DR. ROHWER: Can I begin by just asking for a clarification? These questions are both couched in terms of changes of existing policy, and from what I heard today in terms of FDA policy, the only policy that bears on this is the feed ban. All the other policies are USDA policies.

And is there something I'm missing here?

CHAIRMAN BROWN: I think probably not. Will you say yea or nay?

That is correct. The FDA, aside from the feed ban policy, feed ban regulation, has no current strictures.

DR. HELLMAN: Yes. We have no consistent FDA policy in place with regard to sheep and goat derived material. That's why we brought it to the Committee. We're relying on the policies of the USDA at this time.

DR. DETWILER: Just one further --

CHAIRMAN BROWN: Linda.

DR. DETWILER: -- clarification. So is there anything in your BSE thing that -- so it's totally exempt, sheep and goat; is that correct? I just want to make sure.

DR. HELLMAN: The only one is the letter to the manufacturers of dietary supplements that Dr. Asher mentioned this morning. That did specify ovine. All the other letters specified bovine only.

CHAIRMAN BROWN: That just reminds me to say for the public record I would love the FDA to convene this Committee at some date before my relinquishing the Chair to consider the whole matter of herbals and nutritional supplements.

DR. HELLMAN: That would be interesting.

CHAIRMAN BROWN: Yes.

DR. HELLMAN: I would welcome that. I don't know about others.

CHAIRMAN BROWN: Okay. That was an aside. Yes.

DR. CLIVER: Please stay up there.

DR. FREAS: Do you want to just sit down here, Dr. Hellman?

DR. CLIVER: Or somewhere.

DR. HELLMAN: Fine.

DR. CLIVER: Whatever is comfortable, but running back and forth is going to -- okay. My question was going to try and achieve some perspective on this.

To achieve a year's supply of, say, the largest volume product that's on this list, how many animals have to die, and what is the probable shelf life of the materials?

DR. HELLMAN: I don't really think we can answer that. I don't know how many animals are used to manufacture sutures, for example, and I have no clear idea of what the shelf life of sutures would be, but I would imagine it would be fairly long.

DR. CLIVER: Okay. My point is are we looking at a situation where we couldn't grow enough animals in Australia and New Zealand or couldn't produce the product somewhere and stockpile it for a long period. Are we running out of something urgently?

Is there anything that would drive us to try and develop an absolutely scrapie free animal population in the United States as sources of these, given that we could probably get five years ahead of ourselves and then do all of the quality assurance we wanted to insure that nothing that had to do with TSE was in those products before they were released for use?

These are things we have to think about.

DR. ASHER: Yes, all of the products for injectable and implantable use appear to be relatively limited in their use, and I suppose a legitimate solution that could be suggested would simply be to accept that the United States will be contaminated with scrapie forever, and that all animals must be considered suspect at all times.

It seems to me that there are less extreme solutions to the issue that might be considered.

CHAIRMAN BROWN: One of the products that would not have a long shelf life, I guess, I think you showed vascular grafts. That would be at least one product that couldn't be stored --

DR. HELLMAN: Yes.

CHAIRMAN BROWN: -- for any length of time, but I don't know of any others.

DR. CLIVER: They don't freeze them or anything?

CHAIRMAN BROWN: I don't think grafting is something -- not vascular grafts, but that's just one of many, many products.

DR. DETWILER: A comment on that, versus that drastic. I just want to point out that there are a number of companies in the country that have gone to great lengths to create these scrapie free flocks, and without naming them, I mean, they've imported animals from Australia and New Zealand and put them into the program, monitor, monitor the deaths.

So if you went that drastic, okay, test everything that dies; if you went that drastic, you would preclude or exclude these companies that have spent a lot of money to assure that they have scrapie free flocks in the country, and I think that would be unduly harsh for the ones that have taken that means.

The other point that I'd like to make, and I know Dr. Ferguson showed a slide about Australia and New Zealand and a lot of brains they've looked at. However, you know, we've been criticized in the U.S. for cattle. We looked at 7,000 out of, you know, an adult population of 40 million. They're less than about 2,000, okay?

Again, you're doing -- some of that is random source, but flocks that are monitored under such stringent things that everything that dies get a necropsy is in my mind scientifically more. You've got them more under scrutiny than from countries that you're random sourcing, although Australia and New Zealand, I don't want to say that they do.

There have been questions about even their earlier seed stock that came in because some of that did come from, you know, countries of Europe.

CHAIRMAN BROWN: What Linda is saying, in a word, is if the Committee suggests draconian measures, they might be so extreme as to completely undermine the flock certification program in this country, which is a point to think about.

Stan?

DR. PRUSINER: I would like to elaborate on what Linda said. I think she's absolutely right. I'm more comfortable with doing surveillance and doing assays and really understanding what's going on with a limited number of sheep in the United States than I am with believing that Australia and New Zealand are scrapie free.

I want to go on record and say I don't believe it. I've never believed it, and I still don't believe, and I don't believe that you can take 100 million sheep or 50 million sheep and tell me that these animals are free of scrapie.

This comes back to my little spat with David Asher about --

(Laughter.)

DR. PRUSINER: No, I'm serious. I'm coming back to this because it's a very important point.

You can believe, as David believes, that all these diseases happen by exogenous infection or you can believe as I believe that there are these sporadic cases of CJD that we see in the United States, represent the spontaneous conversion of PrP-c into PRP-scrapie or a somatic mutation, and I would argue that happens in sheep all the time.

And I would argue that for whatever reasons, whatever the culture is in New Zealand among sheep farmers than it is in Australia, we're not seeing cases of scrapie as they appear.

And so I'm much more comfortable having well monitored flocks of a limited size and determining that these animals to the best of our methods that are available at any given point in time are free of scrapie than I am with believing that just because the stuff comes from New Zealand or Australia that it's better.

CHAIRMAN BROWN: Yes, to introduce a slight modification from the chair, I think that that's a decent point, to be more comfortable with a heavily surveyed flock. I would think that if scrapie were existing endemically strictly as spontaneous conversion disease, that it would not be expected for flocks which are scrapie free within a year or two suddenly to come down with scrapie affected sheep after the introduction of a scrapie infected sheep into the flock.

That smells like horizontal transmission to me.

DR. PRUSINER: No, I don't mean to say that there isn't horizontal transmission. I believe in horizontal transmission once a case starts, but I'm just saying that there are spontaneous cases that begin that way, and then the infectious mode takes over, and for reasons we don't understand at all, scrapie is a much more infectious disease, a much more infectious prion disease than CJD is among humans.

CHAIRMAN BROWN: Okay.

DR. PRUSINER: I'm in agreement with you.

CHAIRMAN BROWN: Yes. How would we explain the fact that there just isn't any recognized reported clinical scrapie in Australia? A monstrous conspiracy?

DR. PRUSINER: I think what happens is that in countries where there has been scrapie, a spare amount of it, you see this horizontal transmission going on, and the spontaneous cases represent stochastic processes where it's a relatively infrequent event, and if it's happening anywhere like the number with people, okay, at one per million in older people, age 60, age 70, many of these sheep are going to be slaughtered before that, if we ever see it.

So these are relatively infrequent events, but that doesn't mean that there aren't sheep that are harboring prions for much of their life and we just don't see the disease.

CHAIRMAN BROWN: Yes. Yes, go ahead, Dean.

DR. CLIVER: Well, this is what I was hoping wouldn't happen to the discussion because what it essentially says is that even though maybe we're only dealing with a few sheep here, there's no such thing as a scrapie free flock no matter what you've done up to the point where you derive this material, and for expediency's sake, I wish we wouldn't get off on that because what I asked was simply to define are we talking about a few hundred sheep, a few hundred thousand sheep or how many sheep a year do we have to procure that are as scrapie free as we can possibly guarantee them to be to be able to meet this demand, and I kind of think that's where we ought to be going with this discussion rather than the possibility that somehow or other out there in the outback in Australia there's a scrapie sheep that's being eaten by dingoes or something like that and will never be detected.

