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October 29, 2010: Transmissible Spongiform Encephalopathies Advisory Committee Meeting Transcript

October 29, 2010

The Holiday Inn Gaithersburg
2 Montgomery Village Avenue
Gaithersburg, Maryland

This transcript has not been edited or corrected, but
appears as received from the commercial transcription service.
Accordingly, the Food and Drug Administration
makes no representation as to its accuracy.

Proceedings by:

CASET Associates, Ltd.
Fairfax, Virginia 22030
caset@caset.net

TABLE OF CONTENTS

     PAGE
Opening Remarks, Chair, TSEAC1
Statement of Conflicts of Interest1
Informational Presentations: FDA's Geographic Donor
Deferral Policy to reduce the Possible Risk of Trans- mission of Creutzfeldt-Jakob Disease and Variant
Creutzfeldt-Jakob Disease by Blood and Blood Products and Human Cells, Tisues and Cellular and Tissue-based Products
Review of Current FDA Policies
-David Asher,M.D.3
-Elizabeth Lybarger, M.F.S., M.S.24
Variant CJD in the UK and Worldwide
-Robert Will35
BSE in the USA and Worldwide
-Linda Detwiler, D.V.M.57
USDA Updates
-Christopher Robinson, D.V.M.74
-Troy Bigelow, D.V.M.82
Questions to Speakers90
Open Public Hearing95
Committee Updates
Recent Advances in Development of Devices to Remove TSE Agents from Blood Components
-Introduction: Luisa Gregori, Ph.D.113
-Tomo Yokomizo, M.Sc.117
-Sam Coker, Ph.D.122
-Steven J. Burton, Ph.D.131
Questions to Speakers144




 

PROCEEDINGS
(8:30 a.m.)

TABLE OF CONTENTS

1

Agenda Item: Opening Remarks

DR. HOGAN: Welcome to the third aspect of this meeting. I hope everybody had a good night last night. We have a lot to cover today so I am going to try to keep everybody on time and we will move along. There are some new people here, today, because I would like you to introduce yourself, if you could again, because there are several new people on the Committee today.

(Introduction of Committee Members)

DR. HOGAN: Well, welcome to all of you. We are going to have, before we start, Lieutenant Commander is going to read our Conflict of Interest Statement.

TABLE OF CONTENTS

1

Agenda Item: Statement of Conflicts of Interest

MR. EMERY: This brief announcement is in addition to the Conflict of Interest Statement read at the beginning of the meeting on October 28, 2010 and will be part of the public record for the Transmissible Spongiform Encephalopathies Advisory Committee meeting on October 29, 2010. This announcement addresses conflicts of interest for the informational presentation on FDA's geographic donor deferral policy to reduce the possible risk of transmission of Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease by blood and blood products and human cell tissues and cellular and tissue-based products and the update on recent advances in development of devices to remove TSE agents from blood components. The information presentation and update sessions are not for discussion by the Committee and, therefore, Committee members were not screened for financial interest related to the presentation and update. There may be regulated industry and other outside organization speakers making presentations. These speakers may have financial interest associated with their employer and with other regulated firms.

The FDA asks, in the interest of fairness, that they address any current or previous financial involvement with any firm whose product they may wish to comment upon. These individuals were not screened by the FDA for conflicts of interest. This Conflict of Interest Statement will be available for review at the registration table. We would like to remind members and participants that if their discussions involve any other products or firms not already on the agenda for which a FDA participant has a personal and imputed financial interest, the participants need to exclude themselves from such involvement and their exclusion will be noted for the record. FDA encourages all other participants to advise the Committee of any financial relationships that you may have with any firms, its products, and, if known, its direct competitors. Thank you.

TABLE OF CONTENTS

Agenda Item: Informational Presentations: FDA's Geographic Donor
Deferral Policy to reduce the Possible Risk of Transmission of
Creutzfeldt-Jakob Disease and Variant Cruetzfeldt-Jakob Disease by
Blood and Blood Products and Human Cells, Tissues and Cellular and Tissue-based Products

DR. HOGAN: Thanks. Again I would like to reinforce that today's meeting is informational and no conflict of interest was screened by the FDA. Consequently, members of the committee are encouraged to ask questions of the speakers, but you cannot engage in any advice or recommendation in your discussion because of the lack of conflict of interest. That said we are going to have several informational speakers that we talked about. The first speaker will be a review of current FDA policies. It is Dr. David Asher from the FDA, here.

TABLE OF CONTENTS

3

Agenda Item: Review of Current Policies

DR. ASHER: I am David Asher from the Office of Blood and I am going to introduce today's program. First, I would like to -- because sometimes I run out of time -- I want to make sure that it is clear that everything I know I learned from these people, particularly Luisa Gregori, Pedro Piccardo, and Kitty Pomeroy of our own program, many people within the Office of Blood, Steve Anderson and Hong Yang, who spoke yesterday, from CBER's Office of Biostatistics Epidemiology, Dragan Momcilovic and Burt Pritchett of our Center for Veterinary Medicine, and a particular thanks to Silvia Kreindel, who is sitting on today's committee and Chris Robinson from USDA, who will be speaking later today.

I am going to go over, briefly, some issues relevant to current FDA policies regarding geographic deferral of blood donors at increased risk for CJD and variant CJD, the rationale for the blood donor deferral policy, some recent events relevant to the geographic deferrals of blood donors at increased risk, specifically, potential exposures to the human-adapted vCJD agent and the BSE agent, and will touch again, as we did yesterday, on uncertainties and their implications for the future. Uncertainties that make it very difficult to set a rational course in modifying blood donor deferral policies, which we would all like to be able to do. Then we will have an informational program relevant to variant CJD risk, beginning with a review of tissue policies. I think I will not go through the rest because I will do those at the end of the talk.

The reason for today's review of blood donor deferral policy is the issuance in May of this year of revised FDA guidance, which finalized draft guidance that issued in August of 2006, itself incorporating advice given to the FDA from this committee in 2005. There is now one new deferral policy and that is to defer blood and plasma donors who have received a donation of blood components in France since the beginning of 1980.

A second important issue for the blood industry is that, I believe for the first time, FDA is recognizing the full donor history questionnaire that was prepared by the AABB Donor History Task force in 2008 as an acceptable mechanism consistent with FDA requirements for collecting donor history information. All other FDA policies related to geographic deferrals of blood and plasma donors remain the same from the January 2002 guidance.

On the next two slides, I have summarized for you what those policies are. Because we have been over them so many times in the last nine years and because Lieutenant Lybarger will go over virtually identical policies for tissue donors, I will not review them for you for now. Of most interest, as most of you know, there are 30 countries on a FDA-recommended blood donor deferral list that is almost, if not all countries in Europe, west of the former Soviet Union -- the European Union plus Norway and Switzerland. I want to say right now that this list does not completely match the list of import restrictions of the USDA, which you will hear more of later this morning, or of the latest list of BSE risk countries that is issued by the OIE. I will go into that a little bit and I am sure that the speakers on BSE will do so as well.

The general approaches to reducing risk of transmitting variant CJD by blood products are two. First, to reduce the risk that a donor has been exposed to the variant CJD agent of human origin and that is what we attempt to do by deferring donors with a history of transfusion in the United Kingdom and in France after the beginning of 1980, which is taken as the presumptive beginning of the BSE outbreak in the United Kingdom.

Also discussed in the past at this committee, but not advised, has been the possibility of deferring donors transfused in other countries or undergoing surgery in other countries, surgery being a theoretical way in which someone might have been exposed to the variant CJD agent, latently infecting another person. The second approach to reducing risk is to reduce the risk that a donor has been exposed to the BSE agent, mainly that would be in beef products, dietary exposure. We take as a surrogate for that exposure, residence in a BSE country or a military base that imported beef from the UK -- the so-called geographic deferrals, in which deferrals for a given period of time are related to the risk relative to that in the United Kingdom. The other product of concern has been the use of UK bovine insulin, which is no longer marketed in this country, although there remain a few users who import the product for their personal use. We are not aware of any other bovine-derived products that might be a source of exposure to the BSE agent in this country.

As we have covered in several previous meetings, we would like to see future enhancements to risk reduction that do depend on donor deferral because we realize that donor deferral is extremely wasteful, in that we think most of the deferred donors have not, in fact, been infected. We have had a couple of sessions in which we discussed the possibility of donor screening tests that remain under development, but none of them has been validated for use in donor screening.

Showing some promise would be the use of techniques for removing infectivity from blood components. As you heard yesterday, the preponderance of experimental evidence strongly suggests that those processes used to prepare plasma derivatives are able to remove substantial amounts of spiked TSE agent. Whether it is in the form that is present in blood is, of course, not known, but the techniques in pilot studies remove substantial amounts of infectivity from plasma derivatives and the FDA has allowed claims of reduction of risk, although has not allowed claims that all risk has been eliminated. There are blood filter-type devices that are in development and the use of the devices has been recommended by the UK Advisory Committee for the Safety of Blood Tissues and Organs for certain populations in the United Kingdom. You will hear more about that later today.

This slide has been presented several times before. We will not go into it in any detail. 174 cases in the UK, including the three transfusion-transmitted variant CJD cases. This does not include those subjects that are thought to have preclinical infections. 47 cases outside the United Kingdom. Seven or eight of them probably acquired in the United Kingdom.

You have seen this slide, as well, and know of our concern about the four transfusion-transmitted cases and the plasma-derivative associated case. I would point out here that looking at the difference in years between the peak of the BSE epidemic on the left and the vCJD epidemic on the right, gives some way of estimating what an incubation period in those persons who have come down with clinical CJD might have been, which is about nine years. Another way of looking at the incubation period would be to look at those few patients who were presumably infected in the United Kingdom and then left the United Kingdom. Looking at the time after which they left when they came down with illness as a possible shortest incubation period and the time that they entered the United Kingdom -- in two cases, by birth -- would give you the longest incubation period. Those fall somewhere between nine and 21 years.

An especially informative case is the Japanese patient who spent 24 days in the United Kingdom, twelve years before coming down, which is -- although there is no way of confirming it because Japan also has BSE -- but the most probable source of infection seems to have been the time spent in the United Kingdom, as close to a point exposure as we have seen. The transfusion-transmitted infections appear to have shorter incubation periods, varying from 6.3 to 8.5 years so far.

The plasma-derivative case, if the implicated plasma donation was responsible, which, as you heard yesterday, is not clear, would give an incubation period of more than eleven years. Why are those important? Because it is the incubation period that would determine how long the blood of an apparently healthy infected person would pose a risk to recipients of components from that blood.

On the next four slides, I have given you an abbreviated reference chronology of TSE's and intercalating our FDA blood donor safety policies in there. I will not go over these. We have been over them before. In the package, the issue summary that you have, we have a more extensive chronology, which goes back to the earliest events, which I take to be the Elias -- Norm Emmanuelidis'(?) demonstration in the late 1970's that blood of guinea pigs, if experimentally infected with the CJD agent, contained infectivity.

One issue that I would like to point out is the intervals between blood donation and the implicated donors and the time when they came down with clinical illness because that demonstrates that the blood of one of the donors was infectious for at least three and a half years before the time of infection -- before the time of donation. We do not know how much longer the blood of asymptomatically infected people is infected. As you heard yesterday, to be on the safe side, the risk assessment considered the possibility that the blood might be infected for as long as 75 percent of the total incubation period, but we really do not know.

You have heard about the other issues last year. I will not go over that again, but I do want to draw attention to the typical clinical case of variant Creutzfeldt-Jakob disease, described last year by Diego Kaski and coworkers. The first clinically typical case of variant CJD in a person with the heterozygous PRNP-129 genotype, although the case was not confirmed clinically, there was no reason to think that the patient had sporadic Creutzfeldt-Jakob disease. The implications of that are that a second, we hope, smaller wave of variant Creutzfeldt-Jakob disease cases with longer incubation periods may have begun. We issued revised guidance in May.

Another issue that I want to attract attention to is the recent report in August by Fernandez de Marco and colleagues of a second lymphoid tissue survey in the United Kingdom, which found one of over 9,000 samples of tonsils from persons in Britain and cohort born '61 to '85 that contained abnormal accumulations of prion protein by immunohistochemistry, described as strongly positive in immuno-staining using two adeserine(?). On the right, you will notice two sections do not show that staining, which the authors of the article interpreted as failure to confirm the initial findings. I think it may be a little more ominous than that. It looks to me like it is a different part of the tissue, which suggests that if you do not find the right part of the tissue, you may miss it.

I agree with the warnings from a couple of people yesterday that the prevalence suggested here, which in this case is 109 out of a million persons in that cohort, has to be taken as a minimal prevalence rate, not the likely prevalence rate because if they had only looked at these sections first, they would have missed that node as being positive. Of course, that does not even consider the number of people who are infected, but whose nodes have not yet become positive. I think to be prudent -- by the way the 109 is not statistically significantly different from the prevalence suggested by the earlier appendix survey. We really do not know the prevalence.

In my own mind, I think it is becoming increasingly difficult to justify using the case-based prevalence of two to four cases per million that was used in the early years of the risk assessment for public health decision making purposes. So we still do not know the true prevalence, the presence in blood of people incubating disease, of infectivity, how long it lasts, or the amount of infectious CJD agent in the blood.

You have seen this slide several times yesterday and it just makes the point that there is a striking difference between what has been seen in a relatively limited number of recipients of implicated blood components, where a donor had variant CJD and a similar situation with sporadic CJD. Although there are -- and perhaps Luisa Gregori will repeat this in her talk later this morning –- there are certain limitations to the study reported by Kerri Dorsey and colleagues from the American Red Cross and CDC, that only some of the patients had received -- some of the donors had donated during the last five years before onset and there were no autopsies in the recipients so that asymptomatic infections would have been missed. But you do not see those accumulations of abnormal prion protein in persons with sporadic CJD, anyhow, although their lymphoid tissues are infectious.

Now for BSE, fortunately the epidemic appears to have wound down. We are going to hear a lot more about that later this morning. But it remains a worldwide problem. It peaked in the United Kingdom in 1992 and 93. They have had over 180,000 cases reported, but they still had 12 cases reported last year and they have had a couple of cases reported this year. In addition, 24 other countries have reported cases, including the United States. Cases continue to be reported. Last year, 12 former BSE countries reported no new cases to the OIE for the previous three years, including the United States, but caution has to be observed. Denmark, for instance, had no cases in 2006 through 2008 and then found a case in 2009. A similar situation, shorter disease-free interval observed in the Netherlands.

One cannot really think that the disease was gone during those years when they did not detect any so that the point I am trying to make is BSE fortunately greatly reduced in numbers of cases, but the disease still remains in the population of cattle.

USDA has -- you will hear more about that later this morning -- has an import restriction list. The list here, the information provided to me by Sylvia Kreindel. You will notice there are 22 countries who are under one kind of restriction or another, special category for Canada, because they have had BSE and 15 countries because they have so-called undue risk of BSE, although they have not recognized a case.

The only thing I want to point out here is that this list not only does not match our donor deferral list, but it does not match the list of countries in the system that I am going to tell you about now, set up by the World Animal Health Organization, the OIE. Three of the countries that have been assigned negligible risk status are still on the USDA/BSE list.

The World Organization for Animal Health, called the OIE for its old name listed here, has set up three categories of risk. Negligible risk I have summarized here. That has either no BSE or, if it has indigenous BSE, the last case was born more than 11 years ago. They have had a MBM -- meaning bone meal -- feed ban enforced for more than eight years, compulsory notification and education program and a surveillance program for testing tissues in place for more than seven years. Controlled BSE Risk Countries have somewhat less stringent controls or a shorter history of stringent controls. Undetermined risk countries are those that either submitted dossier and we do not know what countries those are and got turned down for controlled or negligible risk or those countries that have not submitted any data. Of the 177 countries in the OIE, probably many of them have not submitted data.

Here is a summary of the current OIE risk assigned to 45 countries. 13 countries were assigned negligible risk and 32, including the United States were assigned controlled risk. Note that, of these countries, 24 are on the USDA/BSE import restriction list, including three that were assigned negligible risk status. Within FDA, we have certain concerns about the OIE classification system. That is that under controlled risk, it seems to include countries that have quite different reported incidence of BSE. For example, last year we did not have any cases reported. Portugal had an incidence of nine cases per million native cattle older than two years. That seems to us to be -- and the previous year we did not have any and Portugal had an incidence of over 20 cases per million adult cattle. It makes us somewhat uneasy to see such disparate incidence included within a single category. We wonder if they really should not attempt to stratify prevalence's to some degree.

France – I should have put on this – France fall somewhere between Canada and Poland. So we have our reservations about the value of the OIE list for reaching conclusions about the real risk in various countries. There are some other reservations, too, mainly involving the lack of transparency of the OIE process and the lack of independence audits. All the information is self-reported.

The European Union has very impressive legislation regarding BSE and food safety. That was nicely presented to us at the last meeting by Marshall Plantady from the European Commission. He reviewed special measures within the European Union to prevent and eradicate BSE in compulsory legislation. Controls of specified risk material, removals from beef carcasses, animal feed bans, and extensive BSE monitoring program. I summarized at the bottom of this slide those steps taken in the European Union or required by law within the European Union. The removal of risk materials from meet is compulsory throughout the Union. The point I want to make here is that, at least on paper, the materials that are to be removed -- brains, eyes, spinal cord of all bovines over the age of 12 months, vertebral columns and ganglia over 30 months, tonsils and GI tracts, the entire GI tract of all bovines and controlled disposal -- those, at least on paper, are more stringent than those that are in place here in the United states. Perhaps we will hear more about that later.

