1 
		DEPARTMENT OF HEALTH AND HUMAN SERVICES 

FOOD AND DRUG ADMINISTRATION 
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH 
***** 
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES ADVISORY COMMITTEE 
***** 
				Friday, January 19, 2001 

								8:30 a.m. 
Holiday Inn Bethesda Versailles I and II 
8120 Wisconsin Avenue Bethesda, Maryland 

	2 PARTICIPANTS 
Paul W. Brown, M.D., Chairperson 
William Freas, Ph.D., Executive Secretary 
VOTING MEMBERS 
	Ermias D. Belay, M.D. 

David C. Bolton, Ph.D. Donald S. Burke, M.D. Dean O. Cliver, Ph.D. 
Bruce M. Ewenstein, M.D., Ph.D. Peter G. Lurie, M.D. 

Pedro Piccardo, M.D. Stanley B. Prusiner, M.D. Raymond P. Roos, M.D. 
Elizabeth S. Williams, D.V.M., Ph.D. 
VOTING CONSULTANTS 
Linda A. Detwiler, D.V.M. 
	David Gaylor, Ph.D. 

Paul R. McCurdy, M.D. Kenrad E. Nelson, M.D. 
NONVOTING CONSULTANT 
	Susan Leitman, M.D. GUESTS 
Richard Davey, M.D. Louis Katz, M.D. 

		3 C O N T E N T S 
Introductory Remarks			4 
Topic 2: Committee Discussion (Continued)		4 
Topic 3:  Discussion of issues related to deer and elk infected with or exposed to chronic wasting disease in the U.S. and potential for human exposure: 
FDA/CFSAN Regulatory Issues: 
	R. Brackett. Ph.D.	 54 
Background on Chronic Wasting Disease: 
	M. Miller, D.V.M.	 61 
Epidemiological Investigations of Young CJD Cases 
Exposed to Venison: 
	E. Belay, M.D.	 91 
Diagnosis of Elk-Associated and Deer-Associated 
Chronic Wasting Disease: 
	K. O'Rourke, D.V.M.	108 
Industry Perspective: 
	G. Zebarth, D.V.M.	126 
Open Public Hearing 
	L. Riddle		145 
	Dr. M. McDonnell	149 
Committee Discussion		163 
Topic 4:  Discussion as to whether a history of possible exposure to various animal TSE agents should be considered by the FDA in determining suitability of blood donors: 
Introduction, Charge and Questions: 
	D.M. Asher, M.D.	191 
Undifferentiated TSE in Flocks of Sheep in Vermont: 
	L. Detwiler, D.V.M.	197 
Efforts to Initiate a Program to Eliminate CWD from Farmed Elk: 
	L. Creekmore, D.V.M.	210 
Regulation of Ruminant Materials in US Dietary Supplements: R. Moore, Ph.D.	218 
Open Public Hearing 
	Dr. S. Norton	230 
Committee Discussion		233 

				4 
	1		         P R O C E E D I N G S 
	2		          Introductory Remarks 
	3		DR. FREAS:  Welcome to the second day of the 
	4	Transmissible Spongiform Encephalopathies Advisory Committee 
	5	Meeting.  I would like to state that the conflict of 
	6	interest statement that was read into the record yesterday 
	7	pertains to today's discussions as well and we ask all 
	8	members of the audience, if they come to the microphone, 

	9	one, please identify themselves and then, two, publicly 
10	state any financial affiliations with any firms that they 
11	may have. 
12		Thank you. 

13		Dr. Brown? 
14		                Topic 2 
15		    Committee Discussion (Continued) 
16		DR. BROWN:  Good morning.  If we really get 
17	cracking, only half the committee is here, we can probably 
18	get through several of the votes.  We are, in fact, 
19	beginning today with the conclusion of yesterday's 
20	deliberations on Topic 2 which concerns tissues and cells 
21	and cell products. 
22		We held off all of the discussion and the voting 
23	until today.  I think, actually, quite seriously, we can 

24	vote on question 1 because there is no way that we can vote 
25	in any other way than yes.  But, I will read the question 

						5 
	1	and you will see why; compared to the risk of transmission 
	2	of variant CJD by blood transfusion, is there a significant 
	3	risk of transmission of vCJD from human cells, tissues and 
	4	cellular and tissue-based products that are transplanted, 
	5	implanted, infused or transferred? 
	6		The answer has to be yes because the cornea is 
	7	demonstrably infectious.  So I suggest we vote on that and 
	8	get to the important question which is what are the relative 
	9	risks for different cells and tissues. 
10		Is there discussion before we do this?  Ray? 
11		DR. ROOS:  Now, this is variant CJD. 
12		DR. BROWN:  That's right; this is variant. 

13		DR. ROOS:  Do you know that the cornea-- 
14		DR. BROWN:  No; we don't. 
15		DR. ROOS:  Oh. 
16		DR. BROWN:  But we know that the cornea alone, 
17	among tissues with standard CJD, has been infectious and 
18	there is no reason to suppose that, in this one tissue, 
19	variant would be less rather than more infectious than 
20	standard CJD. 
21		DR. ROOS:  I think we probably have-- 

22		DR. BROWN:  Relative to blood, bear in mind, which 
23	is not-- 
24		DR. ROOS:  I think we have no data, Paul, on 
25	natural variant CJD in humans as far as tissue distribution. 

						6 
	1	Maybe I am wrong. 
	2		DR. BROWN:  We have PrP data. 
	3		DR. ROOS:  PrP data. 
	4		DR. BROWN:  In all the tissues that have been 

	5	looked at, the amount of protein in variant CJD exceeds 
	6	that.  In fact, there is not any demonstrable in classical. 
	7		DR. ROOS:  So we know minimum infectivity at the 
	8	moment. 
	9		DR. BROWN:  Yes. 
10		DR. ROOS:  But, clearly, we don't know the tissue 
11	distribution in its natural--you know, of human to human. 
12		DR. BROWN:  Right.  And we have no information 

13	whatsoever on infectivity in blood which we have already 
14	decided posed a potential risk.  That is why I say I don't 
15	think the committee can really justify any other vote but 
16	yes.  But we will see. 
17		Ray, why don't you start the voting, on this 

18	particular question; compared to the risk of transmission of 
19	variant CJD by blood transfusion, is there a significant 
20	risk of transmission of variant CJD from human cells, 

21	tissues and cellular tissue-based products that are 
22	transplanted, implanted, infused or transferred. 
23		DR. ROOS:  Yes. 
24		DR. DETWILER:  Yes. 

25		DR. EWENSTEIN:  Yes. 

					7 
	1		DR. BURKE:  Yes. 
	2		DR. McCURDY:  Yes. 

	3		DR. PICCARDO:  Yes. 
	4		DR. GAYLOR:  Yes. 

	5		DR. BOLTON:  Yes. 
	6		DR. BROWN:  Yes. 
	7		DR. BELAY:  Yes. 
	8		DR. CLIVER:  Yes. 
	9		DR. LURIE:  Yes. 

10		DR. WILLIAMS:  Yes. 
11		DR. PRUSINER:  Yes. 

12		DR. FREAS:  The vote was a unanimous yes vote. 
13		DR. BROWN:  Is Dr. Nelson going to be here? 

14		DR. FREAS:  I have not been notified.  I am 
15	assuming he is on his way. 
16		DR. BROWN:  The vote on that is 15 to 0, is it 
17	not? 
18		DR. FREAS:  That is correct. 
19		DR. BROWN:  Now we have a question about which we 
20	really have virtually no information whatsoever.  We can 
21	discuss it a bit, if you would like, and that is what are 
22	the relative risks for different cells and tissues.  Does 
23	anyone want, for the record, at least, make a comment about 
24	this? 
25		DR. FREAS:  Dr. Brown, may I just correct; the 

