centers sent letters to the entire donor base explaining the deferral.
		So naturally donors would be aware of this, and a large proportion would conclude that they were knowledgeable and simply not come in to donate.  In addition, I think that a lot of centers probably take proactive steps to identify donors before they appear for donation through appointment calls and so forth during a pre-screening, because there are implications when such donors appear for a donation and are deferred.
		Their prior donations have to be investigated for possible air and accident reporting, and there are some strong reasons for these donors not to appear at the blood centers.
		And then finally I would mention that there is an aspect totally unquantitated that some donors simply failed to self-defer.  Some of these questions are very complex for the lay public, and questions might not be understood. 
		They may not have attention paid to them, or there could be some other aspects of why donors don't self-defer.  These are all potential explanations unfortunately and the data are not available.
		DR. CHIAVETTA:  I just wanted to remark on the slide that I showed that all of those donors in that survey had come in, and there have been donors who have actually come in and came in after the deferral.  
		So there are people coming back that should be deferred.  You are absolutely right, Alan, about the last point; is that the way that the questions are asked in the clinic are very different than the way that they asked in the surveys.  
		So my guess is that the questions are not as valid or that the responses are not as valid as they might be.
		CHAIRMAN BOLTON:  Thank you.  Any more questions?  Well, we are running late, and so what I would like to do -- we are about a half-an-hour late, and what I would like to do is take about a 10 minute break now, if that is all right with the committee, and meet back here at 10:55, and we will begin the open public hearing at that time.
		DR. FREAS:  No, we have one more speaker.
		CHAIRMAN BOLTON:  Oh, I'm sorry.  We have Alan Williams' presentation.  
		DR. FREAS:  I would like to ask all those people planning to make a presentation during the open public hearing to please check the list, which is out on the front table, and see where you are in the order of presenters.
		We were asking that you give the audio-visual during the break to the audio-visual technician if you have any audio-visual information.  Also, we are asking the first five or so presenters to take a seat over by the back wall so that you will be right next to the podium.  Thank you very much.
		(Whereupon, the hearing was recessed at 10:45 a.m., and resumed at 11:01 a.m.)
		CHAIRMAN BOLTON:  Would you take your seats, please.  We would like to get started again.  We are going to have another presentation, and then we are going to move into the open public hearing, and if we are to have any time this afternoon, we will need to move soon, soon and quickly.
		(Brief Pause.)
		CHAIRMAN BOLTON:  Our next presentation is by Dr. Alan Williams, who will be speaking on "Blood Donor Deferral Options Related to BSE Exposure; Risk Reduction and Estimated Blood Supply Impact in the United States."  Dr. Williams.
		DR. WILLIAMS:  Thank you.  I'm very pleased to be able to represent the FDA on this important issue.  The evidence regarding the transfusion transmissibility of the variant CJD agent is so far not compelling in either direction.
		Animals models have shown a limited capability for blood borne transmission, but the experiments are largely still in progress and the numbers are small.
		At the other extreme, the large natural experiment of allogenic transfusion in the United Kingdom over the past 22 years has failed to demonstrate a single case of a parent transfusion transmitted variant CJD disease.  
		However, the elderly are those most frequently transfused, and rare transmitted infections with a long incubation period preceding clinical symptoms may never be recognized.  
		Despite this background of uncertainty, and the complex decisions that need to be made today, the goals that FDA seeks from today's public peer review process are relatively straightforward.  Next slide.
		First, our goal is to mount an effective response to the spread of variant CJD and BSE in Europe, and the potential threat to blood safety.  While the threat remains both theoretical and potential, it must be treated as guilty until proven innocent.
		Therefore, FDA intends to institute precautionary measures to protect the public health based upon a perspective of the threat being real.  In doing this, the FDA is very aware of the fragile nature of the blood supply and seeks to form an optimal balance between the variant CJD risk reduction and blood supply preservation.
		This will necessarily involve careful projections of the impact of any new policy and an implementation plan that is sensitive to the dynamics of donor recruitments and blood resource sharing.
		Finally, the FDA very much seeks from this meeting a coherent national policy that can be explained to both blood donors and potential blood recipients.  Next slide.
		I would just like to start by describing a few characteristics about the U.S. blood supply.  It has only been over the past several years that detailed information has emerged about collection and utilization.  
		This work started in the 1980s by the Center for Blood Research sponsored by the National Heart, Lung, and Blood Institute, and was picked up by the National Blood Data Resource Center over the past several years.  
		NBDRC conducts two forms of surveys.  The first is a semi-annual comprehensive survey of blood collection centers, comprising AABB membership, as well as a monthly sample of hospitals that conduct transfusions.
		Data from these two surveys has been invaluable in characterizing our current supply.  Based on the most recent report from 1999, just about 13 million allogenic whole blood/red cell donations were available for transfusion.
		This represents a relatively rapid 10 percent growth over the figures derived from 1997.  There was a major emphasis on recruitment between 1997 and 1999, resulting in a 10 percent gain.  Next slide.
		When you look at the demand side of the equation, the picture is a little bit different.  Monitoring currently is only done by NBDRC from the hospital side of the semi-annual comprehensive survey.
		This latest report showed that 12,022,000 whole blood/red cell units were transfused.  That is 92-1/2 percent of the total available red cell units.  This is an overall figure and really does not account for the fact that different blood types are more in demand than other blood types.
		The margin between the available red cells and the demand for red cells was as low as 5.4 percent in 1997, and improved somewhat to 7.5 percent in 1999.  But still nowhere near the levels of 10 percent and above that were evident in earlier years, in the earlier '90s.
		The study also documented that transfusion demand nationwide increases about 4 percent per year, and this is attributed primarily to aggressive chemotherapy, and increases in organ transplantation.
		This monitoring system has been very effective.  HHS is currently studying ways to conduct monitoring of both supply and demand, and hopefully these systems will be established under contract very soon, particularly with the potential for new deferrals on the horizon.  Next slide.
		A few more facts about the donor base.  Eighty percent of donors are repeat donors through most of the country, and the demographics of the population are changing over time, but the blood donor population as a whole is aging.
		There tend to be fewer large collections because of the work site situation changing, and this used to be the source of a large number of blood collections.  
		The elasticity of supply is a very important issue here.  The figure of 3 percent has been experienced twice.  In 1986, anti-core testing was put into place nationwide to test somewhat non-specific, and up to three percent of donors were rejected at a single time upon implementation of that test.
		Most recently, in the year 2000, the American Red Cross system changed for their hemoglobin sample from ear stick to finger stick and lost approximately 6 percent within the donors, and this can be extrapolated to about 3 percent nationwide.
		And in addition during the same year, although not at the same time, the U.K. deferral was implemented, which resulted in a loss of an additional estimated 2 percent of donors.  So within a year's period, the system managed to deal with about a 5 percent donor loss.  
		The public does definitely respond to blood appeals when they are made, and some were made last year because of local and regional shortages.  However, the long term impact of such appeals is uncertain.  Next slide.
		Blood sharing is also an important consideration.  The transfer of blood between licensed collection facilities certainly does occur.  It is not something for the most part that FDA controls or regulates.
		There are several large systems which facilitate this.  The AABB, the American Association of Blood Banks, runs the National Blood Exchange for the sharing of blood.
		The American Red Cross has its hub system located in St. Louis.  There are various contracts and strategic alliances throughout the country and put together on an individual basis, and I think it is fair to say that a lot of the sharing is really driven by the demand for type "O" blood, the universal blood donation.  Next slide.
		Now, the impact of BSE deferrals we already discussed to a certain extent.  The fact that the original projected loss for the U.K. deferral was 2.2 percent, and the actual loss was not measured, and we know that local and regional shortages were experienced in the year 2000.
		And there were several national media campaigns.  We don't know whether there is a cause and effect relationship between those two figures.  That simply has not been studied.  
		We do know that the impacts of the U.K. deferral and any potential future deferrals will be disproportionate, and this is based on both the U.S. travel survey data, as well as some of the experiences from the U.K. deferral.
		The average figures given for the country.  We know that coastal cities tend to have a higher prevalence of travelers, and this figure can range plus or minus 50 percent, depending on whether you are talking about a coastal city, like San Francisco or New York, or a midwestern area, particularly a rural area.
		The message is that while the coastal cities are hit harder by this, the not coastal cities are hit proportionately less.  And, of course, a major issue of discussion here is that the New York area imports about 25 percent of its blood supply, 145,000 units per year, from Europe.
		And this blood, commonly known as Euro Blood, would be lost by any pan-European deferral.  That is an important point.  Next slide.
		Now, moving along to a little bit of a discussion on the potential risks related to BSE during a CJD exposure.  Next slide.
		We all wish we had an absolute risk model to project number of likely cases, if any, and what effect interventions would have on reducing these cases.
		What we would need to build such a model were at least some of the factors mentioned here, if not all of them.  That would be the likelihood of exposure to the agent, and the length of the incubation period, both the mean and the range, the prevalence of an asymptomatic carrier state.
		Whether or not the variant CJD agent is carried in the blood during the incubation period and the carrier state, and what the susceptibility is of a potential recipient population.
		Now, there has not been a model brought forward and that's because there simply are no solid data to support any of these points.  Therefore, a predictive model, based on absolute risk, just isn't possible at this point in time.  Next slide.
		What has been done previously is to build a linear risk model for estimating donor exposure to the BSEs during the CJD agent by relating potential risks to the duration and likelihood of dietary exposure.
		And in countries where the BSE has been experienced, this is linked to travel and/or duration of time spent in these countries, under the assumption that blood was consumed during that time.  
		This concept was previously endorsed by this committee when it recommended the six month U.K. deferral in 1999, and it does carry several assumptions -- one I will mention now, and several later -- and that is the deferral and risk estimates which arose from the U.S. blood donor travel survey conducted in 1999 in fact reflect a prevalence and cumulative duration of U.S. blood donor travel.  Next slide.
		Now, a second aspect to this model which has been incorporated since the last meeting is to weight this linear risk model for estimating possible exposure.  
		Now, the FDA has worked with several different versions of the model and most recently in collaboration with the Centers for Disease Control, we are putting forth the current model for estimating the risk burden to the donor population and the impact that various deferrals would have on this risk burden. 		So this risk is weighted by geographic exposure based on observations of U.K. beef imports during CJD cases, and indigenous BSE in the country, recognizing that much of these data are incomplete for several of the countries that we were considering.
		The United Kingdom is the epidemic focus for BSE and is considered the index country, with a value of one.  France, similar to the European estimates, based on U.K. beef imports, and observed BSE and the number of variant CJD clinical cases reported, is assigned a value that is 5 percent of the U.K.
		Now, the balance of Europe -- and this includes Euro-blood, and consider that Euro-blood donors have spent their entire life in Europe during the full course of the BSE epidemic for donors who are at least 22 years old.
		Based on indigenous BSE and uncertain surveillance reporting, and food controls, the rest of Europe has been assigned a risk factor of 1.5 percent relative to the U.K., and this is similar to the 2 percent factor used by the Canadian studies.  Next slide.
		Now, we have another population which was discussed at the last meeting, and these are active duty and dependents in the military who have been stationed on European bases since 1980.
		We obtained some very good and extensive data from the Department of Defense with respect to the periods of time that military and dependents were stationed on European bases, as well as estimates of the U.S. and U.K. beef supplied to various bases.
		Based on these estimates, 35 percent of beef appeared to be obtained from the U.K., and this varies as was mentioned earlier.  Southern Europe was supplied from 1980 to 1996, and the later period largely because of some import restrictions in some of the Southern European counties.
		Northern Europe was supplied at a 35 percent level from 1980 to 1990, when the Harkin Act actually forbid importation of U.K. beef to those U.S. bases. 
		Now, this distinction is important because if we can use this in the course of our donor deferral, it does spare the deferral of some donors.  In figures presented at the last meeting, ex-miliary and dependents represent approximately 3 percent of the U.S. blood supply.
		And this may be geographically clustered at this point, and we don't know what these clusters might be.  We know that individual blood centers that have large concentrations of military and ex-military, but that has not been extensively considered.  Next slide.
		And just a summary of the blood donor travel survey, and this has been mentioned at several prior meetings.  It is a probability sample of accepted donors at 12 blood center sites conducted in the winter of 1999.  That is January of 1999.  
		It was conducted by 12 blood center sites, and was analyzed through the REDS coordinating center. It also involved sites that were not part of the REDS program.  
		The survey sampling frame was 19,067 surveys.  It comprised a single-page mailing, with a cover letter, and was designed so as to be anonymous.   We didn't want to know who returned this information.  So surveys without identifiers were returned by 50 percent of the group at the time of the analysis.
		It is important to recognize that this survey is a little different than some of the others that we did, and that we had a very long right hand tail to the returns for some reason.
		And whether or not some of the donors were traveling and late in returning surveys, we don't know.  But at the time of the major analysis, 50 percent returns were available.
		The survey itself collected U.K. and European travel.  The U.K. travel data were much more extensively incorporated because that was the issue at the time.  
		The European travel was captured in a somewhat more skeleton fashion, and we had to extrapolate some of the data for individual European countries.  We also collected demographics.
		Donor survey estimates are reproducible, but they are based on self-reports, and it was a short survey, and we had to make numerous extrapolations for some of the data that are going to be shown.  
		And corresponding to that, I am going to use single integers for most of the estimates, and recognize that the confidence intervals for these is going to be very hard to define, but I think plus or minus 10 percent is probably not unreasonable for some of the risk figures that are being presented.  Next slide.
		Now, two factors will fit into the risk model.  The first is the person years of exposure.  This is derived from the total estimated cumulative time spent by donors in a defined geographic area.
		Donor loss and the estimated proportion of donors who spent time in a geographic area that was at or greater than whatever cut-off value was being defined.
		And these figures quickly for three months travel or residence in the U.K. from '80 to '96 are 1.3 percent; and for estimates which bring that estimate from '96 up to the present, and factoring in the number of years, and the years since '96, that is elevated by about 30 percent, and it goes up to 1.7.
		The DoD with the north-south-of-the-Alps split, all deferrals at six months would be 2.2 percent of the blood supply.  If you accommodate the split, it would be 1.8 percent.
		Residence or travel in Europe from 1980 up to the present, the estimate is 6.3 percent, again with that additive number, and factoring in the years since the survey measurement to the present.
		And Europe five years to present, one percent; and France and Portugal, 10 years, at .4 percent; and Euro-blood, 145,000 units, or about 1.2 percent of the U.S. supply.  
		For example, some of the extrapolations made, the Europe 5 year estimate, the final interval on the survey was five plus years, and so we had to extrapolate within that interval, and since that is the last data point, that is difficult to do.  Next slide.
		Now, from the survey estimates which were presented at earlier meetings, we converted the survey population as a representation of the total U.S. allogeneic donor base, and also incorporated in the data from the DoD, and information regarding Euro-blood.
		And built in the cumulative risk estimates, again derived from the survey, and from what we knew about these other specialized populations.   Shown here are on this pie chart is what I would call a potential risk-burden for the blood donor population, calling this a total risk burden because it incorporates the risk present before the 1999 U.K. deferral.
		The total risk contribution here according to the model that we used, the U.K. contributed 78 percent of the total risk, and the DoD base residents about 14 percent, weighted by the 35 percent factor; and Euro-blood and Europe roughly equivalent at 4 percent.
		And as you will see with the other model, Europe is slightly higher than Euro-blood and that was a rounding of the difference shown there.  But this is the total risk at that time.  Next slide.
		Shown here is taking out the impact of the 6 month U.K. deferral.  This is what we are calling current risk.  This is the current donor base.  The risk is divided into 32 percent U.K., using the same model. 
		The DoD base exposure jumps considerably to 43 percent, and Europe, at 14 percent within the pie chart, and Euro-blood at 11 percent.  So keep in mind specific to Euro-blood that although this is a source of blood used by one region, the fact that these donors have spent the entire epidemic in Europe does in fact add to the weighting, even though the overall weighting for Europe is only a percent-and-a-half.  Next slide.
		Now, I would like to show the three deferral options that we are presenting for the committee for consideration.  The first is the option proposed by the TSEAC advisory committee at the last meeting.
		It is for greater than or equal to 10 years time spent in France, Portugal, or the Republic of Ireland, 1980 to present.
		There wasn't a specific recommendation for DoD exposure, and so what we did was apply what FDA's recommendation would be and added that to the TSC advisory committee option.
		And it would be for a six months exposure on a DoD European base, 1980 to 1996, with stratification by North versus South.  The estimated donor loss is 2.2 percent from this particular deferral, and it may be higher in areas with large military or ex-military populations, and that is something for which we don't have data at this time.
And an implementation of the deferral was not specified.  Next slide.
		Now, if you consider the current risk model presented earlier, what is shown here is the same pie chart, and with the same risk contributions, and the same colors.  
		This is green for Wimbledon and the U.K., and the others -- DoD is royal blue, and Euro-blood is shown as orange, and the European figure is shown as a dark red or purple there.
		The blank parts of the pie are risk that have been removed by implementation of a certain option.  So you can see, for instance, that most of the DoD risk has been removed, with 5 percent of the total current risk still being represented by DoD.
		U.K. is largely unaffected because there was no proposed change in the U.K. deferral, and only a slight proportion of the European risk removed under the model used.  
		The current risk removed is 44 percent, and the only time that I will use the total risk pie chart is for this figure up here, and the total risk reduced by this particular deferral is estimated to be 82 percent.  Next slide.
		I also want to emphasize that these estimates are based on nationwide implementation of these certain deferral policy.  If there are different policies at work, for example, the Red Cross policy in place in the Red Cross system, and X number of other centers, these deferrals would be modified.
		Advantages of the TSE committee's recommendation would be limited donor loss overall, and the Euro-blood and DoD blood supply would be only marginally affected.
		The option is based on observed BSE exposures, and separate questions for DoD bases would allow the North-South separation.  The policy was previously recommended by the advisory committee, and limiting the U.K. deferral to 1980 to 1996 as currently in place recognizes that effective food chain controls have been in place in the U.K.  Next slide.
		Disadvantages related to this option.  Current observations may be biased against deferral where surveillance has been inadequate, and I think we got a sense for some of the uncertainties present in the European situation this morning.
		The potential Euro-blood risk is not removed.  It creates a moving target for blood donor deferrals as the epidemic evolves.  That is in the face of good comprehensive data.
		However, there are concerns that supporting data in fact may be inadequate to make the model responsive to data changes that do occur.  Following the TSEAC model will result in a non-uniform national policy if the Red Cross proceeds with its current plans.
		Donor screening questions will be moderately more complex than they are at present, and that is a factor, and no protection would be afforded against human passage of variant CJD by transfusion; i.e., there is no policy recommendation for transfusion exposure.  Next slide.
		Option Number 2 discusses the proposed American Red Cross strategy.  Deferral would be for greater than or equal to three months in the United Kingdom, 1980 to present; greater or equal to six months in Europe, 1980 to present; and transfusion in the U.K., 1980 to present.
		Estimated donor loss is a range of 7.8 to 9.1 percent.  This includes the loss of Euro-blood, and this deferral would in fact capture the DoD population.  That was not added to the donor loss figure because it was assumed that the survey captured these donors.
		Planned implementation at the current time is throughout the Red Cross system, and at a single time, probably in September of 2001.  And I think the committee needs to recognize that there is some pressure on non-Red Cross blood centers to adopt a policy that is put into place by a system as large as the American Red Cross due to legal and public relations, if not scientific, pressures.  Next slide.
		Shown here is the pie chart for the Red Cross recommendation.  The current risk removed is 76 percent, and total risk removed is 92 percent.  It is actually 92.45.  So that really is a rounding issue that could easily be 93 percent up there.
		The risk left in the supply is a slight amount of DoD risk for military, and under six months; and there is a lot of European risk left, again for short term travelers; and 17 percent of U.K. residual risk left.  The next slide.
		Advantages.  The donor screening is straightforward.  The DoD potential risk is captured without separate questions.  Clearly, this would be the easiest combination of questions for donor screening.
		It forms an aggressive and if followed nationwide would be a uniform national policy.  It is very proactive, and would cover if non-U.K., Europe, BSE, variant CJD, epidemic growth exceeds during observations.
		It does provide some degree of protection against human and human passage of variant CJD by transfusion.  Next slide.
		Disadvantages.  If one considers the model which we have incorporated, where the rest of Europe has a 1.5 percent risk occurring to the U.K., the policy is relatively insufficient under that model as supported by current observations.  
		Secondly, the estimated 8 to 9 percent donor loss is unprecedented in the U.S. system.  The ability of the rest of the U.S. to compensate for severe impact due to this donation, and the estimated 35 percent loss in the New York area is uncertain.
		Let's say that it is untested, and the Red Cross plans to institute major recruitment efforts and feels quite confident that they can cover losses within the system.
		The New York area figure is mentioned at 35 percent, and that's 25 percent coming from Eur-blood, and 10 percent coming from the travel exposure, with the 50 percent increment above because of higher travel in the New York area.
		This policy for U.K. and Europe is extended to the present and does not recognize U.K. food chain controls.  Next slide.
		Finally, the proposed FDA strategy for consideration is deferral for greater than or equal to three months in the U.K., 1980 to 1996; and greater than or equal to 5 years in Europe, 1980 to the present; greater or equal to six months on a DoD European base, 1980 to 1996, with a north-south stratification.
		Transfusion in the U.K.,1980 to the present is similar to the Red Cross proposal.  The estimated donor loss is 4.6 to 5.3 percent; and implementation would be planned to be sympathetic to the blood supply issue.
		And the current thinking is that probably implementation would be recommended to occur six months after final guidance is issued sometime in the spring of 2002.  Next slide.
		The pie chart for the FDA strategy is quite similar to the one for the Red Cross proposal.  The current risk removed is 72 percent, and total risk removed is 91 percent. 
		And again the major portion of risk that is left is related to U.K.  However, trying to get at this risk is very difficult because you get into the shorter term travels and the donor loss numbers go up markedly.
		Again, if the Red Cross policy is put into effect, and two policies are in place, the overall donor loss would be higher in the presence of the two policies.  Next slide.
		Additional considerations for the FDA guidance.  As mentioned earlier, we would like to encourage those centers that want to exceed FDA recommendations with a donor deferral to keep in contact with FDA, and conduct additional deferrals on a pilot basis so as to modulate any additional donor loss.
		And with a defined starting and ending point, at least have the ability to create a fallback position should donor loss exceed expectations.  Due to the large number of error in accident reports related to the travel deferrals, the FDA is considering and will reflect in other guidance the fact that oral interviews probably are advisable for first-time donors, those that have seen the questions for the first time.
		As well as the first time when the implementation of new questions to the existing donor base.  And finally the FDA has been engaged in discussions throughout HHS about sponsored organ tissue and blood donation campaigns which are being planned, as well as larger scale blood supply monitoring efforts.  We support them and plan to actively participate.  Next slide.   
		Advantages of the FDA proposal.  The deferrals tied to the BSE expectations, in the ratio of 3 to 60 months -- i.e., the U.K. to Europe, reflects the worst case 5 percent European estimate.
		That is, the model uses a 1.5 percent risk for the model, but the deferral proposal uses a 5 percent ratio for Europe based on France as a worst case, and allowing for the uncertainty in other European countries.
		The impact on the New York area supply will be severe.  Hopefully it should be modulated by lesser impact elsewhere in the United States.  The pilot provision allows for flexibility for stricter policies.
		Deferral criteria are less prone to frequent revisions, rather than trying to build models about specific European countries.  There is some protection for human passage of variant CJD by transfusion.
		It allows for stratification of the north-south European bases, and does recognize food chain protections currently in place in the U.K., and hopefully develop soon in Europe and which policy could be modified retrospectively to acknowledge this.
		Disadvantages.  This program will result in a non-uniform national policy if the Red Cross proceeds with its current plans.  Donor screening questions admittedly will be complex, in a time when there are efforts being made to shorten and streamline the donor questionnaire.
		Capture questions will help with this, but certainly the institution of these series of questions will be tricky.  The estimated 4 to 6 percent donor loss exceeds past experiences within the U.S. blood supply.
		And the ability of the rest of the U.S. to compensate for severe impact in the New York area is unproven.  Implementation will be designed to help modulate this, but there is no question that a 35 percent blood loss in a certain area is worthy of special consideration.  Next slide.
		In summary, and I apologize as I have to read to make sure that I have gotten everything in that I wanted to, the FDA has taken the position that it intends to maximize precautions to protect the blood supply from variant CJD based on concern over the emerging BSE epidemic in Europe.
		At the same time the FDA recognizes the narrow margin between blood supply and demand on a national basis, and is acutely aware of the disproportional impact that European travel deferrals will have on coastal cities in general, and the New York regional area in particular.
		We have presented three policy options for consideration, and have compared them as comprehensively as possible based upon available information.  
		The proper targeting of donor subgroups with the highest potential exposure to the BSE and variant CJD agent can reduce the total blood supply risk burden by more than 90 percent, with a loss of donors at approximately 5 percent.
		Several factors previously mentioned favor a pattern of European deferral.  Should such a policy be recommended, severe blood supply losses approximating 35 percent in the New York regional area will occur due to the exclusion of Euro-blood.
		These losses will have to be offset by well-designed and well-funded donor recruitment initiatives in the New York area itself, as well as through the sharing of blood resources from the midwest and elsewhere in the country, where the impact of travel deferrals will be far less.
		Provisions for an extended policy implementation period will help to provide stability. However, the FDA does not have control over all aspects of this equation.
		And we seek the cooperation of the major blood collection organizations, as well as the American Association of Blood Banks, and America's blood centers to help ensure reliable blood supplies and accurate blood supply monitoring systems in the future.
		Finally, this issue is confusing even for those of us with a reasonable understanding of the BSE during a VCJD epidemic.  This is unimaginably confusing for members of the general public.  
		It is FDA's hope that with discussion and reassessment of the available options that a coherent national policy will emerge, and when that can be rationally explained to both the nation's blood donors and to future blood recipients.
		So we look forward to the discussions and join you in the sincere hope that no transfusion associated cases of variant CJD ever occur, and that history in fact shows that any precautionary actions to have been well-founded, but ultimately unnecessary.  Next slide.
		I can't specifically mention all the colleagues that have been involved in this series of studies and analyses, but these are the institutions that have been very cooperative in this work, and I would like to acknowledge and thank them.  That's it.  Thank you.
		CHAIRMAN BOLTON:  Thank you, Dr. Williams.  Any questions for Dr. Williams?
		DR. NELSON:  Your analysis focused on the civilian blood supply, but obviously it seems to me that there might be much greater impact on the military blood supply.
		You focused on New York, but didn't mention actually the military, and I wondered if there are any estimates of the effect on the military blood supply, and how that might be compensated, and also what is the degree of interaction between the civilian blood supply and the military?
		Is blood collected from the civilian population used in the military and vice-versa or what is the interaction?
		DR. WILLIAMS:  That is a good point.  The reason that I didn't specifically include it is because DoD does plan an open hearing presentation.  This has also been part of FDA considerations.  
		The military estimates that they have large numbers of collections in Europe, and that this will cost between 21 and 24 percent of their current owner base, and I understand they have already taken steps of -- and the six month referral is what I am referring to.
		And I understand that they have already taken steps to boost recruitment efforts outside of Europe.  This will be dealt with in more depth by Colonel Fitzpatrick.
		As far as interaction between military and civilian supply, certainly civilian collectors collect on military bases.  Military supplies I understand to be largely self-sufficient.  
		So if the military needs to ensure its own blood supply, potentially there could be some tightening of the availability of civilian collections in the area bases.
		CHAIRMAN BOLTON:  Dr. Cliver first, and then Dr. McCullough, and then Dr. McCurdy.
		DR. CLIVER:  I will try and be brief because I am afraid my questions are largely rhetorical.  But we are told that the risk in continental Europe is assessed at 1-1/2 percent than that of the U.K.
		And I am wondering as we get down and down, I know that we are very risk-averse in the United States, but at what point does risk become negligible?  Where are we going to go next with this number?
		On the other hand, in January, we looked at a perceived 20 to 1 risk for France and Portugal, let's say, and Ireland versus the U.K.  And now the FDA is proposing as a compromise that we reduce from 10 years to 5 years Europe-wide based on a 20-to-1 ratio for a 3 month deferral from the U.K.
		And so who except the Red Cross ever said that we ever needed a three month deferral to the U.K.?  And finally as we try and vote on these alternatives, I wish we had available to us some kind of a context of all the other bases for which deferrals are now in place so that we had some idea of all the other things that people in the United States who might give blood are told reasons not to give blood.
		Because taking this out of context I think makes it very difficult to make a real rational assessment.  
		DR. WILLIAMS:  Okay.  Those are all good points and I hope that I can recall them all.  The movement from the deferral for six months exposure in the U.K. to three months exposure in the U.K. basically comes from simply looking at the proportional contribution of risk coming from each of the areas.  
		The Red Cross was actually the first to propose this reduction, but looking at the ratio of risk between Europe and the U.K., the donor loss that is added as a result of shortening from six months to three months is 1.3 percent if you cut off at '96, and 1.7 percent at the present time.
		It is much higher if you go down, for instance, to one percent, and the related reduction in risk is considerable as you can see from the slides.  So while I would say it was specifically recommended, this was based on looking at the potential risk reduction contribution.
		As far as other deferrals that take place, this difference between first-time donors and repeat donors, I think it is important to recognize that in trying to rebuild a donor base that there are two ways to do it.  
		One is to call back your existing donors and try to get them to donate more frequently.  They donated before and they are less likely to have deferrals, and it is a reasonably efficient process.
		The current donation rates are about 1.6 to 1.7 percent within the donor base, and if that can be raised to 2 percent or higher, that would make a big, big difference.
		First-time donors are a different subset. Once you get them in for the first donation, a relatively low proportion actually return for subsequent donations.  
		I don't know the exact figure, but I would say maybe on the order of 10 to 20 percent return for subsequent donations.  In addition, the deferral rates for first time donors are clearly higher based on medical history, and based on hemoglobin levels.
		And deferral rates could be up approaching 9 to 10 percent overall for first-time donors.  Hemoglobin is the biggest deferral, and others are related to medical history, and travel is becoming a major deferral.
		CHAIRMAN BOLTON:  Yes.  Dr.McCullough.
		DR. MCCULLOUGH:  Alan, thanks for the nice summary.  The risk reduction for the FDA and the Red Cross strategies is quite similar, but yet the donor losses are substantially different.  
		Could you just concisely describe the group of donors that constitutes that difference, or  the group that would be salvaged by the FDA proposal that would be deferred by the Red Cross proposal?
		DR. WILLIAMS:  Well, let me say just to begin that it is really very much tied to the model which is being used.  If you use a different model, it changes the proportions.  
		If you accept the observation of the model which is being presented the difference really comes from the five year deferral for traveler or residence in Europe, versus a six month deferral for traveler or residence in Europe.
		Your most efficient deferrals as you saw from the U.K. related calculations come from the smaller group of individuals who have spent the longest time in the country.  That is the most efficient.
		And as you get down closer and closer to capturing the vacation population, the students who have spent time in Europe during the course of their college years, the numbers of donors that you lose in relation to the cumulative time spent there gets more and more inefficient as you go to a shorter time period.
		This is amplified in this particular comparison because of the low relative risk assigned to Europe as a whole.
		CHAIRMAN BOLTON:  Dr. McCurdy, and then Dr. Ewenstein, and then Steve. 
		DR. MCCURDY:  I was curious, Alan, about your suggestion that oral interviews be required for some of these questions, presumably in part because of their complexity.
		I have some incidental and perhaps not quite scientific information that suggests that the amount of time spent with donors in the oral interview and some other aspects of the pre-collection process is unbelievably small.
		And I wonder whether it is possible to get any visual cues and other things if you are going through it that rapidly, and wondered further about whether this was a time to encourage further the development and use of computer assisted interviews.
		CHAIRMAN BOLTON:  I didn't specifically mention the -- what is known as audio-CASI.  That is a computer assisted self-interview with an audio component.
		This is starting to emerge in blood collection centers today, and certainly it appears that it would be a reasonable substitute for a face-to-face interview with a staff member.
		Behavioral studies of AIDS-related risk factors have actually shown this to be a better way of getting sensitive information in risk populations.  As far as time spent with the donor, I think the two factors that lead us to think in terms of complex questions that an oral administration would be better.
		And, number one, if you look at the -- I guess it is the Verizon ads going back to the 1992 literacy survey in the States, some 20 million Americans, I believe, are functionally illiterate.
		And that they are able to get by barely with daily lives, but would not understand the complexities of something like a donor questionnaire.  An oral administration would help that.  
		We know from Air and Accident Reports, and other studies of the donor interview process that often the donors do not understand the questions, or do not pay attention to the questions.  There is an error rate even related to the high risk questions which are used.  
		CHAIRMAN BOLTON:  Dr. Ewenstein.
		DR. EWENSTEIN:  I understand that the interview process and the deferral process might get just impractically complex, but make the case for having the same policy for France and Germany, for example.
		I mean, we heard I thought some very good -- we saw some very good data on just how carefully the herds were now being surveyed.  We have the actual clinical reports from there.  We have the patient reports from there, and to me it looks very different than France, the neighboring country.
		So accepting the fact that there is a simplicity in lumping all of Europe together, from the point of view that your first advantage that the deferral in your proposal would be based on current observational BSE data, could you clarify how the data really do speak to that?
		DR. WILLIAMS:  I think the way that the FDA is looking at this is that the deferral itself is targeted towards France as a worst-case scenario. Other European countries, most likely based on observational data, are at a lower level of potential risk.  
		However, until some of the uncertainties about data collection resolve, we feel that it is best to take the worst-case approach and defer for all European countries at the five percent level, and as we are considering for the U.K.
		And as data become more solid, and as food chain controls come into place, and as testing of cattle shows little or no current infection, those can be back downed from an overall deferral perspective that we are currently recommending.
		DR. EWENSTEIN:  Well, then just to follow up.  Would you foresee beginning to bring other countries back in?  In other words, if you approach 90 percent surveillances of herds -- I am not sure of what all the criteria should be, but at some point do you allow -- and especially large countries like Germany -- and I just pick on that because we saw so much good data from that country.
		But would you see a policy that would begin to allow donors to reenter the pool once we have that level of certainty that you are talking about?
		DR. WILLIAMS:  Well, that is a topic for future discussion, but that is the basis of the thinking.  That once the epidemic is well-characterized, and we can better define what the risks are, that it could be loosened on an individual, or even on a larger basis once we know more.
		For instance, once a test becomes available, and certainly that information would help us to ease these deferrals.  But at the present time, we feel that deferring on a worst-case basis in the face of uncertainty is probably the most precautionary.
		CHAIRMAN BOLTON:  And Dr. De Armond, and Dr. Belay, and Dr. Bailar.
		DR. DE ARMOND:  It seems to me that with regard to the last question that we have no data yet, and until we get the accurate test to look at blood and even the bioassays to test blood for infectivity of people who have traveled to Europe, and donors who haven't, we won't know the answers to these things.
		But in the meantime, we are asked to make decisions in this committee about risk management, and weighing the difference between the decreasing in the number of blood donors based on predictions, and the effect of those decreases.
		And specifically we are being asked to decide whether the older recommendations, which reduced donor loss to 2.2 percent, versus the American Red Cross, which is up to 8 or 9 percent loss, and the FDA proposal, which is 4 to 5 percent loss, is the better way to go.
		But I still don't know from past experience whether a 4 percent loss created in the past, a 4 to 5 percent loss created in the past by the hepatitis testing and the finger prick versus the ear lobe prick, whether that had a significant effect on deaths or morbidity among patients in the U.S.
		And whether you have any concept of whether a 4 to 5 percent loss is significantly different in terms of patient care than a 7 to 8 percent loss, or a 9 percent loss.  Is there any way that you can assess that, because that is what we are going to be asked to do.
		DR. WILLIAMS:  I will have to say up front that I simply don't know the answer to that question.  I am not aware of any instances in recent history in which a national shortage of blood has resulted in deaths or morbidity of patients.
		There are data from the National Blood Data Resource Center about delayed surgeries, and largely elective surgeries.  And during the year of 1999, I believe the figure was .6 percent of hospitals reported some degree of delayed elective surgeries.
		I can't comment further on that.  I simply don't know about deaths related to blood shortage from a national basis.  I doubt that has happened, but I don't know that for sure.
		DR. DE ARMOND:  So what you are saying is that we are being asked to make a decision about more stringent controls on the theoretical risk of getting variant CJD, versus a theoretical non-risk of any problems with a loss of seven percent blood donations?
		DR. WILLIAMS:  I think there is one very important factor that comes into play here, and you see it when disasters occur in a country.  A policeman gets shot, or the Oklahoma City Federal building gets  bombed, the American public responds much more than the need that is there.
		So I think that if a crisis should begin to develop even on a local or regional basis, I think the American public would be responsive to meet that crisis.
		What is unknown is the long term impact, and whether we would still be struggling into the future to maintain sufficient blood supply that is not reported in the media is an unknown.
		But I think in terms of acute shortage, if the blood distribution systems are there, I am quite confident that the American public will respond.
		CHAIRMAN BOLTON:  Okay.  We are going to take four more quick questions.  Dr. Belay, Dr. Bailar, Dr. Prusiner, and Dr. Lurie, and then we are going to move on.  Quick questions and quick responses.
		DR. BELAY:  You would say that despite the current U.K. deferred policy for six months in the United Kingdom that about 32 percent of the potential U.K. risk is still left in the system?  Is that correct in one of your pie charts?
		DR. WILLIAMS:  I believe that is correct, yes.
		DR. BELAY:  All right.  Now, what was the impact or how much of this risk that is currently left in the system would be eliminated by further tightening the first policy to the United Kingdom from six months to three months?
		DR. WILLIAMS:  I think you can see that on the figure comparing the TSE option versus either of the other two options.  I think the difference is something between 32 percent and --
		CHAIRMAN BOLTON:  I think it goes down to 17 percent.
		DR. WILLIAMS:  Yes, 17 percent.
		DR. BELAY:  Now, what would be the margin benefit of taking the option one, which is the TSEAC previous recommendation, and taking in account that option, what would be the margin and benefit of changing the six months to the three months in that option, within that option?
		DR. WILLIAMS:  As far as total reduction and current reduction, I believe -- Dr. Bianco, are you going to address that when you speak?  Well, this is actually under consideration during one of the open presentations.  
		It presents a reduction of current total risk that is moderate between the TSEAC recommendation and the FDA recommendation.  I believe the total risk is something like 87 percent.  
		And the current risk reduction I do not remember, but it is between the two levels.  It is a potential way to consider, because the U.K. six months does allow a large portion of the pie to remain.
		CHAIRMAN BOLTON:  Dr. Bailar.
		DR. BAILAR:  The estimates of risk reduction seem to be based on having accurate information for deferrals.  But we are hearing about errors in that information.  Any guesses about the size of the impact of those errors?
		DR. WILLIAMS:  That is difficult to say.  Studies that have been done, and largely from the NHLBI RED study, have used this technique of conducting anonymous surveys with accepted blood donors.  
		For risk related deferrals related to some of the major deferrals, like injecting drug use, males who have had sexual contact with other men, for instance, we know that there is published information -- this is published in JAMA -- that there is about a half-percent of individuals in those risk groups who do not admit to that risk at the time of donation.
		But do admit to it at the time of the subsequent survey.  So we know that there is some leakage of at-risk populations.  Related to the travel survey, we don't have data.  I suspect that it is larger because of the complexity of these questions.
		DR. BAILAR:  Is there any reason to think that the quality of the information from people at risk is better or worse than the quality of information from others?
		DR. WILLIAMS:  I don't know the answer to that.  It really depends on whether it is based on understanding of the question, or some other factor related to the desire to proceed with donation in the face of knowing that one has risk that would influence it. And so I can't compare the two.
		CHAIRMAN BOLTON:  Dr. Prusiner.
		DR. PRUSINER:  Thanks.  First, I want to thank you for a wonderful presentation.  It was very, very clear.  I want to come to the point of the blood donor travel survey, which this committee as I recall initiated to get the information to come up with a recommendation.
		And then you then said that there was really no follow-up to confirm that the numbers that that survey projected, which are the same -- I presume that you are using the same basis for all these projections, but that there was never a follow-up study done to determine whether the projections after instituting this six month, 1980 to 1996, deferral really had any accuracy.
		Can you elaborate on why that is?  Was this a problem of the FDA, or a problem with the committee?  There seems that there was some lapse in people's thinking about this, because there was never anything done to follow up on this.
		DR. WILLIAMS:  I guess what I will do is refer to my last point at the last TSE committee meeting.  If we have systems in place to get some rapid data collection about our blood system, and about our donors, and about our donations, we can do things like this.  
		The travel survey itself was essentially commissioned by this committee.  The way we put it together was using the REDS resource set that was available, plus other centers that had survey experience.
		It was done in a short time frame with no funding, and we used a one-page questionnaire, and we were able to get what we could.  We had to -- because to do it for under Federal funds, we would need OMB clearance, which would take a year to get approval.
		There are difficulties in getting rapid data of this sort to meet policy needs.  Specific to this issue, why weren't there systems put into place to measure the impact?  
		I guess, number one, there was not a major driving force telling us that that should be done, and we assumed that we would be getting numbers for on-site deferrals, and would be able to assess what the impact was from that basis.
		We know, for instance, that in the San 
Francisco area that the prediction was 3 percent deferral, and it was 2 percent nationwide.  We know that the actual on-site deferral in San Francisco was one percent.
		So the relative proportion remained, but we don't know about the other donors who either self-deferred, didn't defer, or were deferred by the blood center in telephone calls, et cetera.
		DR. PRUSINER:  Can I ask that somehow our Chair come back to this issue at some point, and allow someone like me or someone else to make a motion to recommend to the FDA that whatever we do that there be some follow-up, and that we have some data, because this is going to keep coming up until -- there are very accurate ways of measuring things.
		And certainly there should have been follow-up it seems to me, and there should have been money appropriated by -- well, Clinton at the time, and now George Bush, or the Congress, or whoever, to carry this out.
		Because this is sort of crazy that we don't have any idea -- we can't answer Steve DeArmond's question.  We can't even answer the simple-minded issue of are all of these projections accurate, and what kind of accuracy do they have.
