Sunday, June 24, 2012

FDA Blood Products Advisory Committee June 12, 2012 Overview of the Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents

FDA Blood Products Advisory Committee June 12, 2012 Overview of the Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents

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I wish I could be as reassuring with the bone marrow stem cell project, but I have to report that when mouse bone marrow stem cells -- I like this picture because it’s so colorful -- just to prove that they were stem cells and, in selected medium, could be differentiated into adipocytes. When they were exposed to a mouse-adapted strain derived from a human TSE -- because the Red Cross doesn’t want scrapie in the lab -- unfortunately, they did sustain persistent infection. Is this relevant to human stem cells? We don’t know, but it does suggest that every cell line really has to be evaluated individually before concluding that there’s no risk. It is a dangerous thing.

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Finally, there won’t be time to do this, but some very important work that he is now conducting also at the University of Edinburgh shows that a BSE isolate did not transmit disease to transgenic mice expressing the human PrP gene, but if you passed the same strain through sheep and took it out again, then it would infect those mice, suggesting that passage of the agent through a new host can alter its biological properties, which may be relevant for human health.

Food and Drug Administration

Center for Biologics Evaluation and Research

103rd Teleconference Meeting of the

Blood Products Advisory Committee

Open Session

June 12, 2012

National Institutes of Health

Building 29, Conference Room 121

Bethesda, Maryland

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

DR. HOLLINGER: Thank you, Corey.

I would like to move on to the last presentation, by David Asher, who is head of the Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents.

Agenda Item: Overview of the Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents

DR. ASHER: What folks here can see but you can’t


is that I’m operating today under the disadvantage of having what I hope is the end stage of an unusually bad cold. I’m supplied with my own box of Kleenex and a water source. I hope that I can get through this. Let me ask, is there going to be an open public hearing? Has anybody responded to that? So I can still speak for half an hour. I was scheduled to end at 2:20, which is five minutes from now. Thank you. I will review for you briefly the research activities in the Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents, which is the smallest of the laboratories in our division and, for all I know, in our office. We study mainly the spongiform encephalopathies, terrible, invariably fatal, progressive neurological diseases -- about 300 deaths a year from these diseases in the United States. Slow infections, incubation periods known to exceed 30 years and probably exceed 40 years. The CDC projects that in order to have 300 deaths a year, probably 1 in every 10,000 people or even more must have a lifetime risk of coming down. So although these are rare diseases, they are not as rare as many people have thought. Our laboratory is made up of three principal investigators. I have a small team. Luisa Gregori leads our Blood Safety Team and Pedro Piccardo, our Pathology and


Pathogenesis Team, with a particular interest in the role of abnormal prion protein and other proteins in progressive neurological diseases in general, and the TSEs in specific. We have five staff scientists, two doctoral positions. One staff scientist position is empty due to the untimely death of our lab manager. We hope we have successfully recruited to fill that job, although, frankly, nobody will ever be able to fill Kitty Pomeroy’s job. We also have six fellows, five of them full-time, who support the work. I want to make a couple of points at the outset, some unusual features of spongiform encephalopathy research. First, by its nature, it has to be unusually collaborative. Although each of the three of us has his or her own research projects, usually more than one PI is involved to some degree in the projects. We are largely dependent on outside funding, most recently an interagency agreement transfer of funds from the NIAID. While FDA has been quite generous in supporting us, this is extremely expensive and time-consuming work. Our studies with bovine spongiform encephalopathy -- so-called mad cow disease, of greatest concern to regulated product -- require biosafety level 3 containment. It’s regulated not only by the Department of Agriculture, but also by the security agencies as a so-


called select agent. All those require inspections and a large amount of paperwork. We don’t have an adequate BSL-3 facility within the FDA, so we have major contracts with the American Red Cross and a primate holding laboratory in Rockville. The other agents that we work with are regulated at biosafety level 2, but if they are in animals, they have to be inspected by the Department of Agriculture, which itself requires time and paperwork. Two of our projects are highly leveraged. That is, they are supported by collaborating non-FDA institutions that provide facilities, animals, equipment, and research services, some of it supported under collaborative research and development agreement and some of it just on a voluntary basis by those organizations. Dr. Gregori has a project that I’ll outline for you briefly, and Dr. Piccardo has an ongoing project that has been going on for, I guess, almost ten years with the University of Edinburgh that provides the equivalent of millions of dollars in animal maintenance, tissue processing, and laboratory facilities -- something that the FDA could never support alone. Finally, TSE studies involving infectivity are extremely long. The shortest assays take a few months. If you do blind passages or multiple blind passages -- Dr. Piccardo has one study that has required more than eight


years from the start, and it’s not finished yet. That’s just the nature of the field. Please keep that in mind. I suppose I should stop and remark briefly about the significance in all the research of the prion protein. The prion protein is usually -- although not always -- found to accumulate in an abnormal form in brain and, less often, in other tissues of persons and animals with the spongiform encephalopathies. Whatever else it may be, it usually makes a good assay to determine presumptively that there is an infection. It’s a short polypeptide, 253 amino acid, a normal protein bound to the cell surface. In its normal form it’s readily soluble in detergent-salt solutions and completely digested by the enzyme proteinase K. But in the spongiform encephalopathies it accumulates in a precipitating form. It’s mostly resistant to protease K digestion, although a fragment of about 90 amino acids is cleaved from one N.

Whatever else it may be, the prion protein must be expressed in order to infect animals and presumably human beings. The occurrence of mutations in the prion protein-encoding gene correlates with the appearance of some 10 percent of human TSEs that are genetic -- that is, are familial inherited -- with an autosomal dominant pattern, fortunately not with 100 percent penetrance, at least in most kindreds.


The most widely accepted hypothesis at the moment is that the prion protein, in its abnormally folded form, is the infectious agent, although that remains the object of considerable skepticism. The work of Dr. Piccardo and others demonstrates that the association between abnormal prion protein and infectivity is not absolutely consistent, although most of the time, when you find one, you find the other. That’s important for regulatory purposes, because if the absence of abnormal prion protein does not guarantee the absence of infectivity and the presence of abnormal protein does not mean for sure that the infectious agent is present, it means that tests that detect the prion protein have to be interpreted with that in mind.

The spongiform encephalopathies are very important to the FDA, not only to our Center and office, but to other centers. Classes of product regulated by the FDA and the USDA as well have been responsible for the accidental transmission of TSEs. The most dramatic was BSE in cattle, transmitted mainly in the UK by contaminated feed and, unfortunately, by contaminated beef products, to humans, where it causes variant Creutzfeldt-Jakob disease. But we have also had cases of iatrogenic Creutzfeldt-Jakob disease transmitted to recipients of human pituitary hormones, regulated as a drug by the Center for Drugs, and medical devices, processed tissue devices, dura mater


allografts, and corneal transplants, regulated by our Center. As many of you know, more recently in the UK there have been four transmissions of variant CJD attributed to transfusions of non-leukoreduced red blood cells and one case attributed to treatment with a plasma-derived factor VIII -- fortunately, a product that was never licensed in the United States and, so far as I know, of a purity that has never been considered acceptable in the United States. Iatrogenic CJD has never been attributed to a human vaccine, but twice animal vaccines have spread the similar disease, scrapie, in sheep, as an example of what could happen when an unusual accident of this sort takes place. There were some flocks where more than 30 percent of the sheep came down with scrapie -- flocks that had never had it before.