				8 
	1	total was 14.  The vote was right.  My math was wrong. 
	2		DR. BROWN:  Is there anything we can say about the 
	3	relative risks for different cells and tissues?  I have just 
	4	said that probably, based on what we know, the cornea would 
	5	represent as close to a known relative risk as we have 
	6	information for.  Based on the distribution of infectivity 
	7	in classical CJD, we can presume that the lymphatic system 
	8	would be a system of tissues which would compose a 
	9	comparatively higher risk than, say, muscle or bone. 
10		But the fact is, we have no experimental data on 
11	infectivity in variant CJD.  So we can't know anything; 
12	right? 
13		DR. ROOS:  I guess the other comment that is worth 
14	making is that when tissues donated for a pool, clearly 
15	there is more danger so that a blood donation that might end 
16	up in a large pool for blood products would have more 
17	potential problems from a biohazard point of view than a 
18	donation of tissue-to-tissue to no pooling.  That is true 
19	for dura mater as well as blood. 
20		DR. BROWN:  In other words, a single tissue, 
21	individual-to-individual, is a dead-end track, by and large. 
22		DR. LURIE:  Just sort of to echo, in a way, what 
23	Ray is saying, aside from cornea which is associated maybe 
24	with cases of CJD, the same is true for dura mater.  In 
25	fact, obviously, there are forty or more of those.  So that 

					9 
	1	would be--I think cornea and dura mater are in a separate 
	2	category from everything else. 
	3		DR. BROWN:  That's right.  I had forgotten.  Dura 
	4	mater is--is that correct, FDA people--considered to be a 
	5	tissue rather than--dura mater comes under the aegis of this 
	6	question. 
	7		DR. SOLOMON:  Currently, it is a medical device. 
	8	But we are planning to make it a tissue and it does come 
	9	under the discussion. 
10		DR. ROOS:  The committee has already stipulated 
11	extraordinarily stringent precautions for dura which 
12	probably would make, in practice, singling dura out 
13	irrelevant.  But I agree it should be in there because it is 
14	a tissue. 
15		DR. LURIE:  I think the broad way of thinking 
16	about this, again, is balancing presumed risk against likely 
17	impact in terms of reduced supply if there were any 
18	restriction of any kind, the sort of matrix we have used for 
19	blood donations. 
20		DR. BROWN:  This is question 2, is what you are 
21	addressing now. 
22		DR. LURIE:  I think so. 
23		DR. BROWN:  Question 2 addressed the possibility 
24	of action by the FDA considering the potential impact on 

25	supply.  We are not on question 2 yet.  I agree, it is a 

				10 
	1	consideration, but I think we should defer discussion of it. 
	2		DR. SOLOMON:  Could I ask the projectionist to put 
	3	up the list of tissues that are under consideration? 
	4		DR. BROWN:  That is a good idea. 
	5		[Slide.] 
	6		DR. PRUSINER:  I was just going to say that what 
	7	Ray said really is a double-edged sword because, in some 

	8	cases, of course, where you have an aliquot of something 
	9	from one individual and now it is dispersed and diluted and 
10	the titer of BSE prions is relatively low, then it goes 
11	below the biological level. 
12		So it is not always much worse.  Sometimes it is 
13	better.  But I wanted to say that I just wondered if we 

14	could think about this in a slightly different way.  I 
15	wondered whether, where it is practical--I am sure, in many 
16	cases, it is not practical, such as in stem cells and marrow 
17	transplants, but where tissues have a long half life and a 
18	bank, I wonder if we ought to, somewhere along the line, be 
19	thinking that whatever tests, no matter no crude they are 
20	now, in terms of immunodiagnostics, ought to be applied to 
21	these tissues. 
22		At least there ought to be some thought to begin 
23	to think along that line.  I don't know about specific 
24	recommendations, but I just wonder if we ought to try and go 
25	in a direction where there is a little more knowledge 

				11 
	1	because, as Paul Brown said, at the moment, we really don't 
	2	know anything about the tissue distribution of variant CJD. 
	3		DR. BROWN:  I agree and I think we can, perhaps, 

	4	get into that when, again, we talk about question 2 because 
	5	one of the open-ended questions that they ask is are 
	6	additional data needed, or should we gather additional data 
	7	that might alter any decision we make. 
	8		So this is a list of regulated tissues and cells. 
	9	My own read, just based on classical CJD and what we know 
10	about PrP distribution is really what I said before.  I 

11	think, probably, eye tissues, cornea, sclera, dura mater, 
12	corneal lenticules, and, conceivably hematopoietic stem 
13	cells would be, from what we know, I think, in the hierarchy 
14	of probable ultimate knowledge about the risk would be 
15	probably at the top of the list and everything else 
16	underneath it. 
17		I don't know if that would be useful to the FDA. 
18	I suppose it would be if we make certain votes subsequently. 
19	It won't be useful at all if we don't. 
20		DR. McCURDY:  You mentioned hematopoietic stem 

21	cells.  Yesterday, Dr. Confer commented that at least the 
22	peripheral blood stem cells are heavily diluted by 
23	lymphocytes.  We know that you can find variant prions in 
24	the tonsils and other lymphoid tissue.  Has anybody looked 
25	carefully enough in peripheral blood lymphocytes from 

				12 
	1	variant cases to know? 
	2		Also, it is my recollection that one of the FDA 
	3	people working on this has found PrP, at least in platelets. 
	4	I don't know about abnormal. 
	5		DR. BROWN:  There has been a lot of work on the 

	6	normal protein in platelets which, in humans, is loaded. 
	7	But there is no necessary correspondence between the amount 
	8	of normal and the amount of pathologic.  That is one thing. 
	9		The second thing is, in one study recently 
10	published, the plasma--unfortunately, it is not cellular 

11	component, but the plasma from about twenty-odd patients 
12	with CJD--or, perhaps--I'm sorry; perhaps it was platelets. 
13	Do you remember this paper?  This was a paper about two or 
14	three months ago.  It was a paper that was focussed--it is 
15	from Great Britain. 
16		It was a paper that was focussed on normal protein 
17	and in platelets.  They also studied about twenty-odd CJD 
18	patients--it was almost a throwaway line in the paper--none 
19	of whom had any PrP that was proteinase-resistant.  So the 
20	conclusion was there was no pathologic protein, whereas 
21	there was plenty of normal protein. 
22		The other fact is that we do know that bone marrow 
23	was positive, presumably in a single BSE cow.  It is not 

24	much, but it is all we have and it would be plausible to 
25	suppose that the origin of cells, in blood, which we have 

				13 
	1	already decided pose a possible potential threat, would be 
	2	present at their birth as well as their maturity. 
	3		DR. EWENSTEIN:  I was just going to make the same 
	4	point about the lymphoid tissue.  I think, as we take a look 
	5	at the list in the absence of apparently rigorous dissection 
	6	of all of these tissues that have been available here so 
	7	far, the only other ones that I would worry about would be 
	8	some of the fluids. 
	9		I don't know, for example, in semen, whether the 
10	white cells in that fluid might not have-- 
11		DR. BROWN:  These have been looked at in other 
12	forms of CJD and no infectivity has ever been documented. 

13		DR. EWENSTEIN:  In other forms, I know.  But when 
14	we think about the difference between CJD and variant, I 

15	think the lymphocyte distribution is the difference that I 
16	am concentrating on here.  So I just bring it up because I 
17	think the risk here is of a different nature as well because 
18	we are talking about elective procedures and we are talking 
19	about the possible infection of a would-be embryo. 
20		So I think that one would have to put, I think, a 
21	question mark on that until we had some real data. 
22		DR. BURKE:  The other factor that plays in here 

23	that is a bit different than the blood is the requirement 
24	for close matching in some of these, particularly the bone 
25	marrow.  As I understand it, there may be a significant 

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	1	number of people that would not match if-- 
	2		DR. BROWN:  This is correct, Don.  But I do want 

	3	to stick to question	1.  This is really under question 2; 
	4	that is, all of the benefit aspects will be discussed after 
	5	we make a vote on question 1.  Question 1 really is a 
	6	scientific question. 
	7		DR. BURKE:  Fair enough.  I will hold it. 
	8		DR. BROWN:  This is not, actually, a yes/no vote. 
	9	I don't think, actually, we have to vote on it because this 
10	is a kind of a discussion.  So we are going to escape a 
11	vote. 
12		DR. DETWILER:  Just one other scientific thing. 
13	You said about bone marrow, but in scrapie, in sheep, on 

14	occasion, there had been evidence of infectivity also in 
15	bone marrow.  I think that is maybe why the FDA had asked 
16	Dr. Priola to come and to show the differences in the 

17	diseases and that variant CJD, at least with the peripheral, 
18	may be closer to scrapie than BSE.  But that is just to add 
19	that. 
20		DR. BROWN:  That is a good point.  Scrapie has 

21	been one of the diseases that marrow has occasionally been 
22	positive in. 
23		Let's go on to question 2, then.  Here I think we 
24	need not be restricted just to considering the potential 