		Are you telling us that in San Francisco the number is off by 60 percent?
		DR. WILLIAMS:  That is on-site deferral. 
		CHAIRMAN BOLTON:  That is on-site, as opposed to those that may have self-deferred, which in the other case was 90 percent.  So we have no idea what --
		DR. PRUSINER:  That's right.  We are even more in the dark.
		CHAIRMAN BOLTON:  Exactly.  Dr. Lurie (sic).
		DR. KATZ:  Anecdotes don't apparently make data, but we had 5 or 6 times as many phone inquiries prior to the implementation of the current deferrals.  That resulted in us saying, yes, you are going to be deferred, as we did in the first 56 days of on-site deferrals, and that first 56 days is the inner-donation interval.
		And 5 or 6 times as many phone calls that resulted in a phone deferral, and it is unrecorded.  So that maybe we know about a third of our deferrals, or our donor --
		DR. PRUSINER:  What was your last sentence?  I'm sorry, I couldn't hear it.
		DR. KATZ:  I think that we probably know about less thana third of the donors that we actually lost to the current deferrals, just based on what happened before implementation.  
		Donors calling and saying that I hear that this is happening, and should I come in and donate, and us saying no.
		DR. PRUSINER:  This really doesn't help me though.  I don't understand it any better based on what you just said.
		DR. KATZ:  Except that there is lots of people out there who self-defer.
		DR. LURIE:  My comments aren't quite a request for data, but rather a procedural question which I think anticipates a very difficult vote that is to come here.  
		Obviously there are two ways of approaching this problem, but one is to provide the committee with three different packets and ask us to in general vote on the packets; or, alternatively, come up with one of our own.
		An alternative way is -- and for me I think that this question in a way anticipates this, is to break down the packages into their component parts, and vote on those, and see what we build up.
		Now, I understand that there are advantages and disadvantages to both of them, but I think that at least for some of these questions that it will be relatively easy to vote.  Do we want the transfusion to be part of the packet or not.
		Do we want to extend from '96 to 2000 for the British dwellers or not.  Now, I think that some of those are very straightforward, and it will make easier for some people the problem of liking part of one package, and not liking part of another.  
		If we do that, then I think at least if we pick up those examples perhaps, then we get left with a series of relatively specific data related questions.  What is the impact and efficiency of moving from six months to three months for Britain?
		What is the impact and efficiency of moving from 10 years to 5 years, to six months, for Europe.  I know that isn't what has been put before us, and I am sure that the FDA has considered my suggestion.
		But what I would like to propose is that we knock off some of the easy ones and that perhaps Alan could provide us the answers to some of the more difficult questions, and I think that might facilitate this. 
		CHAIRMAN BOLTON:  What I would like to do about that is to -- is for everybody to hold that in mind, and when we come back to our discussions as a committee, let's revisit that, because I tend to agree that that might be a more efficient way and ultimately provide a better answer in terms of what the FDA is looking for than trying to go through the votes as we have them set up, but let's discuss that.
		I think now what we should do is move on to the open public hearing, and take that now, and we will have to see if we are going to be able to continue on with our discussions, or if we should break for lunch after that.
		I will try to get a sense of the committee after we have the open public hearing.  Now, Dr. Freas will introduce this segment.
		DR. FREAS:  As part of the FDA advisory committee procedure, we hold open public hearings for those members of the public who are not on the agenda, and would like to make a brief statement concerning matters pending before the committee.
		Mr. Chairman, at this time, I have received two letters for this morning's open public hearing.  One letter is from the Jeffrey Modell 
Foundation, and one letter from the Myasthenia Gravis Association.
		The letters have been placed in our meeting dockets, and have been distributed to the committee members.  Copies of these letters and all handouts relating to this morning's open public hearing will be made available to the public, and they will be placed on the FDA home page.
		We have also received 18 requests to speak during this morning's open public hearing.  I will call the speakers to the podium and identify the next speaker so that they can be prepared to make a presentation.
		All presenters will be timed for a total of 4 minutes, and at the end of 3 minutes a yellow light will come on.  At the end of 4 minutes, the light will turn red, and we ask that you conclude your presentation.
		We are also asking all speakers to address any financial conflict of interest that they may have with any firm or product that they may wish to comment upon.  
		The speakers are allowed to use the microphone in front of the committee, or may come to the podium.  If you are planning on coming to the podium, we do ask that you sit in the chairs over here so that there is a shorter walk to get to the podium and it will speed things along.
		I will read the first five speakers so that they can be prepared.  The order of the first five speakers are Mr Chris Healey, Dr. Celso Bianco, Kay Gregory, and Dr. Antonia Novello, and Ms. Jacquelyn Frederick.  Mr. Healey, you're on.
		MR. HEALEY:  Thank you and good morning.  My name is Chris Healey, and I am speaking to you today on behalf of ABRA and the Plasma Protein Therapeutics Association.
		Because this morning's session deals with donor deferral issues, I will be addressing you from the ABRA perspective.  ABRA is the trade association and standard setting organization for the producers of plasma for fractionation.  
		Our members include collectors of plasma both in the United States and Europe.  As an organization, we represent more than 400 plasma collection centers, the vast majority of which are located in the United States.
		Assuring safe plasma is industry's primary goal.  Safe therapies start with safe donors.  Industry's quality plasma program helps assure a safe donor population through such standards as the qualified donor, inventory hold, viral marker limits, and the use of ABRA's national donor deferral registry.
		We are pleased to inform you that ABRA has been working diligently with representatives of the blood industry, including the American Red Cross, to develop standards for the quality plasma program for recovered plasma.  
		We are hopeful that a common set of standards will be adopted soon.  Nonetheless, as a result of these and other industry efforts, plasma therapeutics are safer today than ever before.  
		Notwithstanding these safety gains, industry recognizes the need to remain vigilant about the potential health risks from emerging and newly identified pathogens.  
		As an industry, we stand ready to take whatever actions are warranted to prevent or minimize real risks to plasma safety.  Whether the risks are theoretical or not understand, we believe that a careful balance must be struck between managing perceived risk and the actions that may reduce the availability of these life saving therapies.
		ABRA stands behind the safety of European plasma and the therapies derived therefrom.  However, we defer to the expertise of this panel.  The magnitude of the task that you are presented with today cannot be overstated.
		You are charged with making public health policy recommendations that may impact hundreds of thousands of lives in the United States, in Europe, in Asia, and in virtually all other parts of the world.
		Today, your voice as a health policy making body will be heard around the world and the world is listening.  ABRA's role today is not to advocate, but to inform.  
		We hope to provide you with information that will aid in your decision making.  To that end, we have compiled data on the global plasma market and will report on the results of the donor travel survey conducted to assess the potential impact of the Red Cross donor ban.
		It is clear that the Red Cross donor ban will result in plasma donor losses in the United States.  ABRA conducted a donor travel survey of 30 collection centers during two consecutive days.  More than 4,500 responses were received.
		Depending on the location of the center, donor losses ranged from zero to 13 percent, with the greatest impact at centers located near military bases.
		The overall donor loss appeared to be approximately 3.5 percent.  However, it is worth noting that one of ABRA's member companies conducted its own survey and found an overall donor loss of 5 percent.  And so it is fair to say that this is the range for donor losses.
		However, assuming even a 4 percent donor loss, the impact on finished products on plasma therapeutics is dramatic.  A 4 percent donor loss, the impact on finished products, on plasma therapeutics, is dramatic.
		A four percent donor loss from plasma donors is a loss of 60 million units, and for IVIG the picture is even more bleak.  A four percent donor loss would result in denying IVIG recipients 1,700 IVIG recipients of their needed product on an annual basis. 		So, a four percent donor loss means that 1,700 IVIG recipients will be denied product all year long.  Now, Dr. Williams made some comments about the elasticity of the donor base, and the need to make up donor losses, and I think that's correct.
		However, I think new donors shouldn't be viewed as a replacement for existing donors.  New donors should be used and viewed as an opportunity to increase the global plasma supply, and increase the global amount of products that are available for patients around the world.
		With respect to the global plasma market, it is important to note that the current estimates reflect an already reducing worldwide supply of plasma.
		According to the market research bureau, in 1998, the total volume of plasma collected around the world was 25,000 liters.  The current estimates for 2000 are approximately 21,000 million liters.  
		And this includes a 2 million liter decline in plasma collection in the United States alone.  So, for the year 2000, it is estimated that the United States will contribute roughly 11 million liters to the world supply, and that Europe will contribute roughly 5 million liters.
		There is no doubt that the Red Cross donor ban will strain an already declining global plasma supply.  Furthermore, a rejection of European plasma by the United States health officials will likely like a domino effect around the world, and in fact examples already exist.
		Egypt recently initiated a legislative action to reject all plasma therapeutics manufactured with European plasma, but as since reconsidered.  Similar actions have been reported in other countries in the Middle East.
		And health officials in Japan are intently awaiting the recommendations of this committee.  Thus, while the direct impact on the United States donors may be in the range of 3.5 to 5 percent, Europe's contribution to the global plasma supply and the supply of plasma therapeutics would likely be put at risk.
		This would put extreme pressure on other sources of plasma to meet the global demand, including the United States.  So, in conclusion, we urge the committee to consider both the domestic and global implications of the recommendations you make.
		I hope that this information will facilitate your decision making, and I thank you for the opportunity to address you.
		DR. FREAS:  Thank you very much.  Our next speaker will be Dr. Celso Bianco, senior vice president of America's Blood Centers.
		DR. BIANCO:  America's Blood Centers is a national network of locally controlled, not for profit, community blood centers that collect half of the U.S. blood supply from volunteer donors.  
		Proactively, we operate in 45 States, and serve more than half of the nation's 6,000 hospitals.  American's Blood Centers total blood collections exceeded 6.7 million in the year 2000.  
		America's Blood Centers thank the FDA for the opportunity to participate in this public decision making process.  We welcome this opportunity.  Last year, about 8 million volunteers donated 14 million pints of blood.
		This volunteers spend an hour or two several times a year to donate the gift of life to other human beings.  A similar number of donations is collected by the plasma industry.  Products from these donations are given to 4 million patients every year.
		Many of these patients would die if they did not receive those products.  We congratulate CBER and CDC for the careful balance and thorough analysis of the issues.  
		However, we feel that the recommendations presented to the committee are optimistic regarding the ability of the blood supply to compensate for losses.  Our 60 year experience tells us that recruitment cannot in a short period of 6 or 9 months make up the loss of donors and donations predicted in Options 2 and 3.
		Therefore, America's Blood Centers is proposing an alternative option, which for simplicity's sake we will call the ABC option.  But first I would like to comment on some of the other options.	
		In January 2001, this committee reexamined the theoretical risks.  You decided to extent the current deferral to include people who had spent a total of 10 years or more in France, Portugal, and Ireland.  
		The basis for this option was to provide a balance between protection and availability.  America's Blood Centers supported that option.  Option One would provide an 82 percent reduction of total risk from the current 68 percent.  
		The loss of donors would be limited to an additional 2.2 percent or 280,000 donors.  Provided that the committee agrees that an extension of the current deferral plan is necessary, ABC endorses Option One, and believes that it could be implemented in 6 months as proposed by the FDA.
		But ABC recognizes that there are pressures for an extension of the deferrals beyond Option One.  If the committee feels that further actions should be taken, we suggest an implementation policy that is consistent with new scientific knowledge, and the ability of blood centers to replace lost donations without jeopardizing the blood supply.
		Option Two, the three month deferral for U.K. and six month deferral for all Europe; at the January meeting -- oh, that went fast -- the American Red Cross indicated that it would implement a much more extensive ban than that recommended by the FDA and the committee.  
		The Red Cross plans to permanently ban donations of people from the Europe and U.K.  With a meeting with America's Blood Centers trustees last February, the Red Cross indicated that the approach was based on medical judgment and not new evidence.
		We were told that different physicians see the same patient and come to different conclusions.  In our opinion, medical judgment applies to a single patient at a physician's office.  
		A deferral that jeopardizes millions of recipients is not an issue of medical judgment.  It is a public health issue.  I am raising this matter because the Red Cross approach not only discounted, but also ignored, the decision making process.
		The America's Blood Centers recommends options.  Our option -- well, you have a copy of it, and you also have a copy of a survey that we made of the American public.  
		And we know that one in every five people, or 4 out of 5 people are more concerned about supply than about the Mad Cow Disease.  Our option would be to increase the deferral that is contained in option one by reducing the period spent in the U.K. from 6 months to 3 months.
		This would lead to a reduction in the number of donors from 280,000 and it would add 1.3 percent, and we would lose a total of 490,000 pints.
We would reach using the model presented by Dr. Williams a 87 percent reduction of the total risk, and that gets closer to the models that are presented in Options 2 and 3.
		This protects the availability of the supply, and this could be implemented in six months, and in six months this committee will get together again and review all the options that are available, and we could then considering new knowledge decide if further deferrals are necessary.
		We are in a program to increase blood donations in varying tests, and we will attempt to replace donors, and we certainly are concerned about a number of issues that this committee -- I would love to see this committee respond to on what deferred donors should be told, and what should patients that receive products be told.
		I received products in 1986 and 1995, a total of 46 units, and what should I be told.  I was in New York and I received European blood.  How should we triage the available units in case of shortages.  Who gets blood first; the young, the old, or should market forces decide this?
		And what effect would the identification of a case of Mad Cow Disease in the United States have in our deferral policies.  In closing, we recognize the effort that you are putting, and we just ask that you consider the impact of these decisions, and give us time to be able to implement whatever decisions we are getting there.
		But simply put, the risk of shortages is real, and you have a package in your hands with a number of reports in the last six weeks of blood shortages throughout the country.  
		And we are concerned about the availability of the blood supply.  The risk is real and blood shortages threaten lives, and that's simple.  Thank you.  
		DR. FREAS:  Thank you.  Our next speaker is Kay Gregory, Director of Regulatory Affairs, American Association of Blood Banks.
		MS. GREGORY:  Thank you.  The American Association of Blood Banks is a professional society for both individuals and for institutions who work in community blood collection centers, hospital based blood banks,a nd transfusion services.  
		Our members are responsible for virtually all of the blood collected, and more than 80 percent of the blood transfused in this country.  For over 50 years, the AABB's highest priority has been to maintain and enhance the safety and availability of the nation's blood supply.  
		We appreciate this opportunity to comment. The AABB believes that before any new donor deferral policy is implemented that the most important consideration is the patient. 
		It is critical that a balance be met between all relevant risks and benefits to patients when determining to implement any new donor deferral policies.  
		Although there are no known cases of variant CJD being transmitted by blood transfusion, the theoretical risk cannot be ruled out.  At the same time, availability of blood is also a safety issue that must be balanced against the potential risk of disease transmission through blood.
		The AABB strongly urges the FDA to ensure that any new deferral policy is implemented in an manner and in a time frame that minimizes interruptions in medical care to patients.
		It is difficult to measure the effect of an expanded donor deferral.  Best estimates suggest that it will eliminate between 6 and 11 percent of all current donors.  However, some communities can be expected to experience even more severe donor cutbacks.
		Given the ongoing inadequacy of the blood supply, one cannot predict that there will be sufficient excess blood in one part of the country to offset the shortage of blood in another region of the country.
		Before expanding the variant CJD related deferral policies, we need to be confident that every blood center in every community can meet its patient's needs.  Moreover, estimates of the percentages of donors who will be deferred significantly underestimates the actual number of units of blood, and blood components that will be lost.
		Many of these donors are likely to be regular donors, who on average donate two times a year.  The loss of the platelet phereses units may be even more drastic, because platelet phereses donors are quite dedicated, often donating at least once a month.
		When the National Blood Data Resource Center attempted to collect data regarding the current U.K. deferral, it found a loss of approximately .29 percent of collections, which was much less than what had been predicted in advance.
		You have already heard about the problems with collecting that data, but given the extensive media coverage of the newly proposed expanded deferral of donors who have traveled to Europe, we would again anticipate a large number of self-deferrals.
		Expanded recruitment efforts may be able to make up some or perhaps even all of the shortfalls projected to accrue as a result of the tighter restrictions.
		The Canadian experience over the last several years shows what can be accomplished by an intense coordinated, well funded, nationwide multimedia campaign to increase blood donations.  
		However, the Federal Government has never allocated similar resources to an analogous effort in this country, and the U.S. blood supply is not centrally organized.  
		Expanded donor deferrals should not be implemented absent a serious effort by the entire blood community, as well as the government, to increase the number of blood donors in the United States.
		The AABB has urged the Department of HHS to financially support a national multimedia blood donation awareness campaign so that the transfusion needs of patients can continue to be met.
		In addition, enhanced efforts to monitor both blood supply and utilization are critically needed.  Consistent with the recent recommendations of the Advisory Committee on Blood Safety and Availability, the AABB believes that the HHS should support the collection, analysis, and distribution of these data by an independent entity.
		Without strong data, we cannot understand and prepare for the impact of donor deferral policies and other factors on the fragile blood supply.  The AABB is committed to play a major role in promoting scientific research to improve blood safety, including new screening paths and technologies to prevent transmission of infectious diseases.
		We urge the FDA and the Federal Government to remain vigilant about variant CJD and other infectious diseases, as well as the impact of deferral policies on blood availability.  Thank you.
		CHAIRMAN BOLTON:  Thank you.  Our next speaker will be Dr. Antonio Novello, the New York State Health Commissioner, and former Surgeon General.  Dr. Novello.
		DR. NOVELLO:  Good afternoon, Chairman Bolton, and Members of the Committee.  New York thanks you for having us here to tell us our problems, because the safety of the blood supply and the patient care of the State of New York is of the utmost quality, and the utmost importance.
		What brings us here is the impact of the deferral of blood donors potentially exposed to the new variant of CJD.  This is a serious threat that needs monitoring and needs our consideration.  
		But up to now, we know that there have been no cases that have been documented of the new variant linked to transfusions, and no scientific data has been demonstrated conclusively that transmissions via transfusion can occur.
		Nevertheless, we believe that a conservative, reasonable, message to prevent any possible entry of new pathogens into the nation's blood supply are warranted.  How and when is the question that we are deciding here today.
		But I can tell you that no one in the country really wants to precipitate a crisis in the nation's blood supply, but underlying the present concern is this truism; the country is in a chronic shortage of blood.
		And the recent shortages have been particularly acute, and emerging blood drives in many regions of the nation have shown that.  I can tell you a case in point.
		In the State of New York, on average, approximately 2,400 units of blood are transfused every day, and approximately 1,400 of those units are in surgical units.  
		The patient care in New York has already been comprised when last summer, and as early as January, the scheduled surgeries for transplant operations, heart surgeries, and cancer surgeries, have been canceled or postponed.
		Right now, 8 percent of the hospitals in the New York Metropolitan Area have canceled surgeries because of the lack of blood.  And in other parts of the State, I can tell you that they do not have the necessary 3-day reserve after supplying the hospitals.
		And more than anything else, currently there is even less than a one day's supply of Type "O" negative and other types as well.  If the new donor deferrals are to be implemented broadly and specifically, certain characteristics of New York State make the blood supply particularly vulnerable to experiencing acute shortages, and I would like to share them with you.
		For one, New York includes the largest Metropolitan Area in the nation, and the rate of international travel and immigration exceeds the national norm.  
		In addition, our concentration of hospitals, particularly the tertiary rate hospitals and the specialty care hospitals is unique in the country.
		And such hospitals which treat patients around the nation and the world require a lot of blood.  To meet those needs, New York historically has relied on blood transfusions from elsewhere in the United States and from other countries, and further restrictions on donors who have traveled to Europe, or resided in Europe, would adversely impact our ability to meet medical needs, especially of the average New Yorker.
		Under certain proposals being considered, 145,000 units now imported annually from Europe will become unavailable.  This translates into an immediate loss of 16 percent of New York State's availability of blood supply, and 25 percent of blood availability in the City of New York.
		Further deferrals being considered would result in a loss of approximately 10 percent or more of New York's donors, which translates into 8 to 9,000 units.
		With new donor restrictions, potentially 200 patients per day in the State of New York would not receive the blood they need.  That really means 75,550 patients a year that will not be able to be served.
		Those patients include trauma patients, and those patients include surgical patients.  As much as we recognize then to protect the safety of the blood supply, a shortage of the one that we are talking about here today possesses a major risk to the public's health.
		Therefore, considering New York State's blood supply needs, of all the proposals under consideration, we support most of the proposals put forth by the FDA, although these proposals not only reduces the risks substantially, and moderates the loss of donors, we believe that more of a time frame is needed for us to be able to implement it.
		So as we ponder on what is the best solution to the blood shortage, we strongly urge the FDA with caution in choosing an implementation time schedule that will consider the extent and the impact on donor issues in particular areas of the nation, and New York State in particular.
		And give us an adequate window of time to plan alternatives and to recover from the potential shortfalls.  I can tell you that today's view is that less than 10 percent of the people donate and/or eligible to donate.  
		If every current donor will be able to donate just one more time, I can assure you that the shortfall would be much more minimized, but we in New York can tell you that we will dedicate all our efforts to increase the donor recruitment and the donor retention. 
		We will do everything in our might to do that, but because the blood shortage is national, and it is not only in the State of New York, we strongly urge the Department of Health and Human Services to make sure that they do a massive campaign to all the States, telling them and raising their public awareness of the increased need for blood in particular areas of the country, and New York in particular, because it is the hardest hit.
		I can tell you that we will be with you in all of this, and I thank you from the bottom of New York State to have been able to hear us today.  Thank you for the opportunity.
		DR. FREAS:  Thank you.  Our next speaker is Ms. Jacquelyn Fredrick, Senior Vice President of the American Red Cross.  And before you begin, I would like to just list the next five speakers.  They are Dr. Bob Jones, Ms. Line Robillard, Ms. Doris Varlee, Dr. Geoffrey Douglin, and Ms. Mirian O'Day.
		MS. FREDRICK:  Thank you, Mr. Chairman, and Members of the Advisory Committee.  Discussions about the deferral of donors at risk of transmitting variant CJD has once again elevated the critical public health issue of blood availability.
		Historically, improvements in blood safety have been balanced against concerns regarding availability.  In fact, some have suggested that safety is availability.
		The American Red Cross believes that safety does not have to be compromised to achieve availability.  For over a decade the blood banking community has accepted mediocre performance as the approach to availability, while facing steadily increasing national need for blood.
		Only 5 percent of the eligible donate.  Just as we have made and continue to make the necessary investments in blood safety, we must now invest aggressively to ensure availability.  
		The American Red Cross has learned time and time again that when called on the American public always respond.  We are pleased to share with you our efforts to stabilize and expand blood collections to ensure a consistent and adequate blood supply whenever and wherever needed.
		By taking steps to develop a consistent supply the Red Cross will not only be able to address the theoretical risk of variant CJD, but also risks posed by future unknown pathogens and other threats to availability.
		During last years unprecedented blood shortages the Red Cross recognized that new donor recruitment and more effective blood collection strategies were needed to achieve a sustainable and an expanding blood supply.
		After a successful investment of more than $2 million in pilot advertising programs, valuable lessons were learned which are now being used.  Since the need for blood is always growing, any successful effort to increase blood collection and do so on a sustainable basis will help ensure a safe blood supply for every patient needed.
		As requested by the FDA, I will first outline the Red Cross's plans for an expanded donor deferral related to the risk of variant CJD.  Given the scientific uncertainties surrounding variant CJD and the need to do everything possible to protect the blood supply, in mid-September of this year, the Red Cross will implement a new donor deferral policy to reduce the theoretical risk of the transmission of variant CJD through blood products.
		This policy was developed with serious consideration and deliberation involving leading scientists and epidemiologists from the United States and around the world.
		The Red Cross will defer donors who have spent time in the United Kingdom for a cumulative total of 3 months or more since 1980; or donors who have spent time in any other European country for six months or more since 1980; or donors who have received a blood transfusion in the United Kingdom.
		Based upon modeling available to us by our scientists in January of 2001, and subsequently used by the FDA in this communication with the Red Cross on March 30, 20001.
		This policy will result in an estimated 85 percent reduction in risk.  The FDA has recently incorporated other assumptions into this model.  The calculations in the original model used by the FDA and Red Cross in FDA's revised model with regard to risk reduction and donor loss are based on the recognized incidents of disease in cattle as measured by  reported levels of infectivity in cattle.
		It is recognized that the testing of cattle has been spotty and the slaughtering of cattle less than 30 months of age may be obscuring of BSE during the incubation period.  
		Further, the models do not take into account the porous borders between European countries and therefore may underestimate the number of people at potential risk of exposure.
		As a result the Red Cross and the FDA recognize that donor exclusion must include a European exposure.  The differences between FDA's current proposal and the Red Cross planned deferral is about a loss of about 3 percent of donors.  
		Based on the magnitude of the threat, we believe that our deferral is cautious and prudent.  I would also comment that reports of donor loss that you have heard today, and therefore the impact on patient need, assumes that all the blood providers will not do anything to meet the need for availability.  
		It is our role to ensure availability, and let me describe what we are doing today to ensure that.  The Red Cross has accelerated its plans to increase blood availability starting with the goal to make up whatever donors we lose to expanded deferral.
		Even prior to implementation of this new policy, we launched substantial efforts to more aggressively recruit, retain, and recognize our blood donors.  We are cultivating and expanding the next generation of volunteer donors.
		We are developing long term strategies to meet patient needs through the latest technology, maximizing our existing donor base, bringing in new donors, and leveraging our unique network of more than 1,000 Red Cross Chapters in communities nationwide.
		We are confident that with dedicated resources that we will effectively address availability.  First and foremost the Red Cross has established a plan and made a commitment to grow from our current 6.5 million to 9 million donations annually in areas served by the Red Cross over the next 5 years.	
		I will also say that we heard a comment about plasma, and our intent is over the next year to increase 200,000 liters of plasma for fractionation to ensure availability of those products.
		We will leverage technology by using automated collection technology anticipated to add 300,000 units to the blood supply, and we will maximize our existing donor base.
		Currently, we are in a 12 week campaign, spending almost $5 million.  We will contact over 2 million group "O" blood donors.  We will send a letter asking people to donate, and telling them about the TSE deferral to over 6 million donors, and we are advertising right now in 55 different markets.
		By increasing the donations from 1.7 times per year to two, which is our goal in 3 years, we will  make an additional 1.2 million units available.  As I said before, we will mobilize our chapter base in every community.
		And in addition we will establish what we call a national strategic blood reserve, strategically locating additional reserve supplies of blood throughout the country, both in a liquid and frozen form.
		In conclusion, this month marks the 20th anniversary of the first report of HIV.  As with the debate over how to protect the blood supply from HIV in the absence of a screening test, deliberations concerning variant CJD have once again been framed as a trade-off between safety and availability.
		Then, as now, some are arguing against aggressive donor screening measures because of the impact on availability.  Until we have a test that can better assess risk, donor exclusion by designated behavior is the only way to protect the blood supply.
		We believe this to be an interim solution and not a permanent solution, hopefully soon eclipsed by more scientific information and blood screening tests, and our commitment is repeatedly within the Red Cross to analyze our deferral criteria.
		Moving beyond yesterday's paradine,it is incumbent upon the blood banking community to address the need for availability and establish a sustained and consistent blood supply based on patient needs.
		Consistent with our mission to alleviate human suffering, the Red Cross is committed to ensuring that the right blood product is available every time for every patient.  
		If we are wrong in our more cautious deferral criteria, the only consequences will be a more determined and effective way to collect blood in this country.  If we are correct, the consequence of a less cautious deferral policy cannot be corrected.  Thank you.
		DR. FREAS:  Thank you very much.  Our next speaker is Dr. Bob Jones, President, New York Blood 
Center.
		CHAIRMAN BOLTON:  For the Committee, I would like to suggest that we are going to take four more public presentations, and then break for lunch, so that we all don't lapse into a coma here from lack of food.
		And we will come back -- well, at a time to be determined, and finish the rest of the public hearing, and then go into our discussion and votes.
		DR. JONES:  Just a brief comment about who we are.  "Euro-blood-R-Us."  We have heard a lot about Euro-blood today, and we will hear a little more about it now.  
		The New York Blood Center has always supported and in fact created many blood safety measures through our research efforts.  However, we are now faced with a dilemma which pits blood safety against a scenario where patient safety is clearly in danger.
		Our dilemma is as follows.  Implementation of the proposed deferrals would reduce the NYBC supply, which is 80 percent of the New York area supply by one-third or more.  There is current U.S. and NYBC unmet medical need for RBCs.  We have heard that already this morning.
		Now, obviously, the largest single impact was the loss of Euro-blood, which is a hundred-and-forty some odd thousand red cells.  However, there is a magnifier effect because 55 percent of those are Type "O" blood.  
		So to replace that, we would have to collect 22 percent more of normal type mix.  Euro-blood is a surplus supply from Holland, Switzerland, and Germany, full licensed, and an extension of our NYBC collection system, and as mentioned earlier, is 25 percent of our red cell distribution.  
		Under the current proposed deferrals, we would also lose over 10 percent of our New York area community blood donations due to the cosmopolitan nature of our donor base.
		Again, there is currently no U.S. surplus to fill in this deficit.  All attempts by us to obtain new commitments from U.S. sources have fallen far short of this need.
		Only 35,000 new units have been identified for beginning next January, and this includes all the ABC centers, and the ARC commitments.  Most interested at this point in time are just simply unwilling to make new commitments to increasing their exports because of uncertainty around the deferrals.  What have we done?
		We have been very, very aggressive over the last three years.  We have known that Euro-blood was going away, and for other reasons, and we have increased our own collections in the New York area by 7 percent per year, and over 22 percent over the last three years is a remarkable achievement, particularly in an urban environment.  
		And we have initiated new donor programs and directions, including more intensive community based programs, a hemochromatosis program, a focus on minority recruitment, and increasing retention and frequency of donors.
		We have restructured our whole organization to focus on donor recruitment, with several reorganizations over the last three years.  We have increased our focus on purchase of supply from other U.S. sources, and finally we have made operational improvements to reduce discards.  
		If you look at the next side, this is the New York Blood Center Supply plan, with no deferrals in place, and you can see that over the years we have already passed on this slide, we have in fact increased our collections on the pink line by significant amounts, seven percent per year.
		The top line is the integrated results of those other three supplies, and as you can see, Euro-blood has been in decline, and will continue to decline, with a glide path to disappear almost completely in '04. 
		And our domestic purchases are seeing the bottom line.  This is assuming no referrals.  No slide, please.
		This is what happens if the deferrals proposed by the American Red Cross would be implemented and affect the New York Blood Center, and you can see that our overall supply drops off dramatically on January '02, with the biggest impact obviously being the disappearance of Euro-blood.
		Our own collections also fall off by about 10 percent, and we are assuming a rate or a recovery of 7 percent per year, which we have been doing.  
		This is also somewhat optimistic because we are also assuming these same domestic purchase line, which we had done before the deferrals.  However, we do believe that would probably be lower.  Next slide, please.
		Here are some important factors, and many have already been addressed here.  The U.S. blood supply is not elastic, and certainly not to the extent to make up this kind of need immediately.  
		The blood supply is also not fluid.  It doesn't flow easily from one region to another.  Short term gains from appeals or awareness campaigns are very helpful, but they are not sustainable without resource investments.
		And the U.S. blood care system has no reserves for supply, nor financial reserves.  This is an important point, and there is currently medical need.
		A very important point that has not been brought up, but is important for recovery, is collections reductions translated in proportional reductions in blood center income, thus exacerbating the existing poor financial status of -- an already poor financial status of non-for-profit centers. 
		And finally to this point, without financial resources, blood care organizations will not be able to react quickly to the needs to replace or create new supply.  Next, please.
		Here are some plausible outcomes for the New York area.  The New York-New Jersey hospitals will be incapacitated due to dangerously low blood availability.
		Over 7,000 transfusions per month, or maybe as many as 230 per day, will not take place.  This is also a cumulative need, in that the transfusions that don't take place today are still going to be needed the next day.
		Hospital rationing.  Will some hospitals have to close while others are supplied with enough blood for safe care?  Revenue losses and market forces will drive service fees to unprecedented levels, and the hospitals are simply not financially prepared for this.
		Finally, new modes of donor recruitments will surely emerge over time.  This will go to readdressing replacement programs, and higher incentives will come into play, and maybe even paid donors.  Next slide, please.
		Here are some of the ideas that we have presented, and would like to share with you as to possible remedies.  We feel that the most important element in any solution to this dilemma is time.  
		That we need time to develop a new supply, as well as develop a better understanding of the medical impact of short supply, versus the danger of transmission of Variant CJD.
		We do think that formalized medical rationing of blood supply to assure scarce resources is used optimally.  You can look at this at the national level or local level, or even the hospital level.
		Finally, Federally sponsored and funded national donation awareness campaigns, Federal aid to blood centers to allow for new collection and capacity, and these grants could be over $500 million.
		And finally new blood supply sources as a I mentioned earlier.  Day to day, we know that the medical practice is balancing risks, and all we are saying is that at this point in time, as you consider this, please consider the patient safety, as well as blood safety.  Thank you very much.  
		DR. FREAS:  Thank you.  Our next speaker is Line Robillard.  She is the executive director of the World Federation of Hemophilia.
		MS. ROBILLARD:  Mr. Chairman, The World Federation of Hemophilia is an international, not-for-profit organization representing 95 member countries.
		It is dedicated to improving hemophilia care for the estimated 400,000 people around the world with hemophilia.  The World Federation of Hemophilia is very concerned about proposed expansion of screening policies to further exclude donors, ostensibly to reduce the theoretical risk of variant CJD transmission by plasma products without sound justification that the measures will increase the overall safety of people receiving these products.
		Consider the following facts affecting the supply and safety of blood products today.  The WSH's most recent global survey shows that the majority of people with hemophilia worldwide do not have access to recombinant products. 
		These are available mostly in countries with an average GNP greater than $10,000.  Therefore, safe plasma derived concentrates remain the lifeline for the majority of people with hemophilia.  
		We estimate that this is likely to remain the case in the foreseeable future.  A very large percentage of the plasma used for manufacturing these concentrates comes from the United States and Europe.
		Very few countries are able to collect plasma in sufficient quantity or of sufficient quality.  The chief causes of death among 75 percent of people with hemophilia today are bleeding, HIV, and Hepatitis C.
		This is a result of the lack of availability of plasma derived products, or the use of unsafe plasma products which have not been viral and activated.
		There is currently a worldwide shortage of plasma products for treating people with Hemophilia.  The shortage of recombinant products in Europe, North America, and Japan, threatens to have a serious impact on other parts of the world.
		Plasma derived products that were once available in developing countries are now becoming scarce because developed countries have had to go back to using plasma products to make up for recombinant shortages.
		Implementing policies that restrict donors from giving blood cause additional shortages in developing countries.  Indeed, these restrictions, if adopted by all, may well cause shortages in developed countries as well if the recombinant product shortage continues.
		Fewer available products in the developing countries will lead to an increased number of deaths and disabilities because of the unavailability of products to treat life-threatening bleeding episodes, and the replacement of safe products with unsafe local fresh frozen plasma and cryoprecipitate, or by products manufactured by using lower quality plasma obtained from dubious sources.
		Because of their tremendous world-wide impact, screening policies for donors that further reduce the global availability of plasma products, should be based on sound scientific knowledge, or judgment that the safety obtained by the new screening policies will outweigh the risk of more people dying from lack of treatment products.  
		In this instance, a theoretical risk of variant CJD is being weighed against a real risk of shortages, and this type of a risk assessment is extremely difficult.
		The screening procedures currently in effect have tried to reasonably balance relative risk of shortage with theoretical risk of variant CJD.  However, further attempts to try to reduce the risk to absolute zero amplifies the real risk of death and blood-borne infections for 80 percent of people with hemophilia living outside Europe and North America.  
		Careful assessment of the expected gain in risk reduction in this situation is absolutely mandatory.  Thank you for giving us this opportunity. 
		DR. FREAS:  Thank you.  Our next speaker is Dorothy Varlese, Associate General Counsel, of the Greater New York Hospital Association.  
		MS. WALTON:  I am actually Susan Walton, Senior Vice President and General Counsel at the Greater New York Hospital Association, and I am responsible for the legal, regulatory, and professional affairs on behalf of our membership.  
		Our membership consists of 200 hospitals and long term care facilities in the Metropolitan New York Area.  They are all not-for-profit, charitable organizations, or public sponsored, and our service area includes approximately 18 million people.
		Geographically, we are every hospital that you can think of in New York City.  We extend up into the Hudson Valley, out on Long Island, and into Northern New Jersey.  And as you have probably already figured out, we are the service area for the New York City Blood Center.
		We are there and reliant for 75 to 80 percent of our blood on the New York City Blood Center,and we are also there for, in-turn, very reliant on Euro-blood, and the extent to which they rely on that blood supply.
		We are deeply concerned therefore about any decision about a deferral policy that will result in an immediate drop of what is anticipated to be one-third -- one-third of our blood supply.
		We cannot obviously comment on the part of the standard that you must weigh and must implement that looks at the risk to science.  I am not a scientist, a physician, or an infectious disease expert.
		We are therefore unable to comment in that regard.  But we are thankful that you are undertaking this task to ensure a safe blood supply.  We are committed to safe care and a safe blood supply for our members.
		What we can comment upon, however, is the other half of that balance, which has to do with the disadvantages, perhaps, of implementing a deferral policy.  
		We will be clearly disparately affected, our members, and the 18 million patients that we serve.  We will be, we think, affected should this occur all at one time in a devastating way.
		And in order to get a handle on that, we have over the last several days spoken with a number of our members, the Blood Bank directors, the physicians, and the administrators.  And as you might expect, they already have very strict guidelines on when transfusions can be provided.
		They are very worried about what will happen over the summer.  Forget this deferral policy.  They are very concerned about what will occur during the course of this summer and are already trying to figure out what surgeries will be deferred, and what transfusions will be deferred from a medical standpoint.
		And I echo what the Commissioner of Health from the State of New York has already indicated in terms of the impact on the procedures that will be involved.  
		When I go the next step and I say so what will happen if this policy with respect to deferral is implemented, and should be implemented all at one time, it is very interesting.  They cannot -- they say that they cannot absorb such a shortfall in the blood supply. 
		Remember, it is one-third of the blood supply, and as they talk through the procedures -- let's say cancer care -- they will have to defer certain surgeries with respect to cancer.  In the medical arena, they will have to defer transfusions for people who need transfusions from a life-saving standpoint.
		And they say that people will die.  I have already been requested to pull together our members and start to talk about the difficult ethical, clinical, and legal issues that arise when you ration scarce resources.
		The discussion that we are going to have to have is the blood supply drops in this fashion, and they also say that we don't look forward to playing god.
		We ask that as you consider what you have to consider today, or in six months, that you take into account the impact on the blood supply.  I recognize that it is one region, but it is a very big region of the United States.
		And we ask that if you ultimately do adopt deferral policies that reduce the blood supply that you do take into account time frames, and that it goes hand-in-hand with clear, concrete, enforceable remedies for addressing the shortfall that will occur.
		I welcome the voluntary efforts, and I know that the Commissioner of Health for the State of New York will stand behind the promises that she made. But it is a nationwide problem that New York can't backfill the shortage that will occur.
		And it really needs a national governmental backing to fill that problem that will occur.  Thank you.
		DR. FREAS:  Thank you.  Our next speaker is Dr. Jeffrey Doughlin, Chairman, Emergency Medicine and the President of the Medical Staff at Jamaica Hospital, Queens, New York.
		DR. DOUGHLIN:  Good afternoon, Mr. Chairman, and Members of the Advisory Committee.  As you said, my name is Jeffrey Doughlin, and I am a practicing physician in New York City.  
		And I am a surgeon, and Chairman of the Emergency Medicine, and President of the Medical Board and Staff, and I also sit on our transfusion committee.
		Jamaica Hospital is a level one trauma center, and we have a very busy emergency room, treating approximately 100,000 patients annually, the number of patients seeking care in this emergency room has increased steadily over the past 10 years, and continues to do so.	
		Blood usage in the hospital has of necessity increased significantly during this time frame because of our increased patient load.  Now, we are actively involve in attempts to recruit more blood donors in the New York City area to try to meet the growing needs of the population that we serve.
		And we have collaborated with the New York Blood Center in sponsoring blood collection drives in our own institution.  We are pretty much dependent on the New York Blood Center in meeting our needs for blood and blood products.  
		On a daily basis, we have to deal with the harsh reality of our dwindling blood supply as more donors are deferred, but utilization as a whole in the City trends upwards.
		A seriously injured patient coming into the hospital E/R bleeding to death needs blood right now, and not in 2 hours, not in 2 weeks, not when the supply becomes adequate, but right now if there is to be any hope of saving that person's life.
		And that patient can be any one of us, any one of our loved ones.  Now, the summer months are particularly difficult for us, even with strict guidelines for transfusion and close monitoring of all transfusion episodes, is the usual situation for us.
		The norm for us is to always be on the verge of running out of blood, and it just takes one or two high speed automobile collisions in a brief time frame to tip us over the edge.
		Now, unfortunately, this is not just a theoretical consideration.  Last summer, we experienced this nightmare scenario.  For several hours, we were unable to accept any more trauma patients because we ran out of blood after treating a number of badly injured patients.
		Ultimately, the New York Blood Center was able to replenish our stock.  Now, if we are subject to a precipitous reduction of this blood supply in our region, it will be impossible to provide trauma care and care for those needing urgent or interoperative blood transfusions for all of the many reasons why people receive large amounts of blood, in any kind of structured, systematic, or organized fashion.
		And that scenario is going to be repeated from hospital to hospital.  I can assume you that countless lives will be lost.  An elimination of Euro-blood and more extensive deferral of potential blood donors, with an exposure to the European environment, will undoubtedly have this kind of impact on the New York/New Jersey region.  
		Now, we are totally committed to a safe blood supply.  If there is compelling evidence at this time that our population was at risk for developing variant CJD by continuing to follow the present guidelines related to blood acquisition and blood donation, then we would have no option but to deal with the reality of a 25 to 30 percent reduction in our blood supply.
		If the evidence is not compelling, and if there is no solid clinical or scientific evidence of an immediate and substantial threat to our citizens, then I would certainly urge this committee to leave the guidelines essentially and substantially unchanges as we continue to acquire knowledge and develop strategies for optimizing utilization of blood, and for expansion of our donor base.