The feed ban, as presented by Marshall Plantady, was especially impressive. They have a very extensive control program for compliance with their feed ban. A feed ban is the prohibition of the feeding of most mammalian proteins, all proteins of concern in transmitting BSE to ruminant animals and then to all animals where there is a possibility of cross-contamination. Their program is based on feed microscopy, which is the careful examination of samples of feed, looking for things that are not supposed to be there like pieces of animal bone. Mr. Plantady asserted that they are examining more than 50,000 risk-weighted samples per year.

I do not know how they select the ones at increased risk, but that is what he said. And that they have a zero tolerance. If they see even one particle of bone -- this is a typical particle of a mammalian bone, provided Dragan Momcilovic and Burt Pritchett from their archives -- if they see even one such fragment in a feed lot, the whole feed lot is contaminated. I checked with colleagues at the Center for Veterinary Medicine, in order to examine 50,000 feed specimens it is a tremendous use of personnel.

My understanding is that, at least in the United States, when feed microscopy is performed, the microscopist spends up to four hours looking through the material from a given lot. What we do not have is information about the extent of compliance within the European Union. The legislation is compulsory, but, at least in other spheres, the fact that there is compulsory legislation does not necessarily guarantee that compliance is perfect. Particularly, we do not know when various countries came in to full compliance, if they did. Because blood risk depends not only on exposure today, but exposure for many years previous, each country, we believe, is likely to be different and we do not know when the risk was controlled. So there is another uncertainty.

They have a very active surveillance program in the European Union, increasingly stringent implemented since July of 2001. They claim to test all clinically -- not only all of the sick animals reported, but clinically healthy animals at increased risk because of age and any animal culled for any illness other than BSE. How they audit compliance, I do not know. They are currently doing 10 million tests per year and we will hear more about our US BSE surveillance program later this morning.

Let me conclude in the next five minutes. We have had new vCJD cases appear. Clinical cases appear to have peaked in the United Kingdom. One possible case and several probable preclinical infections have been observed in persons with the prion protein 129 methionine valine and valine homozygous genotypes, suggesting that there is universal human susceptibility to infection. A second wave of cases has probably starting in the UK, clearly having longer incubation periods. We hope that the total number of cases will be smaller than that seen in the first wave. We hope that that is because there is going to turn out to be a lower attack rate, not just because they have a longer incubation period and they died before they expressed clinical disease. I think almost the worst case would be if there are large numbers of people who will never get clinical illness, but whose blood is infectious to susceptible persons, more susceptible persons.

The prevalence of asymptomatic infection may be substantial. It is unknown in other BSE countries. A relatively smaller number of cases has occurred outside the UK. At least 39 probably acquired in the home countries, meaning the contaminated product was presumably present in those countries. Variant CJD infectivity present in blood of infected persons for at least three and a half years before the onset of illness -- do not know how much longer. The agent has contaminated non-leuko reduced red blood cells and plasma. We do not know about other components, but since everything contaminates everything else to some degree, we cannot consider any component to be free of risk. Other forms of CJD have not been recognized to transmit infection via blood component transfusions or plasma derivatives, but blood is infectious in so many animal models that we continue to be concerned about human blood from any person who is incubating a TSE.

BSE outbreaks peaked in Europe and some other European countries, but cases still continue to occur. The OIE/BSE risks system is in place, but has not been universally accepted. Within the EU, surveillance and animal disease controls, specified risk material removal, feed bans, progressive decline observed in diagnosed BSE cases and the increasing age of those cases that do test positive all suggest that the risk of dietary exposure in at least many European countries has declined, but the dates after which the risk went down is still uncertain. The current BSE of some European countries and other countries -- we know, for instance, that Southeast Asian countries, some of them imported a considerable amount of contaminated meat and bone meal from the United Kingdom during the bad years –- the BSE status in those countries is really uncertain.

The OIE/BSE controlled risk status includes countries that continue to report significantly higher incidence of BSE than does the USA. The USDA currently does not allow trade in cattle and cattle products from most countries assigned OIE/BSE controlled risk and three countries assigned negligible risk status. USDA has requested reconsideration of our controlled risk status and you may hear more about that later this morning.

The FDA has, with some exceptions, based its recommendations for deferring blood donors and plasma donors at increased risk for exposure to BSE on the USDA import restriction list for BSE at 9 CFR 94.18, although we have not always followed the USDA BSE list. For example, we consider time spent in the United Kingdom after 1996, when food risk was markedly decreased and time spent in Israel and Japan because we had no data available to estimate the effect on blood supply in certain areas where a lot of people have been to Israel and Japan or formerly lived in Israel and Japan -- we considered those times to be of insufficient concern to recommend deferral, although all three countries remain on the USDA import restriction list.

We currently maintain the BSE-related blood and plasma donor deferral policies described in FDA's May 2010 guidance. We believe that blood establishments have adjusted to the current policy and supplies generally remain adequate. When the FDA -– and we consult regularly with CDC, NIH, other DHHS authorities and, as you know, whenever necessary we solicit advice from this committee when we consider possible future modifications to donor deferral policies. It is possible that today's discordant estimates of the geographic BSE risk might remain unresolved. Should USDA change its policies regarding BSE risk in various countries and alter its BSE-related import restrictions? We will certainly review the information that USDA has used to support those decisions. We would also expect to evaluate other relevant data and recommendations from a variety of sources outside the USA -- the OIE, the EU, and various national authorities -- to assure that our FDA deferral policies remain both science-based and prudent. That concludes what I have to say this morning about our vCJD blood and plasma policies.

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24

Agenda Item: Review of Current Policies

I would like now to introduce Lieutenant Elizabeth Lybarger of CBER's Office of Cell Tissue and Gene Therapy, who will talk about tissue donor policies and then Professor Robert Will, who is from the University in Edinburgh and the United Kingdom's CJD Surveillance Unite, which he founded. Professor Will has again been kind enough to join us and to review for us the UK and the worldwide situation of variant CJD.

Then Linda Detwiler, who is a professor at the University of Mississippi, who consults widely for the food industry, will give her view of the BSE situation in the United States and worldwide. Following which, we will have two updates from the USDA on various aspects of BSE from Chris Robinson and Troy Bigelow, followed by an open public hearing. I am told there are going to be two very interesting and provocative talks already announced for the open public hearing. Perhaps there are going to be others that I do not know about. We look forward to that.

After, at some point, we will have a break. Following the break, we will have a presentation of recent progress in the development of blood filters to remove infectivity from blood components. An introduction to the subject will be offered to us by Luisa Gregori, of our Office of Blood, followed by presentations by Tomo Yokomizo from Asahi, Sam Coker from PallMedical, and Steve Burton from Prometic Biosciences. I have run a couple of minutes over. Thank you very much for your attention this morning.

DR. HOGAN: We are a little bit over. Dr. Lybarger would you like to continue on tissue policy and then we can have some questions after.

LT LYBARGER: Good morning and thank you for your time. I am Elizabeth Lybarger. I am here representing the Division of Human Tissues and pushing buttons already -- representing the Division of Human Tissues in the Office of Celluloid Tissue and Gene Therapies of the FDA this morning. We are going to be talking about transmissible spongiform encephalopathy considerations as they relate to human cells and tissues and other tissue-based products.

I am talking about current regulatory considerations related to human cells and tissues this morning. We are discussing cells and tissues today because future policies affecting blood donor deferral criteria will similarly affect cell and tissue donors. I will briefly touch on relevant communicable disease agents and diseases because in order to require donor screening and testing for cell and tissue donors, an agent must be considered a relevant communicable disease agent or disease. Finally, I will summarize cell and tissue donor eligibility criteria specific to variant CJD.

Because many in the audience may not know what the FDA considers to be an HCT/P, I would like to start with that so everyone is on the same page. HCT/Ps are cells, tissues, and cellular tissue-based products. As defined by the regulations, HCTP's are articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. This obviously, as you can tell by the definition, encompasses a wide variety of products and these products are regulated by the Office of Cellular Tissue and Gene Therapies. Here we see some examples of HCT/Ps. It is everything from musculoskeletal tissues to skin and other cellular therapy products, such as mesenchymal stem cells.

The regulations also specifically exclude certain products from the definition of an HCT/P. Vascularized human organs are overseen by HRSA, which is the Health Resources Administration, whole blood, blood components, and other blood derivatives are not included. That is obviously covered by OBRR. Secreted or extracted human products such as milk, collagen, and cell factors, in vitro diagnostic products, certain types of minimally manipulated bone marrow, ancillary products used in the manufacture of HCT/Ps, and any cells, tissues, or organs derived from non-human animals are also not considered to be HCT/Ps.

The regulations specifically exclude certain products from the definition of HCTPs -- oh, excuse me. The cell and tissue regulations are framed with three major sections to help prevent infectious disease transmission from cell and tissue products. There are requirements for establishment registration and listings so we know who to inspect, for making donor eligibility determinations, which is where the donor screening and testing comes in, and also Current Good Tissue Practices. Current Good Tissue Practices are steps the manufacturer must take to ensure that cells and tissues are not contaminated during processing or manufacture.

In the cell and tissue regulations, there is a baseline assumption that because cells and tissues are of human origin, they do carry a risk of communicable disease transmission from the donor to the recipient. I have already explained how the cell and tissue regulations are designed to minimize the infectious disease risk. Next, I want to talk about how the regulations approach donor screening and testing requirements, since the point of today's discussion is to review scientific information that may later be used to inform donor screening requirements.

For cells and tissues, donor screening and testing are only required for agents that are designated as relevant communicable disease agents or diseases, as I said earlier. I will provide a few slides that list what our current relevant communicable disease agents and diseases are.

Cell and tissue donor screening includes a medical history interview, which for our living donors happens with that donor and, of course, for our deceased donors, this interview occurs with a close family member or relative. It also includes a physical assessment of deceased donor or a physical examination for a living donor and a review of other relevant medical records. HCT/P donors must be tested using an appropriate FDA-licensed, approved, or cleared donor screening test, in accordance with the manufacturer's recommendations and instructions for the package insert. This is done to adequately and appropriately reduce the risk of transmission of relevant communicable diseases. There is currently no donor screening test for variant CJD.

Relevant communicable disease agents or diseases are either listed by name in the regulations or they meet a regulatory definition that has subsequently been designated by the FDA through guidance, in order to allow additions to the list for newly identified agents. I will not discuss that process today, but FDA does provide information about what is currently on the list both in guidance and on the web.

For context, this slide and the next contain our list of current relevant communicable disease agents or diseases for cell and tissues that we require donor screening and, if available, donor testing. Note that TSE is on this list as a relevant communicable disease agent or disease. We provide specific recommendations on how screening and testing of donors should occur in the donor eligibility document. I provide a link to that document at the end of this presentation. Again, this is just the additional list of the relevant communicable disease agents and diseases.

So now, as Dr. Asher said, I will go through the donor screening criteria for variant CJD because that is the basis of today's conversation, however, the donor eligibility guidance does contain additional recommendations for screening donors for other transmissible spongiform encephalopathies, including all other forms of CJD. Geographic-based screening for variant CJD risk is based upon the donor's risk of exposure to the BSE agent. You will note that these criteria are virtually identical to the deferral criteria for blood donors. So anyone who has been diagnosed with variant CJD and any person who has spent more than three months cumulatively in the UK from 1980-1996 is considered ineligible as a cell and tissue donor.

US military members who have lived in specific areas of northern Europe for more than six months over a certain period of time or those who have lived elsewhere in Europe for a different period of time are considered ineligible. Any person who has spent more than five years cumulatively in Europe since 1980 is considered ineligible. Anyone who has received blood or blood products in the UK or France since 1980 is considered to be ineligible. You will note that the only major difference here is that for cell and tissue donors, we do not screen them for the injection of bovine insulin. This is because, obviously, for our deceased donors, it would be very hard to get such detailed information in the donor medical history interview.

The committee does not have a decisional issue today. We want to acknowledge that any future considerations affecting blood donor deferral criteria would similarly affect ineligibility criteria for cell and tissue donors. The geographic-based screening for variant CJD risk is based upon the donor's risk of exposure to the agent and therefore the risk being evaluated by those questions is related to the donor; it is not product specific.

Here are some additional links to our regulations and then the donor eligibility guidance. I would like to thank you for your time.

DR. HOGAN: Thank you. Does anyone have any questions for Dr. Lybarger or Dr. Asher relative to FDA policies for blood or tissues or cells? Dr. Manuelidis?

DR. MANUELIDIS: I have two questions, one for each of you. David, I wondered if you wanted to make a clarification about what you said about zero risk or no cases of BSE in the United States relative to the screening policy of the United States versus the screening policy in other countries for BSE, one being, as far as I understand it, considerably -- the USA being considerably less stringent than let's say places like Japan, in terms of your numbers. I just have a second question or should I --

DR. ASHER: Well, I think you have said it. At least the published surveillance program from the European Union -– and I believe it is no less stringent in Switzerland. I do not know about Norway. I assume it is also very stringent -- they do more testing than we do. We are going to hear later this morning about the testing program in the United States. Of course, they have had a bigger problem in the past than we have. Many of the countries have seen variant CJD in people born in the country.

We have not seen that yet, in both the United States and Canada, although all four variant CJD patients were born and lived most of their lives and presumably were infected outside the United States and Canada -- three in the United Kingdom and one in Saudi Arabia, which CDC believes was probably attributable to halal beef imported from Britain, although obviously you can not confirm that, but it seems a likely source of infection. At any rate, the person involved was a relatively recent arrival in the United States and it is not plausible to think that he was infected in the United States. France, alone, has seen 25 cases of variant CJD, only one of which had a probable exposure in the United Kingdom. They have greater concern about these diseases than we do. About what the USDA policy should be, I leave to the USDA.

DR. MANUELIDIS: Right. My point was that one has to take some of the numbers, perhaps, about the United States with a certain grain of salt since we do not do that kind of reverse testing. We do not know how many cows are really infected. That was my only --

DR. ASHER: As with any infection with a long incubation period, the cases detected are only a fraction of the cases infected. That is going to be true for European countries, as well as for the United States. I simply am not able to compare the surveillance programs in various countries with that of the United States. I could be persuaded, for instance, that Portugal surveillance policy is not perfect and they presumably have more cases than they have recognized. But you are absolutely right, you only detect a fraction of the cases and the number of cases you detect depends not only on the number of infections you really have, but on the intensity of your surveillance program.

DR. HOGAN: Do you have a second question, Dr. Manuelidis?

DR. MANUELIDIS: I do. In the cell and tissue -- I will speak this way so you can hear me, if that is okay -- in the cell and tissue transplant, explants, and et cetera, I was wondering if you ever consider on the donor list people who have neurological diseases or signs of unknown etiology in an older age group. Especially, I would like to point out that cells and tissues can be considerably more infectious than something like plasma pools. So I think you might want to sort of think about that as a kind of category to consider in some of your donors.

DR. HOGAN: I thought there was an exclusion for patients with neurologic disease and cognitive alterations?

DR. MANUELIDIS: It was not on the slide.

LT LYBARGER: Right, so, we very specifically listed the donor eligibility criteria specific to variant CJD risk, however, there are criteria that are further listed in our donor eligibility guidance that do exclude persons with neurological diseases.

DR. HOGAN: This has become an issue for people like corneal donations, which are largely older people and many of them have cognitive disabilities. It is a topic of great discussion. Any other questions? Yes?

DR. KREINDEL: I just would like to make a clarification. The incidence in the European countries, you know, they find cases, however, you have to look at the implementation of the feed ban in those cases and the age of the cases. The case in Denmark, at least, I think it was over eleven years old. Many of these cases are really old so when the feed ban or other mitigations started being in place or were effectively enforced most likely.

DR. ASHER: That is absolutely true. On the other hand, if you still have cases, regardless of when they were infected, that product is still available to infect a human being and that is our concern.

DR. KREINDEL: Yes. That is true. That depends on the implementation of the mitigations that we protect human health and that will be, you know, in the removal of difference or how is the compliance with those mitigations.

DR. HOGAN: Dr. Stevens?

DR. STEVENS: Just as a reminder, cord blood is one of the products that is under the tissue products regulations. In this case, the donor, in terms of risk factors, is the mother, even though the cord blood is coming from the baby. But one thing to keep in mind is that it is very common for maternal cells to get across the placenta and into the cord blood, just as a reminder to the Committee.

DR. HOGAN: Thank you for the information. Any other questions? Okay. Well then, we will move along. We are very pleased at this point to have Dr. Robert Will with us to give us an information update on the situation with variant CJD worldwide and in the UK, specifically. Dr. Will was instrumental in founding the surveillance unit in the United Kingdom, which is a model for surveillance units worldwide. We are pleased to have him here today.

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Agenda Item: Variant CJD in the UK and Worldwide

DR. WILL: Good morning. I am very grateful for the invitation to come and speak at this meeting again. As always, it is always very difficult to follow Dr. Asher because he gives such a very thorough description of the situation. Nonetheless, I will do my best to provide some information about variant CJD.

