ADVISORY COMMITTEE




             FRIDAY, FEBRUARY 13, 2004


This transcript has not been edited

or corrected, but appears as received

from the commercial transcribing service.

Accordingly the Food and Drug Administration

makes no representation as to its accuracy.


      The Advisory Committee met at 8:00 a.m. in the Kennedy Ballroom of the Holiday Inn Silver Spring, 8777 Georgia Avenue, Silver Spring, Maryland, Dr. Suzette A. Priola, Chairperson, presiding.



SUZETTE A. PRIOLA, Ph.D.         Member

JOHN C. BAILAR, III, M.D., Ph.D. Member

VAL D. BIAS                      Member

ARTHUR W. BRACEY, M.D.           Member

LYNN H. CREEKMORE, D.V.M.        Member


LISA FERGUSON, D.V.M.            Consultant


R. NICK HOGAN, M.D., Ph.D.       Member

ALLEN JENNY, D.V.M.              Consultant

RICHARD T. JOHNSON, M.D.         Member

RIMA KHABBAZ, M.D.               Consultant

JEANNE LINDEN, M.D., M.P.H.      Consultant

KENRAD NELSON, M.D.              Consultant

GEORGE NEMO, Ph.D.               Consultant

STEPHEN R. PETTEWAY, JR., Ph.D.  Non-Voting Industry                                   Representative

JAMES SEJVAR, M.D.               Consultant

SIDNEY WOLFE, M.D.               Consultant

WILLIAM FREAS, Ph.D.             Executive Secretary



KAREN MIDTHUN, M.D.              CBER

WILLIAM M. EGAN, Ph.D.           CBER




MORRIS POTTER                    Center for Food

                                 Safety & Nutrition

DOROTHY SCOTT, M.D.              CBER

ALAN WILLIAMS, Ph.D.             CBER


                    AGENDA ITEM               PAGE



William Freas................................... 3



Dorothy Scott................................... 5

QUESTIONS/COMMENTS:............................ 19



Alan Williams.................................. 21

QUESTIONS/COMMENTS:............................ 33



Melissa Greenwald.............................. 44

QUESTIONS/COMMENTS:............................ 50




William Egan................................... 54

QUESTIONS/COMMENTS:............................ 66



Gerald Feldman................................. 79

QUESTIONS/COMMENTS:............................ 90



Martha O'Lone.................................. 95

QUESTIONS/COMMENTS:........................... 105



Morris Potter................................. 107

QUESTIONS/COMMENTS:........................... 111



Bill Drohan - Clearant, Inc................... 118

Chris Penet - Genencor International.......... 122

Hal Baker - Pall Medical...................... 126

Robert Rohwer - Public Citizen................ 130

Patrick Crotteau - Inamed..................... 132


QUESTIONS:.................................... 133


COMMITTEE DISCUSSION:......................... 138



Suzette Priola................................ 202



                                         8:05 a.m.

            SECRETARY FREAS:  Good morning.  I would like to welcome you back to this our second day of the Transmissible Spongiform Encephalopathies Advisory Committee meeting.  I would like to go around and introduce to you the survivors who made it through yesterday's session.  They are, starting at the end of the table, Dr. Richard Johnson, Professor of Neurology, Johns Hopkins University.  We know who she is, she is the star of the show from yesterday, Dr. Lisa Ferguson, Senior Staff Veterinarian, U.S. Department of Agriculture.  She will be right with us.  She didn't make it.

            Next is, and if you would raise your hand, Dr. Arthur Bracey, Associate Chief, Department of Pathology, St. Luke?s Episcopal Hospital.  Next, we have Dr. Rima Khabbaz, Associate Director of Epidemiologic Science, National Center for Infectious Diseases.  Next, we have Dr. George Nemo, Division of Blood Diseases and Resources, NIH.  Next, we have Dr. John Bailar, Professor Emeritus, University of Chicago.  Next, Dr. Sidney Wolfe, Director of Public Citizen Health Research Group.

            Around the corner we have Dr. Nick Hogan, Associate Professor of Ophthalmology, University of Texas.  In the empty seat we will soon be joined by Dr. Kenrad Nelson from BPAC, who is the chair of BPAC.  Next, we have the Chair of this committee, Dr. Suzette Priola from the Rocky Mountain Laboratories.  At the corner of the table we have Dr. Allen Jenny from the National Veterinary Services Laboratory.  Around the corner we have Dr. James Sejvar from CDC.  Sitting next to him is Dr. Stephen DeArmond, Department of Pathology, University of California.

            Next, we have Mr. Val Bias, Co-Chairman, Blood Safety Working Group, National Hemophilia Foundation.  Next, we have Dr. Pierluigi Gambetti, Professor and Director, Division of Neuropathology, Case Western Reserve.  Next, we have Dr. Lynn Creekmore, Staff Veterinarian, APHIS, USDA.  Next, we have Dr. Jeanne Linden, Director, Blood and Tissue Resources, New York State Department of Health.  And at the end of the table, Dr. Stephen Petteway from Bayer Corporation who is our industry representative.

            The Conflict of Interest statement that was read into the public record yesterday at the start of the meeting pertains to today as well and with no changes.  So, Dr. Priola, I turn the meeting over to you.

            CHAIR PRIOLA:  Okay.  Thank you, Bill.  Today's agenda is really a continuation in many ways of yesterday, so many of the discussion points that were raised yesterday will probably apply somewhat to what we are discussing today.  But I think we want to particularly focus on one of the points that came up yesterday, and that is that given the current situation, we want to assess the current safeguards that FDA has in place, see if there are any reasons based upon current scientific knowledge to change those safeguards or address how changes could be made to those safeguards, what the feasibility of that would be, always, of course, keeping in mind the risk- benefit ratio, and also to consider how to obtain or continue to obtain relatively pure and safe bovine materials from other countries in a way that is similar to what we have done for other countries that have scrapie in sheep and goat.

            So with those points in mind, I think we'll go ahead with the first speaker, Dr. Dorothy Scott.

            DR. SCOTT:  The title of my talk is current CBER safeguards for blood products, our approach to products containing or exposed to bovine materials.  Now, I do want to talk about a few other things as well.  Some of these are in your package.  One of them is not simply because it was published after the package came out, but the --

            UNIDENTIFIED SPEAKER:  We can't hear you.  Turn your microphone on.

            DR. SCOTT:  But the other thing in particular I want to mention is European policies that are relevant to this discussion that are a model or at least present some potential solutions to some of the problems that we think we may encounter.  And after I speak, Dr. Williams will be talking about safeguards for human blood with regard to variant CJD.  Next slide.

            Just to very briefly review, and this doesn't apply to blood, obviously, but to all of our products.  There are various strategies for minimizing the risk of BSE exposure to products, this includes how you source your materials, the geographic source of the animals that you use, the tissue source from the particular type of animal, the tissue collection technique, which can be optimized to minimize the risk of cross-contamination of low-risk tissues with high- risk tissues, and herd source and monitoring may also be important depending on the country that one is sourcing from.

            In addition, there is a possibility for many products of TSE clearance during manufacturing.  And something that we won't be discussing much today, but still is important is how equipment is cleaned between batches, particularly batches with intermediate or high-risk material in them.  Next slide.

            So, first, I'm going to go through what we in CBER and particularly in the Office of Blood have already done prior to the discovery of BSE in this country, and the description of the presumptive transfusion transmission of variant CJD.  From 1993 forward, we have sent letters to manufacturers recommending that they not source bovine materials from BSE countries.  But as BSE is detected in more countries, instantaneous source switching becomes very difficult, because it takes time to locate and contract new sources of material and also raw materials have to be qualified.

            You have to be sure that your new source provides you with the same manufacturing or comparability of your product as the old source did.  And then as was pointed out yesterday in the open public hearing, there can be availability concerns.  In other words, it may be difficult to source from other countries if there isn't very much there or at least if it doesn't meet our needs, and I think that discussion was about one of the bovine blood products.  Next slide.

            I just want to give you a sense of the scope of blood products that contain or are exposed to bovine materials, and these are just some examples, and I have divided them into four sub-categories.  First is active substance.  So, in particular, some of our hemostatic products contain bovine thrombin, bovine aprotinin, and bovine gelatin derivatives.  There also may be excipients or adjuvants of bovine or ruminant origin.  However, this is a very minor category.

            Certainly raw starting materials and reagents are important.  As you know, we regulate not only blood-derived plasma derivatives, but recombinant products.  In addition, some of our plasma derivatives are exposed to monoclonal antibody columns.  So all of those require cell culture reagents, and some of these that are commonly used are fetal bovine serum, bovine insulin, and bovine serum albumin.

            Manufacturing reagents may also have some bovine materials.  In particular, tallow derivatives, and I just mention polysorbate 80, which is used for viral inactivation, that can also be sourced from plants.  Bone derivatives, typically gelatin, again.  And equipment qualification materials may contain bovine source material.  And I am talking about what is used for media fills.  This is actually media that is used to test the integrity of an aseptic filling system at the end when you are filling your product into vials.  Okay.  Next slide.

            So, just to summarize, what we have done is we have requested, as I said, our manufacturers to source bovine materials from non-BSE countries, and we have also encouraged them to use non-bovine materials whenever possible.  And indeed we have had some switches to non-bovine materials.  In addition, our IND and BLA product reviewers assess the presence of ruminant materials in any of our new products, their geographic source, their tissue source, and we make recommendations accordingly.  In the past, typically, these recommendations have been sourced from a BSE-free country.  Next slide.

            This Committee has reviewed a couple of topics that are relevant to these issues, and I'm just going to mention two of them.  One is this Committee reviewed facility and equipment cleaning methods with respect to TSEs, very recently July 18, 2003, and you concluded that the current facility cleaning methods, and I'm speaking of plasma derivative facilities, e.g., the use of solutions of sodium hydroxide or sodium hypochlorite followed by extensive rinsing cycles are adequate to minimize the possibility that an infectious dose of the vCJD agent, that's what you were considering then, but we don't really recognize the distinction between that and the other TSEs in this context yet, may be carried over from one manufactured lot into the next.

            On inspections, which are typically held every other year for our plasma facilities, raw material sourcing is confirmed, and facility equipment cleaning methods are assessed.  Of course, some companies are inspected more often than every two years.  Next slide.

            In addition, in February of 2003, this Committee endorsed our consideration of labeling claims for TSE clearance in the manufacturing of plasma derivatives that would be based upon specific demonstration of TSE removal during manufacturing.  And we have encouraged such submissions in the Office of Blood, and we have received some such, and we are in the process of evaluating those.  Next slide.

            I can't show you any of those studies today, but I just want to say that for plasma derivatives there have been a number of studies and most of them have been published in peer reviewed literature.  You can just get a sense of them from their titles.  In addition, by and large, these were funded or supported by manufacturers.  So the methods that are used are typically down-scaled manufacturing processes.  So you can just go on to the next slide, which is more of the same.

            But you can see that there is a literature that is accumulating now on this, but, of course, when we receive a submission, we ask for a great deal of additional detail.  Next slide.

            I also want to mention risk communication and that we have labeling with regard to CJD for plasma derivatives and blood products.  Just in general, the labeling is intended, in a case like this or in the case of viral transmission, to provide an estimate of the risk of transmission of infectious agents.  This is usually a general estimate, not a numerical estimate.  It may discuss, labeling may discuss, measures taken to reduce risks.

            Right now, our TSE-related labeling does not do that.  In the case of viruses, labeling may include results of clearance studies, and overall this allows the public to make a more informed decision about risk-benefit.  Now, labeling claims for viral clearance typically undergo a very thorough scientific and regulatory review prior to approval, I should put.  And labeling claims for pathogen removal in the past have been based upon rigorous and specific scientific evidence.  Next slide.

            This is our current recommended labeling.  This is through guidance for blood products, because this product is made from human blood, it may carry risk of transmitting infectious agents, e.g., viruses.  And, theoretically, the CJD agent.  Now, you will notice that maybe this looks a little passe to you.  We do have CJD as sort of encompassing CJD and variant CJD.

            And based on some of the discussions we've had and on the presumptive transfusion transmission in the U.K., some people might question even the use of theoretically.  But that's a discussion, I think, for another Committee session and not for this one.  But I just want to point out that this is the kind of thing that we expect to be bringing back to you.  Next slide.

            Now, I'm just going to mention some of the European policies that are relevant to these topics.  And the EMEA has proposed guidelines for TSE clearance studies.  This is part of a discussion paper, so they don't have a guidance for this now.  But they are struggling with the same issues that we are that to do a TSE clearance study, you're still dealing with a lot of unknown, since we don't know what form the agent actually takes in blood.

            These studies are difficult to perform.  There is a question of how often a bioassay should be done versus a PrPsc assay when you are assessing the amount of clearance that you have, and there are a number of other issues that make these studies difficult to know how to do, and not necessarily difficult to interpret, but difficult to bridge over to what may actually be relevant.  Nevertheless, I think that we all need to do the best that we can.

            This is what they propose, and we already request this.  The use of actual production materials for scale-down clearance studies and appropriate scale-down models.  They have recommended that spiked infectious material not be more than 10 percent of the final volume.  Obviously, that is going to affect the characteristics of the matrix that you use.  Studies should be in accordance with GLPs.  Partitioning of infectivity should be demonstrated, in other words, to make a claim.  And interestingly, infectivity reduction factors of less than one log should be considered insufficient.  This is a number that is a bit on the lower side, if you consider the precision of some of the assays that are commonly used.  Next slide.

            But I present this really as a model that has a lot of benefits.  Combined-step studies, in other words, throughput type experiments should help support the decision to accept whether or not two or more steps are additive.  And combined-steps are important where a prior step might alter the context or infectivity of the TSE agent.  For example, a solvent detergent treatment might alter the properties, the physical chemical properties of the TSE agent that you are using and might affect its removal by a subsequent step.  So that's called "conditioning."

            They requested a rationale be given for the TSE strain selected in these experiments.  They don't actually mandate a particular type of spike be used, but they recommend microsomal fractions.  Others can be used.  A rationale needs to be provided.  Next slide.

            They suggest bioassays, but PrPsc assays used to identify steps that are most like to remove infectivity, and they suggest that studies should focus first on products manufactured by processes that appear to have the lowest overall capacity to remove TSE agents.  Next.

            They state that all manufacturers must critically evaluate their processes in light of published data, consider modification of processes and that it is highly desirable that manufacturing steps with potentially highest removal capacity are experimentally investigated.  So again, what I'm trying to convey with this is that these studies aren't mandated.  Next slide.  So far.

            Now, I want to switch topics a little bit, but this might be one of the more important topics to this Committee today.  And that is the Note for Guidance that, as I mentioned, you don't have in your packet, because it was just recently published.  It wasn't even up on the website when I got back from the EMEA in Europe.  But this is a Note for Guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products, the topic that we are discussing.

            And this is a guidance, and therefore it has the force of law in the European community.  Very briefly, this has several detailed parts, but initially they suggest or they say that a risk assessment for animal sources in veterinary medicinal products must be made.  And this has to take into account the sourcing of animals.  And when I say animals, I mean cattle, sheep, goats, any animals that are susceptible via oral feeding to a TSE agent.

            Okay.  So this doesn't cover just cattle.  Animal sourcing, the source of the tissue used, TSE clearance manufacturing, just what we have been talking about.  The route of product administration, the quantity of animal material in the final product, the maximum therapeutic dosage, and, presumably, and this is also the frequency of the dosage, since some of our products are taken lifelong, and the intended use of the product and its clinical benefit.  Next slide.

            Getting into the details, they recommend that source animals are sourced from countries with the lowest possible GBR risk, and I will mention what the GBR risk is.  This is defined by the Scientific Steering Committee on Geographic BSE Risk, unless the use of material from higher GBR countries is justified.  So a GBR I country is where BSE is highly unlikely.  This would be, for example, Australia and New Zealand.

            A GBR II country is where BSE is unlikely, but not excluded.  A GBR III country is a country where BSE is likely, but not confirmed or confirmed at a lower level.  That is less than 100 animals per million cattle.  Okay.  And a GBR IV country is more than that.  This document also brings up the concept of negligible risk herds and that those may be considered in conjunction with the GBR classification.

            So what is a negligible risk herd?  Well, actually, the Scientific Steering Committee published in 1999 what constitutes a negligible risk herd for BSE.  And such herds would be comprised of cattle that had no meat and bone meal for at least eight years in that herd.  And they can't be fed any fish or poultry meat and bone meal.  Diet records have to be kept.  Food tracing has to be possible.  There can't be any other domestic species on the property that are fed meat and bone meal, particularly, pigs and poultry.

            They can't import into the herd except from herds that are negligible risk or better, that is GBR I.  Every animal has to be traceable.  All animals have to be proven to have had no meat and bone meal through their entire lifetime, and they can't be fed even tallow, gelatin, or waste.  And all brains of cows that are killed at an age of greater than 1 year-old need to be examined at slaughter.  So that's a negligible risk herd.  And this is the website where that is.  Next slide.

            Now, on to the source tissue, this is subdivided into Categories A, B, and C, and they state that sourcing from Category A tissue shall not be used unless justified.  In other words, they leave possible the opening that one might actually have this as the only source for a certain product, but it would be very difficult, perhaps, to justify it.

            Category A high infectivity, SRM-like materials, lower infectivity tissues include a lot of the tissues that we and others use in medicinal products.  So this is bovine blood, lung, liver, lymphoid tissues, and so on.  And Category C is things like skin, hair, and so on.  I have a list, but I'm not going to go through all of that.  It's four pages long.  Next slide.

            The additional source tissue considerations in this risk assessment include the possibility of cross-contamination of low-risk tissues with high-risk tissues.  The stunning and slaughtering techniques that are used, you need to use ones that assure that brain tissue doesn't contaminate other tissues.  Some of the stunning techniques actually do that.  And measures need to be adopted to avoid contamination during collection of tissues.  They also stated it is prudent to source from young animals, and procedures should be in place to ensure auditing suppliers of starting and raw materials of these ruminant materials.  Next slide.

            This also has special sections for collagen and gelatin.  I'm not going to go through all of these, but some of them, for example, sourcing of amino acids or gelatin from GBR free countries, you have to use certain processing techniques or show that other processing techniques are going to lead to clearance of TSE agents.  But for bovine blood derivatives, I just mention that in particular they specify that all batches have to be traceable to the slaughterhouse and to the farms of origin and that GBR I and II source countries should be used, unless otherwise justified, and that the stunning methods must also be described.

            I think that may be the end.  Yes.  Thank you for your attention.

            CHAIR PRIOLA:  We have a few minutes for questions for Dr. Scott if anyone has questions.  Dr. Wolfe?

            DR. WOLFE:  Just a quick question.  Dr. Scott, you mentioned that one of the criteria for this low-risk would be examining the brains of all the animals after slaughter.  Is that before or after release of the product?

            DR. SCOTT:  It doesn't state.  One would presume that would be before.

            DR. WOLFE:  But we don't know?

            DR. SCOTT:  That's correct.

            DR. WOLFE:  If we could find out, that would be useful.

            DR. SCOTT:  Right.  I happen to have the document here, so I'll read it again and let you know if I can see otherwise.

            DR. WOLFE:  Okay.  Thanks.  That would solve a lot.

            DR. SCOTT:  But I believe it doesn't.

            DR. WOLFE:  Okay. 

            CHAIR PRIOLA:  Dr. Bracey?

            DR. BRACEY:  With respect to the examination of the brain, this would be a microscopic examination?

            DR. SCOTT:  Presumably, this would be according to one of the approved tests.

            DR. BRACEY:  Okay, with the test.  Okay.

            DR. SCOTT:  Including, you know, histochemistry.

            CHAIR PRIOLA:  Okay.  Thank you, Dr. Scott.  The next speaker is Dr. Alan Williams.

            DR. WILLIAMS:  Good morning.  I'm going to discuss FDA recommended safeguards for minimizing the risk of variant CJD from blood products, namely the deferral of blood and plasma donors based on potential risk of BSE exposure.  In several meetings of this Committee during 1998 and early 1999 time frame, there was clearly much discussion about increasing awareness of the BSE epidemic in the United Kingdom and cases of variant CJD in the U.K. and in France, and the potential impact on the safety of the U.S. blood supply.

            That came in concert with recognition that there were no screening tests potentially available to screen donors for prion disease, nor were there any specific targeted measures to assess potential exposure to contaminated materials.  Next slide, please.

            At the meeting of the January TSE Advisory Committee, the Committee felt strongly that there was a need to begin to consider deferral based on dietary exposure to BSE, but was uncomfortable, at that point, of making a specific recommendation due to potential impact on availability of the blood supply, which is fragile in the best of times.  So at that early 1999 meeting, it essentially commissioned a survey on the travel patterns of blood donors to determine information that would help to make an informed policy decision regarding donor deferral.

            That survey took place between February and May of 1999.  It involved a survey of 19,000 blood donors at 12 blood donor sites.  It was conducted in really very good collaboration between the American Red Cross, America's Blood Centers, the AABB, the National Heart, Lung and Blood Institute through the REDS study and other participants.  We got about a 50 percent response rate to that survey, which collected information about travel to the United Kingdom based on intervals from which we could determine cumulative time of exposure.

            Based on the results from those data which were presented at the June '99 meeting of the TSE Advisory Committee, the Committee recommended and subsequently through draft and final guidance, FDA recommended to industry in November of 1999 donor deferrals related to dietary risk to BSE, and these recommendations included travel or residence in the United Kingdom for more than or equal to six months between the period of 1980 to 1996, reflecting the period of the BSE epidemic in the United Kingdom, and the 1996 time frame representing when the Committee felt that food chain controls in the U.K. were adequate to assure with reasonable certainty that dietary risk had been minimized.

            In addition, donors who had received bovine insulin sourced in the U.K. after 1980 were also subject to referral.  And product retrieval and lookback procedures were recommended if a donor was later discovered to have variant CJD.  Now, based on the survey information the estimated donor loss for these deferrals was 2.2 percent.  And there really was quite an intense discussion about, you know, what an impact 2.2 percent loss would have.  And that was very much a risk to donor loss consideration, which resulted in that recommendation.  Next slide.

            Now, in further discussions and increasing awareness of the spread of BSE throughout Europe, we continue to work with the results from this survey as well as information that was being collected concurrently and made estimates for what residual risk might still remain in the donor population.  And this is a pie chart shown at one of these meetings reflecting the proportions of risk estimated to come from different potential donor exposures.

            You see, there is a residual risk for travel to the United Kingdom, because clearly most donors who travel to the U.K. don't stay as long as six months, and you have a cumulative consideration of donors who have been there a few days up to a five month period for which the deferral would not capture.  Similarly, recognition of the epidemic in Europe and travel to Europe was estimated to comprise 14 percent of residual risk.  Based on a risk-weighted model in which Europe, based on the best data available, which was from Switzerland, would have a risk proportion of approximately 5 percent to the risk in the U.K., so this was a risk-based model.

            In addition, about 25 percent of the New York Blood Center blood supply was imported from Europe, and this was estimated to comprise about 11 percent of the risk at that time.  Also recognized was that the Department of Defense imported substantial quantities of beef from the U.K. during the period of interest in norther Europe from 1980 to 1990 and in southern Europe bases from 1980 to 1996, and also added to the risk equation.  Next slide.