CHAIRMAN BROWN: But with a view towards identifying a source or sources for the safest possible product. I mean that, I think is where you're -- no, no, no. I know you're not going to dictate the terms of safety, but the point of the question, to find out what numbers of source animals would be necessary to satisfy a supply, a need, that question implies that, therefore, you would like to kind of focus the sourcing in a way that would make you most comfortable as to its safety rather than just have a kind of open door policy; is that correct?

DR. CLIVER: Yes. All I'm thinking is the degree of rigor that can be applied depends to some extent, one, on how many sheep are we talking about and, two, can we prepare the product well in advance to cushion ourselves against sudden surges in demand and also to allow plenty of time for quality assurance testing before any lot is released.

CHAIRMAN BROWN: Yes.

DR. CLIVER: This is the way FDA operates.

CHAIRMAN BROWN: And FDA cannot now furnish those numbers. So we're going to have to at least take our votes without the numbers.

Bob.

DR. ROHWER: First, I'll begin with Dr. Cliver's point, and that is that it depends a lot on what you're talking about. There may be very high exposure parenteral products or devices that are developed that are used on a very small scale such that the sourcing needs can be met by a closed flock, and I believe that it is possible to create closed flocks or herds of animals that are very, very safe.

But, on the other hand, when you have something that's made in bulk, you may have to go to the bulk slaughter in order to get enough of it to satisfy the mass quantities that are required for your particular market, in which case people may have to go offshore to places like Australia and New Zealand to get something that meets a higher standard on a higher scale.

I agree with Stan. I'm not convinced either that surveillance is good enough in Australia and New Zealand to know that they've never had it or it's not happening at some low rate there, but it's clearly better than it is here.

Finally though, in terms of the certification program which is what I really wanted to address my remarks to, I think that's a fine effort on the part of the USDA to try to prevent the spread of scrapie in this country and perhaps I would hope that ultimately their goal was to eliminate scrapie by this program.

I know that the stated intention earlier when it was first formulated was that there'd be enough economic incentive for joining the program that it would force people out perhaps who were operating at a lower standard, and eventually it would evolve that the entire sheep husbandry program would be brought into this certification program and we'd get rid of scrapie that way.

At two percent, I don't think we're even close or maybe even moving in that direction, but the other thing about the scrapie program as formulated by the USDA is that it's directed towards food safety and not parenteral uses of the products from these animals, and personally I think that the FDA should have their own standards and should develop their own standards for sheep for products that are going to be used parenterally in human beings and for human health from these animals, and I think they have to meet an even higher standards, and I would think that the minimum standard would be a standard more in line with the types of quarantine and isolation that the Australians and the New Zealands are employing in their programs to protect their countries from the import of scrapie.

And those same types of programs could be instituted here for developing closed herds with very high level of security starting perhaps with imported stock from New Zealand and Australia as a beginning.

CHAIRMAN BROWN: Peter.

DR. LURIE: I guess I'm still left with a number of questions about the devices themselves, which are really the issue here. How commonly are they used? What are the alternatives to them?

Some companies evidently are able to source these implantable and injectable products from non-BSE countries, setting aside scrapie for a moment. I feel like we're missing a lot of information about the production of these things. Can you fill me in at all?

DR. HELLMAN: Well, I can speak about the sutures and the vascular grafts to some extent. I'll start with the vascular grafts.

Both bovine and sheep collagen are used for vascular grafts. We have one product. With regard to the sutures, there are 14 manufacturers of cat gut sutures, but I understand that there are other materials that were used as suture material in addition to the "cat gut" sutures.

I can't tell you how widespread the usage is compared to the other forms.

With regard to the biologicals I believe David can speculate about that. I don't believe either of us have too much information about the drugs.

DR. ASHER: Yes, these are all limited, very limited use products, and the issue at least at the moment would not be shortage of supply offshore. What we had hoped to get was some idea about policies that would make it possible to consider safe sourcing from any country, of course, but particularly from the USA.

But could these all be sourced at the moment from Australia and New Zealand? Quite possibly.

CHAIRMAN BROWN: Bruce, you had your question?

DR. EWENSTEIN: Yes. I just wanted to bring the Committee back to the kinds of components that were mentioned at the very beginning of the day, and these include components that are active ingredients in drugs or biologics directly versus those that are used in the manufacturing process.

Now, I mean, I'm not sure how much of a distinction we should make, but it seems that the material that's used for affinity chromatography in the manufacturing process would be of less risk if one had to draw a line somewhere than those that are going to be directly injected into patients.

CHAIRMAN BROWN: Dave.

DR. ASHER: Yes, and there's a precedent for that view in this Committee, which looked at the use of human blood derivatives as manufacturing process reagents and felt less concerned about the use for manufacturing than when the same ingredients were used as excipients or active ingredients.

CHAIRMAN BROWN: Ermias.

DR. BELAY: I'm not absolutely clear about the current practice. Where is this product sourced from? Are they all coming from within the country or are they imported from other countries?

And if they are imported, where are we importing them from?

DR. HELLMAN: You're asking about the suppliers of the materials that are used in the manufactured products. I can't tell you who the suppliers are. If I had to venture a guess, I would say that it could probably be sourced from the U.S. or it could possibly be that Australia and New Zealand, if we went to a scrapie free source, could supply it as well.

But I just cannot give you any details about the suppliers.

CHAIRMAN BROWN: Yes, in defense of the non-information coming from the FDA, if you don't have any regulations, there's no point in knowing where things are coming from. So it may be that we will not be getting answers to many of the questions that are occurring.

Raymond.

DR. ROOS: Just talking about sheep and scrapie, it is true that we have no data that suggests that scrapie can be transmitted into humans and to prion disease.

Nevertheless, I think it would clearly be valuable from a public health point of view to have scrapie free reagents for, for example, gut as well as vascular grafts, if we could achieve that.

We're told that Australia and New Zealand have very low incidence of scrapie. On the other hand, I do agree with Linda. I think it may be at this point we should promote and encourage scrapie free flocks here.

So I'm wondering whether one couldn't make regulations encouraging at least initially in use of certified flocks in the United States that are scrapie free or scrapie free countries or other countries that have a certification program like ours do with respect as -- for their use for products, such as gut and vascular grafts.

With respect to bovine derived products for the gut and vascular grafts and so forth, it seems to me we kind of addressed this at a previous --

CHAIRMAN BROWN: No, this isn't the question.

DR. ROOS: Okay. I get a little confused.

CHAIRMAN BROWN: No, it's scrapie. It's sheep and goat derived.

DR. ROOS: Okay. Sheep and goats.

CHAIRMAN BROWN: Sheep and goat derived products either from countries that have BSE or countries that don't.

DR. ROOS: Well, what I'm saying is that it seems to me that we should promote the certification program here and allow use of material from these certified flocks, as well as other countries that have comparable certifications or scrapie free counties.

CHAIRMAN BROWN: Yes, and that's a good point. We've not obliged to say, "Here are nine possibilities. We pick number three." What you just said, it's not an either/or. It's, yes, we might want to recommend sources for these materials from animals that are as likely or which are likely to be scrapie free in one way or another, whether it's certified or whatever. I mean that would be a kind of a position that we would suggest that the FDA take, that they take care to get scrapie free sources.

DR. CLIVER: In that connection, I think that another item of policy is that the source of the raw material be determined. We're being told now that that's not currently done, and so if you're going to stipulate, then you've got to have some kind of a reporting stipulation built in as well so that when a lot is set up for approval that you know where the raw material came from.

Additionally, it seemed as if from what we were just discussing, that maybe the most ephemeral product was this vascular transplant thing, and then I think I heard something about reconstituted collagen, and that sounds rather like what they do to make sausage casings these days, which suggests to me that maybe the shelf life of these isn't that bad either.

DR. DETWILER: One comment.

CHAIRMAN BROWN: Oh, Kiki, did you want to respond to that?