		To do otherwise at this time will place an insurmountable barrier in our way as we attempt to fulfill our charge to do no harm and to save lives.  Mr. Chairman, I thank you for the opportunity to address the committee. 
		DR. FREAS:  Thank you.  Our next speaker is --
		CHAIRMAN BOLTON:  No, we are going to break.  At this point, we are going to break for lunch.  I hate to do this, but I sense that we have already lost the battle, and I don't want to lose the war.  
		What I propose that we do is break 45 minutes for lunch, and return here at 1:45 or so, or 43 minutes for lunch by my watch, and we will continue with the remainder of the open public hearing and on to our discussions.
		We are far behind schedule, and so those of you who are speaking in the open public hearing, I will hold you to four minutes.  So you have 45 minutes to revise your talks to bring it down to four minutes.
And so we will stand adjourned until 1:45.
		(Whereupon, at 1:03 p.m. the Advisory Committee was recessed.)

  
	A F T E R N O O N   S E S S I O N
	(1:52 p.m.)
		CHAIRMAN BOLTON:  Can we reassemble.  Members of the audience, please take your seats.  Members of the Committee, please return.  
		DR. FREAS:  While we are waiting for people to be seated, if you are going to make a presentation in the open public hearing, we would appreciate it if you would sit over here so that it is a short trip to the microphone and would speed things along.	
		We will continue with the open public hearing.  Going again in the order in which I have received the request, starting with number 10, our next speaker is Mirian O'Day.  Mirian is a Senior Direct of Public Policy, Alpha One Foundation.
		MS. O'DAY:  Good afternoon.  Alpha One antitrypsin deficiency, Alpha One, is a genetic disorder that results in devastating and often fatal lung and liver disease.  
		Individuals with the pulmonary destruction of Alpha One demonstrate precocious onset of pulmonary emphysema, with symptoms including shortness of breath, particularly on exertion, cough, whiz, repeated lung infections, and speed up production.
		Therapy consists of augmentation of the Alpha One antitrypsin protein via weekly infusions of a plasma derivative.  In the absence of therapy, the pulmonary emphysema of Alpha One tends to be relentlessly progressive, often leading to premature respiratory death in infected individuals.
		It is estimated that untreated individuals can have their life expectancy reduced by 20 years or more.  With onset between the third and fifth decades of life, the pulmonary impairment can cause disability leading to the loss of employment, frequent hospitalizations, family disorganization, and the suffering not only to those unable to catch their breath.	
		Lung transplantation, with all of its associated risks and costs, is the most common final option.  The Alpha One foundation is a not-for-profit organization founded in 1995 to promote research towards a cure for Alpha One.  
		The majority of the Board of Directors is either diagnosed with Alpha One or is a family member of an individual with Alpha One.  To date the foundation has funded over $9 million in a broad range of research grants and awards.  
		With recognition of the widening European incidents of BSE, and its anticipated risks for variant CJD in humans, the Alpha One foundation is supportive of efforts to ensure the safety of the U.S. blood supply and plasma derivatives.  
		Currently, only a single therapeutic agent exists to treat Alpha One, and as a representative of those citizens suffering the consequences of Alpha One antitrypsin deficiency, the foundation expresses extreme concern that this life preserving medication continues to be in critically short supply.
		As a consequence the foundation believes that efforts aimed at providing a theoretical increase in the safety of the U.S. blood supply must be combined with consideration of the risks of reducing the availability of blood and plasma products.
		Clearly the evaluation of any plan to further increase donor deferrals must include consideration of the risks to the plasma user community, as well as mechanisms to expand blood and plasma donation in order to avoid further compromise to the availability of blood and its derivative medications.
		The foundation regards the proposed expansion of the donor deferral policy by exclusion of donors at risk of variant CJD on the basis of foreign residency and travel as inefficient, and it makes the weighing of issues related to risk benefit more difficult.
		The foundation recommends that the focus be an increase in funding for research in the areas of testing methodologies for the various CJD infectious agent, studies of various CJD transmission and infectivity, and evaluations of methods for inactivation and/or segregation of the infectious agent during blood product fractionation.  
		The foundation also cautions that efforts to ensure safety may be misconstrued by the lay public and actually reduce the willingness of individuals to donate blood and plasma, as well as alarming donors who are deferred.	
		We have two more recommendations and that is that we evaluate a blood safety compensation system, and put an increase on health surveillance.  Thank you very much.  
		DR. FREAS:  Our next speaker is Dr. Hank Baron. Senior Director of Prion Research, of Aventis Behring.  
		DR. BARON:  I would like to thank the committee chairman and the FDA for having this opportunity.  Actually, I'm speaking and giving a more extensive presentation this afternoon.  Thank you.  However, the presentation that I will be giving will be addressing this notion of geographic risk.
		So I really wanted to get a word in before this committee votes on that, and that's why I have pulled the final slide of my presentation to give you a few bullet points with regard to this geographic risk.
		And I think to give you a piece of information that is on everybody's back burner during the proceedings, but I think really should be pulled out to the forefront is the fact that the risk of variant CJD transmissions through blood or plasma products remains purely theoretical, and unsubstantiated by relative scientific evidence.
		And this is a counter-distinction by the way to HIV and AIDS.  We heard an illusion to the fact that we are in a similar situation with HIV and AIDS in 1980, and we know that HIV and AIDS -- that it became tragically and quickly evident that this was a blood-borne disease within a year or two of the emergence of AIDS.
		And I think that to raise the spector of HIV and AIDS, and considering this theoretical risk of variant CJD and transmission through blood, I think that does a service to no one, and certainly not to the population who really pays the tragic price.
		Despite the fact that this risk is theoretical, and because variant CJD is different from the classical form of CJD, we in the plasma protein industry have taken numerous precautionary measures to implement and further minimize this theoretical risk, and this includes certain donor deferral programs which are in place regarding U.K. travel, regarding exclusion of U.K. plasma.
		It also includes withdrawal of notification measures, and other measures that we are actively pursuing.  Now, the lack of rise in variant CJD in France -- and this is something that you saw earlier today, and its absence virtually everywhere else in the world, I think is notable, and it reflects significantly reduced human exposure to BSE outside the U.K.  
		Perhaps one to two logs of magnitude less in France, and perhaps another order of magnitude less in all of the rest of Europe.  Measures in Europe to implemented since 1996 to enhance food safety, and to reduce the potential for food borne transmissions of BSE prions to humans, these should add further reassurance, even while BSE is rising in certain countries due in large part to active surveillance programs.
		It is important to keep in mind also that multi-manufacturing process steps, and the production of purified plasma derivatives have been shown to have robust prion removal capacities.  
		So in conclusion I want to leave the message that in our opinion that a pan-European approach to further minimize this risk, this theoretical risk of transmission of VCJD through blood or plasma products does not seem warranted.  
		And I think to cast a shadow on the safety of European plasma sends the wrong message to the rest of the world, and I think a declaration that European plasma is unsuitable for the production of purified plasma products will undoubtedly have a considerable effect on the supply of life saving products to people who are in dire need of them worldwide.  Thank you.		
		DR. FREAS:  Thank you.  I am going to change the order slightly.  The next presentation is going to be Craig and Jennifer Sperry.  Their son wants them to speak right now, and so we have given them the go ahead.
		MRS. SPERRY:  Sorry about that.  He didn't have a lunch and he is quite antsy right now.  Back in October of 1999, Kirkland became a half-pint.  He had received blood when he was 2 months old, and he was part of the "Pints for Half-Pints" campaign sponsored by America's Blood Centers, and because of him we are here today to share our story.
		And to put a little human side to all that is going on.  I am definitely not a scientist, but I am definitely a mother, and because of someone's donation, that's the reason I am.  Otherwise, I would not be.
		At two months old, Kirkland contracted RSV, and at that time he also ended up coding on us and going to the intensive care unit, and at that time the doctor came in and said there is another problem that has developed.
		Of course, I said that coding was problem enough to get past that point, but we found out that the blood or the RSV was attacking his bone marrow and that he needed a blood transfusion immediately.
		Well, I didn't think of any problem with it, and I offered my blood because he and I are of the same type.  But of course I was soon educated on the fact that I couldn't just hand over my vein and take my blood.
		And they said that you don't understand.  We don't have time for you to give blood to your son, and as a mother that was hard for me to take.  So their hospital searched another hospital, and his blood type was not to be found in either hospital.
		Luckily, our local blood center actually tracked down his type of blood that was on its way out of town, and if it wasn't for that one pint of blood, we would not have Kirkland today.
		Of course, right now you probably wouldn't be having to watch him roam around, but that is another thing that I would never trade for the world.  But in listening to some of this, I would just hate for Kirkland and any other parent to have to take that chance that that blood may not be there.
		And that is the scare that myself as a mother, and thinking that even back then that the regulations are great to have, but if it wasn't for that one pint of blood, I wouldn't be able to have to put up with him right now.
		MR. SPERRY:  My son's life was saved by one pint of blood, the very last pint that was left of his blood type in our community.  A blood shortage to me is very scary.  
		Our community has already or typically has a very large blood supply.  We come from the Texas Panhandle, and we have actually had shortages three times now in the last year, which is something unheard of from where we are at.
		I can't imagine any parent going to a hospital and not having the blood there when they need it in an emergency situation.  I do lots of blood recruiting on donors, and I use Kirkland a lot, and what I like to tell them is to look in Kirkland's eyes and to tell him why they cannot give blood.
		What I don't want to do is to look into my own son's eyes one day and to tell him that nothing can be done because there is no blood.  Thank you.
		DR. FREAS:  Thank you.  We are going to return back to our original order of speakers, and so the next speaker is Ms. Roslyne Schulman, Senior Associate Director, Policy Development, American Hospital Association.
		MS. SCHULMAN:  Well, that is a hard act to follow.  Good afternoon.  On behalf of the nearly 5,000 hospital health network and other provider members of the American Hospital Association, we appreciate the opportunity to testify before the TSE advisory committee regarding variant CJD related blood donor deferral policies.
		The medical and scientific communities continue to debate appropriate blood donor deferral criteria to address the theoretical risk of transfusion transmitted variant CJD.
		While recognizing that this is a difficult issue to address, we believe that your committee, in collaboration with the many infected parties concerned, has the best expertise to make recommendations to the Food and Drug Administration about the appropriateness of expanding current donor deferral policies.
		We are concerned, however, about the impact of such expanded deferrals will have on the availability of blood in our nation's hospitals.  There is already a serious and increasing shortage of blood in the Unite States.  
		In some areas the shortages have been so severe that elective surgeries have had to be canceled.  U.S. News and World Report recently reported that a patient who desperately needed a liver transplant had his surgery canceled due to a lack of blood.
		If these shortages worsen as a result of the increased donor deferrals, blood intensive hospital services such as cardiac surgery and organ transplantation may be severely impacted in some communities.
		As you have heard, hospitals in New York will experience a particularly severe impact.  The number one concern for the American Hospital Association and its members is patient safety. 
		We believe that blood shortages pose a real and serious threat to public safety, including the possible loss of life for patients who desperately need medical and surgical procedures involving blood or blood products.
		That's why we strongly suggest that the Federal Government forge a partnership with the private sector to step up efforts to increase blood donations.  
		In this capacity, we support the recommendation made by America's Blood Centers, that HHS Secretary Thompson collaborate with stakeholder organizations to develop and fund a major national blood donor campaign to ensure that a safe and adequate volunteer blood donor supply is available to all who need it.  
		The AHA looks forward to being involved in such an effort.  Finally, the AHA believes that it is critical that the blood provider organizations work together to develop common standards for safe blood and blood products in order to meet our nation's needs.
		Blood is a precious life giving resource that care givers need to carry out their mission of providing high quality health care services to our nation's ill and injured.  
		When blood provider organizations work together in a consensus fashion, rather than making unilateral decisions with no input from other affected groups, patients will benefit.
		DR. FREAS:  Thank you.  Our next speaker is Ms. Lauren Larsen, a private citizen, and major blood recipient.
		MS. LARSEN:  And tall blood recipient.  Thank you for having a tall mike.  Hello.  I am Lauren Wood Larsen, and I stand before you today with absolutely no medical expertise, but I stand before you as a very, very grateful blood recipient
		There have been a lot of facts that are flying around today, and I would like to add just a few of my own facts to just muddy the waters a bit.  There is some important deferral discussions going on, and I believe that the people who stand to lose the most from these are people like myself who were unexpected blood recipients.
		Prior to a near fatal illness that I suffered about a year ago, I had never even experienced a medical emergency.  No surgeries, no broken bones, and I had not even been in a hospital except to visit patients with my dog, Spike, through an SPCA program.
		By the time that I became pregnant at the age of 37, I had completed six marathons, and I was in pretty good shape for my age, but after eight months of a very uneventful pregnancy, I was rushed to the hospital for an emergency C-Section with what was originally diagnosed as pre-eclampsia.
		It turned out to be much worse, and is still undiagnosed today.  Just hours after the emergency C-Section, my body just shut down, and an emergency team began to pump blood and blood products into my system as fast as it could tolerate it.
		I stabilized temporarily and then shut down three more times during that evening.  I spent six weeks in the ICU, and I suffered from complete liver and kidney failure.  My weight ballooned to 270 pounds as my body could not eliminate the fluids and toxins that were collecting inside of me.
		I was a status one on the liver transplant for the northwest region of the U.S., and I flipped out of consciousness, and when I regained consciousness about a week later, I had a grand mal seizure.  You can imagine how thrilled all my family members were.
		As if that weren't enough, I then suffered from severe encephalopathy from all the toxins that had gone to my brain.  During this week long period, I battled communist plots against me.  I struggled to free babies trapped in bags, and I had lengthy conversations with my I.V. pole, and I lashed out at the brains that were marching across my bed.
		Also during this time, I told my husband to just let me die, and that our newborn baby girl wasn't reason enough to continue with the pain that I was feeling.  Thankfully, he did not take me up on that request.
		It took two more surgeries, four weeks of kidney dialysis, and an incredible team of medical professionals, a bit of divine intervention, and a heck of a lot of blood products before my body began to improve.  
		All told, I was the fortunate recipient of more than 250 units of blood products.  Some of these blood products were imported because there was a local shortage where I lived.  
		After my release from the hospital, there were still many challenges to face.  I had to learn how to walk again, and how to breathe deeply, and even how to ignore the odd looks that I got when I went completely bald.  This is all real.
		I also had to meet and get to know my daughter who had been living hundreds of miles away for the first two months of her life.  It was months before I understood the significance of the medical trauma that I had endured.
		And once I did, I began to understand the generosity, commitment, and humanity of blood donors, more than 200 of whom helped to keep me here on earth.  I was so touched by their assistance that I vowed to help.
		And three months ago on my one year anniversary of my "play date with God" as I affectionately call it, I launched a personal campaign to repay the blood banks.
		My plan is to run the New York City Marathon in November and raise $50,000 for the blood banks and 500 units of blood.  To date, I am up to $24,000 and 315 units of blood.  
		But here are a few of the less inspiring facts about my campaign.  Of the 220 responses that I received to date, only 84 people committed to donating blood, either themselves or through recruiting friends to donate.
		About half the people that did not commit to blood donations stated that they were ineligible to give primarily due to travel abroad.  On the bright side, several friends committed to hosting their own blood drives.	
		Sandra, a friend from graduate school, managed to get more than 50 people to turn out to her personal blood drive.  And of those more than 50 people, only eight were accepted as eligible donors primarily due to travel abroad.  
		This fact, anecdotal as it is, troubles me.  It troubles me for the future Lauren Larsens who have no idea that their currently pristine health is going to someday go wildly off-track, and their only hope will be the availability of blood products.
		Let me close by recognizing that the job of determining blood donor restrictions is not an easy one.  Safety precautions are a must, but I also recognize that the U.S. does not currently have an abundance of blood inventory that we take for granted.
		In my experience, recruiting new donors is not an easy task.  So keeping the donors we have is imperative, at least until we can prove -- and not 
theorize, but prove, prove that we are able to increase eligible donor activity enough to cover the inevitable blood shortage created by proposed deferral programs.
		The Red Cross earlier outlined some plans to do such a thing.  I can tell you that with 18 plus years in marketing that it takes an awful big budget to do what was proposed earlier this morning.
		And I know that stand for half of the American Blood Supply, and it is just my guess -- and I have no facts, but it is my firm belief that the other half of that blood supply made up by independent blood banks doesn't even come close to having the type of budget that the Red Cross has to work with.
		So I am very concerned about making the deferrals before we have the inventory in place to then look closely at the safety issue.  
		CHAIRMAN BOLTON:  Could you please summarize now.
		MS. LARSEN:  The last sentence; sorry about that.  The last sentence is that I am really just asking for a careful consideration of weighing the theoretical precaution, with the very practical need for blood by thousands of real people, with real medical emergencies, and real families who would be absolutely torn apart if that blood was not available to help their loved ones.  Thank you very much.
		DR. FREAS:  Thank you for sharing your experiences.  Our next speaker is Dr. Mike Busch, Professor of Laboratory Medicine at the University of California, San Francisco.
		DR. BUSCH:  Thank you.  I am from Blood Centers of the Pacific, and Blood Centers of the Pacific was previously Irwin Memorial Blood Bank, the epi-center of the transfusion AIDS epidemic 20 years ago.
		Blood Systems is the nation's second largest non-profit blood collection organization, collecting 900,000 units of blood, and testing 1.5 million donations annually.
		I was at USF in the critical years when the transfusion AIDS cases were first reported, and donor risk factor exclusion policies debated and enacted.  
		The first point that I would like to make is that variant CJD is not transfusion AIDS.  It has been over four years since the first cases of variant CJD were reported in Great Britain.  
		Despite intensive surveillance, no cases of transfusion variant CJD have been reported in humans.  By April of 1985, four years following the first AIDS case reports, 225 cases of clinical AIDS have been diagnosed in hemophiliacs and transfusion recipients.
		The incubation period for transfusion AIDS is estimated at over 10 years, similar to recent projects for variant CJD.  So the lack of reported cases from transfusion is unlikely to be attributed to a long incubation period, but is rather more reflective of a low penetrance of variant CJD into humans, and inefficient transmission by human blood components or derivatives.
		My second point relates to the effectiveness and ethics of donor exclusion policies.  Measures to exclude donors at risk for AIDS due to sexual behavior prevented thousands of HIV infections that would have occurred in their absence prior to the availability of HIV testing.
		Donor behavioral exclusion measures were and remain the first line of blood safety.  However, exclusions based on demographic characteristics of donors, as opposed to behavioral risk factors, are socially and ethically problematic.
		Although recipient safety must always be our number one priority in policy development, we must carefully weigh the real and theoretical safety benefits of demographic exclusions with their adverse impacts.	
		These latter include the extensively discussed impact on the supply of the proposed expanded European deferral, with the very real possibility that patients may die due to lack of blood.
		In addition, this policy will have a major impact on the availability of plasma derivatives.  The loss of 10 percent of currently active repeat donors will necessitate recruitment of new donors.  
		The recent analysis by the NHLBI REDS group documented that first-time donors have approximately 100-fold higher prevalence, and 2-to-4 fold higher incidents rates of blood-borne infectious diseases, compared to repeat donors, which translates into increased risks to recipients of established infections, including HIV, HBV, and HCV.  
		Other adverse consequences of donor deferral policies have received less attention, but may be even more erosive.  Altruistic donors who were deferred to unequivocally false positive test results have been documented to experience significant anxiety and distress, despite our best efforts to reassure them and their families that their personal health is not at risk.  
		Unfortunately, no one has conducted psycho-social impact studies of donors deferred due to geographic origin or travel history.  I suspect that a subset of these persons is seriously impacted by the mixed message we give when we tell them that it is not safe to transfuse their blood into patients in need, including their family members.
		The broader social consequences of marginally justified demographic deferral policies must also be considered.  The backlash from deferral policies targeting racial groups during World War II and persons born in or who have traveled to Haiti and South Africa in the '80s have been well documented.
		Deferral policies based on race ethnicity in Israel and Southern Africa have generated international criticism.  I fear that an exaggerated expansion of geographic deferral policies regarding variant CJD may lead not only to the loss and disfranchisement of millions of currently active donors with European exposure, but to a broader erosion of commitment and trust among active potential donors in the U.S. and abroad.
		Finally, I ask the committee to step back and consider where the slippery slope of deferral policies on CJD will end.  Several countries, including France, Great Britain, The Netherlands, and Japan, have implemented or are considering a deferral policy of all persons previously transfused. 
		In my opinion this policy is based on either a misunderstanding of the association between history of transfusion and prevalent infections among first-time donors, or more recently by the theoretical concern that if transfusions could transmit CSEs, this process could some or how accelerate variant CJD.   
		Based on REDS data, this deferral of previously transfused donors would result in a loss of 7 percent of blood donors, and 9 percent of current donations.  
		If TSEs are transfusion transmissible, perhaps we should also consider deferring persons who have ingested mammalian brains.  A recent REDS survey of over 52,000 donors identified 6.4 percent of active donors as having a history of consumption of mammalian brains, with a range of 4 to 14 percent.
		CHAIRMAN BOLTON:  Could you please summarize.
		DR. BUSCH:  Yes.  The Medical and Scientific Advisory Committee of Blood Systems strongly endorses the FDA's evidence based deferral analysis.  
		We, however, feel that the concerns must be based in the reality that there have been no cases of transfusion CJD despite extensive surveillance in the United Kingdom, the hot zone of the BSE epidemic, where over one million units of British blood are transfused annually.
		We hope that the committee will deliberately consider the impact on availability and the other issues that I have raised with respect to impact on the safety and availability of the blood supply.  Thank you.  
		DR. FREAS:  Thank you.  Our next speaker is Mr. Donald Arthur, private citizen.  
		MR. ARTHUR:  Good afternoon.  I am a resident of New York City, and in April of 1996, I was told that I had less than 6 months to live.  I was going to die.  
		I was going to die unless I received a heart transplant.  But for 3-1/2 years, I waited for someone else to die, and it was a very uncomfortable feeling knowing that someone was going to have to die in order to save my life.
		When I went into survey, there was one thing which I never considered that I was going to have to have, and that was blood.  I was so grateful to my potential donor, but I never thought about those individuals who had also given blood.
		I remember after surgery when I looked when I was in my bed, and I looked up and there was a bag, and I asked what was that, and I was told it was blood products.
		And it really hit me that there were some other people which I may never ever get to thank, and to say thank you.  This afternoon and this morning, I have heard a lot of information, and people talking about graphs, pie charts, percentages and figures.
		I am not one of them.  I am a person that has a name, a face, and a personality, and there are thousands of us out there who are in need of this precious blood.  
		We are not numbers.  We are people.  Each of you here who will be making those decisions today, we are talking about risks.  I knew what my risk was going to be when I was going for that transplant, and I accepted that risk because without it I would die.
		To now be told about a risk without me even being given the opportunity to say, yes, I will accept the risk, but to have that denied me?  There are lives that are at stake. 
		Each of you in this room may at one time or another need those products, whether it is a loved one, a next door neighbor.  Each of you will be hoping that blood supplies will be there, your decision again today.  
		Put a name, a face, and a personality with that decision, and just don't look at figures and pie charts.  We are human beings, and without that precious blood, lives may be lost.  Thank you. 
		DR. FREAS:  Thank you for sharing your experiences.  Our next speaker is Chuck Heldebrank, from the Alpha Therapeutics Corporation.
		MR. HELDEBRANK:  Thank you, Mr. Chairman.  We conducted a study on two consecutive days this month among our entire donor population to determine the effects on applicant qualified donors who are otherwise eligible to donate, and who have not spent six or more months in the U.K. from 1980 to the present.
		We asked them all to fill out a survey with a very simple question.  Have you traveled to Europe since 1980, yes or no, and if so, please give us the duration.  On the next slide, we have the tabular results of over 8,000 responses from our donors on these two days.
		And we have segregated our population into three categories based on the location of the centers; either a college population, a military population, or a general population, and them have total numbers.  
		For those donors who are currently acceptable and reporting a European stay of greater than 3 months, we would then defer 6.7 percent of our college donations, and 14 percent of military, 3.2 of the general population.
		And in our system, weighted the way it is, it is a 5.3 percent donor exclusion.  If a 6 month pan of European ban is put in place, the numbers are 5.5 percent, 12.6, 2.7, with an overall impact of 4.6.
		These are shown geographically on the next slide, and these represent the effect in a plasma fluorosis donor population, providing source plasma of these effects taken with the current populations.  Thank you.
		DR. FREAS:  Thank you.  Our next speaker is Colonel Fitzpatrick from the Armed Services Blood Program.
		COLONEL FITZPATRICK:  Good afternoon.  Dr. Williams asked me to respond to Dr. Nelson's questions, and I would like to clear up one slide that Dr. Williams presented, and to briefly say what the impact of the deferrals will be on the military.
		We collect over a hundred-thousand units of blood annually, and we are almost self-sufficient in supply, in not only our needs for our facilities in the United States, but we shift throughout the world on a regular basis in support exercises in deploying troops.
		If we were to implement the American Red Cross proposal, 25 percent of our active duty population would be ineligible to donate.  If we were to enact the FDA proposal, 18 percent of our active duty population will be ineligible to donate.  Either one is a large impact.
		We have gone on record with Under Secretary Arthur Lawrence of Human and Health Services that having two standards within this nation is divisive.  We consider blood availability an operational constraint for military operations.
		In other words, blood must be available in the support of military operations.  Should the need for blood go beyond our ability to collect blood, we are required and we must rely on the civilian sector to supply that product.  
		Neither the Red Cross nor Red Cross centers alone can supply all our needs.  If there are two deferral criteria in this nation, we are faced with choosing between two blood supplies, and whether there is a safety labeling or not because there will be a perception that we have to deal with.
		We are currently evaluating the policy that we will follow.  We received the FDA policy proposal last week, and have not made a decision as to which policy that DoD will follow in our way to the discussion and recommendations of this committee in making our final decision.
		Given the risk reduction model of 91 percent versus 92 percent if we accept that model, there is no longer a great difference between the two proposals. 
		The advantages of the FDA proposal to DoD would be that it limits the donor loss to the period of 1980 to 1996.  So that 18 percent donor loss is a maximum and will decrease over time as those individuals resign and retire from the service.
		It allows us to continue collections in Europe as we operate a donor center in Germany.  This was the first facility to respond to the embassy bombings in Africa, and deliver blood to South Africa in response to the embassy bombings.
		The second facility was Chesapeake-Baltimore Red Cross, and the third facility was the DoD blood program, procuring and having available 400 units within less than 24 hours for delivery.
		That is a necessity for this nation to be able to have that capability.  If we accept the Red Cross standard, it provides us the capability of having a single standard that we can follow.
		But it reduces the European collections, and would require us to ship blood to Europe in support of our U.S. facilities over there, and deployments over there, meaning that we will have to increase donations and collections in the United States.
		In essence, competing with civilian collection agencies at some facilities that we share while we operate our own program and allow civilians to collect.  
		It is not our position to recommend a conclusion to the committee, or to interpret the science for the committee. But I wanted to make you aware of the situation that faces us awaiting your decision.  Thank you.
		DR. FREAS:  Thank you.  Our next speaker is Rich Vogel, Hemophilia Federation of America.
		MR. VOGEL:  I would like to thank the committee for giving me a chance to speak at the last minute.  I will be brief.  My name is Rich Vogel, and I am president of the Hemophilia Federation of America.  
		We are very sensitive to the potential risks of a blood shortage.  In fact, the hemophilia community is in a crisis product shortage as we speak.  We have had to postpone new replacements and other elective surgeries, and have had to cut back and do away with prophylaxis.
		Many have had to go back to ice and rest instead of treating themselves with a blood product.  We will get through it, but what we won't be able to withstand is what is described as the worst medical disaster in the history of medicine.  
		The same attitude of theoretical and more data is the same exact talk we heard 20 years ago.  A few dozen hemophilia cases was not convincing enough, and 242 started to seem like a good number, and today there are over 5,000 in the United States alone.
		We support the recommendations by the American Red Cross and hope for a system of resource sharing as suggested by GNYHA.  We also support a full-scale blood donor campaign.  
		I am not a scientist, doctor, researcher, or a statistician.  What I am is a 45 year old severe hemophiliac.  I don't know the answers, but what I do know is that I am HIV positive and have been since 1982 when a few dozen hemophiliacs wasn't convincing enough.  Thank you.
		DR. FREAS:  Thank you.  At this time, we are at the end of the list of people who have requested to speak in the open public hearing.  Is there anyone in the audience who would like to briefly address the committee at this time?  
		(No audible response.)
		DR. FREAS:  Seeing none, Dr. Bolton, I turn the microphone over to you.
		CHAIRMAN BOLTON:  Thank you, Bill.  Now we begin our committee discussions, and I have been in discussions with Dr. Asher from the FDA, and has informed me that we must vote on questions of the proposals of 1, 2, and 3 in order, as that is the way that the meeting was set up.
		So what I would like to do is that before we open this up to general discussion and questions within the committee, to just go back to Peter Lurie's suggestion that we might want to consider deconstructing the proposals, and discussing the individual components, and assembling our own, or voting on them individually to assemble our own.
		In order to do that, we need first to vote on the first three proposals.  So if as a committee member you feel that you would prefer to deconstruct the proposals and vote on them individually, then when we come to these votes, you should vote no on each proposal.
		If you find that there is a proposal that you like, then you should vote yes.  But before we get to the votes, I think we should have significant discussion of each of the proposals, or parts of them individually, so that we have a sense of what people are thinking.  Yes, Stan.
		DR. PRUSINER:  David, is there a mechanism by which we can say -- let's say we like 80 percent of one proposal as an example, and now we think that a shortcut to Peter's proposal is that we adopt a modified version of that proposal.  How will you accommodate that shortcut?
		CHAIRMAN BOLTON:  What I would suggest is that in the general discussion before we get to the vote that we might entertain various parts and discuss parts that we like.
		And we can get a consensus, and even construct a Proposal Number 4 that could be voted on before we vote on 1 through 3, and at that point, we will have a better sense of what it is that we are looking at.  
		DR. PRUSINER:  Fine.
		CHAIRMAN BOLTON:  Now, the way that I look at this -- and I will just start this to get the discussion going, is that what we really have is a question of whether or not to subdivide the European Union into individual countries or groups of countries, and there are a number of possibilities there.
		There is also the question of whether or not we should entertain a 6 month or 3 month U.K. deferral policy; and then there is the time frame on whether the deferrals would end in 1996 or continue to the present.
		There is the Department of Defense 6 month deferral, and the North/South split issue, and there is a U.K., and/or French transfusion risk.  So I will put that out there, and open it up to discussion and questions from anybody.  
		DR. NELSON:  It seems to me that it doesn't make a lot of sense to vote no on everything if it is an 80 percent yes; and it would seem to me that one thing we could do is vote on these individual items and then vote on proposals 1, 2, or 3.
		Because otherwise the FDA is not going to know why somebody voted yes on a proposal that they had 90 percent agreement with, because somehow that -- well, our votes, unless each of us makes a speech about what we like and what we don't like. 
		But why don't we just deal with the components.  Don't you think that would work, and we can still vote on what the FDA wants us to vote on after.
		CHAIRMAN BOLTON:  I think the disadvantage of that approach is that one might vote, for example, for the revised FDA proposal in absence of the knowledge that a more suitable proposal was actually available to be constructed, and it had not been constructed yet.
		DR. NELSON:  Yes, but if you had the elements, you can put the new thing together.  It seems to me that if we just vote on this whole package that is heterogenous between the various ones -- I mean, they all have exclusion criteria.  They are just a little different.
		CHAIRMAN BOLTON:  But the way the actual meeting is set up, and the way that the FDA has requested that we do this is that if we vote yes on Option Number One, we stop there.
		If we vote no on one, and yes on two, we stop there.  It is not a matter of voting on all three.  So it doesn't quiet give us that flexibility.
		DR. NELSON:  But it is our meeting.  I mean, we can establish the rule that makes sense to us, and then let the FDA sort of figure out what we meant.  
		DR. PRUSINER:  There is one more option and that is for someone, and not me, to make a motion that we vote no on all three proposals.
		DR. NELSON:  Well, I'll make that motion. 
		DR. LURIE:  The other way of doing this, I suppose, is to do it, Ken, are the same.  We construct our proposal, and that is in effect number four, and we vote on number four first.
		DR. NELSON:  Exactly.  We construct number four, and then we can vote yes or no on it.
		DR. LURIE:  It might turn out.  I mean, obviously we have gone through this, and I think we have gotten an understanding of the conversations still to come.  
		My number four would turn out to be number three, and once I start reconstructing it, it actually to me looks like the FDA's proposal is pretty reasonable.  But that is my belief, and I can't say that is true for everybody.  I think the exercise is useful.
		CHAIRMAN BOLTON:  Yes.  Let me go back to what I said before.  I think that the most effective way to do this is to in fact discuss and construct proposal number four before we vote.  
		That way if we don't come up with something we like, then we can always go back and vote for proposals 1, 2, or 3.  But to vote first and then have to go back and reconstruct what might in fact end up being one of the proposals that we just voted down would not make much sense. 
		So I would like to open it up to general discussion on any of these points.  Yes?
		DR. BAILAR:  I am not sure that we can construct an improved proposal on the spot here.  This will take a fair amount of analysis.  The one thing that has been missing that I would like to see in the analysis is the marginal improvements of going from no restriction, to three months, to six months, to three years or whatever.
		How much do you gain from each step in that I think would be a big help to help, but that would take a little time to develop.  Could we return to this issue at our next meeting?
		DR. NELSON:  Well, weren't those data presented?  I mean, you may not like the outcome, but that is what I heard.  
		CHAIRMAN BOLTON:  Yes, I think they were presented, at least in part at this meeting, and then in the previous meeting that we had.  But I think whether we return to this issue, and I am sure that we will return to this issue in future meetings, we still need to deal with it at this meeting, and particularly voting on the options 1, 2, and 3.
		So whether we vote no on all of them, or yes on one, we will still need to vote, and unfortunately as always happens with this committee, we are dealing with a very limited amount of information.  And a subject that is both emotional and important.  So, who is first?
		DR. MCCURDY:  I wonder if it wouldn't be reasonable to split plasma from the whole blood segments.  I think that the data that we have been provided for later discussion would suggest that there may be some partitioning of the agent, of CJD, during the fractionation process, and that is good.
		These products come from fairly large pools, and I am not quite sure what that means, and whether the delusion is more important for CJD than it was for, say, HIV or one of the others, one of the other agents or not.
		But it seems to me that it might be wise to split the two, and I think I look at them differently.
		DR. DAVEY:  Mr. Chairman, maybe at the risk of moving this along or more quickly than some committee members wish, I would like to make a couple of comments, and maybe propose one option that we can consider as Option Number 4. 
		In looking back at this, I think the committee has been very judicious in the way that it has looked at this issue in the past; a focus with good use of the precautionary principle on the country where the problem is by far the greatest, and that is the U.K.
		And 98 percent of the BSE cases are there, and 98 percent of the variant CJD cases are there.  And we have an opportunity as you know to continue to study that unfortunate unfolding of the epidemic in that country.
		We can learn from it, and we already have, and we can learn more.  But the FDA has observed that there is really not much reason to extend this to other countries and one of their misses, and I think that is correct, with the possible exception of France.
		I also think that what we have heard is that there is really not a substantial amount of new data from what we have heard in other meetings that we need to extend this ban to all European countries.  
		So it is really the U.K. and there is everybody else.  Now, if we look at some of the specific proposals, and let's look at the Red Cross proposal.  We would lose 600,000 to 800,000 donors -- businessmen, students, international workers, travelers.
		It is a problem, and even if the rules are changed later, those people will not come back.  I am a hematologist, and I have spent my life in blood banking, and we are going to lose donors and we don't get them back.
		And we have also heard that there are deferrals under that proposal and the FDA proposal would be catastrophic, and I use that word advisably to New York City and to the military blood programs.
		And I think we have to ask ourselves very carefully do we as a committee want to do that to our military blood program, and to the most populous and most prominent city in America.  I think perhaps no.
		Now, again, regarding the FDA proposal, I don't think there is any reasonable rationale for extending a ban on all European countries, whether it is six hours, six days, six months, or six years.
		Those deferral periods are really arbitrary and they are based on models that are really unsubstantiated, and the FDA proposal does not address the New York City problem or the military problem.
		So I would suggest that we really step back here and look at this issue.  We are on a slippery slope, and I don't think we need to compromise from what the committee has done in the past, which has been reasonable.  It is balance precaution against supply.
		So I think again to maybe use another phrase that the FDA has used, we can draw a bright line here, a reasonably bright line between the United Kingdom, and perhaps France, and the rest of the world on this issue.
		I think that we should continue the deferral policies that this committee has recommended in the past, and they have been well thought out, and make sense, and they don't damage the American blood supply sufficiently.  
		Our job really is to be cautious, but we cannot jeopardize the health of the American patients and recipients, and I think we have heard eloquent testimony throughout the day from patients, from hospital associations, that this is a real problem, a real problem that we have facing us right now.
		The committee -- it may take a little bit of courage in a way to say, look, we have done enough. Let's wait and see, but perhaps it is the best course, and the one that shows our responsibility to the American public in the highest order.
		So I would propose an option number four.  That we look at the United Kingdom very carefully, and maybe tighten up the ban for three months.  I think that makes sense.  We gain a lot in risk reduction without a great loss in donors.
		That we extend that ban from 1982 to present, and I think the reasons for ending it in 1996, while reasonable, are not very substantial.  And along with that, we really need to have an aggressive system for monitoring the United States blood supply, its utilization, and its supply.
		We really don't have that, and I don't think that the government has really stepped forward to give us the data, or to supply reasonable monies through others to give us the data that we need to monitor the impact.  
		So, Ladies and Gentlemen, I think we have a responsibility here, and I think it is clear.  We should focus on the U.K., and draw the bright line around the U.K. and perhaps France, and in that way modify the damage that we may have to American patients.  So that would be my suggested option.  Thank you.
		DR. KATZ:  It has never been quite clear to me what a guest does, but thanks for the invite.   I have had the pleasure over the last year to be in this room and to sit at this table, and listen to these discussions, and I will say that the sound and fury have been impressive, if the data upon which we base decisions has not.  
		My review of the available information suggests that the risk of transfusion transmission does not justify measurable contraction in the face of volunteer donors in the United States.
		The controversy is obvious, and I think that is why we are running over honorable people looking at the same data disagree.  I felt that the recommendations in January, and still feel that the recommendations in January were appropriate, and I support them.
		In the interval since that meeting the impetus to broader deferrals, primarily from the American Red Cross, has taken on a political and scientific life of its own, and which was made abundantly clear to me in a recent meeting earlier this month with Secretary Thompson and Dr. Zoon.
		While I think that the Red Cross circumvented a well designed, established, and public process for decision making, the right to do so is not questioned, and I think that everybody should be clear on that.
		If the volunteer donor base was a spigot to be turned on and off at will, there would be no more bickering.  We would have stringent deferrals, and there would be consensus.
		That is not the nature of the U.S. blood supply, and I guess as a blood banker, maybe that's why I am sitting at this table.  Despite the best efforts of my compatriots in transfusion medicine, emergency appeals in many regions of the Red Cross and independent blood centers represented by ABC are more common and sustainable than ever.  
		And I think you guys got a summary of this spring's media releases describing those appeals.  At my own center in Iowa, we draw from more than 10 percent of the eligible donor base.  Nationwide, that number is somewhere around 5 percent.
		We are more than twice as efficient as the rest of the country, and maybe that is an accident of being in Iowa.  Maybe we use a little less blood.  Having said that, we were unable to ship components to Houston during their recent weather related disaster because of iron-clad commitments that we have made to other urban centers around the country that have chronically inadequate blood supply.
		We could not ship Houston 10 units.  In this system, a 5 to 10 percent additional donor deferral for marginal indications is a luxury with a steep price, particularly if blood availability is seen, and as I think it must be, as a blood safety issue.	
		Where is the effective new donor recruitment strategy.  The Red Cross in public has told us that they can handle it.  I will take them at their word, but one of the strategies is to draw the donors that I am trying to draw in my community.  
		The Red Cross comes to my community, and mines my donor base.  Well, it is not my donor base.  It is the community's donor base.  I am not sure that the supplies are as elastic as you have heard from the Red Cross.
		Where is the realistic strategy to replace an immediate 30 percent New York City blood supply loss.  I don't know where that is coming from.  Understand that whatever we do isn't the business as usual the way we have always done business in blood banking.  
		Emergency appeals don't work.  What they do is that they bring in this month the donors that were committed to donate next month, and delay the ultimate accounting.  
		So whatever solution, whatever comes from the committee, and whatever the solutions are, it is not an emergency appeal.  If this committee in its wisdom sets a precedent by advising stringent deferrals for an unquantifiable, theoretical variant CJD risk, despite ample evidence of the incapacity of the national blood supply at this point in time, the committee must also provide other advice to FDA, and I will tell you what I think that should be.
		Number One, implementation of stringent deferrals should be tied to funding by HHS for a nationwide blood donor initiative developed in partnership with the transfusion medicine community.
		That initiative needs to be aggressively supported at the highest levels of the administration and Congress, and sustained over an extended interval that will be required to replace the donors that we are going to lose with committed new blood donors.
		And when I am talking about extended, I  think I am talking about 5 and 10 years in order to replace what we are talking about in a worst case scenario losing.
		Support must be found for the recruitment phlebotomy, processing, and distribution infrastructure needed to expand the donor base, to include these individuals who are not effectively recruited by current and historic methods.
		If you tell me today that I need another 15,000 units in my 70,000 unit center by the end of next year, I need money to do it.  I need to buy equipment for mobile blood drives.  I need to expand the floor space in my fixed donor sites.  It is not a faucet.  
		Finally, the FDA needs to continue as it has to convene this committee regularly to review the new evidence about the continuing need for any of these deferrals.
		I hope the time comes when the evidence demonstrates to all interested parties that VCJD is not transfusion transmitted.  I am a transfusion clinician first, and a transfusion recipient second, and a blood banker last.