These infections are maybe low-probability, but they are of very high consequence of those events when they take place.

The BSE epidemic in the UK peaked in about 1992. The human variant CJD epidemic peaked in the United Kingdom about eight years later. In 2003, the first transfusion-transmitted infection was reported in the UK, and since then, three additional infections, three of them producing typically variant Creutzfeldt-Jakob disease, have occurred. The plasma derivative case was reported in the year 2009.


So far as I know, no more cases since.

What I’ll do for the remainder of the talk is to just go through, investigator by investigator, as Sanjai did, the projects, which are all dedicated to maintaining the safety of regulated products, and also in response to Mr. Dubin’s useful comment, to support the activities of the USDA, the CDC, and, when called upon, the World Health Organization.

First, my own projects. I’ll talk about one to a greater extent and then briefly about two others.

I have two studies that I initiated that involve the susceptibility of cell substrates used to produce vaccines and other biologic products to infection with TSE agents. The first of these was to look at the hypothesis that infectivity might appear spontaneously through an accidental misfolding of the prion protein -- maybe not my favorite hypothesis, but one that’s very popular in the field. The second is the susceptibility of cell substrates used to produce biologics to exogenous TSE infection. In the second project I was joined very early by Pedro Piccardo, who became principal investigator. I think it’s fair to say that neither one of us could have completed a project of that magnitude by himself. The second project is one that I conducted with the late Kitty Pomeroy, and that is looking at methods for evaluating the


decontamination of TSE agents.

The third is a project that the arrival of Luisa Gregori in, I believe, the end of 2008 made possible. For practical purposes, she has taken it over as principal investigator. That’s looking for methods to detect rapidly abnormal forms of the prion protein in human tissues postmortem to help assure the safety of transplants, like corneal transplants. With corneal transplants, you can’t wait months and months while testing is done. You only have a day or so to test the donor, and that is currently not feasible.

First, the origin of the vaccine project: Actually, it’s a project that can be dated to a workshop that was organized in 1999 by the FDA, looking at viral and other potential contaminants of cell substrates used to manufacture vaccines and other biologics. To that meeting they invited a prominent Canadian investigator -- well, he’s an American, but he works in Canada -- Neil Cashman, who warned them -- and I quote -- that the possibility exists that prion agent may develop spontaneously in cell cultures expressing mutated or nonmutated prion protein, and that vaccines may be contaminated from cell culture components, animal enzymes, or vaccine excipients. At that point, we were just organizing our TSE program, and the Office of Vaccines volunteered to support


us and to solicit funding from the NIAID, which we were successful in obtaining. As I mentioned, the project looked at two separate hypotheses that were embedded in Neil Cashman’s warning: One, that the possible spontaneous appearance of infectivity might cause spontaneous generation of the TSE agent. We decided to look at that by performing a simulation worst-case analysis. We took about the worst cell culture that we could imagine, which is a human cell culture that expresses both neuronal and glial properties, and exposed them to TSE agents at concentrations that were quite unlikely ever to be present in a vaccine -- well, I'm getting ahead of myself. The first project looked at spontaneous infectivity. We engineered those cells, with the help of Kostya Chumakov, who is now associate director for research in the Office of Vaccines, to express known mutations associated with familial TSE. We figured if that was going to happen, it was more likely to happen when the cells had those mutations already known to increase the likelihood greatly of coming down with a TSE. To be on the safe side, we also overexpressed two of the normal variants of the prion protein gene in the same cell lines.

As we reported doing that, we remarked that it would be interesting to see if those cell lines had acquired an increased susceptibility to TSE agents when


they were exposed to them. I got a phone from the NIAID saying that they would be happy to support that research, if and only if we would also look at real cell cultures -- because nobody would ever use a cell of malignant origin expressing human neuronal and glial properties -- but if we would look at real cell substrates exposed to the TSE agents, and especially to the BSE agent, because calf serum is the most common excipient or additive in cell cultures -- it’s of bovine origin -- they would be willing to support it. We obviously accepted the offer, and that’s the project I’m reporting to you now. First, the hypothesis that mutant cell lines might become spontaneously infected. We injected into multiple squirrel monkeys, which at the time were the most widely TSE-susceptible animals known -- they are susceptible to CJD and kuru and scrapie and BSE, although we weren’t sure of that at the time -- we injected with mutant cell lines overexpressing three mutations and two different wild-types, 109 cells or more per each injection. I’m pleased to report that for the past eight years, those animals, with two exceptions, have been very happy. None of them developed the TSE. Two of them have died. with no evidence of neurological disease. One of them was blind-passaged, and the animal inoculated remains healthy.

So there’s no evidence in this limited experiment


that overexpressing a known mutant protein will produce a TSE in a susceptible monkey spontaneously.

I’ll turn to the second hypothesis: If you expose cells to a TSE agent, they might become infected. It has been known for a long time that it’s very difficult to infect cell cultures with TSE agents. A few of them, mostly of murine origin, have been infectable with scrapie and one with a CJD-type agent. But in general it’s very difficult to infect a cell culture, and some of them seem to cure themselves after they have been infected.

The basic protocol was to take cell lines, expose them to a very high concentration of brain suspension containing the BSE agent, variant CJD agent, or sporadic CJD agent, and then carry them for multiple passages and assay them for the presence, at the end of 30 passages, when all the original inoculum should be gone, for the presence of abnormal prion protein and for infectivity by injecting, for the BSE agent, both monkeys and mice, and for the vCJD and sporadic CJD agent, transgenic mice or sometimes conventional mice known to be susceptible. We looked at five cell lines used to make marketed or experimental vaccines: Vero, CHO -- we could not get PER.C6 because the owner didn’t want to stigmatize the line, I guess, so we got HEK-293, which has similar properties -- WI-38, and Madden-Darby canine kidney. We


exposed them to high doses of the infectious agent.

We also used the opportunity to compare the infectivity titers of candidate TSE reference materials in mice expressing human and bovine prion protein genes. Mr. Dubin might be interested in knowing that that was in support of a goal of the World Health Organization that had the interest but not the resources to investigate that sort of thing. We also attempted to see, if we took the inocula of BSE agent and put them into bovine cell lines, if we would get a cell culture assay similar to the ones in mice with scrapie. We failed in that.

Finally, because we’re in the Office of Blood and because one of our contractors is Larisa Cervenakova at the American Red Cross, we tried to do something relative to blood safety, and that was to see if we could infect murine bone marrow stem cells with a TSE agent that had been adapted to mice. I’ll show you briefly the results of that study in a minute.

This is the basic protocol, 17 cell lines expanded into working cell banks and exposed. We titrated all of our three inocula and got titers of anywhere from 5 to just over 6 logs per inoculum. That’s in mice. We were a little surprised and a little disappointed that the BSE agent so far has titered out considerably lower, only out to 10-2 in squirrel monkeys.


But those monkeys have provided an unexpectedly interesting new model for looking at the pathogenesis of spongiform encephalopathies. I’ll show you that in just a few minutes. We have completed all the basic studies with classic BSE, variant Creutzfeldt-Jakob disease, and sporadic Creutzfeldt-Jakob disease, the latter two obtained from the World Health Organization repository. The results are so far very reassuring.