25	impact on supply, although that will be a very important 

				15 
	1	consideration.  Another consideration is a kind of allied 
	2	consideration of what is practical, how long can you keep a 
	3	cornea, how long can you keep stem cells. 
	4		If we are talking about interviews, if we are 
	5	talking about testing, the logistics play into this part of 
	6	the benefit part.  So I will just open discussion on 
	7	anything that you have in mind for question 2. 
	8		Linda? 
	9		DR. DETWILER:  I would want to echo Dr. Prusiner's 
10	thing about the testing.  I think if you look to the animal 
11	world and say that right now, around the world, there are 
12	thousands of tests being conducted.  They are being 
13	conducted in a couple of hours. 
14		The logistics of holding carcasses and moving that 
15	can be done.  So I think you hear, "Well, you know, it is 
16	going to take a while."  That is being done by the 
17	thousands.  So I guess I don't buy that that can't be done 
18	and the logistics can't be set up.  I think if you are 
19	worried about variant CJD of two tissues possible, you have 
20	a number of methodologies, immunohistochemistry, Western 
21	blot, some other techniques. 
22		We have tonsil and brain material that could be 

23	potentially--again, it is not going to eliminate everything 
24	because of the negatives, what does a negative really mean, 
25	but it sure will give you more information than you had.  I 

				16 
	1	think the logistics can be done. 
	2		We heard yesterday that it is four to five days. 

	3	That is definitely doable for these tests that we have now. 
	4		DR. ROOS:  Just to pursue that, I guess what 

	5	surprises me a bit is that there is no commercial test 
	6	available, as I understand it, for humans that can be 
	7	applied.  I wonder whether there isn't some way to 
	8	facilitate the development and approval of such a test 
	9	because I think it would be of benefit. 
10		One other little comment, and it is something that 
11	came up, I think, in the past with respect to blood-pooled 
12	products that were found to have a donor that had 
13	Creutzfeld-Jakob, at least in the old days, and what to do 
14	with that blood pool.  I wonder about a kind of a two-tier 
15	system with respect to some of these donations. 
16		In other words, we are talking about donor 
17	deferral that might have a travel history that is 
18	unacceptable for the blood transfusion.  I wonder, in the 
19	case of critical tissue donations in which, for example, the 
20	stem cells are in short supply and we may be dealing with a 
21	situation that is life-threatening whether particular 
22	tissues that are donated for transplantation that might not 
23	satisfy the rigorous criteria that we are using as far as 

24	inclusion and exclusion could be labeled as such and used 
25	with known risk. 

				17 
	1		It wasn't clear to me whether this was being done 
	2	at all at present; in other words, there might not be some 
	3	tissues that are labeled as biohazards potentially. 
	4		DR. McCURDY:  I think we heard yesterday that the 
	5	National Marrow Donor Program is doing just that for marrows 
	6	and cord bloods and things that come in from U.K. and other 
	7	potentially dangerous geographic areas.  So it looks like it 
	8	is doable and goes through the informed-consent process 
	9	which ultimately goes to the practicing physician at the 
10	bedside but, nevertheless, their policy looked pretty good 
11	to me when it was put up on the board. 
12		DR. BROWN:  Steve, we will hear from you and then, 
13	Sue, would you like to chime in on this. 
14		DR. LEITMAN:  In the case of marrow and stem 

15	cells, if, at the time that an identical six out of six 
16	antigen match is identified and what is called IDM, 
17	infectious disease markers, are measured, at that point, if 
18	a marker is positive, short of HIV, if it is hepatitis C, 
19	hepatitis B, various other surrogate markers, anti-core, 
20	that information is conveyed to the transplanting physician 
21	who conveys it to their patient and it is discussed, the 
22	relative risk/benefit of using the only potential product, 
23	transplantable product, matched problem, is weighed against 
24	the risk of possible infection transmission. 
25		So there is lots of precedence for biohazard 

			18 
	1	labeling and in-depth discussion of the transplanting 
	2	physician with the patient of the risk/benefit 
	3	considerations.  So that could be applied here as it is 
	4	already being applied in different situations. 
	5	          DR. DeARMOND:  Steve DeArmond, UCSF.  I want to 
	6	actually address a question to the committee and maybe Stan 
	7	could help a lot on this because of his knowledge of it, but 
	8	in assessing the risk/benefit and trying to decrease the 
	9	risk, especially for things like hematopoietic stem cells 
10	where you are taking them from living patients and you are 
11	already testing them in great detail for a variety of 
12	markers, wouldn't it be possible to further test the patient 
13	for homozygosity at 129 because, first of all, all of the 
14	new variants occur right now in methionine-methionine. 
15	          We may see a methionine-valine some time in the 
16	future, but that doesn't seem to be the case.  90 percent of 
17	CJD, whether it is sporadic or acquired by infection, occurs 
18	in people who are homozygous.  It seems if that piece of 
19	information were known from a donor that you would at least 
20	increase the population, or retrieve a population, that 

21	could be a donor.  You would increase it by 50 percent 
22	because about 50 percent would be methionine-valine. 
23	          Does that make any sense or is that too 
24	impractical?  These are processes that are also very 
25	expensive. 

				19 
	1		DR. BROWN:  I think it probably makes as much 
	2	sense as, say, a test for PrP. 
	3		DR. DeARMOND:  We don't know sensitivity of that 

	4	test yet whether you can miss PrP in a sample and it would 
	5	still be effective.  That still is a piece of data that is 
	6	missing. 
	7		DR. BROWN:  That is true enough.  On the other 
	8	hand--well, we can discuss that in a minute.  129 might be 
	9	an interesting and possible test to do.  The turnaround on 
10	that test is pretty quick, but it may not be less than a 
11	day. 
12		DR. PRUSINER:  I agree with everything that is 
13	said.  A way to think about this might be, depending on how 
14	fast you need the information back, if the PrP test is 
15	positive, you don't need to do the DNA sequencing; right? 
16	The sample is out the door.  It is in the trash.  It is 
17	incinerated. 
18		If it is negative, then you might want to go to 
19	DNA sequencing.  This is just an issue of time.  In fact, 
20	you don't even really need to do DNA sequencing.  You could 
21	set up a test just to look at 129 and you could get that 
22	information very quickly. 
23		DR. NELSON:  Would you test the donor or the 
24	recipient or both? 

25		DR. PRUSINER:  No, no.  You want to test the donor 

				20 
	1	in this case. 
	2		DR. BOLTON:  But, in fact, in the absence of any 
	3	indication that there would be variant CJD in the individual 
	4	donating, you could be rejecting 40 percent of the donors 
	5	for no other reason than their genotype.  That makes little 
	6	sense to me with a disease that is extremely low prevalence. 
	7		DR. DeARMOND:  But, David, I think the problem 
	8	here is you are already considering rejecting all of those 
	9	people from Europe to begin with.  What this test would give 
10	you is 50 percent of them back with pretty good confidence 
11	that they won't have disease. 
12		So, as an alternative to complete rejection of all 
13	of those Europeans as donors, for instance, for 
14	hematopoietic stem cells. 
15		DR. BOLTON:  For those who would be considered for 
16	deferral based on their past travel history only. 
17		DR. DeARMOND:  Or even travel history; yes. 
18		DR. BOLTON:  To me, the thing that is most 
19	important is some sort of reasonably definitive test for the 
20	presence of prions.  It is either PrP or some other test. 

21	In the absence of that, I think, especially in cases where 
22	the recipient is in dire need of this material, the best 
23	thing to do, in my opinion, is to have physician discuss it 
24	with the patient and let them, together, weigh the relative 
25	risk of an unknown but probably very low risk of danger due 

				21 
	1	to transplantation infection versus the benefit of receiving 
	2	the donation. 
	3		DR. DeARMOND:  I could say, though, as a physician 
	4	sitting across from the patient, "Here we have some stem 
	5	cells for you, or marrow, and the person who is donating 
	6	them who matches with you is a person from Europe who is 
	7	heterozygous for prion protein.  Not only do we not find any 
	8	PrP in the tissue, but this person has a highly low 
	9	probability of having the disease and I think the risk for 
10	you would be extremely low." 
11		DR. BOLTON:  I would agree with that except what 
12	happens when you get to the case where the only match is 
13	methionine-methionine homozygous.  Then, if we make a 
14	recommendation that that be excluded, then they don't have 
15	that option. 
16		DR. BOLTON:  That is a possibility, but this is in 
17	lieu of a blanket rejection of all stem cells from--I am 
18	offering an alterative to blanket rejection. 
19		DR. BOLTON:  To blanket rejection.  Yes. 
20		DR. PRUSINER:  I think that is the point, David. 
21	It is not that we are offering a blanket yes or no here.  We 
22	are offering a procedure.  We are suggesting a procedure 
23	that, then, makes the patient and the physician more 
24	knowledgeable and either more or less comfortable with the 
25	decision. 