            Based on those considerations and an additional hard look at the survey data, FDA presented a series of options for potential additional safeguards, and these were discussed at the TSE Advisory Committee in June of 2001, and based on their recommendations, guidance was subsequently issued to industry in draft, and then in final form in January of 2002.  And this added donor deferrals for risk to BSE exposure in Europe based on five years cumulative exposure in Europe.

            It tightened the U.K. donor deferral.  It ratcheted it down from six months to three months.  And because of concern about donor loss and the impact of an acute implementation, implementation was conducted in two phases, with the first phase, namely the U.K. deferral, recommended for completion by May of 2002 and the European deferral by October of 2002.  And again, based on the survey data, this was estimated to result in a 90 percent reduction of that total cumulative risk that you saw in the pie chart with a loss of about 5 percent of the donor base in this second recommendation, but then combined with the 2 percent realized in the initial U.K. deferral about 7 percent total donor loss.  Next slide.

            I went over this mostly in discussing the last slide.  Briefly, the U.K. deferral was tightened up to three months residence or travel in the U.K. cumulative between 1980 and 1996.  The five year residence or travel in Europe was specific to blood donors, for donors of source plasma it was felt that using the same deferral for all plasma donors would have undue supply impact, so this criteria was applied only to France, which was felt to have 5 to 10 percent total consumption of UK beef, and at that time it also had several recognized variant CJD cases.

            The deferral for exposure on U.S. military bases in Europe was for six months, and this had differing time frames between the northern and southern distinction.  I think in practice blood centers found it easier to simply pool these and defer for the 1980 to 1996 time frame, but FDA did create the option to try to preserve donor loss where possible.  There was also deferral for transfusion in the United Kingdom from 1980 to the present and again receipt for bovine insulin sourced in the U.K.  Next slide.

            Now, the impact of these deferrals has been a topic of a lot of discussion, and, in part, that is due to the fact that there is really no precise way to measure a deferral, the impact of a deferral like that after it has been put into place.  The reason being that deferral happens at many points.  Once a deferral is implemented blood centers make this known to their donor base.  When donors call for appointments, often this information is given over the phone.  It is sent to the donors.

            Clearly, it is advantageous to defer the donor at the earliest time possible when appropriate.  So a lot of the deferral happens before the actual blood collection, and there is also self deferral at the blood collection site, as well as deferral during the interview donor screening process.  And, in fact, while this gets a lot of attention, it is actually one of the smallest components of the donor deferral impact.

            The travel survey estimated a 5 percent overall donor loss from the second phase of deferral with a higher loss in the coastal areas, perhaps as much as double in the east and west coast, and specific to the New York Blood Center, this would be a potential 10 percent donor loss combined with the 25 percent loss from the inability to use Euroblood in the future.  In fact, this observation appeared to be realized once the deferral was implemented, but something not realized at the time was that geographic areas which had high concentrations of military donors were very hard hit.

            We did attempt to capture information from military donors in the very short time frame that we had to run the survey, but, in fact, military populations don't respond very well to surveys.  We had about a 10 percent sampling rate, and we knew it would be excessive, but we really couldn't create estimates.  But, in fact, in subsequent discussions that was, in fact, one of the biggest surprises from implementation of the deferral.

            So the observed onsite deferrals, as I mention, small components, potentially, of the total deferral ranged from 0.1 percent to 3.5 percent as presented by blood centers subsequently.  And this was discussed in some depth at the June 27th meeting of this Committee.  Next slide, please.

            Okay.  I'll just hold on that for a second.  The New York Blood Center presented its experience.  As I mentioned, it was estimated that 25 percent of the blood that was imported from Europe would be lost and 10 percent deferral, based on the survey estimate.  In fact, they realized a 13 percent travel deferral combined with a 25 percent.  They anticipated a lot of this loss in New York, and it secured alternate supply agreements.  It also implemented a very well designed and assertive recruitment program and managed to get through the period and still provide necessary blood supply for their hospitals.

            However, it clearly did make a significant dent in the donor base, and I think in holiday periods subsequently, all blood collectors have felt the pinch of having sufficient blood supplies in the traditionally shortage times.  The American Red Cross implemented a deferral that was slightly different than the FDA recommendation.  The primary difference being deferral for six months cumulative time spent in Europe as opposed to five years, which was the FDA recommendation.  This was implemented in October of the previous year.

            This also followed an extensive recruitment campaign, and losses within the Red Cross onsite deferrals range from .2 to 1.1 percent overall.  But again, some areas like the Norfolk area and the Alabama collection sites were particularly hard hit because of high military populations.  Now, America's Blood Centers also presented at that meeting and showed a range of .3 to 4.6 onsite deferral and presented information from a survey conducted prior to the implementation of the deferral at blood systems, which estimated a 3 percent overall loss, but as high as 7.7 percent in areas of northern California, again related to the military populations.

            ABC maintains a blood monitoring system on its website called a stoplight system with red representing one day supply, yellow two day, green three day supply, and clearly that system has shown that really an uncomfortable percentage of ABC sites have been at a one and two day supply over the past couple of years, and I think this factor was mentioned by Colonel Fitzpatrick in his discussion yesterday reflecting, you know, that there is, in fact, a long term impact of trying to maintain the blood supply in the face of laboratory and donor deferrals.

            And then finally, the military presented their experience.  They anticipated and realized an approximately 18 percent loss of donors due to these donor deferrals.  They combined this with a major recruitment effort, and due to a very high penetration rate of donation within base staff, their donations actually rose subsequent to this deferral by 9 percent.

            I think it is important to mention that while the blood supply has been termed as being generally adequate for patient needs, and this was reflected in a GAO report in July of 2002, there have been a lot of discussions, for instance, at the Advisory Committee for Blood Safety and Availability, that the blood supply is fragile and some of the holiday and summer periods that are being experienced really show not just regional shortages, but also potential national shortages, and there have been national appeals made in both holiday periods over the past two years.

            So there is concern about the, you know, ultimate degree to which the blood supply is resilient and could be made up by additional recruitment, and this recruitment more and more requires resources that could be placed in other areas.  So there is concern really across the board at the difficulty of maintaining adequate supply in the current situation.

            I wanted to mention briefly, I think the donor survey that I referred to probably could not have been conducted, certainly not conducted as well without the presence of the NHLBI supported Retrovirus Epidemiology Donor Study.  This study ran its first phase, a long phase, until, I think it just ended, near the end of 2003, and it is embarking on a new funding period.  That was crucial in supporting that survey, and I'm also just going to show a brief bit of data which I think will help assess the ultimate impact of these deferrals.

            Briefly, the first phase involved five REDS participants and Westat, Incorporated, which is the coordinating center.  Next slide.

            And one of the key data collection elements within REDS is that all donors and all donations at the five sites report additional demographic information, which has really been a gold mine of information for relating to test results and many other factors.  Next slide.

            One graphic that I did want to show you, and this resulted in a discussion with the REDS group, that, perhaps, given this database, we should give a hard look at some of the long term changes in the donor base resulting not only from the donor deferrals related to BSE exposure, but due to implementation of new laboratory tests and so forth.  This is just a fairly simple graphic of the percentage of repeat donors providing donations from 1991 to the year 2000.

            78 percent of the blood supply made up of repeat donors in 1991 to a high of 82 percent in 1993, dropping back down to close to 76 percent in 2000, and we don't have the '01 and '02 data, but one could presume that these figures may even be lower because we anticipated that the BSE deferral would hit hard at repeat donors.  So I think there needs to be additional analysis of this sort to look at the long term impact of these sorts of interventions and assess the dynamics with respect to the blood supply.

            One final note is that BSE, we could create a policy resulting in intervention to protect the blood supply from U.K. exposure and, theoretically, BSE exposure in Europe.  We are not prepared at this point if there should be a recognized BSE outbreak in Asia.  We don't have any data related to donor exposure, and I would hazard a guess that right at the moment we don't even have the infrastructure that we had in 1999 to conduct a survey as we did like that at that time.

            So I think there is a message there that we need preparedness to conduct ad hoc data collections as we can and be able to use those data to drive policy decisions and maintain a logical balance between the science related intervention and the ultimate impact.  Thank you.

            CHAIR PRIOLA:  Thank you, Dr. Williams.  Are there any questions?  Dr. Bracey?

            DR. BRACEY:  More of a comment with respect to the adequacy of the blood supply.  Indeed, we have had difficulties, particularly, in the holiday period.  If you track the numbers, the information is right on target in terms of having a one or two day supply.  But in truth, in January in large areas such as Dallas, there was about six hours worth of supply.  And, in fact, there were cases delayed throughout the state of Texas and various other regions.

            One of the things I think that has been discussed, but I'm not sure that action has been taken, is the application of resources to donor recruitment.  Largely, it is left up to the individual region.  In our region, the regional blood center has invested resources into putting ads on prime time developing a promotional campaign.  Some years ago, it came to my attention that Canada, its health system, funded such activities, and I don't know if there has been discussion of such in the States, but I think that as we look at improving the blood supply, we need to look at the resources to make the blood truly a national resource and to get away from this point of fragility.

            And then one last comment is that with regard to the utilization, I note that our colleagues in Europe are looking at addressing utilization.  If you look at product use review, you'll find that as much as, in the worst scenarios, 40 percent or in the best case, perhaps, 20 percent of transfusions are unneeded.  So I think a major effort that we might also look at is educating -- developing an educational program regarding the use, so that we can approach best practice.

            CHAIR PRIOLA:  Dr. Sejvar?

            LT. SEJVAR:  Yes, just a question about the decision or the rationale about the cumulative time spent in various areas with respect to deferral.  What was the basis or the rationale for the decisions on the time and has adjusting those time frames been looked at in terms of its impact on blood supply?

            DR. WILLIAMS:  The basis for the cumulative time spent in an endemic area really is just an assumption that there is a direct proportion between time spent and potential for dietary consumption of beef and, theoretically, beef which may be contaminated.  We looked at whether there might be reasonable stratification for those who did not eat beef.  In fact, in the survey responses that we got, we found enough conflicting information that we felt it would not be, you know, sufficiently specific to use in donor criteria determination.

            So basically, it's a rather simple correlation between time spent relationship to dietary exposure.  And I mentioned the risk-weighing between potential exposure to U.K. beef in different parts of Europe, both indigenous BSE as well as imported U.K. beef.  As far as reviewing the policy, this Committee meets every six months, and we do periodically raise the deferral criteria for discussion.  And I think, you know, one consideration that was made was cutting off the potential U.K. exposure period at 1996.  I think as other countries implement similar safeguards, there will be consideration of them.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  I was very amazed a couple of years ago when we learned that the military was one of the major sources of blood.  I can't remember what the figure was 10, 15 percent of the total donations come from young military.

            DR. WILLIAMS:  That sounds a little high.  I think it's closer to 3 percent.

            DR. DEARMOND:  Oh, gee.  So, but it was considered to be a major loss when any were excluded.  And you mentioned that there has been some rebound since then.  And that is because they keep turning over rapidly, and the population that was exposed to beef, I presume, are out of the service, and now we have got new people with the same fervor to donate.

            Has the war had any impact on this, because so many of the recruits are in Iraq and Afghanistan and other places?

            DR. WILLIAMS:  I can't comment specifically on that.  I haven't heard a presentation from DoD specific to that.  I guess one might presume that the more troop movement there is around the world, it would affect the deferrals, but I haven't heard specific information on that.

            DR. NELSON:  The war has had a major impact, not because of BSE, but because of leishmaniasis.  They are deferred for a year just based upon a potential leishmaniasis risk if they have been in Iraq.

            CHAIR PRIOLA:  Dr. Linden?

            DR. LINDEN:  This is really just a comment informationally.  Dr. Williams mentioned how hard hit New York was, in particular, because of the loss of Euroblood.  And I just want to mention that something that we did as the Health Department is that we printed up little cardboard flyers encouraging blood donation and giving the 800 numbers for the two major blood centers in our state, English on one side, Spanish on the other.

            And we distributed them by the Department of Motor Vehicles in routine mailings that were already being sent anyway.  And the cost to print these was something in the range of $8,000 or $9,000 per million.  So for less than $50,000 we were able to do five million mailings, because the cost of the mailings themselves was zero.  And this is an ongoing effort.  We don't have any data on whether this was successful or not, but I just wanted to mention this is a strategy that we tried to employ.  And I know Dr. Wolfe asked me about this yesterday, and we would be happy to share information about our experience with anybody else who might be interested in thinking about that kind of strategy.

            DR. WILLIAMS:  One brief follow-up comment to Dr. Bracey's comment.  There was just a meeting of the Advisory Committee for Blood Safety and Availability, which is an HHS Committee, on the role of Government in the blood supply and maintaining the blood supply.  Had some very interesting discussions, including, you know, model systems overseas as well as potential government role in recruitment and maintaining the blood supply, creation of reserves, that would be a very interesting transcript to look at if you're interested in that subject.

            CHAIR PRIOLA:  Dr. Bracey?

            DR. BRACEY:  Just one other comment.  In terms of the donor base, there are issues related to the repeat donor base.  But also, I think, if you look at the impact of recruitment, it has largely been on the European donors, it has been under -- there is under representation of Hispanics.  There is under representation of African Americans.  And as the demographic of the nation changes, I think, we really need to focus on those resources to bring that up to speed.

            CHAIR PRIOLA:  Dr. Rohwer, did you have a comment you wanted to make?

            DR. ROHWER:  Yes, Alan, in your last slide it looks to me like the fall-off in repeat donations occurred before the implementation of the geographic deferrals, and I'm just wondering what conclusion you are actually drawing from that.

            DR. WILLIAMS:  The only conclusion I am drawing from that slide is probably that is a multifactorial dynamic.  I think probably what, in fact, impacted that in the earlier time point prior to 2000 maybe is the implementation of some of the laboratory tests and changes in current laboratory tests that impact some of the longer term repeat donors.  It has a marked effect there, because your repeat donors tend to be the ones who come back more often, whereas the first-time donors, a proportion of them that actually become repeat donors, I forget the figure, but it's close to 20 to 30 percent, I believe.

            So the impact is much more felt on repeat donors.  And if they are suddenly deferred because implementation of a new lab test, they are out of the picture, and it shows an impact.  But I think what I'm saying is it would be interesting to continue the data and look at the time points related to the other deferrals.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  On that chart you show that you kind of pump and then drop off, but the values vary from 82 percent to, what, 76 or something.  It was like a 6 percent change.  Is that statistically significant?  Because if you had the entire chart from 0 to 100, it would be a little blip in there and is this truly a trend or just within statistical variation?

            DR. WILLIAMS:  Well, I guess, the first answer is this is not a sample.  This is actual observation at five sites, so it's a population.  So there is not statistical inference.  This is actual observation.  2 percent loss of repeat donors in the current blood supply represents 200,000 people.  You know, whether it is statistically significant, it is medically significant.  So I think, yes, when you look at populations of this size, even small percentage changes can have major impact.

            CHAIR PRIOLA:  Okay.  Dr. Linden?

            DR. LINDEN:  But, Al, these numbers, though, are percentage given by repeat versus first-timers, right?  It's not loss in numbers.  And I know there have been a lot of efforts to reach out to first-timers.  I mean, like the efforts I was describing of doing, you know, general mailings.  There have been a lot of efforts in schools to reach out to younger donors.  I know there is a lot of discussions in our state about going to 16 year-olds instead of 17 year-olds.

            So couldn't this partially reflect increased efforts to reach out to new communities?  I know there have been a lot of efforts to reach out to Hispanic communities in New York.  For example, there were not previously efforts to really go to the entire borough of Brooklyn, and all of a sudden we were, you know, now going to Brooklyn.  So if the percentage of repeat donors is decreasing, it may be success in increasing the number of first-timers.  I'm not sure that's necessarily a bad thing.  And, you know, if you're talking about a 2 percent change, that's really not a huge number.

            DR. WILLIAMS:  I think that's a good point, Jeanne.  It is multifactorial.  It would encompass both loss of repeat donors as well as an increase in proportion of first-times due to recruitment efforts.  It needs to be modeled.

            CHAIR PRIOLA:  One last question.  Dr. Bailar?

            DR. BAILAR:  It seems to me that I have been reading in the newspaper for at least 40 years that you are running out of blood.  Appeals for people to come in and donate.  It sounds like the situation is a little bit worse than it used to be.  On the other hand, how often do your facilities actually run out?  I'm not counting being able to import blood from something on the other side of town.

            DR. WILLIAMS:  That's also a very important question.  Monitoring systems that have been in place so far, basically, have been covering counting inventory, days' supply available, et cetera.  There haven't been many data collected reflecting, you know, impact on patient care or patient morbidity, that sort of information.  Though some of that has been done within the HHS Monitoring System.  Some of it has been done with the TransNet System that FDA has developed and piloted, actually looking at impact on patient care.

            And running out of blood, no, I don't think that instance happens where you don't have the blood to meet an emergency need, you know in the worst case.  What has happened and, you know, is considered as having an impact on patient care is when you get delays in elective medical and surgical procedures.  That does happen.  It was documented both with the TransNet Program and the HHS monitoring in the holiday period of last year.  And use of Rh-positive blood for Rh-negative patients, again, you know, arguably not an ideal medical practice, but it happens frequently in times of shortage.

            So there are gradations in the impact that it has.  Running out of blood, no, that hasn't occurred and I think that's compatible with the generally adequate statement of the GAO.  But one has to consider what would happen in a crisis if you needed a large amount of blood in a large area and, you know, would we have the reserve support that we need if we're only carrying a one to two day supply in the blood center shelves.

            CHAIR PRIOLA:  Okay.  I'll tell you what, let's move on to the next set of talks, and then we can come back to this.  The next speaker is Dr. Melissa Greenwald.

            DR. GREENWALD:  So good morning.  I am Melissa Greenwald for the Division of Human Tissues in the Office of Cellular, Tissue and Gene Therapies.

            UNIDENTIFIED SPEAKER:  We can't hear you.  Use the microphone.

            DR. GREENWALD:  The microphone is on.  It's on.  So I'm just a little bit shorter than everyone else who spoke before me.  I'm from the Office of Cellular, Tissue and Gene Therapies at CBER, and I'm going to be talking about the ways we have been trying to minimize the risks of TSE agents in human tissues.  Next.

            So the human tissue safety will be discussed in the context of three general approaches to reduce the risk of TSE transmission, careful screening of donors for TSE and for risks of TSE.  We would require testing if and when it's validated, control of recovery and processing to prevent contamination and cross-contamination, as well as using steps during manufacturing to inactivate our clear TSE agents.  However, there is really no current validated methods for human tissues to do this.  Next.

            So FDA's regulatory approach in general, and especially in human tissues, has a whole range of different methods, and we have current regulations or rules, we have current recommendations or guidance, and then we also have a set of proposed regulations, as well as proposed recommendations.  Next.

            Our current regulation that we're operating under right now is 21 CFR part 1270, human tissues intended for transplantation, which was published in 1997.  This requires screening and testing of potential donors for HIV, hepatitis B, and hepatitis C, and does not include requirements to screen or test for TSEs.  It requires written procedures and record keeping, has inspection and enforcement provisions, and 1270.31(d) specifically requires validated procedures to prevent infectious disease contamination or cross-contamination by tissue during processing.  And I highlight this, because I will show you a guidance in a minute that refers back to that.  Next.  All right.

            We have three current guidances right now.  The first one is the Guidance for Industry:  "Screening and Testing of Donors of Human Tissues Intended for Transplantation," which was published in 1997, and this recommends that you defer donors with risk factors for CJD, but doesn't include variant CJD risk factors.  Next.

            The Guidance for Industry:  "Validation of Procedures for Processing of Human Tissues Intended for Transplantation," it clarifies 1270.31 where we were talking about not contaminating tissues during processing.  So we explain that infectious disease contamination does include viral, bacterial, fungal, as well as TSE agents.  And there are currently validated methods available to prevent contamination by viruses, bacteria and fungi, but for human tissues there are no validated methods yet to prevent contamination by TSE agents.  Next.

            There is a new guidance document that was published just this past December, Guidance for Industry and FDA Staff.  It's a Class II Special Controls for "Human Dura Mater," and this was published by the Center for Devices and Radiological Health.  It discusses additional deferral criteria beyond those for CJD and variant CJD, but we're focusing the talk today just on those diseases.  It states that donor screening for CJD and variant CJD should follow the published blood donor criteria, including the travel history questions that were recommended.  Next.

            It also recommends deferral of donors who have classic CJD risk factors, and those are listed, people with degenerative or demyelinating diseases or other neurologic diseases, such as senile dementia or Alzheimer's Disease, and those who have died in a neurological or psychiatric hospital.  Next.

            So now, we go into the realm of our draft regulations and guidances.  So in draft form that was published in 1999 was our Suitability Determination for Donors of Human Cellular and Tissue-Based Products: Proposed Rule.  It includes requirements, would include requirements to screen, including a medical history interview, for risk factors for and clinical evidence of relevant communicable diseases, and those would include hepatitis B, C, HIV, and TSEs.  It also requires testing for relevant communicable diseases, including HIV, hepatitis B and C, and syphilis.  Next.

            In the Current Good Tissue Practices for Manufacturers of HCT/Ps: Inspection and Enforcement was proposed in January of 2001.  This rule would include requirements for controls over facilities, personnel, equipment, environment, incoming materials, labeling, storage, process controls, process validation, record keeping, adverse reaction and product deviation reporting as well as tracking.  Next.

            Contained in the GTPs also are provisions for inspection and enforcement, a requirement to archive appropriate specimens from each donor of dura mater, specific requirements for dura mater to be processed using a validated method to reduce TSEs, prohibition of pooling, and an exemption or alternative form of any of the GTP requirements could be requested by a firm, but they would have to submit that request to us in writing with valid data to be reviewed.  Next.

            But because FDA was concerned about CJD and variant CJD, we did publish a draft guidance document in June of 2002 to discuss risk factors of that even though our regulatory frameworks that require screening and testing were not in place yet, just to give manufacturers guidance on what we were thinking at the time if they wanted to implement screening measures.  And this guidance document was presented to TSEAC in June of 2002.  Next.

            It recommends donor screening recommendations for variant CJD, and they are based on the blood guidance to reduce the risk of transmission of CJD and variant CJD.  That was published in January of 2002, and, really, the recommended donor screening criteria for human tissues are the same as those that are listed in the blood guidance document.  Next.

            And just for everyone's information, I have listed those requirements in an abbreviated form, but Doctor Williams, you know, listed them out last talk, and I won't go back over them.  Next.

            So we are anticipating a Donor Eligibility Draft Guidance Document to accompany the Donor Eligibility Rule when it publishes, and we anticipate that we would be publishing those two documents within a relatively close time frame.  And then, you know, our current thinking is to plan to finalize the donor eligibility guidance as a document that would include the CJD and variant CJD measures that were described in the 2002 guidance document.  But until the Donor Eligibility Rule publishes, really there are no requirements for vCJD screening.  Next.

            And we have published an Interim Final Rule this past January that requires all establishments that manufacture HCT/Ps to go ahead and register and list.  This was implemented for manufacturers? tissues who had previously been regulated under 1270, and then beginning in January to put people on notice that we're going to require it for everyone, whether they are regulated by 1270 or not.