This is a typical result shown here. We’re on slide 17, for those who are on the phone. If you look at the top panel labeled A, you see results out through passage 20 of a line of Vero cells that had been exposed to the BSE agent. You will see in the columns marked with the little minus signs that there is plenty of normal prion protein that is digested by proteinase K. There’s plenty of normal prion protein detected, but no protease-resistant prion protein detected at all. We became somewhat concerned that maybe our protocol wasn’t adequate to infect cells, so we obtained from Sue Priola at NIAID a mouse-adapted strain of scrapie that was known to infect mouse L cells and 3T3 cells. Luba Kurillova in our lab exposed them using the same protocol that we have used for BSE and the other TSE agents. Just as reported, they were promptly infected and remained


infected, with positive abnormal prion protein tests and infectivity, out through the 30th passage. Insofar as one can do it with this sort of model experiment, we validated the basic protocol, the simple protocol, that we were using to expose the cells. Known susceptible cells were readily infected with a strain of scrapie agent that had been reported to infect those cells.

So the basic protocol seems to work. All the practically relevant cell lines exposed to all three TSE agents failed to sustain infection. Pedro Piccardo and others reported all those results in Emerging Infectious Diseases last year.

In conclusion:

• 17 cell substrates expanded.

• We characterized three reference TSE agents, not counting the scrapie.

• All the selected cell lines were exposed to TSE agents and passaged 30 times.

• No infectivity, no abnormal prion protein detected in any culture, except, of course, the positive control.

• We tried some novel PrP assays. Those were not helpful, although Luisa Gregori is now attempting to improve them in our hands.

• Five bovine cell cultures were not infected.


• Monkeys were not infected, as well as mice.

• Three mutant PrPs did not cause a spontaneous TSE in mice.

I wish I could be as reassuring with the bone marrow stem cell project, but I have to report that when mouse bone marrow stem cells -- I like this picture because it’s so colorful -- just to prove that they were stem cells and, in selected medium, could be differentiated into adipocytes. When they were exposed to a mouse-adapted strain derived from a human TSE -- because the Red Cross doesn’t want scrapie in the lab -- unfortunately, they did sustain persistent infection. Is this relevant to human stem cells? We don’t know, but it does suggest that every cell line really has to be evaluated individually before concluding that there’s no risk. It is a dangerous thing. We would like to continue this research, particularly looking at atypical forms of BSE that have been reported in the last several years to have appeared in cattle in Italy, Japan, and now in the United States, where all three of our native cases have been associated with so-called atypical BSE. Whether they really constitute different strains with different properties remains to be determined, but that’s the going hypothesis. We also are looking at an interesting model of variant CJD-like disease in monkeys injected with the BSE


agent. We think that it may offer an opportunity to study asymptomatic carriers of primate-adapted BSE infection. Of course, the animals are more closely genetically related to humans than are mice. Luisa Gregori is now trying to improve our bioassays. Surprisingly little has been done to compare the sensitivity of various transgenic mice to infections with the different agents. Most laboratories, A, won’t share, and B, work only with their own transgenic lines of mice. So Luisa has successfully solicited some of these lines of mice that appear to show promise. She is breeding them up in sufficient quantity to do side-by-side comparisons with various agents.

Here are the acknowledgments for the large number of people involved in this study.

I’ll just rapidly go through a follow-up on decontamination studies that Kitty Pomeroy and I presented at our last site visit about five years ago. There have been a number of iatrogenic cases associated with contaminated instruments and a large number of unfortunate artifacts reported from laboratories because they did not adequate decontaminate equipment. So we looked at two different methods to evaluate the decontamination of TSE agents, which are much more resistant to inactivation when they are dried on surfaces than they are when they are in solution. We looked at them dried on to glass slips and on


to steel wire pins, using adaptations of methods that were previously described in the literature.

We did this in order to help the CDC, which was stuck in an awkward position. They were recommending a series of decontamination steps for hospital use that had been advised by a World Health Organization consultation in about 1999. Those involved treatment of instruments with either sodium hydroxide and autoclaving or sodium hypochlorite followed by rising and autoclaving. The Hospital Infection Control Advisory Committee to the CDC said that they were being silly because, obviously, current practice in the hospitals must be adequate or we would be seeing cases, which were, fortunately, have not. So we were asked to look at the HICPAC-advised methods. We took some of these objects and we cleaned them using a hot alkaline detergent ultrasonic bath, followed by routine rinsing and terminal sterilization. We were able to confirm that infectivity was, in fact, dropped by 5 logs on glass and steel with a scrapie model. However, in each model there was a considerable amount of detectable infectivity left, and it made us very uneasy to recommend a method for clinical use that had failed the pilot study in the laboratory. We then set up a similar study looking at the use of sodium hydroxide with or without detergent, sodium

106 hypochlorite, and one other agent I won’t mention. We found that most challenge animals tested with these contaminated objects, after those methods of decontamination, were, in fact, protected, but we had five unexpected sick animals that had tentatively positive Western blots for abnormal prion protein. We didn’t know whether it was some sort of artifact or whether it was real.

So Kitty Pomeroy set up blind passages, injecting those materials into hamsters and carrying them two years. Sure enough, they were all negative. So we concluded that the five unexpected positives were what we call initially reactive. They were unconfirmed by passage. And the CDC seemed happy to receive that information.

I’ll skip that slide.

This study was done not only by Kitty Pomeroy, but also by Terry Woods and colleagues at the CDRH.

Let me finish my own part by referring to the efforts, now taken over by Luisa Gregori, to set up rapid human tissue prion protein detection tests. This was prompted by observations of cornea and dura manufacturers that they could not test the autopsy tissues of donors, because there was no commercially available test. They were all research use only. In spite of repeated efforts at TSE Advisory Committee meetings and a workshop to


encourage manufacturers to produce these tests, none of them did.

What we decided to do was to take some of these tests that were developed for animal testing -- there are rapid tests for use in sheep and deer and cows that are commercially available, and we thought that some of them might work for human use.

This was the fastest of them. It’s a strip test produced for use in BSE in Europe. In fact, its sensitivity wasn’t particularly good, but keep in mind that it’s not the intended use of the test, nor was it optimized for human use. We did pick up a number of known infected CJD brains. Luisa and colleagues are now working on an ELISA-based test, with an intensely fluorescent target, that may offer greater sensitivity.

Here are five other projects that Luisa is involved in:

• Estimating possible vCJD infectivity concentration in blood.

• Primate vCJD blood reference materials, something that is currently not available.

• Developing an affinity-adsorptive filter to remove bacteria from blood components. This is not entirely removed from TSE, because she acquired expertise in doing this when she took part in a large study to


develop a filter-like device that effectively removed normal prion protein and abnormal prion protein from blood. So she had learned the basic approaches and techniques, and decided, since we were working with a rare disease and had the official mission of also helping with bacterial infections, to see if the same methodology she had worked with, with PrP, might help with bacteria, which are probably the most common transfusion-transmitted infections. Maybe 1 in 3,000 or even more platelet units end up with a bacterial contaminant.

As I mentioned -- I won’t talk about this anymore -- she has been developing TSE-susceptible transgenic mouse lines and also trying to improve the sensitivity and reproducibility of various prion protein amplification techniques which have been claimed to have some potential for blood screening.