DR. HELLMAN: Yes. I just wanted to say that devices can be regulated under the 510(k) process or the pre-market approval process. Oftentimes for products that are through the 510(k) process, we do not necessarily know the suppliers or the source because it's not necessarily required. For those under the PMA process, which would be vascular grafts, we would know the supplier.

So it depends on the provisions of the regulations as to how much information we can require of the manufacturer. However, is a decision is made that even for sutures it's desirable to know the source supplier, then there may be ways that we could work with that.

CHAIRMAN BROWN: Yes, Dave.

DR. ASHER: Yes, for biologicals the source has to be known. When I was -- the point I was making is that there was no formal policy concerning the source.

So, for example, recently the sponsors of a product found it convenient to satisfy concerns about safety by sourcing from Australia or New Zealand rather than bothering to try and figure out what to do in the United States.

It was for that reason that we thought it would be useful to consider criteria that would assure a safe source in some way other than going to a putative scrapie free country.

CHAIRMAN BROWN: Linda?

DR. DETWILER: One of the things I'd point out is that currently the USDA prohibition on the importation of most ruminant products would prevent a lot of these from coming in, especially in like the casing form type because that's specifically in the regs

Where we get into problems, if it wasn't labeled as such that somebody would recognize it as ruminant material, and then there's also cases where it would come under special permit, and most of that is for some scientific or research purpose.

DR. HELLMAN: May I? We just did receive some more detailed information about the drugs, and the approved drugs have sheep wool from New Zealand. There are two of them. Of the investigational drugs, we're considering only injectables and implantables. One sources is from Argentina. Two sources, from Europe, nonspecified which country.

CHAIRMAN BROWN: You have a runner going back and forth to home base hot off the press?

DR. HELLMAN: Carol Vincent just handed me this.

CHAIRMAN BROWN: Okay. Peter.

DR. LURIE: Kiki, if I can just rephrase what you said, what I think I heard you say is that there are medical devices being implanted in people in this country and you don't know what the source of it is in some cases?

DR. HELLMAN: I did not say that.

DR. LURIE: Can you correct me then?

DR. HELLMAN: What I said was that there are two regulatory modes, if you will. There are products that are 510(k) products, which means that they're rendered substantially equivalent to products that were approved for marketing before the medical device amendments came into practice.

Then there are products that are considered that both safety and efficacy must be shown and that you must have clinical data, and those are pre-market approval.

And for those types of applications, one certainly knows the supplier. For the others, since they are substantially equivalent to something that was marketed before the amendments came into effect, we do not always know the supplier, and it's up to the reviewer to find out from the supplier if it is a particularly sensitive product or it is made with particularly sensitive materials.

As, for example, when we had the BSE problem, we inventoried all of the products in the center with regard to their animal tissue of origin, and we then recommended, many times reviewers calling individual manufacturers, recommended that they consider sourcing from suppliers that did not have cases of BSE if, indeed, they were sourcing from a supplier that was using cows from a BSE country.

So in the latter case, we definitely know the supplier. In the former case, the 510(k), we don't always know the supplier. If there is a problem, there are ways that we can find out.

DR. LURIE: Okay. That's my point.

DR. HELLMAN: Does that clarify it?

DR. LURIE: Yes. That's not inconsistent with what I said. There are some devices in the 510(k) process for which you might not learn, perhaps because you choose not to, what the supplier was or from what country they were sourcing.

DR. HELLMAN: Certainly if there is a question with an adventitious agent that may be potentially infectious for the recipient, we take measures to assure ourselves of the supplier and the source material.

CHAIRMAN BROWN: Let me try something here, and that is this. For a little bit, could we refocus on just any missing information that would require -- that you would require before making a yes or no vote on these two questions rather than a discussion of what kinds of -- what kinds of different sourcing, you know, the details?

If there is anything that you would like to know in order to be able to say yes or no to the two questions, let's ask those questions and then take a vote, and then we can have lots of discussion about anything at all.

Bob.

DR. ROHWER: I would like to make a point before I make a vote because I think it would influence the vote. So this is not a request for information. It's just my opinion of vulnerabilities that I see in the scrapie flock certification program, which I would want to see rectified before those animals were considered closed enough and safe enough for the sourcing of parenteral devices or drugs.

And the main vulnerability I see in that program is the opportunity to introduce scrapie via new animals and new breeding stock, and I think that should be, for drug and parenteral use, it should be closed off. It should be genetics can be introduced by embryos and semen only, but you don't introduce new animals into a flock like that once you have it established.

And the reason I say that is that there's just too much history of scrapie showing up in strange places like pastures where scrapie has been before but scrapie free flocks have been put on those pastures. It's very, very hard to get rid of this.

The idea of introducing susceptible sentinels for monitoring scrapie also bothers me a lot because it seems to me like that's just asking for it. There's the opportunity to introduce an animal that's got scrapie without knowing it.

The other things that need to be addressed, of course, are feed. It should be specified that only vegetable feeds are allowed for a flock that's going to be producing medical material.

Another point is isolation. These animals should be isolated from all other contacts with sheep and probably bovidae and cervids.

And those are the three main vulnerabilities I see in the program right now.

CHAIRMAN BROWN: And these are details about -- I don't think --

DR. ROHWER: Well, they're details --

CHAIRMAN BROWN: -- they'll influence the yes or no. What you're saying is it's a good idea.

DR. ROHWER: No, it influences my vote because what I -- because I think these things are needed, I have to say, no, I don't think -- well, I can't remember if this is a negative.

I think that the FDA does need to set their own standards.

CHAIRMAN BROWN: Okay.

DR. ROHWER: They shouldn't ride on what they've got.

CHAIRMAN BROWN: Right, and that would be a yes.

DR. ROHWER: A yes. Right, okay.

CHAIRMAN BROWN: I may try and deceive you later depending on, you know, how --

(Laughter.)

CHAIRMAN BROWN: Larry.

DR. SCHONBERGER: I just want to clarify again. The current safeguards, do they prevent the sutures, the vascular grafts from coming from sheep or goats in BSE countries because of the ban that currently exists?

I thought I heard that you were saying, Linda, that it may not even be recognized as a ruminant product possibly or could get miss --

CHAIRMAN BROWN: Yes, Linda. What does the USDA allow in within the context of these questions?

DR. DETWILER: Actually --

CHAIRMAN BROWN: Or maybe I should say what do they exclude.

DR. DETWILER: Yes. Actually I'm going to kick that to my import-export colleague over there.

CHAIRMAN BROWN: Okay.

DR. DETWILER: Because she would have the real specifics.

CHAIRMAN BROWN: Ultimately we're going to come down to deciding because the FDA is our host what we recommend to the FDA, and what the USDA does is, in fact, irrelevant to what we're going to recommend. It really is, but it would be very nice to know what the USDA does not allow presently.

DR. FERGUSON: Okay. I think it might be easier for me to say what we will allow in, and that's as the reg is written, and as the reg is currently written, we have exemptions. Essentially it is saying no ruminant or ruminant products from all of Europe, and the exemptions are what we have determined, and they are widely accepted not to be a risk.

CHAIRMAN BROWN: And those were the ones that John showed?

DR. FERGUSON: Those are --

CHAIRMAN BROWN: Gelatin, milk, blood. No?

DR. FERGUSON: No.

CHAIRMAN BROWN: All right.

DR. FERGUSON: That's their -- some of them are the same, but some of them are not.

CHAIRMAN BROWN: Okay. What are yours?

DR. FERGUSON: Milk and milk products, hides and skins, semen, tallow, and then certain blood products used in microbiological media, you know, where you've got -- it's essentially a processing agent, and it's not coming into direct contact.

CHAIRMAN BROWN: Are any of these products under the purview of the FDA? That is, you've described a number of products or a number of items, materials, some of which may not be relevant to an FDA guidance.