            However, this does specifically exclude manufacturers of human dura mater and heart valves, which will continue to be regulated as medical devices until all the final rules are in place.  And we do plan to revoke the Interim Rule when the Donor Eligibility and Good Tissue Practices Final Rules are published, when both products will be regulated with HCT/Ps.  Next.

            So that is the information we have about tissues, and does anybody have any questions?

            CHAIR PRIOLA:  Dr. Wolfe?

            DR. WOLFE:  In this transition period where dura mater are sort of floating in cyberspace between CDER and CBER, is there any requirement?  I mean, do we know?  I mean, I have asked this question now to the, I'm sure, boredom of the Committee for about seven or eight years.  Do we know now whether there are companies in the United States that are actually processing dura mater, and are they complying with at least the guidance as it is now?

            I mean, what's going on?  I mean, I realize this is still in CDRH, but what -- I mean, how many people are getting dura mater graphs?  The last time I heard, it was down from thousands to a few hundred, and at one of the meetings one of the companies said that he was not aware of any companies still making this.  Do we have any information on that?

            DR. GREENWALD:  Dr. Durfor from CDRH is coming up.

            DR. WOLFE:  Oh, yes.

            DR. GREENWALD:  He has talked to the TSEAC before about this issue.

            DR. DURFOR:  Yes.  My name is Charles Durfor.  I work for the Center for Devices and Radiological Health.  I don't have information, at this time, with regards to the incidence of dura mater implants or the numbers sold.  That is just not available to us, and it's not something we collect.  I also, unfortunately, don't have the most recent information in terms of inspections, because I am not in the Office of Compliance.  But, we have enacted, and just to call back to your attention, a document that is in your package, the Special Controls Guidance document, which has been put in place in December, and I do know that our inspectors do rely upon this document and do talk very closely and carefully with each of the facilities.

            And I apologize that I did not come in terms of updated, in terms of the extent of compliance actions and NIAs and such as that, but it is our belief that the safety of dura mater has not changed, and that the record in the United States is very good.

            DR. WOLFE:  Would it be possible just to find out how many facilities are currently making dura mater, have been inspected and what the results are, because that's really --

            DR. DURFOR:  I believe that, certainly, it would be possible to get to you.

            DR. WOLFE:  Okay.

            DR. DURFOR:  And as much as would be publicly releasable, we would be happy to give it to you.

            CHAIR PRIOLA:  Dr. Schoenberger, do you want to make a comment or just a moment, doctor.

            DR. SCHOENBERGER:  Dr. Sejvar may remember.  We just wrote an MMWR article updating the outbreak in Japan, which had reached 97 cases and was continuing.  In the process of writing that MMWR article, we did call around, and I think the Miami Tissue Bank was the primary supplier in the United States, and they had told us that they sold around 900, was it, last year?

            LT. SEJVAR:  I'm blanking on the exact number, but during our search for publication of the MMWR, which came out in October, I guess, we found one distributer in the United States, and that would be the Miami Tissue Bank, which is distributing human cadaveric dura mater.  And I believe that Larry is correct on that number.  It's less than 1,000.

            DR. WOLFE:  Per year?

            LT. SEJVAR:  Per year, yes, and I can actually check the MMWR over the break and get at least the information that we came up with through our search.

            CHAIR PRIOLA:  Dr. Gambetti, did you have a comment?

            DR. GAMBETTI:  I may have missed it.  I may have missed that, but in the current recommendation for deferral of dura mater donors, in that slide it's written classic CJD risk factors, classic CJD risk factor.  In other words, individuals with classic CJD risk factors are deferred.

            DR. GREENWALD:  Yes, sir.

            DR. GAMBETTI:  And what are these risk factors?

            DR. GREENWALD:  They are all listed.

            DR. GAMBETTI:  Could you explain them?

            DR. GREENWALD:  They are all listed in the guidance document.  I didn't list them all out, because we're talking about variant CJD mostly for this meeting, but, you know, people with a the family history of CJD and people who had had a dura mater implant and, you know, things along those lines.

            MR. COLYN:  Dr. Greenwald, at this time, are you able to give any guidance?

            CHAIR PRIOLA:  Excuse me.  Could you, please, identify yourself?

            MR. COLYN:  Yes.  My name is Jim Colyn.  I am with LifeCell Corporation in Branchburg, New Jersey, and my question is to Dr. Greenwald.  Is it possible, at this time, to give any guidance as to when we can expect the Donor Eligibility Rule to become a final rule of the current Good Tissue Practices?

            DR. GREENWALD:  Sir, as we have said in public many times before, until it's published, I have no information about when.  I'm very sorry.

            MR. COLYN:  Thank you.

            CHAIR PRIOLA:  Okay.  Thank you, Dr. Greenwald.  Let's move on to the next talk, and it's Dr. William Egan.

            DR. EGAN:  May I have the slides, please?  Let me put my glasses on.  I can't see them.  I guess I don't need any prescription.  Good morning.  In the next several minutes, I hope to inform and update the Committee on the status of vaccines and allergenic products relative to TSE risks, and in particular BSE risks.

            I will note, to begin with, that allergenic products within the Center for Biologics are also regulated by the Office of Vaccines.  This status update will touch on several areas, including estimating risk, managing risks, and communicating risks.  Next slide, please.

            A variety of bovine-derived materials are used in the production of vaccines and allergenic products.  Now, until the end of this talk, I will be concentrating on vaccines.  Comparatively, at least from the point of view of BSE risks, TSE risks, the allergenic products are relatively simple.  The complexity is with the vaccines.

            Bovine-derived materials that are used in the manufacturing of vaccines include fetal calf serum, beef muscle and organ extracts, the organ being primarily pancreas for enzymes, gelatin and processed gelatin, and a variety of small molecules, such as the amino acids, hemin, glycerol and lactose.  Being animal-derived, certain risks are inherent in the use of these products, primarily the potential for adventitious agents, various viral adventitious agents that may be in bovine products, but also the BSE agent, the subject of this meeting.  To the extent possible, the Office of Vaccines Research and Review encourages manufacturers to develop and use non-animal sources for many of these materials or the use of a synthetic media.  Next slide, please.

            These various bovine-derived materials are used in a variety of manufacturing steps, and these include the production of master cell banks and master seed banks, both viral and bacterial, the production of working seed and cell banks, cell cultures and bacterial fermentations, reagents that are used for immunogen purification or processing, and finally vaccine formulation, stabilizers or other excipients.  The next slide, please.

            CBER's policy and necessarily OVRR's policy regarding the sourcing of bovine-derived materials is clear and has been clear.  The policy is and has been that bovine-derived materials from BSE countries should not be used in the manufacture of FDA-regulated products, and BSE countries are designated as those or have been designated as those that are on the USDA, Department of Agriculture's, APHIS list.

            Now, previous recommendations were restricted to bovine material.  The most recent is broader, and includes ruminant, and previous recommendations mentioned only countries in which BSE was known to exist, and the language has now been changed somewhat to risks for BSE based on the broadening of the inclusion criteria in the USDA/APHIS listing.  In any event, the basic message has been clear and simple.  The next slide.

            And these just list some of the various letters and guidances that have been put out over the years beginning in 1991 when a survey was called for, what are all of the bovine-derived materials that are used in the production of biologics, and all of these are available on the Office of Vaccines' website and that address will be given a little later.  It is in the handout.  May I have the next slide, please?

            Although the rules are clear, the recommendations are clear, in early 2000, based on a review of a regulatory submission, it became clear to the Office of Vaccines that these recommendations were not being followed in their entirety.  As a result of this finding, a complete inventory of all licensed vaccines with regard to sources for bovine-derived materials used in manufacture, including preparation of master and working cell and seed banks, was undertaken.  We surveyed all products, and a number of instances were found where CBER's recommendations were not followed.

            Risk estimates were made for the various situations by CBER scientists and by manufacturers, and CBER recommended a set of corrective actions and these were discussed in a joint session with the TSE Advisory Committee and the Vaccines and Related Products Advisory Committee.  Could I have the next slide, please?

            Some of the issues that came to the fore and that were discussed with the Advisory Committee included use of fetal calf serum from the United Kingdom in the establishment of cell banks and viral seed banks, use of European-sourced beef broth, use of European-sourced low molecular weight materials, for example, hemin, use of European-sourced manufactured gelatin derivatives.  May I have the next slide?

            For all of these cases, risk estimates for the various situations were made, and these risks were based on the likelihood that cattle that were used might be infected, the amount of bovine-derived material that might be present in the final product, the inherent infectivity of the bovine materials, using experimental limitations to material where no infectivity had ever been detected.  So although no infectivity had been detected for fetal calf serum, rather than use zero we used what risk could be ruled out.  May I have the next slide?

            Also, many of the cases were, because these products, all sources, were not known, and if a source was not known, we simply assumed the worst case, namely that it came from the U.K. in 1989.  Now, the Joint Committee had several recommendations consistent with those that had already been communicated by the Office of Vaccines to the manufacturers, and these were to find and utilize new sources of bovine materials from non-BSE countries for materials used in production, to rederive working cell banks and working viral and bacterial seed banks utilizing bovine-derived materials sourced from non-BSE countries.  Next slide, please.

            But it was also felt that master viral and bacterial seed banks need not be rederived.  The risk to changing the product during a potential rederivation far exceeded the risk that might attend the product, and finally that these issues were of public concern and the public should be appropriately informed about the risks and which vaccines were affected.

            I mean, our own feeling in the Committee was that recipients of these vaccines have a right to expect that they are produced according to the recommendations of the FDA, and if they are not, then they should be so informed.  May I have the next slide, please, and present an update from that meeting, what has occurred since.

            Now, with regard to the recommendations about this being a public matter, a website containing the transcript of the meeting, various risk assessments, and a listing of the affected vaccines was developed within a few months and put up.  This website still exists and is periodically updated, and the website address is noted in the slide.  Also, an article outlining all of the issues was published in MMWR.  New sources of the affected bovine-derived materials were found and placed into production.  Working cell and seed banks were rederived, qualified and placed into production and, at the moment, most of the affected vaccines are now out of date, the ones that went on into the market.  They are out of date.  Next slide, please.

            Now, why have I gone into this history?  Well, for two reasons.  One is to update the Committee on what has been done relative to their recommendations, and, namely, all were taken and acted upon.  But second, and of considerable importance, to present a lessons learned.  Although the CBER policy, based on source country control, was clear, is clear, it can be problematic as countries, as new countries are put on or added to the list.

            As this happens, we must contend with several facts, that licensed products that have been released remain on the market, and that products that are in various stages of manufacture will go to market.  Secondly, manufacturing time-lines are quite long, greater than one year in almost all cases.  So from the time that a manufacturer decides to put a new source of material into a vaccine and that vaccine gets into the market, more than a year or more is generally taken.  This is because of production time-lines and the controls that are necessary prior to release.

            The status of master and working cell and seed banks becomes uncertain.  Will they need to be rederived, under what circumstances.  Consider a cell bank that was established with fetal calf serum from a country newly placed on the USDA list, and consider that that cell bank was derived 20 years previous to the country being placed on that list.  Consider the fact that it was 10 years previous to being placed on the list, five years previous to being placed on the list and so on.  Are there cutoffs that are scientifically justified?

            Finally, what is the status of products, cell and seed banks that are in development, and that could be anywhere from preclinical investigations through to we're reviewing the biologics license application.  And I think it's apparent that risk-benefit decisions will need to be made and continue to be made.  Source country, of course, and the risk for BSE in that country is one factor in that decisional process, but it's not necessarily the only one.

            I mean, consider the possibility right now that cell banks and seed banks that we discussed in 2000 were rederived using fetal calf serum from North America, which we again need to rederive them and keep doing this on a continuing basis.  This is simply not possible.  May I have the next slide, please?

            Let me now discuss North America.  Bovine-derived materials from cattle that are, in the words of the recommendations, "born, raised or slaughtered" in the United States and Canada are used in U.S.-licensed vaccines and vaccines that are currently under development.  The materials that are being used are inherently low-risk materials, primarily or for example, fetal calf serum.

            Based simply on the number of BSE cases in North America and the additional safeguards that have been put in place by the United States and by Canada, the risks that these materials might pose are several orders of magnitude less than those that were previously considered by this Committee in 2000, and where the risks were deemed to be both remote and theoretical.  So we're orders of magnitude below that.  The Office of Vaccines Research and Review has not requested manufacturers to replace existing Canadian or U.S. sources of bovine-derived material.  May I have the next slide, please?  Can you go one more?  I think I got these out of order.  Yes, thank you.

            Towards the end of last year, the U.S. Department of Agriculture published a proposed rule in October, and this rule would allow the import of certain live ruminants and ruminant products from Canada and, as was said there, other minimal risk regions for BSE, but for the immediate this rule would only be concerned with Canada.  So this makes, you know, the decisions a little more, whatever one wants to do, a little bit more tenuous at the moment.  Go back now, please.

            In looking towards the evaluation of TSE risk, and it appears that we will still need to be making these risk-benefit decisions, there is much that we still need to know.  And I would just like to point out now for this Committee two areas that I think are important.

            I think we need data on the ability of various cells, cell lines, to propagate the BSE agent.  There are a limited number of cell lines that are used in the manufacture of vaccines, Virocells, MRC5 cells, WI-38 cells, that is primarily it, and we need to have more data on the ability of these cell lines to propagate the agent if present.  The studies that were recently published by Dr. Priola certainly need to be carried out with these cell lines.  And in this regard, I will mention that the Office of Vaccines is collaborating with Dr. Asher, the collaboration being that Dr. Asher is doing all the work, to address, in part, this issue.

            Secondly, I think one might also fruitfully look at the ability of some of the manufacturing steps that are used in vaccine manufacture to clear the agent, a BSE agent, at present.  Now, not all vaccines are the same, and not all are amenable to purification procedures.  A live viral vaccine, such as Varicella, is quite delicate and difficult to purify in any rigorous manner.  Others such as hepatitis B are relative hardy and there are a number of purification processes that are used in its manufacture, but the ability of these filtrations, chromatographies to clear an agent that is present is unknown.

            Now, let me come to allergenic products if I may have the last, this slide.  And as I mentioned, these are regulated by the Office of Vaccines, and similar issues were encountered with the allergenic products, except on a much reduced scale and primarily, it was with molds, certain molds that are propagated in culture media that do utilize bovine components, and the master stocks were prepared in this way.

            Subsequent to our meeting, joint meeting with the TSE and the Vaccines Advisory Committees, this issue was discussed with the Allergenic Products Advisory Committee, and in that case the mold master stocks were rederived using bovine components from non-BSE countries.  Unlike viral master seeds, the Committee felt that there was little hazard to the product in its rederivation and accordingly, they were rederived.  If I can have the next slide.  Okay.

            Finally, let me mention one issue with regard to risk communication.  In addition to OVRR's website and published articles, several vaccines employ human serum albumin as a stabilizer, this is present in milligram amounts, and as a blood product the labeling carries the statement that is presented here on the slide about a minimum risk, potential risk, for transmission of viral diseases or the agent of CJD.

            Now, if recombinant human serum albumin were substituted for the blood-derived, and this is in every case licensed human serum albumin that's used, such a statement would not be necessary, it not being a blood product.  That concludes my update.  Thank you very much for your attention.

            CHAIR PRIOLA:  Dr. Wolfe?

            DR. WOLFE:  This will sound analogous to yesterday's discussion about the difference between a recommendation in that case, that it would be nice if states had mandatory reporting for CJD, which some do and some don't, and a regulation or a law.  And really, in part of your, I think, very nice presentation about looking backwards and what lessons can be learned, looking backwards, would you think that it might not have been better in May of 2000 to have a regulation, a rule, as opposed to some recommendation?

            I mean, one of the problems with recommendations, policies, guidances, again whether it is reporting, some do and some don't, and in this case, as you showed in your slide, you put out this May 2000 recommendation and some companies complied and some didn't.

            So looking backward and, again, it's not just simply a regulation, but it has to have some teeth and some enforcement to it, would it have been better to have that be a rule, as opposed to just a recommendation?

            DR. EGAN:  Yes.  I should probably ask the Office of Chief Counsel to comment on this.

            DR. WOLFE:  Your own personal --

            DR. EGAN:  But I won't, and I will give you a personal response.  The Public Health Service Act allows us to recall vaccines if we feel that there is a danger, that there is a risk, so we have that authority to do that.  We have lot release with the vaccines, and we could choose not to release them to market.  We could recall them from the market.

            DR. WOLFE:  But the release, you might not even know that it had been sourced from there, which is the case here, right?

            DR. EGAN:  Well, that is correct.  So I think there are authorities that allow us, when we find something, that we can recall it if we feel that there is a risk.  But if we have a regulation, a law, based on, you know, risks and benefits, one could use discretion in whether one wishes to recall or not.

            So I think my bottom line is that we're talking about six of one and a half a dozen of the other, and it all comes down to recognizing, realizing a situation, making some judgments about risks, assessing them and then deciding what to do, whether one does it under the Public Health Service Act, recalling it, or using that as the basis for the action or using a law as the basis for the action.

            DR. WOLFE:  So you're saying if you had it to do over again, you would just do a recommendation and not put out a rule or a regulation in May.  Is that it?

            DR. EGAN:  My own personal feeling, based on the authorities that exist under the Public Health Service Act, and these authorities are much more extensive for vaccines than they are for other products that are regulated by FDA, and this had to do with the Vaccine Injury Compensation Act that added this into the Public Health Service Act.  So, I mean, my own feeling is it's six of one, half a dozen of the other.  It could be either way, but it's judgment in both cases.

            CHAIR PRIOLA:  Dr. Bailar?

            DR. BAILAR:  I think we're probably all concerned about the diminishing number of countries that are known to be or considered to be BSE-free, and maybe it's time to start thinking about alternatives.  The policies at present are written as if risks start and stop at national boundaries, which is just nonsense, and there might be other ways to go at this, such as distance or marketing and shipment patterns.  I wonder if there has been some thought to alternatives to this national-based approach.

            DR. EGAN:  Well, there has certainly been a lot of thought that has been given to it both within the Office of Vaccines and within the Center for Biologics and within FDA as how to approach different things, and I think, maybe, you know, for some issues, one solution is best and it may be a law.  For other situations, you know, that prohibit things by source, I don't know.  For others, other approaches may be better.

            I think that we do have to consider sourcing, where it comes from.  There is a difference between calf serum that came from the U.K. in 1989 and, you know, calf serum that's coming from Michigan, not to pick on any state, that we have to consider the tissue that's used.  I am loath to use any high infectivity tissue no matter where it comes from, and between fetal calf serum, you know, which has no demonstrated infectivity, as hard as people have tried, and neural tissue there is, you know, nine orders of magnitude difference.  That may, you know, swamp out any geographic consideration.

            There is also the amounts of material that will wind up in a product.  In most of the cases with vaccines, we're talking about very, very, very small amounts of material that might wind up in the product, in a product that may be given once or twice.

            But yes, I agree completely with you.  I think that all of these things need to be considered in our decisions, and I think what was noted yesterday just like, for example, fetal calf serum, industry currently uses about 500,000 liters per year, 65 percent of which is coming from North America.  So I think to say that everything had to come from New Zealand and Australia, it's not clear that there would be enough at least for the near future unless they ramped up those industries.

            CHAIR PRIOLA:  Dr. Nemo?

            DR. BAILAR:  One sick cow in Australia could do us in.

            DR. EGAN:  Yes.  Well, at least if one had a strict country source rule.

            DR. NEMO:  Do you know if your recommendations have created any particular hardship for vaccine manufacture, particularly smaller manufacturers that may just decide well, this isn't worth it, you know, we're not going to pursue development of this vaccine for an orphan disease, let's say?  Have you seen anything like that?

            DR. EGAN:  To date, I don't think we have put anybody out of business because of this, but it --  certainly, I can't elaborate too much, but it has had an impact on certain vaccines that were under development.

            CHAIR PRIOLA:  Dr. Gambetti?

            DR. GAMBETTI:  In view of most of what was said yesterday and of the fact that you are saying that the number of countries that are so-called BSE-free is decreasing, and, therefore, it becomes more and more difficult to obtain products that are used for making vaccine and so on, I wonder what your thoughts are about really starting switching from classifying countries according to whether they are or we perceive them as BSE-free or not with country instead with a kind of classification of countries that perform extensive testing.

            What I feel I see is that we actually, on the basis of what we have seen here in this continent, in North America, that the more testing you do, eventually you will find cases.  So at a certain point, I think what I was saying is that we should probably switch from countries that are classified BSE-free based on lack of import or lack of evidence of import to countries that instead do very extensive testing and, therefore, they have BSE under control.

            DR. EGAN:  Yes.  I understand your point, and this issue about there being a penalty for finding out what the truth is and then learning how to deal with it, as opposed to not trying to find out what it is, yes.  I mean, I think those are important considerations, and I think some of the other things that were talked about the other day about certification of herds, having, you know, closed herds that are extensively monitored, you know, each animal is monitored through testing are certainly things that should be taken under advisement.

            And I guess one of the things that I'm hearing from the Committee is that we are needing to look more closely at these risk-based types of decisional models rather than simply, you know, the strict geographical, and I think we'll need to consider those in greater depth.

            CHAIR PRIOLA:  Dr. Johnson, did you have a comment?

            DR. JOHNSON:  I was going to bring up the issue that he just brought up, and that was the select herds.  But could those be developed in sufficient number in whatever country it was to fulfill the needs?  I mean, are we talking about -- is this pie-in-the-sky?

            DR. EGAN:  Well, the answer may be yes and no.  For higher risk materials that are used in smaller amounts, that may be very, very doable.  For fetal calf serum, the closed herd may be in Australia and then, you know, anything in between.  But for things like some beef extracts that were used in bacterial fermentation, it's probably sufficient to -- I haven't thought about this in great depth, but to have small herds for that.  But I think that is, again, another thing to be explored.

            DR. JOHNSON:  If you do this, it's going to make the product terribly expensive, isn?t it, if you go to the herd or every cow is tracked and none has ever been fed any kind of meal and et cetera, et cetera.  Aren't these going to be pretty expensive cattle?

            DR. EGAN:  Yes.  You know, I don't know the economics of this, but I suspect not.

            DR. JOHNSON:  You suspect not?

            DR. EGAN:  Yes, but economic impact would, you know, certainly have to be considered.

            DR. LINDEN:  Is that right, Lisa?

            DR. FERGUSON:  Well, I guess I suspect that the economic impact would probably be pretty big, and I think, you know, for a realistic type thing, setting up those type of herds, as you said, for high-risk product, if you're using, you know, brain-heart infusion artery or something like that, that it could perhaps make some sense to do that for fetal calf serum, for BSA.  I'm sorry, it's just not going to work.

            And even trying to set up, let's say, the national herd of Australia, I think what we have seen previously, and sometimes in especially the fetal calf serum market, this stuff moves around and you can really create some interesting effects in a market when you put out that type of a regulation, and you see products being labeled as what it really isn't and moving through various channels depending on the economic drivers.

            So you know, we need to be real, real cautious.  I guess some other alternatives to look at, I mean, if we're talking about beef extracts, what actually is going into that beef extract?  Is it a chunk of muscle meat?  Do we really think that's a risk or is it spinal cord?  So those types of things, I think, all probably need to be thrown into the mix.

            DR. EGAN:  Yes.  And, you know, with regard to the fetal calf serum, usually they are made in pools of about 1,500, 2,000 and, you know, the keeping track of where every single cow that was blood raised and slaughtered that went into that is rather difficult.