This is a project that she initiated without any input from anybody else. I mention it because I think it’s really a clever use of the medical literature. While she was waiting for some of her lab-based studies to yield results, she looked at what had been published for experimental transmission of BSE and scrapie agent in sheep. Looking at the data, putting it together with her previous experience, before she came to FDA, she tried to estimate the amounts of infectivity in scrapie-infected


hamster blood. She thought, by looking at those results and combining with the binomial theorem, you could predict what the most likely titer -- this wouldn’t work if all the sheep came down, but some of them did not -- using the binomial theorem to predict which infectivity is most likely to have been present to produce the pattern of sheep that came down with the TSE. She came up with the interesting results, working with the Office of Biostatistics and Epidemiology -- although she was the initiator and coordinator -- that apparent infectivity increased throughout the incubation period, so that in the last quarter of the incubation period it had reached a level of about .8, which is to say that about four animals out of five would be expected to come down if they were transfused.

That was a relatively interesting result. In hamsters the infectivity is considerably higher. Her work with hamsters showed that there was anywhere from 2 to more than 7 infectious units per milliliter of blood, and these results are per unit of blood.

Using the same rationale, she then looked at the transfusion-transmitted cases of vCJD in the United Kingdom. The OBE people got very excited about that work and they developed a much more sophisticated model based on assumptions. Using both her simple binomial method and


that sophisticated model, they predicted the probable level of infectivity in the infected blood donors, who made the donations anywhere from a year and a half to three and a half years before they came down with vCJD. They came up with two interesting numbers, somewhat different, but not an order of magnitude different. Anywhere from one in three to three out of four units were expected to be infected. That study has already had an impact. In the United Kingdom, we read recently a risk assessment for transfusion-transmitted disease that cited and took advantage of her analysis. Even though this was a pencil-and-paper exercise, it has already had an impact.

The next project that she has been involved in is to develop a variant CJD monkey blood candidate reference material. As early as 2002, I had attempted to get for the FDA a collection of blood samples from patients with variant Creutzfeldt-Jakob disease, with no success at all. Clinicians were not willing to take large samples from people who were very sick with variant Creutzfeldt-Jakob disease. For reasons that are not clear to me, they were also not willing to collect large samples at autopsy. For whatever reason, particularly now that the cases have, fortunately, declined in frequency, it was clear that were not going to get enough human material to serve as


reference material.

The next best thing, we thought, was to set up a monkey reference material. Luisa was able to get some outside support and to solicit a monkey-adapted strain of variant CJD from our French colleagues, listed at the bottom. We inoculated four monkeys with variant CJD brain suspension by the intravenous and intraperitoneal routes. I’m pleased to report that since we first presented this in January of this year, a little more than a month ago, one of the monkeys began to show signs of a neurological disease. It’s not entirely specific, but it does look like what the French investigators have reported. We plan to try to assay the amounts of infectivity in mice. We have convinced the veterinary services staff that it’s worth doing a transfusion. If the titers are as low in monkey blood as they were in sheep and human blood, it may not be feasible to detect it even in a highly sensitive mouse model.

The next project is the one that I referred to a minute ago, and that is developing an affinity ligand bacterial removal filter based on the same strategy that Luisa used in developing a prion protein removal filter. That’s to screen random peptide libraries looking for peptides that bind avidly to bacteria. Then those selected ligands are put on resin beads, and then they can be


challenged with spiked bacteria, first in PBS alone, in PBS plus platelets, and then in the plasma plus platelets. In the future, if they are good, those can be derivatized onto membrane surfaces, which would also be challenged, in a filter format, with platelet units.

Luisa has already selected some promising ligands and determined that there are certain motifs in the amino acids in various positions distant from the resin bead that seem to predict, in a general way, how likely they are to bind to bacteria. She has been working just with Staph. epidermidis, but she will then move on to other bacteria that commonly contaminate blood units. Her last two projects we don’t have time to go over.

Let me close, then, by reviewing some projects of Pedro Piccardo. I’m going to go over the new information from the TSE cell substrate study in squirrel monkeys and then some completely independent work of his that has been conducted at the University of Edinburgh showing that mice can accumulate aggregated -- that is, amyloid staining -- prion protein in brain that can be serially transferable and catalyze its own accumulation, but does not cause a TSE. As a matter of fact, it doesn’t cause any detectable disease at all. Our conclusion is that PrP TSE alone is not always infectious.


Finally, there won’t be time to do this, but some very important work that he is now conducting also at the University of Edinburgh shows that a BSE isolate did not transmit disease to transgenic mice expressing the human PrP gene, but if you passed the same strain through sheep and took it out again, then it would infect those mice, suggesting that passage of the agent through a new host can alter its biological properties, which may be relevant for human health. First, briefly, to the squirrel monkey models. Squirrel monkeys had typical spongiosis, shown on the left of slide 39, and accumulations of prion protein, but they don’t form amyloid-staining aggregates. They are quite dramatic and disperse through the parenchyma, as seen here, but they don’t make amyloid plaques.

But also in cells and in the parenchyma are dramatic accumulations of tau protein. Tau protein was thought by many to accumulate in brain diseases whenever amyloid accumulated. I may be mistaken in that. But in this case, amyloid had not accumulated and tau had. So that can’t be right. Pedro hopes to use this observation to develop a test that might serve as a useful surrogate for diagnosis of a TSE.

Another interesting finding came from the monkeys. The mobility of the prion protein in cows with


BSE and human beings with variant CJD is similar. The BSE cows have a relatively light form that migrates at about 19 kilodaltons, and so do human beings. It has been concluded that that 19-kilodalton mobility is a unique and stable property of the BSE-derived prion protein. The work in monkeys shows that that probably is not true, because when you pass it into squirrel monkeys, they get a 21-kilodalton isoform, which is similar to that that is seen in most patients with sporadic CJD. The prion protein glycotype must be influenced by the host and cannot be a consistently stable characteristic of the BSE agent, although it was useful in drawing the conclusion for human beings.

Other work that Pedro has done, also with the University of Edinburgh, was based on earlier work, before he came to the FDA. He was studying a Creutzfeldt-Jakob-like disease called the Gerstmann-Straussler-Scheinker syndrome, which, for practical purposes, is like variant CJD, autosomal pattern of inheritance and amyloid plaques. Most of those cases are associated with a mutation at amino acid 102 in the prion protein-encoding gene and methionine homozygosity in a normal polymorphic site, 129, of the same gene.

Pedro observed two important findings. One, about a quarter of the patients with GSS did not have spongy changes in the cerebral cortex. In addition, when


Western blots were done of their prion protein, the more common GSS patients had prion protein that was predominantly 21 kilodaltons in mobility, but the atypical cases -- remember, these both had a progressive, fatal syndrome, progressive neurological disease -- the atypical ones had a very small prion protein, only about 8 kilodaltons. He passaged these into transgenic mice prepared in Edinburgh that expressed the equivalent of the same mutation seen in human beings. The ones with the typical vacuolating spongiform encephalopathy readily transmitted a typical TSE to mice in less than 180 days. This bred through. Here’s a human, to the left, and a mouse, to the right. But when he took suspensions of brain from patients with the atypical GSS and injected them into mice, the mice did not get spongy changes and did not get sick. However, along the inoculation site, there were accumulations of abnormal prion protein. These mice lived for a normal lifespan. They never got sick at all.

So one could conclude that this accumulation of the abnormal prion protein, unless you want to redefine what the disease is, is not accompanied by transmission of spongiform encephalopathy. It demonstrates that abnormal PrP can accumulate in brain without causing disease. He has now done similar experimental studies using another


model also in transgenic mice.