				22 
	1		DR. BROWN:  It would be in the nature of an 
	2	exclusion, in the language of the FDA.  In other words, 
	3	let's suppose that committee says, "Uh-uh; we don't want any 
	4	corneas from Great Britain for ten years."  The exclusion 
	5	would be if you lived in Great Britain for ten years and you 
	6	were not met-met. 
	7		DR. BOLTON:  I guess I would argue that I would 
	8	not suggest that the exclusion be made at all but that this 
	9	information be added to the knowledge base so that, as you 
10	go down this list of what is the best tissue to transplant, 
11	when you get down to that very lowest part of the list, that 
12	this is one of the factors that could be considered if no 
13	better tissue is available. 
14		DR. BROWN:  The other way to look at this entire 
15	issue of cells and tissues is to consider donations from 

16	deceased people and donations from live people.  Any 
17	deceased person, in our present state of knowledge and 
18	testing, could, if the logistics were worked out, have a 
19	test on the brain for PrP.  I mean, that is done deed. 

20		If I take the eye, in the medical examiner's case, 
21	out so that it not be contaminated, I have direct access to 
22	the brain.  A simple biopsy needle will give you the best 

23	material possible for a positive test and the positive test 
24	turnaround is about six hours. 
25		So this is a doable thing.  It means a tremendous 

					23 
	1	machine of logistics and it means money and it means someone 
	2	is willing to do it.  But it is doable on any cadaver.  The 
	3	situation is completely different with a live person and it 
	4	is a very dramatic split. 
	5		DR. DeARMOND:  I would like to make a comment on 
	6	that because we run into that situation relatively 
	7	frequently with coroners' offices where they are reluctant 
	8	to do anything in detail.  They don't want to contaminate 
	9	even their offices.  A lot of the outside hospitals are that 
10	way. 
11		But when I say that you could go in and take a 
12	needle biopsy from the brain, just drill a little hole and 
13	take a piece of tissue, that, we have found, in cases, is 
14	very helpful and, again, we can get a turnaround on that in 
15	the order of hours. 
16		DR. BROWN:  That is what I am saying.  You don't 
17	have to take the cranium off to get a piece of brain.  You 
18	can go through the nose.  You can go through the orbit.  You 
19	can go through any number of places and it has been a very 
20	useful technique, for example, in these situations where 

21	pathologists flea in panic at the word "CJD." 
22		DR. DeARMOND:  Coroners, also. 
23		DR. BROWN:  Coroners, also.  Morticians, also. 
24	All kinds of people.  Sometimes, they are more comfortable 
25	with the idea of a small needle hole than they are with a 

			24 
	1	limited autopsy.  One wouldn't do a limited autopsy, anyway. 
	2	          DR. BURKE:  Sue told us about the option of 
	3	discussing the potential infectious disease risks.  I don't 
	4	know how broadly that is done for other types of tissue 
	5	transplantations in the list that we have there.  Is there 
	6	anybody here who can tell us is that a common procedure for 
	7	things other than for bone marrow?  Is it, for instance, for 
	8	cartilage and bone and things like that?  What about all of 
	9	the other tissues there?  Is this also done where, say, 
10	there is a hepatitis B marker, that you can waive that if 
11	there is an acceptable--what is seen as an acceptable risk 
12	given the desperation? 
13	          DR. LEITMAN:  Other than hematopoietic stem cells 
14	which are so tightly matched, there is probably not another 
15	organ, including kidney and organs that have been 
16	transplanted for a long time, where you need that kind of 
17	matching.  For kidney and liver, it is AB-O only and there 
18	may be other choices.  That may be logistics, what comes up 
19	at a certain time of the day or week. 
20	          But, in terms of tissue matching, it is stem cells 
21	that that applies to.  You also have the luxury, with stem 
22	cells, in the unrelated matching program, to identify a 
23	donor and then have several days to weeks to discuss that 
24	with the patient, what the other options are, what the next- 
25	best match is. 

				25 
	1		I am not sure this helps, but there is an interval 
	2	for testing.  You identify the best match, based on HLA and 
	3	age and gender and numerous factors that Dr. Confer 
	4	discussed yesterday. 
	5		Then you can go down the list of next-best 
	6	matches, depending on what country they come from, what the 
	7	issues are, discuss that with the patient.  I will say that, 
	8	in the setting of a related donor transplant, if you find a 
	9	sibling that is a genotypical match, it wouldn't matter how 
10	long they had spent in any country in the world, that person 
11	is so much better in terms of potential for cure and long- 
12	term complication-free survival that it wouldn't even--the 
13	risk/benefit is so overwhelmingly in the favor of benefit. 
14		So that is how a transplanter would think of it 
15	probably in the unrelated setting, too. 
16		DR. BURKE:  So it might be in a separate category 
17	from many of the other types of transplantations that we are 
18	talking about. 
19		DR. LEITMAN:  I think so. 
20		DR. BURKE:  So maybe we should discuss that 
21	somewhat differently. 
22		DR. LEITMAN:  I think I might punt this to the 

23	FDA, but I think it is unacceptable to transplant tissue 
24	from a cadaver that has any positive marker as opposed to a 
25	living related stem-cell donor. 

				26 
	1		DR. BROWN:  We are going the have to watch the 
	2	time again so we don't get increasingly behind schedule. 
	3	Quickly, Jean-Philippe? 
	4		DR. DESLYS:  Very quickly, because I was out at 
	5	the beginning.  Two informations; first, technically, the 
	6	test which is commercially available works very well on man. 
	7	It has not been validated for it.  For the moment, in 
	8	Europe, it is used for cattle and it can be used for ovine. 
	9	But it works very well for man. 
10		I am not specializing the commercialization but if 
11	I well understood, as there was no market, people didn't try 
12	to develop it for man for the moment.  But it works for 
13	cattle and you can have a reply within a few hours if you 
14	use it. 
15		The only important thing is to have brain 
16	material.  It doesn't work with blood, unfortunately.  But 
17	it is technically possible. 
18		DR. BROWN:  I would like to summarize what I think 
19	has happened, Dr. Lurie.  In principle, it seems to me that 
20	everything in the body relative to blood has to be at least 
21	theoretically considered at least as infectious as blood.  I 
22	think we have to say that as a matter of theory. 
23		It also seems to me that, in respect to tissues 

24	and cells and cell products, that the benefit side of the 
25	risk/benefit equation is so different, so variable, 

				27 
	1	depending on the tissue, the cell, the living or dead status 
	2	of the patient, that I am not sure the FDA really wants to 
	3	get involved in it. 
	4		It is a funny situation where we have something 
	5	that, logically, speaking might well be considered to be in 
	6	the same category as blood but other considerations would 
	7	seem to me to mandate that it not be put in the same 
	8	consideration as blood. 
	9		Dr. Lurie? 
10		DR. LURIE:  I agree with that but, in addition to 
11	that, the elements we started to talk about were the issues 
12	of alternatives, is one.  And the second issue is the issue 
13	of supply.  I think that cornea and dura mater really are in 
14	a different category, not only because of the living-dead 

15	distinction that I think you helpfully make but for cornea, 
16	we heard that at least for the American market there seems 
17	to be general adequate cornea for our needs. 
18		I am a little bit worried about restricting it so 
19	that they are insufficient for export.  I think that is a 
20	sort of interesting ethical question whether that should be 
21	our concern at all. 
22		But I think that cornea is something for which 
23	there is not an alternative but for which there seems to be 

24	adequate supply.  Dura mater, on the other hand, there seems 
25	to be both inadequate alternative and inadequate supply.  So 

						28 
	1	I think that those two certainly are in a different category 
	2	from everything else where the supply in one equation is 
	3	very different. 
	4		DR. BROWN:  The question we are asking is focused 
	5	on donor deferral.  If there is no more discussion, we will 
	6	take a vote on it.  The question is, the committee has 
	7	previously assessed the risk of transmission of variant CJD 
	8	by blood and has made recommendations accordingly.  Based 
	9	upon the committee's assessment of the risk of transmission 
10	of variant CJD by human cells and tissue and considering the 
11	potential impact on supply, should the FDA recommend donor 
12	deferral criteria for possible exposure to the BSE agent? 
13		Stan, you are first. 
14		DR. PRUSINER:  I say yes. 
15		DR. WILLIAMS:  Yes. 
16		DR. LURIE:  Yes. 
17		DR. CLIVER:  Yes. 