This is a summary slide just showing the situation in Europe, in relation to BSE and variant CJD, showing the situation in the UK. You can see the scale is thousands here, in relation to BSE in other European countries in the hundreds here and then the variant CJD outbreak in the UK in decline and also in other European countries. I think, of course, this is good news. It suggests that the BSE measures have been effective in reducing the epidemics and it looks as though the outbreak of variant CJD will be relatively restricted. However, I think I am going to, in the rest of this talk, echo the uncertainties about this that were suggested by Dr. Asher.

This is the situation in the UK with definite or probable variant CJD cases to date. I think in relation to what I am going to say later, it is important to define what I mean. In early 2001, the WHO held a meeting in order to agree definitions for the case classification of suspected cases of variant CJD. These recommendations were adopted and have also been adopted by European CDC. I do not want to go into great detail about these criteria, but they are very important to allow consistent classification of cases, both in the UK and in other countries. A definite case of variant CJD requires neuropathological verification.

A probable case requires certain preconditions to be fulfilled plus the presence of various clinical features and, in addition, investigations that support the diagnosis. That is either a positive MRI brain scan or a positive tonsil biopsy. We do have cases that are classified as possible, but these are not recorded officially in the UK -- or, indeed, in any other country that I am away -- because of the uncertainty about the diagnosis of a possible case. We have recently published an article validating these diagnostic criteria, which I will not go into. All I would say is that we have had some cases in which the classification was possible with alternative final diagnoses.

Just to address a question from yesterday, 155 of these cases have been tested and all the definite and probable cases on the methionine homozygotes at codon 129 of PRP. The reason that there are some missing cases is that we did not obtain permission to carry out genetic analysis.

This is the number of deaths from variant CJD in the UK, showing this peak that you have seen before and then a decline. As you see, we still have some deaths from variant CJD at the end here. If you look at clinical onsets of variant CJD in the UK, you see the same pattern with a decline, but it seems clear that the outbreak is not yet complete, even in the MM population. It is possible, as with other infectious diseases, that there could be an extended tail to this outbreak.

However, the issue of genotype is very important and there is always -- or for a long time -- been a suspicion that there could be further outbreaks of variant CJD in individuals with alternative genetic backgrounds, MV or VV. Therefore, any case of variant CJD with an alternative genetic background is of great importance. This publication from December described a variant CJD in an individual, heterozygous for PRNP-129. This individual was age 30 years and had a clinical presentation that was consistent with variant CJD. Indeed, the diagnosis was suspected in life. No post-mortem was carried out, however, and therefore this case cannot be classified as definite. An MRI scan was equivocal. This was reviewed by a neuroradiologist who has seen all the scans in the UK and, indeed, many scans from other cases around the world, and the decision was that this scan was not classifiable as showing the pulvinar sign with certainty. There was no tonsil biopsy. Therefore, the final classification in this case is possible variant CJD.

The clinical phenotype, as I have mentioned, was similar to previous MM cases. If this was, indeed, a case of variant CJD, this is important because it may mean that cases with an MV genetic background might well be identified by the surveillance system. There has always been a concern that patients with an alternative genetic background could present with a different phenotype. We have not had previous cases of variant CJD in the UK with a final classification as possible variant CJD. These are not included in the official figures. They are not included in the graphs I have shown you. There have been three previous possible variant CJD cases -- one in 1991, one in 2001, and one in 2002, all MM homozygotes.

This is the scan that was published in the paper, showing high signal in this region, but in order to have the pulvinar sign, by definition, the high signal in this region has to be higher than the caudate and putamen. Later, an article was submitted by the French group showing a scan in what they think is a sporadic case of CJD, showing, indeed, the pulvinar sign. It is difficult to be certain about the classification of the case I have just described, although I think on the balance of probability, this may well have been a case of variant CJD and, for the purposes of public health, it is important to consider this case in relation to risk assessments.

What will happen in the future should there be further outbreaks in alternative genetic backgrounds has been considered by modeling studies. I am sorry this is rather small. This is a study from Clark and Garner from 2005 -- and there was a similar study from Professor Valeron in Paris -- suggesting that if there were to be outbreaks in alternative genotypes, depending on the assumptions made, of course, that this may result in further outbreaks, but these will nonetheless be relatively limited in comparison to the possibility of a very large outbreak. I must stress that these figures depend on a range of assumptions, in particular, whether the alternative genetic background will be associated with increased or equal or less susceptibility and whether it will be associated with an alteration in incubation period. I think, as has already been suggested by Dr. Asher and others, that it is very likely that if we should get further outbreaks in alternative genotypes, these will inevitably be with extended incubation periods.

This is the situation with variant CJD internationally. Again, you have seen this in a different format. This data is presented on the website and updated in real time. This shows the total number of cases in relation to primary cases related to blood transfusion. Importantly, those individuals who had a period of residence of greater than six months during the period 1980-1996, including the two US cases and the Canadian case, who had resided for extended periods of years in the UK prior to developing clinical illness in their country of residence. The implication of this -- this is very likely -- that these individuals, although they developed the illness in the USA or Canada, were exposed to BSE infection while they were in the UK. The Japanese case has already been mentioned, in which there was a period of residence in the UK for 24 days during this period. It is possible that this individual was exposed to BSE during that period, but it is also possible that the exposure took place in Japan, which has described BSE. Dr. Asher has also mentioned this third case of variant CJD in the USA, which originated in Saudi Arabia and had lived there for a protracted period before coming to live in the USA. I think interesting, there is an additional case, indigenous to Saudi Arabia of variant CJD, who has now died after an extended survival of many years.

What this slide does not show is the temporal pattern in these outbreaks. This is the UK data, here, showing a peak in relation to deaths in 2000 and then a decline. In France, a peak in 2005-2006 and then a decline. As you can see, in many countries, there has not been a new case of variant CJD for some years. However, Italy had a case of variant CJD in 2003 and has recently had a further case of CJD, who is still alive. There have been small numbers of cases in recent years in Portugal and Spain. There are four individuals who remain alive in the UK with variant CJD. Three of whom have been treated with a drug called Pentosan Polysulfate, which may have extended survival, but has not been associated with any neurological improvement.

I now turn to the blood study, the TMER study. This is a relatively simple methodology for those who are not aware of it. Every time a case of variant CJD is identified in the UK, the details are forwarded to the National Blood Services and a search is made to identify whether the individual had been a blood donor. If any blood donations are identified, the recipients are identified, also, and their details are forwarded to the CJD surveillance unit to see whether any of the recipients have, themselves, developed variant CJD. This is the current situation – 174 cases, 164 eligible to donate because of their age, 18 in whom components were actually issued, and the number of recipients from these 18 donors is 66.

These are the blood donors by year, the year of death, and the eligible to donate -- the number reported to have been blood donors by their relatives, the number who were actually registered and the number with donations. These columns do not match because there were some individuals who were thought to have been blood donors, who were actually not blood donors. There were people who were registered as blood donors, but did not donate. There was one individual who was thought definitely not to have been a blood donor, who, in fact, was found to have donated blood. It is very important to study this information in great detail with the help of the National Blood Services. You will note that, in relation to donations, there has not been a new donor in the UK since 2007.

This is the fate of the donations, in relation to the type of component transfused -- the number of recipients at the time. I will not go on about this in detail because I am just going to show you a slide of the outcome of the donations. This is a slide which is very informative, although, at first, somewhat confusing. This is the 45 individuals, who are known recipients of vCJD blood components who have died. On this scale is the recipient survival to death, which, in a way, provides the incubational period in those individuals who have developed clinical variant CJD. Along the bottom is the time from the donation to the onset of clinical symptoms in the donor in years. As Dr. Asher has explained, some of these -– these are the three clinical cases of variant CJD related to blood transfusion. This is one preclinical cases with PRP positively in the spleen, who died of an intercurrent illness. The incubational period to date is measured in six, seven, eight, nine years and these individuals donated blood while they were clinically healthy. Some one to three years -- three and a half years -- prior to developing the clinical illness. This shows that there is infectivity in blood in variant CJD prior to the onset of clinical illness. That is during the incubation period. There is this study from the NPU, Houston and Hunter and Gene Manson, which is a BSE transmission study using blood transfusion, in which, I believe, they now have evidence of infectivity in some blood components at 25 percent of the incubation period, which would be consistent with the assumptions that are now made in the risk assessment in the USA.

An important question is whether, within this group, there are other individuals who may have been infected, but were not identified. A study has been done to look at that. This was published in Vox Sanguinis, which was a retrospective review of the case notes of recipients of vCJD implicated blood transfusions. What we attempted to do was to identify case notes of those who had died to identify whether there were clinical symptoms suggestive of variant CJD prior to death, whether there were any tissues available, or post mortems available with residual tissue. This shows a summary of the results. Basically, there were 40 deceased recipients, including three known cases and one pre-clinical case. We obtained clinical information on 33. The bottom line is that there was no evidence of vCJD clinically in any of these individuals. However, there was no residual tissue to study. Post mortem had been carried out in two, but there was no residual tissue and therefore, we cannot assess these individuals in relation to the possibility of preclinical infection. Importantly, also, only a very small number of these individuals survived for more than five years after the blood transfusion.

Any single case of transfusion transmission is very important. I am going to briefly describe a situation in which there is uncertainty about whether the individual developed vCJD because of transmission/transfusion. Again, this is now published. I will talk about this briefly. It is rather confusing and I will do my best to be succinct. This individual died of variant CJD, which was confirmed in 1993 and was known to have received blood component from a total of 103 donors, who are now classified at risk of variant CJD because they were involved in a donation to someone with variant CJD. One of these individuals had also donated blood at about the right time to a hospital X in 1989. In this hospital, at that time, was a child, who had just been born prematurely and received four blood transfusions. However, the hospital records were incomplete and it is impossible to know whether the blood transfusions were actually derived from this single donor. However, you should be aware that this donation was the first donation this individual had ever given and gave another series of blood donations and there were 27 other recipients, who are not known to have developed variant CJD and this donor is still alive. There is a possible link and the question is whether this is coincidence or causal. A recent analysis has been published in the Department of Health website that concludes, in this specific case, infection due to a common donor appears unlikely, in most scenarios highly unlikely. For the sake of completeness, it is important that you should be aware of this occurrence.

These are the surviving recipients of variant CJD blood components. There are 21 of these individuals now. This is an updated, as of 30th of September, showing the same format -- the recipients survival and the time from donation to onset of clinical symptoms in the donor in years. As you can see, these are leuko-depleted red blood cells. These are whole blood or red blood cells. This group have survived, all of them, for nearly twelve years so far, without developing clinical disease or symptoms suggestive of variant CJD. Of course, many of them may never do so. This does include two individuals who received blood from an individual who was within two years of clinical onset.

This is just a summary slide showing the situation in relation to the total alive years since exposure and the current age of these individuals. This is a summary in a slightly different way from what was presented yesterday. It is always very difficult because the denominator here changes as time goes by. As Dr. Scott suggested, we have four infections, which are in red, in individuals who have survived for at least five years along here from the blood transfusion. That is five out of about 32 -- I'm sorry. Four out of 32, which suggests that blood transfusion is, indeed, an efficient mechanism of transmitting variant CJD. There was some discussion about the low levels of infectivity, but, of course, if you assume from animal studies that there are ten infected units per ml of blood, if you transfuse 400 mL's, that is still a significant dose by a route, the intravenous route, that is known to be relatively efficient in transmitting prion diseases.

Plasma products. This is the plasma from vCJD donors that was sent for fractionation in the UK. This is the numbers of units and the time. There were 25 such units sent for plasma fractionation up to 1998. After this time, policy in the UK was to import plasma, mainly from the USA, for the production of plasma products.

You have heard about this case before. This is the detection of PRP in the spleen of an adult hemophiliac patient in the UK. As it has been discussed, I will not go on about it in anymore detail, but it does raise the possibility that variant CJD has been transmitted through a plasma product. The probability of the route of transmission -- this was an analysis carried out last June -- suggested that, although there were a number of potential avenues of exposure from food, from blood transfusions, from exposure to endoscopes, by far the likeliest exposure was through plasma products and counter intuitively, probably the non-implicated plasma products, rather than the implicated plasma products, which were known to contain a vCJD donation. This is on the assumption that there is a background prevalence of vCJD in the UK population and that individuals are donating blood to large pools, which are therefore likely to contain vCJD-implicated donation. I think I should also stress, as I think I did last year, that the likelihood from this analysis by Foster is that the factor VIII that would have been involved in this case was a certain type of factor VIII that used to be produced, which was thought to have a relatively low clearance factor in the production process.

Now, there was an article in parallel with the description of the case earlier this year, which gave you some idea of the denominators here. This is the estimated number of patients, who received plasma products. It is 4,581 between 1980 and 2001 in the UK. Of whom, 792 are notified as being treated with one of more of the implicated batches. However, the units account for only 12.7 of 23.7 million units of the implicated batches and this figure of 792 is, therefore, an underestimate. Further work is going on to look at this in much more detail. There was a recent poster at Prion 2010, Saltzburg by Dr. Zaman from the Health Protection Agency in England, which promises to provide a lot more information that might be useful in modeling studies.

The next question is if there is a case of variant CJD that might be linked to treatment with factor VIII, what about the actual clinical cases, themselves? This has been looked at by Hester Ward. This, against, is a published paper, in which we looked at all the cases of variant CJD to identify whether any of those individuals had been exposed to plasma products. Indeed, and perhaps not surprisingly, some of them had, but this is usually single treatments, sometimes with non-UK derived plasma products, for example, rhesus immunoglobulin, often. Our conclusion from this is that there is really no good evidence that the actual clinical cases of variant CJD are linked to prior treatment with plasma products.

Again, Dr. Asher has mentioned this, but of course the one critical issue in relation to potential secondary transmission of variant CJD in the UK is the prevalence of infection in the general population. A further study has now been published -- and I am very grateful for the HPA for sending me this just a few days ago -– published in the Journal of Pathology. It is a review of the large scale immunocytochemical examination for PRP in tonsil specimens in Britain. And this slide I think you have already seen. This shows a positive section in one tonsil from this study. There were two other positives, but the features of the histology were thought, by James Ironside and David Hilton, to represent background staining and not specific staining.

This is the summary in the 1981 – 1985 birth cohort. We have three positives -- one strongly positive follicle, which is judged to be true positive. Interestingly, PrP 129 genotype MV and two that were probably background staining. Again, interesting, the MV and a VV. Of course, 40 percent of the UK population are thought to be MM homozygotes.

This is a summary of their estimation of the prevalence of infection in the UK population on the basis of this study, which is this one here. They tested the 2004 - 2008 National Tonsil Survey by EIA and found no positivies, then took a sub-group and looked with immunocytochemistry and found just one positive out of 9,160 individuals, leading to this figure of 109 per million prevalence in the UK. This compares with previous studies -- Hilton and Ironside of three positives out of 10,278 in this birth cohort with a figure, which is slightly higher, of 292. But my understanding -- I am not a mathematician -- is that these are not statistically distinct. But it is consistent with the idea that there is a population of individuals in the UK who are infected, but have not yet developed variant CJD and, of course, may not in their lifetime.

There are some interesting points in the discussion in this paper, which I thought I would just point out. One is the PRP res found in the previous study of appendix tissue may conceivably have been transient and eventually cleared without resulting in clinical disease. It is an interesting idea. It is often made the assumption that these positives in appendix are inevitably going to be associated with infectivity in blood. That is an assumption. Secondly, one PrP res follicle by IHC can be interpreted as showing that there is one individual who will go on to develop variant CJD or if a single positive follicle is indicative of an insufficient amount of PrP res to spread and cause disease, there is no one who will go on to develop variant CJD. I think this has to be balanced against the findings in the spleen in the patient with Hemophilia A because, clearly, that required intensive investigation to identify a positive and there is a question about the sensitivity of these methods and about the accuracy of the estimates of true prevalence. Indeed, an ongoing objective in the UK is to carry out further prevalence studies, which are, perhaps, more reliable.

Just to summarize, a codon 129 genotype in subclinical infection with variant CJD, the original appendix study -- two VV's and not done -- could not obtain DNA from the sample. Positive spleen in a transfusion recipient, MV. Positive spleen in a hemophilia A patient, MV. Single positive in tonsil screening, MV. This is an unusual distribution, but what I think it does show is that if these are true positives, that it is quite right that any risk assessment should take account that the whole population may be at risk of infection with variant CJD and not simply methionine homozygotes.

There are a number of other continuing uncertainties in the UK, which I do not have time to discuss. There is the issue of whether there could be transmission through contaminated surgical instruments. We have a study that looks at that in great detail. To date, we have no evidence of such transmission.

There is also the concern that there could be transmission vertically, perhaps through individuals who were clinically affected while pregnant and giving birth, of variant CJD. Fortunately, there are only small number of these individuals and, to date, we have no evidence that any of the children have developed variant CJD. The problem with both of these studies -- the surgical and the vertical transmission studies -- is the period of observation is relatively limited in relation to the potential incubation period in these disease, which can extend decades with low levels of exposure.