More recent studies, also in Edinburgh, have demonstrated that atypical BSEs -- only a small fraction of those cases injected into mice expressing bovine prion protein made the mice sick. But when you look for vacuolation and abnormal prion protein, a very high percentage had them. What’s the significance of that? Well, if it’s similar for cows, it may suggest that there’s more BSE than is picked up by surveillance programs based on the detection of sick cows.

Here are his collaborators, both here at the FDA and at the University of Edinburgh. I’m proud to point out that they are so happy with this work that they honored Pedro by making him honorary full professor of pathology of the University of Edinburgh.

With that, I’ll close the presentation. I’ll answer questions, and both the PIs are available to answer questions as well.


DR. HOLLINGER: Thank you very much, Dr. Asher.

Questions for David.

(No response)

I’m not hearing anything.

LCDR EMERY: I don’t think there are any questions at the time.


MR. DUBIN: A comment, if I may, Blaine. Dr. Asher, you referenced something I would be interested in. More important, as someone who was present for the first special advisory committee on Creutzfeldt-Jakob disease in 1995 -- the Committee had someone on that committee -- to now where the knowledge base has expanded exponentially, what we know today, I can hear the pride in your report and the strength of your team. From an end user’s perspective and someone with that many years in all of this, you have made great strides. It strengthens our view that an independent, strong FDA doing good science is always our best friend on the end user side. I want to congratulate you and the PIs and your team. You probably don’t hear that enough.

But for someone who was very much used to “we don’t know,” I heard some really amazing and informative things today that I’m going to be itching to talk to my people about and some of the other groups in A-PLUS. So thank you very much, Dr. Asher. Today was an example of an active FDA. It’s really a pleasure. Thank you all.

DR. ASHER: Thank you, Mr. Dubin. It’s always nice to hear those things. I welcome more questions like that.

MR. DUBIN: Any time. You have done some really


good work, and your people. Thank you.

DR. HOLLINGER: Any other comments or questions?

(No response)

If none, we have an open public hearing. As you noted, we haven’t received any requests. I’m wondering if there is anyone in audience there at the FDA who wishes to make a comment. LCDR EMERY: I don’t see anybody at this time, Dr. Hollinger, but I’ll say a little bit.

Next on the agenda is the open public hearing. As part of the FDA advisory committee meeting procedure, we hold open public hearings to give members of the public an opportunity to make a statement concerning matters pending before the committee. At this time we have not received any requests to speak in the open public hearing session. Is there someone here today who would like to address the committee on the topic of today’s meeting?

(No response)

If not, we will take five minutes to clear the room for the closed session, unless there’s something else you need to say or want to talk about, Dr. Hollinger.

DR. HOLLINGER: As it’s still open, I also want to comment for the Committee about how much we appreciate the FDA and the people who presented today for the excellent job. This was really quite good and gave us a


good overview of what’s going on at the FDA, particularly in these two laboratories. The Committee is thankful for that and appreciative.

Those are the comments for the open.

MR. DUBIN: Gold standard at those two labs, is what I heard today.

DR. HOLLINGER: Very correct.

You are going to take about five minutes to clear the room. Then we’ll go into the closed committee discussion.

LCDR EMERY: Yes, Dr. Hollinger.

(Whereupon, the open session of the meeting was concluded.)

From: Terry S. Singeltary Sr.

Sent: Monday, June 11, 2012 5:20 PM


Cc: CJD-L ; CJDVOICE CJDVOICE ; bloodcjd bloodcjd

Subject: Amendment to “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products” Guidance for Industry Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products”


“However, based on animal studies, as well as on FDA risk assessments, the possibility of vCJD transmission by a U.S.-licensed plasma derivative, while extremely small, cannot be absolutely ruled out. For these reasons, the recommendations for labeling for plasma derivatives will include mention of vCJD for the first time, and the potential risk for its transmission. The recommended elements of the warning label for CJD are unchanged and continue to describe its transmission as a theoretical risk, given that there is no confirmed evidence that CJD is transmitted by blood (Refs. 4-7).“

IN FULL, as follows ;

Monday, June 11, 2012

Guidance for Industry Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products”

OR-36: A new neurological disease in primates inoculated with prion-infected blood or blood components

Emmanuel Comoy,1 Nina Jaffré,1 Jacqueline Mikol,1 Valérie Durand,1 Christelle Jas-Duval,2 Sophie Luccantoni-Freire,1 Evelyne Correia,1 Vincent Lebon,1 Justine Cheval,3 Isabelle Quadrio,4 Nathalie Lescoutra-Etchegaray,5 Nathalie Streichenberger,4 Stéphane Haïk,6 Chryslain Sumian,5 Armand Perret-Liaudet,4 Marc Eloit,7 Philippe Hantraye,1 Paul Brown,1 Jean-Philippe Deslys1 1Atomic Energy Commission ; Fontenay-aux-Roses, France ; 2Etablissement Français du Sang; Lille, France; 3Pathoquest; Paris, France; 4Hospices Civils de Lyon, Lyon, France; 5MacoPharma; Tourcoing, France; 6INSER M; Paris, France; 7Institut Pasteur; Paris, France

Background. Concerns about the blood-borne risk of prion infection have been confirmed by the occurrence in the UK of four transfusion-related infections of vCJD (variant Creutzfeldt- Jakob disease), and an apparently silent infection in an hemophiliac patient. Asymptomatic incubation periods in prion diseases can extend over decades in humans, and a typical disease may or may not supervene. We present here unexpected results of independent experiments to evaluate blood transmission risk in a validated non-human primate model of prion disease.

Methods. Cynomolgus macaques were inoculated with brain or blood specimens from vCJD infected humans and vCJD or BSE-infected monkeys. Neuropathological and biochemical findings were obtained using current methods used for human patients.

Findings. Thirteen out of 20 primates exposed to human or macaque blood-derived components or potentially contaminated human plasma-derived Factor VIII exhibited an original neurological disease (myelopathy) previously not described either in humans or primates, and which is devoid of the classical clinical and lesional features of prion disease (front leg paresis in the absence of central involvement, lesions concentrated in anterior horns of lower cervical cord, with no spongiosis or inflammation), while the 12 brain-inoculated donor animals and one transfused animal exhibited the classical vCJD pattern. No abnormal prion protein (PrPres) was detected by standard tests in use for human prion diagnosis, but higher amounts of protease-sensitive PrP were detected in cervical cords than in controls. No alternative cause has been found in an exhaustive search for metabolic, endocrine, toxic, nutritional, vascular and infectious etiologies, including a search for pathogen genotypes (‘deep sequencing’). Moreover, all the three animals transfused with blood treated with a prion removal filter remain asymptomatic with a one-third longer incubation period than the two animals transfused before filtration, which both developed the atypical syndrome presented here.

Interpretation. We describe a new neurological syndrome in monkeys exposed to various prion-infected inocula, including a potentially infected batch of plasma-derived Factor VIII. Our experimental observations in the absence of evident alternative etiology is highly suggestive of a prion origin for this myelopathy, that might be compared under some aspects to certain forms of human lower motor neuron diseases. Similar human infections, were they to occur, would not be identified as a prion disease by current diagnostic investigations.