18		DR. BELAY:  No. 
19		DR. BROWN:  No. 
20		DR. BOLTON:  No. 
21		DR. NELSON:  No. 
22		DR. GAYLOR:  Yes. 

23		DR. PICCARDO:  Yes. 
24		DR. McCURDY:  No. 
25		DR. BURKE:  No. 

						29 
	1		DR. EWENSTEIN:  Yes. 
	2		DR. DETWILER:  Yes. 
	3		DR. ROOS:  Yes. 
	4		DR. FREAS:  To verify the no votes, the no votes 
	5	were Drs. Burke, McCurdy, Nelson, Bolton, Brown and Belay. 
	6	That is six no votes, nine yes votes, no abstentions. 
	7		DR. BROWN:  What deferral criteria should the FDA 
	8	recommend; exclusion only for certain types of cells and 
	9	tissues?  Let's tackle that one first, those who have voted 
10	for some form of deferral.  Linda? 
11		DR. DETWILER:  Paul, as I understood it, or this 
12	is another question here, there is this other possibility of 
13	testing, like on the cadavers, or is that-- 
14		DR. BROWN:  That is not, I think, a part of any 
15	yes vote; that is, there are no qualifiers attached to that. 
16	You can add, or we can add, that as a deferral criterion. 
17		DR. DETWILER:  That is where I would like to go in 
18	that realm of adding that as a deferral criterion. 
19		DR. BROWN:  Let's add, as small Roman numeral v. 
20	here-- 
21		DR. PRUSINER:  Big Roman numeral V. 
22		DR. BROWN:  Big or little, how do you want to word 
23	it, as a recommendation for PrP testing, a recommendation 
24	for PrP codon 129 testing? 
25		DR. DETWILER:  I will leave that to the human but 

					30 
	1	definitely PrP in tissue. 
	2		DR. BROWN:  So as a criterion, we will say, PrP 
	3	detection test. 
	4		DR. LEITMAN:  Is this recommendation for all 
	5	cadavers from which tissue is to be harvested?  Any tissue? 
	6		DR. DETWILER:  That could be discussed.  I 
	7	definitely think for, like, cornea and the dura mater, these 
	8	very high-risk situations. 
	9		DR. LEITMAN:  For brain tissue that makes sense. 
10		DR. DETWILER:  Or eye tissue. 

11		DR. LEITMAN:  That's brain. 
12		DR. BROWN:  I think it would have to be brain 
13	tissue.  I think you might get some false security if you 

14	got a negative on any other tissue that we know about.  So 
15	it would be PrP detection test on brain tissue. 
16		DR. LEITMAN:  So my question, if you are 
17	harvesting and it is not a recent death and it is not part 
18	of the brain, if it is recent death and you are harvesting 
19	kidneys or-- 
20		DR. BROWN:  My understanding is that then you 
21	would get a brain biopsy before you administer the kidney. 
22	Is that right?  Do we all understand that? 
23		DR. DETWILER:  Correct. 
24		DR. CLIVER:  Would this apply only to people who 
25	would be deferred under the criteria we have established for 

					31 
	1	blood, though?  We are not going to say universal brain 
	2	testing for every donor, say, in the United States. 
	3		DR. BROWN:  I think the exclusions are totally up 
	4	for grabs.  They are not dependent on what has been already 
	5	recommended for blood. 
	6		DR. CLIVER:  But, once again, people who have 
	7	never set foot outside the United States would not come 
	8	under this at all, I should hope. 
	9		DR. BROWN:  That is the way I read it.  We are 
10	talking about deferral. 
11		DR. CLIVER:  Okay; that is what I wanted to 
12	verify. 
13		DR. PICCARDO:  Paul, regarding PrP testing, Linda 
14	mentioned two things, which is immunohistochemistry and 
15	Western blot.  My question to the FDA people is if the 
16	Western blot has been approved as a diagnostic test.  I 
17	think it has not. 
18		DR. BROWN:  I think the answer is no on both 
19	counts.  There is no validated test for PrP in this country. 
20		DR. PICCARDO:  Anyhow, I agree with what has been 
21	said.  I think it is a valid way to go. 
22		DR. BROWN:  Since we are talking cadavers, could 
23	we also add that it should be a Western blot rather than--or 
24	should it be an either/or?  I think most people consider the 
25	Western blot, a quick tissue extraction and Western blot to 

				32 
	1	be the most sensitive detection of PrP. 
	2		I would think, since we have got a dead body, that 
	3	we ought to get the optimal test. 
	4		DR. DeARMOND:  I don't think you know that.  We 
	5	don't know whether if a two-site immunoreactive--we are not 
	6	sure that a two-site IRMA or some other type of biochemical 
	7	test isn't more sensitive and is as specific.  That hasn't 

	8	been determined.  So I would leave it open that PrP testing 
	9	by Western or any other technique that will specifically 

10	identify it.  I don't think you want to box yourself into 
11	Western. 
12		DR. BROWN:  That is probably a good idea.  I don't 
13	see, at the moment, any way that you can persuade a critic 
14	that any immunohistochemical test is not picking up normal 
15	PrP.  I don't buy into that but a lot of people do. 
16		DR. DeARMOND:  I don't either because I do the 
17	immunohistochemical and we can see the smallest amount in 

18	one brain region.  But, in the practicality, you can't do 
19	that for a rapid test because that requires serially 
20	sectioning the brain. 
21		DR. McCURDY:  You might get around it by just 
22	recommending a validated test and let FDA decide how it 
23	should be validated. 
24		DR. BROWN:  That is a good idea.  Let's word it, 
25	"a validated PrP detection test on brain tissue." 

				33 
	1		DR. LEITMAN:  This is still very fuzzy.  The 
	2	commerce, the commercial traffic, in organs from cadavers 
	3	from overseas must be infinitesimally small unless I am 
	4	missing something.  Most of the deaths from which organs are 
	5	obtained in the U.S. are traffic accidents or murders or 

	6	homicides or I am not sure what in which case most of the 
	7	time, you can't get a travel history. 
	8		So I don't know what this is going to be applied 
	9	to.  For someone who dies who was a former immigrant from 
10	England, but that is going to be a very rare case--so what 
11	are we asking that this be applied to? 

12		DR. BROWN:  Cadavers that have lived more than six 
13	months in Great Britain. 
14		Jay, did you want to say something before Dave?  I 
15	didn't recognize you.  I'm sorry. 
16		DR. EPSTEIN:  I think the committee has gotten 
17	around to recognize that FDA cannot recommend an unapproved 
18	test.  So we hear the comment that when tests become 
19	available, we should make use of them.  I think that is self 
20	evident.  I think the point Susan is making is in what 
21	setting is it applied? 
22		Is it applied to all donations?  Is it applied 

23	only when there is a positive travel history, a residency 
24	history, or is it applied only when you have both a travel 
25	history and a high-risk tissue or is it applied always to a 

					34 
	1	high-risk tissue regardless of the travel history? 
	2		I think that is the useful thing to be advised on 
	3	now.  To tell us to recommend a test when there is no test 

	4	is sort of moot although I appreciate the importance of 
	5	raising our awareness that that is where we want to go. 
	6		DR. BROWN:  I think the FDA should take under 
	7	advisement the committee's enthusiasm for testing and, 
	8	perhaps, initiate or invite candidates to validate. 
	9		DR. BURKE:  Let me point out there is not a 
10	consensus on the enthusiasm for this.  We have not 
11	established that point. 
12		DR. BROWN:  Okay. 