DR. FERGUSON: Well, I think where a lot of the confusion comes in, and I think this is what Linda was referring to, is how these products are manifested when they come. You know, it's in a container or pallet that's arriving at the port, and our inspectors, many of them are very good, and they know how to flag these things on a manifest or on a declaration as a ruminant product, but some stuff they very well might not know, and that would be some of these more derived antibodies, that type of stuff that might be a bit iffy.

Now, we think we're getting most of them, but that's where the lines cross, and where it gets confused.

CHAIRMAN BROWN: That is just one more layer of confusion. I mean if I'm -- that's not exactly what I asked, but now if you're talking about incompetent inspectors who look at a pellet when it comes in the port, and don't know what it is, good Lord, huh?

DR. DETWILER: No, Paul, wait. I've got to correct that because it's a pallet, and like say a drug comes in, okay? A manufactured drug comes in at the port, and it doesn't specify that it contains sheep or goat material. It's labeled as whatever the name of the drug is.

Well, no way, unless you had some kind of ingredient, would they know that that's how it was manufactured, and that's where we can have it where they have are reg that approves that drug with this sheep or goat material in there, and theoretically our reg should keep it out, but there's no way to know that's what was in it.

Does that clarify it more?

CHAIRMAN BROWN: Well, it clarifies it to the extent that I'm a little more uncertain about import screens, shall we say? I mean if a pallet is coming in and it contains -- I mean, and let's say it's -- I don't know -- it's labeled what, albumin, without specifying that it's albumin from a cow that died with a neurological disease in England. No, that would concern me a great deal.

DR. HELLMAN: If I may.

CHAIRMAN BROWN: Kiki.

DR. HELLMAN: Of the items that Lisa tallied off, the ones that would find themselves in FDA regulated products would be tallow derivatives and those for microbiological media, if they were for in vivo use. And when we had our Advisory Committee and we discussed tallow derivatives --

CHAIRMAN BROWN: Yes, Yes.

DR. HELLMAN: -- if you recall, we considered that with the processing that the tallow would have to go through, we needn't worry, quote, unquote, about tallow derivatives.

CHAIRMAN BROWN: Yes, Yes.

DR. HELLMAN: So it's the microbiological media if it finds itself into an in vivo biological.

CHAIRMAN BROWN: Right. So, I mean, this is beginning to clarify things. Of the list that you gave us, tallow, which the Committee has already considered and the FDA has our recommendations on it, and the other one was microbiologicals did you say or biologicals? What?

DR. HELLMAN: Elements for microbiological media.

CHAIRMAN BROWN: Microbiologicals.

DR. HELLMAN: And if -- if -- if the microbiological media is used to manufacture biologicals for in vivo use, then that would be a consideration. So from that list, that's probably the only one of concern.

CHAIRMAN BROWN: Right, and so the microbiologicals could come in on a pallet rather than a pellet and not be specified as to source, that is to say, coming from a ruminant?

DR. DETWILER: Because Carol Vincent just told me that one of the things is doxirubicin.

CHAIRMAN BROWN: Yes.

DR. DETWILER: And that would be one of the examples that that's how it would come in, labeled "doxirubicin."

CHAIRMAN BROWN: Okay. Without specification as to source?

DR. DETWILER: Well, I don't know with FDA -- with labeling, but that's possible, yes, for us.

CHAIRMAN BROWN: Is that right? Doxirubicin is a wool derivative?

DR. ASHER: Yes. It contains a component that's noted to be extracted from wool, and we were less concerned about wool than we were with things like tissues.

CHAIRMAN BROWN: Okay. Other comments? Ray. Oh, excuse me. Why don't you go ahead?

DR. FERGUSON: Yes. Let me just add a couple of additional clarifications. One that Larry asked me here kind of on the side and just to clarify, casings and collagen, that type of stuff is restricted under our current regs You know, it is prohibited.

Then also the point where you were using the example if something came in and it's labeled as albumin. That would be flagged for our inspectors, and somebody would be asking, you know, "Well, what is this? Is it bovine serum albumin?" They would be querying for further questions, you know, and a determination would be made.

So those types of things probably would be caught. It's the finished product, doxirubicin, coming in, you know, in a container that would be an issue.

CHAIRMAN BROWN: Again, further questions that will allow us to make yes or no votes on the issue of whether we want current practices, we recommend current practices either be left intact, and the current practices essentially are carte blanche. That is, there are no regulations, or whether we would recommend that some kind of oversight regulations be instituted?

Bob.

DR. ROHWER: A clarification. So if something like doxirubicin is imported and it goes into an FDA regulated product, the manufacturer nevertheless has to identify the source of the doxirubicin to the FDA, do they not? So you will know.

DR. ASHER: Yes. It's from New Zealand.

CHAIRMAN BROWN: Ray?

DR. ROOS: Yes. I hate to beat this to death, but so just getting back to gut sutures and vascular grafts, could those be received from BSE countries, sheep derived, and escape our scrutiny at the moment?

DR. FERGUSON: No, they really couldn't. Those are controlled under ours. We have informed our inspectors of specific things like that. So, no, those probably wouldn't.

CHAIRMAN BROWN: Would the Committee like to just take five or ten seconds to see whether they're prepared to take a yes or no vote on at least one of the two questions, probably both, because they're similar, although they have one significant difference?

If the Committee is ready to vote, we can take votes or we can continue discussing, you know, things that we would recommend.

Yes, Barbara.

MS. HARRELL: I am very unclear as to whether or not we're talking about bringing in live animals.

CHAIRMAN BROWN: No.

MS. HARRELL: No, we're not talking about that. Just the --

CHAIRMAN BROWN: Products.

MS. HARRELL: Just the products? Okay. Already processed products, is that what we're talking about?

CHAIRMAN BROWN: I think, if I'm not mistaken, it could be, for example, it could be an intermediate to a finished product, or it could be a finished product. It's certainly not walking on four legs.

MS. HARRELL: Okay, and so the other part of that is what I think Lisa -- is that your name?

CHAIRMAN BROWN: Larry.

MS. HARRELL: -- has said, you know. She said that the casings and all of that is prohibited by USDA. Then that's something that we really could not even vote on because it couldn't get through because of USDA regulations. Right?

CHAIRMAN BROWN: Well, that's what they say, but there's no reason we can't put up a second wall if you choose to.

MS. HARRELL: So we could allow it even though it couldn't happen. Is that what you're saying?

CHAIRMAN BROWN: Well, that wouldn't happen. We're not saying we allow it necessarily. We're saying that if you did that, you would say that the FDA doesn't need to take any pro or con position on it in part because the USDA already has sufficient safeguards.

In other words, you could say -- you could say no. That is to say the FDA needs no further guidance, needs not to guide, and the result would be, if the product was already covered or the material was already covered by a USDA exclusion, it would be excluded.

If it wasn't or were not covered by a USDA exclusion, then it would continue to come in as it has always in the past.

MS. HARRELL: Okay. Lastly, I would like for the Chair to summarize his feelings about this.

CHAIRMAN BROWN: I'm sorry. Feelings about?

MS. HARRELL: About Question No. 1, our recommendation, as you did yesterday.

CHAIRMAN BROWN: Hmmm.

(Laugher.)

CHAIRMAN BROWN: I don't know, Barbara, if it's really appropriate for the Chair to do that. I can give you my own opinions. I would actually --

MS. HARRELL: You do that all the time.

(Laughter.)

CHAIRMAN BROWN: Touché.

(Laughter.)

CHAIRMAN BROWN: Well, you know, as I said, you get me as the Chair; you get the whole package.

(Laughter.)

CHAIRMAN BROWN: So I can do that very quickly. I think -- I think -- I think that scrapie per se remains a non-problem. I don't anticipate scrapie to be a problem as long as it stays scrapie. That's taking maybe a minimal risk because you never know what can happen, but historically scrapie simply is not responsible for CJD.

Therefore, I am not concerned about scrapie in any shape, form, or manner, even as an injectable.