Sunday, June 3, 2012

A new neurological disease in primates inoculated with prion-infected blood or blood components

Tuesday, May 29, 2012

Transmissible Proteins: Expanding the Prion Heresy

Wednesday, May 9, 2012

Detection of Prion Protein Particles in Blood Plasma of Scrapie Infected Sheep

Friday, May 11, 2012

ProMetic Life Sciences Inc.: P-Capt® Filtration Prevents Transmission of Endogenous Blood-Borne Infectivity in Primates

Wednesday, August 24, 2011

All Clinically-Relevant Blood Components Transmit Prion Disease following a Single Blood Transfusion: A Sheep Model of vCJD

Wednesday, August 24, 2011

There Is No Safe Dose of Prions

Sunday, May 1, 2011

W.H.O. T.S.E. PRION Blood products and related biologicals May 2011

Monday, February 7, 2011

FDA’s Currently-Recommended Policies to Reduce the Possible Risk of Transmission of CJD and vCJD by Blood and Blood Products 2011 ???

Sunday, August 01, 2010

Blood product, collected from a donors possibly at increased risk for vCJD only, was distributed USA JULY 2010

Tuesday, September 14, 2010

Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting October 28 and 29, 2010 (COMMENT SUBMISSION)

Sunday, July 20, 2008

Red Cross told to fix blood collection or face charges 15 years after warnings issued, few changes made to ensure safety

Saturday, December 08, 2007

Transfusion Transmission of Human Prion Diseases

Tuesday, October 09, 2007


Saturday, December 08, 2007

Transfusion Transmission of Human Prion Diseases

Saturday, January 20, 2007

Fourth case of transfusion-associated vCJD infection in the United Kingdom

vCJD case study highlights blood transfusion risk 9 Dec 2006 by Terry S. Singeltary Sr.

THIS was like closing the barn door after the mad cows got loose. not only the red cross, but the FDA has failed the public in protecting them from the TSE aka mad cow agent. TSE agent ie bse, base, cwd, scrapie, tme, ...

vCJD case study highlights blood transfusion risk -

Saturday, May 26, 2012

Are USDA assurances on mad cow case 'gross oversimplification'?

in the url that follows, I have posted

SRM breaches first, as late as 2011.


MAD COW FEED BAN BREACHES AND TONNAGES OF MAD COW FEED IN COMMERCE up until 2007, when they ceased posting them.



Friday, May 18, 2012

Update from APHIS Regarding a Detection of Bovine Spongiform Encephalopathy (BSE) in the United States Friday May 18, 2012

Sunday, May 18, 2008


Saturday, January 16, 2010

Evidence For CJD TSE Transmission Via Endoscopes 1-24-3 re-Singeltary to Bramble et al

Evidence For CJD/TSE Transmission Via Endoscopes

From Terry S. Singletary, Sr 1-24-3

Saturday, December 3, 2011

Candidate Cell Substrates, Vaccine Production, and Transmissible Spongiform Encephalopathies Volume 17, Number 12—December 2011

Sunday, January 29, 2012

Prion Disease Risks in the 21st Century 2011 PDA European Virus-TSE Safety Dr. Detwiler

Dr. Detwiler published Prion Disease Risks in the 21st Century 2011 PDA European Virus-TSE Safety Forum\Presentations TSE\ Page 33 and 34 of 44 ;

The documents below were provided by Terry S. Singeltary Sr on 8 May 2000. They are optically character read (scanned into computer) and so may contain typos and unreadable parts.


Mr Cunningham CMP3 From: D O Hagger MBI

Dr Salisbury MED/IMCD3

Mr Burton PD/STB/PG1B B/17/2 Date: 15.02.1989

Mr Dudley PD/AD4


1. The purpose of this minute is to alert you to recent developments on BSE as they affect medicines and to invite representatives to a meeting in Market Towers on 22 February 1989.

2. The report of the Working Party on Bovine Spongiform Encephalopathy (BSE) was submitted by the CMO to the Secretary of State for Health and Minister for Agriculturer on 9 February.

3. The summary at the end of the report records, inter alia: 'we have drawn the attention of the Licensing Authority to the potential of transfer of BSE agent in human and veterinary medicinal products. In paragraph 7 of his submission (Annex A), the CMO notes:

"I am also putting work urgently in hand to satisfy myself that everything possible has been done to ensure .... that transfer of the BBE agent in human and veterinary medicinal products does not occur."

4. The Veterinary products Committee meets on 16 February and The committee on Safety of Medicines on 23 February when each will be considering a draft of some joint guidelines for manufacturers of medicinal products which use bovine material as an ingredient or an intermediate in the manufacturing process (Annex B).....

6. Although a wide range of medicines may be implicated - and the present proposal is to write to companies for more information - an "instant" telephone survey of manufacturer of vaccines used for children has already been undertaken in response to a request from Dr Harris. The results are in Dr Adams' minute of 14 February (Annex C) - the proviso in his second paragraph, last sentence should be noted.


89/02.15/11.2 MF580439/1 0584


1. I attach a list of questions on BSE and medicines compiled with the aim of providing question and answer briefing to DH and MAFF Ministers upon publication of the Southwood Report. I have suggested names of those who may be able to provide answers.

All recipients are invited to consider which if any important areas have been missed. Also attached is copy QA briefing being proposed by MAFF. I understand MAFF have produced General QA briefing on the reports as a whole.


MF580439/1 0585 Question

1. Which medicines are affected? (person to provide reply) Dr. Jefferys

2. Are the risks greater with some medicines than others? Dr. Jefferys

3. Why are medicines affected? Dr. Jefferys

4. Are some affected products available over the counter from pharmacies or shops? Dr. Purves

5. Are only UK products at risk? Dr. Jefferys

6. Are existing stocks safe? Dr. Jefferys

7. Are pre 1980 stocks available? Mr. Burton

8. Are these alternatives to the use of bovine material? Dr. Purves

9. Why can't we throw away suspect stock and import or manufacture safe medicines? Dr. Jefferys

10. Which patients are at risk? Dr. Jefferys

11. Are some patients particularly vulnerable? Dr Jefferys

12. What risks exist to those who have already used these medicines? Dr. Jefferys

13. HOW might patients be affected? Dr. Jefferys

14. Can BSE be transmitted to patients by medicines? Dr. Jefferys

15. How long will it be before risks are quantified? Dr. Jefferys

100 89/02.17/10.2 MF580439/1 0586

16. What research is going on to find out if medicines can transmit this disease and if any patients have been affected? Dr Jefferys

17. Could recent cases of Creuuzfeld Jacob Disease have been caused by transmission of BSE through medicines? Dr. Jefferys

18. What action is the Licensing Authority taking to ensure proper scrutinising of source materials and manufacturing processes? Dr. Jefferys/Dr. Purves

19. Are the guidelines practical? Dr. Jefferys/Dr. Purves

20. Will the guidelines remove the risk? Dr. Jefferys

21. How will the guidelines be enforced? Dr. Jefferys/Dr. Purves

22. How soon will they come into force? Dr. Jefferys

23. Will the guidelines be published? Mr. Hagger

24. What is being done to reassure patients, parents etc? Mr. Hagger/Dr. Salisbury

25. What advice is being given to doctors, pharmacists etc? Mr. Hagger

26. What advice is the Government giving about its vaccination programme? Dr. Salisbury

27. Is the vaccination programme put at risk because of BSE? Dr. Salisbury


Q. Will government act on this?

A. Yes - thymus is not used in preparation of baby foods but it is contacting all manufacturers to seek their urgent views on use of kidneys and liver from ruminants. Will consider any necessary measures in the light of their response.