13		DR. EPSTEIN:  You see, the thing is that right now 
14	we don't have a test and right now we could ask for history. 
15	So we want to be advised on whether we should be doing that 
16	as an interim measure or a permanent measure, whether or not 
17	tests come down the road. 
18		I think the comments, obviously, are helpful about 
19	testing although whether to do it and when to do it is, I 
20	think, the tricky part. 
21		DR. BROWN:  It is true, and I am somewhat to blame 
22	for confusing the issue because I was thinking about testing 
23	globally, not just in terms of residence histories but one 
24	of your criteria for regulation or guidance in terms of 

25	safety of tissues and cells irrespective of deferrals and 

					35 
	1	travel history, just as a good idea to include in the mix of 
	2	things that you consider for safe administration of tissues 
	3	and cells. 
	4		DR. PRUSINER:  I think you are absolutely right. 
	5	That is, I think, the sensible approach that you come to as 
	6	you go through this discussion. 
	7		DR. BROWN:  Don, you were not enthusiastic.  Tell 
	8	us about that. 
	9		DR. BURKE:  In principle, I am enthusiastic about 
10	using tests where they are available, but the implementation 
11	of a test before it is ready can lead to huge problems.  I 
12	lived through the development of the AIDS diagnostics and 
13	the criteria for interpretation of Western blot and what you 
14	tell people who you have false-positives with. 
15		So there are a huge number of potential problems 
16	that come out of employing a diagnostic before it is ready. 
17	That is my reason for conservatism here. 
18		DR. BROWN:  We did include the word "validated" in 
19	this criterion. 
20		DR. BURKE:  That's fine.  And, as was pointed out, 
21	when it is validated, then it may be time to talk about it. 
22		DR. BROWN:  Well, you can talk about it any time. 
23	We are not recommending a test be done before it is 
24	validated.  We are not recommending implementations.  We are 
25	simply saying that this would be an excellent criterion if 

				36 
	1	such a test is validated. 
	2		DR. BURKE:  And I will be very supportive at that 
	3	time. 
	4		DR. BROWN:  Then I can reinsert the word 
	5	"enthusiastic?" 
	6		DR. BURKE:  You can use enthusiasm for a validated 
	7	test; yes. 
	8		DR. CONFER:  Dennis Confer from National Marrow 
	9	Donor Program.  I would like to give the committee a little 
10	information that might help you put risk in perspective. 

11	Regarding hematopoietic stem-cell transplant recipients, 
12	particularly the unrelated donor type that we are really 
13	concerned with, the vast majority of these patients have a 
14	life expectancy without transplant that is on the order of 
15	one to two years. 
16		75 percent of the people we transplant have 

17	cancer.  Those are almost all leukemias in various forms or 
18	lymphomas.  The remaining 25 percent either have acquired 
19	bone-marrow failure, aplastic anemia, or they are children 
20	with various inborn errors of metabolism like the Hurler's 
21	syndrome and the like who have a life expectancy of a few 
22	years untransplanted or they are children with immune 
23	deficiencies who have a life expectancy of several months, 
24	untransplanted. 
25		Patients who undergo hematopoietic stem-cell 

				37 
	1	transplant from an unrelated donor have a 40 percent 
	2	mortality in the first three months.  So these patients, 

	3	when they have decided to go to transplant, have already 
	4	accepted huge risks, have terrible underlying diseases. 

	5		I think that discussing with these patients the 
	6	risk of TSE in that setting is a minor risk to those 
	7	patients.  I don't think that testing should be done on the 
	8	unrelated donors, on their stem-cell products.  I don't 
	9	think that these donors should be deferred when they are the 
10	best donor for the patient who is trying to survive what is 
11	otherwise a fatal disease. 
12		DR. BROWN:  Of course, that could apply also to 
13	dura mater which is used very often on patients with 
14	diseases just as serious as those you have mentioned, but we 
15	still do it. 
16		DR. McCURDY:  Thinking it over, it seems to me 
17	that, to address Jay's question, where you should use it now 
18	might--now being when it is validated for this purpose-- 
19	would be when you are transplanting neural tissue, corneas, 
20	dura, and that sort of thing, that when you get a test that 
21	is validated for use on blood, then it might be reasonable, 
22	or will be reasonable, I think, to apply it to other tissues 
23	most of which are perfused with blood. 
24		But recommending application of a test to other 

25	than neural tissue at the present time is quite a ways in 

				38 
	1	the future, I think. 
	2		DR. BROWN:  We have already decided that we are 
	3	not going to do that.  In fact, the question is worded, "If 
	4	yes, what deferral criteria should FDA recommend?"  It would 
	5	be reasonable to answer that, "validated positive PrP- 
	6	detection test in brain."  That would be a recommended 
	7	deferral criterion. 
	8		What about deferral criteria otherwise listed in 
	9	terms of different cells and tissues, countries of 
10	visitation and time of exposure?  Do we need to consider 
11	each one of these in turn? 
12		DR. BOLTON:  I would like to say that, except for 
13	dura mater and cornea, I would prefer that no deferrals--of 
14	course, I voted no to the first part, but if we are going to 
15	suggest deferral criteria, I think, for those two tissues, 
16	it makes sense.  For the other ones, I would still prefer to 
17	see that decision left up to the transplanting physician and 
18	the recipient. 
19		DR. EWENSTEIN:  I think we are trying to grapple 
20	with an almost bewildering number of different tissues for 
21	which we have not had the same sort of formal presentations 
22	and analyses that we were able to have for blood.  But I 
23	think that what we are trying to leave the FDA with is a 
24	sense that there are high-risk tissues that I think we agree 
25	on, that there are probably very low-risk tissues. 

				39 
	1		I think that the high-risk tissues should be 
	2	considered at least with the same criteria that we have 
	3	considered blood which is probably a low-risk tissue, except 
	4	that we do a lot of it. 
	5		I just reiterate my own personal concern about the 
	6	semen donations not in the personal-donor-directed use but 
	7	especially in the anonymous banks because I think there is a 
	8	different level of responsibility with that kind of tissue. 
	9	I would just leave that one in an unknown category until we 
10	have some additional data on that. 
11		DR. BROWN:  So we have exclusion only for certain 
12	types of cells and tissues.  Question; which ones?  We will 
13	vote on this but, in terms of phrasing the question, should 
14	I put down, for which ones, cornea, dura.  Is there any 
15	sentiment for listing others other than I think you want 
16	embryos and semen?  That is a difficult thing to vote on 
17	because some people, for example, might not agree with semen 
18	and embryos but they would want cornea and dura. 
19		It is possible that we should not vote on this at 
20	all and just discuss it and give the FDA a sense of what 
21	tissues.  On the other hand, you guys have already said you 
22	want a deferral.  You have got to have it concrete. 
23		DR. DETWILER:  Just semen, again, in the animal 

24	species with TSEs, both in sheep and in cattle, in sheep 
25	even with wide peripheral-tissue distribution of 

				40 
	1	infectivity, the work done with semen--again, the animal 
	2	numbers were limited--but when you took semen and inoculate 
	3	right into mice, they were unable to cause disease and then, 
	4	collected from infected rams, watched the progeny and there 
	5	was no evidence of transmission. 
	6		The same thing with BSE with even more work done 
	7	with BSE. 
	8		DR. BROWN:  Those of you who voted yes, you better 
	9	come up with something. 
10		DR. EWENSTEIN:  There was a slide, and I don't 
11	remember exactly how it was phrased, but there were certain 
12	exclusions that the FDA had placed.  I think some of our 

13	concerns were already recognized on that slide.  Could we 
14	look at that again because I think it covered--I think it 
15	left the appropriate doors.  It had to do with medical 
16	emergencies.  It had to do with some other very particular 
17	circumstances where I think we would all agree that the 
18	benefit outweighed the risk. 

