Dr. Asher.

DR. ASHER: Thank you, Dr. Brown.

Can you hear me? Can we have the slides, please?

Good morning. I'd like to introduce our next topic, which is safe sourcing of materials from sheep and goats in countries not free of ruminant TSEs.

Can we start the slides, please? Great. Thank you.

So I'll briefly address the issue, list some sheep derived and goat derived materials found in or used to make FDA regulated implantable and injectable products, and give the first reading, charge in question.

Then I'll begin a review of the risk to humans from TSE agents of animal origin, aspects of which will be covered in detail by our invited speakers.

BSE I will leave to Professor Almond, who has so kindly agreed to be here today.

Scrapie I'll address myself. I'll mention just in passing other animal TSEs. Then I'll note several uncertainties about the risk to humans, list some of the regulations, policies, and practices of the U.S. government intended to reduce the risk, and close by listing several discussion topics, that is, possible actions that might be considered in efforts to reduce still further the risk of human exposures to TSE agents of goats and sheep.

There are two demonstrated sources of human infections with TSE agents, first from human material, as was discussed yesterday and in today's first topic, and from animal material, and I list here a third possible source just to be complete, though it remains hypothetical.

Of greatest interest today is the BSE agent because it is the presumptive cause of new variant CJD and must be considered a demonstrated risk to human health. The scrapie agent poses a theoretical risk to human health.

Today we ask you to consider the implications of two theoretical possibilities: the first, that sheep and goats in BSE countries theoretically might be infected with the BSE agent, and Professor Almond, who headed a subcommittee of the United Kingdom's Spongiform Encephalopathy Advisory Committee, has agreed to review that topic for us today.

Then scrapie, which theoretically might be a human pathogen, though there's no hard evidence for that, and of course, some number of sheep and goats in many countries, including the United States, are infected with the scrapie agent.

Now, let me say now that no U.S. government regulatory authority would ever knowingly permit humans or animals to be exposed to a product containing the scrapie agent, but considering the nature of the scrapie agent and the disease, we are not so naive as to think that such exposures have not already occurred.

We in the FDA and our colleagues in the USDA are well aware that there are other animal TSEs in the USA, specifically chronic wasting disease of deer and elk and transmissible mink encephalopathy and other animal TSEs have been postulated.

However, few FDA regulated projects, none injectable and implantable that I know of, are directly affected by the two known diseases. The extent of human exposure to those diseases remains uncertain, and the agents are not known pathogens for human beings.

We in the FDA's TSE working group agree that public health implications of those animal TSEs are an appropriate topic for discussion, but that will be on another day.

Sheep derived and goat derived materials are found in a variety of regulated, implantable, and injectable materials. Sutures and vascular grafts are prepared from sheep materials. There are several injected enzymes of goat and sheep origin, a variety of therapeutic antibodies prepared in normal and transgenic animals and allergens are derived from sheep and goats, and some examples are listed here on the slide.

With the possible exception of sutures, these products are not widely used.

Sheep and goat derived materials are also used to prepare injectable biologics, as immunoaffinity purification reagents, bacteriological culture media, and some other materials. This is not an exhaustive list.

Although the products may not be widely used, the people treated with them and the FDA staff are concerned that all source materials be as safe as possible, especially injected in implanted products, routes where smaller amounts of TSE agents are needed to infect than by oral routes.

In our center, in response to concerns about theoretical risks from scrapie, some sponsors have concluded that it would be prudent to obtain sheep derived and goat derived material from countries free of both BSE and scrapie.

The FDA has never articulated specific criteria sufficient to assure the agency that such materials are free of the agents when obtained from animals in countries with TSEs of ruminants, like the USA, and it would be desirable to have a consistent FDA policy on the issue.

The TSE Advisory Committee is, therefore, asked to consider whether current policies of the FDA, an agency which relies on import restrictions and other policies of the USDA, are adequate to protect humans and animals from potential exposure to the BSE agent in FDA regulated products containing or produced with materials derived from sheep and goats originating in BSE countries, or if additional precautions are needed.