Q. Can medicines spread BSE to other cattle/animals?

A. The report describes any risks as remote.

Q. How can risks be avoided?

A. In liaison with the DOH the Veterinary Products Committee is examining guidelines for the veterinary pharmaceutical industry which will be issued shortly.

Q. What will Guidelines say?

A. In essence they call for non-bovine sources to be used if possible, including synthetic material of biotechnological origin. Where this is not possible the industry should look for sources which are free of BSE and which are collected in a manner which avoids risk of contamination by the BSE agent.

89/02.17/10.4 MF580439/1 0588

A. Bovine source material is used in [garbled, cannot read...TSS] and some other medicines.

Q. How many medicines are involved?

A. Computer records show that about 300 of the 3,050 veterinary medicines licensed in the U.K. are manufactured directly from bovine source material. However, other medicines may be produced from bovine sources and a letter is going to all license holders so that a comprehensive list can be drawn up.

89/06.19/8.1 BSE3/1 0191 Hr J Maslin (MAFF) Ref: Maslin3g

From: Dr H Pickles Med SEB/B Date: 3 July 1989


I was interested to see the list of by-products sent to the HSE. Those of particular concern included:

* small intestines: sutures (I thought the source was ovine but you are checking this)

* spinal cord: pharmaceuticals

* thymus: pharmaceuticals

Are you able to give me more information on which UK manufacturers use these materials? Our proposed ban on bovine offal for human consumption would not affect these uses, I assume.

Id No. 1934/RD/1 89/08.10/6.1 117A


Miss M Duncan (Chairman)

Mr W Burton

Dr E Hoxey

Mrs J Dhell

Ms K Turner

Dr S Whittle

Mr N Weatherhead


5. The MCA had sent 2700 questionnaires out, 1,124 had made valid returns; of these 122 use animal material of some kind and there are 582 products involved.


6. The MCA/BSE working group will meet on 6th September. Their aim is to review responses from professional officers in MCA who have suggested seven categories of importance (with 1 being the most important} for medical products:

ID 2267/NRE/1 89/08.21/10.1

1. Products with Bovine brain/lymph tissue administered by injection.

2. Products with bovine tissue other than brain/lymph administered by inection.

3. Tissue implants/open wound dressing/surgical materials/dental and ophthlamic products with bovine ingredients.

4. Products with bovine ingredients administered topically.

5. Products with bovine ingredients administered orally.

6. Products with other animal/fish/insect/bird ingredients administered by injection/topically/oral routes.

7. Products with ingredients derived from animal material by chemical processing (eg stearic acid, gelatine, lanolin ext.

The BSE working group will decide which of these are important, and should be examined more closely, and which categories can be eliminated.

The responses by the companies were presented by Ms Turner and were categorised by MCA standards, the products that were discussed were all low volume usage products eg sutures, heart valves.

8. As the responses included some materials of human origin it was decided that more information should be sought about CJD. There had been 2 recent deaths reported associated with human growth hormone. These were being investigated.

9. Re-editing of the Paper on "Incubation of Scrapie-like Agents"

It was suggested that the document could be sent out to companies with the non-standard sterilization Document. The document could have severe implications on the companies whose products have a high risk factor as decided by the MCA working group....

11. The Need for a list of High Priority Implantables The commitee decided that no list is necessary as all implantables, including ones from a human source are of high priority. Concern was shown over Killingbeck who use human material but had not yet responded. The company will be chased for a response. Concern was shown over the fact that there may be other scrapie-like organisms in other animals and further enquiries should be made.

2334q/RD/4 89/08.21/10.7


Glutaraldehyde, formaldehyde, and ethylene oxide are used in the sterilization of these devices.

However, glutaraldehyde 4,10,12,19 formaldehyde 5,10,11,13,19 and ethylene oxide 19,23 are all reported to be ineffective methods for sterilization of material infected with the agents of CJD or scrapie.

Previous advice and research using the agents of CJD and scrapie, has concentrated on the decontamination of equipment; protection of health care workers from contaminated human material; human growth hormone; and dura mater. The methods developed may not be directly applicable or transferable to material of bovine origin for use in human implantation.

2334q/RD/7 89/08.21/10.10 BSE11/2 020 SC1337


Richmood House 79 Whitehall, London SW1A 2NS

Telephone 01-210-3000

From the Chief Medical Officer

Sir Donald Acheson KBE DM DSc FRCP FFCM FFOM

Mr K C Meldrum

Chief Veterinary Officer

Ministry of Agriculture, Fisheries and Food

Government Buildings

Hook Rise South





3 January 1990

Dear Mr. Meldrum,


You will recall that we have previously discussed the potential risks of BSE occurring in other Countries as a result of the continuing export from the UK of meat and bone that may be contaminated by scrapie or possibly BSE.

I remain concerned that we are not being consistent in our attempts to contain the risks of BSE. Having banned the feeding of meat and bone meal to ruminants in 1988, we should take steps to prevent these UK products being fed to ruminants in other countries. This could be achieved either through a ban on the export of meat and bone meal, or at least by the proper labelling of these products to make it absolutely clear they should not be fed to ruminants. Unless some such action is taken the difficult problems we have faced with BSE may well occur in other countries who import UK meat and bone meal. Surely it is short sighted for us to risk being seen in future as having been responsible for the introduction of BSE to the food chain in other countries.

I would be very interested to hear how you feel this gap in the present prcautionary measures to eliminate BSE should be closed. We should be aiming at the global elimination of this new bovine disease. The export of our meat and bone meal is a continuing risk to other countries.


Sincerely Donald Acheson

Did the US import fetal calf serum and vaccines from BSE-affected countries?

3002.10.0040: FETAL BOVINE SERUM (FBS)

U.S. Imports for Consumption: December 1998 and 1998 Year-to-Date

(Customs Value, in Thousands of Dollars)

(Units of Quantity: Kilograms)

<--- Dec 1998 ---> <--- 1998 YTD --->

Country Quantity Value Quantity Value


WORLD TOTAL . . . . . . . 2,727 233 131,486 8,502

Australia . . . . . . . . --- --- 19,637 2,623

Austria . . . . . . . . . --- --- 2,400 191

Belgium . . . . . . . . . --- --- 17 32

Canada . . . . . . . . . 900 110 30,983 3,220

Costa Rica . . . . . . . 500 20 4,677 169

Federal Rep. of Germany --- --- 105 21

Finland . . . . . . . . . 1 8 9 83

France . . . . . . . . . --- --- 73 7

Guatemala . . . . . . . . --- --- 719 42

Honduras . . . . . . . . --- --- 1,108 88

Israel . . . . . . . . . --- --- 24 165

Netherlands . . . . . . . --- --- 1 5

New Zealand . . . . . . . 26 5 65,953 913

Panama . . . . . . . . . --- --- 1,195 64

Switzerland . . . . . . . 971 8 1,078 23

United Kingdom . . . . . 329 82 743 756

Uruguay . . . . . . . . . --- --- 2,764 98



U.S. Imports for Consumption: December 1998 and 1998 Year-to-Date

(Customs Value, in Thousands of Dollars)

(Units of Quantity: Kilograms)