            CHAIR PRIOLA:  We'll have Dr. Creekmore and then Dr. DeArmond.

            DR. CREEKMORE:  Actually, I think my question has been answered in a variety of ways, but the basic question was how do we currently source bovine-derived products in North America?  Are there cattle that are specifically produced for the purpose of some of these products, or in general is it the population at large?

            DR. EGAN:  To the best of my knowledge, you know, within the material that is sourced in the United States is just general.

            DR. DEARMOND:  I would disagree with the idea that this would not be economically feasible.  In fact, that's just not knowing the history of the United States.  We have been founded on this competitive free market system where the person who builds a better mousetrap often will get the money and will sell the product.

            And indeed, some drug companies already have their own herds that they keep because of the cost of having a failure.  A drug company will go out of business if something goes wrong.  And again, the example is this, it's kind of a silly example, but the silicon breast implants destroyed a company and products that were used for a lot of other things, and it wasn't even a product that was dangerous, as we learned later.

            In my opinion, and in the way of knowing the free marking system as it works with some federal help with tax benefits, these cattle can be raised and they can be raised, if you look at the cattle industry, you begin with small herds, young cows, young calves that are fed off of land, and those are then moved to other sources of food.  And when you look at the Japanese, by golly, they hand feed the animals and massage them, and they can still sell their product and even give them beer on top of that.

            I mean, this can be done, and it's the way the enterprise system works.  It isn't the way government works, but it's the way things are done successfully in the U.S., and we could get guaranteed herds of cattle that could be used for any number of products.

            DR. EGAN:  As I said, I haven't done the economic analysis.  I mean, that's well out of my --

            DR. DEARMOND:  But you don't have to, because we know the success of the system.  Whenever you have a crisis, somebody comes up with a new method of doing things, and it becomes economically feasible.

            DR. EGAN:  And I think, as I have said, I think it probably is.  And I think a relevant example of what you're saying, it's not cattle, but it's chickens.  For some of their, you know, vaccines, I think Merck, for example, bought SPAFAS, created SPAFAS, bought SPAFAS, and these are closed herds of chickens for the eggs that are used in the production of some -- these are specific pathogen-free eggs, herds that are monitored continuously.  They are closed and monitored for that purpose.  So, I mean, it's done with other animals for vaccine purposes.

            CHAIR PRIOLA:  Dr. Nelson, did you want to make a comment?

            DR. NELSON: This is kind of a side comment.  I have reviewed for the IRB some new like HIV vaccines, and in the 15 page consent form, there is a paragraph that we can't assure that you won't get Creutzfeldt-Jakob Disease, and nobody who reads that knows what the hell that means.  You know, it's a legal or whatever, but, you know, it's, I guess, a fallback against some legal action, but a lot of the vaccines contain statements about Creutzfeldt-Jakob based on bovine serum albumin or fetal calf serum in the cell culture system.  You know, I don't know how effective that really is in terms of educating the public, warning them, or even knowing what people are signing when they accept a vaccine.

            DR. DEARMOND:  I hate to say this against my daughter who is a lawyer, but it sounds like a lawyer wrote that statement, not a scientist.

            DR. EGAN:  Well, I mean, you know, sometimes it's one, sometimes it's the other.  We have had discussions about this, this area, putting in some statement about a risk that you estimate to be you are one in 10-20 relative to some other risk, for example, getting bacterial infection accompanying the injection, that may be 15 orders of magnitude greater.

            You know, you can't put in everything, because then nothing has meaning or importance.  But it's a difficult area about, you know, what to put in, things that really are of large risk.

            DR. DEARMOND:  Is that an FDA requirement that such a warning be listed or is that just a legal fallback, BSE?

            DR. EGAN:  Well, with regard to serum albumin, human serum albumin, in the vaccines, yes, we did tell the manufacturers to put that in.

            CHAIR PRIOLA:  Okay.  I think we'll move on to the next speaker.  Thank you, Dr. Egan.  The next speaker is Dr. Gerald Feldman.

            DR. FELDMAN:  Good morning.  As this slide demonstrates and as the Madame Chairperson had mentioned, my name is Gerry Feldman, and I represent the Center for Drug Evaluation and Research, and my purpose for the next 10 or 15 minutes is to provide to you, members of the TSE Advisory Committee, an overview of the scope of involvement of bovine components in CDER-regulated products, as well as the mechanisms by which the Center for Drug Evaluation and Research attempts to minimize risks associated with those bovine components.  So if I may have the next slide.

            Bovine components in CDER-regulated products fall into three categories, as you have heard already from the numerous speakers that have presented already.  We categorize them as active ingredients, excipients or inactive ingredients, and reagents or raw materials that are used in the production of the final product, and I will in the next slide begin to describe what those actually are.  So if I may have the next slide.

            As active ingredients or parts that are injected for the purpose of treating a disease, we have as examples, glucagon, which is derived from the pancreas of cows, aprotinin, which is derived from the lung of bovines and other animals, heparin, collagen and amino acids, and a number of these components have already been described and discussed at various TSE Advisory Committees over the years, and I will allude to those in a few minutes.

            In the next slide, we have those materials that are used as excipients or inactive ingredients, and they include gelatin, which has been described and discussed on numerous occasions in this Committee, amino acids, which were described and discussed in October of 2001, I believe, at this Committee, and glycerine and Polysorbate 80, which are tallow-derivatives, which have also been discussed at this Committee.  You will notice that amino acids also appeared as an active ingredient.

            And you will find, as you will see in the next slide, that amino acids also form the final category of reagents or raw materials that are used in the production of a wide variety of regulated products.  Also included in this group are bovine serum albumin or fetal calf serum or other sources of serum, which has been discussed at great length by Dr. Egan, human transferring, which is another blood component.

            And I provided this list, as well, Protein A, which is not usually considered a bovine-derived component and, in fact, it is not.  It's a bacterial component.  But unbeknownst to the majority of people in the industry, we have found, as well as scientists who use it, Protein A can be and usually is derived over a human IgG column for purification purposes, which brings into play the discussion of risks involved with human plasma-derived components, so we also address the risks involved with using Protein A for the purification of monoclonal antibodies, which are a CDER-regulated product.  So if I can have the next slide.

            The assessment of risk that CDER utilizes is similar to what has been discussed already in the Center for Biologics and will be discussed by the Center of Devices in a couple of moments, and that is we look at the source country, the country from which the animal, in these cases the cows, originally come from, were born in or raised or slaughtered.  We look at the source of the component, from what tissue or organ it came from.  We also examine the proposed use of the component, whether it's going to be used as an active ingredient, an excipient or starting material.

            In addition to that proposed use of material, we also examine and use as a basis for our assessment of risk how that component is going to be used, in other words, what indication it is going to be used for, whether it's a serious and life threatening disease or something that is not serious or life threatening, as well as how it is going to be administered, whether it's an oral, topical or IV injected product.

            Finally, we look at what is known regarding the inactivation by the manufacturing process of potential TSE infective agents both in terms of the manufacturing process of the component, e.g., high temperature for glycerol derived from fat or gelatin, as well as whether or not there is anything known regarding the manufacturing process of the final product.  For example, when that glycerol or amino acids that have already undergone acid hydrolysis are used as a raw material for the production of a recombinant protein, what is known regarding the process by which that final product is purified or manufactured that may impact on either the presence or infective capability of the TSE agent.

            So these are the components that comprise our assessment of the risk in bovine components, and the next slide demonstrates our efforts to manage that risk, and these include communication of the risk through industry letters, FR notices, industry guidance that have been described at great length in previous presentations.

            In addition, the Office of New Drug Chemistry has a series of MAPPs or a Manual of Policies and Procedures in place for internal use that, essentially, describe exactly how our own reviewers will go about assessing the risk.  Step one, if there is a bovine component, what is the source country, what is the source tissue, etcetera, etcetera.  This comprises part of the application review both for products that are in IND or NDA development, as well as under license application or have already been licensed and are marketed in this country.

            The use of bovine components is also accurately tracked both by the Center for Drug Evaluation and Research, as well as the Center for Biologics Evaluation and Research, such that any component that is used anywhere in the process of manufacture of a regulated product is put into a computer database, so that we can, at any time, pull out what component or what country is using what component for what type of animal, for what type of tissue and whether or not a country that is on the APHIS list is a source for any of those components.

            And all this impacts, or is utilized to assess our own risk assessment plan on a continuous and iterative process, such that as new data is derived at or demonstrated or published, we look again at our risk assessment and at the mechanisms we use to manage those risks.

            So overall, as you will see in the next slide, the management of the risk that CDER utilizes is a generalized prohibition of use of raw materials originating from countries with known BSE or considered at risk for BSE, and this is identical to what Dr. Egan had just mentioned a few moments ago.  And in fact, you will not find anything new in my entire presentation over what you have already heard over the course of this morning's presentations.

            There are specific exceptions to this generalized prohibition.  As you know, gelatin, tallow derivatives, for instance, amino acids, which was discussed previously in October of 2001 and, as Dr. Egan had also mentioned, there have been no actions taken against either Canada or the U.S. in terms of the products that are made using bovine components from either of those two countries.  So this prohibition of use of raw materials originated from countries with known BSE or considered at risk does have specific exceptions.

            Also, as a method to manage the risk in CDER-regulated products, we strongly recommend, where possible, where feasible, that bovine components be changed to non-animal-derived ingredients in reagents, but, as Dr. Egan alluded to, it is not always possible, feasible or wanted to do that.  Although, if it is done, that is highly preferable.  The next slide, please.

            So the management of risk that we utilize in the Center for Drugs is similar to the management of risk that takes place in the other sectors.  Also separate the components out by how they are used and where they go, such that for active ingredients we have certain exceptions that may not exist when we're talking about a raw material.  So the general restriction for active ingredients in compliance with 1996 FDA policy is that no bovine-derived components from BSE positive or high-risk countries are utilized.  However, there are no restrictions for other ruminant sources.

            But specific exceptions do exist, as was referred to in the earlier presentations, milk-derived components, for instance, or hide and hair-derived components are also specifically excepted for use for any bovine source material, and there are also other exceptions that the Committee is already aware of.  The next slide, please.

            It refers to the management of risk for excipients and, again, the restriction is the same as for the other types of components, but here there are other exceptions.  Gelatin, for instance, with specific caveats that denote that the gelatin may come from BSE positive countries providing certain limitations are present.

            However, unlike that for active ingredients, gelatin cannot be used for injected products if it does come from a BSE positive country.  It can only be used as an oral or a topical use if it comes from a BSE positive country, even though the head and the vertebral column are removed.  Tallow derivatives are also some of the components used as excipients either for stabilization of the final product or something like that, and there, too, there are caveats with exception.  As you know, the tallow derivative must be derived from a validated process that has been demonstrated to remove or inactivate the TSE agent, as has been discussed in this forum over the course of the last several years.

            And in the next slide, we present the management risk for raw materials or reagents.  The restriction is identical here as it is for the other types of components, but here, too, there are specific exceptions.  As Dr. Egan referred to, master cell banks, because of the inherent problems with changing or rederiving them, which could and quite often does change the final product that is used, the Center for Drug Evaluation and Research has not recommended going back and rederiving the master cell banks.

            Amino acids are another exception that has been discussed at this Advisory Committee.  The Center for Drugs does allow the use of amino acids even from BSE positive countries as a raw material for the production of the recombinant proteins.  However, amino acids are not allowed to be used as an active ingredient if they do come from a BSE positive country.  There, the amino acids are required to be sourced from plants.  So here, too, is another specific exception for specific use of the component.

            And in the next slide, which is my last slide, I present to you the ongoing activities in CDER for managing the risks associated with bovine components.  As I mentioned, and as Dr. Egan mentioned, there has been no official action taken against the United States or Canada in terms of the use of bovine components derived from either of those countries.

            Yes, there are pending regulations, as has been referred to by previous presenters on the current TSE and BSE policies.  There are also pending revisions to the gelatin guidance based on the last TSE Advisory Committee where recommendations had been made regarding changing that guidance document and the Center for Drugs is reviewing those recommendations and will be revising that gelatin guidance accordingly.

            And finally, and I think most importantly, we continue the tracking of all materials that are used anywhere in the process of, in the production of the final product that may come from any animal, in fact, and from any country and this is done both by contacting the companies directly, by our biannual inspections of all companies that have licensed products before us and by continuing with any curative reevaluating the products that are regulated by the Center for Drugs, such that we hope to have and continue to have and continue to maintain an up to date and well characterized database from which we can track all components in all countries and all uses of the bovine components, and all other animal components that are used in the production of drugs used and marketed in the United States.

            And with that, I thank you for your attention and open it up to questions.

            CHAIR PRIOLA:  Questions for Dr. Feldman?  Dr. Nelson?

            DR. NELSON:  Yes, I too am concerned about the geographic exception.  I wonder how the Europeans have dealt with this for vaccines that are licensed, you know, made and licensed and sold in Europe.  Do they also have a geographic exception or do they have registered herds or some safety measures other than just excluding the use of materials from areas that are BSE positive?

            DR. FELDMAN:  I think that's a question better directed to Dr. Egan from the Office of Vaccines, but before you do answer, Bill, in terms of the components that are used in drugs and recombinant proteins made by European companies, most companies have been using components first from the United States, Canada, Australia and New Zealand for the production of those types of products.

            In fact, I can tell you that when Japan came out to the APHIS list with its first diagnosis of BSE, we contacted all the companies that were in our databases that suggested that they use Japanese components and were told unilaterally that companies who had used those Japanese components also had in their system the ability to use North American and Australian and New Zealand components.

            So the switch from Japanese to U.S., Canada, Australia and New Zealand components was easily made and very rapidly made.  I don't believe there were products on the market at that time that had to be recalled, but manufacturing was switched almost immediately.  There was no down time in changing those components.  And now, I'll let Dr. Egan respond to Dr. Nelson's question.

            DR. EGAN:  Yes, the Europeans have done things similar to what we have.  And so following, you know, our discussion of the sourcing issues and vaccines with the TSE Advisory Committee and the Vaccine and Related Biological Committee, the Europeans looked at this as well, and they came up with a similar set of recommendations and things to do.  So their fetal calf serum is actually sourced primarily from Australia and New Zealand and the United States and Canada.

            And they source most of the bovine components from outside of Europe.  Now, in part, this is because, you know, the vaccine industries are kind of global and, you know, GSK or Aventis Pasteur have been making vaccines for the world, you know, they are here in the United States, Canada, Europe and so they try to find that highest common denominator.

            CHAIR PRIOLA:  Well, Dr. Egan, before you sit down.  With the current discovery, of course, of the BSE case here in Washington in December and the one in Canada earlier and the other cases there, Europe has made no change in their sourcing, in that they still come to North America for sourcing their vaccine components?  That hasn't affected that?

            DR. EGAN:  Yes, I believe that they said there is no particular risk from materials in Canada.

            DR. FELDMAN:  If I can add one thing, if you would, to what Dr. Egan just mentioned.  When Canada found its first case of BSE, we did not implement any action against or directed towards bovine components that may be sourced from Canada.  We didn't contact some companies to determine what was happening and other companies contacted us to see what we were going to do regarding the presence of Canada on the APHIS list.

            And because most of the countries, as I already said, had in place mechanisms for switching quickly to another source, those companies that did use Canadian drug components quickly switched to U.S. source only or U.S./Australia/New Zealand source components only, not at our request, but on their own volition.  Probably and undoubtedly for reassuring the general public that they are not using materials derived from BSE positive countries.

            CHAIR PRIOLA:  Dr. Epstein?

            DR. EPSTEIN:  Yes, I believe that there are countries whose laws prohibit importation of materials from BSE countries similar to our own.  And I'm aware that at least in one case in Korea they are rejecting U.S. plasma on that basis.  I'm not sure how extensive this phenomenon is at the present time, but it would not be correct to say that there are no countries presently rejecting U.S. or Canadian source material.  There are.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  I think though there is a danger in assuming that we're absolutely pristine.  We know we're not.  And I would agree with Pierluigi and experience in Europe.  If you test more, you'll find more.  And the fact that we've been bringing in which I never had understood before was that one to two million head of cattle every year being imported in here and we've identified one case of BSE, and that's only because it was a downer and I don't know how other heads of cattle were slaughtered at one point or another for some other purpose that we have not -- and it was never identified that they had the disease.

            So we don't even know the extent of the disease in the country.  And I know when I'm interviewed by newspapers, radio stations about the extent of BSE and in the past I've always said well, there isn't any BSE in the United States.  And then they say, but how do you know?  We know that people don't tell us everything.  And I said well, you know, I can't judge that.  I can't judge that somebody is hiding it.  But by not testing we are in de facto hiding the extent of the problem.  So we need to know this.  We really need to know this data and we need to know the full extent of it.

            CHAIR PRIOLA:  Dr. Gambetti?

            DR. GAMBETTI:  Serum plasma of this product from bovine origin for these purposes are obtained at which point or when from the time of slaughter or out of special animal that are producing this materials?  The reason I'm asking that is because maybe those animals could be tested, so you know already whether the animal producing this material will affect it or not.  So in a sense, that would give assurance that that particular plasma serum is not BSE contaminated.

            DR. FELDMAN:  My understanding and somebody, please, correct me if they know otherwise, is that the majority of serum used is derived at the place of slaughter.  However, I am aware of several companies that used closed herds that they started on their own, so that they have a pristine source of serum for their own purposes.  I am not sure of any other sources or any other uses or other sources by other companies or other countries for that matter.

            CHAIR PRIOLA:  Okay.  Thank you, Dr. Feldman.  Let's move on to our next speaker, Martha O'Lone, Commander Martha O'Lone.

            CDR O'LONE:  Good morning.  I am Martha O'Lone and I am a Commander in the United States Public Health Service.  Thank you, Dr. Priola.  And I am also a nurse with over 20 years of neuroscience nursing experience.  Currently, I am assigned to the Center for Devices and Radiological Health as a medical device reviewer in the Infection Control Devices Branch, and I'm also the chair of the Center for Devices and Radiological Health, TSE Working Group.

            And today, I'm going to talk about the steps that we are taking at CDRH to minimize risk of TSE.  So before I do that, I thought that I would cover our mission, which for the Center for Devices and Radiological Health, is to promote and protect the public health.  And we do this by ensuring that medical devices are safe and effective for their use and we also have a responsibility for protecting the consumer and the country from radiation that is unnecessary in medical, occupational and consumer products.  Next slide, please.

            My objective for today is to provide an overview of our CDRH measures to minimize risk of TSE agents in medical devices.  And I thought that because we have such a broad range of devices and we have to take, therefore, a broad approach that I would discuss implanted medical devices, and then include information about neurological devices and general surgical instruments to give you a picture of how we look at TSE-risk.  And before I finish, I will talk a little bit about in vitro diagnostic devices in relationship to TSE.  Next slide, please.

            So the way that we carry out our mission at CDRH is through these procedures and approaches.  First, we have our premarket review and for the devices I'm talking about most of them are Class II or Class III devices, and we use 510(k) IDEs, PMAs to review those products.  As far as post market surveillance goes, we have device tracking and we also have the opportunity to have medical device reporting.

            And prior to yesterday, I had already planned to make a plug for medical device reporting and say that this is the responsibility of every practitioner to try to let us know what is going on with medical devices in the community.  And we do take those seriously.  I was very surprised when I came to the FDA as a nurse who had been practicing for a long time in clinical centers to find out that each report is looked at very carefully.  So the more reports we have, the more information, the better we can pursue this.

            As far as scientific research, we did talk last July about the fact that we have our Office of Science and Technology and they have been looking at TSE and doing some research on decontamination of devices, along with Dr. Asher.  They have worked on other things with concerns for TSE.  Also, our staff and my colleagues have looked at TSE as far as what research has been available to us and attended seminars and tried to maintain education throughout our staff, as far as what is going on with this.

            Even for the engineers of my division, I will sit up there and talk about what TSE is, so they have an idea of what is going on in the world before it becomes a problem for devices that we review.  Field inspections, our Office of Compliance carries out inspections.  They also are able to track through that and find out what is going on with devices, for the devices that are tracked.  Let me think what else I wanted to tell you here just for a second.

            And one of the things that they do to inspect is look at quality systems and the general manufacturing practices that the people have to make sure that they are accurate.  And they do include in that, even though we don't have any particular directive, at this very moment, they do look at problems that are occurring in science and look at TSE if it is warranted.

            The biggest thing that we do for risk management right now is risk communication, and we talk with industry, and we have done that through letters and guidances starting back in the early '90s, and we have also talked with health professionals.  Not only clinicians in practice and academia, but also with our sister agencies, CDC, NIH, EPA, USDA, to make sure that we are all providing a consistent message and we keep up on what is going on with the other agencies.

            As far as communication to consumers, we do have our websites available and we do communicate with foreign governments through letters also.  Guidances, we have available for both manufacturers and for our reviewers to look at and our public meetings.  Next slide, please.

            So for implanted medical devices, I thought that I would review what I'm talking about here just briefly.  For the purpose of this discussion, I'm going to talk about the devices that we have with human and bovine tissue.  For the implanted medical devices that are human, we can look at whether or not it goes into the blood or into the CNS.  For human devices that would go into blood contact areas, we would look at cellular wound dressings, bone void fillers, human collagen, pericardial valves and human dura mater would be for the CNS.

            And we do look at CNS contacting-risk as being the highest risk based on the WHO Guidance for biologicals and the title that I have just now forgotten.  And for animals we are looking again at the absorbable hemostatic agents, the pericardial valves and collagen implants as being blood contacting and then dura substitutes as being a higher risk with the CNS contact.  Next slide, please.

            So to minimize the TSE-risk for implanted medical devices, pretty much we have to use the tools that we have.  We have our premarket review and when we are aware that a device has animal tissue in it, we do look at that on a case by case basis.  We do consider the source.  We have guidance about BSE-free countries and about ? now even more defined guidance about the actual herd and other information that came out in our human dura guidance.  We, in our premarket review, have other factors to look at like manufacturing and sterilization.

            The guidances that we have for the human guidance, I did include in your packet, the human dura guidance and that is consistent with what CBER has talked about this morning.  We do the same things as CBER does.  We look at the tracking and all of the elements that they have listed earlier.  For the guidance for animals, we have had that guidance since 1998, and that animal tissue guidance came out and talked about, again the source and went into great detail about what we would ,be looking for in animal tissues.

            One of the things that we did with that guidance was also announced to the public that we have an animal tissue biomaterial database that we maintain, so that we are aware of where the devices are and what has been coming in since that time.  As far as post-market surveillance, we have still our device tracking with that, and we also have the opportunity to go after and inspect for just regular routine practices, as I mentioned.

            As far as inspections go of manufacturing facilities, it is routine, so for a PMA every site is approved before by inspection before it is allowed to bring the products to market.  And then afterwards for 510(k)s and follow-up with the PMAs, you would have quality system reviews, and also general manufacturing practices would be checked.  We do have the ability to go in and do further assessment if it is needed, if it is warranted in our inspections, so that is something that is available to us.

            One of the main things that our Office of Compliance has done, who is the one that performs the inspections, was in January of last year, 2003, 25,000 letters were sent to manufacturers, suppliers and importers to remind them of the items that we have in our animal tissue guidance.  And this was highlighting the importance of maintaining records of animal sourcing and manufacture.  And that also gave us a more up-to-date database that we have a very good idea of the manufacturers that we have for all animal tissues and especially we can look at that for bovine or whatever else we would like to look at.  Next slide, please.