The Committee is also requested to consider appropriate precautions including sourcing, selection of animals, veterinary scrutiny, monitoring of animals, feeding practices and other measures that might be adequate to assure the agency that materials obtained from sheep and goats from the USA or from other countries where scrapie occurs are free of the scrapie agent and can be used safely in FDA regulated products intended for injection or implantation.

After considering risks and benefits, we ask you to advise the FDA whether there are safeguards that might be sufficient to insure that sheep and goats from BSE countries would nonetheless provide acceptable sources of materials for manufacture of regulated products intended for injection or implantation both as components of the products and as manufacturing process reagents.

And you'll hear in a few minutes that there are current precautions and policies of the FDA that are in place, and any relaxation of those policies would constitute a reduction in safeguards.

After considering possible risks and benefits, we finally ask you to suggest safeguards adequate to assure that sheep and goats originating from or residing in countries where scrapie occurs are scrapie free and acceptable sources of materials for manufacture of FDA regulated products intended for injection or implantation.

Most of what follows in my talk and those of the invited speakers address estimating the risk of the TSEs of sheep and goats for human health, that is, to assess potential exposures and the effects of those exposures.

As I mentioned, Professor Almond will address BSE, and I will begin our consideration of the theoretical risk of scrapie by reviewing attempts to detect that risk.

Dr. Richard Race has agreed to speak with us here by telephone to review his classic studies with Carl Eklund and Bill Hadlow on the distribution of scrapie agent in tissues of sheep and goats, and share his thoughts on today's topic.

Diane Sutton -- has Diane come yet? Okay, good -- will speak with us about the prevalence of scrapie in U.S. animals and in other countries and then begin a discussion of efforts to mitigate risk by summarizing USDA regulations and programs.

John Honstead from our Center for Veterinary Medicine will discuss the FDA ruminant protein feed ban, our major effort to stop food borne spread of ruminant TSEs.

And then Lisa Ferguson will outline additional measures to consider.

Finally Kiki Hellman will summarize the day's events and deliver the final charge in question.

We in the FDA are aware of no convincing evidence that scrapie, unlike BSE where the evidence though incomplete is highly persuasive, has infected humans. Individual case reports of Creutzfeldt Jakob disease have been sufficiently dramatic to convince us that human pituitary hormones, corneas, contaminated electrodes, dura mater were the sources of infection, but except for a few anecdotes, there have been no comparable case reports linking scrapie to Creutzfeldt Jakob disease, although people have kept, killed, and eaten sheep during the more than 200 years that scrapie has been known.

Through the 1960s, scrapie research facilities both in the United Kingdom and here observed very few precautions in handling infected materials, and there were no reported transmissions to staff. Scrapie appears very unlikely to be a major source of CJD.

Creutzfeldt Jakob disease has occurred in at least four lifelong vegetarians, and the incidence of CJD in scrapie free Australia, which is shown here for the year 1993, is no less -- actually in 1993 probably because their surveillance program for CJD began in that year, the incidence was substantially higher in Australia than it was in the five European Union countries listed here.

And note that many of the patients with CJD in Australia had never left the continent of Australia.

Epidemiological surveys and case control studies are sometimes invoked as supporting the hypothesis that scrapie or some other TSE of animals may be a source of known infection. I reviewed six major case series and eight case control studies of CJD beginning with Dr. Roos' series in 1973 through this year, and if I missed some, I apologize.

For each series or case control study, I tried to summarize the conclusions about occupational exposures, other exposures to animals, dietary exposures, and surgery or trauma. A whole variety of intriguing associations were reported, and obviously we don't want to review them all this morning, except to remark that most of them were found in one study and then never seen in any of the other studies.

I'm going to rush through the next nine slides to show you a few of those associations and simply to demonstrate that none was observed consistently.

For example, in Dr. Brown's French survey, in the first approach, urban residence was an intriguing association noted, although it disappeared in a further study, and no association with exposure to sheep, goats or their products was noted, not only in that case series, but in any case series.

Case control series yielded the most associations. The earliest suggested some possible link to pig brains, although oysters were even more impressive, a very puzzling association.

In a study in which I participated, Zored Davanipour found more than 20 significant associations between Creutzfeldt Jakob disease and a variety of exposures. There was a slight excess in the consumption of roast lamb, but that was no more than for a variety of other foods, and you'll notice that pork products were even more highly associated with patients with Creutzfeldt Jakob disease.