I am going to finish there. I hope I have been able to summarize the variant CJD situation. I hope that has been helpful. I just wanted to reiterate that I think there are still many uncertainties that remain unanswered. I am going to finish with my acknowledgements. We could do none of this work at all without the help of patients with vCJD and their families, neurologists and neuropathologists who refer cases, all the staff at the Unit, Patricia Hewitt, Charlotte Lowell, and the National Blood Services in relation to the TMER blood study, UK Hemophilia Center Doctors Association, who were involved in the study with James Ironside in relation to the positive spleen, the Health Protection Agency, and I think, importantly, what is often forgotten is CJD Systems Internationally, who provide the variant CJD data from each country on a voluntary basis. I think it is a huge amount of work to provide these figures, including negative data. All of our work is funded by the Department of Health, the Scottish Government, and European CDC. Thank you very much.

DR. HOGAN: Thank you very much, Dr. Will. A lot of information. Anyone have any questions for Dr. Will at this point?
MS. BAKER: Yes, thank you. That was most informative. Thank you, also, for the definition of possible cases. I am wondering if that definition is harmonized with the US, with the FDA's.

DR. WILL: Well, the situation is that there is a harmonized system for CJD surveillance in Europe, which was funded, initially, by DG Research then DG Sanco and now by European CDC. We share agreed case definitions for all forms of CJD, including variant CJD. A number of countries have joined together with us, in order to carry out CJD surveillance and share data internationally. It includes a number of countries, including the USA and Canada. The USA system is run partially by CDC -- Larry Schoenberger and Ermias Belay and also by Dr. Cambeti in Cleveland. My understanding is that we all agreed to classify cases according to the shared WHO definition.

DR. MCCOMAS: You mention that you import plasma from the US. I was just wondering what do you do about whole blood donations?

DR. WILL: This is not my area of expertise, but my understanding is that there really is no practical possibility of importing whole blood components for transfusion. Indeed, all the blood transfusions that take place in the UK use UK-derived blood components.

DR. HOGAN: Any other questions? Well, I have one and I promised my wife I would ask you. She is a gastroenterologist and I better ask you has there ever been a case of transmission of variant CJD via endoscopy.

DR. WILL: Do you want the short or the long answer? The short answer is no. The reason that we are confident about that is -- just to be clear about this -- is that in every case of variant CJD we obtain a detailed history of their past medical background, including surgical history from the hospital records, from GP records, and from direct interview with family members. We have a database, in which ever surgical event in every case, including endoscopies, is put on a database and we look for any potential links between surgical events that may have taken place at approximately the same time in the same hospital. That is how you would look for a direct link between cases. We have no such evidence of such a link to date.

DR. HOGAN: Thank you. Dr. Geschwind?
DR. GESCHWIND: Professor Will, you showed a slide looking at the factors that might have been given to the vCJD patients. It looked like there were a lot of patients who got immunoglobulins or factors -- it just seemed that it was out of proportion to what you would see in a normal young population.

DR. WILL: That is a very interesting question, but I think the answer is that the -- for example, the number of individuals who had received rhesus immunoglobulin was as expected for this size of this population. I think a lot of it was travel immunizations. Some of them were travel immunizations, which, again, is a fairly common thing to be given. We do not think that the number of absolute exposures is more than we would expect from the general population.

DR. GESCHWIND: Oh, I see. So they looked at immunizations and things like that. That was not just IVIG or things like plasma products.

DR. WILL: No, no. It was anything that could have included -- been derived by plasma, theoretically from a plasma pool. You should understand that many of those individual treatments were given from material that was derived non-UK sources -- that is number one -- and often they were single exposures. One of them predated BSE, therefore our conclusions -- and you can read the paper, if you want to see the justification in full -- is that we do not think any of these are likely to be implicated in variant CJD to these individuals.

DR. HOGAN: Thank you very much, Dr. Will. As always, informative. Now we are going to move into the BSE issue. We will have discussion by Linda Detwiler, currently at the College of Veterinary Medicine at Mississippi State University and a very well known expert on BSE.

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Agenda Item: BSE in the USA and Worldwide

DR. DETWILER: Thank you. I will take exception to the word expert on there, but I am glad you said Mississippi State because in the program and what not University of Mississippi -- let me tell you, my university wants me to say I am from Mississippi State. So we got that correct.

Thank you. Good morning. Like Dr. Will, Dr. Asher covered a lot, but hopefully I will get down more into the weeds. Dr. Manuelidis' questions -- maybe this will shed some more light on it because I give you a lot more numbers and a different perspective about the way surveillance is conducted in different countries.

Dr. Asher, if I forget to mention this, you said about human exposure so if I do not near the end talk about human exposure in the dietary, remind me in a question. Your question prompted some information here.

We are going to talk about global BSE cases and the trends and different things with surveillance, the OIE classifications and kind of what they mean and to me what is next and what is in it for the future. A lot of you know that I have been around working on this issue since 1985, pre-BSE, when scrapie was a minor disease in a minor species so I can give you at least some historical perspective, here.

This is just a map put out by the OIE, just to show the countries. They classify it a little bit different versus just the BSE haves and have nots. You can see the pinks or clinical cases. The US is put in purple. It has a zone because of the atypical cases there. Most of the world has never reported BSE and you can see that there.

Surveillance over time -- I think that is important for us because of the question Dr. Manuelidis asked is really to look at how surveillance has progressed over time. There are two things. One, what type of surveillance was done early on and even the diagnostics? When we first started BSE the only surveillance we had was passive, basically waiting for cases to be reported by owners, by producers, by veterinarians out in the field, maybe at the slaughter plant and then for those to be turned in for diagnostics and to be confirmed.

Then we started to develop more the rapid test, so the immunohistochemistry, even at first, the ELISAs, even some rapid western blots for the detection of the abnormal prion protein. Then we were able to move more into an active surveillance where it was targeted certain risk populations and you did not have to wait for anybody to report it. This was done on a larger scale. I will show you some here. There were two things that kind of happened over time on there. When I first started and even in the early days of BSE the only diagnostics we had were histopathology and mouse bioassay and if the tissue got frozen or autolized into the mice and wait a couple of years. So that is how far we have come.

This is a case going back just to show you that the trend to positive cases in the European Union -- actually, the EU 5 so the original EU members. So here is the United Kingdom and basically, this was all passive surveillance. This was the cases that they found over time by people reporting and by veterinarians reporting. This was the surveillance in the European Union -- the EU 15 -- over time as well, with passive.

Now, as Dr. Asher mentioned in 2001 there was a mandate by the European Union to go into active surveillance and hence you see the number of cases. It is probably a combination of, one, the incubation, the movement of feed stuffs out of the United Kingdom over to Europe and that incubation with the cattle. That is probably one that shifted it, but also then putting on top the surveillance -- the mandatory surveillance that you have the increase of cases there. Please note, they are different tables. Very, very important. Here are the cases, the numbers for the UK. You can see this is a peak at 35,000 so that is a much different scale than the peak in Europe at a thousand. I just wanted to point that out. So it is not equivocal. The scales are not equivalent here. By far, the United Kingdom had more cases, over 180,000.

Again, as Dr. Asher mentioned, this is a representation of the UK epidemic, but this is what was visible, what was found and this was probably what was missed and it was estimated that finding 180-some thousand missing approximately even up to three million or so. That is what surveillance can uncover. Some of that was because of the passive and others was because the long incubation and where you are in the diagnostics. Diagnostically, we can only pick it up not too much before the onset of clinical signs.

I wanted to put Switzerland, too, as an example to show you. Switzerland really jumped on the gun. Once the UK reported BSE, they jumped in on surveillance and they found their first case here. They did a really good job as far as their passive surveillance and reporting and they would go out to find cases, as you can see. Over a while, they were pretty high -- they were ranked in a higher risk category with the United Kingdom. That was a lot because they are active, but yet they remained under 70 cases all total. They saw a drop that was because of some actions that they have done there with the feed ban, taking out things. Then Switzerland did something that was now the movement to some immunohistochemistry, some rapid tests, prionics had developed, also, a rapid test, a western blot that could be done and Switzerland went into starting to look at their population of at risk animals -- so the down animals, the fallen stock, as they call it, and they started to do that on a wide-scale basis. You see, it did not really drop and then come back up. It was just they started to focus now more away from passive and actively go after what they deemed as a high risk population.

Dr. Bigelow, I really stayed away from the United states because he is going to come, but I will just tell you because I lived through that, we started using immunohistochemistry in 1993 and because of a theory by Dr. Richard Marsh that we may have had a different form of BSE in the country, we also started to also look at downers in about '94 or so. But Switzerland did it on a larger scale and showed that was a great population to look at as far as risk. Switzerland, just by the way, from 2007 on, they have not detected cases of BSE. They did not, unlike the European Union -- the European Union, as you will see in my next coming slides, mandated testing of healthy animals at slaughter over a certain age. Switzerland never made it a regulatory requirement, although they left it optional and most of their industries, because the European Union was doing it, most of their industries did adopt that and were doing it on a voluntary basis. For many years, the Swiss population of healthy normals going to slaughter was tested, but it was never mandatory. It was always on a voluntary basis.

I wanted to show you, though, the decline in the UK. You saw the peak at 30-some thousand, but starting -- they dropped down below 3,500 in 1998 and they are well on their way. They have had, last year, twelve cases as Dr. Asher mentioned and this year seven. But you can see they have really made an extreme drop on that. They, too, because of regulations in the European Union have moved to testing on a mandatory basis, both their at-risk population and healthy normals going to slaughter. For a number of years, the UK -- again, it is hard -- my big point for you in this is it is apples and oranges in many countries. Even the UK with the rest of the European Union because after 1996, when the link was made with variant CJD, the European Union made a decision that animals that were sent to slaughter over 30 months of age would be slaughtered, rendered, but fully destroyed. That went on for a while so they were not testing all of those. Even when the European Union moved to test that slaughter population, they were like we are destroying these and it was not until within the last couple years that they moved away and started to test that. Again, even the UK with the rest of Europe, it is still some apples and oranges there.

This I do not want you to worry about what is on there other than the European Union starting in 2001 put some mandatory things as far as fallen stock, you know, their high risk animals, over 24 months of age, okay, the healthy slaughters over 30 months of age. Yet, some countries could make their own, as long as they were more stringent. Germany, you saw, they went to 24 months even for the healthy slaughter. Again, there was some variation, even within the European Union, at least if it met the minimum requirement. Now, in 2008, they passed legislation, effective 2009, that the countries in both targeted categories can go up to the minimum of 48 months. That is the difference there.

The other thing I wanted to point out for you and I am sorry I talk pretty fast. I am from New Jersey, here, so I will try to slow down. Again, some different things that you have to look, even within the European Union. You have you are supposed to test the at-risk populations of the fallen stock, down animals, emergency slaughter -- that is a high risk population. You will hear Dr. Bigelow talk about that in regards to the United States. Even within, I just want to show you the great variation of percentages of those risk populations. Lithuania it is less than two percent.

These countries here and the Czech Republic, it is over ten percent. So is it certain countries have that much at risk versus others? It may be that it is what is available. If you think about it, if an animal was down or dead on the farm, does it get reported? Does it get sent in? Their mechanisms in order to get those animals available? This is just a scale. This was done in like the mid-1990's, mid-2000 by Dr. Hyman. That was just to show that even within the European Union with the legislation, there is variation of what comes in and is considered at risk. I think you will find that in North America as well and how much percent is actually presented for testing.

Again, the total number of tests, as Dr. Asher said it hovers right around 10 million. That is all the categories of testing in the European Union. This would be now the EU-27. The vast decline. You can see here even more so after 2008. There are now less than about 48 cases -- I am sorry, overall it has dropped even more in 2009 and 2010. Here is the prevalence, here. Just to show you the decrease in prevalence. It is on a decline. Very, very important. The other thing to show, also, and this is just the evolution in prevalence per -- the active monitoring per healthy slaughter. So you can see it is much less now found in the healthy slaughter animals versus the risk. This is just the decline, but both categories you can see a decline. There was never much prevalence in the healthy slaughtered animals, as you would expect.

Before I go out of the European Union, one last note and that is important as far as the age. It is important to look at the age because the animals that are older that they are finding most likely were exposed and just have a long incubation period. So, cases in the European Union that they have found, the later ones were born -- they have had one 2004, one 2005. That is what is really to watch. Same thing in North America that we have to watch and I will show some slides on that. You also have to take into consideration that you are not going to find cases born in 2008 or 2009 because they have not gone to the incubation period. I always caution people to say, well, we have not found any that were born just recently. Well, they are not old enough for you to find them. I put that caution as well. You have to have enough time in order to find those to pass.

Here are the total BSE cases out of Europe. Again, I point out the scale. So we are only talking a scale of ten. The green is Japan. The blue is Canada. The red is the United States. I wanted to point out -- because Dr. Bigelow is going to talk about the US and I am not -- about BSE testing in Canada and the numbers. Now, Canada does not test healthy normals going to slaughter. They do not test those at all, but they do test the at-risk population. Dr. Bigelow will cover the OIE, the criteria for that. Similar to the target risk populations that the European Union does -- so that is very, very similar.

You can see here the numbers that Canada -- this is wrong. I am sorry. For some reason I did not put the right number in here. That should be up around there so I will make sure I correct that. They peaked at about 55, 56, 57 cases in 2006/2007. 2008 should be up in the 40,000. This is last year, thirty some thousand cases. And they are about targeting right there. I apologize. This is wrong. It is up higher than 40,000 there.

BSE in North America, I talk about since most of the cases have been in Canada. There are 20 total cases. Two were US-born, 18 Canadian born, 16 classical BSE in Canada, 2 atypical BSE in Canada, 2 the US were atypical -- no classical detected. It has been in both beef and dairy breeds. I want to really point this out, here. Two Canadian cases were born in 2002, one in 2003 and Canada has had a case born out into 2004 that was found earlier this year. So, again, they have had infectivity -- I will show you this slide here -- in their system. It is probably -- the thought in Canada and in North America is that we had imported cases from the UK and some other countries up until about 1990, '89 for us and 1990 for Canada.

These cases probably went into the system because not all were pulled out and we had then what resulted in undetected domestic cases somewhere around 1996. These undetected cases, some probably went back in the system, went in to be fed, and then the first domestic clinical case was found in 2003 in Canada and then shortly thereafter the US found the imported case that was born in Canada.

These arrows just represent cases that were found and I showed you that we always know that when you find a case, there are other cases that are undetected and possibly going back into the food and feed system. Again, the recycle back to cattle is how strong is your feed system? We know in Canada there have been, although the ruminate -- the mammalian ruminant feed ban was put in place in '97. There were cases born out to 2004 so we know there was some slippage, cross-contamination most likely in Canada up until at least 2004. The good news is that Canada, in 2007, took out all the high risk material, the SRM's, from all animal feed. We are hoping that will put an end to that transmission cycle past that.

I do want to point this out, though because I think this you need to take into -- this is the amount of cattle imported into the United States from Canada, the number of head per year. You can see in 2002 it was 1.6. It really dropped after their first case and the border was closed for a little bit. In 2008, it almost returned there. It has dropped down a little bit in 2009, 2010. I have to point out the number here. 80 percent of those animals of that number go directly to slaughter and of those, mostly are feed lot cattle, about 25 percent might be cows and bulls coming from Canada. I think the US has to consider that risk, the potential risk as well.

OIE, David covered this so I am going to kind of throw this out. I do want to point out the difference for those of you that may not be as familiar with the World Organization for Animal Health and WHO. The big difference to me is that the WHO makes recommendations for healthy policies for humans. OIE does for animal health. I think one of the big differences in my mind is that under the mandate of the WTO Sanitary and Phytosanitary Agreement, their standards actually influence world trade and I think that is an important thing to point out. The OIE standards influence the trade in animals and animal products.

David showed this slide. I will not show this slide. Then the controlled risk, again to point out. I will point out, though, in regards to the standards for the OIE in regards to what you have to do to import products -- animals and animal products from controlled risk versus undetermined.

The undetermined risk is considered kind of the highest risk category for BSE. The chapter actually -- the guidelines are getting very close. There is not too much difference between what you need to do in order to export animals and animal products from both control risks. Dr. Asher, even more so than just the range within the controlled risk, the difference between standards between the controlled and the undetermined in the OIE is getting to be, in my mind, minimal. For example, to do live animals from controlled risk countries, it is animals that were born after the date of an effective feed ban.

For the undetermined it is animals born two years after the date of the infective feed ban. SRM removal is 12 months for undetermined risk and 30 months for a controlled risk. Again, to me they are getting pretty close even in the standards.

I always put this in because I am a big believer, through my career, the long incubation periods where you do not know what is happening, you always have to think that if you knew it was going to happen, whatever it was -- some adverse event was going to happen tomorrow, what would you have wanted to do yesterday? If you take the action when you find it, you are years too late. You have already seeded in.

So I always look at the things that bite in regard to the TSEs. So things that I think you should probably keep on the radar screen, I think, as alluded to here, we do have movement of meat and bone meal going into Asia -- this was awhile ago, we had some movement of lives animals coming down here, movement of meat and bone meal, live animals so these countries have not reported BSE so has it spread there? Did they have enough controls to stop it? And would it be found, if it was reported? I think we always have to keep that in mind.

Complacency. As Dr. Asher said when I was introduced, I do do a lot of consulting for different food and pharmaceutical companies, especially the food companies. Our biggest harm, I think, is complacency with these risks. As we talk about no more BSE, I hear governments talk about it all the time and it is not just here, I go all over the world and, oh, BSE is not an issue, BSE is not an issue, BSE is not an issue. So in the slaughter plants, that is the message that gets conveyed to the work force there and to the industry. I think that is something -- you know, if we say SRM removal is protecting our human population, we better still mean it.