            So minimizing TSE-risk for neurological- general surgical medical devices, in addition to the devices that I discussed with tissue, these devices are of potential concern in the transmission of CJD.  And according to CDC, iatrogenic transmission of CJD agents has been reported in over 250 patients worldwide, and that is something that they have currently on their website.  But it is important to know that in six of these cases, they were linked to the use of contaminated equipment, and four were associated with neurosurgical instruments, and two were stereotactic EEG depth electrodes.

            And although there hasn't been additional data since this 1976 time, CDC and FDA are still concerned about the potential for transmission of TSE agents with the reuse of surgical instruments.  We consider this risk in our premarket review of devices that are known to be used with high infectivity tissues, such as inside the CNS and for general surgical instruments and medical devices that are not specifically labeled for use in CNS or other high-risk tissues.

            And as I discussed in the July 2003 TSEAC meeting, we are also considering the risk for devices that are used in reprocessing medical devices such as sterilizers.  Next slide, please.

            The approaches that we use to minimize TSE-risk for these medical devices are again the premarket review of the neurological medical devices to the general surgical devices.  And each submission again is considered on a case-by-case basis in the review.  And in each submission, we are carefully looking for labeling for reuse to see if there are any reprocessing instructions after exposure to TSEs.  And as we've discussed in July, if they did have those kinds of instructions, we would want to see validation as we had asked for in general for all medical devices for reuse in our 1996 labeling guidance.

            Currently, CDRH has not cleared or approved any medical device with claims that it can be reprocessed or used to reprocess medical devices, such as scalpels, forceps after exposure to or potential exposure to TSE.  And we continue to work with CDC on recommendations.  The current information from the CDRH/CBER research that was discussed in July has been incorporated into the CDC website.  And the initial research on decontamination of medical devices exposed to TSE that was completed by CBER, which is Dr. Asher, and CDRH, which was Dr. Brown, was presented last July, and there are ongoing steps now to look at additional parts of the study.  So the next slide, please.

            Now, the reason I'm bringing up in vitro diagnostic devices is really more of a solicitation.  The CDRH Office of In Vitro Diagnostics would be the appropriate part of FDA to review a test to aid in the diagnosis of variant CJD or infected and at risk for developing CJD.  And just like CBER, CDRH has the mechanisms to meet with sponsors early and to try to establish a least burdensome pathway to market, as well as procedures for expediting review of new and break- through diagnostics with significant public health impact, which, of course, a device like this would be.

            So for sponsors of tests that would aid in the diagnosis of variant CJD or for patients infected and at risk for developing CJD, I would urge them to contact the Office of In Vitro Diagnostics as listed on this slide.  Next slide, please.

            And in conclusion, I have discussed and tried to be succinct about the steps that we have to go through to take action to minimize TSE risk, and I think that we have continued to work on that, and I want to thank the CDRH TSE Working Group, which has been very diligent over the years, to continue to pursue this issue and for their hard work recently in response to the finding of one cow in the United States.

            I did include the guidances at the end of my slides, just in case you were not familiar or wanted to see what I was referencing.  So thank you very much.  Are there any questions?

            CHAIR PRIOLA:  Dr. Nemo?

            DR. NEMO:  I would assume that in the diagnostic tests we're talking about, if it were a screening test for the blood supply, then that would come under the auspices of Jay's group?

            CDR O'LONE:  Yes, it would be in CBER.  And I was going to explain that in my speech, but then I thought you might have thought that is what we do, so I just left it out.

            DR. NEMO:  Yes.

            CDR O'LONE:  But that's exactly right.

            DR. NEMO:  Okay. 

            CDR O'LONE:  Any other questions?

            CHAIR PRIOLA:  Dr. Asher?  Hold on just a minute, Dr. Gambetti.  Dr. Asher?

            DR. ASHER:  If there were to be either a diagnostic test or a blood screening test submitted to the agency review, George, I can assure you that both Centers would review it jointly.

            CHAIR PRIOLA:  Dr. Gambetti?

            DR. GAMBETTI:  As far as the danger of contaminated surgical instrument, especially for human medical treatments, I want to underline that there is another very important issue for ? to have a good National Surveillance Center, and it is very important that that Surveillance Center render a diagnosis on a case that had surgery as soon as possible.  The situation has presented itself several times of the patient that was not suspected to or having CJD and now to be CJD after surgery, when the instrument that had been used on other patients already.

            CDR O'LONE:  Right.

            DR. GAMBETTI:  So that's very important that diagnosis be made and that the diagnosis be made quickly.  That's why the Surveillance Center is really trying very hard to have not only as many cases to examine not only as many cases as possible, but to have also turn-around extremely short, as short as possible.

            CDR O'LONE:  Thank you.  And I would note that Dr. Edmiston, who is the chair of our General Hospital Panel, who came last July, had discussed that risk problem as well, the need to be able to turn around and decide what they should do as far as a potential exposure or a known exposure of instruments after a CJD case.

            CHAIR PRIOLA:  Any other questions?  No.  Thank you, Commander O'Lone.  Our last speaker of the morning is Dr. Potter.

            DR. POTTER:  Thank you and good morning.  As we all know, the focus of this meeting is on medical products.  Do you want me to talk into this thing?

            CHAIR PRIOLA:  Yes.

            DR. POTTER:  All right.  I'll see if I can remember to do that.  The focus of this meeting is on medical products, but I just couldn't bear the thought of having you all here assembled and not say anything at all about food, and Suzette and Bill very graciously gave me a few minutes here at the end to remind you what we have been doing and what our intentions are to enhance the safety of cosmetic and food products, including dietary supplements, food ingredients, food additives.

            The Committee has discussed to a considerable extent the difference between guidance and regulation.  And what we have been using up to the present to enhance the safety of food and cosmetics is a series of letters to manufacturers, announcements in the Federal Register and guidance documents to encourage and cajole the industry to assure the safety of their sources and the efficacy of their effectiveness of their processes.

            Since 1992, the agency has recommended that firms manufacturing or importing foods that may contain bovine tissues or their derivatives assure the safety of their source.  Also, since 1992, FDA has advised dietary supplement manufacturers and importers to assure that no dietary supplement ingredients come from cattle born, raised or slaughtered in countries that are at elevated risk of BSE.

            Since 1994, we have recommended that firms manufacturing or importing cosmetic products that contain bovine tissues or their derivatives take the necessary steps to assure the safety of those products and ingredients.  And in 1997, FDA published guidance on the production of gelatin for its many oral and cosmetic uses that recommended removal of skulls, spinal column and spinal cord and made recommendations on safe sourcing of bones and hides.

            During the last Advisory Committee meeting on July 2003, you heard evidence of the effectiveness of the gelatin process in activating prions and evaluated possible changes to our gelatin guidance.  We are considering your advice as we review the gelatin guidance in light of our pending regulatory changes.  As we review the guidance and as we draft the Interim Final Rule, we will likely find it appropriate to bring back to the Committee a new draft gelatin guidance to ask for additional advice and comment.

            Yesterday, Mary Porretta from FSIS outlined the USDA response to the documented presence of BSE in the United States, and briefly in January USDA published regulations that prohibit the inclusion in human food of non-ambulatory disabled cattle, SRMs from cattle older than 30 months, plus the small intestine and tonsils or at least the ileum and tonsils of cattle of all ages and mechanically separated beef.  FSIS has also established new standards for advanced meat recovery to limit central nervous system tissue in that product.

            On January 26th of this year, FDA announced its intention to publish parallel regulations to provide the same level of increased protection for food and cosmetic products regulated by FDA.  If I could have the slide now, please?  Thanks.  And with these new regulations in place, the flow of FDA food and cosmetic products comes down through animals inspected in past for human food and comes down into edible trim and I think advanced meat recovery used for, among other things, foods that contain just a small amount of beef and are therefore regulated by FDA, instead of USDA, like pizza toppings and soup and some frozen dinners and perhaps some baby food.

            Edible fat gets rendered into edible tallow for food use and food additives, ingredients, titrate supplements, soaps and cosmetics also use a tremendous amount of tallow.  You see it showing up at present in a couple of boxes here on this slide as this current supply of edible tallow is inadequate for all of the purposes that tallow and tallow derivatives are used for.

            Edible byproducts include brain, spinal cord and eyes from cattle under 30 months of age, and from cattle of all ages the liver, kidneys, hearts, spleen, thymus, testicles, pancreas, placenta, esophagus, bile, mesentery stomachs and probably a few other body parts.  These get used in dietary supplements and other food and food ingredients, including soups, stocks, flavorings, extracts, collagen, amino acids, bones, as you recall are transformed into gelatin, hides for gelatin, collagen come down the inedible side, because of the way slaughterhouses are constructed.  I think tracheas are probably harvested over there as well.

            Now, we are still in the drafting process for the IFR.  Because it is an Interim Final Rule, it will go into effect when it is published, and will continue the process that has been ongoing for the last dozen years of concentrating the flow of regulated foods and cosmetics down this right hand side of the slide.  And with that, I will end this discussion of food and cosmetics, and will hope that this sort of finds the Committee for future meetings when we can focus on this more interesting aspect of what FDA does.

            CHAIR PRIOLA:  Thank you, Dr. Potter.  Dr. Wolfe?

            DR. WOLFE:  Am I understanding the lower right hand corner correctly?  Does it actually say that for cattle under 30 months that it is okay to use the brain, cord and eyes for dietary supplements?

            DR. POTTER:  Right.  Those are not included in the definition of specified-risk materials.

            CHAIR PRIOLA:  Dr. Khabbaz?

            DR. WOLFE:  As you know, it is not exactly easy to figure out what country these things come from, but given that at least Dr. Brown's study shows that whereas the brain itself may not start getting affected until over 30 months, the other parts of the body are affected under 30 months.  This seems like a literally crazy idea to encourage dietary supplement manufacturers to include brain as long as the animal is under 30 months.

            DR. POTTER:  The IFR process does have a comment period.

            DR. WOLFE:  I will comment in writing myself.

            DR. KHABBAZ:  Yes, Morrie, I have a question, again, regarding supplements.  And I'm always looking at that because I have the same reaction saying everybody buy product supplements and you went through the list and I think I looked around and many people in the room were kind of, you know, rolling their eyes.  I'm thinking of people who, you know, by choice avoid bovine material and by choice, you know, don't eat many products here and then go and consume supplements.  I mean, have there been discussions about labeling as to origin and what goes into supplements?

            DR. POTTER:  That gets a bit beyond things that I know very much about.  Labeling issues are fairly difficult.  I think part of the problem is how far back does one label amino acids and fatty acids, things like that may be derived from bovine products.  But at some level a can of motor oil has relationship to a prehistoric fern and we don't consider it a vegetable product.  And I wonder, you know, on a label that contains fatty acids or amino acids, is it informative to include all of that information.  Tough questions.

            DR. DEARMOND:  It is a reasonable question though, because there is a number of things.  I watch the golf channel and they are always advertising some supplement that has got growth hormone or something else to improve your golf game.

            DR. WOLFE:  Or brain.

            DR. DEARMOND:  Or brain.  It probably does.  I am very surprised at that lower right hand corner, too.  But then you said the labeling is very difficult and yet I called one of those companies, because I was on this Committee, and I said where do you get those hormones and they couldn't tell me.  It has got to be -- reasonably they should know that and it should be labeled.

            CHAIR PRIOLA:  Dr. Johnson?

            DR. JOHNSON:  Excuse me.  I think there are two different issues in the lower right hand corner.  Sid and I come from different cultural backgrounds.  My grandparents were Swedish immigrants in the Midwest and they ate brains very likely with scrambled eggs for breakfast.

            DR. NEMO:  That's why you got involved in food.

            DR. JOHNSON:  Yes, that's why I got involved.  There are a lot of Midwesterners who, in fact, eat brains, cow brains and pig brains and all kinds of brains as food.  Then there is a different issue and that is the supplements like the one I have in my hand, which is called "Body Fortress," and this is not from some quacky store.  This is from the local vitamin shop in suburban Baltimore and it contains raw brain, if anybody would like to try some?  There is a lot of this on the market shelves.  The problem is you need a magnifying glass.  I've got one right here.

            DR. NELSON:  It wouldn't be licensed if they had ephedra in it though, would it?

            DR. FERGUSON:  That's okay.  Actually, it says raw gland complex (heart, brain, carotid, eyes, stomach and kidney).

            DR. JOHNSON:  Even better.

            DR. WOLFE:  I want to thank you for the kind offer.

            DR. JOHNSON:  You know, you can barely read that.

            DR. WOLFE:  This does sound like a no-brainer.

            DR. JOHNSON:  This is sold.  I mean, there are lots of them on the shelf.  If you go into your local store, your local shop, grocery store or whatever it is, but you need a hand lens and you will find out there is all kinds of brain being sold in there as a supplement.  Which I think is quite different than the stuff that is in the meat counter that is marked calf brains, which is for people who want to eat brain.  This is for people who don't know what they are doing.

            DR. WOLFE:  Well, it's also ? unlike calf brains, this is regulated by the FDA.

            CHAIR PRIOLA:  Okay.  I want to refocus the discussion now, back on the medicinal product, which is the basis of this meeting.  But I'm sure this will come up in the future.  It has in the past and it has now.  So we've been asking questions of the presenters.  Are there any other questions or comments the Committee members would like to make before, I think, we will just go right to the open public hearing part, unless there are any other comments or questions.

            DR. WOLFE:  We're going to need to leave.

            CHAIR PRIOLA:  Well, our lunch is scheduled for 11:30.  Is that right?

            DR. WOLFE:  We'll need to check out.

            DR. WOLFE:  Are we going to need to really have lunch?

            CHAIR PRIOLA:  You really need to check out?  You'll get charged?  Oh, I guess so.  All right.  That's a good point.  Thank you.  Do you want to take a 10 minute break, so that you guys can all check out?  Thanks for reminding me of that.

            DR. WOLFE:  Okay. 

            CHAIR PRIOLA:  And then we'll come back for the public open hearing.  Sorry.

            (Whereupon, at 10:54 a.m. a recess until 11:11 a.m.)

            CHAIR PRIOLA:  If the Committee members could come back and take their seats?

            SECRETARY FREAS:  We are going to begin with the open public hearing, at this time.  This is the opportunity for the public to address the Committee on matters related to the agenda topics.  The public is welcome and encouraged to participate.  Our presentations will be limited to six minutes and again, the Chair has been asked to read a statement regarding disclosure of Conflict of Interest issues at this open public hearing.

            CHAIR PRIOLA:  Both the Food and Drug Administration, FDA, and the public believe in a transparent process for information gathering and decision making.  To ensure such transparency at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual's presentation.  For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the Committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting.

            For example, the financial information may include the company's or a group's payment of your travel, lodging or other expenses in connection with your attendance at the meeting.  Likewise, FDA encourages you at the beginning of your statement to advise the Committee if you do not have any such financial relationships.  If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

            SECRETARY FREAS:  Normally, I would like the participants to the microphone in the order in which I have received their requests.  I would like to make a little change, if I could, just because we are set up right now for overheads and I would like to do the overhead projection first and then go on to the others, if that's okay with you.  Okay.  So our first presenter with overheads will be William Drohan from Clearant, Incorporated.  He will --

            MR. DROHAN:  Right.  I will.

            SECRETARY FREAS:  Oh, okay.  He doesn't.  Yes, go ahead.

            MR. DROHAN:  Yes.  I'm Bill Drohan and I represent Clearant, a biotechnology company in Gaithersburg, Maryland.  I would like to thank the Committee for an opportunity to present today.  Also, in terms of a Conflict of Interest, I am a full-time employee at Clearant, so my salary goes to the Universities of Virginia and California where my daughters go to school.  So I am compensated fully.

            Our company has developed a technology, which basically allows us to deliver gamma radiation to biologics under conditions where we can actually recover the activity of the biological material.  We have been able to demonstrate that we can inactivate bacteria, viruses and, more recently, prions.

            About 14 months ago, we published a paper in Vox Sanguinis in which we presented data in which we could inactivate one to two logs of prions while recovering the majority of the activity of a 25 percent albumin solution.  This was done in the hamster scrapie model that Bob Rohwer presented yesterday and, in fact, was done in collaboration with Dr. Rohwer.

            In lieu of time, I have made two overheads, and the first one basically describes the delivery of gamma radiation to fetal bovine serum.  It's a non-reduced gel.  It's an SDS PAGE gel and what one can see in lane, let's see, this would be lane three, is an unradiated fetal bovine serum sample as a control.  About 50 percent of fetal bovine serum in the United States is radiated to 25 kilograys, and what you can see in lane four is the result of that.

            What we have done has been to deliver additional doses of gamma, between 25, and if you look in lane 10, 105 kilograys of gamma, and what I hope to convince you in this overhead is that there is little change in terms of the size of the proteins, little change in the high molecular weight proteins, nor accumulation of small molecular weight, which would indicate a lack of degradation.

            Does this basically have any impact on biological activity?  There is another overhead there, if I could encourage someone to change the overhead.  What we have done in an admittedly preliminary experiment is to look at the ability of the fetal bovine serum treated to 105 kilograys to sustain the division of Chinese hamster ovary cells, a cell line that you well know is involved in the production of many biologics.  And what one can see, hopefully, is that at 55 or 105 kilograys, the doubling time for the ability of those cells to become confluent is unchanged.

            The reason that I bring this to the Food and Drug Administration is that we believe that this technology, the inactivation of prions in biologics, especially fetal bovine serum, can be considered one of perhaps a portfolio of different approaches to ensure the safety of biologics as they are manufactured.

            Certainly, diagnosis is important.  Certainly, prion removal is important, but we think this technology along with other ones demonstrates that the prion protein can actually be inactivated by this technology.  We also encourage those who are funding this type of research to continue to do so.  We have benefitted from dialogue with George Nemo and his group at the National Heart, Lung and Blood Institute.  We are currently funded by that Institute.

            And in a final point, I would like to mention that in the presentation that Bob Rohwer made yesterday, he demonstrated that there are 5 to 25 infectious units per ml in the serum of morbid animals.  That is truly a low level of infectivity if you compare it with the level of infectivity one sees in the viremic stage of other infections, such as HIV, hepatitis C and parvovirus infections.

            Being able to develop diagnostic tests, which basically effectively can pick up that level of infectivity, we think, is hard to do.  It's certainly worth doing, but a challenge.  Well, if you look at the level of infectivity, technologies like inactivation of the prions at 100 kilograys where you might get two, three or four logs could be clinically relevant in terms of the safety of those products.  Thank you very much.

            SECRETARY FREAS:  Thank you for your comments.  Is there anybody else, before we put the overhead projector away, who needs an overhead projector for this morning's open public hearing?  If not, we will go back to the order in which the requests were received, and the next will be a PowerPoint presentation from Chris Penet from Genencor International.

            MR. PENET:  Thank you, Dr. Freas.  It's a pleasure to be here to present an update to the Committee on some enzyme work that has been done in collaboration with Genencor and the Health Protection Agency Branch of the Ministry of Health in the United Kingdom.

            Genencor's role in this has been in the later stages.  The HPA had stated this work previously.  They were known as the Center for Applied Microbiological Research or CAMR.  Genencor got involved in the second phases, which I will play out as we go through.  It is a co-funded program with the HPA at this point.  First slide, please.

            I also will point out that I was not supposed to be the original speaker.  The original speaker was supposed to be Dr. Neil Raven from the HPA.  Unfortunately, he was not able to join us this morning, but this is the background of why the HPA or CAMR was interested in looking at solutions to decontaminating medical instruments, as they were charged by the Ministry of Health to look into more environmentally and user friendly processes versus some of the science that was coming out of Europe and using high caustic and high pressure treatments.  So they were charged with finding an effective and applicable, practical process to be able to do this, and I won't go through all the points.  Most of them have been touched on by this Committee in the past.  Next slide, please.

            But this is the basic of the science that they had looked at.  They originally started out in the late 1990s looking at basically every enzyme that was available in the marketplace.  They screened over 40 different enzymes through analytical techniques, such as Western blots, but then realized that they needed to take that analytical data to the next level to be able to ensure infectivity was being actually reduced, and so they started combining their analytical work with in vivo studies using mice.

            And I don't have the data for all the different enzymes they looked at, but the Properase enzyme, which is a commercially available product, was -- and again, the original work was funded by the EC and the CEAC Committees and the European community.  Properase was one of the enzymes that they saw some efficacy in reducing infectivity by about three logs, and then the MC3 product is when Genencor got involved and designed, based on genetic engineering, a more efficient enzyme for them to look at.

            They basically were looking at mouse-passaged BSE strain 301 that was then treated with a pH 12 at 60 degrees C for 30 minutes with the different enzymes, and then injecting them back into the mice for monitoring the infectivity reduction.

            The next slide is just a quick look, and you have seen many of these Western blots before, where the enzymes have been able to decrease analytically the prion protein, but the next slide is the one that shows the key data that they wanted to present.

            This orange line back here is the Properase enzyme that was originally identified.  All the other lines are different dilutions of the untreated mouse brain homogenate being treated back into the mice, and then this is the engineered enzyme, which is now showing roughly 500 days of survival of the mice compared to the first enzyme that they saw, which was back at about 175 days, and the straight material showing the mice being killed off in less than 150 days.  Next slide, please.

            So basically, where they are at in the process is that two enzymes are shown to be able to completely remove the immunoreactive material analytically, but there is a significant difference in the levels of observed infectivity through the mouse model.  And at the choice for the mouse model is a relevant combination of the agent and the animal, which is showing a significant reduction in infectious dose.  Next slide.

            So basically, the HPA has added this point in working with the Ministry of Health is they were showing, approximately, a seven log reduction in the infectious dose with the BSE model and with in vivo studies.  We have some further studies underway looking at injection versus wire implementation into the mouse cranial area.  The interesting thing is it's compatible with current disinfection practices.

            There are many products out there today that have enzyme-based pre-soaks, if you will, in formulations, so we're not talking about a major cost, hopefully, to the sterilization units.  It's a safe, environmentally friendly process and the interesting thing has been able to engineer an enzyme specifically for the prion inactivation.

            And there is also ongoing work looking at the MC3 enzyme for rendering bone meal, the prion for bone meal.  And actually, that's where the CAMR work originally started, was looking at a process to be able to reduce the backlog of infected bone meal that was built up in the U.K. from their outbreak in the mid '80s and early '90s.  And I believe that was the last slide, and these are just the acknowledgements of the HPA and the Genencor people.  Thank you.

            DR. DEARMOND:  Can we ask a question?

            SECRETARY FREAS:  I would prefer waiting until all these people have an equal opportunity, and then if you have questions, we can call somebody back.  Our next presenter on the agenda as received, in the order in which they were received, is Harold Baker, Technical Director and Principal Scientist, Pall Medical.

            MR. BAKER:  Good morning.  I am Hal Baker and I am here today as a representative of Pall Corporation.  Pall Corporation is a world leader in the field of filtration, separation and purification technology.  We provide leading edge products to meet the needs of global customers in transfusion medicine, biotechnology and pharmaceuticals.  I earn my livelihood as the senior vice president for the Medical Division, and our Medical Division is conducting animal studies on the removal and detection of infectious prion from red cell concentrates.