With respect to the possibility that BSE may have already been or may be reintroduced into sheep, that concerns me a little more, and like the blood issue yesterday, there is absolutely no way at this time to know whether this has happened or whether it's going to happen, but I think it is an issue that is arguably dangerous, and so I would consider these two questions legitimately separately, and I would vote accordingly.

Robert.

DR. ROHWER: I think this first question is limited not to the U.S. situation, but simply to the import situation, and there I'd like more guidance from the USDA themselves. Do they feel comfortable with the restrictions and the surveillance that they have in place and their ability to monitor that they can actually cover this situation where they can prevent the import of products like this that might make their way into biologicals for parenteral use just by virtue of APHIS essentially? I mean, the barrier is APHIS here.

And I guess the other question that's not clear to me is that because manufacturers have to reveal to the FDA what they use in their products, isn't that something that the FDA already has, is a tool for monitoring this and controlling it? I mean do they need anything else?

Do we need to tell -- does the FDA want us to tell them that, indeed, we don't want manufacturers using sheep and goat products in parenterals derived from BSE countries? Do we need to say that explicitly? I would just assume that that's -- I would just presume that that's already de facto the case, that they can eliminate that without us telling them that.

DR. ASHER: I think it would be helpful.

CHAIRMAN BROWN: Stan?

DR. PRUSINER: I'm sorry, Kiki, to say that I think this is really unnecessarily convoluted, this question. I mean it's --

CHAIRMAN BROWN: It's Proustian.

(Laughter.)

DR. ASHER: A camel is a horse designed by a committee; is that right?

DR. PRUSINER: Is it not -- let me try to state this in another way, a simple way. I mean, isn't the first question asking us if we think that the FDA should argue that you can import sheep and goat products from countries where there has BSE been reported?

DR. HELLMAN: Yes, that's exactly right. Can we import sheep and goat derived material from BSE countries or can we -- can we use sheep and goat derived material from BSE countries for injectable or implantable products or not?

DR. PRUSINER: Right. So can't we vote on this now? This is -- this makes it a little bit more straightforward

CHAIRMAN BROWN: That's a nice clarification.

DR. HELLMAN: yes.

CHAIRMAN BROWN: I think we can.

DR. PRUSINER: Before we lose the thought.

DR. HELLMAN: Yes.

(Laughter.)

DR. DETWILER: Amendment, amendment, though. BSE affected countries, do you want to broaden it to "high risk" to keep concurrent with your cattle definition or keep it to those that just reported it?

CHAIRMAN BROWN: High risk.

DR. ASHER: BSE countries and status unknown countries.

CHAIRMAN BROWN: Okay. Is that clear? The question has become: Should the FDA allow importation of products or sources of products from sheep and goats residing in countries either with BSE or of uncertain status?

Larry?

DR. SCHONBERGER: Part of the issue here, as well, was that was the question I was just asking the Department of Agriculture, and they said at the present time this would not happen. So part of the issue here is almost interagency coordination, is it not, as to how -- right now the state of affairs is that this is not going to happen.

CHAIRMAN BROWN: At least for the products which the USDA current has a policy for.

DR. SCHONBERGER: Right.

CHAIRMAN BROWN: Which could change.

DR. SCHONBERGER: So part of our recommendation to them would be perhaps, yes, let's say, I don't want that to happen, but they need to coordinate --

CHAIRMAN BROWN: Well, I think we --

DR. SCHONBERGER: -- their efforts.

CHAIRMAN BROWN: Yes. Well, you heard yesterday blood. We've got three committees working on blood and CJD.

DR. SCHONBERGER: That's right.

CHAIRMAN BROWN: Two, you know, is a bargain. So why don't we go ahead and vote?

DR. SCHONBERGER: Yes, that's fine.

CHAIRMAN BROWN: I mean, I agree part of it is coordination. We can discuss that later.

David?

DR. BOLTON: I was with you right up until the change in the question.

CHAIRMAN BROWN: Okay.

(Laughter.)

DR. BOLTON: I thought I understood the original question.

CHAIRMAN BROWN: Okay.

DR. BOLTON: Now I'm not so sure I understand the second question.

CHAIRMAN BROWN: Stan, rephrase the question for us.

DR. BOLTON: Well, let me try to rephrase the first question. I thought that the original question was asking whether FDA should change their current policy --

CHAIRMAN BROWN: Right.

DR. BOLTON: -- without any specification one way or the other, and my understanding is the current policy really is no policy.

So now the question is are we adding an exclusion, "don't do this," or are we saying, "Now you're free to make a decision to do something," but not specifying what that something is?

CHAIRMAN BROWN: I suppose I should exercise direction, but I really don't feel like it. Why don't you --

(Laughter.)

CHAIRMAN BROWN: Why don't -- I mean Stan's rephrasing was a good one. It was nodded to by our FDA people. Why don't you again state it and see if everybody understands it?

DR. PRUSINER: I forgot what I said. Okay. So my understanding of this at this time is that FDA is asking us whether we think that there are products made from sheep and goats, where these animals originate in BSE countries, either known BSE or high risk for BSE, that these products should be imported into the United States.

DR. BOLTON: And a yes answer means they should be imported or a yes answer means they should not be imported?

CHAIRMAN BROWN: I think we can sort of say should the FDA be allowed to, and if you say yes --

DR. BOLTON: Import.

CHAIRMAN BROWN: Yes.

DR. PRUSINER: Yes, it's import; no, you don't want them to import it.

CHAIRMAN BROWN: That's right.

DR. ALMOND: But the confusion here --

CHAIRMAN BROWN: I think my executive is trying to write this down so we can -- he's not making any progress.

(Laughter.)

CHAIRMAN BROWN: Jeff?

DR. ALMOND: Isn't the confusion here arising from the fact that if the FDA were to -- or you were to say the FDA were to decide, yes, they could allow things in from sheep and goats in BSE countries, they would be in violation of USDA rules anyway so they couldn't do it.

CHAIRMAN BROWN: Jeff, this is not the source of confusion. It's one source, but it's not the source.

DR. HELLMAN: Well, if I may, that's exactly right, and the original question had whether the safeguards are sufficient. In other words, are the safeguards sufficient to keep out sheep and goat derived material from BSE countries or status unknown countries? And those safeguards are primarily USDA, or do we, the FDA, need something further?

CHAIRMAN BROWN: Before you --

DR. ALMOND: I think that's a very good way of putting the question, Chairman. To me as an outsider, that seems to encapsulate it. You have a layer of rules in place. They do keep out most things. Do you need an extra layer which is imposed by the FDA?

My only response to that, again, as an outsider, I think you do, and I think you can very easily come to that decision, but I still have a difficulty in concluding that you will be doing much because it's clear that you can identify things like sutures. It's clear that you can identify things like blood serum derivatives that go into bacteriological growth media that might then go into a manufacturing process that produces a biological.

You don't gain anything from the second one unless you also stop the importation of the biologicals that were manufactured outside the country that also used those materials in their biological production process, and I'm not sure that you do.

So you have to be careful whether these measures, even if you vote for them, have any teeth at all.

DR. HELLMAN: Very good. Thank you.

CHAIRMAN BROWN: It occurs to me that you could rephrase the whole question by saying: does the FDA agree that the USDA precautions are satisfactory?

I mean if we're going to get into this kind of an interagency dependency, one of the issues here, I thought, was consistency, and that the FDA wanted a policy that was consistent, and if you're going to allow the USDA to be your umbrella of consistency, it doesn't seem to me you've achieved the goal you set out to do.

Bob?

DR. ROHWER: When I asked the question explicitly, I feel the answer I got implied that the FDA would like to have the ability to ask a manufacturer what the source of their ovine tissues is, and I think we should give them that ability.

CHAIRMAN BROWN: Did you want to say something, Dave?

DR. ASHER: Yes, for biologicals, of course, and I assume for devices, we have the ability to ask now and sources of all material in all products are disclosed, unless I'm mistaken, and finished biologicals produced in a foreign country have to be made to exactly the same standards as products in the United States.

DR. ALMOND: So, therefore, you have all the powers that you need already.