Chronic Wasting Disease. Although there has not been a link with human health, I think we cannot let that off the radar screen. You can see here are the areas of infected wild populations here in the yellow. The states with captive population. If you went back ten, fifteen years, this would have been very small areas. You can see that continues to spread. Right now there are no measures that can really impede that spread. I think that is something that we always have to be aware of here, even in change there.

Other things -- then I will wrap up here -- atypical BSE. Although it does appear to maybe be a sporadic disease because it appear infrequently, there is the L-form -- the H-form and the L-form -- the L-form does appear, at least in animal models to be maybe more virulent than BSE so that is something that we cannot let go. If it does occur sporadically, no country in the world who has cattle can get rid of it.

Atypical scrapie. This is one I really think we need to watch. Some countries it is now becoming more than 50 percent of the cases of scrapie found. For example, some of the countries of Europe where they are looking at it, for example, France, even the occurrence can be as much as four, four and a half per million. Everybody wants to say this is a sporadic disease, but if it occurs at that high rate, it is pretty high occurrence. Just recently at Prion 2010, it was reported that atypical scrapie because it was thought that it probably does not spread, but I think we have to watch two new research findings. It can be transmitted, at least experimentally, orally.

This is one thing and I was thinking as Dr. Will was up here presenting, it is now found in some of the tissues -- and there are two papers submitted for publication -- that there is infectivity in the absence of detectable PrPSE in peripheral tissues. Despite looking immunohistochemistry, western blot, ELISA, they have not detectable PrPSE, but when they put these peripheral tissues in transgenic mouse models, they are finding significant levels.

DR. HOGAN: Thank you, Dr. Detwiler. We are a little behind. Dr. Christ -- willing to go ahead with the USDA update, please? Dr. Christopher Robinson is going to talk, first of all.

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Agenda Item: USDA Updates

DR. ROBINSON: Good morning everybody. I am Dr. Christopher Robinson. I am the Assistant Director with the National Center for the Import and Export. I am currently the BSE Comprehensive Rule Project Manager. The comprehensive rule is the rule that we are in the process of developing, whereby which we are going to align our beef import rules of all regulations with the OIE. I should say closely align with the OIE. What I hope to say to you, very quickly, is from our perspective, APHIS' perspective, to give our reasoning for why do we need this rule, to acknowledge what our current BSE regulations are, what will the proposed rule do, and what are the differences?

The purpose of the rule is to adopt a science-based, internationally recognized BSE standards that are actually based on the OIE recommendations. In addition, this rule will also allow us to streamline the process for recognizing the status of BSE regions. I will walk about that later. This rule will also allow us to maintain a consistent message that we have been giving to our stakeholders.

Currently -- Dr. Asher touched on this a little bit –- when you look at our current BSE regulations, currently we prohibit the live importation of live ruminants and certain ruminant products from regions that have either had BSE or we consider to present an undue risk for BSE. Currently, we do allow products in from Canada. We have another category for BSE, which we call minimal risk. Canada is a country that we do recognize as having minimal risk for BSE. While we do recognize Japan as having BSE, we did do a risk assessment and we have allowed them to import certain cuts of beef, boneless cuts of beef.

Currently, when you look at our current rule making BSE process what would happen is that currently a country would come to us and they would request to be evaluated, to be recognized as a minimal risk region. We would conduct a risk assessment and then do notice and comment rulemaking doing both a proposed rule and a final rule to add that country as a minimal risk country to our CFR. That can be a very lengthy process. What we are going to do with this rule – with the comprehensive rule – is we will adopt the OIE BSE categories of negligible control or undetermined risk. In the rule, we will describe and adopt the OIE criteria for classification. I think Dr. Asher touched on a slide that actually showed you the criteria for classification. We will recognize OIE evaluations after public comments. We will also propose to do in the rule, for those countries that are not evaluated by the OIE, if they would like to be evaluated by us, we will conduct the evaluation. Also, for those countries that want to import live bovine, we will do a separate evaluation to determine the date of the effective enforcement of the feed ban, something which the OIE does not do.

We will align our BSE import requirements with OIE guidelines. We will list the commodities eligible for unrestricted trade. I think that is an important point to mention that there are under the OIE, irrespective of whether you are a negligible control or undetermined risk region, there are commodities that can be traded with no restrictions. Then we will base our other import requirements on BSE risk status of the country. On this part, right here, where we recognize Canada as minimal risk and the boneless beef that we get from Japan -- Canada and Japan will fall into the control risk category, as they are currently recognized by the OIE.

Another reason why we are taking this approach to BSE is because it will eliminate the need for us to do rule making that is specific to region and/or country and/or to commodity. So for those countries that have been classified by the OIE, what we will do is that we will do an informational notice and we will request comments. In other words, we are not just going to say, okay, the OIE has now recommended and accepted the country as controlled risk. We will come back and actually take comments from the public on us concurring with that decision.

For those countries that wish to import live bovines to us, we will have a notice of availability, we will have feed ban enforcement information, and we will request for comment, for example, like we have done for Mexico. In that case, the information that we gleaned from that country to determine the effective enforcement of the feed ban, we will make that information available for comment. Then, for those countries that wish to be evaluated by APHIS, we will do the same thing and then we will also put the supporting documentation that we receive from that country so it is available to the public for comment.

Right now, we are just proposing the rule, but right now, when the rule is proposed and then we finalize the rule, there will be a 60 day or more wait period, if you will, to implement the rule after publication. Concurrent with the rule -- we may actually change this part. I have not had a chance to really update -- this is not the presentation I wanted to show you guys because the one I had I could not upload.

Anyway, this part right here talks about concurrent with the publication of the final rule, we may also publish comment to also have the public comment on to recognize those countries or to concur with recognizing those countries that are currently controlled risk or negligible risk by the BSE.

I think with the rule we actually may propose those countries actually within the rule -- to recognize those countries as actually negligible control risk within the rule. Also to minimize trade disruptions with Mexico because we do take in a lot of live cattle from Mexico, we will publish a notice for comment on how we determine the effective date of the feed ban enforcement for Mexico.

Currently, again, I think you saw this with Dr. Asher's presentation, but our current regulation of 9 CFR 94, we list countries as either having BSE, we recognize countries as having undue risk for BSE, or the one country, Canada, that we recognize for minimal risk for BSE. Under the comprehensive rule, we will use the OIE categories of negligible, controlled, or undetermined risk. Also, when you look at our current regulations, restricted countries right now to be recognized for BSE, again, they need to request to be evaluated by APHIS. APHIS, we would perform a risk assessment based on the country's BSE status.

All countries will be considered unrestricted for BSE. Here, under the comprehensive rule, APHIS, we will recognize the OIE BSE classifications. For countries not already classified, APHIS will conduct independent evaluations using the OIE criteria upon the request of the country. Right here, all other countries not evaluated by us or the OIE will fall into the undetermined risk category, as opposed to now being unrestricted for BSE.

Now, when it comes to rule making the big difference, right now rule making is required each time a country is added to the CFR for recognition as minimal risk. APHIS, we would need to conduct new rule making to establish additional classifications or commodities. Under the comprehensive rule, we will add countries to an online list for publication of federal registered notices.

Now, when it comes to trader commodities, currently we prohibit live ruminants and certain products from countries we recognize for having BSE or being at an undue risk for BSE. We do allow live ruminants and ruminant products from minimal risk countries -- Canada with certain restriction and we do allow fresh cuts of boneless beef from Japan. Under the comprehensive rule, we will allow live bovines and certain bovines, based on their BSE risk status. Certain commodities will be eligible for importation from any country of any risk, even for undetermined risk. And risk mitigations will vary, based on the risk status.

This slide was thrown in because some people have said, well, you know, you guys show the OIE for some things, how come you do not follow the OIE for other diseases. Let me hurry up. Okay. This is just a brief slide to demonstrate why we are looking to embrace the OIE based on the BSE disease. Why we look at the OIE and what the OIE has done based on the science and why we are going that approach. And why we have not embraced the OIE criteria for FMD. The biggest reason, right here, is that FMD is highly contagious and we do conduct a rigorous onsite evaluation. OIE does not.

We will have, supporting the rule, a risk document, environmental analysis, the environmental assessment. We have been having interagency discussions on this rule. We will not be doing a traditional risk assessment for this rule. What we will be doing is that we will be presenting what we call a risk document. Basically, it will be a peer-reviewed or a document that will show peer-reviewed scientific publications. It will analyze the criteria for recognizing a region's BSE status and also support why these commodities can be safely traded, based on the BSE category of the exporting region. I do want to point out that risk assessments will be conducted as part of the OIE process or the APHIS evaluation.

Part of the OIE classification criteria to evaluate a country -- I do not want to get into that too much, but it does require a risk assessment. The OIE does require the country to have compulsory notification program and a BSE awareness program. They must talk about the BSE history and the epidemiological situation in the country. They must also, Linda pointed out, have a BSE surveillance program, including appropriate laboratory diagnostic procedures. I do want to say -- oh, I do have this slide. Okay. Good.

The OIE recognition process -- I want to go through this real quickly. Dr. Asher mentioned one of the things about maybe certain problems that people may have with the OIE is the lack of transparency. I do want to say that in this slide we talk about the OIE recognition process. Right here, when a country wants to be evaluated by the OIE, they do need to submit a dossier and all the member countries, they do have the right to request the dossier from the country.

This is basically just a slide showing what our economic analysis will do. We have done environmental session. We have had discussions with FDA, FSIS, and CDC about the content of this rule. We have shared that information with the various agencies.

In conclusion, again, for us this approach will adopt internationally recognized standards. It demonstrates our support for the OIE when it comes to this particular disease process. Also, it will streamline our process to recognize the BSE status of various countries. And it is consistent with promises that we made to our stakeholders.

DR. HOGAN: Thank you very much, Dr. Robinson. Dr. Bigelow, would you please continue with the update from FDA so we still have some time for questions. Sorry, the USDA.

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Agenda Item: USDA Updates

DR. BIGELOW: All right, thank you for allowing me to speak today as a representative of the USDA from National Animal Health Programs. I am Troy Bigelow. I am the interim BSE program manager. I am filling in for Janet Hughes, who spoke last year at this meeting, who now took a new position out in Fort Collins with our National Surveillance Unit. My background is I am a swine veterinarian with the USDA. I deal with pseudorabies and swine brucellosis. I took this challenge on to manage the BSE Program for a short time, until a new program manager can be hired.

I am going to give a brief overview of our BSE program, where we are at today. Many of you already know our BSE program, our changes, and what we are doing today. It is like what we did last year and our previous year. So I am just going to give an update and history for those of you who do not know what we are doing in our US cattle population to try to protect animal health.

I will give a brief history. I will go over a little bit of OIE information and how we base our surveillance program, why did we design our surveillance program the way we did. I am going to give you some objectives of our USDA surveillance program. What are we testing today? What kind of animals are we testing? Why are we testing those animals? I am going to give you an overview of some of our current BSE testing numbers, what we did last year and fiscal year 2010.

This is a fairly short presentation so I think I will get you back on time. Our active BSE surveillance started back in 1990. With that active surveillance, it allowed us to find the cow that stole Christmas in 2003 that we found in December. After that finding, we started the enhanced surveillance program that we implemented in 2004, as a response to that cow that stole Christmas. The enhanced surveillance program, within that program we tested over 750,000 samples during that time. It allowed us to find the two animals, one in Alabama, one in Texas of the atypical cattle that were identified in 2005 and 2006. After those findings, we went to the ongoing surveillance program. The ongoing surveillance program is what we currently have today for surveillance measures and I will get into more discussion on that later.

The overall history of our BSE surveillance program is we use a lot of the science behind the data from the EU that Linda talked about, where you are most likely to find BSE cases in those that are showing clinical signs. So our CNS animals, those that are having change of behavior, change of attitude, do not want to go into open doors that they usually go through. Our downer animals, why did they fall? It starts asking those questions. So we start looking at those animals that actually are showing clinical signs because those are the ones you are most likely to find BSE in. Our surveillance program we have today designed to detect one case out of a million cattle. There are currently 42 million cattle, approximately, in the US today. This surveillance program, our enhanced surveillance program allowed us to find the two we have today. Both the Alabama and the Texas cow that we found in 2005, 2006 were born before the implemented feed bans, but again, as Linda mentioned, they were the atypical cases, too.

Our surveillance program is based off of the OIE standards. Dr. Robinson gave a good talk on the OIE and how we are trying to align our regulations more with the OIE. Our surveillance is designed to try to find BSE. Random surveillance we know is not effective in trying to find those cases. We are trying to find those cases to prove our population is what it is. The OIE requires, for countries with large cattle populations that we try to have a surveillance program detect -- designed to detect one case out of a million adult cattle with a 95 percent confidence. Our surveillance program that we have today is designed to detect one case out of one million so it is ten times more likely to find an infected animal. This is for countries with large cattle populations.

The OIE surveillance program, I am not going to get into a lot of detail because many of you probably know way more about it than I do. There, again, it is based on a point system where you accumulate points and each animal that you collect, depending on where the animal comes from, it gives you different points due to the likelihood of that animal having BSE. You have more likelihood of finding BSE in a four to seven year old animal that is actually showing clinical signs -- it is falling, it is change of nervous behavior, nervous twitches, it is kicking differently when you are trying to milk it. Those animals that are not progressing to treatment, you are more likely to find it than taking an animal that died on a farm for an unknown cause or a routine healthy slaughter animal is very low points, if you are collecting a routine animal, a healthy slaughter animal at slaughter. So we are trying to base our surveillance system to actually find BSE in those cases.

Our ongoing surveillance program that we have today -- our goal behind there is we want to continue to assess and monitor change in the US cattle population. APHIS' goal is to safeguard animal health. That is on all of our presentation slides, safeguard animal health. We want to identify those cases, make sure the mitigation measures are out there and working today to prevent establishing disease in our US animal population. Our surveillance program, we want to provide mechanisms to detect prevalence increases. Again, we want to protect our US animal population. With all of APHIS' goals, our goal is to help establish trade, help our stakeholders in working with trade. So we want to meet or exceed the OIE standards that are established out there for trade or trade purposes.

Our ongoing surveillance program is more sensitive than the OIE recommends. There, again, our focus is on high value samples. What are those high value samples that we collect today? It is all cattle with CNS disease. As a practitioner -- I practiced in Iowa for a few years before I worked for the USDA -- the first thing that any practitioner should always suspect if you have a CNS animal is always think of rabies. Rabies is fairly common in cattle, especially in certain regions of the country. All those animals that get sent in for CNS disease, are not responding to treatment, including your rabies animals that are sent in, they get tested for BSE. Those are high likelihood. We have history behind them. We know the history. We know they did not respond to treatment. They were either tested for rabies -- all animals with CNS disease we are testing. There, again, we are also implementing, within our surveillance plan, is working with FSIS. With FSIS, any animal condemned over 30 months old, during ante mortem inspection, we are collecting samples and testing. We are testing cattle over 30 months of age that have signs similar to BSE, but is not necessarily CNS signs. Some of those could be non responsive to treatment, over 30 months of age, maybe other changes of behavior that is not similar to BSE associated with BSE that we have seen in Europe with the variant. So we are testing those animals. We are also testing cattle sent to 3d 40 facilities. These many times are ones that we do not know the history to. If we do know the history to and if it was a cow that was struck by lightning, a cow died for an unknown reason that is not likely to be BSE, those we do not test. But many of these animals are tested, if we do not know the history to, that are over 30 months of age, and again they are a very low point scale for us. We are more likely to find BSE in these populations that we are testing up here.

To give you an overview of what we tested in 2010, I designed this slide a month ago so these numbers were not official at that time when I put this slide together and that is why it says not official yet, but at that time we had collected over 45,000 samples from US cattle within that surveillance population, within those CNS animals, within those cattle over 30 months old of age, within those ante mortem condemns. We tested 44,000 of those at that time. You might ask why is there a difference between the 45,000 and the 44,000. The sample might have been submitted without OBCs. The practitioner or the person collector who collected the sample might not have gotten the correct sample. There might have been autolysis of the sample. Or there might have been an unknown reason why the sample was not tested at that -- where they could not test that sample that was sent in. Out of those samples that we tested, it allowed us to get over 900,000 OIE points and over two million BSE points, which far exceeds the OIE standards that are required today.

In conclusion to my program, our goal as USDA is to protect animal health. In fiscal year 2010, no positive cattle were identified from the surveillance program that we have designed that has identified at least one infected animal out of a population of one million. Our ongoing surveillance program will continue to test, as we did last year, from those streams that I talked about. And our surveillance program is over ten times more sensitive than the OIE design that we have today. I open it up to questions, if allowed.

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Agenda Item: Questions so Speakers

DR. HOGAN: Thank you very much, Dr. Bigelow. Does the Committee now have any questions on BSE of any of the speakers? No? Dr. Geschwind?

DR. GESCHWIND: I am not sure who to direct this to, but I was curious about Canada and why they are considered minimum risk -- why they are different than some of the other BSE countries? I do not have all the numbers in front of me, but it seems that Canadian cases actually have more than some of the European countries recently. I am just wondering why they are minimum risk or maybe I misread those figures.