            We're doing this investigation in cooperation with the New York State Institute of Basic Research.  We're grateful to Dr. Freas and Dr. Priola for granting us the opportunity to share with you briefly the latest results of this work.  Now, my plan was to have our principal scientist, Dr. Sam Coker, briefly walk you through a PowerPoint presentation providing information on study design and results today and, unfortunately, he got snarled in LaGuardia traffic today, so I'm going to briefly read a statement where I have gone through his presentation and pulled out some of the key information that I would like to share with you today.

            The occurrence of a variant CJD in the United Kingdom, together with recent animal data, and the evidence that the distribution of vCJD may differ from the classical Creutzfeldt-Jakob disease has raised the question of the possibility of transmission of the causative agent by blood transfusion from infected individuals with no clinical symptoms of the disease.  In the present study, we are evaluating the use of a prototype of a new leukoreduction filter for the removal of infectious prion from red cell concentrates.  I will tell you briefly about the study design.

            Units of whole blood were collected into blood bags containing 63 mls of CP2D anticoagulant.  Red cell concentrates were prepared from whole blood, then resuspended in AS3 additive solution according to standard blood bank protocol.  10 percent scrapie brain homogenates in buffered saline were prepared from brains of hamsters infected with hamster-adapted scrapie.  The scrapie brain homogenate was clarified by ultracentrifugation, and the scrapie brain homogenate was added into the red cell concentrate.  The scrapie brain homogenate-contaminated red cell concentrates were filtered at room temperature with a prototype prion reduction filter.

            The presence of the scrapie brain homogenate in the red cell concentrate was determined before and after filtration, using a Western blot assay with 3F4 and 7D9 prion-specific monoclonal antibodies.  In addition to the Western blot, different dilutions of aliquot at the pre- and post-filtration scrapie brain homogenate red cell concentrate were injected through the intracerebral route into scrapie-susceptible hamsters.

            Preliminary results have shown removal of the infectious prion from full units of red cell concentrates to a level well below the limit of detection of the Western blot assay.  After 26 weeks, none of the animals injected with filtered scrapie brain homogenate red cell concentrate had developed any clinical symptoms of the disease.  But some of the animals in the control group are beginning to show signs of scrapie disease, and the disease is confirmed in one of them.

            The present results show that the prototype of a new leukocyte reduction filter are encouraging in removing infectious prion from red cell concentrates below the level of detection of Western blot.  The use of this type of filter may help reduce the risk of transmitting infectious prions through blood transfusion.  However, additional in vivo studies with the red cell concentrate from scrapie infected hamsters and other forms of TSE in clinical and pre-clinical stage of the disease are needed and are currently planned.

            By combining white cell filtration technology already widely in use in most countries to reduce donor leukocytes in red blood cells with the ability to reduce infectious prion below the level of detection of current methodologies, Pall Medical is taking one preventative step to eliminate concerns about circulating prions in human blood.

            This new technology development program is based on our surface modification chemistries that have demonstrated an affinity for prions.  We look forward to the opportunity to keep you apprised of progress.  Thank you for your time today.

            SECRETARY FREAS:  Thank you.  The next request is from Dr. Robert Rohwer.  He would like to speak to you as a private citizen instead of an invited speaker.

            DR. ROHWER:  There has been a lot of discussion around the table about closed herds as a potential source for sourcing of bovine materials, and wearing my hat, not my academic hat, but my hat as a consultant to Western Agricultural Services and the Prather Ranch, I wanted to make people aware of one such herd that does exist in North America.

            It has been in existence for over 30 years.  They have feed records that go back to prior to the emergence of BSE in Europe, prior to 1980.  These have been meticulously kept.  This is a herd, which has been -- I guess it would be called a hobby herd originally.  It has now been taken over for the express purpose of maintaining these animals in their pristine state.  They have never been fed anything, except food that has been raised on the premises of this property.  They have never received any meat and bone meal, for example.  It has been closed with respect to breeding in the sense that new genetics are introduced only as semen, so no animals are brought into this property.

            About 10 years ago, we designed and built a slaughter facility on the premises, so the animals never have to leave the property before the relevant bovine materials are taken off the animals for medical use and medical purposes.  The company that is primarily using the tissues from these animals at the moment is Collagen Corporation, but there are other companies that are using tissues from these animals and, as far I'm concerned, the herd is rather tragically underutilized.  So I guess I'm also speaking in the role of an ad hoc business development officer for this concern.

            But nevertheless, a herd like this does exist in North America and if there are people here who are interested in using these materials, they should get in contact with me and I'll get you in contact with those folks.  It's not a big enough operation that this is something that could solve the fetal bovine serum problems and that type of thing, but for focused high value products and use, it is an option.

            SECRETARY FREAS:  Thank you, Dr. Rohwer.  Is there anybody else in the audience who, at this time, would like to address the Committee?

            MR. CROTTEAU:  Hello.  My name is Patrick Crotteau.  I am vice president of Quality Systems for Inamed Corporation, and I would like to thank Dr. Rohwer for the endorsement.  Collagen Corporation was acquired by Inamed Corporation in 1999 and we maintain and manage this ranch for the sourcing of collagen for injectable uses.  So again, just to correct Dr. Rohwer, the Collagen Corporation has been acquired by Inamed.  We do now manage the ranch.

            SECRETARY FREAS:  Thank you.  Is there anyone else at this time?  If not, Dr. Priola, I turn the meeting over to you.

            CHAIR PRIOLA:  So what we have scheduled for the rest of the day is lunch, first of all, which is important, and then a discussion in the afternoon over the issues of current safeguards, possible future safeguards in relation to medical products that are regulated by FDA.  Are there any questions or comments that anyone would like to make before we break for lunch and come back at 12:30?  I know you had one.  Dr. DeArmond and then Dr. Johnson.

            DR. DEARMOND:  So I had a question for the, let's see, Genencor International, the protease, the protease person, Properase.

            MR. PENET:  Yes.

            DR. DEARMOND:  Oh, I see.  So you run this at a pH 12, and the question that we're always asked, because the main issue is not being able to eliminate infectivity.  It's being able to prevent destruction of all of the equipment that people want to deal with, and pH 12 can be destructive itself.

            Have you looked at a variety of stainless steel and other equipment to see whether they maintain their edge and things like that?

            MR. PENET:  That is currently underway.  That is part of the ongoing studies, but we're also looking at further engineering of the enzyme to get as much efficacy at a lower pH as we are at 12.  We realize 12 is still on the ragged edge, as well as 60 degrees is as well, but, you know, it's the first set of results and obviously using mouse models, it takes a while to do that and we're just getting into the formulation aspects of it.  We're not promoting that the enzyme itself is actually going to be the solution.  We really do believe it's enzyme plus chemistry plus process to get there, but that's work that is ongoing.

            DR. DEARMOND:  Great.

            DR. JOHNSON:  Yes.  I want to ask Bob Rohwer about how many other herds are like this.  I noticed that our local Wholesome Foods Store or whatever they call themselves, the natural food store, had a full page ad out this week in Baltimore saying that all of their meat comes from X packing plant, which never uses bone meal and is a closed group, and so on and so forth.  I have no idea.

            Is that common?  Are there multiple herds like that around?  And is there a greater source, that is, for safer serum and whatnot?

            DR. ROHWER:  I'm sorry, Dick, I can't really answer that authoritatively.  I am very familiar with this herd, because I helped develop it.  But I know that there are claims for closed herds, but I don't think it's a controlled definition and -- Lisa, you can correct me on that if I'm wrong, but my feeling is you can use that term freely, and so it means different things to different people.

            In some cases, it just means they are closed to breeding or the breeding is controlled and tracked, but it doesn't mean, it has nothing to do -- and typically, it means nothing about feeding.  Feeding is not part of the definition.  And so in this particular instance, this was kind of unique.  The origins of this herd are extremely unique, and I would be sort of surprised if there are others like it, yes.

            DR. FERGUSON:  I think, you know, what you see in certain supermarket chains, there are claims about natural beef.

            DR. ROHWER:  Yes.

            DR. FERGUSON:  Organic beef, etcetera.  At this point really, truly, what does that mean?  It's a bit difficult to say.  I think as Dr. Rohwer just mentioned, definitely with those it's probably not a true closed herd, in the definition that a scientist would think of a closed herd.  Also, you probably have to look real carefully at, you know, what are their practices and what really does that mean.

            I would also just point out that in certain European countries, there have been cases of BSE found in closed "organic herds," organically raised beef herds.  So you just need to be real cautious on your definitions.

            CHAIR PRIOLA:  Dr. Jenny?

            DR. JENNY:  Yes.  The definition varies from state to state and industry to industry, and so if you were going to try to do something like this, you would have to standardize what you're talking about.  I know there are a few organic herds that are very careful and actually analyze their feed, but a lot of them depend upon certification coming from the feed manufacturer and, you know, the certification is as good as the quality control process behind it.

            CHAIR PRIOLA:  Okay.  If there are no other questions or comments, let's adjourn for lunch and return at 12:30 for discussion.

            (Whereupon, the meeting was recessed at 11:38 a.m. to reconvene at 12:37 p.m. this same day.)



          A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

                                        12:37 p.m.

            SECRETARY FREAS:  Since many members do have flights to catch this afternoon, we would like to go ahead and resume the meeting.

            CHAIR PRIOLA:  Okay.  So it looks like most of the Committee members are back in the room and are at the table, so I would like to resume, so that we can get out on our deadline,  so that those of us who have flights can actually catch them this afternoon.  I think what we have to do this afternoon for the discussion is to focus on the topic of medical products and how, in light of the variant CJD, the probable case of variant CJD transmitted by a blood transfusion, the recent discovery of the BSE cow in Washington, how we have to take those into account when we consider risk-based sourcing of bovine material that is used in medical products, how the safeguards for FDA-regulated medical products have already addressed those concerns, how those safeguards, based upon the current science, might be improved.

            As an example, in terms of blood donation, we have to consider that now that we have, again, a case of a probable vCJD transmission via blood, does the FDA have to begin to consider deferring donors now with a history of transfusion?  Are broader and more restricted deferrals necessary?  Is leukoreduction a good safeguard?  In terms of vaccine production as another example, do we have to start worrying about testing cell lines now for susceptibility to BSE agent or variant CJD agent, etcetera?

            So as a reference, you could go back to Dr. Scott's talk earlier in the day around the slide on the top of page 6 of your handouts, give some topics that you can think about and address and discuss, some of which we already have.  So I would like to open up this discussion for comments, questions.  Dr. Wolfe?

            DR. WOLFE:  This is not meant as a diversion and it will probably take about 30 seconds is all, and in just trying to summarize some of the things that happened yesterday, which is that even though our charge is to sort of say did this Committee, which I think they did an excellent job anticipating the possibility of transfusion case, which now has happened, and I think that we look good in retrospect.

            But aside from that, the issues of: (A) Traceability of cows; (B) The feed ban and; ?) The testing, which were all discussed yesterday, even though this is not our topic, our comfort at making any kind of recommendations are going to be very different if we can be assured in the future that these have been seriously addressed.

            I mean, the traceability was a big problem and even though the International Committee told them to stop looking for cows, by the time they told them to stop looking, they probably would have been able to find more cows with what was an excellent disease outbreak investigation, hampered only by the traceability problem.  And secondly, the feed ban still has got some holes in it and, as was pointed out yesterday, if you look only at the feedlots, the feed manufacturers and don't ever look on the farms, you may miss some stuff that's going on.  And then third, the testing.  I mean, I think that at least a number of people on this Committee were probably not aware of the fact that no normal cows have been tested at all, and whereas one might not want to test every cow as in Japan or even every cow over 30 months, some consideration needs to be given.

            That is really all I wanted to say, and I think that from what I heard from other people here, we would support just the idea of encouraging those three things, some of which are USDA, some of which are FDA, the feed ban, to just make as rapid progress as possible, because that will ensure the larger picture that we're worried about.

            CHAIR PRIOLA:  Dr. Johnson?

            DR. JOHNSON:  Well, viewing it as titres and when you're looking at 108 in one organ and 101 in another, you just realize that volume for volume, some things are important and some are pretty trivial by comparison.  So it seems to be the brain and the spinal cord that are the big concern.  What would be the problem, just logistically and economically, of removing the brain and spinal cord from rendering, just bury it and not process it back into the food chain, be that food chain human or animal.

            DR. WOLFE:  Or the food supplement chain.

            DR. JOHNSON:  Food supplements, and I will even give them up for breakfast.

            CHAIR PRIOLA:  Dr. Ferguson?

            DR. FERGUSON:  Yes, just to answer some of this.

            DR. JOHNSON:  I waited for you to come back before I answered the question.

            DR. FERGUSON:  Sorry.  Thanks.  Some of the implications of those type of recommendations, it's somewhat straightforward to think of that in a slaughterhouse environment where, you know, it's easy to remove those and that's not necessarily a problem.  You know, you can divert those one way or the other.

            Where the issue comes in is in the dead stock and more the animal disposal end of things, and I think perhaps what a lot of folks in the Committee don't necessarily recognize is, you know, that's another component of rendering, where they are picking up dead stock and they are not set up to remove specific parts from that animal.

            DR. JOHNSON:  Yes.

            DR. FERGUSON:  That hide comes off, the whole carcass goes in the grinder, and you go.  So that is where the issue comes in and at least my understanding is sort of where the industry is, at this point in time, if those type of requirements were put in place, essentially, what a lot of the renderers would say is, I'm not going to pick those up.  So then we're stuck with a large pile of dead animals that we have to deal with in some way, shape or form.

            CHAIR PRIOLA:  Dr. Nelson?

            DR. NELSON:  Are the new plans for the Department of Agriculture to test dead stock, in addition to those that can't walk very well and have fallen over?

            DR. FERGUSON:  Well, I think if you look at the slides that I presented yesterday, we already have been testing dead stock.  For the past two and a half years, we have been including dead stock in our testing population.

            DR. NELSON:  So are you confident that there is no BSE in that population?

            DR. FERGUSON:  Okay.  Again, our surveillance is not meant to identify specific sub-populations and the prevalence in that sub-population.  Our surveillance is geared to identify presence of disease in the U.S. at a given level.

            DR. NELSON:  But is all dead stock, with the new plan, now to be tested in the future, or just up to 40,000 animals?

            DR. FERGUSON:  You mean the Surveillance Plan?

            DR. NELSON:  Yes.

            DR. FERGUSON:  Well, first of all, again, you know, there's a lot of options still under consideration for surveillance with, you know, many different recommendations have been forwarded to us both from the International Review Team and lots of things swirling around out here.  As we're continuing with our 40,000 goal, that does include dead stock as part of the targeted high-risk population.  I mean, I can put the slide back up again, yesterday, that says these are what we include in our targeted high-risk population, non-ambulatory dead stocks, CNS, etcetera, etcetera.  So those are included in the population.

            CHAIR PRIOLA:  And I think in terms of sourcing for materials to be used in human and veterinary medical products, the high-risk category, Category A, spinal cord and brain, they are not used anyway, if I understand correctly.  They are not sourced unless it's absolutely justified, and if they are sourced, it's from a low-risk BSE country.  So those are at least some of the safeguards that are in place for that, from the FDA's point of view, if I understood Dr. Scott's presentation this morning.

            DR. JOHNSON:  But even if it's a downer cow like the cow in Washington, we kept hearing the comment that don't worry, the brain and the spinal cord didn't go into the human food chain, it went to a rendering plant.  But it seems to me that, you know, they may only be making vitamin supplements and mascara and stuff like that out of that and not making, you know, sauteed brain, but it's still in the food chain in an indirect way.  Isn't that right?  I mean --

            DR. FERGUSON:  Well, I think the offal from that type of a facility, which would have included the, you know, stuff from this animal, that's not edible rendering.  That's inedible rendering, you know, so that's not going to be in a dietary supplement, per se.

            DR. JOHNSON:  Soap.

            DR. FERGUSON:  Yes, soap.

            DR. JOHNSON:  Cold creme.

            DR. FERGUSON:  I don't know.  Actually, I don't know where cosmetics manufacturers -- if they obtain their product from the edible rendering chain or the inedible rendering chain.

            CHAIR PRIOLA:  Well, that's something that I don't know that we have to address here with the cosmetics.  I want to steer away from the dietary supplement, cosmetic thing, because we all know that's an issue, but I would rather stay focused for a moment on the medical products, because that is sort of the charge of the Committee today.

            DR. NELSON:  I don't know.  What would be the problem with testing all dead cattle or downer cattle, and is that under consideration as a possibility?

            DR. FERGUSON:  Well, there are lots of things under consideration as a possibility, and I guess I would just encourage the Committee any time we're talking about surveillance, you know, let's decide what we're trying to do with our surveillance.  This is the point that I was trying to make yesterday.  You know, it's not just a matter of oh, test all of this or test all of that.  You know, what you need to do is decide what is the question you're trying to answer, and then you set up your program to do that.

            And, you know, I guess, internally within the Department, you know, we have set up lots of different questions that we could try to answer, and those are all the different things that are being considered.  You know, it ranges from continue with our, you know, one in a million and a 95 percent confidence interval in a targeted high-risk population, it could go up to one in 10 million, a 99 percent confidence level, again continue in the targeted high-risk population.  But you need to decide what question you want to answer, and then you decide how you're going to do it.

            DR. NELSON:  Well, it seems to me that once you have found that the rates are higher than one in a million in the one downer cattle that has been detected, then you have got to readjust and find out what now are you going to do.  And, you know, after blood donors were found to be HIV positive, they decided to test them all, and I can't see any real difference here between particularly edible products and BSE testing of cattle.

            CHAIR PRIOLA:  Dr. Bailar?

            DR. BAILAR:  Well, this brings me to something about which I have had a growing concern over a couple of meetings, and especially the last two days, which is the strength and reliability of the many risk assessments that we have heard about.  This is, fortunately, an uncommon condition here, so we don't have a lot of positive data, but we do have a fair amount of reliable laboratory data and more on the way.

            But overall, as an old-time risk assessor in other contexts, I am very deeply troubled by the fact that we really don't know what the risks are.  We see risk assessments.  We have seen some here that are presented with an air of some authority and go to two or three decimal places.  I am not sure that any of the ones we have seen here are correct within a couple of orders of magnitude.

            There are too many unknowns, uncertainties in the risk assessments, and I think it would be useful for FDA to make a major effort to improve the database to identify the uncertainties in each of the risk assessments, see how much slack there is in them, and try to come out with not a single figure, but with a plausible range of risks, because at our present state of knowledge, I think that's the best we could possibly do.  The risks may be much greater than we think.  They may be much smaller.  I have no way to tell.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  Yes.  Following up on that, I think what has been learned ? since at least it became newsworthy on December 23rd ? that somehow there is a BSE cow in the United States, the confidence level of what has been done dropped dramatically.  First of all, that there was one here, that it snuck in from Canada that we learned a couple of days later, but also that now there is huge numbers of cows that have been coming in, and that the only criterion so far for testing is that they are downers.

            So we have missed probably many of them.  We don't even know.  I think the confidence level dropped that I have had, is we have no idea now, and that the sentinel one says we don't know an awful lot about what's going on.

            CHAIR PRIOLA:  Dr. Gambetti?

            DR. GAMBETTI:  Yes.  I agree, I agree with what was also said yesterday.  I just really cannot resist the temptation to add something or repeat myself again.  European countries went through the same procedure, decision process.  They always had to -- they had to deal exactly with the same problem, so we don't have to reinvent the wheel.  They have done it already and they make a decision.

            The least I think we can do is analyze what led them to that decision.  You know, the European, at the time, if I remember correctly, at the time it was decided to test animal above 30 months of age, some of the countries were, essentially, BSE immune.  But once they started testing, those countries also found a certain number of cases.  So I really urge all of us to analyze the data and see whether really, on the basis of what the data tells us, whether really we should adopt this same procedure.

            DR. FERGUSON:  Actually, I think that's a good point, to analyze the European data and to talk with the Europeans in regards to their experience, specifically in testing the clinically normal animals over a certain age.  They took that decision to include that population in their testing for consumer confidence reasons, essentially, and they sold that decision for consumer confidence reasons.

            I think if you look at the data, you know, that's not where they are finding disease.  I think their percentage of positives in the clinically normal population is .003 percent.  And if you speak with them, you know, most of the European regulators and the experts, you ask them if they would back off of that decision, most of them would back off of that decision.  And I think some of that is shown in the report that we got from the International Review Team, is, you know, testing clinically normal animals at slaughter is not scientifically justified.

            I think they would all agree that a targeted surveillance program, you know, looking in your highest risk population if you're wanting to find the disease, that's the way to do it.  And, you know, that's one of the things, again, in 2000, 2001, it wasn't just that they said test clinically normal animals.  It's that they said okay, we're also going to test the targeted high-risk animals that they hadn't necessarily been testing before.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  Well, there is something in that statement that I find difficult.  Certainly, consumer confidence is a very important aspect, and we have to acknowledge that, because, even myself as a consumer, I don't want to eat contaminated beef and I certainly don't want my kids to.  If I eat it, it doesn't matter.  The incubation time is going to be longer than my life.

            But that is a very important part.  And then if the other idea is testing, because they don't want to identify it, they have identified a low level, but they have already been listed now as on the more endangered, they have a problem in their country, so people aren't going to buy their beef as they used to.  And I sometimes wonder in the United States whether we're not doing that.  We don't want to find any problem here, even if it's .1 percent, because people will then list us as a Class III or IV country, in terms of beef.  But that is contrary to science.

            I think the science is to look and to get data.  We don't have data, which you want to analyze data.  We have no data.  We have one cow, and a lot of possibilities that there are more of them because of the uncertainty, and we need to analyze data.  We need to get more.  To analyze data, we have to have data to analyze.  So we have to test more.

            CHAIR PRIOLA:  Dr. Wolfe?

            DR. WOLFE:  We already have lost, not a large chunk, but at least a number of countries, just because of this cow are not buying U.S. beef and it isn't that they aren't buying downer cows or dead cows anymore.  They are not buying healthy cows, and I just think ? I agree with both what Pierluigi is saying and what you're saying, Steve, is that not to do any testing at all in normal animals, whether it is a combination of consumer confidence, both consumers in this country and consumers in these other countries, doesn't make an awful lot of sense.

            Within the scope of Europe, there are, at one end of the spectrum, the United Kingdom where they had a huge number of cow cases and human cases, but the other end of the spectrum includes European countries that are much more like the United States, where they had one human case and it didn't even arguably come from that country, or they had one that did come from the country.

            So I think that if one looked at all of the policies there, and they differ, even though there is a EU, they have different policies, that we might find something that is instructive and, you know, we could maybe modify something.  But I think not to look -- you know, I'm sure that some of them may be sorry for what they did, but maybe it's only in retrospect.  You can't, in the absence of data, make a decision saying well, if it comes out this way, I'll be glad and if it comes out this way, it won't be good.  That is not a scientific approach to this problem.

            CHAIR PRIOLA:  Mr. Bias?

            MR. BIAS:  I guess I'm the guy without any letters after my name that is just looking at it from a consumer perspective.  One of the things I see is we need to decide whether we're regulating the beef industry or whether we're enabling the beef industry, and I realize that these changes will be costly and I think that they will be very difficult for the industry to adapt to, but over time they will, just as the blood industry had to adapt when HIV hit the market.