CHAIRMAN BROWN: Well, that's the --

DR. ASHER: But we don't have a policy on whether the theoretical risk of scrapie in sheep and goats constitutes an imminent danger.

CHAIRMAN BROWN: Well, that's Question 2.

DR. ASHER: BSE. We're not talking about scrapie. That's Question 2.

CHAIRMAN BROWN: Dave?

DR. BOLTON: Yes, it seems to me that the FDA and the USDA really serve different constituencies, and that the needs, the regulatory needs, may be divergent now or may diverge in the future, and so it seems that it would be prudent to have the FDA formulate their own policies on this just in case.

Even in some cases where they may overlap substantially and coordination obviously would be good, it would seem to me that separate regulations or policies would be worthwhile.

CHAIRMAN BROWN: Yes, Lisa.

DR. FERGUSON: Actually I would like to build on that point, and I feel compelled to make this statement.

We have already started somewhat of an interagency process in relation to our regs, but let me just clarify USDA APHIS regulations. Our authority is limited to animal health, and sometimes it's kind of stretching it in some of these products to say that there's a possibility that these might get exposed to the domestic animal population.

Now, we have never really been challenged with that, and our regulations are very broad, but I just want everybody to be aware of the fact that that is the limitation of our authority, and that very well could be challenged at some point in time in the future.

CHAIRMAN BROWN: Ray.

DR. ROOS: It sounds like the Committee agrees that we should not get products derived from sheep and goats from BSE countries, and it sounds like we want the FDA to have the powers that are necessary to insure that that's carried out.

Maybe the FDA could guide us as to what they would really like at the moment. You know, I get the feeling that somehow you're dissatisfied with the status quo or you're concerned about it, and maybe you can guide us as to what you want, and that might help with the wording here.

Because I have the feeling everybody around the table has the same desires here, and it's just a question of some agenda here and what programs you would like to have implemented.

CHAIRMAN BROWN: Yes, I think the Chair -- just a second -- the Chair agrees. I think if we took a vote right now, we would have a 100 percent consensus if people understood what a yes meant and a no meant, and this whole business about USDA looks to me like a red herring. I think it has terribly confused the issue. In a sense, it's punting the issue. I really don't think it ought to be a consideration.

Yes, I think, Dean, you had a --

DR. CLIVER: Okay, but the amended wording we took down during the most recent presentation asks whether any changes in current practices are needed, et cetera, et cetera. I think that's the essence of the question. If we're not satisfied with the status quo, then the answer to that question is yes.

CHAIRMAN BROWN: Right. It's all right with me. I was satisfied with that from the beginning. I know what it means, but if there is confusion about what it means on the part of any Committee member, speak now.

DR. EWENSTEIN: Well, I would suggest that we take a stronger stance rather than just saying something should be said because I think we're clearer than that, and the wording that I would suggest, if possible, would be that it is the advice of the Committee that the FDA take appropriate steps to insure that sheep and goats originating from or residing in countries where BSE occurs or are high risk are not acceptable sources of material for manufacture of, and continue the resolution the way it was.

And the appropriate steps then would be up to you in terms of rules, regulations, coordination with USDA or whatever else is necessary.

DR. HELLMAN: Yes, and in fact, I would say with regard to implementation of the recommendation, we have different means that we can use than to implement that. What we would like from the Committee is a clear articulation of your recommendation. Then we can translate that into appropriate policy and use implementation appropriately.

CHAIRMAN BROWN: I'd tend to go back to the original --

DR. HELLMAN: That's fine.

CHAIRMAN BROWN: -- question rather than say they should not be imported from BSE countries because there may be circumstances and precautions that are achieved that would permit that, and so as a total exclusion, I think it probably is more than some of us would agree to, whereas I'm sure -- I'm almost sure -- all of us would agree to the question as it is currently written, that is, know what it means and will vote one way or the other clearly.

So let me --

DR. ROOS: Well, the total exclusion is not correct because there's tallow and there --

CHAIRMAN BROWN: In any case.

DR. ROOS: -- are some products, in fact, that -- but I like the idea of the second part of the suggestion, and that is -- and maybe you could read that again -- that the FDA allow --

DR. EWENSTEIN: Well, the advice of the Committee is that the FDA take appropriate steps to insure without getting into whether -- you know, how that would work, and then the rest of it just read as the original question read.

But if you didn't want it to say specifically that it's not acceptable as sources of material because it's too exclusionary, that could -- that piece could be changed to further take steps, take the appropriate steps to clarify conditions under which sheep and goats can be used as sources of materials.

CHAIRMAN BROWN: I'm going to interrupt you for a second. I'm going to call a five-minute recess, and I'd like Kiki to come back at us with a new question, in view of what everybody, you know, has said, and nobody can rephrase his own question twice because it gets complicated and they forget the middle part of the sentence.

DR. ALMOND: Can I just say one thing? That I really would caution against and would be very worried by a very positive statement that says, you know, sheep and goat material from countries with BSE are unacceptable sources.

CHAIRMAN BROWN: Right. We agree.

DR. ALMOND: You've got that. If you do that, that will be taken as this Committee telling Europe that it's got BSE in its sheep, and the consequences of that in the media could be horrendous over the next few days.

CHAIRMAN BROWN: Right.

DR. ALMOND: And we are not saying that.

CHAIRMAN BROWN: Yes, and we're not saying it either, and that was the point of the last two minutes, and that's fine.

So let's just wait for two or three minutes and get a new question, phrasing, that is a little simpler.

(Whereupon, the foregoing matter went off the record at 2:35 p.m. and went back on the record at 2:45 p.m.)

CHAIRMAN BROWN: Will the Committee reassemble around the table, please?

Here is the suggested revised question, and it is essentially the original question, simplified a little bit.

After considering possible risks and benefits, the Advisory Committee is asked to advise the FDA as to whether the FDA should take measures to insure that sheep and goats originating from or residing in countries where BSE occurs are acceptable sources of materials for manufacture of FDA regulated products intended for injection or implantation, both as components of the products and as manufacturing process reagents.

All of the baggage of the last part of this is simply specifying in more detail the kinds of things that they're interested in. We could, for purposes of comprehension, stop after "occurs." In other words, we're asked whether the FDA should take measures to insure that sheep and goats originating from or residing in countries where BSE occurs are acceptable sources of materials for manufacture of FDA regulated products.

DR. CLIVER: Could that be phrased in the form of a question?

CHAIRMAN BROWN: Okay.

DR. CLIVER: If we skip after "considering" and so on?

CHAIRMAN BROWN: Okay, okay. So we could say "should"?

DR. CLIVER: Yes, something that ends with a question mark.

CHAIRMAN BROWN: Okay, Yes. That's fine.

Yes, it is. I can tell you that.

DR. ALMOND: Do you mean should have the power or should have a policy to decide on such things? Is that --

DR. PRUSINER: No, it's the meaning of "is."

(Laughter.)

DR. CLIVER: It's the meaning of "assures."

CHAIRMAN BROWN: Yes, we've heard that recently.

Should the FDA take measures to insure that sheep and goats originating from countries where BSE occurs are acceptable sources of materials for manufacture of FDA regulated products?

It's understood that this is for injection or implantation and that they're products or manufacturing process reagents. That's baggage for specifics, but the sense is: should the FDA take measures to insure that sheep and goats residing in countries where BSE occurs are acceptable sources of materials for manufacture of regulated products?

For "acceptable" you could substitute the word "safe." It might be even better.

DR. BOLTON: Is it just residing in or residing and or originating from?

CHAIRMAN BROWN: Originating from or residing in. In other words, the source.

(Laughter.)

DR. ASHER: It's language that we have to use so that it doesn't include just those animals born there, animals transported through. It's language that we have to use.

CHAIRMAN BROWN: Yes. Should the FDA take measures to insure that sheep and goats originating from or residing in countries where BSE occurs are safe sources of materials for the manufacture of FDA regulated products?