DR. HOGAN: Dr. Detwiler could you take that?

DR. DETWILER: I will not answer for the classification. I will answer for the numbers, though. Yes. Canada now, in certain years, has surpassed some of the European countries on their -- classification actually is based on USDA. Also, the difference of surveillance with Canada is more like the US than the European Union. But I will let USDA answer for why the classification.

DR. ROBINSON: Dr. Kreindel can probably answer this question better than me, but I will give it a shot. The minimal risk classification came from when the OIE actually had a five tiered approach to BSE. There was -- you were the free, provisionally free, minimal risk, and I forget the other two. The OIE went to adopt to a three tiered approach, which was negligible, controlled, and undetermined risk. At the time we looked at the minimal risk classification, we went on and adopted the -- embraced the OIE minimal risk criteria, under their five tiered approach category at that time.

DR. KREINDEL: The minimal risk classification is very similar to the controlled risk classification and allows the trade of particular commodities and live animals, provided they were born after the date of the effective implementation that APHIS defined for Canada.

DR. GESCHWIND: So I guess why does that not apply to other countries, then? Why only to Canada?

DR. KREINDEL: At that time, we received that request from Canada and we had trade that had to continue with Canada. The intention was to come up with a more comprehensive approach. That is why we started developing the comprehensive rule so we can follow the international standards.

DR. HOGAN: Any other questions?

DR. KREINDEL: I would also like to add that for us to pass any regulation we take a very long time. Once we started thinking about the comprehensive rule and where we are now, we take many, many years.

DR. HOGAN: Thank you. Dr. Monroe?

DR. MONROE: Just to follow up on that so what is the current date of the effective implementation of the Canadian feed ban?

DR. KREINDEL: It has not been a change in the date. It is the date that was defined in the minimal risk, too, that I think was published in 2007, March 1st, 1999.

DR. HOGAN: Good information. Dr. Detwiler?

DR. DETWILER: I just want to add if you look at the 1999, there have been more cases born after 1999 in Canada than there have been born before. I think that is important for you to consider. One thing I forgot to mention, but what Dr. Asher said in there, is about the risk from Europe to the food -- in the food thing. Because Europe is screening all the cattle now -- some countries over 30 months, some over 48 months now of age -- they are taking at least the end stage disease animals.

So they are not only removing high risk material, but they are taking the end stage disease. Why that is important and I think it is important for Europe that if the animal is near end stage disease, there is new scientific information that there might be a retrograde movement of infectivity back into the peripheral nerves, et cetera. So in some respects by Europe doing that testing and taking out those end stage animals, they are probably protecting their food very well -- their food source very well.

DR. HOGAN: Thank you. Additional questions? This topic came up in from of this committee a couple of years ago and one of the questions that was asked that in any surveillance program if you are looking for a downer cattle or cattle with CNS signs or disease, it is dependent on the inspector or the individual who is looking for that cattle -- that cow to find it. So there were some questions about the numbers of inspections that were being done at rendering plants and the compliance of the rendering plants with the criteria. Can the USDA tell me how that is going?

DR. KREINDEL: I can just add, actually, we were looking at those numbers -- who is reporting the clinical signs in the US? These high risk animals are usually reported by veterinarians or the farmer will call USDA and a trained person will define most likely, over 95 percent of the time, if the animal is a high risk animal or not.

DR. HOGAN: What is done with the carcass of a high risk animal?

DR. BIGELOW: High risk animals that are tested at a rendering plant, those carcasses are retained and kept until test results are back as negative.

DR. HOGAN: And then?

DR. BIGELOW: Then, as long as they have received the negative test result, it would be used as a normal tested that is not tested.

DR. HOGAN: And if positive?

DR. BIGELOW: And if positive, it would be disposed of by a method -- landfill, incineration -- known to destroy BSE.

DR. HOGAN: The reason I ask that question is that my understanding from the meeting a couple years ago is that they were being buried and that, of course, does not eradicate the agent.

DR. BIGELOW: And I cannot answer on that one.

DR. HOGAN: And I cannot recommend, but I think you get the implication.

DR. BIGELOW: And to expand on what Silvia mentioned on her previous talk -- your previous question was, as you mentioned, CNS practitioners collecting, I cannot speak for FSIS, but I know FSIS -- the USDA FSIS in their slaughter establishments does have notices and regimented training programs to train their public health veterinarians on what CNS is, how to collect those animals to make sure that those public health veterinarians in those federally inspected slaughter establishments are collecting samples per the directives and notices described.

DR. HOGAN: Thank you. Any additional questions or comments from the Committee? Well, we will move ahead then. We are back on time. We will start the public meeting portion then -- the open public hearing.

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Agenda Item: Open Public Hearing

DR. HOGAN: We have three registered speakers and I have to read this before we have you speak, but if Dr. Germain could get ready, I would appreciate it. Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making. To ensure such transparency at the open public hearing session of the Advisory Committee Meeting, FDA believes that it is important to understand the context of an individual's presentation. For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement, to advise the Committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting. For example, the financial information may include the companies or groups' 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 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. Thank you.

If you could introduce yourself, please, Dr. Germain?

DR. GERMAIN: Thank you. My name is Marc Germain. I am the Vice President of Medical Affairs at Hema-Quebec. I am also acting as the Medical Director for the Tissue Bank Institution. I am obviously paid by Hema-Quebec for doing my work. This morning I am here on behalf of the American Association of Tissue Banks, in order to make a statement with regard to geographical exclusions of donors, who might be potentially at risk for variant CJD. I do not have any financial compensation from the AATB to do this.

I would like to thank you for the opportunity for giving this short presentation. Just briefly, as a matter of introduction in order to explain what the AATB is, the American Association of Tissue Banks is the only tissue baking organization in the United States. It is dedicated to improving and saving lives by promoting the safety, the quality, and the availability of donated human tissue. We do this by published standards for tissue banking, which are basically used worldwide, mostly in the US and also in Canada. It operates an accreditation program and currently we have 110 tissue banks that are accredited by the AATB. This represents tissues recovered from more than 30,000 donors annually in the US and it corresponds to distribution numbers in the order of more than two million allografts that are distributed both nationally and internationally. In fact, the overwhelming majority of tissue banks that distribute tissues for transplantation in the US and also in Canada, for that matter, will come from AATB accredited tissue banks.

I will not spend too much time here trying to explain the regulations that apply to cells and tissues in the US. We have heard the details of this this morning. Just to remind you that basically since 2002, the tissue industry is following almost exactly the same rules that apply to blood donations and then the industry has been in compliance with these rules since then.

The main point of this presentation this morning is probably not specific -- certainly not specific to tissue transplantation. It also applies, I think, to blood donation. I will obviously insist more on the tissue side of this point, but I would like to put the question to you whether the current precautions that we apply to prevent transmission of vCJD through tissue transplantation and blood transfusion are still justified today? The reason for asking these questions have been, I think, well presented to you this morning. It is basically the fact that now that we are ten years later after we started thinking about this potential threat, new and very relevant information has become available. We have heard that the Mad Cow Disease epidemic in the UK and Europe, although it certainly has not completely disappeared, is now well under control, at least compared to the situation in the 80's. The variant CJD epidemic, the human form of the disease, has peaked several years ago and seems to be declining. Although, we admit there seems to be some residual cases happening. There are only a few new cases of vCJD each year. Quite importantly, the total number of human cases is around 220 worldwide. This is very important fact compared to the scenarios that we were envisioning about ten years ago when this potential threat was in the room and where we were basically thinking that maybe the number of cases, even just in the UK, could be in the order of thousands if not tens of thousands of human cases. So far there is no evidence that it will go to such high numbers.

There is also no evidence that we will have at least a significant second wave of the disease, although we recognize that some additional cases might arise in alternate genotypes. It is also interesting to note that after almost ten years of application of these precautions, there is no evidence that the geographical exclusions that we have applied to blood and tissue donors have prevented the transmission of the disease, in North America anyway.

That is not to say that those precautions were not warranted at the time because, obviously, we did not know what the burden of the epidemic would be. But it just shows that because of the small magnitude of this epidemic down the road, basically these precautions never had any real impact on the safety of tissues and blood.

Finally, in the case of tissues, it is important to remind ourselves that there has not been a single case of documented transmission following a tissue transplantation for variant CJD or for other forms for variant CJD. It is not the case for other forms of TSEs, obviously.

All of this is such that we believe that the current risk posed by vCJD is considerably smaller. We are not saying that it has disappeared, but it is considerably smaller than what had been envisioned initially. Because of this, we believe that the current precautions in terms of the geographical exclusions may no more be proportionate to the risk that they are trying to mitigate.

Now, in terms of the special considerations regarding tissues for transplantation, we think there are some important differences that need to be pointed out. First of all, I would like to remind everyone that the criteria that were applied to blood donors, in terms of their travel history to countries at risk for vCJD were basically based on the impact that these criteria would have on the donor pool.

In order to achieve the current criteria that are applied, there were extensive surveys conducted among blood donors to assess their travel history and the durations that are currently allowed are based on these surveys, in order not to have too much of an impact on the donor pool. This was never done for tissue donors. It was basically a copycat application of the criteria that were used for blood donors.

 

Unfortunately, we do not have good data to estimate the current impact of the deferral criteria on tissue donors -- the geographical deferrals that is. These rates are difficult to get at because we have so many different members and the data is not easy to collect. However, it is fair to say that most likely the impact of the deferrals should be fairly similar to what we observe in first time blood donors. These rates can be relatively high in the order of five to seven percent. We have data from one of our members, a sperm bank, a large sperm bank. Over a period of two years, they, in fact, observed a deferral rate of five percent.

Perhaps a more important aspect of these criteria is the fact that, for the majority of tissue donors, as was explained to you this morning, of course, we are dealing with deceased donors and we have to obtain the travel history from the next of kin. As you know, the criteria -- the geographical criteria that we need to apply in order to qualify the donors are quite complex, in terms of the list of countries that are targeted, the time periods that we need to consider. It is already quite difficult to get precise travel history from a living person. As you can imagine, it can sometimes be impossible to get at this information when the information is obtained second hand from next of kin. This can lead, obviously, to inappropriate deferrals because of the lack of information.

Now, I just want to make a special case of reproductive tissue before I conclude. There is no documented transmission of any form of TSE between sexual partners. This is also true for variant CJD. BSE has not been shown to be transmitted by sperm or eggs or embryos in cattle. No documented transmission of other TSEs gametes in any species, to our knowledge. In fact, this is reflected by some of the regulations that apply to the importation of semen and embryos from the UK, which permit the importation of these products as long as the herds have been BSE free in the last few years.

So what is it that we recommend? Well, we believe that TSEAC -- I know that today is not a day to make specific recommendations -- we believe that TSEAC should reassess the current relevance of geographical deferrals for potential vCJD exposure. We are not saying that all of these precautions should be abandoned at this point. There are some remaining uncertainties. We realize that, however, the level to which we think these uncertainties reside are such that we could envision relaxing some of the current criteria that we apply. For example, this could take the form of having travel restrictions that only apply to countries at high risk, in this case it would be the UK, I think, or having period of travel durations that are allowed period of travel that are longer than what it is currently. And in the case of reproductive tissues, I think there is a case to be made that maybe all of those restrictions could be lifted.

In closing, I would like to remind everyone that all of these precautions were taken about ten years ago and we all said that we were basically applying the precautionary principle. We were very much in favor of doing this. I was personally involved in this process. I would like to remind everyone that the application of the precautionary principle also mandates that we should revisit the evidence as new evidence comes along and readjust our precautions as these data become available. I think this time has come. With this, I will end my talk and thank you.

DR. HOGAN: Thank you very much, Dr. Germain. We appreciate your input. I am sure the staff has heard you and we can perhaps visit this in the future as it is not entirely in our agenda today. Dr. Brown? Dr. Paul Brown? Hello? In the back of the room. Dr. Brown has asked to speak today, as well. Do you have a presentation, Paul? Dr. Brown is a past chairman of this Committee.

DR. BROWN: I have been asked by a company based in Denmark, which is a Danish sperm bank named Nordisk, to make this plea to the Committee. I am being recompensed by it, but I want to tell you right off the bat that if that influences the Committee, I will forgo the compensation because everything I tell you today I believe, whether it is for money or not.

The question is on the screen. This is the question I am addressing. The considerations, which you are probably long since tired of seeing, are the geographic source, the tissue source, the processing, and the usage. This is kind of the drill that all risk analysis people go through.

In terms of the geographic source, we are looking at the European setting. You have seen versions of this before, but I worked on these slides for so many hours I wanted to show it again. There is one little modification here. For vJCD I have separated the non-UK from the UK numbers. I thought -- clearly, you can see that both outbreaks are in the process of disappearing, but I thought it would be nice to look at the last five years in some more detail and I think this is also self-explanatory. BSE is clearly disappearing from the earth, both from the UK and from the non-UK countries. There have been only a handful. Notice the scale on the left for BSE is now reduced to a scale -- it is a scale, which means that this year just a handful of cases. Fewer than fifteen total cases of BSE have been reported for this year. That will increase a little bit as time goes on and the rest of the year is tallied.

There are -- some heads got in the way when I was looking at your slides, Bob -- but, at last report, as far as I know, there have been no new onset cases of variant CJD anywhere in the surveillance area. Is that correct? In this year, 2010? Beg your pardon? One onset, okay. So you can put a very narrow line under '10 for the red. It does not alter the trend. As everybody knows, all epidemics tail out. I do not know of any exception to that so you will see a case once in a while of vCJD in the European Union and the UK in the years to come, but I think we can say from these slides that essentially both epidemics are very rapidly becoming history.

Tissue source infectivity data. You heard this just a minute ago, but no case of variant CJD or any other type of TSE has ever been identified in children conceived by artificial insemination. Approximately 20,000 donors, including 1,000 residents of Denmark and 1,000 residents of the UK, itself, since 1960 and there have been approximately a third of a million recipients, almost all of which live in Europe and in Europe vCJD surveillance and surveillance in general is extraordinarily thorough. SO they would be detected. There has been no case of vCJD or any other TSE identified as a spousal cross-contamination. Finally, there has been no infectivity or pathological PrP identified in semen or semen from humans or animals with a variety of different TSEs.

You will never see an experiment in which vCJD semen is used. I think you can understand the reason why. Like many other things, we have to use the next best and the next best is to look at every other kind of TSE that we have information for. That is the most recent WHO table. You can see that -- these are the reproductive tissues and an awful lot have not been tested. Semen has not been tested for vCJD. It has been found negative for PrP. For sporadic CJD we have a handful of infectivity inoculations that were negative. By handful, I think the number is three. PrP has been looked at in many, many more and that is negative. Infectivity has been looked at in BSE and in scrapie, in both cases negative. The rest have not been tested. It is not probably fair to say there is no evidence for transmission because there is a lot of evidence against transmission. I think that is the way to express this particular issue.

Processing -- because semen contains white cells, leukocytes, there is a possible risk from leukocyte contamination. They start out with about a million leukocytes per milliliter. A couple of processing steps -- density gradient and washes and concentration, bring the final WBC count down to 500 per ml. That is similar to source plasma and source plasma may be imported.

It's used, unlike blood transfusions or plasma protein therapy, it involves a small volume, single administration usually, unless the insemination fails, and a suboptimal root of administration.

To recapitulate, semen is from a low BSE/non-vCJD country, Denmark. The tissue, in this case semen, is, I think it is fair to say, not infectious based on what we know. WBC contamination has been reduced. There is only a single small dose. That all adds up to a negligible risk.

On the other hand, when Nordisk presented this information to the FDA in 2008 and the decision was finalized in 2010, Dr. Krux is responsible for this particular quote, based on the FDA's current understanding of the disease -- a potential for vCJD transmission by semen exists. Well, yes. I guess it does, but this was a published paper three or four years ago in which a survey was taken of a number of prion experts and the consensus opinion was that the risk of transmission was less than one in 10 million, even for UK men. Hence, the ultra-conservative risk avoidance would have a minimal impact on public safety. This could be, if needed, even further reduced, if donors with the codon 129 MM genotype were excluded and this can be done.

If none of this has been persuasive, here are two countries. I challenge you to pick the one from which you would rather have sperm allowed. Well, the top is Denmark and the bottom is Canada. Denmark is banned and Canada is allowed. That just does not make sense.

Finally, these rules were promulgated, I think, this guidance when I was Chairman. I was worried at the time about Newton's first law of motion and inertia. So I have changed it to reflect my feelings at the moment. The ball is in your court. Thank you.

DR. HOGAN: Thank you very much, Dr. Brown. Do you have a comment?

DR. GESCHWIND: Just a clarification for the Committee, we do not import source plasma from outside of the United States. It is a matter of policy, not law. I think what Dr. Brown was alluding to is that the donor exclusion policy for source plasma donors, whereas it includes history of residence in France for five years, does not include history of residence in Europe in general, for four or five years or more. There is an exclusion for three months or more of exposure in the UK. Again, we do not import plasma from outside the United States.

DR. BROWN: Can always count on you for a correction. Thank you so much.

DR. HOGAN: Is there -- I am feeling restrained here. I know the issue of tissue exclusions is going to come up as some point in the future. Your points are well taken. Unfortunately, it is not the exact topic for today's discussion so we will have to just leave it at that.