		In all three roles, I implore this committee to provide defensible advice to FDA based on a review of the available science, ignoring the politics of blood banking that will protect those of us whose lives have been, and I hope will be, saved by the availability of blood products in the future.		
		CHAIRMAN BOLTON:  Dr. Lurie, you are up next.
		DR. LURIE:  Would you mind if I presented a transparency.
		CHAIRMAN BOLTON:  Oh, yes.  Absolutely.
		DR. LURIE:  There is nothing like a good transparency to clear things up.  
		CHAIRMAN BOLTON:  Well, on the other hand.  Is it backwards, or --
		DR. LURIE:  It's in Hebrew.  Well, I will try and -- I guess this is the laser point, and so I will read for you.  What I tried to do here is take Alan Williams' very useful data and to try and turn them into the form that Dr. Bailar asked for, or at least allow you to do that.
		And what I have tried to do here is to divide our question up into its two component parts, and the first part being the amount of risk that we can remove; and the second part being the percentage of people who have this amount to travel.
		So this is a current risk.  Remember that Dr. Williams had two parts, the current risk and the total risk.  This is strictly for current risk.  I think it is probably worth remembering that we probably have already eliminated most of the risk simply by what we have done in Britain already to date.  I think that is important contextual information.
		But speaking to current risk, what I have done is that I have made the assumption that the transfusion part is straightforward, and that the committee will agree that the transfusion restriction is worth doing, and that impact upon, in terms of -- well, that it will be very small because that will be a very large number of people, and that will be the efficient thing to do.  And so transfusion does not appear on the slide.  
		CHAIRMAN BOLTON:  Let me clarify.  What you mean by that is that anyone who has received a transfusion in the U.K. would be deferred?
		DR. LURIE:  Right.  That was a proposal that was put forth, and that I am going to just for the sake of simplicity assume we are going to go for that, because you lose a certain amount of risk, but not very large.
		But there is basically no impact upon the donor supply, and so it is just out of the picture for the sake of this presentation.  And then I have divided it up into the four essential elements, and not the '96 to 2000 extension, but the other elements.
		And those are what we would do in Europe, and what we would do with the DoD, and what we would do with Britain, and what would happen to E-blood, and I have got that again first for the risk, and then for the travel.
		And then for each I have got the impact of the remaining risk for each of the three recommendations; the TSEAC, the Red Cross, and the FDA.  Now, this is the remaining risk at this moment in time.  As I said, there is a hundred, because it is about the current risk.
		And of that, 13 percent is in Europe, and 44 is in the DoD, and 32 is with Britain, and 11 is in the E-blood system.  Now, the TSEAC proposal removes 5 of those 13 percent, and the ARC removes 11 of those 13 percent, and the FDA removes 7 of those 13 percent.
		All three of them would have the same restriction on the DoD, and so all of them removed, 39 out of 44 percent, almost all of that risk.
		The TSEAC proposal has no incremental effect upon the risk from Britain, because we are not proposing to change that under the TSEAC.  But the ARC and the FDA, which have similar restrictions, would take out 14 of those remaining 32 percent, and the TSEAC would take out none of the E-blood risk, but both the ARC and the FDA would.
		And then you have these totals; 44 percent of total risk removed by the TSEAC proposals; and 76 and 72 by the Red Cross and the FDA.  That is the risk side.
		Now, the travel side.  According to the travel survey, less than one percent, or I think it is close to one percent, but less than one percent, are people who have had European travel that would "violate" what TSEAC is currently proposing. 
		Whereas, the ARC proposal is that 6.3 percent would violate it, and only one percent would violate it for the FDA.  For DoD, it is 2 percent that would violate it all together.
		And for Britain, for TSEAC there is no change, and so there is no incremental number of people affected by the travel ban, and 1-1/2 percent for each of these other two proposals; and it is really not applicable for the E-blood situation since it is essentially incorporated in Europe.
		Now, if you go back and you start dissecting it, it seems to me relatively straightforward to say that we can get risk of most of this 39 out of 44 parts of what is the largest fraction, the DoD, 44 out of a hundred.
		And all three agree that 39 out of 44 can be eliminated, and they have all got the same proposal.  So it seems to me straightforward that we should be doing what is being recommended for the DoD, and moreover, the increments in travel is obviously not only the same, but is relatively modest.
		The E-blood is not -- you can't really consider it on an efficiency level because the travel  is folded into Europe.  So really the two remaining questions are whether it is worth making a change in Britain and a change in Europe.
		Now, if you make the change in Europe as proposed by the TSEAC, you get five additional percentage points and lose less than one percent of the donors because of their travel.
		The FDA is actually quite similar -- seven percent, a little bit more of the donors -- but the big difference is that the Red Cross then has -- it only removes 4 percent more risk altogether, and it is this huge increment from 1 to 6.3, in terms of the fraction of people who will be banned because of their travel.
		That strikes me as not a good idea.  The more difficult question is what to do about the situation in Britain, where whether or not these two are in effect the same, and whether this additional 14 percent that you could remove is worth this 1.5 percent of donors that you would lose.  That is a more difficult question.
		But if you answer that in the affirmative, then you essentially have the FDA proposal, which would be 72 percent of the residual risk would be removed, and this amount of additional donors would be lost.  That is my presentation.
		CHAIRMAN BOLTON:  So is that a vote for the FDA's revised proposal?
		DR. LURIE:  That is a very long way of saying that, I suppose, but what I am really hoping more than anything is if my presentation off the top of my head, and without any practice, made any sense at all, that these numbers will allow us to look and make the incremental calculation that Dr. Bailar is saying is necessary by just comparing the different numbers across, and comparing the increments in people who are lost.
		CHAIRMAN BOLTON:  Go ahead.
		DR. BELAY:  Peter, so looking at this, wouldn't it make sense that Option 4 would be tightening the deferrals in the U.K. from 6 months to 3 months, and leaving the TSEAC recommendation for the rest of the population intact?  
		In a sense, I am saying isn't Option 4 what you reflect and presenting in the table, and that is, is additional risk by tightening the deferral of donors who travel to the U.K. from six months to three months, and leaving the other part of the TSEAC recommendation intact?
		DR. LURIE:  I'm sorry, but I sort of lost you in all of that.  
		CHAIRMAN BOLTON:  What he is saying is that under the TSEAC proposal under Great Britain line, take out the zero and add another 14 percent there.  In other words --
		DR. BELAY:  Well, it would make sense to have our Option 4 as tightening the U.K. further, and leaving the other population alone.
		CHAIRMAN BOLTON:  Tighten the U.K. restrictions of the TSEAC proposal from 6 months to 3 months.
		DR. LURIE:  Yes.  Well, it is relative clear that if you are choosing between -- I mean, this is where the benefit is to be, the easiest benefit; the 14 percent decrease for a 1.5 percent loss in donors, right?
		DR. BELAY:  Right.
		DR. LURIE:  So, from 14 to 1.5.  The other question is whether either of these, the 5 or the 7, are worth doing for the about one percent.  
		DR. BELAY:  That's correct.  But it makes sense to me to have that proposal as an option.
		CHAIRMAN BOLTON:  Well, in that regard, Peter, while you are still there, one of the concerns that I have is that on that first line, the question about addressing the EU or various parts, remember that under the TSEAC proposal that we have a 10 year restriction on the Republic of Ireland, Portugal, and France.
		DR. LURIE:  Right.
		CHAIRMAN BOLTON:  It has been communicated to me from the FDA, and I think I have the same feeling, is that that question of the bright line, is that really warranted.
		And I think that Dr. Davies pointed out that if we simply go to a 6 month prohibition on France alone, 3 months on the U.K., you gather almost all of that benefit, and you don't have the problem of losing the German blood, for example, in the Euro-blood question, because that blood is not coming from France.
		I think that is a compromise that might work as well.  So, in other words, you have a proposal like yours, where you would eliminate anyone who has had a U.K. transfusion. 
		You would have the 6 month Department of Defense restriction, and whether it had north-south splits, we could debate; a 3 month U.K. deferral; and a French 6 month deferral.  And that would capture, I think, everything that is available.
		DR. LURIE:  No, there is no question that it is more efficient to -- among the European countries, the most efficient thing to do is to restrict France alone.  There is no question about that.
		But that is not the only thing that we have to consider.  It is not simply efficiency.  It is also what fraction of the risk that we remove.
		CHAIRMAN BOLTON:  Right.  But let me suggest this.  
		DR. LURIE:  Let me finish the thought.  The disadvantage to the France thing, I am not per se arguing against it.  But the disadvantage is that we have seen a certain amount of information suggesting that the data are difficult to interpret, et cetera, et cetera, across Europe, and there are the difficulties of drawing lines.
		But moreover, it evades the problem of anybody ever coming back to this committee again if we go for Europe and get it over with once and for all.  I mean, there is a certain neatness to that, which I think is worth considering.
		CHAIRMAN BOLTON:  There is, but then you end up with a five year European, as opposed to a six month French restriction, and I think there is a real difference in those.  
		Let me also say this, that one of my motivations is that we have two countries now in which we know that there are new variant cases, the U.K. and France.
		And it is also possible that we could entertain a proposal where the countries are classified according to documented cases of variant CJD, and then as a case appeared, then that country would automatically become or come under a six month deferral.
		Now, it has the unfortunate effect of changing the questionnaire for blood donors periodically, and hopefully it will never change.  Maybe we won't see any more new variant cases outside of the U.K. and France.
		But that at least captures the fact that the real risk to the blood supply are individuals actually infected with variant CJD.  And granted that there is some time period between infection and clinical disease.
		But there is much evidence that suggests that the agent in the blood, the prions in the blood, probably only occurs late in the disease, in terms of at or around the onset of clinical science.  So the real risk to the blood supply might be minimal during the silent incubation period.
		DR. NELSON:  The other side of that, of the supply question, I think of avoiding the European deferral at this point.  Remember that the committee was asked to review this periodically, and I think it was 6 months or something like that.
		And we know two things.  First of all, we know that the New York area is heavily dependent on Euro-blood at the moment.  We know also that the Euro-blood does not come from France or the U.K.  
		And we know that the New York Blood Center is planning to gradually over time discontinue the importation of Euro-blood.  And it is likely that the current risk, given that there have not been new variant cases elsewhere, and that the number of bovine cases is lower, although present in Germany and The Netherlands, that it seems like that this could be phased in or considered to be phased in, at which time we might have more data as to whether or not there were cases appearing, and what is happening to the bovine, and with better surveillance.
		But I think we could avoid a crisis of a shortage of blood supply in New York.  I don't want to kill people with our recommendations, and it is conceivable that we could do that.
		CHAIRMAN BOLTON:  Dr. Cliver first, and then Dr. McCullough, and then Dr. Prusiner, and I am not sure who else after him. 
		DR. CLIVER:  Everybody.  I was here two years ago when we came up with the 6 month deferral number, and was bothered by it.  I came away with the feeling that although this was a panel of experts that that particular decision could have as well have been derived at with a Ouija board.
		And we are experts, but our problem is that we are expected to make these kinds of decisions on the basis of conflicting opinions, and very few hard data, and we are in the position of the blind man and the elephant.
		So we make a decision, and two years later we are told that six months isn't enough.  But I have not heard anything regarding the U.K. other than what we looked at two years ago that led us to that six month conclusion.
		Now it sounds like a better than 50-50 chance that we are going to 3 months, and I don't see why.  Now, I understand why the FDA keeps inviting us back.  They are in a very difficult position.  
		We heard from some survivors today, but we will not hear from people who died because there wasn't blood.  Have not and will not.  So we have to look at the way that decisions are viewed in the United States.  
		If one VCJD case occurs in the United States that is perceived to have come from blood, Congress and the press will lynch the Food and Drug Administration.  And all the expert input that they have supposedly gotten from us will not preserve them from that kind of treatment.
		So my feeling is that we are in a situation where we are being consulted, but in effect what we are looking at is the FDA being put in the position of needing or appearing to be in charge, and so they are playing chicken with the American Red Cross.
		And we are in the prospect of having two classes of blood in the United States; the ARC standard, and everything else comes in second, and I guess we could live with that, except that when we look at the plasma situation, all that stuff that is being made that is saving lives as derivatives from blood, every time you change a criterion, everything that was collected under the old criteria is no longer useful, whether it came from Europe, or whether it came from here, or whether it came from here.
		Under our standards versus ARCs, or whether it came from our new standards, or say or old standards when we had a 6 month deferral, versus when we have a 3 month deferral.  
		We may need to throw out all the old product, and start over again.  It is not just about questionnaires.  So the perception of the validity of whatever this is that we are doing here depends to some extent on needing solid new data to revisit any decision that we made previously.
		Otherwise, we might as well have not been here two years ago, because it is a whole new game every time we walk in the door.
		CHAIRMAN BOLTON:  Dr. McCullough.
		DR. MCCULLOUGH:  Yes.  I would like to stay on the issue of whether or not distinguish grants from Europe as Dr. Nelson was pointing out.  I think this nice chart that Dr. Lurie put together though doesn't bring out or focuses on the somewhat reduction in risk by taking action against Europe en bloc.
		But the one percent donor loss I think does not really bring out the magnitude of the impact of the loss of Euro-blood, the loss of those travelers, plus the impact on the plasma availability, the availability of plasma.
		And so I think the impact of all of Europe versus France is much greater than it would appear from the graph up here, and it is an important point to continue to consider.  And I sort of agree with Dr. Nelson's way of thinking about it.  
		CHAIRMAN BOLTON:  Right.  And I would just like to emphasize and add to that, that we have to remember that the French risk is 5 percent of the U.K. primarily because of the importation of U.K. beef, and not so much for the BSE incidents themselves.  
		So when you compare the incidents of BSE in France versus Germany, and versus other European countries, that is only part of the equation.  The French imported a substantial amount of U.K. beef during the peak of the epidemic, and that I think is a substantial part of the risk that comes in from that.  Stan.
		DR. PRUSINER:  Well, I think that issue of how much beef was imported, and how much meat-and-bone meal was imported, that these are very, very complicated issues to assign weighting factors to.  
		I think that it is important that we all realize that there are real differences between now and two years ago, and I thought I would summarize these very briefly, because I think on the committee there is not a uniform appreciation of this.
		The number of VCJD cases is now in triple digits.  That was not true two years ago, and two years ago, we thought -- and I think that if you will look at that handout that I think Dr. Baron will show in his talk, but in there you see the number of cases per year.
		And I think we all thought in 1999 that the number was going down, because it went from 17 in '98, to 12 in '99.  Then in the year 2000, it went to 27.  So things are much different now in terms of the total number of VCJD cases.
		If you just talk about new variant CJD in France, there are a total of three cases.  Two of them are from 1999, and one of them is much earlier.  So that is about 5 percent of the total.
		Now, what about BSEs?  BSE is being detected everywhere people look by very insensitive techniques.  These techniques at best are seeing animals that would be sick within probably six months, and that is a very large number.  
		My guess is that it is closer to three months, but I don't have the numbers because the kinetics are not known.
		So what is happening is that everywhere these immunobloting tests are being used, whether they are ELISAs or Western blots, there are cases coming up.  And I think Christl Donnelly in her presentation showed this very nicely.
		So we saw, and we know this to be a fact now.  I mean, the latest one is the Czech Republic, and it is really pan-European.  It is different numbers in different places, and it in-part depends on how good the looking is.  
		The reason that Switzerland is probably so high is that Bruno Ursh and his company, Prionics, has a relatively small geographical area, and they work very hard to look at all of the fallen cattle.
	And the more they look, the more they found, and he is the first to tell you this in quite dramatic presentations.  Then the third thing that people need to understand is that there has been over the last two years a very concerted effort to look at a large number of tissues that contain lymphoid cells, cells that are traveling between these tissues and the blood in VCJD cases.
		And the tonsils are positive, and the lymph nodes are positive, and the appendix is positive,and the spleen is positive by very insensitive techniques.
		These same techniques would probably find positives in sporadic CJD if the same technique were a hundred times more sensitive, or a thousand times more sensitive.
		I don't know for sure, but that is just a hypothesis.  But the facts are that these tissues are positive.  So there are a series of new facts that I think are important, and I think it is driving this discussion that the FDA wants us to consider.  
		So this is by way of facts, and I am going to come back later to what I think about the proposal.
		CHAIRMAN BOLTON:  Lisa.
		DR. FERGUSON:  I would like to just add something in here, primarily from an animal health point of view, but I think it has applications here to the public health aspect.  
		And this is just on the general subject of can we subdivide Europe.  From an animal health point of view, we have found that next to impossible to do in regards to BSE, primarily for the reason that the import data is misleading if you look at it and say, okay, well, this was beef from the U.K. that went to France and stopped there.
		I think there has been so much transhipment and products change, and that there is a part of the product that goes to the continent, and it is then manufactured into another product, and goes through the rest of the continent.
		It is extremely difficult to say, yes, this simply went here and stopped there.  So I don't know that you can say primarily that exposure is limited to France, or limited to anywhere else.  
		And I think that we need to keep that in mind.  I think as the different countries are looking more for BSE, I think they are demonstrating this fact that there were products that moved throughout Europe fairly freely, and exposed a wide range of animals to a fairly large extent.
		And it is just now coming out.  You know, I have no idea if the human exposure is probably similar.  I guess I probably would have to say could be.  But that is one factor that I think that we need to keep in mind.
		I also would like to address the comments that have been made about the Euro-blood.  This does not come from France.  Can we actually say that?  I know that it is actually being shipped in and it is collected in Germany, and I forget where the other two countries are.
		But if we are going to say for purposes of this committee let's make the assumption that we will say we are going to defer a donor if they have spent six months or greater in France.  
		How do we know that the Germans that they collected that blood from didn't have that same risk factor.  Can we make that distinction.  
		CHAIRMAN BOLTON:  That's a good point.  Pedro.  A point of clarification though.  Euro-blood Centers are FDA licensed and those donors are screened according to FDA criteria.
		DR. PICCARDO:   To understand the situation of the different countries in Europe, or for that matter for any country in the world, we have to look at how hard they look at surveillance for BSE, but for multiple, we have to look at the surveillance in humans.
		So what do we know about the surveillance of VCJD in the different European countries, because the bottom line is who is infected with VCJD.  So the human part, I think we are underestimating the surveillance on the human side. 
		CHAIRMAN BOLTON:  Is there anyone on the committee, or anyone in the audience, that can address that question of the surveillance for VCJD throughout the EU?
		DR. KREYSA:  Maybe I can just clarify this point from the EU point of view.  You are just to know that in Europe now there have been heads of the Euro-surveillance system for the VCJD with notifiable VCJD throughout Europe.
		And any VCJD case has to be reported first nationally, and if there is any cases of VCJD, then this is a European evaluation which is carried out thanks to the teams from the blood banks in the U.K.
		So we have a European surveillance system, and one point that could demonstrate that European surveillance system is that it is efficient at the moment is that the number of reports in front of this surveillance system has increased in the 15 member States.	
		That does not mean that we are having VCJD reports in the member States, but at least we have more reports in the 15 member States.
		CHAIRMAN BOLTON:  And how long has that been in effect?
		DR. KREYSA:  The system has been put in place as of 1997, and the last figures that we had for were from 2000, and apparently the system is efficient towards surveillance of VCJD.  But I can tell you that there is a Euro-surveillance system in place.
		DR. PICCARDO:  I don't want to single out any country, but Christl Donnelly said today that there are some inconsistencies in data that is coming from Portugal.
		And so I wonder -- I mean, it is not only which country reports VCJD, but what about the total numbers of cCJD that are being seen in the different countries, because that, I think, will reflect the active proper surveillance in humans.
		But we want to know what happens with regular VCJD and then from there how to extrapolate how well the surveillance is being done.
		CHAIRMAN BOLTON:  I believe that is how the surveillance system works.  CJD itself is notifiable since 1997, and those cases are screened to see whether they are variant CJD.
		DR. PICCARDO:  Right.  But my point is, for example, because I just don't know, is Portugal reporting the number of cases that they should have according to the population it is -- I don't want to single out any country.  I am just saying how active that surveillance is, and how real those numbers are.
		CHAIRMAN BOLTON:  Dr. Bailar.  
		DR. BAILAR:  I suppose that somebody should put on the record that absence of proof is not proof of absence.  We talk, and talk, and talk about how the risk is theoretical, but there may be a real risk behind that theory, a risk that would not only have its direct effects, perhaps quite serious, but would also be immensely destructive and disruptive to the whole blood supply system and beyond.
		CHAIRMAN BOLTON:  Dr. Lurie.
		DR. LURIE:  Back to the question of whether France should be singled out as it were.  I guess I disagree with Dr. Piccardo that it is really the CJD or really VCJD cases and the surveillance that really matters.
		I mean, I would like to know the data as much as you would, but in the early phase of that epidemic, when you only have about a hundred or so cases, particularly an evolving one, you can get all kinds of anomalous findings on the basis of really only a hundred cases.
		If you had made an AIDS policy based on the picture in 1985, you might have concluded that there was next to no epidemic in Africa.  And over here I think that for me the more important data are really the cow data.  
		They are not the human data, because the numbers are still much too small.  There happen to be three in France, but I don't find that particularly indicative or necessarily a much bigger problem in France than elsewhere in Europe.
		Now, the last time that we discussed this, I raised the question of the cow data.  And at that time all we had were the number of positive cows per population of cows in the country, and it was pointed out accurately that there might be differences in the surveillance systems for those countries, and some countries might have looked harder than others.
		That was all that we had to go on at the time, and those kinds of data implicated Portugal in particular rather strongly.  But things are different now.
		Dr. Donnelly has presented what I think are very important data, which are the data on the healthy cattle which seem to be as far as I can tell, and correct me if I am wrong on this, but randomly selected health cattle, with no particular reason for bias, in a similar way across a number of countries.
		And what we see is that France is not even the first of those.  France is the fourth of those.  There is a 3 per 10,000 rate of positive cattle in Spain.  In France, it looks like about .3 per 10,000.
		And these are the data, and I will just hold them up to show you.  There is no bright line here, and suddenly it is not France, which is down in the fourth position.
		CHAIRMAN BOLTON:  Additional discussion?  Everybody is suddenly quiet.  
		DR. EWENSTEIN:  Well, let me just suggest a way to proceed administratively, and I guess we need the FDA's okay on this.
		But perhaps since we are going to consider the FDA option first, we could take what we would call a friendly amendment and therefore create a modified FDA proposal and vote on that first.
		And that might be easier than trying to construct or to vote no on everything, and then construct an Option 4.  So I guess we need their okay for that.
		Let me just make a couple of other comments.  I think I appreciate very much the FDA's point of view, and for that matter the philosophy expressed by the ARC in trying to create the safest possible plan.
		That said, I think I am personally very moved, and maybe just as a practicing hematologist, by the fact that we don't seem to have in place today any sort of assurance that we can deal with any sizeable further loss in donors on the ground today, especially in certain geographical areas.
		And so I think that one of the positives in the FDA approach that I would like to see amended even further is some flexibility in the implementation. 
		Now, besides the fact that that sort of flexibility in the time line in the implementation would avoid a potential disaster on the use of blood products, I think it also has some scientific basis.
		And that is that I do think that we may be looking at temporally different situations in different places.  I think in the U.K. it is not as if the risk existed simultaneously in my mind throughout Europe, including the U.K. now, just at different levels.
		I think that there is a kinetics to this, and I think that in my mind the U.K., and France to some degree, can be separated out as having been in the first wave. 
		And there may be a second wave, and that may eventually get through the food chain, and that may eventually get into human donors.  But that will allow for a little bit of a delay in the risk in the donor population.
		And that I think becomes a rationale, in addition to the fact that we can't absorb the tone or loss for having a bit of a delay in the implementation, and that is just my perspective.  
		And the final point is that I think it is okay to have a standard that some fractionators, for example, or suppliers of individual blood fractions might want to provide, that is set and can be exceeded by others.
		We have that today.  I mean, not every provider of plasma products, for example, has the same questionnaire for donors.  Not every provider of products has the same BSE testing or methodologies, or even the viruses that are being looked for.
		But certain standards have been recommended by the FDA and their advisory committees, and in some cases those are being exceeded, and that is okay as long as the minimum standards are being met.
		And so if some organizations decide to exceed what we advise today, I don't think that is without precedent or would necessarily create havoc in the blood product industry.		
		CHAIRMAN BOLTON:  Bruce, did you have a specific recommendation, in terms of how implementation might be delayed, or how long it might be delayed?
		DR. EWENSTEIN:  Well, I think the FDA was mentioning that, and if I understand the fifth bullet point, it was 6 months.  But I think it sounds to me, and maybe some feasibility data would have to be provided by the folks most affected, but it sounds like that is going to be a little bit too short of a time line for some folks.
		It may take a year, and it might take two years, but I would like to build in that concept into the final proposal, but I think that six months may be a little too short there.
		CHAIRMAN BOLTON:  Well, let me ask Dr. Asher to comment on that.  Would it be all right if we add friendly amendments to Option Number 3, or any other option as we vote on them?
		DR. WILLIAMS:  You are free to add anything as long as the basic questions are addressed.
		CHAIRMAN BOLTON:  Yes, Dr. McCurdy.
		DR. MCCURDY:  Along the line of trying to move things forward, as I mentioned earlier, it would simplify things for me if the whole blood segment and the plasma segments were separated.
		And if it is all right with the Chair, I would like to make a motion that we do that.
		CHAIRMAN BOLTON:  All right.  If you would like to make a motion, that's fine, I guess.  I am not sure personally, but I not sure that it makes it easier for me.  
		DR. KATZ:  Well, there is another aspect, and that is that recovered plasma is part of what we do, and will necessarily since it is a bi-product of the whole blood donation, is necessarily impacted and impossible to separate.
		And that would be that if -- is it about 3 million liters a year in this country, or 2 million?  Well, about 2 million liters of the plasma supply, is a recovered product that comes out of whole blood donations.
		CHAIRMAN BOLTON:  And so what I would suspect would happen is that whichever was the most restrictive is what would be used, and so I am not sure that it makes any sense.  
		DR. KATZ:  I think that the fractionators would demand that, and I won't speak for them.
		CHAIRMAN BOLTON:  Right.  Yes?
		DR. PRIOLA:  I would just like to make one comment.  In listening to all the discussion that has gone on here today, that it strikes me that we are dealing with as we all know a set of data that concerns theoretical and estimated risk, and are being asked to make a decision on that based on an estimation of how we can replace the lost donor supply in the future.
		So we lose the 6 percent if you extend the deferral across Europe, and we are being told that that can be made up.  But that in and of itself is still theoretical.  They are making projections.  
		And so for myself, I feel uncomfortable making a decision to increase the deferral European-wide based upon estimated theoretical risk to start with, and based upon estimated theoretical projections to end with.
		And that for me, before making a decision like that, there should be a system in place, where the donor population is increased and is steadily increasing.
		So that we can take or we have that sort of legal room that you would need in order to increase broad based deferral.  It is a little bit like putting the cart before the horse.  We will make the deferrals and catch up later.	
		I think you have to have the system in place where you know that you can catch up, and the data is there to catch up before you make such broad ranged deferrals.
		CHAIRMAN BOLTON:  Dr. Klein, I'm sorry I neglected you.
		DR. KLEIN:  Not at all.  You almost took the words out of my mouth.  I would like to make three points here.  The first is that before you do any extension of the deferral recommendation, realize that this idea has now been floating around since January.
		And yet I have seen no data to tell me that the blood supply is better now.  I don't see any strategic depots and I still when I call up my regional supplier in this area, I am told that there is no "O" available except on an emergency basis.  I am not alone.
		And so I would like to see some evidence that in fact we are moving data, and that we can get those data, and that we are moving toward increasing supply before we have increasing deferrals.
		The second point that I would like to make is that of a risk model.  I mean, I see the models for deferral of donors, but what I don't see is something like the Canadian model that we saw earlier telling us based on some model what the potential number of deaths or disability would be in hospitals if something went into effect.
		We need those data.  Now, unlike the data with BSE, where we don't know so much, and we can't get it, we could get these data.  You could have gotten them if someone had put a system into place two years ago, and I am hoping that perhaps someone will put that part of the risk model into play soon.
		And the final point is related to that, and that is -- and I have said this in any fora before, that it is really tragic that we don't have a system in the United States for looking at monitoring the blood supply, and not only collections, but utilization.
		And not a quick and dirty system, but a system that is based on surveys, science, and a system that is based on epidemiologic principles.  And I hope that you will be asking the FDA to see if there is a source of funds to get such a system ongoing, and not a one time only survey, for monitoring the blood supply.  Thanks.
		CHAIRMAN BOLTON:  Stan.
		DR. PRUSINER:  Jay, will you -- do you mind if I ask you to comment on what you told me earlier?
		DR. EPSTEIN:  On the question, and looking to see if Steve Nightingale wants to respond, but it was recognized in 1999 that if we were to put into place the geographic deferral for exposure in the U.K., we would need to closely monitor the impact of the blood supply.	
		And an ad hoc mechanism was indeed put in place and it consisted of contract funding for the national blood donor resource center, which is an independent subsidiary of the AABB.
		And the commitment was for monthly monitoring of supply.  Now, when I say supply, at that level we were talking about blood collections.  There was releases from collection centers.
		And it was recognized at the start that that didn't tell us the whole story, because in order to really look at what we were worried about, which is risk of shortage, you have to look at supply and the demand, and you have to look at the dynamics.
		And you have to look at the reserve and what is happening to the reserve, and at the ratio of the inventory to the outflow, and so forth.  But it was a crude first cut.  
		We did indeed obtain and are still obtaining monthly data on supply, which went back from some retrospective collection to October of '99.  And remember that although our guidance became final in November of '99, the guidance called for implementation within six months, which was not until the end of April of 2000.
		So the U.K. deferral in most parts of the country went into play in April of 2000.  At that point in time, we did indeed have at least monthly monitoring of supply ongoing, and the data which we were actually shown at the January meeting of this committee showed that the supply did remain flat.
		So that is point one, and point two is that the deficiencies of that model have been recognized.  It was a survey that was done at 26 centers, and they were selected so that they could be monitored statistically to represent the U.S. blood supply.
		However, there were those limitations, and there was a limitation of the periodicity.  You know, one month is a long time to look at fluctuations that might go on daily or weekly.  
		That the data were only be received one month later than they were being collected, and that it might not fully represent the U.S.  So there is now a second initiative which the Department of Health and Human Services is funding.
		The original effort was funded ad hoc by the NHLBI, and I believe it was originally a 3 year commitment.  There was an extension to continue that funding through December of this year.
		Now, the second initiative is focused on daily monitoring of inventories in hospitals.  That is different than monitoring of distributions from blood collection centers, and the concept is that it should enable us to get one step closer to recognizing when we are in a difficult situation of supplying a hospital in the United States.
		And I believe that that effort is being brought about through contracts with a number of hospitals.  Data will be obtained, I believe, from the majority of the America's Blood Center hospitals, as well as selected other hospitals.
		And that the contracts were supposed to be in place by the end of July.  I am not in a position to comment on whether that is actually going to occur, but there is some optimism.
		So we are moving toward putting in place systems that can monitor the availability of the blood, as well as the utilization of the blood, and also look at the health of the inventory.  
		Is there a 3 day stock, a 2 day stock, a one day stock, or an out of stock situation, and how does that stratify according to the blood groups, because as we have heard the relative proportion of collections and demand is not the same for the different blood groups.  
		There tends to be a shortage of Group "O" for which you have to over collect all groups to have enough Group "O" on hand.  So that is what is happening.  Now, it is still short of having the kind of system that Dr. Klein is calling for, which is a comprehensive on-going, full established, and funded monitoring system.	
		We are still talking about efforts that are ad hoc, and will have a limited lifetime pending a decision to create some form of permanent monitoring system, either run by the government or run by the private sector, and somehow funded by one or the other, or both.  We are not there yet.
		But we do have these government funded efforts as I say, and the one that has been looking since October of '99 at blood made available, and the one that we hope will start up soon after July to look at hospital inventories, and that is just where we stand today.
		DR. NELSON:  Jay, is there a plan to also look at plasma products, IVIG, in the same way?  Because we have heard comments here from hemophilia organizations and others needing special products.  Is it feasible to do that than to have to do it later?
		DR. EPSTEIN:  It has been mentioned, and Steve is now at the microphone, and perhaps can give a more up to date answer.
		DR. NIGHTINGALE:  I think that Jay summarized the situation very well.  What we are trying to do is to do two things, and these are right now actually on direct orders from the Secretary.  
One is to get the thing started as quick as we can, and number two is to make better as quick as we can.
		The Secretary has been made aware of the need to monitor the plant and the supply, as well as the blood supply, and where we are with the monitoring of the supply side as Jay said is that we have monthly data on both blood and plasma collections that we have had for about 2 or 3 years.
		We had a meeting of our advisory committee in April, where we discussed some ways where those could be improved, and one of the items that we are in continued discussions right now is how we can improve those models, and where are we going to get the money for them. 
		I believe that is an answerable one, however.  And having established with limited data on supply, we are now moving to the first phase of measuring demand, which is measuring blood on the shelves or in the refrigerator of the purchasers.
		And the first purchasers will be the hospitals.  Very briefly, we are going to spend $250,000, and $150,000 on 29 sites, and $93,000 on a secured website.  
		I sent out 18 of the 27 contracts yesterday afternoon, and the website contract yesterday afternoon, and expect to have the remainder at least in the mail by the close of business on Monday, and those would be verbal commitments.  
		There are several people in the room who have made verbal commitments to participate in this system.  We hope to begin collection as early as July 2nd.
		When we get the system up, and not until we get the system up, but hopefully we will have everybody on July 30th, and that will be the time when I hope to initiate discussions about the plasma supply.
		And one of the ideas that has been floated is that there are 36 Children's Hospitals in the United States, and they use a lot of gamma globulin.  They use a lot of clotting factors, and their equipment people we need to talk to.
		We need to talk to the patient service organizations.  We need to talk to the middle man, and we need to talk to FFF, and a couple of their major distributors.
		This is not rocket science stuff.  The rocket science actually is getting consensus on how to collect or how the material should be collected, and when one should initiate a process, and when one should get started.
		And my own view, which has prevailed for the moment, is get started and try to make it better, and the first public data which we are going to try to make it better is on August 24th of this year, when the Advisory Committee on Blood Safety and Availability will meet to review the progress to date, and to make recommendations.
		However, recommendations between now and then are more than welcome.  My name is Steven Nightengale, and my direct line is (202) 690-5558.
		CHAIRMAN BOLTON:  Dr. Belay, and then Stan.
		DR. BELAY:  I support collecting this kind of data on the blood supply situation in the United States and also blood utilization, but unfortunately we have to make a decision today in the absence of this data.
		But there is one data that we can use and that is presented to us today, and that is that we don't have to be a genius to figure out what would happen to the blood supply in the New York area, because we have been told that 25 percent of the blood supply is obtained from you.  
		In addition, the other foreign policy based on the travel history may impact on the New York area for an additional 10 percent, and probably bringing the total percentage to 35 percent.
		And that is a substantial amount, and so this is data that we can use to make a decision today as we go along through the process.  
		CHAIRMAN BOLTON:  Stan.
		DR. PRUSINER:  What I wanted to -- well, I am happy that we just heard about all of the things that are in place and going forward, and all the caveats of this, but it is my understanding -- and I would like Jay to respond to this again.
		That besides the 2.2 percent loss that the committee created when it set this six month policy in the U.K. from 1980 to 1996, there was another event going on that had to do with the American Red Cross, and it had nothing to do with this.
		And which then created a shortfall of approximately 3 percent for the whole country.  So the blood supply was flat, with an actual reduction in donors during that time of 5.2 percent.  And maybe, Jay, you can explain it better than I can.
		DR. BELAY:  You have stated it accurately that the Red Cross implemented a change in the donor screening process, moving from the ear lobe stick for the hematocrit to a finger stick.  
		That resulted in a loss within the Red Cross system of about 6 percent of the donors, and given that there are 44 or 45 percent of the whole system, that is a loss in the range of 3 percent for the system as a whole.  
		Within the same year the 2.2 percent loss for the entire system was incurred consistent with the FDA recommendation on the U.K. deferral.  So we do believe there was something in the neighborhood of a 5.2 percent loss nationally occurring over that approximately year or year-and-a-half period.
		And the evidence from the supply monitoring contracted for with the NBDRC was that supplies stayed flat.  Additionally, Jackie, you are here and can tell us, that the Red Cross reported that within their own system they were able to offset their aggregate a plus percent loss, with increased collections somewhere in the neighborhood of 9 percent, actually resulting in a net increase, if that is a correct statement, Jackie.
		So we do know that losses of that magnitude have been offset and in recent history.  But the question is how readily can it be done again, and what kind of resources would be needed to make that a success nationally, and what do we want to see in place first before we incur the deferrals.
		CHAIRMAN BOLTON:  Okay.  One more.  Steve.
		DR. PETTEWAY:  Thanks, David.  I would just like to follow up on what Dr. McCurdy has suggested relative to blood and plasma, and the differences between blood and plasma.  
		And there is a significant difference in overall risk relative to blood products and the administration of blood products, and the development of plasma derived products with processing and potential removal.
		And while it maybe somewhat complicated, it is not unreasonable to potentially look at the risk at the donor level, or the donation level, differently between the two because of the way the products are produced, and the risk reduction during production before they go into patients.		
		CHAIRMAN BOLTON:  Would someone representing the blood collection agencies like to again respond to that, or is it -- my sense is that it is a nice argument, but that as a practical matter the collections are done -- will probably be done under some uniform set of standards.	 
		DR. KATZ:  There are going to be more deferrals than there are now, and I think there is nobody that doesn't recognize that.  You give us enough money and enough time, and we will make it up. 
		I mean, I want to make that clear.  Enough money and enough time, and we will get the donors.  I mean, we use payday advertisements in my center, and we have an enormous advertising budget and for us it works.  
		And one of the reasons that we have an advertising budget is that recovered plasma is a nice byproduct that somebody gives us a bunch of money per liter for.  
		So take it away, and I want to know where the resources come from.  We are talking about money and time.
		DR. PETTEWAY:  Not to push the debate further, but remember that in the plasma industry that we plasmapherese.  So our point of collection and what we collect, and what we fractionate is really different from blood and recovered plasma.
		CHAIRMAN BOLTON:  Okay.  Stephen.
		DR. DE ARMOND:  I guess I am the only one who hasn't said anything this afternoon.  It seems to me though that -- and I have listened to this tremendously being a rookie member on the committee, and there is lots of tremendous insight, but I don't see where it is going.
		And I don't get to a bottom line, and each insight doesn't tell me how I should vote.  And as I see this process, it is an evolving process of recommendations about balancing the risk of variant CJD and blood products, versus the risk of causing deaths or morbidity by not having blood products.
		And the three choices that we are given, and possibly a fourth, have their pluses and minuses, but it is clear that both the FDA and the ARC changes in the policy from 6 months ago in response to real data that tells us what there is an increase in variant CJD in Great Britain, which is disturbing.
		And with some projections, depending on incubation time, going out to a hundred-thousand people or more.  So there is some reason to become a little more stringent in the way that we deal with that.
		Also, the increasing BSE or the more awareness of BSE in a variety of countries and on the European continent also has raised the alert.  And basically what we need is new data, and I am sure that we are going to meet in six months, and we will have a lot of new data.  
		We certainly need to have testing of blood and blood products to see what the real risk is.  We need to know more about variant CJD in these other countries.  
		And as for the choices that we have, it looks like it is between not doing anything, which again with the increasing data suggesting that there is increasing variant CJD tells us that maybe we have got to be a little more stringent.
		We have got a choice then between ARC and FDA, and ARC, I think, goes too stringently.  They get a good reduction in risk, but at a very high cost in terms of blood.  
		The FDA gets virtually the same reduction in risk, and at half the effect on the blood supply.  And yet I don't know how to say that we can split up Europe into different parts.  It seems to me that the FDA has done a relatively decent job in trying to piece this whole thing together.
		And so unless I can hear somebody say that definitely we have to split Europe into its individual parts, and vote on each one of them, I think we are at -- I have not heard anybody really say that we are going to have anything greatly different from the three choices that exist.
		CHAIRMAN BOLTON:  Let me freeze things here for a moment, and give you my sense, and that is that we are close to being able to resolve this question, and that in fact if we were to look at Option Number 3, the FDA proposal, there are probably 3 out of the 5 lines that we could get a sense that we are in agreement on.
		And I would just like to informally do that by a show of hands, and that in the second item under Option 3, "To defer donors who spent any cumulative period of 3 months or more in the U.K. from 1980 through the end of 1996," would all those in favor of that item just raise their hands?
		(A show of hands.)
		DR. FREAS:  There are 17 voting members at the table, and 12 voted in favor.
		CHAIRMAN BOLTON:  So, 12 out of 17, and this is informal, but those who would vote no on that to defer donors, would they please raise their hands?
		(A show of hands.) 
		DR. FREAS:  Let me go by names, because we do want this for the transcript.  That would be Dr. Burke, Dr. Williams, Dr. Prusiner, Dr. Cliver.  So, four no's.  
		CHAIRMAN BOLTON:  And this is informal.
		DR. CLIVER:  If it informal, why do you need our names for the transcript?
		DR. FREAS:  We do use these transcripts in subsequent deliberations and it is nice to have a name with a vote.  
		CHAIRMAN BOLTON:  And abstentions?
		DR. FREAS:  Shirley, you were a no-vote?
		MS. WALKER:  Yes, because I thought that the argument for just restricting it period was a good one, instead of using or splitting the country in half.
		CHAIRMAN BOLTON:  Oh, no.  This was just considering this second item.  This is just 3 months or more in the U.K., versus the current recommendation of 6 months.
		MS. WALKER:  That's fine.  I misunderstood.  The 3 months will be fine.
		CHAIRMAN BOLTON:  So that would be another yes vote.
		MS. WALKER:  That will be a yes.
		CHAIRMAN BOLTON:  Stan.
		DR. PRUSINER:  I think there is an important modification to that data that we are skipping over, and that is that I think I would like to just see you take another straw vote and just change 1996 to the present.
		That to me is very problematic.  We were discussing this, and I don't know exactly where you are headed, but I am just throwing that out to you if you want to do it later.
		CHAIRMAN BOLTON:  Well, we can take that straw vote, but I would do that in addition to what we just did. 