19		DR. BROWN:  The other way that I could handle this 
20	would be to ask those people who did vote yes individually 
21	to stipulate which tissues they want to be the subject of 
22	deferral. 
23		DR. EWENSTEIN:  If we could just look at the 

24	slide.  I think this was well thought out and I think it 
25	covered a lot of the issues that we would be most concerned 

				41 
	1	with.  I think that we have already discussed this in a 
	2	couple of different possible settings but I think if you 
	3	think about it, it eliminates most of the risk to the 
	4	benefit, if you will, of some of these procedures. 
	5		So what we are really left with are either the 
	6	more anonymous donations or the donations where there is-- 
	7	well, by this exclusion, there is not an urgent medical need 
	8	that will be unmet. 
	9		DR. BROWN:  It is not prohibited if there is 
10	documented urgent medical need.  A neurosurgeon might say 
11	there is an urgent medical need.  I am in the middle of an 
12	operation.  I better use a dura.  Urgent medical need is a 
13	loose phrase and subject to a great deal of interpretation. 
14		DR. EWENSTEIN:  Even for the use of unapproved 
15	drugs where we don't even have the time, necessarily, to get 
16	the proper human subjects' consent and the like, we are 
17	always allowed, as physicians, that last escape clause.  I 
18	think that is appropriate.  You do have to justify it 
19	afterwards. 
20		DR. BROWN:  You had brief comment? 
21		DR. DuBORD:  Yes.  Paul DuBord.  I am speaking as 
22	a transplant surgeon and not as a representative of any 

23	organization.  I heard the description of CJD being very 
24	high risk.  I think it is important to recognize that you 
25	have the stability of CJD elsewhere in the world except for 

						42 
	1	variant CJD of 1 to 1.2 in a million. 
	2		To describe that as high risk, I think we have to 
	3	be careful of how we look at that. 
	4		DR. BROWN:  We are talking exclusively about 
	5	variant. 
	6		DR. DuBORD:  We are talking exclusive variant CJD. 
	7		DR. BROWN:  And we don't know what the risk of 
	8	variant is. 
	9		DR. DuBORD:  And we don't know a whole lot about 
10	this particular disease process. 
11		DR. BROWN:  It seems to me what you are saying 
12	about classical CJD is irrelevant to the discussion. 
13		DR. DuBORD:  Okay.  We will discard that.  But the 
14	classic CJD is pretty stable.  Variant CJD, there are so 

15	many unknowns about that.  It has never been transmitted, 
16	that we know of. 
17		DR. BROWN:  It has only been around a little 
18	while. 
19		DR. DuBORD:  That's correct and we have long 
20	incubation periods. 
21		DR. BROWN:  I will let you continue; go ahead. 
22		DR. DuBORD:  Thank you.  But I think we have to 
23	look at the risk-management issues here and look at the 
24	risk/benefit ratio we have for the donors.  Some of the 
25	things that you are talking about or throwing around this 

				43 
	1	morning have enormous negative impact, from the 
	2	administrative point of view, from the technical point of 
	3	view, from the financial point of view, and, basically, may 
	4	have no real benefit to the patients. 
	5		That is the bottom line is what benefit are we 
	6	going to give these patients.  Are we kidding ourselves here 
	7	when we don't know a lot about this particular issue.  I 
	8	think we really have to look at the risk-management issues 
	9	and the benefits of the decision that you are making. 
10		Thank you. 
11		DR. BOLTON:  I would like to make a comment on 
12	that as well, that in the case--we are going back and 
13	comparing this with the risk of blood contamination in the 
14	blood supply.  I think that there are different 
15	epidemiological considerations in that. 
16		The blood supply, if it were contaminated, 
17	especially in pooled blood or there were systematic problems 
18	that were resulting in many units being contaminated, that 
19	could result in an amplification and a much more serious 
20	epidemic whereas most of these issues are one recipient at a 
21	time and it is much less of a concern. 
22		So I think that it makes more sense to allow the 
23	recipient and the physician to consider these on an 
24	individual basis rather than trying to legislate things or 
25	make exclusions from a much broader population. 

					44 
	1		DR. BELAY:  I agree with what David said.  The 
	2	single overriding decision-making process, in my mind, 

	3	should be whether or not we are hurting any patients, 
	4	whether or not we are decreasing the supply or the 
	5	availability of any tissues or products for the patients. 
	6		That is one of the reasons I voted no for this 
	7	question. 
	8		DR. BROWN:  I think we can vote on A.  We have 
	9	just been relieved of the responsibility of having to vote 
10	on B.  The committee always wants additional data so why 
11	don't we vote on A. and send a signal to the FDA that we 
12	need more data, if they haven't already got it. 
13		DR. BOLTON:  A. only comes into play if we voted 

14	no.  Since we voted yes--I mean, the yes carried.  I didn't 
15	vote yes. 
16		DR. BROWN:  I can't have it both ways. 
17		DR. BOLTON:  That's right. 
18		DR. BROWN:  I had hoped no one would notice that. 
19		DR. BOLTON:  I should have been quiet. 
20		DR. ROOS:  David's point is that these issues 
21	should be discussed between the physician and the recipient, 
22	but, in order for that discussion to be held, you need data. 
23	So I think travel history and the issues with respect to 
24	blood provide some useful data.  This doesn't mean that the 
25	donor is deferred and won't be used.  It just means that 

				45 
	1	these donors and the donations are in a different category 
	2	and labeled as such, and there is information available that 
	3	might be of value. 
	4		In other words, it could be that if you are the 
	5	recipient, you would prefer to get an American cornea than a 
	6	U.K. or maybe even skin from an American rather than a U.K. 
	7	So I think this is valuable information, especially because 
	8	we really don't know the tissue distribution. 
	9		I am not saying that we would discard the tissue 
10	but just label it and get the information that is important. 
11		DR. BOLTON:  Ray, I would agree with you but my 
12	understanding is that if the FDA were to adopt a deferral 
13	policy, that, essentially, those tissues would not be used, 
14	and those donors would not be-- 
15		DR. ROOS:  Yes; my definition of deferral here was 
16	different from yours.  In other words, I think they are 
17	identified and described and I think of things, perhaps, in 
18	two tiers and designated as such rather than rejected. 
19		DR. EWENSTEIN:  But I think you have to think 
20	about what we are saying here.  A man shows up and says, "I 
21	have been in the U.K. for a year during the high-risk period 
22	and I would like to give some blood today.  I would also 
23	like to sign a card that, if I get into an auto accident on 
24	my way home, you can have my cornea." 
25		And we say, "No; you can't give the blood but we 

				46 
	1	are not going to worry about it when it comes to the 
	2	cornea."  Yet, we have never transmitted a TSE to a human 

	3	through blood but we at least have one documented case-- 
	4	obviously, the denominators are going to be very small 
	5	because the natural incidence of CJD is so small. 
	6		We already have at least one documented case, 
	7	maybe a couple of other cases, plus some experimental data 
	8	that it may be possible.  So it seems to me, administrative 
	9	concerns aside, that it makes no sense to have that same 
10	person deferred from blood and not from cornea. 
11		There may be circumstances where we just don't 
12	know.  I am not sure that the risk is great enough that, in 
13	the absence of a medical history or travel history, we are 
14	going to defer the unknown patients.  Maybe that is an 
15	unreasonable position.  But if we know, and we have already 
16	deferred him from blood, I can't see taking the cornea. 
17		DR. BOLTON:  But I specifically said dura mater 
18	and corneas.  I don't have an objection to that deferral. 
19	But if you are looking at a bone-marrow transplant and your 
20	perfect match has been in the U.K. for seven months, that 
21	seems to me an insignificant risk considering everything 
22	else that is going on. 
23		I would rather have the physician and the 
24	recipient be able to make that decision rather than the FDA 
25	to say, "I'm sorry; that donor is deferred.  You can't have 

					47 
	1	that bone marrow." 
	2		DR. EWENSTEIN:  Yes.  I think in donor-directed 
	3	cases, and you can define it in a couple of ways based on 
	4	tissue matching or for reproductive reasons based on family 
	5	circumstances, then you can do this as a one-on-one 
	6	discussion.  Where it is going into an anonymous pool, I am 
	7	saying it makes no sense to put the cornea into an anonymous 
	8	pool if you have decided you can't put the blood into that 
	9	anonymous pool. 
10		DR. BROWN:  Nick, quickly, and then we are going 
11	to finish. 
12		DR. HOGAN:  I want to make a couple of quick 
13	recommendations here from my perspective.  First of all, if 
14	you are talking about exclusionary criteria with history, 

15	you are talking about all of the medical-examiner cases 
16	probably not being able to get histories, so we are 
17	excluding all of those that we talked about yesterday. 
18		So you are not going to be able to get a travel 
19	history from those.  That is fine as long as you are aware 
20	of that. 
21		DR. BROWN:  We are not on this question, yet, 
22	Nick.  That is the next question. 
23		DR. HOGAN:  Secondly, there are no corneas 
24	imported from Europe.  Thirdly, if you implement a test, we 
25	are talking about 45,000 cases for a very small risk, huge 

				48 
	1	administrative problems.  I know you have already addressed 
	2	that but it is important to consider when you talk about an 
	3	unvalidated test. 
	4		DR. LEITMAN:  Could I say one thing? 
	5		DR. BROWN:  Yes; go ahead. 
	6		DR. LEITMAN:  In this slide and the one preceding 
	7	it--no; not this one, the ones that Bruce asked for that 