We have a third speaker, who is registered. Dr. Cargreen, could she please -- could you turn on the microphone at the back of the room, please? Could you introduce yourself to us, please?

DR. CARR-GREER: Allene Carr-Greer with AABB.

DR. HOGAN: Could you tell us what AABB is, please?

DR. CARR-GREER: Sorry. That is the American Association of Blood Banks, formally. My remarks are in response to Lieutenant Lybarger's presentation this morning. Yesterday, I spoke briefly to the donor history questionnaire we have for donors of whole blood and we also have one for hematopoietic progenitor cell donors. The one in existence now is for those donors, who are providing peripheral stem cells by aphaeresis and also for bone marrow. Although, this next year we will be -- the same task force will be putting one together for donors of cord bloods. There are some nuances that are different for those donors that were alluded to a little bit this morning. The user instructions for the current questionnaire do state -- the user instruction has a statement that says it is not intended for donors of cord blood, although, of course, an establishment could modify it.

Specifically, this morning, there was a brief discussion about other neurological diseases so I quickly looked up our questionnaire to find exactly how that question was stated. We do have a specific question that says have you ever been diagnosed with any neurological disease? I fool myself by not putting on the glasses. To go along with that question on the flow chart, we have a donor eligibility statement that reads -- the capture question is broad. Have you ever been diagnosed with any neurological disease? This is outside the question about a family member who maybe has been diagnosed with variant CJD. Once a donor has responded yes to this question about neurological illness, then the historian would go to a flow chart and help lead the donor through what these illnesses might have been.

The eligibility statement says any donor who has been diagnoses with variant CJD or any form of CJD, dementia, any degenerative or demyelinating disease to the central nervous system or other neurological disease of unknown etiology may not be eligible to donate HCTP. In the event of urgent medical need, additional criteria may be used to evaluate donors with neurological disease other than vCJD or CJD. Because, of course, with the HCTP donors, the products are special products and if they are the only ones who have been matched to a donor, there may be urgent medical needs situations where, despite the reason that they are not deemed eligible because of communicable disease issues, they might be the product of choice for the donor anyway. So donors are reviewed for other neurological disease. That is the question that currently exists on that questionnaire. It has not been reviewed by FDA, although there were FDA liaisons on the task force when we put this together. But there is no guidance document that has accepted this particular questionnaire, as there has been a guidance document that accepted the questionnaire for whole blood donors. I wanted to make that distinction, also.

DR. HOGAN: That is very helpful and it is good information. I thank you for providing that for us. Is there anyone else in the audience that would like to make any public statement at this time? Not seeing that -- yes, Madam? Would you please come up and use the microphone and identify yourself, please?

DR. MATTHEWS: My name is Theresa Matthews and I spoke last year at TSEAC in the public hearing. I followed up this year with a written submission. I did not think I would be able to make it to the meeting. If the audience would just kindly look at the folder, that is the public submission.

DR. HOGAN: That is very good. Thank you.
 

DR. MATTHEWS: There is also an additional one in the book as well from another commenter, who could not be here today.
DR. HOGAN: Thank you for pointing that out. Anyone else? Not seeing that we will take a break. It is a fifteen minute break so be back here at 11:45 please. BREAK

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Agenda Item: Committee Updates

DR. HOGAN: This time we are going to change a little bit. Rather than policy programs, we are going to talk about recent advances in development of devices constructed to remove TSE agents from blood components. Are all the Committee members here? Yes. Okay. So we will go ahead and start. So if Dr. Gregori could please -- I am sorry. Eyes in the back of my head. She is well known and I look forward to her introduction.

Recent Advances in Development of Devices to Remove TSE Agents from Blood Components

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Agenda Item: Introduction

DR. GREGORI: Thank you. I am here today and my task is just to briefly introduce the last three speakers on this topic of development of devices to remove TSE agents from blood components. You may recall that last year we reviewed and updated the Committee on new developments on screening and diagnostic tests for vCJD. This year we thought it was time to review a different strategy, a different approach and that is removal of the agent, instead of detection. We have invited the three manufacturers of devices to present their data today.

Before we do that, you have seen this slide many times now. This is the BSE pattern over the years in the UK. This is the vCJD pattern. What I have done here, I have changed the scale just to highlight that the BSE cases are still present in the UK. Few cases, obviously much reduced compared to the early years, but there is still some BSE -- background BSE in the UK and UK is not the only country. Like has been already said, this is 2009. Several countries have reported more than ten cases of BSE in that year. Obviously, the BSE cases have been reduced but are not completely gone.

If we also look at the vCJD curve from 2000 when the peak of vCJD cases occurred, we have now a much reduced number of cases, but since 2005, we have about three new cases per year. The question, now, is what does this long tail mean? And really is this an indication that vJCD is -- there are more cases of vCJD. We think that this is not the case and I will explain to you why we think so.

To answer the case of prevalence of vCJD in the UK, there have been several studies all done in the UK. Those are the studies here, reported by the first author. They use appendix or tonsil. The important part on this slide is the prevalence per million. You see the numbers are different, but if one considers the 95 percent confidence interval, those numbers are not that different. This point has already been made by other speakers today.

We think, then, the tissues survey conclusion is that the studies so far are in agreement and the prevalence is about 100 to over 200 infections per million of the UK population. Of course, this prevalence is higher than that estimated from known vCJD cases. In addition, we should also consider that we do not know when and for how long PrPTSE is present in lymphoid tissue. We also do not know the specificity and sensitivity of the immunohistochemistry test that is used. It appears there are technical difficulties with sampling and staining of tissues, which suggests that some vCJD cases probably have been missed. The prevalence is likely underestimated -- the prevalence based on the tissue studies, tissue surveys.

At this point, our conclusions are that it is highly likely that more individuals in the UK are infected with vCJD, but are asymptomatic. For this reason -- for what I have told now, we think the precautionary measures against blood transmitted vCJD are still needed and should be maintained for blood. In the US, among various precautionary measures concerning blood, we have donor deferral policies. We also encourage companies and manufacturers to develop a vCJD screening test. And we will hear today an alternative to a screening test, which is infectivity reduction by devices.

I would like, also, to remind the Committee that this is not a new topic. Actually, as early as November 2005 the TSEAC Committee was asked to comment on a series of validation criteria for devices to remove TSE infectivity from blood components. Here I have two slides from Dr. Asher summarizing what the Committee, at that time, had indicated. The Committee suggested that there should be at least 3 logs of reduction of spiked infectivity as shown by western blot and by bioassay. Also, the removal should be shown for endogenously infected animal blood and it should be to below the detection limit of the bioassay. There were also two animal models and two strains of TSE agent, one strain related to BSE and one strain related to vCJD. Of course, the filtered blood components should maintain functionality assay by conventional tests.

The Committee also indicated that they would like to see endogenous infectivity removal studies done in a whole unit of blood that is a full scale in large animals, possibly using the same animal species as a test bioassay. If that is not possible, transgenic mice would also be acceptable. Reproducibility of results will ideally have been done in different sites, separate studies, if that was possible. And also the study should be large enough for statistical validity. If a device is able to meet all of these requirements and criteria then those studies will be then in support -- might support -- at label claims for reduction of TSE infectivity from blood products.

We would like to add now that we know that infectivity in blood is at least in two different compartments -- the plasma compartment and the cellular compartment, mostly in white blood cells. We would like to see that the device or the process in which the device is a part of to remove both forms of infectivity from blood.

The three manufacturers that we have today, the first to come here will be Mr. Yokomizo from Asahi. He is a chief research at Asahi Kasei Medical. Then we have Dr. Coker, who is the principal scientist at Pall Medical and the Technical Director of the project. Finally, we have Dr. Burton, who is the present CEO of ProMedic BioSciences. With that, I invite the next speaker to the podium.

DR. HOGAN: Thank you. Mr. Yokomizo? The agenda lists 55 minutes for the speakers for this portion, but only 45 minutes until we adjourn. Obviously, we are not going to be adjourning at 12:30. I urge all of the speakers to try and stay on time because people have to catch planes. Thank you.

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MR. YOKOMIZO: Thank you for giving me such opportunity to introduce our development combination filter, Sepacell Prima. My name is Tomo Yokomizo with Asahi Kasei Medical. We have many types of leukocyte reduction filters, widely used in the world. We also have nano-filtration technology for virus removal in plasma fractionation. And now we are trying to add prion reduction filter here.

Today, I would like to introduce some measured test results to demonstrate our development status. I will skip general information like epidemiology. Time is limited and you are the specialists in the field. Concept and technology. The concept of the filter is simple. It is a one step filter. It means a simultaneous reduction of prions and leukocytes. It is reducing prion from blood cell concentrate and covering current leukocyte filter functions. That means there is no additional operating time in blood bank and no impact on customer SOP and no further blood product loss. Besides, it is also possible to be implemented as just a leukocyte reduction filter independently of the level of prion risk.

Key point of technology is also simple. It has polyester fiber as a base material. On the surface there is a new material, which also prion protein with its high affinity to prion protein. Filter design can be same as current leukocyte reduction filter. Our prototype is equivalent to the current European filter because we plan to introduce this technology into European countries fast.

Next, this is the scheme of spiking test. Microsomal fraction prepared from brain homogenate of scrapie infected hamster with 263k scrapie strain. It spiked into SAG-M RCC. Then blood is filtered with our filter and post- and pre-samples are evaluated with western blot method. We use leukoreduced RCC in the test to eliminate possibility of phagocytic effect.

This is the result of prion spiking test. That table is a little bit busy. We test at two different sites, laboratory X and Y. We use different filter to evaluate the sterilization tolerance. In lab X, we repeated same test three times. Two unique RCC pool and spread into two aliquots and one is filtered with the filter sterilized with steam and another one is filtered with E-Beam. In the lab Y, filter C was used instead of filter B. It was sterilized with steam twice to give the CBR impact by the steam. All gave high prion reduction factor while the control filter gave only low reduction.

This is test results to evaluate the incidence of plasma protein. We put four units of leukoreduced RCC and then subdivided into four aliquots and we added FFP to increase the plasma protein concentration. In parallel, we also used non-leukoreduced RCC, too, to evaluate the impact by white blood cell. All gave high prion reduction factor, while control filter gave only low log reduction factor less than one.

This is the scheme of bioassay test. Filtration was performed in the same method and pre- and post-filtration sample was taken and dilution series were prepared. One point zero five milliliter sample was inoculated intracerebrally to healthy Golden Syrian hamsters and we observed up to one year.

This is the result of the bioassay test. This is also a little bit busy table. Blue part shows the dilution series and yellow block is the result with post filtration sample and bottom is the result of pre filtration sample. You can see the difference of survival rates. Based on Spearman-Karber method, it showed 4.2 Log of infectivity reduction. We have no abnormal or unexpected observations in the control groups.

This is the iteration(?) results as a leukocyte reduction filter with one day whole blood at ambient temperature. It shows sufficient leukocyte reduction capability and sufficient hemoglobin content. There was no significant different from control filter, Pure RC, used in Europe. This is the same test result with two day whole blood at four degree C. The results are almost the same with ambient blood. There was no significant difference from control filters in this test, too.

For RCC quality, we evaluated in these parameter at day zero and 21st and 42nd days after filtration. The results were comparable between sample and control in all of the test results. As an example, I show you the hemolysis results. European guideline is 0.8 percent at 42 days. Control sample filter showed 0.4 percent at 42 days. Due to one irregular data, control filter showed relatively high value, but this is widely used in Europe without any problem. Anyway, our filter gave sufficient level of hemolysis after 42 day hold.

We also perform biological safety test, in compliance with ISO 10993 with both E-Beam or steam sterilized filters in these tests. We also performed Ames test to evaluate mutagenicity. All of the results showed the sufficient safety of the new filter.

This is a summary table. We confirmed prion reduction capability with western blot method and exogenous test method. We confirmed the sufficient leukocyte reduction performance with RCC quality comparable to the current filter. We confirmed sterilization tolerance of the filter. We also confirmed biological safety.

We are now trying to put CE marking of the new filter in the SCD kit, workable filter. Our in-house tests are ongoing now. Thank you very much for your attention.

DR. HOGAN: Thank you very much, sir. We can have one or two questions quickly, if you have them now. Nothing? Thank you very much. Dr. Coker, would you come up please?

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DR. COKER: Thank you very much for the invite to present here. What I am going to talk to you today is basically some information on the filter that Pall developed for simultaneous removal of infectivity as well as leukocytes. At the same time, I want to introduce a new technology for evaluating this particular filter.

Most of the studies regarding prion, especially for clearance studies, rely mainly on the use of surrogate marker for evaluation, some of these could be western blot or conformational dependent immunoassay or even bioassay have been used to evaluate most of these filter.

However, there are disadvantages in using some of these current in vitro methods, one of them being that the infectivity may accumulate in the absence of any detectable level of the surrogate marker. Most importantly, the cost of some of these biossay is just too high to allow one to be able to do repeated studies even for a very large company. A single study could cost anywhere from 250,000 - 500,000 dollars. Therefore, there is a need for a new highly sensitive technique that can at least help most of the manufacturers to do the screening studies without having to incur a large amount of expense in the initial evaluation.

The main objective of our study now is to evaluate this new cell culture based infectivity assay using some of the various filters that Pall had developed. I also mentioned here the leukocyte reduction filter, which we sell, as well as some of the variants that we have for prion reduction.

In designing the filter that we have, we incorporate leukocyte reduction chemistry as well as the various chemistries that we have in-house for removal of infectious prion. The differences between the filters is mainly in terms of their hydrophilicity and their hydrophobicity, which may or may not actually affect the prion reduction. In terms of leukocyte reduction, most of the information has been available from Pall for years, where essentially we remove most of the biomechanical trapping by surface modification, by activating some of the white cells for interaction with platelets, which form microaggragates that can then be removed.

In terms of this particular assay, we use the RML scrapie screen to prepare ten percent homogenate, which we will inject into appropriate mice. At the end of that, sacrifice the mice, take out the brain, and then prepare the ten percent brain homogenate. The next part of this study is to now take the brain homogenate and inject it into the blood samples. We use a red cell concentrate, four units and then just collect about 5mls. This is the schematics of the experiment. Collecting five units of red cell, pull them together to a greater pool, and then split them up into five fractions. Add the necessary brain homogenate into that. On this side, we have standard leukocyte reduction filter and we have the prion filter and at the extreme here there is no leukoreduction step because the filter, itself, does leukoreduction, as well as prion removal.

The cell culture assay is based mainly on the fact that this particular cell, the CAD5, is highly susceptible to the scrapie strain. This has been developed by Professor Weismann at Scripp. Once you have identified this cell and you have identified this strain, the other requirement is the method for identifying the infected cells. I will not go through the whole procedure, but this is a schematic. Taking the brain homogenate, you have your CAD cells in the microtiter plates. You run them through three propagations and then you perform ELISPOT by transferring these cells onto a membrane where you can then do your ELISA, essentially. Then you can count the number of infected cells by 20,000 of the CAD cells and that will give you the level of infectivity. This is just the type of spots that you can count. Typically, as I say, you count the number of infected cells by 20,000 of the CAD cells.

Now, we also did additional study to determine whether some of the red cells actually interfered with the assay, itself, in terms of the inhibition of the propagation of the CAD cells. This is the calibration curve, in terms of the number of infected cells against the concentration of the various amounts of the brain homogenate. We also did some inhibition studies to ensure that if you do have something that inhibits the propagation of the cells, you can clearly distinguish them from the cells that are specifically infected by prion. Again, this is just another of the calibration curve. If we look at the standard filtration -- whether some of the red cell sample are actually very inhibitory, based on the dilution that we used for this particular study, which is one in 30 dilution, you can see very clearly that there is no inhibition. So this is the starting concentration and as you use different amounts of red cell samples, there is no inhibition in terms of the propagation of the CAD infectivity.

When we look at leukocyte reduction filters that do not have this particular prion removal, you can see, again, very clearly, this is the pre-filtration level and this is the standard leukocyte reduction filter. You can see there is very little reduction in infectivity using standard leukocyte reduction filter.

If we look at the standard filter that Pall had developed, which is a combination of leukocyte reduction with different layers of prion removal capability, this is the pre-filtration level. This is the ten layer filter, which we have published on. These are the 22 layer filter, containing 22 layers of the prion removal chemistry. You can see very clearly that the infectious prions were removed below the limit of detection of the cell culture assay.

In addition to that, what we are going to do is to now see whether there is any relationship between the data that we have over here between the ten layers and the 20 layers, looking at endogenous infectivity study. We conducted an endogenous infectivity study, again using standard units of red cell from scrapie infected hamster. Those infected samples were injected into normal hamsters and they were monitored over 300-500 days to see whether they developed scrapie.

In terms of the result that we obtained with the cell culture assay, we can see very clearly that the 22 layer was very much more effective than the ten layer filter. We also saw the maximum reduction that we could see with this cell culture assay was about two logs of reduction. The ten layer variant though it removed some of the infectivity, but did not completely abolish it. So you still have some residual amounts of infectivity.

This is the schematics of the endogenous infectivity study, initially obtaining brain homogenate, which you inject into normal hamster, collected blood from about 500 to 1000 hamsters, process them into red cell, and then the red cell is then processed with the leukocyte reduction filter. The filtrate is now injected into normal hamsters and then we monitor them over 500 days to see whether they develop scrapie.