		DR. PRUSINER:  Okay.  Fine.
		CHAIRMAN BOLTON:  So those that would accept deferring donors for 3 months in the U.K., from 1980 through the present, raise their hands if they are in favor of that?
		DR. FREAS:  There are nine yes votes.  
		CHAIRMAN BOLTON:  And those who are opposed to that?
		(A show of hands.)
		DR. FREAS:  Dr. Burke, Dr. Williams, Dr. Lurie, Dr. Cliver, Dr. Priola, Dr. Belay, Dr. Ferguson.
		DR. LURIE:  I misunderstood.  I need to change my vote.  
		CHAIRMAN BOLTON:  To yes or no?
		DR. LURIE:  No, it should be through the present.
		CHAIRMAN BOLTON:  Through the present?  Okay.  Are there abstentions?  I think that is 10 then, and one abstention.
		DR. FREAS:  One abstention.  
		CHAIRMAN BOLTON:  Now, I will try to make this clear.  On the subpart of Option 3, to defer donors who spent more than six months on a European Department of Defense base from 1980 through the end of 1996, with or without segregation of north versus south, and on the general concept, those that would be in favor of including that, would they raise their hands?  In favor of Item Number 3, Option 3?
		(A show of hands.)
		CHAIRMAN BOLTON:  I will read it again.  To defer donors who spent more than six months on a European Department of Defense base from 1980 through he end of 1996, or from 1980 through 1990, if all exposure after 1990 was on Department of Defense bases north of the Alps.
		DR. DE ARMOND:  And that is essentially the same as your original -- 
		CHAIRMAN BOLTON:  Yes, that is the original.
		DR. DE ARMOND:  -- from six months or more.
		CHAIRMAN BOLTON:  That's right.  That's current.
		DR. EPSTEIN:  I'm sorry, but there is no current deferral for exposure on military bases unless they happen to be in the U.K.  What we are saying here is if there was exposure on any European base.  So this would be a totally new policy.
		CHAIRMAN BOLTON:  Okay.
		DR. EPSTEIN:  All right.
		DR. PICCARDO:  Can we make it to the present?
		CHAIRMAN BOLTON:  Yes, we can make it to the present, but let's get the first vote as it stands.  I just want to have some sense of whether this is acceptable or not.
		So as it stands, reading Item 3 under Option 3, will all those who are in favor of that raise their hands?
		(A show of hands.)
		DR. FREAS:  There are 11 yes votes.
		CHAIRMAN BOLTON:  And those voting no?
		(A show of hands.)
		DR. FREAS:  The no votes are Dr. Burke, Dr. Williams, Dr. Priola, Dr. Nelson.  Four no votes.
		CHAIRMAN BOLTON:  Any abstentions?
		DR. FREAS:  There is one abstention, Dr. Cliver.
		CHAIRMAN BOLTON:  And finally, and probably the easiest one, and that is to defer any recipient of a blood transfusion in the U.K. from 1980 to the present.  All those in favor, raise their hands?
		(A show of hands.)
		DR. FREAS:  There are 17 votes.  It is a unanimous 17 votes in favor.
		CHAIRMAN BOLTON:  So Peter was correct in that, and that that is a no-brainer.  But the only one perhaps.  So I guess my sense of being close -- well, no, those are the three easy ones.  
		The problem that we have now are Items 1, certainly, and possibly Item 5.  So, Item 5 may be the easiest.  Dr. Ewenstein had suggested that we might recommend that the implementation have some delay, and we didn't get a specific, but perhaps it be just communicated that it should be flexible?
		DR. EWENSTEIN:  Well, if we need to come up with an amendment for today, I would make it 18 months instead of 6 months.
		CHAIRMAN BOLTON:  Implemented within 18 months.  So let's start with that one first.  All of those who are in favor of altering Item 5 in Option 3 to read to implement deferrals within 18 months of final FDA guidance, would their raise their hand?
		(A show of hands.)
		CHAIRMAN BOLTON:  Okay.  Let me read again.  The current Option 3, the FDA proposal reads, "To implement the deferrals within 6 months of final FDA guidance."  Dr. Ewenstein has suggested that we change that to read, "Implement deferrals within 18 months of final FDA guidance."
		That is that it would give the blood centers an extra year to adjust to this policy.  So that it would not occur within six months of the guidance, but would occur and be implemented within 18 months of the guidance."
		DR. LURIE:  Just making a point that the guidance is probably a year away probably.
		CHAIRMAN BOLTON:  Right.  The guidance may be a year away from coming out anyway.
		DR. PRUSINER:  Are we talking about duration of residence, or --
		CHAIRMAN BOLTON:  No, we are talking about implementation.
		DR. BURKE:  I find it difficult to vote on how long we are going to wait until we implement a policy if I don't know what policy it is that we are going to implement.  So I think we have the cart a little before the horse on this one.
		CHAIRMAN BOLTON:  Well, it is all sort of a package.  
		DR. BURKE:  Okay.
		DR. NELSON:  And the other point about delaying implementation is that this committee meets periodically and revises the guidelines.  So if we don't want something implemented for 18 months, we could vote on the policy six months from now, or 12 months from now when it is perhaps more clear on what we need to do and when.
		So although I appreciate the fact that you need to know what is coming down the road, but to me it is not --
		DR. BURKE:  I'm not asking for a vote at this point.  It is just that I think it needs to be voted on at the appropriate time.
		DR. EWENSTEIN:  And if I could just respond to that.  I think there is a big difference between waiting a year to vote on something that has a six month implementation, and voting on something now that has an 18 month implementation.
		And I do take the point that one has to know what the whole package is, but what I am trying to respond to is the fact that once we set a policy, and recognizing that it could change again, but once we set a policy, this will give folks more time to respond to that policy.
		If we spring it on them with only six months notice, it may be harder for them to respond to that policy.
		DR. EPSTEIN:  Yes.  I just want to comment on -- and this comes back to a point that Dr. Lurie made very early in the meeting today.  We will most likely first issue recommendations as a draft guidance, and then have a comment period, and then review comments.  
		And then issue a final guidance for implementation.  So if we say we would recommend implementation within six months of final guidance, in all likelihood we are talking about a year from now. 
		So it could be 9 months to a year.  It just depends on how quickly we can move this process alone.  So I just mention that to you so that you are aware that if you say you recommend that FDA should advise implementation within 18 months of final guidance, you have to add the time it may take to get us to final guidance, and as to when this might be a policy in effect.
		CHAIRMAN BOLTON:  Dr. Katz.
		DR. KATZ:  There is a practical matter here, and I don't know exactly how to get to the kernel of it.  But I think we have heard from the Red Cross, and this is likely a done deal in September.
		And the independence floating around out there, each of us smaller or larger operations than the other, will have enormous pressures in a policy vacuum that was going to go on for 18 months or so.
		I don't know that this committee saying we will delay it for 18 months makes any difference.  Without some pretty clear guidance from FDA in the short run, we are stuck with half the blood supply doing this, and the other half trying to make up their minds.
		CHAIRMAN BOLTON:  So the suggestion is not particularly helpful?
		DR. KATZ:  I don't think it avoids the precipitating problem.
		CHAIRMAN BOLTON:  Shirley.
		MS. WALKER:  I think what we are basically of mind to take on this would be that if wouldn't be all that bad to have a two-tier type of system.  The FDA system would be the minimum standard and ARC could be the maximum.  
		This way we have some flexibility and if we err, we err on the norm.  That way we have a win-win situation, and nobody loses.  The FDA as a minimum standard which everyone could buy off, and we are not playing children with the American Red Cross.
		And the American Red Cross can do whatever they wish to do and have a larger standard.  But that way the blood supply is adequate when we take into consideration all factors.
		CHAIRMAN BOLTON:  Well, let's just find out how people stand on this.  So, again, repeating -- and vote your conscience.  Would you prefer the 18 month revision, and so those that would prefer that that item be changed to implement deferrals within 18 months of final FDA guidance, raise their hand in the affirmative.
		(A show of hands.)
		DR. BELAY:  David, we still have a problem of which package, which option.
		CHAIRMAN BOLTON:  Any package.  This is not a formal vote.  This is a straw poll.  So I don't see an overwhelming response.  Should I ask for those who prefer that we implement deferrals within 6 months as it reads now for the final FDA guidance?  Please raise your hand.
		(A show of hands.)
		DR. BELAY:  You have six months?
		CHAIRMAN BOLTON:  Six months.
		DR. FREAS:  So, 12 yeses.
		CHAIRMAN BOLTON:  Well, the bottom line here is that except for the question of all of Europe versus part of Europe, we seem to find the FDA's option three proposal as satisfactory.  So perhaps what we -- 
		DR. EWENSTEIN:  David, can I just add one other possible amendment, which was actually the language that was used in the advantages to Option 3, but never made it up to the bullet point.  
		And that was that if you look at Advantage Number 3, that the impact on the blood availability is unknown, but it is estimated to be controllable by instituting both the National Recruitment Campaign and a system to monitor adequate blood supply.
		And I would like to see the National Recruitment Campaign and a system to monitor the adequate blood supply built into the proposal, and not just stated as an advantage when it isn't part of the package that we are voting on.
		And I think that if we listen to many of the concerns of the folks who supply these blood products, that is what we heard, and that was that there was a need for a government-blood industry partnership to carry out both the National Recruitment Campaign and the monitoring campaign.
		CHAIRMAN BOLTON:  Okay.  Well, I think the only way really to handle that then would be to entertain a motion to modify Option 3 to include that as part of the recommendation.  Otherwise, this is going to get too complicated.
		DR. EWENSTEIN:  Sorry.  Well, that is what I was proposing as an amendment, that that be included as part of the proposal that we are voting on.
		CHAIRMAN BOLTON:  This is getting impossibly complicated.  The motion has been seconded.  Do I hear any discussion?
		DR. BELAY:  I think we should come back to that issue after we vote on each option, because if this option is not selected, basically it could become moot.
		CHAIRMAN BOLTON:  Well, this is the first option that we will be voting on, and so the question is whether we should modify it to include as a recommendation that a national recruitment campaign, and a system to monitor adequate blood supply, be part of the recommendation.  Further discussion?
		DR. DE ARMOND:  I think it is a great idea.  We don't have data on anything.  We need data.  It has to be part of it.
		CHAIRMAN BOLTON:  Okay.  The motion has been made and seconded to add as a recommendation that a national recruitment campaign, and a system to monitor adequate blood supply be added to Option 3.  All those in favor?
		(A show of hands.)
		DR. FREAS:  Fifteen yes votes.
		CHAIRMAN BOLTON:  No votes, please raise your hand.
		DR. BURKE:  I vote for data.
		CHAIRMAN BOLTON:  I'm sorry, but you vote for data only?
		DR. BURKE:  Yes.
		CHAIRMAN BOLTON:  Well, that's not an option.  You vote for the amendment or not.  No votes?  Abstentions?
		(A show of hands.)
		CHAIRMAN BOLTON:  Okay.  That carries.  So, now we have that amendment, and the question that I would like to put before you informally is that Item 1 under Option 3 is to defer donors for cumulative travel for residents of 5 years or more in any European country, except the U.K., from 1980 to the present.
		It has been suggested that we alter that to include only part of Europe, or something.  I am not sure.  For example, France alone.  Is it the desire of the committee to vote on this issue as it is written, and as we have amended it, or would you prefer to entertain a motion to alter that first item in any way?  Discussion.  Stan.
		DR. PRUSINER:  I mean, if you do some very simple-minded math, and say that the risk of variant CJD in France right now is 5 percent of what it is in the U.K., and now you say that France either has porous borders and all of Europe is the same, or France is different.
		That is a separate issue.  But the 5 percent number, if you now multiply 5 years times 12 months, that is 60 months, and 3 months, which we all think is appropriate now for the U.K., is 5 percent of 60 months, I think the numbers are approximately right.  That is what I am trying to say to you.
		I am trying to say that 5 years is not an unreasonable number relative to the 3 month number for the U.K. that people seem to want to adopt.  So then it seems to me that it is a geographical issue after that.
		That five years is an okay number relative to variant CJD cases in the U.K., versus the number outside the U.K.  And I don't know the right answers to whether it is France, the countries that border on France, that it is all European countries.  I just don't know the answer.
		CHAIRMAN BOLTON:  Well, let me give you my concerns here, and that is that -- and I believe you are right, Stan.  It is primarily a geographic issue, and if it France alone, Euro-blood is still in the picture for the New York-New Jersey Metropolitan area.
		If it is all of Europe, then Euro-blood is out, and I think that has a significant impact on the blood supply in the northeast.  And for me that is the primary concern.  It is a weighing of a marginal increase in safety by adding all of Europe in addition to France, versus a real impact on the blood supply.
		And as it has been stated here several times, we will revisit this issue in six months or in a year, and as things change, we may adjust this policy.
		DR. NELSON:  Why don't we vote on three proposals then; with France as one, and all of Europe for 5 years as another; and all of Europe for 6 months as a third, which is the Red Cross.  And we could on each one of those separately yes or no.  Does that --
		DR. LURIE:  I agree that the situation in New York is definitely a particular problem, but what I did see though is that the representative from New York indicated that by 2004 or '05, and I can't remember which, they are planning on not using Euro-blood anyway.  
		So it strikes me that a reasonable approach actually to draw a little bit form what was said before, that to have a specific phase-in just for the Euro-blood probably by 2003.
		And then leave it, and then that takes care of your concern about the northeast, and then we can vote for all of Europe if you choose to.
		DR. CLIVER:  What I am not hearing said in this is that we are setting it not as the steps between the advent of BSE in a country, and the risk to the consumer.  
		When we voted a little while ago to move form 1996 to the present in the U.K., we essentially said -- and had not said before, that those measures about food supply in England were well taken, and were probably effective.
		Suddenly, forget it.  They have got BSE and we see that they have got VCJD, and surprise, surprise.  But, okay, so nothing that they have done since 1996 is regarded as effective.  
		I personally think that now that most of continental Europe is aboard with the same kinds of precautions, as far as the human food supply is concerned, it isn't that relevant whether this country or that has some BSE in it.
		I think we are doing a pretty good job keeping people from getting it via the food supply, and from that standpoint the fact that we already know that we have got a BSE that led to a VCJD problem in France, I think that is compelling.
		But I don't think it is a necessary concomitant that every place where there is BSE that the consumer is equally at risk of VCJD.  I think we ought to pay attention to the fact that there are these food precautions.
		DR. BAILAR:  If I understand this, I don't entirely agree.  I think there is a substantial difference between primary infection from the food supply, and the secondary infections from blood products for which I would expect a long and sort of delayed or smeared out period.
		CHAIRMAN BOLTON:  Where are the donors --
		DR. BAILAR:  I am thinking about the donors who are already infected, but are not apparently ill yet, and this may take a long time to resolve itself.
		CHAIRMAN BOLTON:  Stan, and then Dr. Burke.
		DR. PRUSINER:  I would like to respectfully disagree.  I don't know that we know about the safety of the food supply.  There have been very few measurements that I believe, and the reason that I say that is that the assays showing me that non-CNS tissues are virtually devoid of prions have been done in in-bred mice, called R3 mice for the most part, and some other mice.
		And it is now very clear that those mice have titers which are 10,000 fold lower than transgenic mice, that carry a bovine PrP gene.  And none of these studies have been done on these transgenic mice.
		So I just don't think that we know the answer, and really a lot of this work has come from applying work that was done earlier by Bill Hadlow 20 years ago in sheep, and there again the mice assays were inadequate to tell us what the real titers are in these other tissues.	
		And so I just don't know the answer, and I don't think anybody knows the answer.  So I think that they are real assumptions to which I have difficulty buying.
		CHAIRMAN BOLTON:  Don.  
		DR. BURKE:  After Dr. Donnelly's presentation, I asked her specifically whether or not on why she had just used the animals and not factor in the feed control, the food control of the human food chain in her models.
		And her answer to me -- and I will let her answer again -- is that it is very spotty across Europe, the application of the control of the ingestion of animals older than 30 months, and the use of mechanically recovered meat, and it varied substantially from country to country.
		And so that we can't use that right now as a factor in our decisions, or at least that is my understanding.  Did I restate that correctly?
		DR. DONNELLY:  Yes.  Yes, that is what I said, in terms of looking at that, it is very difficult to estimate, especially when you are looking at risk to humans, and what sort of production you get with these various restrictions on particular tissues.
		And we know that those regulations change when additional data becomes available.  But what I would like to point out is that the one thing which I think is very heavily police, and very important in protecting people from infection from the consumption of beef in Britain is this over 30 month rule.
		That is very tightly controlled.  There is a cattle passport scheme which is that you can no longer have passports falling off of ears and things, and it is very tightly policed.  It is very heavily patrolled.
		And the recent intense, sort of inspection of cattle with foot-and-mouth has shown that there wasn't a problem with that.  That said, I think if you are comparing risk to people who have been in Britain for six months or more between '96 and 2000, which is -- well, if you are comparing that to Britain and other non-British countries that don't have an over 30 month rule, as I have shown you data for France and Ireland in particular, they had higher risks if you are just looking at that time period.
		So if you are actually going to compare Britain in '96 to -- or '97 to 2000 to other countries, you really are dealing with a very small, and very little evidence of infection in Britain compared to the other countries, because they have these animals over 30 months.  So it is a very difficult balance.
		DR. FERGUSON:  Can I just add something?  I would like to just kind of second what Dr. Donnelly just said.  I mean, that is what we have found out through essentially investigations on the animal health side, is that there is a big difference in -- well, first of all, when some of those measures were implemented in European countries, and then also when they were realistically implemented.
		And when were they put on paper and when were they actually put into effect.  So definitely it is a bit spotty across Europe.  But I would like to perhaps build a bit on what Dr. Lurie said, and also a suggestion that you had made about separating out France, and that that would address the Euro-blood situation.
		I have some concern with what kind of drawing that arbitrary line is mostly based on, and the benefits of the Euro-blood outweighing that risk. I think that is completely an arbitrary distinction.  And if we are saying we really need the Euro-blood, then let's just phrase it that way.
		But I think realistically what we are looking at is that the FDA has to go through a noticing and commenting policy on a guidance, and if we make a decision today to recommend a differential, then they go through that.
		We are talking 9 months to a year, and then we are talking an additional 6 months.  Okay.  We are in the middle of 2001 and that already puts us at the end of 2003, which is when this is being phased out anyway.  So I am not sure how much we need to factor all of that in.
		DR. LURIE:  Well, it would be a pity -- and just to follow up on that, but it would be a pity if we actually thought that there should not be a line drawn in France to draw the line on the basis of a distinction that will end up being irrelevant, and then we would have lost our opportunity to extend it if that is what you wish.
		CHAIRMAN BOLTON:  Jay.
		DR. EPSTEIN:  Just a comment for Dr. Ferguson.  Whatever we decide to do here will be on a very fast track.  So, I don't think we should project that there won't be guidance in place until 2003.  We hope to be able to move quicker than that.
		But I think the essential question really is can we draw a line somewhere in Europe and part of the dilemma is that the committee in January advised the FDA against a 10 year deferral for all of Europe, and that was non-U.K. Europe.
		But on the other hand, when the committee voted in favor of a deferral for 10 years exposure in France, which was clearly linked to U.K. beef consumption, the committee felt compelled to further recommend that we do likewise for Portugal and the Republic of Ireland.
		The problem with that recommendation is that it said to the FDA that the committee was indeed concerned that we should do something about the "indigenous" BSE now recognized and emerging in Europe, and the dilemma is where do we draw the line on indigenous BSE.  
		Should we have a deferral for Portugal, but not for Spain, for example?  Should there be deferrals for other countries that have had a large number of cases prior to their food chain controls?  For example, Switzerland?
		So the committee itself gave us a mixed message, and that was part of the FDA's problem in going forward.  We thought that we had made the matter simple by saying, okay, there is France, and let's have a vote on France.
		And then there is Europe, and let's have a vote on BSE in Europe.  But what we got was a mixed message that said, yes, France, but no, you can't ignore BSE elsewhere in Europe.
		But then the question came back to the FDA, well, where do we draw the line, and what is the underlying principle.  You see, that is the difficult part, because we don't want to draw an arbitrary line.  We want to have a line drawn on the basis of some concept.  
		You know, what concept is it.  Is it the concept of BSE incidents, or prevalence per million head?  Is it just the absolute number?  Is it the absolute numer with and without evidence of food chain control?
		Does the date of food chain control matter?  So, you see, we have sort of moved from having a yes-no on should we be there at that point in time, January 2001, addressing BSE indigenous in Europe through an appropriate donor deferral or not, and back to the question of how can we stratify.
		And the problem that the FDA has come to is that we see no clear pathway towards stratifying in Europe unless a principle gets articulated that tells us how we ought to do it.
		And so I think that if the committee wants to turn around and once again recommend some stratified scheme, that it falls to the committee to state what the principle is, because otherwise we won't know whether another country meets that standard or doesn't meet that standard 3 months from now or 6 months from now.
		CHAIRMAN BOLTON:  Dr. Davey and then Dr. Burke.
		DR. DAVEY:  I think that what Jerry says is right on it.  It is very difficult when we embark on a slippery slope that we have perhaps as a committee embarked on trying to identify and focus on specific countries, or specific percentages of infected beef, et cetera, because that is a slippery slope that is going to continue.
		And that's because eventually we are going to have to ask about Eastern Europe, and eventually about Asia, and eventually about Africa.  And then perhaps about brain consumption in the U.S. which Alan mentioned.
		It is a slippery slope that we have to embark on with a great deal of preparation.  It is difficult to draw a line, a line in the sand, and we don't have the data to do so.
		So I think we can identify certainly the U.K., and perhaps France, and when we look at France, it is a country which by far had the greatest importation of British beef, beef that was consumed by the French.
		And this probably in all likelihood led to those three cases and perhaps a few more.  However, I have been reassured by some of the measures that have been taken in other European countries, and while we have to make a tough decision, I think we can draw the line with U.K. and France.
		And to balance that again -- if we extend it to all of Europe, again, the real, the known, and the very dramatic damage to the U.S. blood supply.  I think we have to remember what the people said at that podium this afternoon.  This is a serious problem.  
		We have an opportunity to make some prudent precautionary measures and not damage the blood supply.  So I would again recommend drawing a line around the U.K. and probably France, with 3 months for the U.K. for transfusion deferral, and that makes sense.
		CHAIRMAN BOLTON:  Don.
		DR. BURKE:  Earlier today, you made a proposal that I thought was quite sensible that we haven't discussed, and that was using the criteria of clinical cases of human variant CJD as the criteria on which to define the geography for exclusion from the donor pool.
		I right now wouldn't know where to begin when it comes to the prevalences in the testing, and the testing is going to be increasing, and probably have better specificity and sensitivity.
		The clinical cases of BSE, and the country-to-country varying policies of food chain protection, all of which are going to in influence the human risk, and make it virtually impossible to have a sensible internally consistent and logical set of principles on which to make these decisions.
		And I think that your proposal earlier today made eminent sense to me.
		CHAIRMAN BOLTON:  Well, I appreciate that.  Is there any additional discussion on that point?
		DR. SCHOENBURGER:  I just wanted to remind the committee that when I was on it before that one of the underlying principles that several of us used was not so much trying to draw the line about the risks of BSE by various countries, but more what the risk on the supply side would be.
		One of the reasons for the six months that people have asked me, versus three months, or any visit to England for a criteria for selecting out donors, was a look at the curve of the impact on that particular decision on the supply issue.
		And the reason for that is that we were not sure, and it is not clear to me that we are still sure today, that the risk that we are talking about is any greater than the risk that we experience in this country with regard to classic CJD and its ability to transmit through transfusion medicine.
		We are concerned because of many of the things that Stan and others have pointed out, such as the peripheral increase in titers in the spleen, and in the tonsils, and so on, which are worrisome.
		And that's why we go ahead and put in the restrictions, but still it is a theoretical risk, and the fundamental question in making these hard decisions was not trying to carefully draw a line between England, which we didn't think has much of a risk in Europe, and Germany.
		But rather which countries can we eliminate that would not create a shortage problem in the United States.
		CHAIRMAN BOLTON:  Stan, and then I am going to move on.
		DR. PRUSINER:  I guess my feeling is that we are getting caught in the middle of specific blood supply issues in the New York area, and this concerns me, and that we are not being able to enunciate to Jay Epstein and others of the FDA of real general principles.
		And my own personal view as a physician, and taking care of people; whereas, someone who unfortunately might be in an auto accident and need blood in the New York area, I would hope that it wasn't Euro-blood.
		And I would hope that this could get phrased out, and then in some way I -- you know, I am not sure that I believe these graphs.  They are all just future projections, with a lot of points on them that aren't real.
		So in some way I think we need to be a little careful of this, and I am not sure how to do it, and I am not sure how to think about this, but I personally think there ought to be some way to get rid of this without jeopardizing the blood supply of the country.
		And there ought to be some directive, some recommendation from this committee, to tell the FDA to figure out how to get rid of it over some period of time.  So I have put in my two cents.
		CHAIRMAN BOLTON:  Okay.  Well, I think at this point that I would like to entertain any motions that would be made.  We have at this point Option 3 essentially as it stands, with the amendment to add the recommendation for a national recruitment campaign and a system to monitor adequate blood supply.
		And I would at this point entertain any motions to modify the first item, which is the question of time of deferral or time of residence, to in Europe, or part of Europe, or any other modification.  If there are no modifications, then I think we should go ahead and vote on it.
		DR. LURIE:  Why don't we just vote on it, and if it turns out that people don't want it, then we can decide if you want to go more restrictive or less restrictive.
		DR. PRUSINER:  I was going to suggest that we make one modification.  
		CHAIRMAN BOLTON:  And that would be?
		DR. PRUSINER:  And that would be that we would have a clause that would direct the FDA to specifically deal with the Euro-blood problem in a way that doesn't jeopardize the national blood supply.
		DR. NELSON:  I would make one modification, and which we would vote on separately, and that would be that countries in which there were variant CJD in humans would be residents in those countries would be excluded from, and so that would be an exclusion criteria.
		And that gives some logic at least to what we did previously, which was that we recommended Ireland and France.  And if we found one in the Czech Republic, then it would be --
		DR. PRUSINER:  That is a terrible idea, because what that will do is push it all underground.
		DR. NELSON:  Thank you.
		DR. PRUSINER:  This has been the whole problem in the AIDS world, and I think that is the way to have a country -- well, I think that is to punishment a neurologist with death if they ever reported a new variant CJD case.
		DR. CLIVER:  Well, the other thing that goes with that is that we have a case now, and I think it is probably authentic, in Hong Kong, and it certainly was not contracted in Hong Kong.
		So the mere fact that she was diagnosed in Hong Kong would put the onus on Hong Kong unnecessarily.  
		DR. PRUSINER:  Well, the onus on China.
		DR. NELSON:  Okay.  But Hong Kong is China. 
		DR. CLIVER:  Okay.  But not everybody in China had equal access to the U.K. during the period when she was there and apparently got infected.  So we are in the situation where a fortuitous diagnosis in some place should not be held against the whole population of that country.
		CHAIRMAN BOLTON:  Well, clearly that is sort of a criterion that would have to include some statement about someone not having previously resided or traveled a certain amount of months in a country that already has had a new variant CJD case.  And it begins to get extremely complicated, and I agree.
		DR. SCHOENBURGER:  Just a point of information.  That is a case that was clinically compatible in a pulmonary sign by MRI and has a tonsil biopsy that shows the evidence for the new variant CJD.
		CHAIRMAN BOLTON:  And this individual did reside in the U.K. for a period of time?
		DR. SCHOENBURGER:  They did reside in the U.K. for over 5 years.
		DR. FREAS:  For the record, that is Dr. Schoenburger from CDC.
		CHAIRMAN BOLTON:  Okay.  Well, I think I am going to take up Peter's suggestion, and we will take a formal vote on Option 3 as it stands, and I will read these individually, plus the amendment that was approved.
		So, Option 3 is to defer donors for cumulative travel or residence of 5 years or more in any European country, except the U.K., from 1980 to the present.  To defer donors who spent any cumulative period of 3 months or more in the U.K. from 1980 through the end of 1996.
		To defer donors who spent more than 6 months on a European Department of Defense base from 1980 through the end of 1996 or 1980 through 1990, if all exposure after 1990 was on Department of Defense bases north of the Alps.
		And to defer any recipient of a blood transfusion in the U.K. from 1980 to the present, and to implement deferrals within 6 months of final FDA guidance.  
		And to institute both a national recruitment campaign and a system to monitor adequate blood supply.  That is the question.
		DR. DAVEY:  David, I thought we were just going to vote -- I mean,w e are just going to vote on the European -- on the extent of the European deferral at this point.  Am I wrong?
		CHAIRMAN BOLTON:  No, I think -- I've made a Chairman's decision.  So go ahead and vote on this, and I will explain that is the question before us.  If you believe that the first item, the 5 years or more in any European country, except the U.K., is not what you would like to see, then please vote no.
		If that is acceptable and all the other components are acceptable, please vote yes.  If this is voted down, we will begin entertaining this or another modified proposal.  So this is the FDA's Option Number 3 proposal, with the added amendment of a national recruitment campaign, and a system to monitor adequate blood supply.  
		Bill, would you prefer a voice vote or a name vote, or by a show of hands?
		DR. FREAS:  We will do a show of hands, and then whatever is the minority, I will call out the names.
		CHAIRMAN BOLTON:  Okay.  All those in favor of the question, please raise their hands and signify aye.
		(A show of hands.)
		DR. FREAS:  Ten votes in favor.
		CHAIRMAN BOLTON:  All those opposed please raise their hands signifying no.
		(A show of hands.)
		DR. FREAS:  The opposed are Dr. Burke, Dr. Williams, Dr. Cliver, Dr. Priola, Dr. Bolton, and Dr. Belay, and Dr. McCurdy.
		CHAIRMAN BOLTON:  So what is the tally on that?
		DR. FREAS:  That should be seven opposed and ten in favor.  There were no abstentions?
		CHAIRMAN BOLTON:  Oh, I didn't ask for that.  Abstentions?  No abstentions.  So we are through with that question.  The motion carries, and so that precludes needing to vote on Items 2, 3, or 4.
		I am not sure if the FDA needs any -- yes, Bruce?
		DR. EWENSTEIN:  I just wanted to say, and this is after the vote, but I think what Dr. Prusiner said before, and I think what several of us have been concerned about probably should go into the record.
		And that is that some policy, and independent of Option 3 now, should be put in place to deal with the Euro-blood situation, because I think that is exceptional and needs to be addressed by one means or another on whether it is a deferral of the time line for implementation of Option 3, or some other approach.  It needs to be addressed.
		CHAIRMAN BOLTON:  Would someone like to put that in the form of a motion?  Is that appropriate?
		DR. EWENSTEIN:  Well, I would suggest that as a motion.
		CHAIRMAN BOLTON:  Okay.  Let me see if I can paraphrase it.  It has been moved -- or do we have a second on this, or should I -- well, Stan seconds it.  Can I paraphrase this?  
		That we are recommending to the FDA that they determine a method of dealing with the or compensating for the loss of Euro-blood in a way that will not jeopardize the national blood supply.  Is that an adequate statement of the question?  Discussion?
		DR. BURKE:  It doesn't make any sense at all.
		CHAIRMAN BOLTON:  Well, have I done a good job?
		DR. BURKE:  We ought to at least provide some concrete suggestions about what that is other than to say that our vote just created a terrible problem and that somebody else needs to fix it.
		DR. EWENSTEIN:  Well, I had suggested one approach, which was with respect to Euro-blood now, to have a delay in the implementation of Option 3 that we just approved.  That is one approach that comes to mind.  I mean, there may be others.
		DR. PRUSINER:  Okay.  I have an approach.
		CHAIRMAN BOLTON:  Stan.
		DR. PRUSINER:  That the FDA create some time line with decreasing amounts of Euro-blood in consultation with the New York City area blood banks.
		CHAIRMAN BOLTON:  But I think the critical question is where is the extra blood going to come from,and I don't --
		DR. PRUSINER:  Well, that's their problem.
		CHAIRMAN BOLTON:  That's their problem?  
		DR. NELSON:  We could since there are several components to this, to the FDA recommendation, or in other words, with regard to the U.K. residence, et cetera, we could delay the implementation of that one -- the Euro-blood issue beyond which the other components, and --
		DR. PRUSINER:  No, no, no.  I think there has to be some pressure to get this done, and so there has to be some -- I mean, I don't think we have to have a vote on this.  I don't think we have to give the FDA guidance.  Jay is a smart man.  He will figure it out.   
		(Laughter.)
		DR. PRUSINER:  Karen, will you give him a raise?
		CHAIRMAN BOLTON:  I think that they have heard our concerns about this, and I am sure that they will do something.
		DR. EPSTEIN:  I don't think a vote is needed and I think it is a difficult problem which we will seek to address.  
		CHAIRMAN BOLTON:  And likewise I don't buy on this topic, is for us to comment on steps that should be taken to monitor and ensure adequate national and regional blood supplies, et cetera, et cetera.
		I think we have had adequate discussion on that, and we clearly incorporated a recommendation for that in our vote.  So I think we can move on from there.  And that, ladies and gentlemen, concludes topic one.  We are only about four hours late.
		The question now is whether we can adequately move on to topic two.  Bill, is that -- okay.  Let's take a 10 minute break, and come back at, let's say, 4:50, and we will begin, I think, with Topic 2.
		The committee update by Dr. Nightingale is going to be postponed until after Topic 2.
		(Whereupon, the hearing recessed at 4:38 p.m., and was resumed at 4:58 p.m.)
		CHAIRMAN BOLTON:  Can we get the committee members seated, please.  We would like to start the second topic of the day, and welcome to the FDA prion marathon. 
		Topic Number 2 is the "Safety of FDA-Regulated Derivatives Prepared in Establishments Proposing to Use on the Same Manufacturing Line, Plasma Which Does and Plasma Which Does Not Comply With Current U.S. Standards, With Regard to Donor Deferral for VCJD Risk Factors."
		And our first speaker is Dr. Dorothy Scott, and she is going to introduce the topic, and give the committee the charge on the questions.  Dr. Scott.
		DR. SCOTT:  Welcome to Topic Number 2 and good evening.  Next slide.  The FDA is aware that many manufacturers process plasma from both U.S. and European donors in the same facility.  The manufacturers were given FDA approval to do this in their license applications.
		U.S. and European plasma pools of process to separate batches in sequential steps, which are referred to as campaigns.  After, for example, European plasma is processed, the equipment is cleaned using cleaning procedures that are FDA approved. 
		And after cleaning, U.S. plasma may be processed using some or all of the same equipment, depending on the manufacturer and the specifics of their license.
		However, cleaning procedures were approved prior to appreciation of VCJD risk in Europe, and the FDA has not previously formally recommended cleaning or other strategies that would be relevant to variant CJD.
		So if as a precaution the FDA recommends deferral of blood and plasma donors based on possible BSE exposure in Europe, which appears more than likely at this point, manufacturers that process European plasma will be in the position of manufacturing what is technically referred to as suitable and unsuitable plasma in the same facility.
		That is, plasma that meets U.S. donor deferral criteria will be manufactured using the same equipment as plasma that does not meet our criteria. 
		As our first question, we are asking the committee to comment on the significance of VCJD risk from campaign manufacturing processes that could result in the potential crossover contamination of U.S. plasma by European plasma.
		The risk of VCJD transmission by plasma or plasma derivatives is unknown and theoretical as you have heard.  However, an experimental model of TSE, such as hamster scrapie, and amounts of active VCJD, low levels of plasma infectivity, and even lower levels of plasma derivative infectivity, have been demonstrated.
		Specific steps in plasma processing, such as precipitations, chromatography, and depth filtration, for example, can remove prions and infectivity during the preparation of plasma derivatives.   Of course, all of this has been done in experimental settings.
		However, I would like to point out that information is not available about the availability of specific manufacturing steps to inactivate or remove the VCJD agent or the TSE from plasma derivatives, although it is our understanding that the studies are ongoing.
		I just wanted to make some points about a risk model for the likelihood of VCJD contamination of plasma, and this would by necessity have to incorporate some problematic functions, in terms of our ability to be accurate about them.  
		In particular, the prevalence of VCJD in Europe is unknown, and the infectivity of plasma from a VCJD incubating donor is unknown, and in fact no such infectivity has been documented.
		The relevance of VCJD to existing studies showing the removal of TSE agents by plasma fractionation is uncertain and debatable at this point.  The likelihood of VCJD removal by discreet manufacturers' processes is unknown, although specifics of manufacturing steps based on studies of BSEs may be critical.
		And finally the likelihood of carryover contamination of VCJD from European to U.S. plasma is uncertain.  Since detailed aspects of processing could affect partitioning of TSE agents, the risk assessment, if done, may best be performed in a specific, rather than in a general, fashion.
		Dr. Baron will be presenting aspects of European donor plasma risk of variant CJD infectivity, and Dr. Davies will present a case study risk assessment for IGIV in the context of facility cleaning.  So those two talks will cover aspects of risk assessment, and not to the second question.
		A second question to the commitment is whether you believe that any additional steps, besides risk assessment, should be taken at this time to address the use of common manufacturing lines for European and U.S. plasma.
		And the third question should follow, and if so, which of the following steps should the FDA consider at this time.  And that should be consider, because we don't want you or ourselves in the absence of certain kinds of detailed information to any one of these particular steps.
		If indeed additional strategies could be useful, which of the following should we consider.  For example, should we consider recommending additional labeling for plasma products made in facilities without dedicated or separate manufacturing lines, which also process European plasma.  
		Now, I will come to each of these, in-turn, and tell you a little bit more about some of the things that need to be thought about.  Other means of addressing the issue could include institution of additional facility decontamination cleaning between U.S. and European campaigns, and/or the use of dedicated equipment for U.S. and European plasma.
		These approaches need not be mutually exclusive.  Additional suggestions for FDA consideration from the committee will be appreciated. 
		I will now mention some points about each of these strategies, many of which will be expanded upon by the presenters.  The FDA has already recommended general labeling relevant to CJD.  
		In our 1999 guidance, we recommended that all plasma derivatives contain a labeling statement about the theoretical risk of CJD, stated just as CJD overall.
		The recommended labeling in the warning section states, and I quote, "Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically the CJD agent."
		New labeling related to processing in facilities which also process European plasma would appear to differentiate products from each other with respect to this theoretical risk.  
		These are some considerations for cleaning and decontamination procedures.  First, as Dr. Rohwer will discuss, adequate TSE decontamination in experimental settings is best achieved by combined physical and chemical methods, such as, for example, audoclaving combined with sodium hydroxide.  
		But some equipment may not withstand single or repeated treatments, and for others it may not be technically possible.  It would take some amount of time to institute and evaluate new cleaning procedures, as well as cleaning validation methods.
		Our international colleagues have told us that thorough facility cleaning on a one time basis could take several months, and of note is that unlike the situation for viruses, for TSEs to date there is no validated intentional inactivation or removal procedures during plasma processing, although clearly there are steps in plasma processing which may cause removal.
		But there have not been steps designed specifically for this.  Dr. Davies will be discussing aspects and complexities of facility cleaning.  And finally the use of U.S. plasma from dedicated manufacturing lines would seem to in effect eliminate the theoretical risk of VCJD contamination by European plasma.
		It should be noted that replacement of some equipment could take time, and the time required to install, validate, evaluate, and inspect additional equipment in facilities could have adverse consequences on the supply of plasma derivatives.
		Dr. Busenbark will present a case study and concerns with institution of dedicated manufacturing lines.  And Mr. Healey will address anticipated effects on supply of plasma derivatives in this setting.
		So thank you for your attention, and if there are any questions, I will take them.  Otherwise, we can turn to our first speaker, Dr. Rohwer.  
		CHAIRMAN BOLTON:  Are there any questions from the committee members?
		DR. BELAY:  Yes.  Dr. Scott, how many manufacturers are we talking about in this category?
		DR. SCOTT:  Virtually all of the major plasma fractionators are involved, without naming names.  I believe it is 5 or 6.
		DR. BELAY:  And what percentage of the plasma derivatives will be supplied by manufacturers in the United States roughly?
		DR. SCOTT:  It is not precisely known for the coagulation factors, but Dr. Healey will present an estimate that approximately 50 percent of IGIV will be affected.  It is more uncertain so far, and I don't think we have all the data for plasma-derived Factor 8, for example.
		But there will be a variety, and mos products will be affected, and a few of the products might even be relatively unique.
		DR. BELAY:  Will there be a presentation to better define what we mean by European plasma, in terms of where it is coming from, the specific country?
		DR. SCOTT:  Well, by that I mean plasma that is essentially taken from European donors, and used to make products for the European market or other markets.  So it may come from anywhere in Europe.  
		Do we have a breakdown of specific countries in all of these facilities that are processing U.S. and European plasma?  No, we don't have a list of all the countries for all the products for all the facilities at this point.
		DR. BELAY:  Would that include the United Kingdom, for example?
		DR. SCOTT:  Pardon me?
		DR. BELAY:  Would that include the United Kingdom?
		CHAIRMAN BOLTON:  The U.K.
		DR. SCOTT:  Oh, none of the -- well, the Europeans also have a 6 month U.K. travel deferral, and so that should not include the U.K. plasma.
		CHAIRMAN BOLTON:  Other questions?  Okay.  We will move to our next speaker, Bob Rohwer, who is going to talk to us about the scientific aspects of decontamination methods for transmissible spongiform encephalopathies.  Bob.
		DR. ROHWER:  Thank you, and I am going to talk about some issues which I feel are sensitive to the specific considerations of this particular problem, and that is the effectiveness or lack thereof decontamination of these agents by those methods which are most affected in decontaminating these agents.
		And their applicability to cleaning and cleaning of surgical instruments, for example.  And the points that I am going to make are based on experiments that I did 20 years ago, and it is interesting to me to see that this has become of interest again.
		I have given this talk several times recently, and so I ask for your forbearance for those of you who have heard this before.  I am going to make four main points, and address four main points.
		One is that the susceptibility to inactivation of TSE agents is actually within the normal range for the more resistant conventional viruses and spores, and that TSE infectivity is, however, nevertheless less resistant to disinfection and/or sterilization.