A similar case control study in the United Kingdom found no increase in exposures to meat, brain, or sheep in Creutzfeldt Jakob disease cases compared with controls, although a variety of other statistically significant associations were noted. The authors of that study modestly concluded, and that presumably applies to the other case control series, that it is unlikely that the few positive findings are related in any way to the etiology of Creutzfeldt Jakob disease.

When over 100 factors are examined, some statistically significant results are to be expected by chance.

One study, the second one on this slide, pooled and reanalyzed the three previous studies that I mentioned, found a slight increase in exposure to cows and sheep, but no association with eating raw meat or animal brains.

Last year a large, collaborative case control study in the European Union found no significant association with eating raw meat or brain or any food or occupation.

Finally, a carefully matched Australian case control study just published found associations with work and residence on farms or truck gardens and work in butcher shops, but there is no scrapie known in Australia.

So, in summary, these studies have really not revealed any consistent association. This presumably, the findings noted presumably resulted from biases, respondent bias, recall bias, because it's really not possible to match carefully the controls with the cases. The cases, of course, have died, and they're always surrogate respondents.

The studies also suffered from a low statistical power and from the multiple comparison effect that we noted for the U.K. study. When you ask so many questions from so few people, there's a high probability of getting significant differences by chance.

So general conclusions from the case series and case control studies are that there was no previously unknown risk factor for CJD common to any of the several studies, and that exposures to sheep and goats and their products were not identified as a risk factor.

A small number of experimental studies conducted by Joe Gibbs at the NIH may be relevant here. Four chimpanzees inoculated with two strains of scrapie many years ago are still alive more than 30 years after inoculation. Can we conclude from that that there is an anthropoid species barrier to infection with a scrapie agent? It would be comforting to think so, but there remained uncertainties concerning the theoretical risks to humans from exposure to scrapie.

Perhaps most troubling is that BSE is suspected to have originated from some strain of the sheep scrapie agent. Multiple strains of scrapie agent exist, and some of them might be transmissible to humans or they might become so after passage through animals.

The negative experimental studies with scrapie in chimpanzees were very small, and used only two strains of scrapie agent, while several species of monkeys inoculated with scrapie agents by intracerebral and peripheral and oral routes developed a TSE 17 months to 20 years later.

So there cannot be an absolute primate species barrier to infection with all strains of the scrapie agent.

The weakness of the epidemiological studies I've mentioned, and human exposures to sheep-derived, goat-derived, injectable and implantable products have been much less frequent than exposures to food so that an association there would be even harder to detect by a case control study.

And it's hard to be sure of how an infection is not acquired when you don't know how it is acquired, at least in most cases.

There are regulations, policies, and practices of the U.S. government that should reduce opportunities for human exposure to TSEs in sheep and goats. In 1997, the Animal, Plant Health Inspection Service of the USDA issued an emergency amended regulation that restricted importation of ruminants, and that's ruminants, not just cows; that's all ruminants and meat products from ruminants, not only from BSE countries, but also from countries of unknown BSE status, and they also removed previous exceptions that had allowed imports of some meat and meat products from BSE countries.

In November of 1992, the FDA sent a letter to manufacturers of dietary supplements recommending that they reformulate their products using neural or glandular tissues assured to be BSE or scrapie free.

Then in December of 1993 and in 1994, the FDA sent letters to manufacturers of drugs, biologicals, devices, animal products, and FDA regulated animal products, and manufacturers and importers of dietary supplements and cosmetics recommending that bovine-derived materials from BSE countries not be used. Scrapie was not specifically addressed.

FDA's most important action has been in the form of regulation, the ruminant feed ban of 1997 that John Honstead will discuss, and note that a successful ruminant feed ban would reduce food borne spread of scrapie as well as of accidentally introduced BSE.

Other U.S. government policies and practices are also intended to protect humans from exposure to animal TSE. The USDA has a voluntary scrapie flock certification program that we'll hear about. The Food Safety and Inspection Service has inspections. Agricultural Research Service has diagnostic and research programs, and there are other activities.