This is the unfiltered control in the first experiment that we did. Seven out of 187 of the normal hamsters that received unfiltered red cell developed scrapie. However, three out of 413 of the normal hamsters that received red cell that had been filtered with the ten layer developed scrapie. However, if you look at the 22 layer, none of the animals that received filtered blood developed the scrapie, which, again, confirms the culture assay in the sense that the 22 layer is much more effective in protecting the hamsters from developing scrapie.

We look at the survival plot. This is just to indicate -- that shows very clearly that the ten layer, you can see some of the animals developing scrapie, and this is the control, although the ten layer did prolong the onset of the disease. The normal hamsters that received unfiltered red cell, the numbers are based on 130 days to the onset. With the ten layer filter, you have 230 days. If you compare that to the 22 layer, of course the control started developing scrapie very quickly, but we have not seen, even up to 600 days, none of the hamsters that received 22 layer filter red cell developed scrapie.

Just to summarize what we have done today, we have been able to show that the 22-layer filter is very effective in protecting the hamsters from developing scrapie. There are certain levels of residual amounts of infectivity with the ten layer, which again confirm the data with the cell culture assay infectivity assay. So this endogenous infectivity assay is more or less in agreement with the cell culture assay, essentially.

In conclusion, these results demonstrate the utility of the cell-based infectivity assay for screening prion reduction filters. We believe that the use of this particular technology may eventually help to expedite the screening of filters that have been developed for reducing the risk of vCJD and most importantly to also reduce the expense of doing a bioassay. I just should mention that this assay, this cell culture infectivity assay, does not replace the bioassay. It merely allows you to do a lot more screening up front. Maybe towards the end of the validation of the product, one can then introduce a limited amount of bioassay. I would like to express my appreciation to some of the investigators that help us significantly, especially Professor Charles Weissmann that developed the cell culture assay and a few others that took part in the endogenous infectivity study.

DR. HOGAN: Thank you, Dr. Coker. Do we have any questions for Dr. Coker?

DR. MANUELIDIS: I am curious about -- the animals that you injected with 263k, these initial ones, are coming down very late, which means that you have actually challenged these animals with low infectivity amounts. That was true in the last talk as well. The other question I have is, of course, that particular cell assay has a background that you have to cut off, which is arbitrary and it really can only tell about two logs. Do you want to say anything about that? Did you ever try challenging 263k material on the filters? Really it has very high infectivity. It is over nine logs per gram.

DR. COKER: The problem with the customer using red cell, the filter is designed for red cell. So when we collected the whole blood from the infected hamsters and we processed them into red cell, you have to remove the plasma. You are left with red cell with a limited amount of about 20 percent plasma, a residual amount. We have not challenged it, which is what I believe Dr. Wright did that at some point using whole blood, where you have a much higher level of infectivity. We did not do that in this particular study.

The second question, regarding the background, the background for the cell culture assay using the CAD5 cell is 15 spots by 20,000 CAD cells. That is arbitrary, but that is what is regarded as their background.

DR. EPSTEIN: I just wanted to -- Dr. Coker, if you could comment on the relative sensitivity of the cell assay to brain inoculation of mice or hamsters. Are there direct comparative data?

DR. COKER: The only direct comparative data that I can think of is the one the Professor Weissmann had done. In his lab, they believe it is comparable to the mice bioassay, in terms of sensitivity. But in our hands, as you can see in this result, we were only able to detect only two logs. Again, that is because as you go higher, there is a possibility that you may begin to dampen the sensitivity.

DR. HOGAN: Thank you, Dr. Coker. Now, Dr. Burton.

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DR. BURTON: In the interest of time, I will breeze through some of the slides at the beginning and end of the presentation so we can focus more on some of the data in the central portion in relation to clinical experience with prion reduction devices. As we have heard, we know that all components of blood carry prion infection. This is known from animal studies, from work with hamsters, and more recently from work with sheep because there is work reported this year by Sandra McCutcheon and her colleagues at the Roslin Institute. We also know from both of these studies in hamsters and sheep that leukoreduction is not able to remove all of the infectivity so it is only a partial solution.

We know, unfortunately, that human blood carrying infection is capable of transmitting this infectivity to another human. We have heard this morning that four cases have been identified in the UK of transfusion transmission. There are a further two possible cases of transfusion transmission, but these cannot be verified at this point in time. That figure of four cases actually may be considered as the minimum.

Why should we be looking at prion removal/ prion filtration as a means of dealing with this issue? Well, we know in the case of prion detection, this is obviously the most obvious solution to a problem like this -- to undertake assays. Today, there is no assay capable of detecting prions in blood or plasma to the required level of sensitivity. Prion inactivation -- we know that this is a highly resistant agent and it is simply not possible to destroy this agent in the presence of cells and other blood and plasma components. Donor deferral, it is an option for countries where there is a low incidence of BSE and vCJD and it is possible to identify a small proportion of the population that represents the highest risk. In other countries, such as the UK, where a very large percentage of the population has been exposed to the BSE agent, deferral is not really an option. This leaves us with prion removal, where, by use of selected affinity agents that are able to bind to and capture the infectious agent, this does provide a means of protection. Of course, it protects not only against the prions that we know of today. It also provides a potential level of protection to defend against new prion diseases that may arise in the future.

Very briefly with what we are trying to achieve here, is by use of an affinity ligand is something that will bind to the prion agent and capture it and remove it from the other components. We do not want binding of other components, especially important in the case of plasma, where those other components are performing quite important biological functions. Because these are single use disposable devices, obviously the selection of the affinity material is very important. For that reason, we have chosen to investigate materials based on small synthetic chemicals, rather than more expensive biological agents such as antibodies.

This work has been presented a number of times in the past so I will only briefly mention this. It is essentially how we identified the specific binding affinity ligands. We screened a very large number of potential agents, affinity agents, in excess of eight million. On the basis of that screening, we were looking for the binding of normal prion PrP, the normal prion protein, and also the PrPSC form of the protein. From that screening process, we identified five materials, which were capable of binding both PrP and PrPSC from a wide variety of sources, including sporadic CJD and variant CJD from human brain samples and also in the case of a mouse brain sample the Fukuoka strain, which is related to the GSS in humans. Only those ligands, which bound a very broad spectrum of prion infectivities were included for the next stage of the development. In that stage, we were looking for the binding of infectivity by spiking human blood with hamster scrapie derived infectivity. We are able to determine if the filter has bound this infectivity by extracting material from the filter and analyzing that by western blot. In the flow through materials or the filtered blood, we are then able to examine by bioassay in hamsters. From that we found that all five of the ligands we had identified were capable of binding prion infectivity and all of these gave removal in excess of three logs, one of which gave removal in excess of four logs.

We then proceeded to look at binding of endogenous infectivity. This is the form of infection that is found in the blood, rather than the somewhat artificial situation of spiking into blood a solubilized brain extract. In this experiment, hamsters that have been infected with the hamster form of scrapie, their blood was collected to form a unit of infectious blood. That unit was then passed through the affinity material. And then the treated blood was then injected into a panel of otherwise healthy hamsters. Then they were observed over a period of 550 days for signs of infection. There was a control group that was undertaken in relation to that same experiment.

What we found in the case of whole blood, so with no treatment here, we saw 21 out of 47 animals coming down with infection, again indicating that this really is quite an infectious agent. With leukoreduced blood, we found 15 out of 99 were showing reduction. Again, leukoreduction is not effective in removing this agent. But in the treated sample, we found zero out of 100 animals were showing infection. This, essentially, is removal to the extent of the limits of the bioassay. That calculates to greater than or equal to 1.2 logs10 removal of endogenous infectivity.

That material was then incorporated into a commercial product, the P-Capt filter. This filter is manufactured by a French company, Macopharma and uses the affinity absorbent that was developed by ProMetic and PRDT. This is a single use device. It is a dockable filter, designed for use in combination with leukoreduced red blood cells. We have chosen to take this approach essentially at the request of the UK Blood Services that wanted a filter that could be used in combination with their existing leukofiltration sets that were being used in the UK. The device was CE Marked approved in Europe in September of 2006. It conforms to the UK Blood Services requirement -- the minimum requirements for a prion reduction filter and that is greater than three logs reduction of brain infectivity by bioassay and greater than one log reduction of endogenous infectivity.

The filter, itself, is composed of multiple layers of this prion removal material. The material, itself, is composed of alternating layers of membrane and the resin beads to which the affinity ligands are attached and then sandwiched in between the layers of membrane. We have taken this approach because resin Bs have a very high surface area in comparison to membrane materials, approximately an order of magnitude higher. This gives us a very large surface area for absorption prion in relation to the volume of the filter, itself.

We know from experiments where we have challenged this filter -- there are eight layers of this composite membrane. If we challenge with a very large concentration of infectivity, then we see that it is possible to exhaust the filter's capacity to bind prions. So these do not bind an infinite amount of prion. They bind a finite amount. If we load with a very large amount, we do see material passing over to the second filter. As we reduce back the prion in the load, we see that, in the case of the .005 percent spike, that the filter is quite capable of removing that infectivity. We do not see any evidence by western blot in the final layers of the filter.

At that level, we are many, many logs higher than the infectivity that we would expect to see in the case of an infectious unit of human blood. In this case one milliliter of this resin is capable of binding in excess of one million units of infectivity. It is currently believed one milliliter of infectious blood contains in the region of ten to twenty units of infectivity. These experiments are a vast overloading in relation to what we would expect to find in practice.

We performed the same experiment with human variant CJD brain extract. We have shown that the filter, again, is capable of removing human vCJD brain material and also sporadic CJD brain material, as well, infectivity by western blot.

This particular filter has now been extensively investigated in terms of its properties, its effect on blood, and the safety of the blood in human patient studies. The UK Blood Services commissioned the Health Protection Agency in the UK to conduct an independent study on the capture of exogenous infectivity. That study was conducted in a slightly different way to the way that we conducted the study. The UK's Safety Advisory Committee for Blood, Tissues, and Organs, in their minutes of October of last year, made the comment that even though there are differences in the studies that this particular filter is effective in binding prion from blood to the extent required. Also, in another study that was reported last year from a group in France, they also found the P-Capt filter gave greater than three log removal of exogenous prion infectivity from leukoreduced red blood cells.

In terms of the impact of this filter on blood, there have been extensive studies conducted now, both by ourselves and by the UK Blood Services and the Irish Blood Services. This is a summary of all of the studies, here. Essentially, there is no impact on the quality of red blood cells, whether stored in SAGM or plasma. There is a small loss of hemoglobin and this is due to physical entrapment of blood that remains within the filter at the end of the filtration process. Hemolysis is well below the level, maximum level allowed. There was no effect on complement or coagulation factor activation. There is no activation of platelets. And it has been shown that prion binding is effective in the presence of a wide variety of solutions that are used in the context of preservation of red cells.

A volunteer clinical study has been undertaken, looking primarily at red cell recoveries and the formation of new antibodies, neo-antigenicity. That volunteer study, consisting of 29 volunteers, showed that there was no significant increase -- differences in red cell recovery after 24 hours and there were no serious adverse events reported. In the terms of neo-antigenicity, by a variety of different parameters that we evaluated, there was no evidence of any formation of new antibodies.

A number of clinical patient studies have been taken now with this filter. The clinical study, here, is in the context of the filtered blood. The first study that was reported took place in Ireland, where 20 patients were transfused with one unit of P-Capt filtered red cells. There were no adverse reactions reported for that study. In a six week follow up study, there was no evidence of any antibody formation. Also, in the context of that study, six of those 20 patients were re-transfused with a second unit of filtered blood and again there was no adverse reactions and no evidence of any antibody production.

In Ireland, now, they have moved on to more extensive use of this filter. A hundred patient study is being completed. One hundred patients were transfused with a total of 180 unites of P-Capt filtered blood. Again, no adverse reactions have been reported. The hospital that was undertaking this study in Ireland, the Cavan Hospital, they are now using P-Capt filtration of blood cells on a routine basis. This is ongoing. They are targeted to transfuse at least 1,000 patients with follow-up for any adverse reactions. No adverse reactions reported to date. The new study is being planned in Ireland for the transfusion of pediatric patients, the Crumlin Hospital, but I am not aware that that study has yet commenced. Ireland is also conducting a health technology assessment in relation to this particular product and the results of that assessment should be known by the end of this year.

In the UK, there is currently underway a very extensive study. This is known as PRISM. There are two parts to the study. PRISM A is a non-randomized clinical trial in surgical patients. The intention is that each patient will receive a single transfusion, although because this is a clinical treatment, what has happened in practice is that each patient, on average, is receiving two to three units of P-Capt filtered red cells. The study consists of 270 control patients and 270 filtered patients. There are currently eight hospitals involved in this study in the UK, all of which are now transfusing patients. As of May of this year, this is the last reported data that we have, 154 patients have been transfused with 320 units of prion filtered red cells. To date, there are no reports of any adverse events and no evidence of any incidence of red cell alloantibodies. That study is due to be completed, in terms of the filter arm of that study should be completed later this year. The PRISM A study should be completed in its entirety, on completion of the follow up, in the middle of next year.

Study B is not required for any kind of decision of P-Capt in the UK. This is a planned study that has not yet started. This is a study looking at multiple transfusions so different transfusion episodes with the same individuals.

In terms of the current status of this filter in the UK, November of last year SaBTO recommended to the UK Department of Health that this filter should be used to filter blood transfused to children, to individuals born after the first of January, 1996. That recommendation is likely to be implemented in the form of individuals under 16 years old and adults with hemoglobinopathies. It is down to the Minister of Health to make the final decision on that recommendation. The NHSBT has been preparing itself for the implementation of the filter. An implementation plan is now being developed. There is an Impact Assessment that is nearing completion. The results of that should be known soon. And the decision is subject to the completion of the PRISM A study.

There are a number of reasons why implementation should be considered in countries where there are high incidence of BSE and CJD, particularly because leukofiltration is currently not sufficient. It is a highly infectious agent and there are a number of questions, which are currently unanswered in relation to this disease. As we know, virtually all of the cases of this disease are MM genotype. So will we see a second wave from MV and VV genotypes? Will MV and VV genotypes be a silent carrier for a portion of the population that may never really go on to show symptoms of the disease, but may transmit it by transfusion to MM genotype people? Again, there is no screening test currently available.

Who should implement? Countries like the UK, Ireland, France, who have a known history of BSE and CJD, within the endogenous population. Also other countries that may wish to protect themselves from certain donor groups, who have resided in Europe. In this case, it is notable that very recently the Blood Centre in Macao and China has started routine use of the P-Capt filter for Caucasians who reside in Macao, but previously have lived in Europe so that they can continue to donate blood in Macao and it provides an extra level of protection in that regard.

Very briefly, this same technology has been applied to other plasma components -- other blood component, excuse me, such as plasma. We know that this technology can be applied to fresh frozen plasma and it is now being applied to SD treated plasma. A product has been developed by the Swiss company, Octapharma that now is approved in Germany, Switzerland, and Austria, and approval is pending in a number of countries, including the UK. Essentially, the same affinity material is able to remove prion from plasma and SD plasma with very high efficiency, again, in excess of six logs of infectivity per mil of this affinity material. Importantly, this has no impact on all of the main important components of plasma, such as clotting factors and various other factors and inhibitors that are clinically relevant in plasma. Octapharma demonstrated that by applying this technology to SD treated plasma, they are able to gain an additional five logs of safety, in terms of the potential for prion transmission.

On that point, I will stop. Thank you.

DR. HOGAN: Thank you, Dr. Burton. It is quite far along. Does anyone have any questions now for any of our speakers in this session? Yes?

 

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Agenda Item: Questions to Speakers

DR. BIANCO: I am Cecil Bianco. I am the industry representative with no vote in the Committee. I just want to make a request to FDA, to CBER to again, following the presentation by Dr. Marc Germain, to bring back to the Committee to reconsider the precautionary measures that have been implemented, in terms of blood, considering the current status and how much we know. It is not a question of having or not having the deferrals and the approaches. But it is a question of instead of just pursuing zero risk that seems to be what we are pursuing, to have a more proportional application of the precautionary principle, in terms of the amount of risk that we see there is diminishing. That affects, tremendously, both the blood donor population and particularly the tissue and cadaveric donor population. Just for us and for the Committee to reconsider. Thank you.

DR. HOGAN: Thank you. Dr. Geschwind?

DR. GESCHWIND: Question regarding the PRISM study. It says that it is a non-randomized study. I am curious about that.

DR. BURTON: The PRISM study is an entirely independent study of ProMetics so I am not really able to comment on the construction of that study. That is probably a question best addressed to the UK Blood Services. That is the information that I have in terms of the description of the study.

DR. HOGAN: Okay. Any other questions? Comments? Well, then I guess that is it. I thank all of the speakers today for the information that was provided to us on both policy and procedures and these very interesting new devices that are under production or in testing. I would like to thank the FDA staff for getting all of this together. It takes a lot of time and a lot of hours to do these meetings. We appreciate that. I would like to personally thank all of the members of the Committee. You have all been contributory and you have all had good information. I would like to thank Rosanne and Gail for getting arrangements for us to get here and go home. With that, I wish you all a good day. Thank you.
(Whereupon, the meeting adjourned at 12:30 p.m.)