		And what I mean by that is that you can kill most of it, but you can't kill all of it.  And the way the majority of it behaves is quite conventional, and the way that these resistant sub-populations behave is quite extraordinary in some cases.
		And that the susceptibility to an activation is an intrinsic property of the agent, and it gives us some idea of what the agent might be, or what its intrinsic properties are; whereas, the resistance to an activation, and this ability to escape total inactivation, is context dependent.  
		It depends on the known year which the infectivity finds itself, and it is therefore a property of the infectivity milieu.  These are the publications on which this talk is based, and you can see that they were published some time ago.
		This is a review that more or less covers the experiments and rationale for them in more discursive fashion, and a more accessible way.
		Finally, I would like to also direct your attention to this document right here, which was put together by the WHO as part of a panel, which included myself and David Taylor.  
		We put together the inactivation section of this guideline, and we are in concurrence of the recommendations there, and I think that this is actually one of the better extant guidelines for how to deal with infection control of these agents.  And a copy of it can be obtained from this site at WHO, this URL.  
		So let me begin by just talking about the process of inactivation so that we are on the same wavelength and so you understand where I am coming from in making the claims that I am going to make for the inactivation process.
		This is a typical inactivation curve.  It could be the inactivation of anything, but viruses, spores, bacteria under some settings, and what have you, and basically the two axis are this.  
		You have your exposure to whatever your dose is down here on this axis, and in this case it is time of exposure to some chemical inactivant, or to a heat treatment, for example, and over here you have your surviving fraction.
		So up here at 10 to the zero, you have got a hundred percent survival, and at 10 to the minus 1, you have killed 90 percent of the population; and at 10 to the minus 2, you have killed 99 percent of the population.
		And another way of looking at that is by considering it up here, if you had a hundred percent of the population available, and you had a hundred organisms, by the time that you are here, you have got this many left.
		And by the time that you are here, you are down to only one survivor.  There is a lot going on in this very early part of the inactivation process, and in fact chemically and biologically, you talk about the sensitivity of an agent on the basis of its initial rate of inactivation, and it is the extrapolation of that rate back to zero.
		The other important thing to realize is that down here on this axis, 90 percent of what is going to happen has happened already before we are even at one minute of exposure in this particular case.
		The next 10 percent is covered before we are even at 99 percent is even before we are at one  minute, and at 99.9 percent, we are out here at a little over a minute.  
		And really this part of the inactivation represents only about .01 percent of the infectivity that is actually associated with this material.  
		So this is the extrapolation of the initial rate, and this is telling us how the infectivity is behaving intrinsically, and 99.9 percent of the infectivity.
		And this is describing how a subpopulation, representing only .01 percent, one part per 10,000 in this case of the population, is behaving.
		So what does this mean in terms of -- well, how do we interpret this?  This susceptibility to inactivation, which is intrinsic to the agent, this is a far less complex part of the inactivation to analyze, and there are far fewer controlling perimeters.  They are agent specific.
		And whereas over here, when we start talking about this region, we have a lot of different parameters that can affect the shape of this curve, and you can get different shapes, depending on how you balance these various factors.
		And so among those parameters are the container itself, where there are potential sanctuaries where the infectivity can hide.  There are cold factors which may be present which may protect or shelter the infectivity from Ph temperature, buffers, reductants, and that type of thing.
		The actual type of tissue that you start with or the other components of the mixture can affect this.  For example, if there are surfactants present, or oils.
		Whether you mix, actively mix, or you just do a static exposure, and then there are other technical issues which can also affect the outcome of an experiment like this.
		And this is just to point out that when we talk about the sensitivity to inactivation, we are talking about an inactivation rate constant that is characterized by inactivation rate constant, which is reduction in survival as a function of the interval of dose.
		And so in this particular family of curves, if we -- this inactivation at this rate, this is showing more susceptibility than curve two, curve three, or curve four.
		So in comparing agent properties, we are looking at the properties which are intrinsic to the agent, which are reflected in the initial rate of inactivation, and this represents the vast majority of the inactivation that is occurring, and the interpretation is less complex.
		The side of the residual fraction is a complex function of environmental parameters, and it cannot be used to compare the intrinsic sensitivities of agent strains.  
		Now, I am going to talk about some specific experiments with the TSE agents, and first we will consider chemical inactivation.  There are two main chemicals which everyone has agreed on that are effective in killing these agents.  One is bleach, and the other one is hydroxide.
		So in the case of bleach, this is an experiment in which a 10 percent brain homogenate was exposed to bleach at the concentration at which it is recommended to be used for disinfecting diapers, for example, a half-percent.
		And these are the inactivation kinetics for scrapie, in red, and fora couple of test viruses which were mixed with 10 percent brain homogenate, and inactivated at the same time as this experiment.
		These are bacteriophages.  This is a bacteria stage that is very similar to a parvovirus in structure.  And this is our FD, which is a close relative to M-13, the virus we use in the lab for cloning.
		In the presence of a brain, you can see that the scrapie agent has killed very, very rapidly down to the level of 99.9 percent, killing just upon contact with hypochlorite at this concentration.  
		David Taylor has done experiments at 5 percent hypochlorite, which drives this right down to a total killing in a very short time as well.  We haven't actually looked at kinetics, but within a 30 minute exposure, for example.
		But what is notable here is that when you put PhiX 174 in brain, or FD in rain, you also get plateaus for these viruses as well.  They are at a somewhat lower level, but these are real effects here.
		This is not an unfamiliar phenomena.  It is something that has plagued water purification for years, vaccine production by inactivation of viruses, et cetera, and it depends on the total amount of interacting organics that are present in the mixture that provides some sort of protection or sanctuary to the total inactivation of the virus.
		Over here we have these same viruses in PBS in a highly purified state, and they are killed very rapidly to the limits of detection.  Next slide.
And the next example that I am going to give you is sodium hydroxide.  
		This is the inactivant that we are most comfortable with in my laboratory for routine disinfection of these agents, and this is an experiment in which I did with Paul Brown quite a long time ago, in which we looked at a guinea pig model of Creutzfeldt-Jakob disease, and the hamster model of scrapie, at two different time, and at three different concentrations.	
		And what you can see here is that there has been a lot of effect by 15 minutes, and by an hour of exposure at one normal, we have killed to the limit of detection.  That means five logs or greater.  
		We couldn't detect more than that, because that is all that we put in, and that is all that we could assay by the time we diluted and assayed.  And then in the case of scrapie, we got the same result over here by 60 minutes.  
		Nevertheless, we had quite a high level of effectiveness, even at a tenth normal, and at the same times and concentrations.  At .01 normal, a 10-fold dilution of a tenth normal, it is becoming marginal. 
		So somewhere between a tenth normal and one normal, we lose efficacy in this procedure.  This is done at room temperature.  And by going to one normal, we have given ourselves quite a large margin of safety in using this reagent.  
		These are two other conditions which are similar and fall consistent with this, but let's go on.  We don't need to discuss that here.  Now, sodium hydroxide has been looked at by lots of other people, and this is a table just summarizing those experiments here.
		There are a number of different conditions, different times of temperatures listed here, and here are the results, and the things that I want to point out is in yellow here I have highlighted those procedures which gave complete destruction of infectivity to the limits of detection of the assays that were being used.
		But a lot of people saw survival under some of these conditions, and usually at sort of the limits of detection.  So it is not a perfect method, and there are conditions where the infectivity can escape total inactivation by this method.
		Now, we are going to come back to that in a little bit, but first we are going to talk about heat activation, which shows a very similar pattern.  Next slide.
		This is an experiment looking at 121 degrees centigrade, which was the old standard for autoclave; one atmosphere of pressure, 121 degrees, for some period of time.
		This is an experiment which was done with highly dispersed brain homogenate in the hamster model.  It was prepared by sonication, and it was sealed into ampoules, and these serum bottles were placed in an oil bath so that we could take the samples at very precise times.
		We had thermistors imbedded in one of these bottles so that we could monitor the temperature, so that we knew exactly how much exposure we were getting at each one of these times.
		And what this shows us is that the infectivity of the 263 model is highly sensitive to inactivation by 121 degree wet heat.  By the time that we got the temperature, and when we took the first sample here, we had already killed 99.9999 percent of the input infectivity.
		Nevertheless, there is a residual amount of infectivity which took longer at the limits of the assay, and we actually had an animal eventually that came down at 60 minutes, after 60 minutes of exposure, and a long incubation period, one animal in the undiluted material that showed infection out here.
		Well, let's go on.  Well, this is -- there is another way that you can look at these experiments, and David Taylor has done a large number of experiments like this.  They are in several publications of his, and in which instead of starting with a highly dispersed brain homogenate, he starts with a macerate.
		What a macerate is, is a mushed up brain.  here is no dilution.  There is no buffer added and nothing like that.  He mushes up the brain, and puts it in a tube, and then puts it in the autoclave, and actually does the experiment in a real autoclave. 
		Autoclaves under these regimes for this amount of time, there is a lag time for getting to 134 degrees, and a lag time for getting down to a temperature at which you can open the door again.
		And rather than looking at the kinetics, he just looks at the end point of these experiments, and here you get as you would expect, 19 out of 19 animals that did not get the treatment still show infectivity.
		But even after 134 degrees at 60 minutes, he has got animals surviving this procedure.  Now, how do we interpret this kind of data?  I think it is important to realize that what we are looking at here are limiting pollution titrations.
		You are inoculating 22 animals,but only 14 animals get sick, which means that you have killed almost everything.  You are out at the end, but there is still some infectivity left.  
		And what do we mean by eliminating dilution titration?  This is a case where we inoculate a bunch of animals with -- by the intercerebral route the most sensitive method of inoculating an animal for detecting the infectivity.
		And we can only inoculate a small amount into every animal, but my inoculating 50 microliters into 20 hamsters, for example, you can look at a milliliter of infectivity, of sampling, next.
		If five of those animals get sick after a year of monitoring, you can say that you had 5 out of 20 get sick, and five dead out of a mil of sample that was inoculated, and you have a titer of about one infectious dose per mil.
		If we analyze the Taylor data in that way, and put it on next, and put it back on this curve, it is indicated in the red right here.  So it is not at all inconsistent with this data.  
		In fact, it is quite consistent with it, and it just means that a macerate in this form produces a lot or a significant amount, or rather a small amount of survival out at even these high exposure levels to what heat next.
		So what is responsible for this.  Well, there is several different possibilities.  One, there could be interesting differences between this material that is surviving this heat.  Maybe it is heritable.  This is something that certainly needs more study.
		But to the extent that it has been looked at, it doesn't look to me like this is the explanation actually.  And arguing strongly against it is this context dependency.  It depends on what form you put the agent in on how much survival you get.
		Aggregation could definitely contribute to something like this, but we get a very different kinetic picture if it was aggregates.  We should see a plateau at the beginning of the inactivation, and which falls off later as the aggregates are wiped out.
		And finally that leaves us with compartmentalization, and this is what I favor.  My guess is that the inactivant is not actually reaching the infectivity, and you have to open or destroy the compartment in which it is hiding in order to destroy the last little bit.
		This is easier to understand in the context of sodium hydroxide than it is in the context of steam sterilization, where everything should get hot.  But maybe we can explain it.  Let's go on.
		This is just considering this again and let's go on.  And let's just compare again the difference between the experiment fit that I was doing and the experiment fit that David was doing.
		This was highly dispersed material, versus a whole brain,a nd it was sealed in a bottle, and in carefully controlled conditions.  It was basically an idealized situation, because I was interested in looking and answering this question of what is the intrinsic sensitivity to heat of these agents.
		David had a different objective in mind.  He wanted to know what is the worst case situation.  If we had something like a macerate, a piece of tissue contaminating our process stream, or our flask, or our scissors, how could we really kill it by these methods.
		And so he is looking at a -- instead of a constant steam, it is static, and it is a worst case situation.  Also bearing on this is the sensitivity of these agents to dry heat sterilization.  
		Dry heat is far less effective than wet heat at these temperatures in sterilization.  This is an experiment that was done by Paul Brown some time ago, about 10 years ago, looking at dry heat sterilization.
		And it is not terribly remarkable.  I mean, some spores in this range as well, but he gets limited -- there is limited inactivation, starting with 10 to the 9th or so infectious doses in this particular experiment.
		He is only killing down to a level of 10 to the minus 2 and 10 to the minus 3 after 10 minutes, or 60 minutes of exposure to 160 degrees centigrade.  Next slide.
		So what is going on here?  Well, it seems to me that what may be happening in these experiments is that at a very low frequency we are actually drying some of the material on the walls of our vessels.  It is being protected possibly by brain fat.
		And fat can produce an anhydrous environment, and when fats are oxidized, they become varnishes.  Varnishes are essentially plastics, polymerized fats or plastics.
		And essentially you put your infectivity in a different type of container than the aqueous environment that you are seeking to test.  Next slide, please.
		And the lesson here is that if the reagent can't reach it under those circumstances, it can't inactivate it.  And this is quite plausible it seems to me in the autoclave situation, especially where you ramp up the temperature, you are at temperatures where you are not inactivating.
		But you may be drying the substance on to a surface, or to the walls of the vessel, and creating a population that can survive the infectivity.  Next slide.
		And what I want to remind you here again by looking at this again is that this is something that can be a problem even if it happens very, very rarely.
		And what this data is telling us is that this is a very rare occurrence.  It is a parts per million occurrence, or parts per 10 million occurrence.  It represents a very small part of the population.  But it is nevertheless a serious issue for decontamination and sterilization.  Next.
		Again, just to summarize, 132 degrees centigrade is a significantly higher temperature than 121 degrees centigrade for a steam sterilization, where the inactivation takes place in minutes.  
		However, for a dry heat sterilization, 132 degrees centigrade is only incrementally more effective than 121 degrees centigrade, and where the inactivation could take days at those temperatures for some agents.  Next.
		So, my take home here is that with steam sterilization, these agents are not intrinsically resistant to steam sterilization.  The problem is with the delivery of the inactivant.  Next.
		And the same thing could be happening in the case of sodium hydroxide, though it is a little hard to imagine how it is escaping.  But I will say this.  I do know that if you put the infectivity in a plastic bag and throw it into your one normal sodium hydroxide, you are not going to inactivate anything.
		And if at the levels of parts per million we have got little plastic bags in there hiding a very small, unrepresented as part of its population from the sodium hydroxide, and that could come in the form of micelles, or something else of this nature, that could account for what we are seeing as the resistant population.  Next.
		So how do we get around this?  Well, it is important -- the lesson here is that for effective sterilization by these methods, you want things that are -- you want well dispersed materials, and homogenization can help, and surfactants can help hopefully.
		You want to eliminate sanctuaries, and you can do that by agitation.  You want to keep things wet so that they can't dry out.  And my guess is that as you refine materials, you provide less and less opportunities for protective associations.
		You get rid of the fats, and you get rid of these random associations which may protect, though that is not something that has been studied in a systematic way.  Sterilization prevents drying, and that is one of the most important lessons that we have learned from this comparison.
		And in our laboratory, we make sure that we emersed our things in water prior to steam sterilization, or subsequent to use.  We store them in water and then get them in the autoclave, and combine two or more methods, heat and hydroxide.  
		There have been several studies looking at this combination, and this is always been highly effective.  Next slide.
		Now, because of the topic here, there may be special vulnerabilities of instruments to TSE contamination that we should be considering.  The buildup of tissue in hinges, joints, knurling, teeth, and other irregular surfaces or pockets.  
		These are things that we should be aware of and should be addressing.  The drying of tissue on to instruments and surfaces, and the inaccessibility of mating surfaces.  For example, in forceps and scissors.  
		And then imperfect contact with the inactivant once we bring it into contact.  If there are bubbles, or residues that are keeping the inactivant from actually reaching the infectivity, we are not going to get an activation.  Next.
		These are the conditions that we use for sterilizing instruments in our laboratory.  We wipe them clean between uses if we are doing a series of dissections, for example, and using either PBS or 2 Normal sodium hydroxide to keep the tissue load down. 
		If we emersed them under sodium hydroxide for at least an hour, and usually overnight, and then we transfer -- if they are sensitive, we transfer them to water before sterilizing, though we don't let them dry.
		And if they are not sensitive, we autoclave them in the presence of sodium hydroxide.  There are a lot of stainless steels which takes this just fine, and can be treated this way.
		And then once we are finished with our decontamination step -- and we consider this a decontamination -- that's when we clean the instruments, package them, and sterilize them for use or reuse just as you would normally.
		Now, the topic here was to consider between batch sterilization and a process environment, and these are the things that come to my mind, in terms of the special vulnerabilities of process equipment.
		Head spaces where you have got air, and opportunities possibly for drying out potential problems.  If you have got places that are inaccessible to the disinfectant, those are the other problems.
		The modern methods of CIP disinfection really have tried to address this in a very effective way, and I think this is -- that these are remarkable pieces of equipment, and remarkable methods.  But whether they are effective for these agents, it is hard to know.  
		Incompatibility with TSE inactivants is another problem.  The conditions required for TSE inactivation may require impracticable amounts of time, temperature, and reagent concentration for this use.
		And what I think is really the biggest problem is the lack of TSE-appropriate assurance methods.  You know, how are we going to know whether we have really accomplished this or not even if we think that we have.  Next.
		These are some of the strengths of these methods, and I think that people are going to go over these in great detail in a moment.  So I think we can just go on.
		And finally I just want to emphasize that any method that claims to be able to inactivate TSE agents really has to be validated, because these methods are very sensitive, or can be very sensitive to the details under which they are conducted.  
		And we have had unexpected surprises in the past and we don't really want them in the future.  And I just mention this paper right here as a warning in this nature, and that is a paper by -- that came out of the Weissman lab, talking about the infectivity that is associated with stainless steel surfaces.
		And this is actually quite an alarming report, in which they have shown that by contaminating a stainless steel wire by simply exposing it to brain homogenate, and then extensively washing it with PBS, and then similarly inoculating animals with this wire, they didn't see any reduction in incubation time in these animals through several passages through these animals, or I mean, several passages of this wire through animals.	
		And there has been some more work done on this, though it has not been published, but I was privileged to hear this at a meeting recently.  And it seems to be holding up that -- it is actually quite difficult to get this infectivity off this stainless steel surface.
		This is something that really needs to be looked at much more thoroughly than it has so far to see whether this is a problem or not, and especially if it is a problem in the context of these various strong denaturing agents, sodium hydroxide and other alkaline reagents.  Next.
		Now, this is my own take on this, and I don't know that this will come up, but I have got the lecture at the moment, and so I want to make this point here, and that is when considering the efficacy between batch cleaning and this idea of separate facilities and that type of thing, I think it is important from my perspective, that it seems important at least to consider the fact that geographical deferral does not remove all risk.
		The best that we are hoping for in the discussions that have taken place today is a removal of 90 percent of the exposure.  And moreover there is no recommendation for withdrawal, for lapses in this policy, where mistakes are made.
		So when we are talking about a cleaning protocol between batch cleaning protocol, I don't think it should be held to a higher standard than the standard that we are actually asking for in our deferral policy.  
		And as an example, you have to consider if we go to the big effort of separating North American plasma from European plasma fractionation, how are we going to handle the fact that there is actually a residual 10 percent risk associated with North American plasma that is irreducible at this time.
		And what is going to happen when we do see a variant CJD case in North America, and I think that you can argue that given enough time that we are likely to see such a case.  Next.
		Finally, while I am on the soap box here, let me just point out one other point about this analysis, and that is when we consider this survival in response to 1N sodium hydroxide at these very high temperatures in a steam environment, and the things that escape breach, does this really tell us anything about what is causing these diseases, whether it is viruses or prions, as represented by PrPres here.
		Well, in fact these methods are very, very aggressive methods.  They kill viruses as we know them,but they also destroy PrPres as we know them as well.
		So if you are going to invoke this as evidence for the existence of prions, it is really not very supportive of this model.  And if you are going to invoke prions, and if you are going to invoke this as evidence, you have to invoke something else besides PrPres.
		And the only thing that has been -- I mean, there have been suggestions that things like inorganic ions are responsible for this, and that type of thing.  But I don't think it is really taken very seriously.  Next.
		Finally, I think we do need more research in this area.  We need to understand the underlying principles of resistance.  What I have given you here is really a hypothesis, and not proof.
		We need to develop a more robust and comprehensive methods for TSE sterilization that are compatible with the materials that we need to sterilize; and we need to establish the vulnerabilities and limitations of existing and future methods.
		And finally we need to validate existing and future methods.  This requires infectivity models because we need to look at infectivity, and this is costly and time consuming, but the sooner we get started the better.  Next.
		This is just again to remind you that this is a good place to go for a general discussion of this topic, and for a much broader discussion of infection control of these agents, and I believe that is the end.  That should have been the last slide, and I will finish there.
		CHAIRMAN BOLTON:  Thank you, Bob.  Questions?
		DR. CLIVER:  Yes.  I followed your argument reasonably well, but one thing I was hoping to hear you mention is in March of last year, Paul 
Brown and co-workers reported having ashed infectious hamster brain at 600 degrees, and resuspended it with phosphate bumper saline, and have gotten 5 out of 35 intracerebral inoculated hamsters develop TSE.
		And the obvious control of ashing normal hamster brain wasn't done, or at least it wasn't reported, but having said that then, if ashen wasn't obviously exempt from any of the inactivants that would do this, I think it possibly calls in to question the validity of the assay system. 
		DR. ROHWER:  It is a validity of the assay system or the validity of the experiment.  And I think that is an experiment that definitely needs to be reproduced with controls, and your criticism is well taken.
		CHAIRMAN BOLTON:  Dr. Belay, first, and then Dr. Prusiner.
		DR. ROHWER:  But that was the experiment that gave rise to this speculation; and, well, if it is not protein, then it must be something else, inorganic, that can survive ashing.
		DR. CLIVER:  It could be hamster brain with latent TSE and that relationship.  
		DR. ROHWER:  Well, I see.  Well, there are -- I don't want to go through a detailed analysis of that experiment, but I will say that I think it merits doing over.
		DR. BELAY:  Bob, I am trying to understand one of your conclusions.  I think you said that if you take 10 percent brain homogenate, and then autoclave it at 121 degrees celsius, then you indicate a dramatic decline in the percentage of the concentrate, or there is a decrease in the concentration of the agent.
		But there was a small group of what you called resistant subpopulation that would remain in the system.  And in this so-called resistant subpopulation, it is not intrinsically resistant.  It could be -- I think I heard you say it could be that they are probably hiding in some of the tissues, and not necessarily intrinsically resistant.
		DR. ROHWER:  I'm sorry that I didn't get my point across, but what I was trying to point out here is that by comparing the wet heat inactivation and the dry heat inactivation, is that that temperature of 121 degrees is a very effective temperature for steam sterilization of these agents.
		But it is a very ineffective temperature for dry heat sterilization of these agents, and so what I am proposing is that somehow someway that at the level of parts per million in that sample, there was material that only saw a dry heat environment.
		And one of the ways in which I think that might have happened is if it did dry on the side of the vial in the process of -- well, when you plunge this thing into an oil bath, it boils immediately and throws the liquid into or on to the sides of the vial.
		And if it flashes off and dries there, with a nice lipid barrier over the top, it may never see steam.  That part of the infectivity may actually be exposed only to the dry heat environment, and as a consequence, that's why it survived.
		DR. BELAY:  That's right.  So --
		DR. ROHWER:  And that's why it would be a problem for something like head spaces and that type of thing in tanks, where you have an agitator throwing things upon the walls and that type of thing, and you have the opportunity for something like that to happen.
		DR. BELAY:  So one possible intervention could be then to treat the tissues with some kind of chemical that would disintegrate the tissues so that the agents would be exposed to the heat?
		DR. ROHWER:  Well, I think that is -- one of the reasons why a combination of sodium hydroxide and heat is -- well, sodium hydroxide becomes incredibly more aggressive at higher temperatures than it is at room temperature.  So that is probably the main reason.	
		But certainly using diagonal methods, and using a chemical method, plus a physical method, is a very smart way of conducting any type of sterilization procedure.  And it seems to work in the case of these agents for hydroxide and heat.
		DR. BELAY:  I have reviewed that study that you mentioned from the Weissman group.  One of the things that they didn't do was they -- I guess they treated them with PBS and other chemicals, but they did not go ahead and autoclave the instruments and see if there is any infectivity left after the autoclaving process.
		Now, do you know any group that is doing a similar study to basically replicate the kind of situation that you would see in a hospital situation, where they would treat the instruments, and get rid of the tissues, and wash them away with some kind of chemical, and then subsequently autoclave the instruments and see if there an any infectivity left on the instruments?
		DR. ROHWER:  We have --
		CHAIRMAN BOLTON:  Let me interrupt for a second, Bob.  I just wanted to assure everyone that we have been told that this is a false alarm,a nd so there is no fire ongoing.  We will not be heat inactivated.
		(Laughter.)
		DR. ROHWER:  We do this on a routine basis, in the sense that we can't afford to throw our scissors and forceps away at the rate that we use them.  So we go through this very extreme sterilization protocol to make sure that we are not transferring infectivity from experiment to another. 
		And I would take as evidence of the efficacy of that that we have done these -- a large number of these blood studies over the last four years, where we have inoculated hundreds of animals, and never infected any of them, and with instruments that were processed in this very way.
		And these were animals where we were looking for residual infectivity in, say, Fraction 2 or Fraction 5, from a plasma infractionation.  So we have that evidence, which is antidotal, and it is not systematic, from our own handling of these utensils, and treating them in this fashion.
		And which makes me believe that this can work if you do it right.  I do know or I have heard at least that there was a major, I believe, EC or else U.K. award, to look at stainless steel of different makes and types, and finishes and that type of thing.
		And the ability of those surfaces to retain infectivity, and the ability to remove that infectivity by these types of sterilization methods or various types of sterilization methods.  But I have no idea where they are in those studies, and I am not actually sure who is doing them.
		CHAIRMAN BOLTON:  Stan.
		DR. PRUSINER:  Just a very quick comment.  Coming back to the ashing experiments.  The number of animals that became ill after one minute of ashing or three minutes of ashing, I guess it was, in exposure to these extreme temperatures was very, very few.  
		And more animals became ill if the ashing procedure was prolonged to 15 minutes.  Now, I just think that this paper should have never gotten published.  
		DR. ROHWER:  That data is summarized on that complicated slide that I skipped over, but there were a number of flaws there.
		CHAIRMAN BOLTON:  I think we can feel comfortable, but those data should be reproduced before the committee bases any decision on that level of resistance to inactivation.  
		DR. EWENSTEIN:  This may be naive, but at least for coagulation proteins, and getting away from the steel, and to the resins --
		DR. ROHWER:  I am having trouble hearing you.
		DR. EWENSTEIN:  Okay.  Sorry.  Turning away from the steel and the hardware to the resins that are used for some of the coagulation proteins.  As you know, they use monoclonal antibodies in a light of the production, but can you imagine from your own work, and from the reading of the literature, sort of what approaches would be possible that would preserve those resins and still inactivate PrPres?  
		I mean,is that theoretically possible, or do you know if there is data that shows that it is possible?
		DR. ROHWER:  I think you could assure yourself a very nice retirement if you could come up with that solution.  
		DR. EWENSTEIN:  That's what I thought.
		DR. ROHWER:  Those biological materials attached to resins like that are a real point of vulnerability in these fractionation systems, and I think the solution is that you have to protect those resins so that they never see that exposure to begin with, or else you have to have something downstream with those resins that is very effective, in terms of removing any residual infectivity which may have come from those chromatography steps.
		With that said, there are resins, the plastic resins, the plastic ion-exchange resins, which do quite nicely in 1N sodium hydroxide, and it can be regenerated with 1N sodium hydroxide.
		And they don't have the beautiful ligand specificity of a monoclonal antibody, but they are also used in these processes, and I think they present less of a risk for that reason, provided that they are decontaminated in that way.
		On the other hand, I haven't seen anybody, and we have not been asked to look at decontamination of a plastic resin with sodium hydroxide just to test how effective it is.  I don't know actually.  
		DR. BELAY:  Rob, I'm not sure if I made myself clear, but most of my concerns --
		DR. ROHWER:  I'm sorry, but I can't hear you.
		DR. BELAY:  I'm sorry.  The primary concern that I have with all this inactivation studies is all this inactivation studies use either grounded up brain tissues, or brain homogenates, and in common sense infection control principles, they tell us that we do not inactivate tissues.
		We inactivate instruments that potentially came in contact with the tissues, and it would be most appropriate to replicate this kind of studies on the instruments that have been cleaned and properly disinfected, and see if any one of these methodologies that you described would actually work in completely activating the agent.
		If you just inactivate or try to apply the heat for homogenates or grounded up brain tissues, you would potentially just cook the --
		DR. ROHWER:  I get your point, and it is a valid one, and I think that is why the Weissman Laboratory established this stainless steel wire model.  
		They wanted something that was eminently inoculatable, which they could test, and they were very surprised by this first set of experiments that they did.  They are not the only ones that can work with it.  
		They told us how they did it, and it certainly does need to be pursued, just in the way that you suggests here, and it is a nice paradigm I think for looking at exactly that type of question.
		CHAIRMAN BOLTON:  Bob, I thought that there was a published study -- and unfortunately my addled brain cannot think of it now, but where that was done, and where brain tissue was placed on a stainless steel surface, and then washed, and then autoclaved, and then assayed.  But I don't recall where that came from. 
		DR. ROHWER:  Dr. Asher has done some -- what are called use dilution tests, but I think he used glass, and not stainless steel.  But if you would like to say something about that, that might be appropriate, yes.
		DR. ASHER:  We used class because it could be pulverized, and because it was based on a conventional viralcidal (phonetic) model.  Some day, if the regulatory load decreases, I will publish that.
		CHAIRMAN BOLTON:  Other questions for Dr. Rohwer?
		DR. PETTEWAY:  Yes, just a comment.  I think that this is consistent with what you are saying, Bob, is that we need to be careful about generalizing about stainless steel and prions adhering to stainless steel, and inactivation.
		That it is likely that where prions go, and whether they are resistant or not, or what they associate with, be a function of independent and individual processes.
		And the matrix and the materials that those prions associate with, or would associate with, in those processes.  So I would just caution against generalizations in this regard.
		DR. ROHWER:  Well, I think I did make it clear that context is everything here.
		DR. PETTEWAY:  Exactly.
		DR. ROHWER:  And you really have to know the context, and you really have to validate what you are doing, or what you are claiming.
		CHAIRMAN BOLTON:  Dr. De Armond.  
		DR. DE ARMOND:  I think one of the interesting fallouts from the Weissman study is that certainly prion proteins certainly seems to be -- that the abnormal form of the protein coats this material, this solid material.  It is hard to get rid of it.
		And you can stick it into a brain and it will cause infectivity, which can be a way of assessing the efficacy of cleaning these instruments for batch plasma preparations if you can have a piece of tube that you run your system through.
		And you then clean it with sodium hydroxide or however it is going to be done, and that can then be inserted into the brain of a susceptible animal, and like a TG bovine PrP mouse, and see whether it was actually clean.
		CHAIRMAN BOLTON:  I hope that you are suggesting that as an experimental study and not a quality control issue.  
		DR. DE ARMOND:  I think it could be a quality control issue also.
		CHAIRMAN BOLTON:  I think that might be a bit cumbersome, but you can entertain anything.  
		DR. DE ARMOND:  Well, it depends on how safe you want to be.  Do you want to know whether there is infectivity there or not, which is the idea.  And if you can't measure it by an assay, a standard immunoassay, then a bioassay would be helpful.  Then you would at least know the answer.
		CHAIRMAN BOLTON:  I think the difficulty that I would have with that would be if you had meters of tubing, which three millimeters do you take to assay, and how do you validate what does that mean, in terms of a meter of tissue or of tubing.
		DR. DE ARMOND:  At some point, you have to validate whether you have cleaned your instruments properly, and so it could be a one shot deal, but at least it is interesting.  
		And the Weissman study says it is possible, because it is interesting that you can stick just a monofilm of PrP on to a surface, and it will induce the disease in an animal.  That is fantastic.
		CHAIRMAN BOLTON:  Stan.
		DR. PRUSINER:  Well, I think that you just cut this meter in two pieces like Bob showed you and assay a thousand animals, right, Bob?
		DR. ROHWER:  Well, the thing is that you can make these measurements.  It is just a matter of whether there is enough will to do them.
		CHAIRMAN BOLTON:  Any other questions for Dr. Rohwer?  If not, very good.  We will then move on to our next presentation.  
		DR. ROHWER:  When do we get the pizza?
		(Laughter.)
		CHAIRMAN BOLTON:  It's not on the schedule.  Our next presentation is Dr. Henry Baron, from Aventis Behring, and he will be presenting VCJD Risk Assessment, and Dr. Baron has already spoken with us earlier.  So we welcome him back.
		DR. BARON:  The fire bell kind of brings a metaphor to mind.  I kind of feel like a fire fighter who shows up with his water hose after the house has burned down.
		I came here to bring you the take home message that geographic European deferral is not warranted, but of course you a have already exhaustively debated this, and you made a decision about that.  However, to err is human.
		(Laughter.)
		DR. BARON:  If this were Broward County, Florida, I would ask for an immediate and manual recount, but here in the bastion of our democracy, I guess I couldn't pull that off.  So what I will try and do over the next few minutes is take the opportunity to show you why you were wrong.
		(Laughter.)
		DR. BARON:  I would like to do a reality check on this notion of geographic risk with respect to safety of blood and variant CJD.  Now, everything that we hear and fear about CJD and blood comes from speculation, conjecture, modeling.
		But none of this changes the fundamental fact -- and this to me is a key message -- that there is currently no evidence that persons with pre-clinical or clinical CJD -- and that includes variant CJD -- carry infectious prions in their blood, or have transmitted infectious prions through blood or plasma products.
		Now, therefore this risk remains truly theoretical.  This is a statement which was true five years ago, a time when the FDA implemented its first policy of withdrawal and notification for sporadic CJD, when a donor is subsequently diagnosed sometime after his donation.
		This was by the way a measure that was repealed a few years later in 1998.  This is a statement which is factual today, and I hope to god that this is a statement which will be factual five years from now, at a time when we may be reviewing some of the consequences of the decisions that we are making here.
		This statement is based on a wealth of information related to classical CJD.  We all agree that we do not benefit from the vast epidemiological perspective that we have for classical CJD with variant CJD, although there is some information, there is some data, and I will go through some of that as we move along.  Next, please.
		I don't need to go through all of the experimental data and epidemiological data which concluded that there is no convincing scientific evidence of prion infectivity in blood of CJD patients, nor that prions have been transmitted through blood or plasma products.
		I will just focus on a few significant negatives; a study by Joe Gibbs and Paul Brown, in which blood from 13 cases of CJD sporadic were inoculated into non-human primate hosts, including chimpanzees, and there was no evidence of transmission in any of these cases.
		Now, in these instances, whole units of blood were transfused.  Blood from CJD patients were transfused to chimpanzees, with no evidence of disease.
		A second study, which was conducted at Stan Prusiner's lab, using transgenic mouse hosts, which are highly susceptible to human prions.  Again, 13 CJD cases were examined, or bloods from 13 CJD cases, and 12 of these were sporadic, and one familial, and again there was no evidence of transmission.
		And as far as the epidemiological data is concerned, of course we have had in the U.K., and in the United States, and in Germany, studies of identified recipients from CJD donors, looked back at retrospective studies, and never has a case of CJD been demonstrated in any of these recipients.
		And of course the studies of special increased risk populations, and we know, for instance, that there has never been a case of CJD in a hemophilia patient in the history of the world.  And again this calls to mind that CJD and AIDS are very different.
		Within a year of the emergence of HIV, within a year or two years, we started to see AIDS in hemophilia patients.  Next, please.  
		Now, what about variant CJD?  What is the current state of knowledge with respect to this issue of variant CJD in human blood?  What we do know is that whole blood, red blood cells, and platelets, in the United Kingdom, from U.K. donors, have been and continue to be administered to U.K. recipients in the United Kingdom.
		An estimated 30 to 40 million transfusions have occurred in the U.K. over the past 10 years.  Not a single case of variant CJD has been linked to a transfusion.  Several patients with variant CJD actually received transfusions, but none of these cases could be linked to a donor who had variant CJD, or for that matter classical CJD.
		And in several cases of variant CJD where blood donors, but in no cases of either classical CJD or variant CJD, have ever been noted among identified recipients of blood or plasma products from any of these known variant CJD donors.
		So to date there is no evidence in the United Kingdom, a country which represents 99 percent of all reported BSE, and 96 percent of all reported variant CJD in the world, there is no evidence that variant CJD has been transmitted through blood or plasma products.  Next, please.
		Here is a little bit more detail with respect to the studying of the U.K. on variant CJD and blood products, and this is publicly available information which can be obtained from the U.K. CJD surveillance unit.
		Eight variant CJD patients received blood transfusions -- and again as I mentioned, no donors have been identified with CJD, classical or variant.  And 14 variant CJD patients were blood donors, and eight variant CJD donors could be traced to 22 recipients, primarily from labile blood products.
		And none of these recipients have had their names show up on the national CJD register in the U.K. to this time.  Now, this is a list of the labile blood products which were administered.
		Primarily, red blood cells, and then BC-depleted red blood cells, fresh/frozen plasma, whole blood, cryo-poor plasma, and cryoprecipitate in a few individuals.
		Also, eight donations from these donors went into plasma pools for the production of therapeutic proteins, which then were administered to tens of thousands of recipients.  Again, no recipient of plasma proteins to date has been identified with variant CJD.  Next, please.
		This is redundant, but I just want to call again to your attention the fact that of the 105 cases of variant CJD worldwide, 101, or roughly 96 percent, have occurred in the U.K.  
		The one case in Ireland, and the one case in Hong Kong, both have spent considerable time in the U.K. during the at-risk period, and really could be associated with the U.K. cases. 
		So the only country that stands out is France, with three de novo cases of variant CJD.  These persons never went to the U.K., but we do know that France imported large quantities of U.K. beef and beef products.
		And another important thing to note in this is that there have been cases of variant CJD since the initial onset in 1994, and every year through until the year 2001.  
		France, on the other hand, there has been no such -- there hasn't even been a flat line for variant CJD.  There has been one case in 1994, and the two in 1999.  The next slide, please.
		And this just shows you that data in graphic form, and this is what Stan Prusiner was relating to earlier when he expressed that we are now in the triple digits with variant CJD, and this caused a great deal of concern to Stan.
		I would like to point out to my good friend, Stan Prusiner, that this tendency to arise is certainly far from what one would call an expediential rise, and I really don't think that with all of the best modeling in the world that we can ever predict exactly what is going to happen in the future. 
		But again look at France.  These are deaths and not onset.  But the one case in '96, and the one case who died in 2000, and then the third case died in 2001.  This obviously is indicative of a significantly reduced exposure to BSE in France compared to the U.K.	
		We heard all of that this morning, to an order or two orders of magnitude less exposure.  And of course one could assume that in the rest of Europe, which imported less U.K. beef products, and which have lower numbers of BSE, you would even have another order of magnitude less exposure.  Next, please.
		In contrast, the rise in variant CJD, which is a slight tendency to increase, to this tremendous increase of BSE in the U.K. over the period from 1987 until 1992, when BSE peaked, again there is no comparison to the rise in BSE and the current rise that we are seeing in variant CJD.  Next, please.
		Now, this slide just gives you the numbers of BSE throughout the world.  Again, the rest of the world pales in comparison with the U.K.  Only four countries have had a hundred or more cases of BSE.  
		What is of considerable concern today are some of the countries with lower numbers, such as Belgium, Germany, and Spain, which have had a considerable increase in the number of cases within the last 6 to 10 months.  The next slide, please.
		So in spite of the fact that this risk is purely theoretical, and I can't say it enough, we continue to approach this issue as though the risk were real.  And that's why we already implement rational science-based precautionary policies to minimize the theoretical risk.
		I think in view of the fact that the U.K. has 99 percent of all the BSE, and 96 percent of all the variant CJD in the world, it is a rational precautionary measure to implement individual donor deferral criteria for people who have traveled in the U.K.
		And I think that rejection of U.K. source plasma is another rational precautionary measure to minimize a theoretical risk.  We also withdraw and notify in case of a variant CJD donor, a situation which has never occurred for us, or for that matter for anyone else in the world outside of the United Kingdom.
		We have also been investing very heavily throughout the plasma-proteins industry in research on prions, and I think that the plasma-protein industry may have invested more money in research in this field than most groups, and governments, and who else, today.
		And this research has been directed towards the development of extremely rapid and highly sensitive methods of prion detection.  These methods are being used today to continue to research prion infectivity in the bloods of CJD cases, including variant CJD cases.
		They are being used in the assessment of prion partitioning in manufacturing processes.  They are being used to evaluate potential prion removal methods in manufacturing processes.  
		And perhaps in the future tests can be used for the potential screening of incoming plasma, and finally the industry at large is involved in conducting appropriate and well-designed prion clearance evaluations aimed at reducing uncertainty and providing relevant meaningful data.  Next, please.
		Now, the assessment of prion partitioning of the manufacturer of human plasma proteins is in itself complex.  Since, as I have said before, prions have never been detected nor transmitted to a human plasma or plasma derivatives, we have no knowledge as to the physical or chemical nature of the theoretical prion contaminant, if it fact it even existed.
		So therefore there is uncertainly as to what would be the appropriate relevance of a prion spiking agent for the study of prion partitioning and manufacturing processes.
		Now, this is just a list of some of the things that have been used by different laboratories; brain homogenate; microsomal membrane fraction, caveolae-like domains, which is a specialized membrane compartment; prion rods; and the purified molecular spiked purified PrP scrapie.
		The good news from all of this is in spite of the uncertainty, data from several laboratories, using different spiked forums, show multiple process steps in the plasma vaccination and infractionation schemes with robust prion removal capacities.  The next slide, please.
		And so this was the slide that I showed you earlier today when I tried to get into the public session before the deliberation.  Again, the risk of variant CJD transmissions through blood or plasma products remains purely theoretical and unsubstantiated by relevant scientific evidence.
		I might add something today because one of the scientific experiments that is often used and passed out on the safety of human blood with respect to variant CJD is that experiment of transfusion in sheep.