Within the FDA, in product reviews, efforts are made to assure a source is free of all extraneous agents, including all TSE agents, regardless of whether the agents are known to be human pathogens or not, and at least in the Center for Biologics, there is a statutory requirement for that.

And let me close by suggesting possible actions that might be considered to reduce the theoretical risk to humans from scrapie in sheep and goats, and these, of course, are simply for discussion purposes. You may well think of others.

First, scrapie free regions might be determined in countries that otherwise have scrapie. New flocks might be derived from known scrapie free progenitors. For production of implantable, injectable materials, closed flocks might be maintained. Satisfactory feeding histories for sheep and goats might be presented; that is, certifying that they were never fed mammalian protein.

Sheep might be bred selectively either for susceptibility to reveal scrapie in a flock or for resistance to reduce the likelihood of infection. Intensity of surveillance should almost certainly be introduced. Sentinel animals might be kept in flocks. There might be routine PrP testing in the brains of old animals, animals found dead, and all disabled animals. And of course, in general we think that the surveillance for TSEs in animals in the United States, including those in contact with sheep and goats, should be introduced.

But we feel that surely even in countries with ruminant TSEs, like this goat with scrapie, it should be possible to assure clean sources of sheep and goats to prevent transmission of human disease like this.

I thank you. I haven't used the 50 minutes allotted, and if there are any questions that I can answer, please feel free to ask.

CHAIRMAN BROWN: Thank you, Dr. Asher.

Questions for Dr. Asher?

All right. Then -- yes.

DR. PRUSINER: There's a page in here, and I'm worried that we come away with the wrong conclusion. I thought it was a very nice presentation. There was one point. Let me see if I can find it now. Here is it.

DR. ASHER: Which page, Stan?

DR. PRUSINER: It's on these slides that say uncertainties concerning theoretical -- twenty-eight. Thank you.


DR. PRUSINER: I can't see that with my glasses.

DR. ASHER: Uncertainties concerning.

DR. PRUSINER: Right. So it says sources of infection and sporadic CJD are unknown. I mean I would argue all of these epidemiologic studies, I think, clearly argue that sporadic CJD are -- what people are now calling classical CJD -- don't come from infection. Would you agree with that?

I don't understand the Point 6.

DR. ASHER: Don't come from infection? No, I think that the whole issue is still open. They certainly are associated with an infectious agent, and when subsequent subjects are exposed to them, they become infected. I don't believe that the issue is settled at all.

I mentioned the possibility, which is certainly possible, but certainly not demonstrated, that the infection is of endogenous origin, but more than that I wouldn't be prepared to say.

I believe that rigorously the cause of sporadic CJD has not been -- the source of sporadic CJD has not been determined.

DR. PRUSINER: Okay. I just want to make it very clear from my point of view that this is not a scientifically defensible point of view at this point. That's my --

DR. ASHER: I don't think any point of view at the moment is scientifically defensible. I think it's simply not known.


CHAIRMAN BROWN: Can we resolve the issue by noting that the source of infection can be the brain itself?

DR. PRUSINER: It's not going to be resolved. I just want to make the point --

CHAIRMAN BROWN: No, but I mean is that -- is that -- if we accept the fact that source of infection does not necessarily imply an external source --

DR. PRUSINER: That's fine.

CHAIRMAN BROWN: -- then, you know, then I think we're talking the same language.

DR. PRUSINER: That's fine.

DR. ASHER: I don't believe that an external source -- that the state of knowledge today permits an external source to be excluded.


DR. ASHER: I don't think this is the place to have this kind of discussion, but it is important that these differences, I suppose, that these differences be aired.



DR. ROHWER: I don't want Dr. Asher to have to stand alone on this either, and I agree with him fully.

CHAIRMAN BROWN: Maybe we should have what, a seminar, two, three hours?


CHAIRMAN BROWN: We have time, don't we?

DR. ROHWER: No, we could have a vote.


CHAIRMAN BROWN: That'll take too much time.

Thanks, Dave.

We'll now proceed to the next speaker, who is Professor Almond from Pasteur-Marieux Connaught in France, whose title is "The Potential Risk of Introducing BSE Agent into Sheep and Goats in Europe."