            Now, in retrospect, which is always 20/20, you could say if we had implemented certain blood tests early on in the HIV crisis, they would have been very costly to our system, but they probably would have saved us billions of dollars in health care costs, in hindsight, and lots of lives.

            So I would urge everyone to take a new look at this.  This industry will survive whatever changes are imposed on them.  That is what capitalism is about.  They will adjust.  It will take them time.  It will be painful.  It will be costly, but as the Federal Government, we can't enable them, when it's the safety of the American population's health that's at stake.

            We have to make certain decisions, and it will take them some time to make these adjustments.  And in some cases, it will be costly, and in some cases, we'll have to help them make these adjustments.  But if we say that, you know, brains and spinal have to be removed and sent to a different place, and the rancher says well, I'm not going to pick that up, well, they are out of business.  That's the way life works.

            It's, you know, sort of we have to make a decision about which side of this coin we're going to be on.  And right now, just on the information that was provided for us yesterday, I'm not feeling a lot of confidence, and I think many of the other members of the Committee aren't feeling that confidence either.

            So before we make a mistake, maybe we ought to plod it out and start it slowly, and maybe we ought to give them the benefit of the doubt, give them the opportunity to make some changes, but let's go forward.  Let's not go backwards.  Let's not stop ourselves with speculation.  Let's figure out what it is.

            CHAIR PRIOLA:  Dr. Creekmore?

            DR. CREEKMORE:  I guess I would put out there that testing is important and it's a part of the equation, but all of us have some knowledge about how tests work, and we know that testing will detect animals at a certain point in the disease process through the clinical course.  But, you know, testing isn't something that is the magical bullet that is going to detect every animal.

            And I guess I would ask the public health professionals out there, you know, how do you view the other safeguards that were put into place, in terms of the things that are really, truly protecting human health?  You know, from the animal health side, the SRM, the new SRM Rules, the feed ban are the really critical components to me to protecting animal health.

            CHAIR PRIOLA:  Dr. Bracey?

            DR. BRACEY:  Again, thinking about this from the perspective of the blood industry, when we are given a risk, perhaps sometimes even a theoretical risk, we consider the test, but if we are told that the risk is at the level of about one in a million, which is what we have heard from some of the projections, which may be off, and there is a test, then, in fact, we do offer that test.

            I am somewhat concerned about, as has been voiced before, in essence, a double standard.  That is, we're very concerned about what we're going to give intravenously, but for some reason or another we're not equally as concerned about what we're going to consume by the oral route.  I mean, to me it's just a double standard, and I could not defend having such a double standard.

            The other point is that in terms of looking at only the sickest animals, although the window may be short, you know, we have been looking for emerging diseases, and if we test only the sickest animal, we'll see it too late.  Maybe it won't show at 12 months, but we have heard that already it's shown at 20 months for some animals.

            So again, I think that having these cutoffs are somewhat arbitrary, and I would propose that we consider looking for emerging disease, rather than disease after it's manifested.

            CHAIR PRIOLA:  Dr. Bailar?

            DR. BAILAR:  Other parts of FDA do regulate on a basis of lifetime risk of one in a million.  Is that an option here?

            CHAIR PRIOLA:  What do you mean by an option?

            DR. BAILAR:  Well, I know a little bit about how they regulate possible carcinogens in food, for example, and the standard there is, at least it used to be, a lifetime risk of one in a million.  In this context, is there a possibility of regulating on the basis of a lifetime risk of one in a million?  I don't know.

            CHAIR PRIOLA:  Dr. Jenny?

            DR. JENNY:  Are you saying one in a million people being infected?

            DR. BAILAR:  Right.  I'm talking about human risk, over a 70 year life span, of one in a million.

            CHAIR PRIOLA:  Well, I think in some ways with the blood deferrals that have been put into place over the last seven years, that's what they are doing.  They are actually putting forth recommendations based on a theoretical risk that's significantly less than what you just said.  So they are able to do that, in that regard.  Dr. Nelson?

            DR. NELSON:  Well, I think we probably have a fair handle on transfusion-transmitted CJD, but I don't think we have a very good handle on vaccine-transmitted CJD or other biological, other products.  I mean, I don't know how we would identify a case unless we had a huge cluster of cases that somehow were related to a product, an injectable product, or a food.  I mean, we might see, because I think the risk is probably fairly low, and, you know, the risk of -- well if we found variant CJD, I suppose we would go back and look, but I think it would be difficult to know.

            CHAIR PRIOLA:  Dr. Johnson, did you have something to add?  Oh, did you want to finish?

            DR. JOHNSON:  I would have to say that the risk of --

            CHAIR PRIOLA:  Well, hang on just a minute.  Dr. Bailar had one more comment, then I'll give it back to you.  Sorry.

            DR. BAILAR:  I have a related question, again, from ignorance.  In devising new regulations, is the focus at FDA on the best estimate of risk, on the highest plausible level, maybe an upward 95 percent confidence bound, the lowest plausible level or what?

            CHAIR PRIOLA:  Well, someone from FDA would have to answer that.  I know we're not advising in that regard, but perhaps you could give us the information.

            DR. MIDTHUN:  Karen Midthun, Acting Deputy Director for Center for Biologics.  I mean, obviously, this is a question that impacts on a number of centers at FDA.  I think that we look at all those factors when you come out with a regulation if that's what we're to do, you know, to assess, you know, what are we trying to -- what's our goal here.  And I think, in general, you do try to, you know, limit the risk, but within, you know, what's feasible and also within what's known.

            DR. NELSON:  I think, you know, BPAC, we have been -- I mean, as close to zero as possible.  There is no guideline of one in a million or anything.  We have recommended procedures, you know, where the risk is probably one in a million.  I think that there isn't any magic figure over which you accept a certain risk.  I don't think that, you know.  And applied to this debate, it becomes interesting.

            DR. BAILAR:  I don't have any particular difficulty with the notion of accepting a small risk as long as we know what the risk is and make the rational decision that the benefits of accepting it outweigh the risk and the costs of it.  But the situation I see now is that we really don't have a good idea of what the risks are of any of these things.

            CHAIR PRIOLA:  Dr. Johnson?

            DR. JOHNSON:  Yes, I would agree with that.  We don't know.  We do know that we all do have a risk and it's one per 100,000 per lifetime, about, or about that number.  And do we know anything that absolutely increases that?  Yes, living in England between 1980 and 1996 does and we're not even sure it's eating meat.

            It may be exposed to rendering product by some other method.  All you can say is living in England during that period does it.  Getting a dura graft does it, having pituitary hormone does it, and we're pretty much in the dark beyond that.  So I find it very difficult to know how to say we don't know that blood transfusion increases the risk at all.  I mean, there is one case and that's only in England.  So I think it would be very hard to come down to a number.  I don't know how we would do that.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  Yes.  I don't want to sound like a broken record here, but our problem is we have no data.  We don't.  We can't make a risk assessment, at this stage, and the events over the last couple of months have told us that we really don't know, and we don't know how many of these animals that are killed before they are downers for all the variety of products that are derived from them might have the disorder.  We have no idea.  Just looking at downers doesn't tell us about the ones that don't get that far.

            And it's not just for our food, because it impacts the blood industry.  It impacts the pharmaceutical industry.  There is a lot of cost to all of this.  And are we going to have a stage where we say that people living in the United States from 2000 to 2003 can't donate blood, because we don't know what the risk is, but there probably was a risk then?

            So we really need to know this and we need to know where it is, where it's located.  We have to know some sense of whether we can contain it and whether we could stop it, and we don't even know the origin of the risk, because we don't have any data.  It's possible that with some data over the next couple years, we could stop the whole thing.

            CHAIR PRIOLA:  Dr. Wolfe?

            DR. WOLFE:  I would just like to go back briefly to what I was saying before, is that in the absence of any human case of blood transfusion, in the absence, at that time, of even any animal transfusion, the intracerebral injections were the main known animal transfusion, but back three, four years ago, there weren't any animal-to-animal, you know, cheap and whatever transfusions.

            The Committee made a very wise decision, a very cautious one, saying if you have been in that country or those countries during that period of time, it doesn't make sense to allow you to be a blood donor.  And similarly, a lot of the decisions made in Europe were made in countries after they had or when they started having or slightly before they started having human cases.

            And, you know, there is obviously something to be said for the idea that a repository of infectious prions at some threshold is necessary before you get a human case.  We don't have any human cases in this country, so we have no data on human cases, and we have no data.  I mean, at this point, technically, there has never been a cow in the United States, indigenous U.S. cow, that has been infected, but it is largely, as Pierluigi had said several times and Steve has agreed, we haven't looked ever at anything other than those kinds of cows.

            So I think that the charge that we are given, namely to advise FDA on blood products, and this we can say, thus far, you seem to be moving in the right direction to tighten up and reduce the chance via a whole bunch of different ways and some new ones that we heard about today.  Given that we have no idea, for example, I mean, let's assume that in New Zealand and Australia where they have done some testing, they have never found a cow.  In the United States and Canada, we have, you know, three cows now, one came here, two were still up there.

            I just don't know, and I'm just reflecting in a slightly different way what other people have said, how we can be asked based on no information, there is no human risk data, there is no animal risk data, how we can go terribly beyond what we have and look at these processes and say yes, that looks like it will make this product slightly safer or that much safer.

            I mean, in my optimism, even though I am accused of being a pessimist, we do have from the data from the U.K. and elsewhere, this is a bolus of infected material that seems to be moving out of the world.  How quickly it moves out of the world, we don't know.  And certainly, there will be more human cases.  Whether there will ever be a human case in this country, we don't know.

            So just to summarize all of that, I just think that in the absence of any information about human risk or animal risk in this country, and we're talking about sourcing that is more from this country than elsewhere, we have already dealt with some of these sourcing problems for gel, for instance, from Germany and other countries that actually have BSE, I just think we can -- and I suppose that's why we were wisely not asked to vote on anything, because I don't think we could vote on anything.  All we can say is keep moving in a better direction.

            And again, to reemphasize what other people have, pay a lot of attention to the tracing and the feed ban related to that or downwind from that or down the line from that, the testing.  Think about doing some testing of normal cows.  I think that's the main advice we can give.  I just can't imagine it isn't to discriminate between blood and blood products and vaccines and biologics or, I mean, the only one that's relatively easy is the food one.  I just think that isn't even worth discussing at all.

            So, I mean, that's my views and I don't know.  I would like to know what other people think about that.

            CHAIR PRIOLA:  Dr. Nemo?

            DR. NEMO:  You know, I think the question has been framed.  I think we want to know what the magnitude of the problem is.  What's the magnitude of the problem?  Now, I don't think that it is necessary to test the entire country, but it is going to require some testing and some serious testing.  And you go to the source.  You look for the BSE.  And I think we have units in place to look at human cases.  Dr. Gambetti and Stanley Prusiner is getting every brain he can get his hands on, and he looks at it.  So we have --

            DR. WOLFE:  Steve is getting the brains.

            DR. NEMO:  Okay.  Okay.  Steve, excuse me.  Excuse me, Steve gets them.  And so I think the question is how much do we test?  I mean, that's what we want to do and why are you doing it?  The USDA asks, because we want to know how big of a problem this is.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  Just to follow-up on your cite.  I am not a pessimist, either, although every time I come to this Committee, I seem to be.  You sound better when you say it though.  I feel that the positive side is we can't do anything until we know.  It's like building a rocket ship.  You have to have all the data.  You have to know what the extent of the problem is and we don't know that and so we can't even start to solve the problem at this stage.  And maybe there is no problem.

            CHAIR PRIOLA:  Dr. Bailar?

            DR. BAILAR:  Just as a reminder, I would like to put on the record that if FDA does go to an expanded sampling plan, as I think most or all of us hope they will --

            DR. WOLFE:  USDA.

            DR. BAILAR:  Or USDA, that it must be on the basis of a sound sampling plan.  Sampling randomly is not the same as haphazard and there has to be a proper randomization, some kind of a randomizing mechanism to make sure that you get a really representative collection of animals for testing.

            CHAIR PRIOLA:  I want to make a quick response to something that Dr. DeArmond just said, and that was that you can't do anything until you know.  And, in fact, this Committee has done that in the past with the blood and currently the FDA has done it and we have advised them to do it in terms of these risk materials entering into the human food chain or the medical product chains, so we can do that based on theoretical risk.  And it is theoretical because we don't know.

            One thing that I'm sitting here wondering is, let's say, from the USDA's point of view, which is not our purview here, obviously, but from the USDA point of view, they do decide okay, we're going to test every animal.  Does it change the way I'm thinking?  If there is one positive BSE cow in the U.S., we're going to try to take steps to protect the food chain, the medical product chain, the manufacturing chain.

            If there is 100, we're still going to take the same steps.  I don't know how we can change the basic steps we're going to take.  Does it change my basic thinking in what we should do?  I don't think it does.  But it is important scientific data to have, but I'm not sure that it is essential for absolutely everything we're discussing.

            DR. WOLFE:  You were first.

            CHAIR PRIOLA:  Yes.

            DR. DEARMOND:  Well, I think though if you know that there is 100 and you know that there is a common source of them, you can stop the source.  If you know there is 100 and there is a feed problem, you can stop the feed problem.  We don't know where this is coming from or whether there is something festering in the United States, at this stage.  So the numbers do tell us something and their location and which herds and what they have been eating.  There are a lot of reasons, a lot of things to be learned by getting numbers.  And again, maybe there is only one and we don't have to worry at all, but we don't even know that answer.

            CHAIR PRIOLA:  Well, but we are worried about just the one.

            DR. WOLFE:  Sure.

            CHAIR PRIOLA:  Yes.  Dr. Wolfe?

            DR. WOLFE:  Well, it would matter greatly as to sourcing, for example.  Now, right now, we are assuming that it is okay to source in the United States, because this cow was a Canadian cow.  And it may turn out after some testing, whatever it is, what random percent of over 30 month cows is tested that it turns out there are no cows found.  It may turn out that there are 5 or 10.

            But all I'm saying is if really any of them turn out and in a way it doesn't make a difference whether it is 2 or 5 or 100, we will no longer be a BSE-free country.  And the fear of becoming that is not a justification for not doing testing.  It works both ways.  I mean, this may seem like a digression, but it isn't.  I was asked by the College of American Pathologists to give a talk at a meeting that they had about eight years ago on autopsy.  And one of the arguments that had been made for the decrease, and this was alluded to yesterday, the autopsy rate was 45 percent in this country after the second World War.  It is about 7 percent now.

            One of the arguments that was made was that hospitals were afraid of being sued because if they did autopsies, they might find something that went against them, and it was someone from a medical malpractice insurance company, St. Paul's who is no longer doing this, said, you know, if you look, it goes both ways.  In as many cases, the findings will exonerate the hospital or the doctor from any kind of blame as they will to point the finger in that direction.

            So I think that testing, which I think is analogous to doing an autopsy in a way, literally it is at some level, it can go both ways.  I mean, for those countries that have stopped buying American beef, if they are assured based on testing that we actually don't have cows, that's a plus.  If, on the other hand, we find some, then we can't keep pretending that we are a BSE-free country.  So at that level, it does make a difference whether we find any or not, because right now it's none, literally.  I mean, the Canadian cow is a Canadian cow.

            CHAIR PRIOLA:  Dr. Khabbaz?

            DR. KHABBAZ:  Yes.  You know, I think as a Committee we probably can and have pride in serving, in the back, in terms of actions already recommended and taken to mitigate a theoretical risk.  And I think we need to commend the FDA and the USDA in terms of their response to the one cow that we found and actions taken.  I think what we have on the table now with regard to all of these products and how much more should we do or do we need to do?  And really to answer that is critically linked and I'm disagreeing with you, Suzette, to surveillance.

            I mean, we have discussed for the past two days surveillance.  And what are the goals of surveillance?  Well, surveillance estimates the prevalence of a condition and allows you to monitor the success of prevention and control programs.  And where this surveillance that wasn't existent, because, you know, it allowed recognition of the test and one can argue how, you know, what the estimates, the confidence estimates around it are, we found a cow.

            But now the question is what is the magnitude of the problem?  And I think what I've heard us say and, you know, what has been said outside of here is that, you know, do we have enough of a confidence, you know, in the surveillance as is or as was to determine with certainty the magnitude of the problem, and I'm hearing us say is that probably not.  It probably needs to be improved.  Now, not to the extent of testing every cow, but targeting populations at risk and groups at risk and I think there is a number of ways that that can be done.

            But to find the magnitude of the problem is essential to address the question of how much more do we do and how much more should we do.  And I want to get back as well to something that came up yesterday, which is the feed bans.  And I think the bans with regard to the human side are great.  But we do have the potential of mix up and lots of other things really are to the animal feeds.  And I think there are other ways, perhaps, to address that.  But that is what needs to be at the table in terms of things that we can do to, you know, strengthen the basis of our level of confidence in terms of everything that we're discussing today.

            CHAIR PRIOLA:  Dr. Bailar?

            DR. BAILAR:  I would just like to emphasize that the need for an expanded testing program is very closely linked to the need for identification of individual animals, sort of a lifetime history of ownership and place of, what you would call, residence.  The ideas that when you find a problem in the testing, then you should be able to trace it back to the place of origin to see what might have gone wrong and whether it is fixable.

            So that the tested animal is, in a sense, representing not just a random sample from the U.S. herd as a whole, but representing a particular collection, small collection of animals somewhere that might have additional problems.  I think this is done in a way already, but I would like to see it made more formal, including this link between animal identification and testing.

            CHAIR PRIOLA:  Dr. Johnson?

            DR. JOHNSON:  Yes, I would like to.  I think everybody here seems to agree that we have to do more testing.  But on a different subject and one that I haven't really heard before today, and I thought it is worth discussing, and that is with the idea of biologics and vaccines and bovine serum and so forth.  It seems to me the idea of sort of moving to Australia is not the solution, because I happen to be one of the people who believes that this occurs spontaneously in cows like it does in humans, and that Australia will have a case eventually just like we'll have more cases.

            So that maybe what we really ought to do, which seems to be more reasonable, would be to look into these negligible risk herds, which I never really heard or thought about before, and I'm sure there aren't enough of them, like everybody agrees, but we don't know how many there are.  We don't know how many of them are pure like the ones that Bob told us about or how many of them are sort of a mixed bag like the ones that are run by, what's the grocery store chain?

            DR. WOLFE:  Whole Foods.

            DR. JOHNSON:  Whatever they are.  The place where Sid shops.

            DR. WOLFE:  That's very personal.

            DR. JOHNSON:  And that proves he is a pessimist.

            DR. WOLFE:  They have very good stuff there.

            DR. JOHNSON:  Yes, I buy my beef at Giant.  Anyway, I think that it would be -- what we could do is if we can have some idea of how many of these sort of herds there are and how much there is and how difficult that would be to expand, and then which products are really at greatest risk, whether it is the serum and vaccine or whatever it is and then you could sort of have a list of the agents and a list of these.  You could really see how this might -- how you might pattern, what more you need to do.  What you would have to do.

            It seems to me it would be good to start on this now to get ahead of the game, because this may be a direction we have to.  This may be a direction we're forced to go in the future and it would be hard to start from a total -- get started from a total stop position, I think.  So I think the FDA should start looking at that as a potential option and backup at the present time, starting now.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  Well, after Dick's lucid production there, I don't know what I have to say.  But I just wanted to follow-up again on some of our -- one of the reasons we are, at least I am, a little less confident is that over the last 10 years, what is it, about almost 20 million head of cattle have come into the United States from Canada, and I don't know how many tons of feed have come from other places.

            And a lot of the -- and then I understand all the downers are ground up or at least the dead ones are ground up and then they can go into feeds for chickens.  Is that right?  But then the chicken feed, farmers being very frugal, will buy that and give it to their cows.  So it is getting very confusing and there is a lot of opportunities in there to generate BSE in the United States.  And, again, that's why the need for more data.  But we also need to stop some of these things.  If we can really identify how prevalent chicken feed to cows is, that would be interesting to know also.

            CHAIR PRIOLA:  Okay.  I feel that I should clarify that I was not against surveillance, continued surveillance for BSE and variant CJD in the U.S.  I guess I was just trying to look at it from the opposite point of view, which is that surveillance is absolutely essential for sourcing issues, as everyone has rightfully pointed out.  Are the stop gaps after that?  So the prohibitions on the high-risk materials being incorporated into products that can be injectable or ingestible into humans, the blood supply deferrals, are those a sufficient stop gap in the presence of one cow or 100 or 1,000 BSE cows?

            Are they still a sufficient stop gap no matter how many animals you detect by surveillance?  I guess that's my point.  Because there is another potential, they are designed to protect the public at a later stage than the source and material, their recommendations for TSE clearance and manufacturing are specifically targeted towards that.  So that's what I was just trying to get at to see what other people had, the opinions of the other members of the Committee.  Dr. DeArmond?

            DR. DEARMOND:  Yes.

            CHAIR PRIOLA:  Thank you.  That was good.  That was the shortest answer today.  Dr. Nemo?

            DR. NEMO:  Yes, I think we're pretty much at our limit what we could do with the blood supply based on what we heard today from Dr. Williams that we are really pushing the envelope as far as availability is concerned, and I don't see any added benefit of adding a new regulation or restriction or broaden the deferral, at this point.

            CHAIR PRIOLA:  Mr. Bias?

            MR. BIAS:  I would again suggest, a suggestion that I made yesterday, that there be a more formalized relationship between the agencies regulating who have jurisdiction.  We do that for the blood supply and it has worked very effectively to have the heads of those agencies meet and discuss this as an ongoing issue, and I would suggest that here.  If you have got four different agencies working at a problem, even if they are cooperative and they like each other, you have a greater chance that something is going to be missed.  I would just suggest that they formalize that relationship, that that group be given a charge and then move forward from there.

            CHAIR PRIOLA:  Dr. Johnson?

            DR. JOHNSON:  I have a question, because I think we all agree that it would be nice to take brain out of material where it is not listed as being brain or not obvious that it is brain you are buying and eating.  And I was just wondering if because of the Congressional Bill which unleashed the nutritional supplements, is FDA going to have to prove deaths from eating brain before brain can be taken out of nutritional supplements?  Because that was what would happen with the ephedra.  You had to show 100 deaths or something.

            CHAIR PRIOLA:  Dr. Wolfe?

            DR. JOHNSON:  Sid would know that.

            CHAIR PRIOLA:  Yes.  Dr. Asher probably has some comments.

            DR. WOLFE:  The law, the Dietary Supplement Health and Education Act of 1994, gives FDA the authority to ban something if two conditions are met: (A) It poses an unreasonable risk of harm; and (B) If it is used as recommended.  So initially for several years, the FDA claimed that that authority didn't enable them to ban ephedra, which we asked them to ban two and a half years ago, and they finally agreed that it could be banned using that standard.

            I would suppose that given the virtual impossibility of finding out the source of brain that one could easily say that ingesting a dose of brain that is arguably much larger than that needed to cause an infection could post to -- you know, be viewed as posing an unreasonable risk of harm.  So, you know, we have certainly pursued that since that little lower right hand corner of Dr. Potter's diagram is sort of inflammatory.

            CHAIR PRIOLA:  Dr. Asher, do you have a comment?