<--- Dec 1998 ---> <--- 1998 YTD --->

Country Quantity Value Quantity Value


WORLD TOTAL . . . . . . . 25,702 26,150 550,258 378,735

Austria . . . . . . . . . --- --- 45 225

Belgium . . . . . . . . . 14,311 12,029 248,041 199,036

Canada . . . . . . . . . 1,109 1,527 15,798 16,305

Denmark . . . . . . . . . 80 234 246 682

Federal Rep. of Germany 1,064 4,073 12,001 6,329

France . . . . . . . . . 3,902 4,859 87,879 92,845

Ireland . . . . . . . . . --- --- 120 478

Italy . . . . . . . . . . --- --- 2,359 81

Japan . . . . . . . . . . 445 1,903 11,350 11,298

Netherlands . . . . . . . --- --- 94 6

Republic Of South Africa --- --- 2 1

Spain . . . . . . . . . . --- --- 60 30 Switzerland . . . . . . . 716 353 9,303 4,271

United Kingdom . . . . . 4,075 1,172 162,960 47,148



U.S. Imports for Consumption: December 1998 and 1998 Year-to-Date

(Customs Value, in Thousands of Dollars)

(Units of Quantity: Kilograms)

<--- Dec 1998 ---> <--- 1998 YTD --->

Country Quantity Value Quantity Value


WORLD TOTAL . . . . . . . 6,528 237 87,149 2,715

Canada . . . . . . . . . --- --- 2,637 305

Federal Rep. of Germany --- --- 104 5

Netherlands . . . . . . . 138 64 472 192

New Zealand . . . . . . . 6,390 173 83,882 1,895

United Kingdom . . . . . --- --- 54 318

Sunday, May 18, 2008


Sunday, May 18, 2008


Sunday, May 18, 2008



Tuesday, February 8, 2011


Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001

Date: Tue, 9 Jan 2001 16:49:00 -0800

From: "Terry S. Singeltary Sr."

Reply-To: Bovine Spongiform Encephalopathy


######### Bovine Spongiform Encephalopathy #########

Greetings List Members,

I was lucky enough to sit in on this BSE conference call today and even managed to ask a question. that is when the trouble started.

I submitted a version of my notes to Sandra Blakeslee of the New York Times, whom seemed very upset, and rightly so.

"They tell me it is a closed meeting and they will release whatever information they deem fit. Rather infuriating."

and i would have been doing just fine, until i asked my question. i was surprised my time to ask a question so quick.

(understand, these are taken from my notes for now. the spelling of names and such could be off.)

[host Richard Barns] and now a question from Terry S. Singeltary of CJD Watch.

[TSS] yes, thank you, U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?

[no answer, you could hear in the back ground, mumbling and 'we can't. have him ask the question again.]

[host Richard] could you repeat the question?

[TSS] U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?

[not sure whom ask this] what group are you with?

[TSS] CJD Watch, my Mom died from hvCJD and we are tracking CJD world-wide.

[not sure who is speaking] could you please disconnect Mr. Singeltary

[TSS] you are not going to answer my question?

[not sure whom speaking] NO

from this point, i was still connected, got to listen and tape the whole conference. at one point someone came on, a woman, and ask again;

[unknown woman] what group are you with?

[TSS] CJD Watch and my Mom died from hvCJD we are trying to tract down CJD and other human TSE's world wide. i was invited to sit in on this from someone inside the USDA/APHIS and that is why i am here. do you intend on banning me from this conference now?

at this point the conference was turned back up, and i got to finish listening. They never answered or even addressed my one question, or even addressed the issue. BUT, i will try and give you a run-down for now, of the conference.

IF i were another Country, I would take heed to my notes, BUT PLEASE do not depend on them. ask for transcript from;

RBARNS@ORA.FDA.GOV 301-827-6906

he would be glad to give you one ;-)

Rockville Maryland, Richard Barns Host

BSE issues in the U.S., How they were labelling ruminant feed? Revising issues.

The conference opened up with the explaining of the U.K. BSE epidemic winding down with about 30 cases a week.

although new cases in other countries were now appearing.

Look at Germany whom said NO BSE and now have BSE.

BSE increasing across Europe.

Because of Temporary Ban on certain rendered product, heightened interest in U.S.

A recent statement in Washington Post, said the New Administration (old GW) has a list of issues. BSE is one of the issues.

BSE Risk is still low, minimal in U.S. with a greater interest in MBM not to enter U.S.

HOWEVER, if BSE were to enter the U.S. it would be economically disastrous to the render, feed, cattle, industries, and for human health.

(human health-they just threw that in cause i was listening. I will now jot down some figures in which they told you, 'no need to write them down'. just hope i have them correct. hmmm, maybe i hope i don't ???)

80% inspection of rendering

*Problem-Complete coverage of rendering HAS NOT occurred.

sizeable number of 1st time FAILED INITIAL INSPECTION, have not been reinspected (70% to 80%).

Compliance critical, Compliance poor in U.K. and other European Firms.

Gloria Dunason Major Assignment 1998 goal TOTAL compliance. This _did not_ occur. Mixed level of compliance, depending on firm.

Rendering FDA license and NON FDA license

system in place for home rendering & feed 76% in compliance 79% cross contamination 21% DID NOT have system 92% record keeping less than 60% total compliance

279 inspectors 185 handling prohibited materials

Renderer at top of pyramid, significant part of compliance. 84% compliance

failed to have caution statement render 72% compliance & cross contamination caution statement on feed, 'DO NOT FEED TO CATTLE'


1240 FDA license feed mills 846 inspected

"close to 400 feed mills have not been inspected"

80% compliance for feed.

10% don't have system.

NON-FDA licensed mills There is NO inventory on non licensed mills. approximately 6000 to 8000 Firms ??? 4,344 ever inspected. "FDA does not have a lot of experience with"

40% do NOT have caution statement 'DO NOT FEED'.

74% Commingling compliance

"This industry needs a lot of work and only half gotten to"

"700 Firms that were falitive, and need to be re-inspected, in addition to the 8,000 Firms."

Quote to do BSE inspection in 19 states by end of January or 30 days, and other states 60 days. to change feed status??? Contract check and ask questions and pass info.

At this time, we will take questions.

[I was about the third or fourth to ask question. then all B.S.eee broke loose, and i lost my train of thought for a few minutes. picked back up here]

someone asking about nutritional supplements and sourcing, did not get name. something about inspectors not knowing of BSE risk??? the conference person assuring that Steve Follum? and the TSE advisory Committee were handling that.

Some other Dr. Vet, whom were asking questions that did not know what to do???

[Dennis Wilson] California Food Agr. Imports, are they looking at imports?

[Conference person] they are looking at imports, FDA issued imports Bulletin.

[Linda Singeltary ??? this was a another phone in question, not related i don't think] Why do we have non-licensed facilities?

(conference person) other feed mills do not handle as potent drugs???

Dennis Blank, Ken Jackson licensed 400 non FDA 4400 inspected of a total of 6000 to 8000, (they really don't know how many non licensed Firms in U.S. they guess 6000 to 8000??? TSS)

Linda Detwiler asking everyone (me) not to use emergency BSE number, unless last resort. (i thought of calling them today, and reporting the whole damn U.S. cattle herd ;-) 'not'

Warren-Maryland Dept. Agr. Prudent to re-inspect after 3 years. concerned of Firms that have changed owners.



snip...see full text and more here on tissue donor herds and the TSE Prion disease ;


Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001

Date: Tue, 9 Jan 2001 16:49:00 –0800

From: "Terry S. Singeltary Sr."


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