		Just three weeks ago, I was at a meeting in which Nora Hunter, one of the senior investigators in that study, gave an update on that study.  And it is now nine months after the Lancet publication, and yet this one transfused sheep is the only animal in that study to have come down with the disease.
		The positive controlled animal study, which had received an intravenous inoculation of U.K. beef brain homogenate, is not yet sick.  So I really do not feel confident that that data could be used to in any way influence our thinking about variant CJD in blood.
		But despite the fact that this remains a purely theoretical risk, and because we know that variant CJD is different from classical CJD -- and one of the differences is again what Stan Prusiner pointed out earlier, is the presence of variant CJD prions, or the PrP scrapie for variant CJD patients in the lymphoid tissues of variant CJD patients.
		And which by the way does not necessarily mean that it is in the blood, because in scrapie in sheep, it has been classically demonstrated that prion infectivity is found in lymphoid tissues, but it has never been detected in blood.
		Nevertheless, we continue to implement numerous precautionary measures in order to further minimize this risk.  The lack of rise of variant CJD in France, and its absence virtually everywhere else in the world, is notable, and reflects significantly reduced human exposure to BSE outside of the U.K.
		And measures have been implemented in Europe since 1996 to enhance food safety, and reduce the potential for food borne transmission of BSE prions to humans, and this should add further reassurance, although in Europe, they didn't go into an official specified risk material ban until the year 2000.
		And other individual European countries, including France, Italy, Spain, such measures were already implemented in 1996.  And I think it is a pity that we didn't have somebody here today from the European commission who really knows all the numbers about when some of these measures were in place, because a lot of the deliberations and discussions that you had were based on knowledge that nobody was sure of.
		Finally, multiple manufacturing process steps in the production of purified PrPsc have been shown to have robust prion removal capacities, and in our opinion, and it is still our opinion, a pan-European approach to further minimize the above-mentioned theoretical risk does not seem warranted, nor should European plasma be considered unsuitable for the production of purified plasma products.
So we can not start the recount and I thank you.
		CHAIRMAN BOLTON:  Thank you.  Any questions?  Steve.
		DR. DE ARMOND:  Hank, I think that your comments, and Dr. Cliver's comment about being sued out of existence if one case of variant CJD would show up as a result of a transfusion, and so we are in dammed if we do and dammed if we don't situation.
What would your recommendation have been regarding the European blood supply?
		DR. BARON:  Number 1, I don't have a crystal ball, and I can't say what is going to happen in the future.  But my recommendation is right now is that this risk is truly theoretical.  There is no evidence or no relevant scientific finding to support it.
		And my recommendation is that we should not defer donors who have spent time in Europe outside of the U.K.  I would not even propose that we defer donors who have spent six months in France, not with three variant CJD cases.
		CHAIRMAN BOLTON:  Other questions?
		DR. BAILAR:  I think we are looking at this backwards.  It is not the risk that is theoretical.  It is the safety that is theoretical.  The BSE epidemic has passed.  The episode of the VCJD is far from past.
		The numbers are still going up, indicating I think that there is a delay of years, and maybe decades, for the average case between the time of infection of the human being, and the appearance of the disease. 
		I am not really concerned about the continuing infection of humans from food consumption.  I am very much concerned about what is going to be happening over the years to come with the people who may already be infected.
		I think we may just be seeing the very beginning of what is going on there.  Do you have some way to reassure me about this?
		DR. BARON:  My answer is that I don't have a crystal ball, and neither do you, nor does anybody else in this room.  I think that we have to consider the supply issue, along with this very, very theoretical risk.
		And I don't like to speculate and conjecture.  I like to stick to facts.  I think what you said earlier that the absence of proof is not proof of absence.  
		But I think over the years we have begun to accumulate evidence of that, and certainly with classical CJD, and now we have 10 or 15 years of people getting transfusions in the U.K., and we still have not seen variant CJD showing up in any of those transfusions, and I tell you that without a doubt that there will not be one one day?  No, I cannot.
		Can I tell you without a doubt that the City of Washington will have an asteroid fall on it?  I cannot do that either, but we are not going to evacuate the city next week because of that.
		CHAIRMAN BOLTON:  Dr. Cliver.
		DR. CLIVER:  Just a thought.  We don't know what the minimum incubation period is for VCJD, but it would be helpful as we see the record of VCJD blood donors and the surveillance of recipients, to have some years of cumulative potential incubation period presented.
		Because let's say it has been 10 years since somebody got a transfusion from somebody who came down with VCJD, that is a lot more persuasive than if it has been two.
		DR. BARON:  You are absolutely right, and unfortunately most of these products -- and not all of them, but most of these products -- have been administered within the last 5 years.
		But some of them were administered as far back as 1981.  So you are right.  This unfortunate human experiment is not finished.  Nonetheless, the fact today is that there has been no transmission.
		Oh, by the way, also with respect to the incubation period.  You know, I don't think we can assume what the incubation period would be in human-to-human transmission via an intravenous route or an intracerebral route or whatever; as opposed to the incubation period of BSE going into humans, causing variant CJD?
		Because now if you are talking about variant CJD, you no longer have a species barrier to pass through, and theoretically the incubation period should be shorter than for bovine prions, especially by an intravenous route.
		Of course, you are infecting the blood and theoretically would also have a lower titer.  So it is difficult to make an assumption on what the position is here today.
		CHAIRMAN BOLTON:  Other questions?
		DR. NELSON:  You cast some doubt on the sheep experiment.  Could you elaborate on that, on the transmission?  Is that still valid? 
		DR. BARON:  Yes.  That experiment, that study -- well, the study was not published.  What was published was a single, isolated result from the study.  
		Twenty-one sheep were fed 5 grams of bovine brain.  Then they were left alone and they were bled at different time points after the oral challenge. Then this blood was transfused into naive, previously normal, sheep.  
		Now, one of the orally challenged sheep came down with sheep BSE if you like, and a transfusion from that sheep to a naive sheep was related to disease in the transfused sheep after 600 days.
		Actually, the incubation period was the same as the incubation period of the oral challenge with the BSE brain.  It took 600 days for that sheep to get sick by eating it, and then 600 days from the transfusion.
		But again as I said the positive control, which received a high titer BSE brain homogenate by the intravenous route has not gotten sick yet, and it was not sick at the time of the publication, and it is not sick today.  It is now 9 months later.
		So it is already up close to that 600 day incubation period, and that just does not make sense.  And anybody who has followed this field can tell you that there have been a lot of red herrings and false alarms due to improperly controlled studies.
		And contamination or sample mix-up have to be considered a possibility.  And I don't think you can say also that 1 in 20 actually got sick, because that is significant, because as David actually pointed out earlier this is a study where large volumes of blood are being transfused, 400 ml.
		This is not a study where a 30 microliter sample of blood was inoculated into the brain of the animal.  So, theoretically, if there is even a small quantity in the blood, it should have occurred in more than one sheep.  
		CHAIRMAN BOLTON:  I don't think that we want to spend much time debating the specifics of that particular experiment, because I don't think that we have the time, and I don't think it has particular value.
		I think what we should say is that the results are not certain, and there are explanations on either side of the question, and additional studies on that particular animal and the material from it, and the completion of the remainder of the study needs to be done before we can really make much sense out of that.  Yes, Bruce first, and then --
		DR. EWENSTEIN:  I was wondering, Dr. Baron, if you could comment on your point of view on the specific questions, or pieces of the specific questions that are before us on this section.  
		And that was that assuming that we discover as the tests become more sensitive that there is infectivity in plasma, what would be your recommendation based on your knowledge of the manufacturing process and of prion disease?
		What would be your recommendations in terms of additional decontamination procedures, dedicated manufacturing lines, and that sort of thing?
		DR. BARON:  I would prefer to defer that question, because there is going to be a full presentation on that by another industry representative following me.
		So perhaps following that, we can get involved in that discussion.  I don't want to do that now.
		CHAIRMAN BOLTON:  Dr. Schoenburger, and then I think we will move on.
		DR. SCHOENBURGER:  There was some discussion about the data that may or may not exist in the U.K. about blood transfusions, and who has --  
		CHAIRMAN BOLTON:  Transfusions from VCJD?
		DR. SCHOENBURGER:  Yes.  Want I am aware of -- and this comes from Dr. Robert Will, is that there are eight new variant CJD patients that have been linked to 22 recipients of blood.
		DR. BARON:  That's right.
		DR. SCHOENBURGER:  And these recipients, the year of the blood transfusion ranged between 1981 and 1999.  And I wasn't planning on presenting this, because there is some key information that is missing, and that is the information of exactly what happened to these recipients, and how long they would survive.
		And what he does have is that he knows who these recipients are, and he knows who the new variant CJD cases are, and he has linked them, and they do not link.
		DR. BARON:  That's correct.
		DR. SCHOENBURGER:  And so I would say that 14 of these 22 were presumably followed for at least 5 years if they had survived, and that is the key missing data.
		And we are doing a similar type of study for classic CJD, and that is why we were sharing some of this information.
		CHAIRMAN BOLTON:  Thank you.  Okay.  Thank you, Dr. Baron.  We will move on.  Our next speaker is Dr. Jeff Davies, and he will speak on Considerations for Facility Cleaning.
		DR. DAVIES:  Thank you for the opportunity to speak on the topic of facility cleaning relations to TSEs.  My name is Jeff Davies, and I work in Switzerland, in Bern, at ZLB Switzerland, which is in the middle of Europe.
		In the year 2000, ZLB supplied approximately 3,600 kilograms of IVIG for the United States, and 22,000 kilograms of plasma, and we also supply IVIG to Europe and the rest of the world through our distribution agreement with Aventis.
		And at ZLB, we processed approximately 1.8 million liters of plasma per annum derived from USA and European sources.  In all cases, donors who have resided in the U.K. for a period of six months during 1980 to 1996 are deferred.
		Only products derived from USA plasma is provided to the USA.  It is very important to realize that all manufacturers need to have procedures in place to ensure that there is no cross-contamination occurring between batches.
		In today's presentation, I will speak on the current approach to cleaning, and an explanation of cleaning within our manufacturing facilities, and I will present a hypothetical on the worst case scenarios in order to highlight the existing processes in place in order to ensure batch-to-batch segregation, address the issue of segregation of EU from USA plasma, in relation to theoretical contamination with TSEs.
		If a variant CJD contamination was determined to have been present in our manufacturing pool, all products prepared from that pool will be recalled.  That is a matter of policy within the industry.  
		But the question that we really want to address is, is there a variant CJD list to products in the next manufacturing pool prepared in this equipment.  
		We need to establish the routine cleaning between batches from those prions, and that no dose of any product in the next batch contains an infectious dose of prions.
		The routine approach for cleaning validation between batches from those prions includes mapping for worst case locations, and looking for the reservoirs if you like, the bells and so forth, and total -- analysis.  
		Cleaning consists of pre-rinsing with and water and treatment with either half bottle of sodium hydroxide, or one percent Ikalin, which is a sodium hydroxide-hypochlorite detergent mixture, and subsequent rinsing with water.
		Cleaning validation is performed on product contact equipment.  TSE is determined on swab samples, and also on -- on a routine basis, and swab samples are taken before and after the cleaning procedure.
		The results from our cleaning validation show that we can demonstrate consistently a 1,000-fold reduction.  We are limited to 1,000-fold reduction by the limited detection of TOC.  We reduce the total organic carbon to the limit of detection.
		I now want to talk about the manufacturing process that we use for IVIG in very simplified terms.  The manufacturing process can be divided into five modules, each one separated from the other by a process that shows significant reduction of TSE agent in model studies, and this was work done in Dr. Oh's laboratory.
		We were able to demonstrate a reduction of 15.4 log, and there were two types of agents used.  There was purified PrP and brain homogenate, and the results were not identical, but were similar with the two.
		I now want to consider the cleaning within this particular facility in a hypothetical and simplified manner.  We know that the cleaning process reduces total organic carbon by at least three logs, and the assumption that I want to make is the total organic carbon reduction is proportional to proteins, including TSE agents, and that is an assumption that we are making.
		So for the hypothetical case, let's assume that a production pool was contaminated with a variant CJD donation, and we know that there has never been a case of a plasma contaminated that we have been able to identify with prions and plasma from a variant CJD patient.
		The total load of the TSE agent would be 5,000 infectious units based on the estimation of Brown, et al., and that any TSE agent would be present in a diseased person that would not exceed 20 Ius per mil. 
		Now, this is -- we have not had a diseased person, and this is a hypothesis that we are putting forward.  This has come from my studies and so this is a totally hypothetical case.  
		Then I want to propose that all the TSE agent adheres to the surface of Module One in the manufacturing process.  So, we have 5,000 infectious units in our pool, and 3.7 logs all adhered to Module One at the completion of that batch.
		We know that cleaning will reduce that by at least one-thousand fold.  It may in fact totally eliminate it, but on the basis of our total organic carbon analysis, the most we can claim is a 1,000 fold reduction.
		This leaves potentially 0.7 logs to carry across into the next batch, and if we assume it carries on into Module Two, and it adheres to Module Two, then I think it adheres to Module Two in the next batch.	
		If we continue this model, we can end up making assumptions for the remaining modules, which in the very much worst case, and we would get a reduction associated with cleaning of minus 8.3 -- well, not a reduction, but we will get a potential contamination of minus 8.3 log that could end up in the final bulk product.
		This is totally hypothetical, and it is totally ignoring the manufacturing process steps, and we will come back to this in a minute.  Next slide, please.
		Okay.  So if we have a level or we have a manufacturing pool of 2,000 liters of plasma, we produce approximately 8,000 grams of IVIG, and we can calculate that there would be approximately 6.3 by 10 to the 3rd infection units per gram of IVIG.
		If we look at the maximum batch, a maximum dosage of approximately 200 grams, which would be a 100 kilogram man getting two gram per kilogram, which is a very high dose of IVIG, we can estimate that the probability that a dose would be infectious is of the order of 1 in 100 million.  Next slide, please.
		On the basis of those assumptions, we can conclude that cleaning a line is effective and includes as a safety margin against TSE.  The estimate does not take into account a possible activation of TSC agents used during cleaning, and assumes no clearance by the process.  Next slide.
		That situation, however, is not realistic. If one assumes that theoretically present TSE agent does not or only partially adheres to the equipment surface, which is reality, the TSE agent would be reduced by the various production steps.
		These showed an elimination capacity in model studies comparable or superior to reduction during cleaning, and there is a probability that one containing one infectious unit will be less than one in a hundred-million on those assumptions.
		I now want to move to the cleaning and inactivation agents.  We know that one molar of sodium hydroxide has the potential to inactivate TSE agents, and inactivation deficiencies are increased by elevated temperatures.
		So we need to ask the question can one molar hydroxide or hot caustic agents be used in cleaning regimes.  Cleaning validation is a major undertaking for the industry.  
	Changing the agents is not a trivial exercise, and what hot hydroxide may inactivate, it also has the potential to precipitate and fix prions on surfaces.  Any changes to cleaning processes need to be properly validated prior to implementation.
		The current manufacturing equipment in most plants around the world is not designed for such harsh chemical treatments, such  as one molar of hydroxide at 60 degrees.  
		We know that the chromatographic resins and ultrafiltration membranes used in plants throughout the world generally would not use such conditions.
		We also know that treatments of seals, gaskets, hosing materials, with hot caustic might contaminate the plant and products and would break down compounds from rubber and polymeric materials.
		Hot caustic agents are also hazardous for employees, especially when equipment has to be cleaned manually, and we need to take that into account as well before introducing these sorts of procedures.
		I now want to talk a little bit about cleaning and validation with infectious agents and many of these points have been raised in the previous talk.  Cleaning validations involving infectious agents are important, but they do have limitations.
		We need to limit conditions of CIP processes in sterile systems.  The selection of TSE or the TSE agent itself is very important.  What preparation is most appropriate was a point raised in the previous talk.
		The recovery of potential residual infectivity can be challenging.  For example, the recovery from a swab, or the use of aggressive reagents to recover the infectious agent may destroy infectivity, or even immunogenicities if you are using an immunogenic probe.
		This is an area which warrants further investigation.  So, in conclusion, I would just like to say that on the basis of this evaluation, existing cleaning processes are already in place to provide assurance against TSE carryover.  
		Harsher cleaning conditions, such as the use of hot hydroxide, or hot caustic agents, have to be carefully investigated, and they could be detrimental to plant product and employees.  
		We need to conduct more research on the ability of cleaning fluids to inactivate TSE, and this is supported by the industry.  And we also need to extend research on the detection of trace amounts of TSE agents on the surfaces of stainless steel and equipment.  Thank you.
		CHAIRMAN BOLTON:  Thank you, Dr. Davies.  I think what I would like to do now is to hold questions until after the next two talks, and we will take all the questions for these talks at the completion of the industry presentations.  
		So our next speaker will be Gordon Busenbark, and he will speak on the Complexities of Manufacturing.
		MR. BUSENBARK:  Good evening, Ladies and Gentlemen.  My name is Gordon Busenbark, and I am President of Global Operations for Baxter BioScience.  First of all, I would like to thank you for the opportunity to come here today to offer our perspective on the concepts to require manufacturers of plasma products to provide dedicated processing equipment and production lines based on the geographic origin of the plasma used to manufacture those products that are sold in the U.S.
		Like all of us here today, Baxter is committed to the highest level of safety and quality for the plasma derived products that we manufacture.  In today's presentation, I intend to show that product line segregation would contribute to the safety of U.S. plasma derived products.
		As a control measure for variant CJD, segregation has no credible scientific support.  What this measure would do unfortunately is lead to a reduction in plasma derivative manufacturing capacity, and as plant capacity is currently the supply limiting factor, segregation would end up substantially reducing the production of these critical therapeutic products.
		Segregation would have a devastating consequence for patients both in the U.S. and around the world who depend on these critical therapies.  Next slide.
		To help you appreciate the impact of segregation on the production of plasma derivatives, I would like to describe the current manufacturing logistics for plasma derivatives using our company, Baxter, as an example.
		Baxter is one of the major manufacturers of plasma derivatives.  We currently process over 4 million liters of plasma a year in five manufacturing plants, two in the U.S., and actually four in Europe.
		The plasma that we process is collected from donors both in the U.S. and in Europe, but as required by our product licenses, all of the products that we distribute and sell in the U.S. are currently produced from U.S. plasma only.
		However, it is important to understand that the products that we make for the U.S. market out of U.S. plasma are manufactured in both our U.S. plants and in our European plants.  Next slide.
		In each of our plants the manufacturer of these therapeutic products occurs as a complex, multi-step continuous process.  The process flow for our Vienna, Austria facility, which is shown here as an example, illustrates from the initial plasma pooling step, to final product packaging.
		The output of each process step serves as the input for the next process step.  This complicated and meticulous manufacturing process, including the associated quality and regulatory review of every lot of product that we produce, results in a manufacturing process time from start to finish of anywhere between 6 to 9 months, depending on the product.
		The collection process alone for plasma has a 60 day hold period from the time of collection to entry into the fractionation process.  Next slide.
		Baxter is, of course, very conscious of its responsibility to provide a safe and continuous supply of product to our patients.  After all, at Baxter our philosophy is that there is a patient waiting for every vial or product that we produce.
		With a very long lead time to produce plasma derivatives, it is critical for us to achieve optimal operating efficiency and reproduability of our manufacturing process.
		Therefore, we have designed and operate our production facilities so that there is a high level of equipment usage and through put is maximized.  The sequence of operations is carefully planned and executed so that there is always a careful balance of inputs and outputs at each step.
		Furthermore, each of our facilities is designed to operate on a consistent 24-hour basis, seven days a week, at its optimum plasma through put level.  Next slide.
		The inherent complexity of the manufacturing process means significant deviations from the design capacity of our manufacturing facilities either could not be accommodated, or would result in a substantial loss of production output capacity.
		Given the need to optimize the use of our production equipment, and to coordinate the manufacturing process carefully, it is clear that separate production lines for plasma of different geographic origin would require substantial modifications to our existing facilities and process flow.
		Segregation would introduce severe constraints on equipment utilization, require extensive facility and equipment duplication where none currently exists, and disrupt the very precise scheduling of operations.
		The end result would be a significant reduction in output and availability of product for our patients.  Next slide.
		Again, using our Vienna facility as an example, product line segregation would result in disruptions in production of all U.S. distributed IGIV manufactured out of Vienna.  
		Our anti-inhibitor coagulant complex Fiba is an excellent example.  All of the Fiba that is used to treat Factor VIII inhibitor patients world wide is manufactured in Vienna, both out of U.S. plasma and European plasma.
		Factor IX concentrates and fibrin sealant produced at the Vienna facility would also be impacted.  In the short term, there is no way that this facility could accommodate its current production with segregated equipment.  
		For patients in the U.S., this would be more than an inconvenience.  It would be a health risk impacting the lives of thousands of American patients in an already constrained supply market.  
		A case in point is our fibrin sealant product.  As the sole supplier product in the U.S., all supplies of this plasma derivative are manufactured in Vienna, and as such would be affected by this proposed line of product segregation.
		And I would just highlight for those of you who aren't looking at the chart, that what this shows is that at the start of our process, we start processing both U.S. and European plasma in our Vienna facility.
		We make a whole variety of products, both on the left side of the screen, as well as on the bottom of the chart.  But we specifically highlighted up all the products that we manufacture in Vienna, and the ones that are circled in red are the ones that are actually sold here in North America.  
		So as you can see, some of the products that we manufacture in Vienna are sold exclusively outside the U.S., in Europe and in Asia, and Latin American; while a number of the products that we manufacture, those highlighted in red, are sold in both the U.S., Europe, and the rest of the world.  Next slide.
		Baxter's Vienna facility would not be the only site impacted by production line segregation.  Now, some of you may think that this is a New York subway map, but it is actually a pictorial depiction of Baxter's manufacturing network in the various manufacturing plants that we have.
		To maximize output and efficiency, all of our manufacturing operations are highly integrated on a global basis, and what this means is that some products are only manufactured in one facility, and some products are manufactured in multiple facilities; and some products may be manufactured to a certain step in one facility, and then finished in a second facility.
		As you can see, to optimize our ability to prepare these critical products requires frequent interaction and movement between plants.  A case in point is our Lessines, Belgium facility, which does the manufacturing for all of Baxter's immunoglobulin product.
		And which to put that in perspective, Baxter's share of the worldwide IGIV market is slightly over 20 percent, all of which is manufactured in our Lessines, Belgium facility.  Next slide, please.
		To delve further into the Lessines issue so that you understand the complexities, this facility receives the starting material for immunoglobulin in Fraction II from three locations.  
		Fraction II comes from our Los Angeles facility, our Rochester, Michigan facility, and from our Vienna facility.  A portion of the manufacturing process for both U.S. and European intravenous immunoglobulin utilizes common production equipment, common production tanks, and intravenous immunoglobulins, as I think everyone knows, are in short supply globally.
		And any disruption at this single production site to accommodate segregated production lines could have the potential to have a significant impact on the patients who rely on this critical therapy of IGIV (sic).
		In order not to impact product supply, the production line segregation being considered today could only be achieved by designing and constructing new production facilities.
		For our company current manufacturing facilities would have to be either substantially modified to accommodate separate production lines approximately sized for each type of plasma.
		This change could be extremely complex and would realistically take years to implement.  Next slide.
		Current plant modifications underway at our Los Angeles manufacturing facility provide some perspective as to the effort associated with the facility modification in our industry.  
		At present, we are upgrading a portion of this facility in which the cold ethanol fractionation step is performed.  The total cost of upgrading our Los Angeles facility is budgeted at $105 million, or at a cost of more than $1,000 per square foot.
		And which will require 5 years to implement, from inception to licensure, by the FDA.  Considering that this change involves just one portion of one facility, you can see that implementing completely segregate production lines at all of our facilities would involve an enormous expenditure of resources, and take many years to implement.
		In the meantime, product supply would be significantly impacted while these changes were underway.  Next slide.
		The disruption of the supply of these valuable products, and the substantial costs associated with the provision of segregated production lines, could be justified if in the end there was a commensurate improvement in patient safety.
		However, as you have heard today, and will hear from others, product line segregation is intended to address a theoretical concern.  All evidence to date is consistent with the view that plasma derivatives do not represent a variant CJD risk.
		In addition, even if the threat of transmission of variant CJD by plasma derivatives was in fact real, product line segregation would not assure that products from U.S. plasma would be free from the risk.	
		Given the large number of American donors who potentially could have been exposed to variant CJD, segregation would not assure safety.  Next slide.  What measures should we consider then?  
		We believe that it is more useful to support continuing investigations leading to effective control of the spread of variant CJD and research into the agent's behavior.  We encourage this committee to support those investigations, rather than requiring companies to implement ineffective segregation schemes.
		Examples of the investigations currently under way by this industry will be described in the next presentation by Chris Healey of the PPTA.  In closing, I would like to extend our gratitude to the committee for the opportunity to provide our perspective on this important issue.  Thank you very much.
		CHAIRMAN BOLTON:  Thank you, and as I said before, we will hold questions until after Mr. Healey's presentation, and that is who is next.  Mr. Christopher Healey is going to speak on the impact of VCJD measures regarding European donor deferrals.
		MR. HEALEY:  Good evening and thank you again.  I am speaking on behalf of the Plasma Protein Therapeutics Association.  The PPTA is a global association of the major producers of plasma therapeutics around the world.  
		My presentation tonight is really just a sum up of some of the messages that you have heard from the presentations and I will address some of the important issues on the impact of the potential for segregation on the market for plasma therapeutics.
		PPTA member companies include those that you see here, and those are the previous speakers.  So just to give you a sense of who we represent.  Next slide, please.
		In summary then, there is no evidence or no convincing evidence of prion infectivity in human blood or plasma, nor transmission through human blood or plasma products.  This is a point that has been made repeatedly this evening.
		In addition, fractionation processes achieve meaningful prion clearance.  Some of that evidence has also been presented.  Current cleaning procedures are robust and obviate cross-contamination issues.  The ZLB presentation highlighted this nicely, I believe.
		And then finally, Dr. Scott raised the issue of labeling, and we believe that labeling requirements that are already in place adequately address this theoretical risk.  Next slide.
		In terms of segregation, and the impact of segregation on the marketplace, the data that we have collected through our monthly data reporting on product distribution, plasma product distribution in the U.S., indicates that 50 percent of the IVIG in the U.S. marketplace today is manufactured in part or in whole at facilities that also fractionate European plasma.
		So a decision by this company, or excuse me, by this committee to segregate manufacturing lines for U.S. and European plasma would basically be putting all European plasma at risk and saying that 50 percent of the IVIG on the marketplace in the United States today is at risk.
		This could have tremendous implications for the availability of these products, and in the perception of risk and health that the patients who take them have.
		In addition, the full range of plasma therapeutics would be implicated.  As Dr. Scott indicated, Factor VIII and other factors, clotting factor concentrates would be implicated.  
		Inhibitors would be implicated, and immunoglobulins as I said, and albumin, and fibrinogen.  Perhaps most importantly though the future of IVIG and other plasma therapeutics would be dramatically impacted.
		We know that a number of companies currently are pursuing FDA licensure for IVIG to bring it to the U.S. marketplace.  Many of these companies are located in Europe, and also process European plasma.
		It is ironic that just a few years ago in 1998, when industry and when patients were faced with a dramatic shortage of IVIG, the FDA and consumers worked aggressively to find approximate clinical trial protocols to help speed IVIG to the marketplace.
		And that the actions that you are considering there today would completely undo those efforts, and would basically eliminate the possibility of adding future IVIG to the U.S. market.  Next slide.
		With regard to cleaning, any recommendation must consider the impact on the manufacturing process, and Dr. Davies went into this in detail.  But some of the other issues to think about are the production cycle for IVIG and all plasma therapeutics is roughly 270 days from the day of donation to the date that the vial is distributed.
		That is a long manufacturing time, and even minor disruptions in the processes can extend that significantly.  So things like segregation, like additional validation, and cleaning steps, can have seemingly minor impact, but relatively major impact in terms of production cycles and getting product to market.
		In addition, some of the other issues associated with cleaning include the need for facility shutdowns during validation, equipment retooling, refitting, and other issues of that nature.  And I know that we will be responding to questions like that in just a few moments.  
		However, as an industry, we do believe that more can be done here, and we believe that collaborative efforts are going to yield the kind of information that we need to make sure that cleaning procedures in place are adequate.
		So you will see from a later slide that we look forward to working with regulators, with the FDA, with representatives from the EMEA, to make sure that we are all comfortable with the cleaning procedures that are in place, and that we can get a better understanding of what it means to validate these procedures with respect to infectious agents.  Next slide.
		Turning to labeling, Dr. Scott, as I had noted, mentioned this as a potential consideration for the committee.  And as I said, we believe that the current labeling is adequate.  
		You can see from the overhead what the current labeling requirements are, and albumin is labeled as having an extremely remote risk, while IVIG and other products are labeled with the language that says may carry a risk of transmitting infectious agents, e.g., viruses and theoretically CJD.
		We believe that nothing has changed here.  We believe that the risk is still theoretical and that this labeling adequately captures the theoretical nature of that risk, notwithstanding segregation, and not withstanding additional cleaning procedures.
		The risk remains theoretical and that is captured in the current labeling requirements.  In addition, we think that additional labeling along these lines, or additional labelings with regard to the nature of the threat, would simply cause fear and confusion among patients, and among doctors and treaters, and wouldn't add to the safety of the products.
		So we do believe that because labeling is intended to ensure an informed physician and consumer that what is in place is sufficient.  Next slide, please.
		Risk assessment is another concept that has been discussed, and product-by-product risk assessment is something that might also yield additional information.  We have heard that product manufacturing processes vary by company-to-company, and that the manufacturing steps for each process and product vary considerably as well.
		So it is important to take a close look at each of those steps and get a better understanding of the risk and benefits associated with each of those steps, in terms of prion removal, and cleaning, and so forth, to come up with a concrete picture of what this risk may present on a product-by-product basis.
		A uniform and global approach to this kind of risk assessment simply wouldn't do.  Next slide, please.
		So, PPTA considerations, as Dr. Baron said, our member companies are leading providers of research funds totaling 10s of millions of dollars each year.  We have some of the preeminent prion researchers in our member companies and here with you today.
		So it is our intention to continue this level of funding and interest, and to continue to support research on prions, and get a better understanding of the nature of the disease, and the nature of its transmissibility, and continue this dialogue with you.  
		These other points have already been said.  Current PPTA surveillance in the EU countries will minimize food borne transmissions.  There is additional information about the precautionary measures that have been taken there.
		We also believe that the U.K. is a unique circumstance, with a high BSE and VCJD rate, and that it stands alone.  That the experience there can't be translated to other European countries.  
		And finally we believe that it is important that any policy that this committee considers, or any other regulatory bodies consider, should anticipate the ultimate appearance of BSE in this country and of VCJD in this country.
		I think it would be negligent to not plan for that in the event that does arise; and to set a policy that excludes all risk of VCJD, and then to find that it is here in the United States, would cause a lot of confusion, a lot of fear, and a lot of concern among patients.
		Additional recommendations are that segregation of manufacturing lines is unwarranted, and will significantly impact current and future product availability, which is an important point.
		That current cleaning procedures are adequate, but that we should work with agencies and regulatory bodies to get a better understanding, and to come to a common understanding of how to go about additional cleaning procedures.  And that additional labeling isn't warranted.
		Our next steps.  The PPTA recently held a workshop in Europe to get all the evidence and all the information out on the table that we had available to us about prions and human TSEs.  
		We are planning on holding a similar workshop here and inviting regulators and patients to come and share in the dialogue, and try and get all the risks out on the table, and come to a better understanding, and an open and frank dialogue about the true risks.
		So we look forward to conducting that workshop, and you can rest assured that the committee members here will be invited.  In addition, we would like to develop a task force to further address the cleaning issues.  
		We think that this is very workable and that this task force could meet on a regular basis, and in fact bring information back to the committee to help them form any future policies that the FDA may put before the committee.
		And then finally the point about continued research.  That cannot be emphasized enough.  As I said, our member companies are one of the leading funders of research, and we look forward to continuing that.  Thank you.
		CHAIRMAN BOLTON:  Thank you.  Now we will take all questions for Dr. Davies, Gordon Busenbark, and Christopher Healey.  Let's see.  I guess we are going to need each of them to be near a microphone somewhere.
		And in the interest of efficiency, perhaps all at the podium, or pick a microphone and stand near it, I suppose.  Yes?
		DR. KATZ:  I think probably Chris can answer my question.  I am a little dense at this point in the day.  It is my understanding that there would be reluctance to further pursue licensure by those companies that are in the process now if segregation occurred.  Would they attempt to not market their products in this country?
	      MR. HEALEY:  The point is that we know that there is some companies with manufacturing facilities in Europe that are currently pursuing FDA licensure, and are pursuing FDA licensure for plasma products manufactured from U.S. plasma, but manufactured in Europe.
		So if this committee were to make a recommendation for complete segregation, it could potentially put that -- could derail that process.
		CHAIRMAN BOLTON:  Bruce.
		DR. EWENSTEIN:  If we assume that it is not practical for the foreseeable future to segregate plasma, or change the overall production, and given how many different nuances there are in the production of the various products, and by different manufacturers, would it be possible for you folks to individually or by consensus sort of come up with a recommendation that we could talk about?
		And then maybe the FDA would eventually adopt, and which would speak to how many log reductions, for example, one should be able to demonstrate, and similar to the viral certifications that go on today.
		So that one could say, okay, if there is a theoretical risk in the plasma, we can say that there is a 3 log or a 5 log, or I guess that is what I am asking, is an X-log reduction.
		And that if the FDA could be satisfied that for a given product and a given manufacturing sweep, that that was accomplished, then it would become moot in terms of the source of the plasma going into the process.
		MR. HEALEY:  I am by no means a scientist, but from what I have heard from my colleagues, I understand that to even speak in terms of log reduction can be misleading, because the infectious dose, if there is one for brands, is not truly understood.  I am sure that other can address that more completely.
		With that said, I can tell you that the industry is very willing to work with the agency.  As I have said, we want to develop some kind of working task force to address the cleaning issues, and it may be that that is an appropriate issue to take up as well.
		So I think that the answer to your question is yes, that we would be more than willing to engage in a dialogue about how to define the issues, and how to come to some consensus on what appropriate steps are.
		DR. NELSON:  I think that the data or the ideas that you presented on segregation and cleaning, et cetera, were fairly clear and illuminated some issues.  
		But one of the issues that I wanted to ask, and that I still don't understand, is in the first half of the meeting we talked about deferring some European donors.  
		And how would that discussion, if implemented, our votes, affect this operation and preparation of IVIG or plasma products?   What have we done in the first half of the meeting?  Is that a fair question, or do you know it?
		DR. DAVIES:  I think it is a fair question. I think that a numer of people have raised the issues that we will have to deal with in relation to segregation, and the issues -- certainly there are issues that we would have to address in the notion to what kind of plasma we process.  It can have a profound impact on businesses as we heard in the previous presentation.  
		DR. NELSON:  I was concerned about this earlier, but it really wasn't addressed.  The plasma industry's problems weren't really discussed the way I think they should have been before we took the vote that we did at the first half of the meeting, or the first three-quarters, or however along we are now.
		MR. HEALEY:  I certainly share your concern and I agree with you.  We didn't feel that they were fully vetted if you will.  We were very encouraged by Dr. McCurdy's suggestion that plasma should be considered separately.
		Ultimately, it might be that the same policy would be decided by this committee, but to have a full and open discussion of the plasma issues.  The brief presentation that I read indicated that there would be, let's say, a 4 percent donor loss.  
		But the other issue is that casting a shadow over all of the European plasma skews the market dynamics.  That plasma is going to have to be made up somewhere else, and it strains the entire global plasma products marketplace.  That is the issue that we were trying to communicate.
		CHAIRMAN BOLTON:  Steve.
		DR. BUSENBARK:  Yes, I was just going to make the comment that I think these issues are all interrelated, and that to the extent that all plasma products sold in the U.S. have to be made out of U.S. plasma, irregardless of where they are manufactured, to the extent that we have additional deferral criteria, which we talked about in the earlier half of the day, just like that will affect whole blood collections, and it will affect collection of source plasma through plasma phereses.
		Because we will have to implement the same deferral criteria, and I think as many of you know, there is already a critical shortage of U.S. plasma right now that is hurting the availability of IGIV, and of plasma derived Factor VIII.
		So the decision made earlier today will reduce the amount of source plasma available for U.S. products.  Now, the second issue is that it has the potential to be compounded by the fact that if various European governments read into the decisions that were made today that there is now a higher risk associated with European plasma, then there is a very high likelihood that European governments may put forth initiatives to try to convert from using their own European plasma to U.S. plasma.
		And which just like the issue with trying to recruit more donors for whole blood, we are going to have the same issue, and we are going to have more people chasing after the same limited supply of U.S. plasma.
		And then the third issue that I think is interrelated to this is that if there is a perceived risk based on the discussion that we had today associated with European plasma, then it calls into question all of the fractionators that have facilities in Europe where they process both U.S. and European plasma.
		So even though in those facilities the products going back to the U.S. are made out of U.S. plasma, I think it is very important to recognize that they are being manufactured in plants using the exact same production equipment, the exact same filling equipment, the exact same critical systems like air handling that is used to manufacture U.S. versus European plasma.
		So that's why I think it is really important to understand that the decisions that are made by the committee today have some pretty far-reaching implications.
		CHAIRMAN BOLTON:  Dr. De Armond.    
		DR. DE ARMOND:  From what you presented, plasma -- and what Hank Baron presented, plasma presents or is a special subset of blood, in which there is an even greater evidence that there is no infectivity theoretically.	
		DR. BUSENBARK:  That is absolutely correctly, and a couple of people mentioned that this morning, and because of the manufacturing process itself, it actually reduces the prion level.
		DR. DE ARMOND:  And you also end up with fairly large volumes at the end, because you start with a full plasma, and it seems that you have a chance at least at the end of these multiple steps to actually check for prion protein. 
		Are you doing that and has there been any attempt to do some sort of immunoassay for it, or even bioassay?  Or what is your plan for that, because that is really the ultimate test?
		DR. DAVIES:  Well, there are no assays for blood or in blood, and that is an issue, and that is something that is being developed.
		DR. BUSENBARK:  This is protein.  You precipitate the protein, and you can do a variety of things.  You can concentrate it.
		DR. DAVIES:  Well, there are people working on assays, and there are other people here who may want to talk to that.  But that is a key issue, and because of a lack of that technology, we can't assay in final product.  But what we can do is scale down and do further studies.
		DR. BARON:  And perhaps Steve Petteway might want to address this after me, but Steve, we are all engaged in evaluating the different process steps, and that plasma fractionation interpretation involves 
precipitation steps, and it involves absorption steps, all of which are going to remove prions.  
		And using different methodologies in our laboratories, we use the CDI, the Confirmation Dependent Immunoassay, to measure and to put in different steps.  
		And if a buyer has a big program in which they are evaluating different manufacturing steps, and there are numerous steps which show robust removal, and there are still uncertainties about which is the appropriate spike.
		But what is nice to know is that even studies using different spikes are showing robust removal, and maybe Steve wants to pick up from that. 
		DR. PETTEWAY:  Yes.  Now, just to follow up, I think an issue was made earlier that many of the studies that have been done so far have been done with animal model systems.
		And we now have data where we have looked at removal or petitioning human prions, both classical CJD, and we now have some data where we have just looked at variant CJD and done a comparison.
		And the removal of classical and variant is exactly the same as the removal of the hamster or sheep.  So I think we have reached the point now that we have enough research data that we can get together and look at the potential of how we would set up validation and provide some assurance of removal of prions through these processes.  And that I would encourage the committee to think about that as a recommendation going forward.  
		DR. DE ARMOND:  So the recommendation, I guess, is -- and I guess what I am hearing from you and from the others is that you are validating that there is an elimination of PrP prions.
		DR. PETTEWAY:  We have determined on a research scale that it is potentially feasible, and that the animal studies relate to human; and what we are suggesting is that we ought to meet with regulators and with the appropriate individuals to establish what the criteria for validation would be.
		DR. DE ARMOND:  On individual batches that are made?
		DR. PETTEWAY:  Yes.
		DR. DE ARMOND:  So that you could certify that we have done all the proper tests on this batch?
		DR. PETTEWAY:  Just like we do with our own studies about validation.
		CHAIRMAN BOLTON:  Dr. McCurdy. 
		DR. MCCURDY:  This comment and question -- actually, it is a question.  There is more on the risk assessment and the repeated statement that risk is strictly theoretical.  
		In Europe, fibrin sealant, fibrin glue, has been used for a considerably longer time than in the United States, and it is also used in neurosurgery as I recall to control bleeding. 
		My question is whether there is any fibrin glue been used or that was used in Europe for neurosurgery, and made long enough ago so that perhaps some U.K. or French donor plasma might have been used in some of those pools.
		And if so, is there enough active surveillance for a long enough period to know whether placing this material directly on the brain, which is the way it is assayed in animals, whether that does or does not cause any infectivity?
		DR. BARON:  I know that Bob Will in the U.K. does have some data, and for a limited time period -- I think it is an 8 to 10 year time period -- he does have for one hospital, one institution in Scotland, access to all of the patients who have undergone neurosurgery with fibrin sealants.
		This is a question that we have also been looking at, and we have been working on putting together an epidemiology study looking at neurosurgery risks and neurosurgery, plus fibrin sealant risks.
		And the data is very limited, and in the U.S., I don't believe that fibrin sealants have ever been used in neurosurgery.  They have been used in some European countries.  I believe in Germany and in the U.K.
		And the only person who really has data, or who has put together data on that, is Bob Will, and we are currently actively trying to put together data in Japan and in Europe as well.
		And the data that Bob Will has does not show any individuals who have undergone surgery with fibrin sealants who have been afflicted with CJD.  But again it is another one of these situations where it is a short time frame that has been looked at.
		CHAIRMAN BOLTON:  Dr. Epstein.
		DR. EPSTEIN:  Yes.  If I could be permitted to follow up with Dr. Petteway.  Your statement that you have current studies with the variant CJD agent int he fractionation process is the first that I have ever heard publicly of any such result.  