DR. DETWILER: Or high risk countries.

CHAIRMAN BROWN: Where BSE occurs.

DR. EWENSTEIN: And stated that way, that would actually cover drugs that were manufactured outside and brought in, correct? So that's even better. Okay.

CHAIRMAN BROWN: Something that's not grammatically correct about this, but I'm not sure what it is. I think it's probably the reversal of we're advising the FDA to insure that the sheep and goats are safe rather than the products are safe. Again, we understand perfectly well what the damned thing means, but I think we're really saying to insure that the sources of materials, that sheep and goat sources of materials for the manufacture of FDA products are safe.

Again, these are rephrasing. We still haven't got it perfect, and it might be that we're going to wind up with my saying: does the Committee understand what we're talking about?

We are talking about the FDA taking measures that will enhance the safety of products derived from sheep and goats in BSE countries. Stripped of all its baggage, that's what we're voting on, and if the Committee is prepared to vote on that, we'll go ahead and vote now.

Okay. Larry, we start with you.

DR. SCHONBERGER: Yes.

CHAIRMAN BROWN: Stan.

DR. PRUSINER: Yes.

CHAIRMAN BROWN: Raymond.

DR. ROOS: Yes.

CHAIRMAN BROWN: Ermias.

DR. BELAY: Yes.

CHAIRMAN BROWN: Peter.

DR. LURIE: Yes.

CHAIRMAN BROWN: Dr. Hoel?

DR. HOEL: Yes.

CHAIRMAN BROWN: David?

DR. BOLTON: Yes.

CHAIRMAN BROWN: McCullough voted yes.

I vote yes.

Dr. Ewenstein?

DR. EWENSTEIN: Yes.

CHAIRMAN BROWN: Dr. Detwiler?

DR. DETWILER: Yes.

CHAIRMAN BROWN: Mrs. Williams?

DR. WILLIAMS: Yes.

CHAIRMAN BROWN: Or Dr. Williams.

Ms. Harrell.

MS. HARRELL: Yes.

CHAIRMAN BROWN: Dr. Cliver?

DR. CLIVER: Yes.

CHAIRMAN BROWN: Fourteen of 14.

We're on a roll. Let's go to Question No. 2, or I really -- I think we can. If you, on the other hand, would like to have a little more discussion before we vote on Question 2, which is fundamentally exactly the same question, but we're now talking about countries that do not have BSE. We are talking about non-BSE countries.

And the question as phrased is whether the FDA -- should the FDA take any safeguards to insure that sheep and goats originating from or residing in countries where scrapie occurs are scrapie free and acceptable sources of materials for the manufacture of FDA regulated products, again, with the extra baggage about injection, implantation, products and manufacturing process reagents?

So here we are not concerned with the risk of BSE. The concern here is about a hypothetical risk from scrapie itself. Here we're asked to decide whether such safeguards should be taken to protect us from the potential danger of being exposed to scrapie.

Larry.

DR. SCHONBERGER: Yes.

DR. BOLTON: Stan?

DR. PRUSINER: Yes.

CHAIRMAN BROWN: Ray?

DR. ROOS: Yes.

CHAIRMAN BROWN: Ermias?

DR. BELAY: Yes.

CHAIRMAN BROWN: Peter?

DR. LURIE: Yes.

CHAIRMAN BROWN: Dr. Hoel?

DR. HOEL: Yes.

CHAIRMAN BROWN: Dave?

DR. BOLTON: Yes.

CHAIRMAN BROWN: Dr. McCullough also voted yes.

I vote no.

Dr. Ewenstein?

DR. EWENSTEIN: Yes.

CHAIRMAN BROWN: Dr. Detwiler?

DR. DETWILER: Yes.

CHAIRMAN BROWN: Dr. Williams?

DR. WILLIAMS: Yes.

CHAIRMAN BROWN: Ms. Harrell?

MS. HARRELL: Yes.

CHAIRMAN BROWN: Dr. Cliver?

DR. CLIVER: Yes.

CHAIRMAN BROWN: Damn. Okay.

(Laughter.)

CHAIRMAN BROWN: Well, it's good to be different once in a while.

Okay. So you have your two votes now, FDA, and we can now just discuss at will any issues that you'd like to discuss before the meeting ends. Is there anybody on the Committee that, you know, would like to express opinions or recommend ways in which or recommend measures that the FDA might be particularly recommended to look at?

David.

DR. BOLTON: Well, I'd just like to echo Bob Rohwer's statement about trying to encourage the use of closed herds and certified flocks as much as possible.

DR. ALMOND: Could I just?

CHAIRMAN BROWN: Yes. Kiki?

DR. HELLMAN: We have heard the term "closed herds," but would someone venture a definition of what would constitute a closed herd?

CHAIRMAN BROWN: Probably Linda would be the best one to answer that.

DR. DETWILER: There are actually variabilities in what you consider closed. You can have it closed to the movement of live animals. That would be just sheep and goats.

You can have it closed to all livestock and poultry, depending on what disease you're trying to keep out.

Dr. Rohwer had mentioned something, too, he would recommend: no cervids, no bovids. I don't know if there's any kind of scientific information just on lateral contact, but you could require that, and if you wanted a totally closed flock-herd, you could even go to the extreme of preventing an introduction of germ plasm, although that's very difficult for even a pharmaceutical if you're going to maintain genetics because you're going to introduce hereditary problems in that. So you might not want to totally close it to germ plasm introduction.

And you could close to even the outside environment, again, not for a TSE issue, but for other pathogens in the PSP.

So there's really broad definitions of closed.

CHAIRMAN BROWN: Other Committee comments? Bob.

DR. ROHWER: But I would like to emphasize that one of the most important things to close it to us feed routes of contamination. So feed should be carefully regulated, and the easiest way to do that is make sure they only get vegetable feed.

And in terms of genetic isolation, I don't think you have to go that far, but because you can maintain and improve the genetics through semen, but I think it is very important to make sure that these animals don't have direct animal contact with other sheep, and the idea of bringing in animals themselves to improve the or maintain, you know, genetic health of the flock I think is a very bad idea.

CHAIRMAN BROWN: As another strategy that was already mentioned, FDA probably ought to be encouraged to themselves encourage alternative products to natural base products whenever they can be used. For example, the vascular grafts from goats, presumably -- it was goats, wasn't it? Goat vascular grafts or was it sheep? Sheep?

Probably in the next year or two or five, they'll disappear as technology improves, but always be alert to the possibility of using a substitute if it's nearly or just as good.

DR. EWENSTEIN: Yes, I was going to say in a similar vein that I see more use of these transgenic animals. Already there are some products that you have listed as transgenic products, especially in goats, and that that would be of particular interest because I see that as in a lot of people's minds the escape route out of a lot of the infectious problems in the biologics. So it would be important to make sure that the sources of those transgenic products were free of the pathogens that we're trying to get away from in the human sources.

CHAIRMAN BROWN: Ray?

DR. ROOS: A couple of things with respect to the transgenics. It would be good to target the transgenics to have some resistance genes as well. So that might be valuable with respect to the sourcing.

I'm all for promoting flocks that are certified as scrapie free because I think, you know, it's a valuable goal in this country to try to get scrapie free sheep. I just don't know how realistic that is. Maybe you can comment, Linda.

And the idea that pastures can remain a source for the agent for years or at least that's what one reads, and if that's the case, then one should get an infected sheep in one of these certified flocks. It's a worry of mine that there's a continuous nidus for contamination.

So although I think these are good goals and all, I'm just maybe a little bit pessimistic about how successful we're going to be nationwide.

DR. DETWILER: I think you can do it, and I think there are companies already that have done it for sourcing, as well as private owners that have done it.

One, the best scenario would be to start where you've never had sheep and goats housed before, and that's what a number of either people have done or companies have done to do that.

The other thing if you wanted to go right to the top is bring in animals from Australia and New Zealand, or start with known especially breeds here. There are breeds here that we have not diagnosed scrapie. To get those as source and start them from the bottom and bring them up.