            DR. ASHER:  In response to Val Bias' suggestion, I just wanted to point out that there is a coordinating committee at the level of the Department of Agriculture and the Department of Health and Human Services represented by upper management from the FDA, and I believe the NIH.  Lisa may have attended that.  I mean, I cannot comment on how effectively it works, but the need for such a coordinating body has been recognized by both USDA and FDA and Secretary Thompson's Office.

            DR. JOHNSON:  I don't think they would deal with this kind of an issue though.  I mean, if we're talking about the issue of banning raw brain in nutrient supplements, as an irrational thing to do, which is potentially dangerous, the interagency committee is not going to deal with that.

            DR. FERGUSON:  Can I jump in and just say yes, it has, because, I mean, we have had longstanding interagency committees, both at the policy level, at the technical level, at whatever level you choose.  They have existed and they have worked very well, you know, in response to the Canadian case in May.  There were many discussions amongst the agencies, because of the impact, and none of us can do anything in a vacuum.

            We can't make our own decisions on our own.  We well recognize that that whatever decision we make at APHIS impacts what FSIS does and it impacts what FDA does.  I mean, at least, within USDA, we have APHIS and FSIS under the same department.  But, you know, that's exactly the type of things that those policy groups, at all the levels, have dealt with.  You know, we get together at all levels to say, hey, these are the regs that we're going to propose.  Do you guys agree?  Do you disagree?  How is it going to impact you?  You know, here is your draft.  Where do we go from here?

            DR. JOHNSON:  That doesn't happen on the one I sit on with for NIH.

            CHAIR PRIOLA:  Other comments from the Committee?  Any comments as to the potential BSE variant CJD contamination of vaccine related products, which was a subject brought up by Dr. Egan?  Dr. Wolfe?

            DR. WOLFE:  Well, just that the elegant study from your lab and the conclusions of this study, namely that it will flourish in fibroblasts begs, as someone said this morning, that you got to look at the other cell lines that are used for making vaccines and check out whether they are susceptible as well and make decisions as to what is done in the future about vaccines, and that's an obvious research follow-up to this study that you all did.

            CHAIR PRIOLA:  Thank you, first of all, for the compliment.  Any other comments?  I want to make sure that the Committee has aired all of its views and concerns, that the FDA has heard most of what it needs to hear.  I mean, it's apparent that there is a great reluctance to give any sort of definite, I don't want to say recommendations, but discuss any definite changes to what is currently in place because of the testing issue that everyone is very concerned with the surveillance issue.

            DR. WOLFE:  Just two seconds.  I mean, I think there is a great reluctance.  On the other side, FDA did not ask us any specific questions, which is, I think, the first meeting we have had and I think that it goes both ways.  I think there is some appreciation for why no questions were asked and why we can't answer them.

            CHAIR PRIOLA:  And I think that's true.  The FDA, yes, acknowledges that it is an ongoing situation that requires more data.  And, yes, that's why the lack of questions.  They are very interested in the discussion, though, which is why I'm, you know, making sure everyone has commented themself.  Dr. Bailar?

            DR. BAILAR:  I have a question that would help me in my own quantitating thinking.  What is the price elasticity of beef?  If the price goes up 1 percent, what happens to purchases?  Does anybody know?  Does it go down by 1 percent or .25 of a percent of 5 percent?

            CHAIR PRIOLA:  Any of the USDA people want to tackle that one?

            DR. FERGUSON:  We let our economists deal with that.

            DR. WOLFE:  Any beef industry people in the audience quietly sitting there?

            DR. BAILAR:  It seems to me this will be one critical input to decisions about any new steps that are reasonably costly, like a major expansion of testing.

            DR. WOLFE:  The flip side of that is that there has already been a measurable mass of loss of money to this industry, and I have to say it's probably because we haven't tested at all and we therefore can't assure them of anything at all.  So that is already a factor that has gone into affect without having even made sort of the downside of not having tested as opposed to the benefits.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  I was going to say the same thing, but then in simple calculations of the cost per pound of beef, Stan Prusiner says .2 cents a pound increase.  And if you look at a saleable amount of beef for food products now is around 500 pounds out of  a cow.

            DR. NELSON:  Is this testing every cow?  Is that what you are saying?

            DR. DEARMOND:  Yes.  Say for a cow that is tested, you get 500 pounds.

            DR. WOLFE:  Using his test or using which one?

            DR. DEARMOND:  No, all of the tests are running about the same.  And he says he could come in under that.

            DR. WOLFE:  This is the "under that" price.

            DR. DEARMOND:  Yes.  So say it is 500 pounds and it is $30 a test, well, say $20, that's how much, how many cents?  It comes out at about .4 cents or less.  So it's not a huge amount.

            DR. GAMBETTI:  It's that already, because I read .3 cents.

            DR. WOLFE:  There you go.

            CHAIR PRIOLA:  Dr. Nelson, do you have a comment or Dr. Bracey?

            DR. BRACEY:  Yes.  There was one topic that you brought up that we haven't covered.  And earlier yesterday, my thinking was that perhaps leukocyte reduction would offer a reasonable benefit.  But, in fact, I think that after really considering the data, there still would be enough transmission that it would be more a matter of perception than actual significant risk reduction.  So I think as a Committee, we should make some sort of a statement in terms of whether or not we would want to recommend mandating a universal leukocyte reduction.  And based upon what I heard yesterday, I'm not sure I would be at that point.

            DR. NELSON:  I think BPAC has already discussed this issue and has recommended it, but not based on the CJD risk.  Based on HLA sensitization and post-operative fever and other things, we specifically weren't supposed to discuss the CJD risk, but it looks like, you know, it ain't perfect, but it looks like it may help a little bit.  And given that the risk may not be high, we've found one case so far, then maybe a 50 percent reduction would be significant.  It's hard to know.

            CHAIR PRIOLA:  Yes, and I think it gets back to the issue of threshold level of infectivity that Dr. Brown brought up that the 50 percent may very well be a big chunk of that or all of it.  Any other comments?

            DR. ROHWER:  This is Dr. Rohwer.

            CHAIR PRIOLA:  Oh, I'm sorry.

            DR. WOLFE:  He doesn't like to speak.

            CHAIR PRIOLA:  Dr. Rohwer?

            DR. ROHWER:  Yes, no.  Just to clarify, I think that in any measure that is taken to remove the infectivity from blood, you're going to have to start with leukocyte reduction.  There is two quite different physical states of the infectivity in blood.  One is cell-associated and one isn't.  You're going to have to get rid of those cells first before you can tackle the problem of removing the non-cell-associated infectivity.  So it is a -- I think the way I put it was I see it as a necessary, but not sufficient step in the process of solving this problem.

            CHAIR PRIOLA:  Bob, before you sit down, can I ask you a question?  I thought of this yesterday while you were talking.  It gets to the soluble PrPsc or infectivity that you see in the blood versus the cell-associated.  What is that based on?  You said, you know, the nature of the agent.

            DR. ROHWER:  You mean the solubility?

            CHAIR PRIOLA:  Yes, it might be different in blood.

            DR. ROHWER:  Well, I guess, it's more accurately called plasma-associated and it remains stably in the plasma in the absence of cells with which it could be associated.  So it's non-cell-associated.

            CHAIR PRIOLA:  Thank you.

            DR. NELSON:  I've heard incidentally that there will be a substantial cost to a unit of blood by filtration, but it was felt to be justified.

            DR. BRACEY:  Yes, well, I think that considering again the fact that, I guess, at this point, probably the majority of the country is using leukocyte reduced blood.  Well, at least 50 percent of it.

            DR. NELSON:  I think all of the Red Cross blood is leukocyte reduced.

            DR. BRACEY:  Yes.  Yes, they are.  The figures I have heard are anywhere from 50 to 55 percent.  I think that hearing the information then perhaps we should take a stand or make a recommendation for a universal leukoreduction.

            CHAIR PRIOLA:  Dr. Linden?

            DR. LINDEN:  Well, two comments.  In that regard, I don't know if Dr. Page can comment on that.  I'm not sure that is true for platelet concentrates necessarily.

            DR. PAGE:  Peter Page, Red Cross National Headquarters.  The Red Cross currently will provide red cells that are leukoreduced or not leukocyte reduced, based upon what the hospital customer requests.  After that policy was made, we now provide over 90 percent leukoreduced.  In the non-leukoreduced, which is less than 10 percent, that includes autologous units.  So our customers have chosen, basically, to stay with leukoreduced red cells.

            All platelet phoresis products, I believe, in the country are leukoreduced.  As far as platelet concentrates provided from whole blood, as Dr. Linden asked, Red Cross currently is leukoreducing them all.  That's not a requirement, however, of FDA or AABB, so I believe that there are some non-leukoreduced platelet concentrates that are available in the United States.

            UNIDENTIFIED SPEAKER:  Is there a price difference?

            DR. PAGE:  There is a substantial increase in cost to leukoreduced red cells and platelet concentrates, yes.  And that has basically already occurred through over 90 percent of the red cells that Red Cross provides.

            DR. LINDEN:  I don't think that's necessarily true though of non-Red Cross areas.  It would not necessarily be as high.  But my other question really relates to the question of is a 50 percent reduction really that significant and can experts in this really explain that to me, because for other pathogens, we always talk about log reductions.  And, you know, we're expecting many, many logs when we look at, you know, viral inactivation, for example.

            So why is it that we think that a mere 50 percent reduction for prions would be a significant contributing factor in infectivity?  I mean, how is it that this is different from other pathogens in accumulation or risk?  Can that be explained to me by an expert?

            CHAIR PRIOLA:  Dr. Rohwer, do you want to address that?

            DR. ROHWER:  Yes, I'll comment on that.  Yes, I have the same problem.  If we're just looking at plasma and we go from 10 infectious doses per ml to say 4, 3 or 4, but we are infusing 500 mls of that, we've still got 1,500 units of infectivity or at a 10 percent efficiency of transmission, maybe 150.  By definition an infectious dose is the amount that is required to initiate an infection, we're still going to have an infection.  And that's why I made that statement rather casually, I guess, yesterday, but I did mean it.

            It's not clear to me whether there is enough benefit in that to merit leukoreduction on the basis of a 50 percent removal.  That doesn't negate what I just said a few minutes ago that I think to have an effective removal strategy for blood and blood components, you're going to have to have leukoreduction as part of that strategy.  That will be essential.  But on its own and by itself, it is something that I think has to be evaluated very carefully to know what kind of benefit you are getting from that, and that evaluation depends on exactly how those products are used and administered and I'm not an authority on that.

            I mean, I'm working from the assumption that typically you give a full unit of plasma, and we get the -- and I'm making my estimates on that basis.  There may be circumstances under which it is used in smaller quantities or something like that where a twofold difference could make an actual -- could be important.  I'm not sure.  But, indeed, what we are usually looking at is log removals.  And we are a long ways away from that here.

            DR. NELSON:  Well, a leukoreduced unit still has 106 PBMCs in it.  So it's not -- it ain't free of cells.

            DR. ROHWER:  That's true.  It's not free of cells, but it's probably free of cell-associated infectivity or largely free cell-associated infectivity, because you're starting with 109 going 106 and you're right there at the level.  You've removed 1,000 fold or greater of the cells and you only started with 103 infectious units or 5 times 103 infectious units to begin with, which means that that part that is cell-associated is probably gone or negligible, at that point.

            DR. LINDEN:  Yes, wait, Dr. Rohwer, if I could just follow-up, though.  Is it your opinion, speculate your expert opinion that if a donor had, you know, prionemia as it were, because of variant CJD, and donated a full unit of blood that current leukoreduction technology would not be protective of recipients of components.  I mean, I hear you saying that would be an important starting point from manipulation to perhaps plasma derivatives or other technologies.  But that the components would still likely be infectious.  Am I understanding you correctly?

            DR. ROHWER:  Yes.

            DR. LINDEN:  I mean, aside from like the Pall next generation filters and stuff we're hearing about.

            DR. ROHWER:  Right.  No, you are understanding me correctly.  With this proviso, I am talking about a simple component separation.  Plasma, buffy coat, red blood cells.  Now, a red blood cell concentrate goes -- you were expressing some more plasma out of that fraction as being taken back up and adenine and that kind of thing, and we haven't actually had, though we have prepared those materials, a chance to test them.  So I don't know how much actually gets -- as you move toward platelet concentrate, platelet-poor plasma, those kinds of things, we haven't made those specific measurements on that material that was fully leukoreduced in this full scale experiment.

            We have on a scale-down process, as part of that Cohn fractionation that I showed you before, we have looked at some of those fractions, but they are not -- that's not done in the same rigorous way that this leukoreduction experiment was done in the sense that it was scaled-down.  It was done in a Sorvall centrifuge.  You know, on a smaller scale instead of in a blood bag.  And we have those materials.  We would like to look at them, but they are expensive to titrate, and that's the hitch there.

            CHAIR PRIOLA:  Dr. Bracey?

            DR. BRACEY:  Yes, I'm not sure that we will know the answer any time soon, but it just strikes me that the BPAC has made the recommendation.  Although some of the initial indications, there have been some trials that have come up to raise questions about that, there still are positive studies.  There are also other potential benefits such as problems with alloimmunization for transplant patients, etcetera, etcetera.  There is a large market share that has already moved toward this.

            Great Britain is currently leukocyte reducing.  We do know that there has been transfusion transmission.  I guess, you know, I see no real harm for making a recommendation, aside from economic harm, for this universal leukocyte reduction.  Again, the data are incomplete, but if you look at it from a risk-benefit assessment, there really is minimal risk, I think.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  It seems like the precautions that are already set in place are protecting the public for the most part from any vCJD infected blood getting in, I mean, for the most part.  There is going to be something that will slip through.  And as for a 50 percent reduction, it may work in some people and not in others.  So like that's getting to the point where a couple of animals in an animal assay would get sick and there are lots of factors with humans.

            Some humans would be exquisitely sensitive to even a small amount and others would be resistant.  And we don't know what the injury state of the patient is that might get this stuff into the brain, for instance, and set off the disease.  So the human situation is very complicated.  You wouldn't be able to predict what even a small dose would do in a human.

            CHAIR PRIOLA:  Go ahead, Bob.

            DR. ROHWER:  If I could revisit Dr. Linden's question again.  Another way to look at this is that the only thing that we throw away in a component separation is the buffy code.  And unless you leukoreduce, you don't throw that away either.  But if you leukoreduce, you are removing that component.  The rest of that infectivity is redistributed among other fractions, all of which get used and go into products which get used one way or another.  And so that infectivity, what I'm not sure about is what that redistribution is, but that infectivity is still there.  Does that help you at all?

            DR. LINDEN:  Well, it does.  And, I guess, I mean, I hate to disagree with Dr. Bracey, because I agree with him on almost everything else, but I'm just not hearing that we have scientific evidence that a universal leukoreduction would really significantly provide benefits in this regard.  I mean, I fully agree there are other reasons to do leukoreduction, but I have not heard that there are significant benefits to merit recommending universal leukoreduction for purposes of preventing variant CJD, at this meeting.

            CHAIR PRIOLA:  Dr. Nelson?

            DR. NELSON:  Well, it seems like the risk of transfusion transmitted variant CJD is not high.  And classical CJD is even lower.  And it may be that some decrease in the risk provided by a 50 percent decrease in the number of transfused prions might affect whether or not there would be cases or how many there would be, because of the fact that we are not at a point in the curve where large numbers of people are at risk, despite the fact that there have been a lot of transfusions.  In classical, we showed what was it 116, 300 and 116 have been over five years, I think it was.

            We have had one out of, you know, only in the teens now, but the likelihood is that the risk isn't high, but that it is there.  Therefore, you know, if there is a feasible way to reduce the risk even by 50 percent, you know, it may be prudent to do it.

            CHAIR PRIOLA:  Dr. Wolfe?

            DR. WOLFE:  It sounds from what Dr. Nelson said though that the decision to leukoreduce is being made independent of this issue, so you can almost say it doesn't matter whether we're going to get 50 percent reduction or not as sort of a ride-on or add-on to a number of other diseases where there clearly is going to be reduced risk to say nothing of transfusion reactions and everything.

            So it is not -- we don't have to even visit this decision at all, because it is being visited on a much larger scale for a whole bunch of other reasons and this is sort of a tag-along.  So it fits in with Bob's sufficient, but not -- "necessary, but not sufficient" towards some larger scheme in terms of blood safety.  It is already happening.

            CHAIR PRIOLA:  Let me have Dr. Epstein comment to see if he can clarify some things.

            DR. EPSTEIN:  Well, I just want to try to clarify that evidence for removal of 50 percent of infectious units from a blood component should not be equated with 50 percent reduction of clinical risk.  Those are two different metrics.  What I'm hearing Dr. Linden say, with which I agree, is that we don't know if there is any reduction of clinical risk if you reduce 50 percent of infectious units in the transfusable component.

            And I think that the important point that Dr. Rohwer has made is that if there is an effective strategy to remove some number of logs, not just half, but 10-fold or 100-fold reduction, that it is logical to remove 50 percent up front by removing one unneeded component and then using other technologies to deal with residuals.  But unless and until we hear that there are validated technologies to remove the remaining infectivity from red cell concentrates or plasmas, I think we have to be somewhat skeptical about the clinical benefit.

            Even at that point, I mean, even if we remove one log or two logs, questions will remain, because we have been told that a typical unit may start out, correct me if I'm wrong, Bob, at about 5,000 units in the whole blood.  So, you know, there is a long way to go before we can talk about a de minimis risk if there is an infectious donor.

            The second point that I would like to make is that the potential benefit is dependent on how much vCJD you think there is in the donor population.  We think we have a very different situation in the United States than in the U.K.  I mean, in the U.K. there is a credible estimate that quite a number of donors may be incubating vCJD.  I don't know that number, but it may not be small.  Whereas, in the U.S., the thinking is that because we haven't had a massive BSE epidemic and because we have had donor exclusions in place, that the donor pool is unlikely to have very many infectious individuals.

            So even if there were a proven benefit of techniques to remove infectivity in blood components from infected donors, we would still have to think about whether it makes sense to implement against the background of how many infected donors might there be.  And I don't know the answer to those questions, but I'm just trying to put the issue in its proper context.

            CHAIR PRIOLA:  Dr. Linden, do you want to respond to that?

            DR. LINDEN:  Well, I was actually about to say exactly the same thing, except Dr. Epstein is so much more eloquent.  Yes, I agree completely that a 50 percent reduction in load does not remotely mean a 50 percent reduction in risk.  I think that we do not know the infectious dose.  I mean, that's one of our problems here.  I mean, when you look at bacteria, there are some bacteria we need a pretty high dose to get infection of others, like Shigella, where a very small number of organisms will transmit infection.

            I don't think we know that here, but I think it is certainly reasonable to speculate.  I don't know the animal experiments, you know, well enough.  I don't think we know in humans what the infectious dose is.  But, you know, basically,  I agree with, you know, all of what Jay has said.  And until we know that, it doesn't sound like we have, you know, sufficient evidence to say that this would be useful for components.

            But certainly if you're then using another method for inactivation, it sounds like a very good method.  But certainly, I look forward to hearing more from, you know, Pall and other manufacturers about other methods that may be useful for inactivation or filtration of, you know, these types of agents in the future.  It sounds like a very exciting field.

            CHAIR PRIOLA:  Dr. Rohwer?

            DR. ROHWER:  An infectious dose is an operational definition in this field since we're not absolutely sure what the infectivity is or even, for those people who are sure, what the relationship of the infectivity with protein is.  And as a consequence, by definition it means that dose, the minimum dose that's required to cause an infection.

            So in that sense, we do know what an infectious dose is.  The route is also important and possibly the matrix is important.  And the transfusion experiments that I showed you yesterday shows, at least in the hamster system, if you give intact blood by the IV route, the infectivity is a lot lower than we would have expected by at least another order of magnitude, and so there is an issue there as well.

            What I really wanted to address was something that Jay brought up just a moment ago, and that is where does the risk to the blood supply come from in the United States?  And it's not clear to me that our exposure to a very low level of BSE cattle in the United States, a yet to be measured and determined level of BSE cattle in the United States, would be the major source of risk for variant CJD in the United States, as opposed to the 90 percent target for deferral and removal of risk by deferral.

            In other words, my guess is that we're  more likely to see variant -- we may be more likely to see variant CJD cases in the United States from people who have traveled to Europe and spent time in Europe or have traveled in France or traveled in Italy even than we are from our exposure to BSE cattle themselves presuming that that epidemic is under control.

            And again, unless we make the measurements and find out, I still want to be persuaded of that as well.  But nevertheless, I think, in terms of thinking about where variant CJD cases would come from, we have to consider both sources and the traveler risk just seems much higher to me, because we have a lot of travel exposure.

            CHAIR PRIOLA:  Dr. DeArmond?

            DR. DEARMOND:  Yes.  I agree with that, but getting back to the issue that was raised.  It's true that we know what the smallest infectious dose is in an inbred mouse strain or hamsters, which are outbred, but we understand that very precisely.  In humans, it's very complicated.  So the idea of if 100 people got infected blood, how many would come down with the disease, and it could be very small even if they had the maximum dose that one would predict from a variant CJD patient.

            Certainly, you would have to worry about the methionine-methionine individuals, but the others may be resistant.  And even among the methionine-methionine, there is probably a lot of other factors.  So infectivity in a human is extremely difficult, because unfortunately or fortunately, we're not inbred mouse strains.

            DR. NELSON:  Did you say fortunately or unfortunately?

            DR. DEARMOND:  There was a program, a British comedy about space, where these people are traveling and God is a mouse.

            CHAIR PRIOLA:  Dr. Bracey?

            DR. BRACEY:  But again, with regard to the issue of the travelers and the risk posed, again, I think we face the real risk if we further adjust the number of donors that are eligible, that, in fact, the delays that we see in terms of surgeries will, in essence, turn into really bad outcomes and we will see people that will have terrible outcomes related to inadequate blood supplies.  So I think that, you know, we are on the precipice right now of just having a totally inadequate blood supply.

            CHAIR PRIOLA:  Dr. Rohwer?

            DR. ROHWER:  I don't want my remarks being misunderstood as recommending a tighter deferral.  I don't think that's -- that was not my intent, and I don't think there would be -- the cost effectiveness of that would be --

            CHAIR PRIOLA:  Dr. Hogan?

            DR. HOGAN:  Yes.  I just wanted to echo that in terms of tightening the deferrals.  It can be even worse for tissue than as opposed to blood, because there is fewer donors and it's harder when you are talking with a dead donor to find out where they have traveled.  It's all circumstantial based on what the family knows about it.

            UNIDENTIFIED SPEAKER:  It's insurmountable.

            DR. HOGAN:  Well, okay.

            CHAIR PRIOLA:  Any other comments, questions from the Committee?  Does FDA have anything they want to add or make sure the Committee should address before we adjourn?

            DR. MIDTHUN:  No, but I would like to thank everyone.  It has been an extremely helpful discussion and certainly, I think we all recognize that more data would be very helpful to help us go forward, but certainly, in the meantime, your input in helping us to assemble how best to go forward is much appreciated.  Thank you.

            CHAIR PRIOLA:  Okay.  Thank you very much.  Thank you again to the speakers and the Committee members.  Everybody have a safe trip home, and we're adjourned.

            (Whereupon, at 2:04 p.m. the meeting was concluded.)