		We, of course, have been awaiting such a result.  I have been aware that there have been studies with the BSE agent in Europe, none of which have been reported to my knowledge in any public or private way.
		So with regard to your own experiments, could you just clarify a couple of things?  First of all, what was the maximum clearance at any process step; and second of all, what was the readout assay?  Are you talking about immunoassay or Western blot, or are you talking about infectivity, and are you also doing infectivity?
		DR. PETTEWAY:  Well, if you will remember in the paper that we just finished in transfusion, where we correlated prion clearance and infectivity and established that.  The methods that we used for --
		CHAIRMAN BOLTON:  Steve, could you move closer to the mike?
		DR. PETTEWAY:  I am right on top of it.  The methods that we used for the experiments for the classical CJD prions and the variant are the same as the methods that are in those papers.
		And we have done studies with a low level clearance method, like cryoprecipitation, and also with a precipitation step that removes all animal, classical CJD, and sheep prions, and we just did that step for variant, and it, too, removed all the variant prion that we spiked.
		The readout was a Western bloc assay.  The quantitative Western bloc that you saw, and the method for which it was published in that paper.
		DR. EPSTEIN:  And the levels of clearance achieved was the maximum for any single step?
		DR. PETTEWAY:  For this particular step, it was greater than four logs.
		DR. EPSTEIN:  And were there more than one step that had at least four logs?
		DR. PETTEWAY:  Well, we chose three steps -- a low, an intermediate, and a high -- to assure ourselves that if we saw similar removal that it meant something, and it wasn't just an accident of the step that we chose.
		And we have looked at the low, and we have looked at the high, and there was correlation with the low and the high, and we are doing the intermediate now.
		I mean, as you can appreciate doing experiments with the variant and a human are kind of difficult.  We are doing them with Richard Rubenstein in New York and Paul Brown.
		DR. EPSTEIN:  And presumably this was a brain homogenate?
		DR. PETTEWAY:  It was a one percent brain homogenate, exactly like all the other studies that we were doing.
		DR. EPSTEIN:  Thank you very much.
		DR. BARON:  Could I just add that we are currently also doing a study on keys steps, and which we are comparing three different prions; hamster prions, sporadic CJD, and variant CJD, in parallel on key steps, using two different spiked forms.
		There is the purified PrP scrapie, and the molecular spike, and microsomal membrane fraction.  So that data that is being generated now, and we will probably have it available soon.
		CHAIRMAN BOLTON:  Peter.
		DR. LURIE:  I have two questions.  One is for Dr. Davies, which is that you indicate that this data about the different modules in the purification and product development process, but can your or somebody else who has done these kinds of studies speak to the appropriateness of adding up the number of logs the way you did?
		I mention this because I noticed that Dr. Rohwer's study for tomorrow is that he makes the point that some of the different steps in the purification process in effect inactivated the same prions, the same fraction over and over again.
		And so it raises the question to me that if it is really legitimate to add up the logs like that.
		DR. DAVIES:  Well, with regard to the petitioning, it is relevant.  They are different steps, and in each of those modules there is a different step.  
		With regard to the cleaning, and the inactivation on cleaning, it was to provide an example as the sort of behavior that is being put forward on manufacturing processes, and it was purely done as a hypothetical case, and adhering to equipment.
		And the sorts of behavior that we are talking about that it needs to continue to convey, in terms of contaminating a plant.  So it was merely put forward to address that issue.
		But certainly you can have the logs when you have distinct separation processes.  And certainly the cleaning procedures that we put in place at those different modules apply at each different module.
		CHAIRMAN BOLTON:  Peter, I respectfully disagree.  I think that it depends on the individual steps, and that in fact the bridging experiments that were talked about are often necessary to prove that those affected reductions are additive or not.
		Because oftentimes you are removing the same prions, and once they are removed in Step A, you can't remove them again in Step B.
		DR. LURIE:  There was a second point if I may, and that has to do with the mechanics if you will, Dr. Busenbark, about your six plants and so forth, and you showed these elaborate diagrams about what is produced where and so forth.  
		And it is clear that it is a very elaborate process, and with a certain amount of duplication, and I can't tell from the diagrams that every one of the steps occurs at more than one place.
		But it did strike me that there was a fair amount of duplication, and other than insisting that it is impossible to do, have you actually sat down at a computer, if nowhere else, and rearranged the boxes to see if there is literally any way you can comply with separating and segregating?
		DR. BARON:  Yes, I think the answer to that is that is going to take some additional work on our part.  This is something that we just looked at closely here over the last couple of weeks.
		But our initial assessment is that, number one, we don't have the space in our existing facilities.  And when you start to talk about segregation and the space -- first of all, there would be a requirement for space just to put in duplicate sets of equipment, and duplicate sets of tanks, duplicate sets of critical systems, like HVAC.
		That, coupled with the fact that you would really need to look at it in terms of was it giving you the segregation you need, because as you saw from the process diagram that I had in Vienna, there are a multitude of steps.
		And those are from the initial plasma thawing and plasma cooling, and all the way up to the pharmaceutical filling of the final product.  And if you in fact wanted to have a full segregation scheme, you would need to segregate at every single step of the process, which could be a very complicated task.
		DR. LURIE:  I guess my point is that perhaps here is a way of organizing your assets as it were to minimize the duplication.  I mean, there is a certain amount of duplication, and certainly these steps occurred more than in one plant.
		So I understand the problems of doing everything double.  I mean, that is an obvious problem.  But I don't think that that is the only scenario here.  It is clear that you do certain things uniquely in some plants, and then ship the product down to the next place for processing.
		It is equally clear that some things are done at two plants or more.  I mean, have you really thought about this?
		DR. BARON:  Yes, we have given it some thought.  Actually, the only product that we make the same product in multiple facilities is albumin, and interestingly the albumin process that we use even in those two separate plants in Vienna and Los Angeles is two different processes based on how they evolve.
		Otherwise, outside of albumin, all of the products that we manufacture are not made in multiple plants.  
		DR. LURIE:  It is the steps that matter, right?
		DR. BARON:  Right.
		DR. LURIE:  And not so much the product though?
		DR. BARON:  Right.  
		DR. LURIE:  So the point with albumin is interesting, but the point is where are the steps duplicated, and they are in multiple places.  I think that is what I took out of your drawing.
		DR. BARON:  No, I don't think so.  If that was your impression that is not really the case, because what it was showing was that we make different products in different plants, and in many cases we would manufacture a product in a given plant up to a certain step, and then move it to another plant.
		But there are really no instances where we are manufacturing the same product with similar production steps in different plants.
		CHAIRMAN BOLTON:  Dr. Belay.
		DR. BELAY:  Going back to the clearance studies.  One of the problems that I have with the clearance studies is that it assumes that the spiking actually mimics natural infection, which may or may not be true.  
		We don't know where the infectivity would be.  If, for example, blood contains the prion agent, or the infectious agent; and if this concern is valid, then the data that is collected or obtained from this clearance studies cannot necessarily be applied to the natural infection in humans.
		And another comment that I have is that you can also make the argument that plasma derivatives could actually be riskier than the components, and that is because as you know blood derivatives are produced by pulling tens of thousands of donors, which would increase the chance that one of the donors could have potentially been incubating the disease if the agent is found in the blood.
		And not only is there the pulling of plasma derivatives in the production process, but they are also distributed to millions and millions of recipients, thereby increasing the chance if there is any risk that recipients may actually be at risk in developing the disease.
		DR. BARON:  Okay.  You are right about the fact that since prions have never been found in human blood, we don't know what the physical chemical form of the prions in the human blood would be if it were indeed in human blood.
		Therefore, I presented a slide in which I indicated that different laboratories have approached this differently.  Some have used brain homogenate, and some have used microsomal membranes.  
		We have used a whole range of spikes.  We have actually taken it from the most crude form of infectivity, which is the crude brain homogenate, and going through a series of more purified forms, to the most purified form of infectivity, which is the purified PrP scrapie.
		And what we have done is compare the clearance at different steps with these different forms of the prion agent, and what we have shown in our laboratories is that membrane brain spikes, whether it is microsones, caveolae-like membranes, or brain homogenates, kind of partition the same way.  
		The purified molecular spike partitions differently for certain steps.  So our conclusion is that we do it on a worst case-best case scenario.  I think we are covering all the possibilities.
		You know, Paul Brown in a 1999 publication called Transfusion, and in this endogenous mouse model of blood infectivity.  So this is a wild type mouse that you are not going to inoculate intracerebrally with -- I think there were GSS prions -- and so the mice developed prion disease.
		And at a late stage, they have very low levels of prion in their blood.  But again, remember, this is artificial.  It is endogenous and they are being inoculated intracerebrally.
		So what he found was that there was some infectivity in blood, at very low levels, primarily in the white blood cell component.  But very low levels; 1 to 20 infected units per ml in the plasma.
		And when he looked at that plasma under the electron microscope, he reported that there was no membrane debris associated with that.  So what I am saying is that we looked at one edge of the spectrum, and the other edge of the spectrum.
		And I think the best that we could do is provide a range.  The answer is somewhere between these two, but I think at least at this stage you are getting into something meaningful, because you are covering all the possibilities.
		DR. BELAY:  Right.  But what I am saying is that we have to be cautious in our interpretation of the data that we are collecting.
		DR. BARON:  Of course.  That is why we took this multiple spike approach, but I think what encourages me is that when I look at the data from all the different laboratories that I continue to see robust clearance at lots of steps.
		CHAIRMAN BOLTON:  Do you have a comment on that?
		DR. PETTEWAY:  Yes, I would just like to a point, and that is that the sheep studies that we have done, and the human studies, have been with prions from natural infections.  So they are the agent of natural infection.
		The issue is whether the agent, if it gets into the blood, is different.  But clearly the removal that we see, compared to the experimental hamster model from humans and sheep is from naturally infected hosts.
		CHAIRMAN BOLTON:  I doubt if people want to beat this to death, but I thought about this a lot, and it is an issue that you really cannot resolve experimentally, because there are not enough natural prions in blood to do the experiments.
		So if you do the experiments on natural prions in blood, you can only do part of one step and that's it, because if there is any removal at all, they are all gone.  
		So you are almost forced to rely on an artificial spike, and then you are forced to accept that, using various spikes.  And the data that you get is at least representative of what happened, or what would happen in real life.  Dr. Ewenstein.
		DR. EWENSTEIN:  Well, I was going to make just a couple of points.  From the point of view of at least the coagulation factors, I think it is important to emphasize -- and I think some of the public comments mentioned this -- that we are currently in a very dramatic period of shortage right now, especially with respect to Factor VIII.
		And that going forward that it is not clear exactly when that is going to end.  And when we talk about plasma products, if you include albumin, then you would have to even think about the recombinant Factor VIII, or at least the major recombinant Factor VIII that is available.
		We might say almost the only recombinant Factor VIII that is available right now, and so we are really talking about an area that would affect the entire hemophilia A population for all intents and purposes.
		That said, I think that we would also have to think about a sort of whether it is possible to truly distinguish U.S. plasma as safe, and European plasma as unsafe.  
		And we talked about trying to reduce risk before, and I voted for that proposition.  But that is not to say that there is zero risk.  So there is still a U.S. donor who is coming in with 2.8 months of exposure in the U.K., and he is not a zero risk person.
		We have to think about the fact that beyond donor screening and deferral, we can't do testing of plasma at this point, or testing of donors. So then you get to the next step in the blood safety net, which is inactivation.  
		I don't think it makes sense to beat on the donor deferral piece for the plasma derivatives so much as to try to pool what we have heard, and really encourage in our recommendation to the FDA that levels of validation be set at this point, imperfect as they might be.
		And to say for the various plasma derivatives that the steps in a given manufacturing process, and not just a hypothetical one, but for each product that is licensed, has met a certain amount of reduction to the best of our current knowledge.  I don't think you can get any more safety out of bifurcating the stream of plasma.
		CHAIRMAN BOLTON:  I am going to take one more question, and then I think we ought to move on.
		DR. BAILAR:  I would like to urge that we do what we can to get away from these log reduction models.  They can be quite useful, helpful, informative, in the study of individual laboratory experiments.  
		But several things can go wrong when you start applying them in sequence, step-wise, to working systems.  The first thing is that some of the assumptions may fail.  
		For example, what I have seen has had the implicit assumption that the successive steps are statistically independent and that may not be true.  There may be some questions about the data input, and what you used in the laboratory really matches what goes on in the field.
		There can be equipment failures in the field, and there can be human failures.  When I look at all of these together, I have some real concerns about the use of those models.  So I would ask that we be very careful about how we use them.
		I am not saying that we shouldn't use them, but they need to be seen with a lot of skepticism.
		CHAIRMAN BOLTON:  Yes, I think that is an issue that has been addressed, and is revisited frequently when these kinds of validation studies are done, and I think the FDA are well aware of that and will consider that.
		I would like to move on given the lateness of the hour.  I would really like to move on and entertain the questions for the committee.  Oh, that's right. I can't move on quite that quickly.  That's right.  We do have an open public hearing.
		And we have, I believe, at least two speakers.  So our first speaker will be Mr. Chris Lamb, from the American Red Cross.
		MR. LAMB:  Good evening.  My name is Chris Lamb, and I am the Chief Operating Officer for the Plasma Services Unit of the American Red Cross.  Thank you, Mr. Chairman, and Members of the Advisory Committee for giving me the opportunity to speak today on behalf of the American Red Cross.
		The American Red Cross plasma derivatives  meet approximately 25 percent of patient need for these therapies in the United States.  At present, the American Red Cross contracts with for profit manufacturers to process approximately 1-1/2 million liters of plasma recovered from volunteer blood donations, anti-hemophilic factor, albumin, and intravenous immune globulin, IGIV. 
		IGIV and some albumin distributed by the American Red Cross and the United States are manufactured in European fractionation facilities.  All other plasma products distributed by the Red Cross are manufactured in the United States.
		The American Red Cross is committed to providing the safest possible blood and plasma products to patients and physicians treating those patients.  
		As we discussed with you earlier today, the Red Cross implemented an expanded donor deferral policy to reduce the theoretical risk of transmission of variant Creutzfeldt-Jakob disease through blood and plasma products.  
		Consistent with our policy of expanded donor deferral, the Red Cross believes that U.S. plasma should not be processed using common manufacturing lines as those used for European plasma.
		Therefore, we are working with firms fractionating American Red Cross plasma to achieve segregation in the manufacturing process.  Let me talk a little bit about the risk of variant CJD and plasma derivatives.	
		The Red Cross will continue to evaluate the presence and partitioning of prion plasma and plasma derived products.  Our conclusions to date are as follows.  Infectivity is present in plasma of experimentally infected animals, hamsters, and mice. 
		This was work that was done with Dr. Paul Brown and Dr. Robert Rohwer.  Dr. Brown did the work with the mice, and Dr. Rohwer did the work with the hamsters.	
		In experimentally infected animals, infectivity partitions into multiple fractions, including cryoprecipitate, and Fraction One Plus Two, Plus Three, the starting materials for Factor VIII and IVIG respectively.  Again, this was work done with Dr. Brown and Dr. Rohwer.  
		Various degrees of removal of prion infectivity might be achieved through specific steps in the fractionation process.  However, studies examining this process have used brain derived laboratory strains as a model agent. 
		Results from variant CJD agent and human plasma may be different.  There is evidence that prions adhere to surfaces as has been shown for stainless steel surgical instruments.
		Thus, there is a risk that the infectious agent can bind into equipment cross-contaminant subsequent batches of product.  Pulling in multiple donations increases patient exposure to any infectious material.
		Because we know very little about transmission of variant CJD through blood products, we must be mindful of the history of transmission of pathogen through pool plasma products.  Confirmed cases of BSE continue to spread throughout Europe.  
		The movement of BSE cases into Eastern Europe, highlights that we do not know much about the human reservoir that might be affected by this disease, with a multiple-year incubation period.
		Consequently, we need to take all possible steps to protect the U.S. supply of plasma and blood products from potential contamination.  The Red Cross is taking the following actions to reduce the potential risks of variant CJD in our plasma products.
		Only plasma used in the manufacture of plasma derivatives and distributed under the American Red Cross label will be that collected by our regions, and from non-Red Cross blood centers that comply with our donor deferral policy. 
		The American Red Cross plasma is fractionated by contract manufacturers under their own FDA licenses.  We aggressively seek fractionation facilities decided to processing plasma from U.S. sources.  
		And because FDA registration is necessary for changes to the contract manufacturing facilities, we would look to the FDA for expedited approval, if necessary.  
		In the transition period, we are consulting with leading experts to evaluate and determine the best cleaning and sterilization procedures for fractionation where plasma will be processed.
		Implications for availability.  As we work with the firms to manufacture IGIV to achieve segregation, there is the potential that the supply of Red Cross IGIV might be temporarily reduced. 
		Assuming that we have reasonable cooperation with the manufacturers, the Red Cross believes that we will be able to meet the needs of patients being treated with our IGIV product under FDA approved uses during the time it takes to achieve manufacturing separation.
		We do not anticipate any impact on the availability of albumin or Factor VIII.  Our conclusion is that given the scientific uncertainty surrounding variant CJD, and the potential for transmission through plasma products, the Red Cross believes that there should be segregation in the manufacture of U.S. plasma products from European-derived plasma.
		Existing scientific studies have outlined the potential infectivity of certain plasma fractions by prions require us to take steps now to address manufacturing issues.
		This action, combined with an expanded deferral for blood donors, will help ensure that patients or recipients of U.S. blood or plasma products will have a reduced risk of exposure to potentially harmful TSE pathogens.
		As with our variant CJD donor deferral policy, if we are wrong in a more cautious manufacturing approach, we have expended more resources than necessary.
		If we are correct, the consequences of a less cautious manufacturing policy cannot be corrected.  Thank you very much.  
		CHAIRMAN BOLTON:  Thank you.  Our next speaker will be Mr. Jason Bablak, from the Immune Deficiency Foundation.  
		MR. BABLAK:  I am Jason Bablak, Vice President of Public Policy for the Immune Deficiency Foundation, and I have summarized my previous statement to a few bullet points to try to expedite this tonight.  
		IDF represents the primary immune deficient patients, and approximately 70 percent of those use IVIG to maintain their health.  For our patient population, supply is a safety issue.
		Recent IVIG shortages in the U.S. highlighted serious health consequences resulting from an inadequate supply.  Currently, not enough is known about variant CJD.  We believe that in the absence of scientific facts that it is prudent to take action to reduce theoretical risks so long as that action does not result in actual harm itself.
		Supply of IVIG remains tight, and therefore any action that results in reduced availability could have significant negative impact on our community.  
		And finally we look forward to working with the plasma manufacturers in the industry workshop on risk assessment that they talked about earlier today.  Thank you.
		CHAIRMAN BOLTON:  Thank you.  And I guess now we will entertain any other public comments from the floor?
		MR. HEALEY:  I just wanted to reiterate the fact that the data that PPTA presents each month on the availability and distribution of products indicates that a 50 percent loss in the IVIG currently distributed in the U.S. today would be implicated through segregation. 
		I know that the Red Cross had raised a different number, but the numbers that we distribute each month include the Red Cross IVIG.  So that 50 percent is inclusive of that.  
		The other question we would have for the Red Cross is whether given their concerns about the risk that they are perceiving with the products, would it be their intention to pull current products off the marketplace.  Thank you.
		CHAIRMAN BOLTON:  Thank you.  Additional comments from the floor?
		MR. YAMBURG (phonetic):  Yes, my name is Yamburg, and I am the PPTA president, and I am European, and I live in the States, and I work on the road, and I see every day the consequences of disharmony in policies that are made, whether it is in the States or any other part.  
		The reason that I want to stand up is this.  We are very concerned about the patients that need their products.  You have heard enough this morning about the emotional statements that were made.
		And when I talk about these needs, I become emotional, because I accept responsibility that we as a manufacturer have to do everything possible to manufacture safe products.
		What you did today is that you created another disharmony.  Let me give you one example, and then I will stop because it is late.  One of the things that we have to do as an industry is that we need to work in harmony and we need to work as a piece.
		We have to use donor deferral criteria.  What happened this morning is you are forcing the industry to work with two different donor deferral criteria; one in the States and one for Europe.
		The one that you discussed today can never be implemented in Europe, and for reasons that you well know.  The other thing -- and you can hear it in my voice that I am really angry, because you heard our experts standing up about what we do in the industry.
		And I do not understand why the American Red Cross stands up and talks about things that we have to do which have a tremendous impact on the patients that need our products.  
		CHAIRMAN BOLTON:  Thank you.  Other comments from the floor?  Seeing none, we will move on to the committee discussion then.  Peter.
		DR. LURIE:  Yes.  I am not sure if this committee has any obligation to follow the regulations of other countries, and I'm sorry that is the cost of doing business for you, but frankly I am sure that the donor criteria are different in other ways from country to country.
		And I am sure that it complicates things, but that doesn't make me want to retract what we did for one minute.  I do have a question for the Red Cross gentleman though who spoke up earlier.  
		And he seems to have confidence that the segregation can be accomplished, and so I just want to invite him to perhaps share his thoughts on that in greater detail.  How will it be done mechanically, as I think it is a mechanical issue, and how you think it can be done.
		And how to the extent that you found places that are in a sense compliant, and how they are doing it.  Could you perhaps enlighten us on that?  
		CHAIRMAN BOLTON:  I am going to ask that you very briefly comment on this, because I really would like to move on to consider the questions at hand.  So, please.
		 MR. LAMB:  There is no way really to give a short answer to that.  I think you have to look at the overall industry, and I don't know that there has been enough of a discussion of the way in which the plasma derivatives industry is organized.
		There are really five main fractionation facilities that serve the United States.  There is the Baxter facility in Glendale, California; and there is the Alpha facility in California; and there is a Bayer facility in Clayton, North Carolina; and here is the ZLB facility in Switzerland; and there is one more, the Aventis facility.
		I think you really need to take a look at where the products that are really coming into the United States, where they are coming from, the facilities, and which facilities.  Not necessarily the -- well, many of these companies have many facilities, but those facilities may not provide the U.S. market.
		So I really think you need to take a look at the industry as a whole, and what plants are where.  For example, the Bayer facility in North Carolina -- and I don't mean to speak for Bayer -- processes only U.S. and Canadian plasma.
		The issue is European plasma, and so I think you really need to take a thorough look at each of the plants, and what products are coming out, and what plasma is being processed here, and then from there what can be done.
		In my mind, here are a relatively small number of products where there is a real issue.  Mr. Busenbark talked about the fibrin product which is used to treat hemophiliacs that develop an inhibitor,
and that is correct.
		And that particular Vienna facility is probably difficult to correct, but I think the committee has to look at are there other available therapies.  There are two other available therapies in the United States, and is that an appropriate solution.
		So I think you really should look at each of the products, and the facility, and which of those facilities has U.S. and non-U.S., and get more information to better determine what can be done and what can't be done.
		I personally have been in the industry for 16 years and I don't believe it is as dramatic, but in a couple of minutes it is difficult to walk through that, and we, took, at the American Red Cross have a commitment to patients.
		And I don't think this is an issue about one group or another group having a more or less interest in the patients.  I think we all want to serve the patients.  We just look at the data, and we believe that we should err on the side of caution, and that is all that we are saying.
		DR. BUSENBARK:  Can I state something?
		CHAIRMAN BOLTON:  One brief comment.
		DR. BUSENBARK:  I wold like to just talk specifically about three products in terms of the Baxter situation.  We have talked a lot about IGIV and that is very important, because as I mentioned before on a global basis, Baxter produces in excess of 20 percent of the IGIV that is sold worldwide.
		And of that 20 percent that we produce worldwide, about 80 percent of it goes back to the U.S.  But I think it is important to recognize as I pointed out in my diagram -- and this underscores the complexity of the segregation -- is that we tear down and fractionate plasma at three manufacturing locations; two plants in the U.S. and one in Europe.
		And to the intermediate States or Fraction 2, which is the intermediate that is used to produce IGIV.  What then happens is that Fraction 2 immediate from those three plants is sent to one plant, in Lessines, Belgium.
		And they then process that IGIV into final product.  So there is no alternative.  All of the IGIV that is manufactured worldwide -- and we make IGIV out of every liter of plasma that we process.  
		All of the intermediates, whether they come from L.A. or Rochester, or Vienna, go to Lessines for final processing, both out of U.S. plasma and European plasma.  
		They are using common manufacturing equipment, common tanks, and we in essence to achieve this segregation scheme that has been outlined would have to have a dedicated separate facility in Lessines for processing European plasma and that would be independent from the facility that we have for U.S. plasma.
		DR. LURIE:  But your example makes the point that for the three previous steps, I think you said there are three separate plants, right?
		DR. BUSENBARK:  Yes, that is correct.
		DR. LURIE:  So for those three steps, you would not need to duplicate.
		DR. BUSENBARK:  That is correct.  But the other point that I would bring out is that for two other critical products that we manufacture, fibra, which is used to treat inhibitors for patients with hemophilia A, and fibrin sealant, and those are only manufactured in one plant worldwide, and that is in Vienna.
		And where roughly half of the product that we manufacture is made out of U.S. plasma for the U.S. market, and about half of the product we manufacture is sold in Europe out of European plasma.
		And in that case the only way that we could segregate once again would be to construct a totally separate manufacturing facility, and totally separate equipment, and totally separate critical systems.
		So we in essence would have to duplicate the plant that we have in Vienna to allow for segregation, and I just wanted to point that out to underscore the fact that it may seem simple and straightforward, but in fact when you get into the details, it becomes very complicated.
		CHAIRMAN BOLTON:  I am going to hazard a guess and go way out on a limb, and guess that we are not going to resolve that complex issue here tonight.  So I don't know exactly how we can advise the FDA on that, except to begin to consider the questions at hand.
		And unless there is a pressing question -- Dr. Ewenstein, you had one, but --
		DR. EWENSTEIN:  No, it wasn't a question.  I was just going to comment that I thought at least about the product that I am most familiar.  I mean, it seems that it would not be easy if at all possible to substitute products around as has been suggested.
		I think that without getting into specifics of a lot of different products, but there is one VWF factor A concentrate, and as far as I know, it is made only in Europe, for example.
		This market has become totally integrated, at least for the part that I am aware of.  I think we are likely to have sensitive tests for the plasma in a much shorter time period -- and I may be going out on a limb here -- than it would take to build or to rebuild the plant and get them approved based on my outside experience with these kinds of approval processes.
		So we have to think of the practicality. It is not the money, but it is just the time line that it would take to redo all of this manufacturing.
		CHAIRMAN BOLTON:  I think the issue is far too complicated for us to do much, in terms of considering any kind of specific issues there.  But let's move on to the questions that the FDA has asked us to consider.  
		The first one is to please comment on the significance of the VCJD risk from campaign manufacturing involving exposure to European plasma, and I would hazard a guess that we can say that the risk is essentially unknown, and probably very low.
		I don't know that we can add much more detail to that unless somebody has superior knowledge to my own.  Stan.
		DR. PRUSINER:  I think you are right.  We don't know the risk, and nobody around this table can define the risk, but I think there are pluses and minuses in this whole thing, and I think we ought to lay them out.  I mean, we hear very strong arguments from one side, and then we hear very strong arguments from the other side.
		And I think it is worth for just a second saying that if there are significant level of prions in new variant CJD people, in their plasma, and these prions behave in any way, shape, or form like those in brain, then they may well be accumulating in columns, in various fractionation steps in the equipment.
		And depending upon the stringency of the sterilization that is used between the batches, they could pose a problem.  We don't know.  But I think to dismiss this as a non-issue, and to dismiss it as an issue that -- well, we can't produce or we can't segregate this for whatever reasons, I don't think is in the best interests of the health of people in the United States.
		I mean, I don't think that this committee is really concerned about the health of the Europeans. I mean, we have Europeans who are angry, and we have Europeans who are upset.  We have them telling us that we are doing bad things here, but that is not the object of what is going on here to be very frank and open.
		We are charged with this issue, and we are not charged with a globalization.  I mean, when I hear all this stuff about globalization of the plasma products industry, it makes me shudder.
		It makes me feel like when I have these arguments with airplane designers and the airlines that they want bigger and bigger airplanes, so that I can get sicker and sicker every time I get on the airplane.	
		I want smaller airplanes, and I am not sure that this is all going in the right direction.  I mean, this is a big industry, doing it as efficiently as possible.
		But I a not so sure that this is such a great thing the way it has evolved.  Now, I am not saying that I know the answers, and I am not saying that I understand all this.  
		But with the bigger the batches, the bigger the problems sometimes, and if we look back on human pituitaries, this is why it all happened there, because with these enormous batches that were processed.
		So I just think that we need to step back from this for a moment, and I don't know the answers, and I agree with you, David, but I think that these are considerations.
		CHAIRMAN BOLTON:  Steve.
		DR. DE ARMOND:  Well, I think, Stan, that you really meant to say that you really care about the lives of individuals in Europe.  As a physician, you don't want them to get sick, but we really as physicians, we really care about everybody, regardless of race --
		DR. PRUSINER:  Of course.
		DR. DE ARMOND:  Even if they are French.  Being of French descent, I think I can say that.  But it seems to me that we are stuck in a sense trying to make recommendations to the FDA, and it looks like plasma is relatively safe, even from what we can understand so far.
		But we don't know the answer to that, but it does seem safe, and it looks like the processing process captures or somehow eliminates a lot of the prions.  The only issue I have is what additional thing would you recommend.  
		You could leave it like that and say we believe that the final product is clean, regardless of whether it comes from Europeans or from U.S. Citizens.
But we can do more.  I guess we could recommend further testing, and how would you recommend to do that, or what should be tested? 
		Do we test the equipment?  Do we look more closely at inside the equipment to see if there is infectivity?  We learned from these studies in Weissman's lab that you can't even wipe the infected particles off after multiple wipes.
		Even with sodium hydroxide, they stick to it.  So even a wipe test isn't going to tell you necessarily that there is PrP in the equipment.  And the other is that because you do have big batches, you can test the batches. 
		You can precipitate the proteins and concentrate them, and perhaps look for PrP.  But if you do those things and find that you are negative, and there is no PrP, are you then -- is that a test that you are assured that those batches are free of prions?  Stan, do you have any comment on that?  Is the negativity in a batch --
		DR. PRUSINER:  The problem is a volume problem.  You can only test a small volume, a small aliquot of any one of these products, or otherwise you use up the whole batch of what you made.  
		And you don't know that the prions are distributed homogeneously.  I think that is an issue that we have not discussed at all here.  I think that you don't even know that the prions are homogeneous themselves.
		There is no reason for them to be and that is what David Bolton was alluding to, which I felt was a very interesting observation and a very interesting comment, that when you have such heterogeneity that if you do this batch removal kind of -- you do it once, and then you do it by another technique, and then another technique -- and let's say the prions are in groups A, B, and C.
		You may each time be removing 10 to the 4th out of 10 to the 7th, but it may be Group A for each of these different processes.  And you may be left with Groups B and C, and you can't tell that based upon these model studies where you do these added removals and you now say we have a removal now of 10 to the 15th.
		DR. DE ARMOND:  So do I understand from that that are current testing procedures, even the most sensitive ones, will not be of help?
		DR. PRUSINER:  Yes.  I think when you think about this, you really need to go back to the source.  The source is the most important thing.  If we had a blood test that was a hundred percent, and that would tell us that there were no prions in the blood, and this person was not producing prions, that would be the very best way to do it.
		And, of course, that is the way that the plasma products industry operates when it can do that. That is what it does to make sure that there are no HIV particles floating around in the plasma that it is going to fractionate, and that is really the ultimate way to do it.
		DR. DE ARMOND:  So you would start with the fresh -- the blood that comes out, and take the buffy coat, because that would have the highest possibility of --
		DR. PRUSINER:  Well, yes, I guess so at this point.  But this has not been worked out, and so I think --
		CHAIRMAN BOLTON:  Yes, I think we want to avoid trying to work out specific details of things here.  We clearly do not have enough information to start proposing specific policies or recommendations in that way.
		DR. PRUSINER:  Exactly.
		CHAIRMAN BOLTON:  I think that there are a few general things that we can talk about.  I would like to suggest that one thing that I see clearly out of this is that industry representatives need to get together with the FDA, probably in consultation with this committee, and begin to look at this issue going forward.d.
		And what can be done, and how can it be done, and what studies need to be done, and what kind of validation tests are going to be acceptable, and how they can be done.
		We are not going to resolve that issue tonight.  There just is not enough time, and there isn't clearly enough information.  So what I would like to do though is to -- if anybody has any more specific comments that they would like to give to the FDA regarding the significance of the VCJD risk from this mixed process, and/or Peter, the second question, any additional steps that you think should be taken at this time to address the issue of common manufacturing lines. 
		Let's focus on those things for the next few minutes, and try to get that out of the way.  The third issue is the other specific recommendations that we can vote on, but if you can put in your mind things about the risk, and what is the significance of the risk in this process, and what additional steps can be taken or should be taken.
		DR. DE ARMOND:  I don't think we can do that because we don't have any data.  All we know is from what the industry tells us, is that it is a pretty clean process, and the final product, regardless of whether you run it in series, U.S. and European, and series, you end up with a clean product.
		And we have to believe that at this stage because we haven't tested the blood up ahead, or ahead of time, and we haven't tested throughout the system.  So what can we say?  That it sounds like it is all right.
		DR. LURIE:  I guess one observation that I have is that compared to the discussion on the blood, we are talking about many more products at least, and with very much less data.  We poured an incredible amount of attention and analysis on to the blood thing, and we don't have anything remotely like this.
		And really each of the products merits its own separate analysis.  Obviously, we can't do that here.  But what I think needs to happen is the FDA needs to call in everyone of the manufacturers of the plasma derivative that wishes to market their product in the United States, and literally go through the production sequence, every single step of it, and have them justify to them why that step is non-segregatable.
		If it turns out that it is a straightforward matter to be able to segregate for that particular step, then I think that the manufacturer should be encouraged to do that.  That's what I think we should be recommending.
		CHAIRMAN BOLTON:  Okay.  There is a recommendation.  Any additional recommendations, comments, suggestions at this point?
		DR. NELSON:  I think just like we talked about the supply issue with regard to blood, that needs to be considered here, too, because there are a critical group of patients that are going to die, or get sick, or have real problems.
		And there has been a shortage of IVIG and other products that has created problems, serious problems for a subset of patients.  And I think that needs to be taken into consideration.
		And I agree that anything that could be done to improve the theoretical or actual safety, and that is a real issue that was brought up, that here we are dealing with not one donor, but a pool of 10s of thousands, and we are dealing with one pituitary out of 10,000 or whatever.
		But that there might be because of that, and because of the fact that batches go into all of this equipment, I can see that even though there may not be a risk, if there is any infectious material in blood, in plasma, this is where it might show up.
		And I think we can be encouraged by the fact that there has never been hemophilic with Creutzfeld-Jakob, but of course the variant is not long enough.
		But still I think we really need to look at the people who need this product.  There could be recommendations made that would really jeopardize their health.
		CHAIRMAN BOLTON:  Dr. Davey.
		DR. DAVEY:  Yes, just a couple of comments.  I agree with Dr. Nelson.  I think it is important that these highly transfused populations over many years have not demonstrated any sign of the disease, and I think that is important information, because this has been going on now for several years.
		And what I have heard -- and again maybe similar to this morning, but we do have some fairly distinct facts on the table.  Number 1, I heard the industry say that they are robust in activation processes.
		I am not an expert here, but I was impressed by what they demonstrated and some of the comments from people around the table.  Number 2, I hear that the change at this point is an immense undertaking of money and time, hundreds of millions of dollars, and many, many years.
		Thirdly, I have heard that any steps along this line to segregate, or to build new facilities, more clearly have an impact on the supply.  And I think we heard this morning -- and we have heard from some of the others now -- that the supply is very tight for IVIG and for Factor VIII, and patients will clearly suffer.
		And also I would perhaps disagree with some of the comments around the table.  When we can harmonize with our European colleagues on these issues, we should.  There is no reason to think that we have a monopoly on how to do this.
		And when we can harmonize with Europe, work with them on a single standard on a way to approach this, we should.  We can't do it all the time, but when we can, we should.  
		So I would leave the situation, in terms of segregation, alone right now, work on new tests, and have the industry consider what they can do to improve safety whenever possible, but segregating it seems to me seems to make no sense.
		DR. DE ARMOND:  That was very clear and lucid, and I think ideal.
		DR. KATZ:  Let me bring it to a clinical level.  Was it in the fall of '97 that IVIG went away?  Was that when it was?  That's when I got a satellite beeper, because my blood center holds the inventory for our system hospitals.
		And I have been approving every allocation of intravenous immunoglobulin since that time.  There have been times when we had a little more and times when we had a little less.  
		I have had to tell people with hypogammagloblin anemia that they only get a half a dose this month on more than a few occasions.  We have had to recommend alternate therapy, including invasive procedures like plasma exchange, for people because there wasn't enough IGIV to treat their polyneuropathy or whatever else it happened to me.
		So I will be very, very cautious about taking a step like segregation now that will take years to bear fruit if retooling is required, and anticipating the availability of testing I hope in that interval, I would be very, very cautious about taking that step.  The supply is very tight.
		CHAIRMAN BOLTON:  Very good.  Additional comments?  The final question -- and I am assuming then that no one has any more comments from issues of the -- from questions one and two.
		The FDA would like to know more or less informally -- and this is not something that we have to vote on these specific things, but they would like to know whether or not some of these other steps listed in A through D are things that should be considered at this time.
		And we can just talk about these generally, or I think we can dispatch with them fairly quickly.  Labeling to identify campaign manufacturing, involving potential exposure to European plasma.  Should that be changed?  Should the labeling be changed to indicate some additional risk.
		Should additional decontamination procedures be used?  Should the use of dedicated manufacturing lines -- well, I think we discussed that and it seems at least in my opinion to not be warranted at this time.  And any other measures.  
		So I guess let me just put my comments out there.  The labeling at this time to me seems to be adequate, although it would be perhaps worthwhile for the FDA and the industry representatives to discuss that.
		The use of additional decontamination procedures I think needs to be examined, but they really need to be validated in some way before they are launched into.  
		And the question there, I think becomes one of -- and I don't know how this works, but if that would affect the licensing situation.  Is that something that has to be revisited.  So those are my questions.
		DR. NELSON:  I may have misinterpreted it, but my interpretation of the labeling is that there is labeling already warning of the risk of theoretical CJD.  But there isn't labeling that this particular product was campaigned if you will.  
		And I think what they are asking is should an additional label identify this batch, as opposed to another one.  That there was a different sort of potential or a different mixing.  
		And I think that maybe there is something to be said for labeling, because these are patients who desperately need a product, and they maybe should be able to make a choice of do they want this, even though the risk is not defined.  
		Maybe it is close to zero, and maybe theoretical, and maybe a long incubation period, but at least they know what they are getting into.  And maybe there is an argument to add something to the label of a product that was manufactured with mixed --
		CHAIRMAN BOLTON:  Does anybody else agree with that?  Other comments?  Stan.
		DR. PRUSINER:  Yes, I agree.  I think it is a difficult product, and there are people in the world who would choose one over another.
		DR. NELSON:  And they should have the right to choose.
		DR. PRUSINER:  I agree.
		DR. NELSON:  If they don't want to get sick tomorrow, and take the risk --
		DR. PRUSINER:  I agree.
		CHAIRMAN BOLTON:  That's something that could be implemented with very little cost.  Additional comments?
		DR. DAVEY:  Well, I am not sure that is a great idea.  If we are not going to feel that we need to segregate, and if we feel that the process is robust enough in their activation, then why do we need to set up a standard of labeling that is going to scare some patients that they are getting some product that has additional risk over another product when we can't really say that.  I think the labeling now is adequate, and I would leave it alone.
		DR. PRUSINER:  Well, I would like to respectfully disagree with you completely.  I think you are wrong.  I now that I would want to know.  I would want to know if I had a child, and I certainly would want to know that information.
		And I think for you to not tell me that information would be terrible, and for you to have prevented me from knowing that information if I had a child who was a hemophiliac would be terrible.  
		DR. DAVEY:  Well, we have to respectfully disagree, Dr. Prusiner.
		CHAIRMAN BOLTON:  Bruce.
		DR. EWENSTEIN:  Well, I was going to say that one of the mistakes that we made in the hemophilia world years ago was not being totally forthcoming, and I would certainly come down on the side of trying to explain as best we can what we are talking about here.
		And if you are talking about labeling material as having been derived from outside the U.S., I think that is a concept that could be explained on a label to the average patient.
		And for many plasma derivatives, and not for all, but for many of the derivatives that we are talking about, whether it is the Alpha One product.
		And to some degree, IVIG, and certainly for the coagulation factors.  These are very sophisticated patient groups.  They have organizations that can help explain what we are trying to say on the label as well.  So I would favor transparency, in terms of what is in a product.
		CHAIRMAN BOLTON:  And where it was processed or how it was --
		DR. EWENSTEIN:  That's what I mean, in terms of where it came from, et cetera.
		CHAIRMAN BOLTON:  Peter.
		DR. LURIE:  My general instinct is to agree with that, but I guess my question is how does this actually work?  I mean, where is the label, and how is it that the patient gets to see the label?  What is the mechanics of that?
		DR. EWENSTEIN:  Well, it certainly is very different for something like Factor VIII, where they take it at home, and they open the box and there is the label. 
		For some products -- you know, if you are getting albumin in the hospital in the ICU, you don't know that.  You don't see the label and I understand that that is a problem, and the only person who could explain that to you would be the ICU doctor.
		CHAIRMAN BOLTON:  Steve.
		DR. DE ARMOND:  Aren't there already FDA guidelines about labeling products, whether they are from human or animal, and the country of origin?
		DR. NELSON:  Yes, there are labels, but they are not with regard to this particular issue of mixing a source or two.  It doesn't specify as I understand this level of detail at the moment.
		CHAIRMAN BOLTON:  There are specific risk aspects of the labeling currently, but they don't address this mixed process issue.  But it could be written to do so.  I don't think that is an insurmountable problem.  
		Additional comments or suggestions?  If not, I hate to say, but we may be done.  Is there no more?  If not, then I believe that we would stand adjourned for this evening.
		(Whereupon, at 8:24 p.m., the meeting was concluded.)