And the other thing is to constantly monitor your deaths loss in there, and then I think with precautions, and you know, Bob pointed out something that is really important, that we have certain guidelines for our program in the country, and in some respects, we have to keep those broad or else we would totally not have participation because you can't start up a program in this country and preclude your genetics altogether, genetic improvement on other things.

But for sourcing of injectables and biologics, the FDA can definitely put more -- build more, you know, stringent requirements into that basic thing and require that as well. So I think there's even more things you can build in.

CHAIRMAN BROWN: Dr. Hourrigan, all of this must seem like deja vu, and I wondered if you would like the opportunity to say 30 seconds' worth or five minutes' worth of your own thoughts and give us a little historical perspective.

I don't mean to put you on the spot, but if you'd like to, we'd love to hear you.

Could you come to the microphone, please?

DR. HOURRIGAN: It's nice to be here and not to have to vote yes or no on any of the questions.

(Laughter.)

DR. HOURRIGAN: A problem has always been in situations of this kind that whatever work we do is going to be reviewed by the Monday morning quarterbacks, and there are very severe critics usually, and sometimes we're put out with them, but often we can't wait until Monday morning.

We have to vote today, and perhaps if we could wait until Monday morning, we might vote differently, but that's not the way it goes.

And perhaps it's well that we do have Monday morning quarterbacks so we can do even better than our best to try to come to the best answer we can for our various problems.

And I have been involved in scrapie for a number of years, and these same questions come up, and you certainly have a lot more answers now than we had then, and most of the things you're talking about we hadn't even heard of when we first started into the scrapie program, but some things haven't changed all that much either.

And it's nice to be here, and godspeed.

CHAIRMAN BROWN: Did you want -- have you got any thoughts for us about achieving a scrapie free U.S. based on your vast 30, 40 years of trying?

DR. HOURRIGAN: Well, I had a boss at one time that was always bugging me on when are we going to get rid of scrapie, and he'd do that about twice a day.

(Laughter.)

DR. HOURRIGAN: And I said, "Well, yes, if we do everything just right."

And he said, "What would that be?"

I said, "Kill all of the Suffolk sheep."

Well, he said he didn't think that was feasible, which obviously it wasn't, and it's going to be a hard row to hoe, and we used to say and we used to hope instead of -- we always sat on the fence. On one side we said that it's an infectious disease spread laterally. On the other side of the fence we said it's a genetic disease, and we seemed to have to do that, and it was a very uncomfortable seat to sit on, but it seemed to be one that we had to occupy.

But we thought that if it ever did become genetic, perhaps we could get out of it. That would solve all of our problems, and we see that scrapie is considered more genetic in many respects and so are most other disease and conditions than they were years ago, and we find that even though this partial goal of looking at the genetics of scrapie is more a reality than it used it be, it still hasn't answered all of our questions. Perhaps it never will.

And we used to argue if you could get rid of scrapie in one flock, you can in all of the flocks in the county, and if you can do it in the county, you can do it in the state, and so on and on.

With a number of diseases that does work, and in the case of Australia and New Zealand, they really didn't have the intrinsic disease problem that we have with scrapie and many other countries. They could do that because they weren't really infected, except through imports, and then only recently.

I would hope that it would be successful, but it won't be seen in my time, and I hope it will be perhaps in some of your times.

CHAIRMAN BROWN: Well, we rather hope it might be seen in your time as well, Dr. Hourrigan, from both our points of view.

Stan.

DR. PRUSINER: I'm just sitting here trying to think if I'm a sheep farmer and I want to create a flock and I want to be able to supply the most possible scrapie free products for injection or implantation.

So how I would begin -- I'll just be very brief -- is I would go out, and I would need some advice on the number of animals that I would collect sperm from that are RR 171, and then I would bank these sperm, and I would bioassay these sperm, and I would also immunoassay some portion of these sperm.

Then I would have this bank. Then I would use that to turn the -- and then I would have to be very careful about how I selected the females that I would impregnate with those sperm.

And then I would have to choose a piece of land where there had been no history of scrapie. I'm just reiterating a few things that have been said already by several people.

The feed obviously is critical. Isolation from all other farm animals I would believe is critical, and I would autopsy every single animal that dies or is sacrificed for scrapie.

I think those are really key ingredients, and I think that the USDA and the FDA should get its act together, and it should create this bank of sperm that could be used then to breed these animals to homozygosity for 171 because that's clearly a risk factor, and it clearly renders animals quite resistant.

It may not be 100 percent perfect, but they're quite resistant to prions, and I think that's something that government should do and then make it available.

CHAIRMAN BROWN: Does anybody know what the genotype of Dolly is?

(Laughter.)

CHAIRMAN BROWN: That's a few years down the road, but it's an alternative.

DR. PRUSINER: Yes.

CHAIRMAN BROWN: Bob?

DR. PRUSINER: There are people trying to make Dolly-like animals, in fact, I think at the same Rosslyn Institute that are PrP null, and whether that's going to work or not is unclear because one doesn't know what the phenotype of those animals will be a year or two or three or four out from birth.

CHAIRMAN BROWN: She was four when she was born, so she is hitting the age of maximum susceptibility or we can expect something to happen soon or nothing at all.

Bob?

DR. ROHWER: I think another critical element of a closed herd program is sentinels, but I wouldn't create the sentinels by bringing them in from the outside or by necessarily creating highly susceptibles.

I think the way you go about this is that you hold some proportion of your stock for their lifetime, and so that they have an optimum opportunity to develop the disease if it is in the population, and you use the animals that you're breeding anyway.

I think one of the problems with the sperm bank idea -- I'm not an expert on this, Stan, but my understanding is that in breeding, you're breeding for other traits besides scrapie susceptibility. In other words, you're looking for animal health and vigor traits, and you can't always get that from just one particular sire. It's the mixture of sires that have to go into that program.

DR. PRUSINER: Well, that's why I'm suggesting that multiple animals be banked, not one.

CHAIRMAN BROWN: Yes, this is almost like breeding tomatoes. You've got six different characteristics that you like, and they're all on different genes, and that's what the breeding, you know, is all about.

Yes.

DR. ROHWER: There is one other thing though that this breeding business brings up, breeding for resistance instead of susceptibility, and that is that I have heard it proposed by Katherine O'Rourke at a meeting I attended recently that instead of populating your flock with resistant animals, you should populate it with susceptibles because you have a higher probability of seeing the disease in a susceptible.

This is completely counterintuitive from my point of view, but it is seriously being proposed by people in the USDA, and I think maybe that's something we should weigh in on.

I'm not sure that's the way to go.

DR. DETWILER: Can we correct about the USDA? That's a research arena, the USDA, not APHIS. It's not, at least to my knowledge, not being seriously proposed by APHIS.

CHAIRMAN BROWN: Yes, it sounds like a fun research project, and that's fine.

One other thing, we're talking strategies. Something that really hasn't been brought up or emphasized very much -- I'm surprised that Bob hasn't brought it up -- and that is don't overlook the possibility of decontamination procedures, processing steps for any individual product that could further reduce risk even if the source is a little dicey.

Yes?

DR. HOURRIGAN: Some of you may recall that Alan Dickinson attempted to select susceptible and what he called short incubation sheep, and he was highly successful. The incubation period got shorter and shorter, and in his flock he was losing out on his sheep that lived longer because they came down with scrapie when they were about ten or 11 months old, and eventually his flock died out because they didn't live long enough to reproduce.

CHAIRMAN BROWN: Would any Committee member like to express further comments or statements or opinions?

(No response.)

CHAIRMAN BROWN: In that case, I hereby terminate this two-day meeting and thank very much the members of the Committee for their participation.

DR. FREAS: I would just like to thank our Chair and everybody for participating in these public discussions. We appreciate you taking your time to come here to Washington, D.C. for these very important meetings.

Thank you.

(Whereupon, at 3:10 p.m., the meeting was concluded.)