	8	were put up, FDA already has policies in place for donor- 
	9	directed tissues, if you will.  I propose that those are 
10	adequate from the discussion that I have just listened to 
11	now from the data that was presented and that we don't 
12	recommend that FDA make any changes right now in those. 
13		There is already a requirement for biohazard 

14	labeling, for the physician being notified of results, for 
15	getting informed consent.  So that seems to be adequate 
16	right now, given the uniqueness of those tissues. 
17		And then I want to comment on Bruce's comment. 
18	Blood is available in greater--slightly, hopefully, greater 
19	supply than the need.  But we have heard today and yesterday 
20	that organs are not.  That is the big difference.  I have no 
21	problem telling a donor that they are excluded from donation 
22	because of a one-year sabbatical in London, which we do all 
23	the time. 
24		I have a problem telling them to take their organ- 
25	donor card out of their wallet.  I think it is a different 

				49 
	1	level of urgency, of need, of tissues that can be obtained 
	2	and impact on patients. 
	3		DR. BROWN:  I'm sorry, committee.  We are moving 
	4	on.  What we are leaving the FDA with is what they are-- 
	5		DR. SOLOMON:  I just wanted, for the record, to 
	6	say we are not considering organs in this discussion. 
	7		DR. BROWN:  That's right.  Organs are not covered. 
	8	It is clear, the one thing from this discussion that is 
	9	clear is that there is a great variety of approaches to this 
10	issue as discussed by this committee, that there is no 
11	consensus by the committee on the exact stipulations of 
12	donor-deferral criteria.  That message has come across very 
13	clear. 
14		A close vote on whether or not the FDA should get 
15	involved in donor deferral at all and no possibility of 
16	arriving at a consensus as to what kind of criteria should 
17	be used.  So the FDA is satisfied with our discussion, our 
18	marginal but definite decision, that the FDA should consider 
19	deferral criteria and an inability to have a consensus about 
20	exactly what those criteria should be. 
21		We are moving on to the next question which is the 
22	final question on this topic before we move to chronic 
23	wasting disease and that is, if a deferral policy were to be 
24	put in place, could information about the donor's risk 

25	factors for CJD and variant CJD be obtained; i.e., is a 

				50 
	1	donor medical history interview required. 
	2		If there is no discussion, we will vote on that 
	3	question.  The question is, is a donor medical-history 
	4	interview a requirement for--actually, that is not how the 
	5	question reads.  I mean, I read the question, but if a 
	6	deferral policy is put in place, should a donor medical- 
	7	history interview be required. 
	8		DR. BOLTON:  Since we can't settle 2B about a 

	9	deferral policy, I think it seems pointless to argue and 
10	discuss much about 3. 
11		DR. BROWN:  I am happy with that. 
12		DR. CLIVER:  One small afterthought, though.  I 
13	think we could recommend that, at such time as a validated 
14	PrP test for human brain tissue is available that, in these 
15	instances--not across the board for cornea donations, 
16	whatever, but in these instances, that we recommend that 
17	that be applied as a criterion lacking a donor medical- 
18	history interview. 

19		DR. LURIE:  I think, Paul, the other question here 
20	is a legal one that I certainly can't answer which is these, 
21	in effect, are state laws, unless I am incorrect about that. 
22	There is a question of whether or not the FDA has any 
23	authority to, in effect, overrule the state law for this 
24	limited group of people. 
25		MS. WARNER:  If I can clarify that last point 

				51 
	1	about the state laws.  We do have authority to overrule or 
	2	preempt those state laws if it were appropriate, in the 
	3	interest of public health.  So what we are asking is whether 
	4	it would be appropriate to preempt those laws to the extent 
	5	that it would be necessary to obtain a donor medical 
	6	history. 
	7		DR. BROWN:  Stan? 
	8		DR. PRUSINER:  I was just going to say that I 
	9	think, stepping back from this for a moment and trying to 
10	look ahead, there will be validated tests.  They will come 
11	along and, at that point, then whoever is on this committee 
12	will sit down, reconsider all this and, from that landscape, 
13	you will come away with, I think, some much more clear 
14	recommendations. 
15		We are having a very fuzzy time because we are 

16	trying to put several hypothetical issues on the table, 
17	things that are going to happen in the future.  So I think 
18	that to try to come to conclusions now is extremely 
19	difficult because we don't have these kinds of things in 
20	place. 
21		DR. ROOS:  We, of course, actually made 
22	recommendations with respect to dura mater both local as 
23	well as international sources in which we recommended a 

24	validated test.  I think that that is reasonable, perhaps, 
25	to extend to corneas when that test is, in fact, available. 

				52 
	1		I think, with respect to the travel history, if 
	2	one cannot obtain a history, from my perspective, the cornea 
	3	still could be used for transplantation.  But, again, 
	4	perhaps some description of this cornea in the absence of a 
	5	travel history should be linked to that particular tissue. 
	6		In other words, I think it would be a mistake to 
	7	restrict the supply of corneas because of somebody in an 
	8	accident and this inability to obtain a history in time.  On 
	9	the other hand, I think it might be a good description of 
10	the sample, itself, and information that could be shared 
11	with the recipient. 
12		DR. BROWN:  Laura? 
13		DR. MANUELIDIS:  I still have a little bit more 

14	concern about bone marrow than the rest of the committee 
15	even more so than blood because remember that these cells 
16	can live for a long time in the recipient.  So it is not 
17	like something that is thrown out.  I think that is the 
18	problem with tissue and cells is that they can harbor 

19	something in a small amount and come out much later simply 
20	because you don't get rid of them. 
21		I think that is one of the problems with something 
22	which is acellular, for example, like dura mater which can 
23	just harbor some stuff and nonspecifically stick to 
24	infectivity.  I think that you really have to think about 
25	that when you talk about tissues. 

				53 
	1		So I think that is something that you should not 
	2	exclude, necessarily. 
	3		DR. DAVEY:  Paul, I think, also, and maybe the FDA 
	4	can help me there--I think the FDA, on occasion, has 
	5	allowed, in their information sticker, if you will, on a 
	6	biological product, some kind of information stating that, 
	7	"This product has certain inherent risks such as," whatever. 
	8	Maybe there could be just a blanket labeling of these 
	9	products saying there is a small, but undefined, risk for 
10	certain diseases such as new variant CJD.  That might cover 
11	it. 
12		DR. BROWN:  A question, I guess, is whether or not 
13	the FDA really wants to get involved in anything on so 
14	little scientific evidence.  It may be a very prudent thing 
15	not to be ultraconservative for the next six to twelve 
16	months and wait until we have a little data on the 
17	distribution of infectivity in variant CJD before they 
18	promulgate recommendations. 
19		Clearly, the committee is at a loss simply because 
20	we don't know.  It has been my experience as the chairman 
21	that when these discussions become progressively diffuse, it 
22	is a good signal that we are arguing from no facts. 
23	Therefore, I think that is the end of this discussion. 
24		You can say what you would like. 
25		DR. KENNEDY:  Dr. Brown, what I was wanting to 

				54 
	1	mention is just a point from yesterday that the donors 
	2	obtained through legislative consent are much younger than 
	3	the other donors and so our calculations of risk that were 
	4	presented yesterday was that the risk among those donors is 
	5	approximately 40 percent less already than it is among other 
	6	donors. 
	7		If you lose those donors by requiring a medical- 
	8	history interview, you may actually end up leaving the 
	9	average level of risk in remaining donors greater than what 
10	it is now. 
11		DR. BROWN:  Right.  I think we appreciated that 
12	from your talk, Dr. Kennedy. 
13		We are going to move now on to Topic 3 which is a 
14	discussion of issues related to chronic wasting disease and 
15	its potential for human exposure. 

16		                Topic 3 
17	 Discussion of issues related to deer and elk infected with 
18	or exposed to chronic wasting disease in the U.S. and 
19	potential for human exposure to various animal TSE agents 
20	should be considered by the FDA in determining suitability 
21		            of blood donors 
22		DR. BROWN:  For this topic, we have a series of 
23	five speakers, the first of whom will talk about regulatory 
24	issues.  That is Dr. Brackett from the FDA. 

25		      FDA/CFSAN Regulatory Issues 

				55 
	1		DR. BRACKETT:  Thank you, Dr. Brown. 
	2		[Slide.] 
	3		My name is Bob Brackett and I am a senior 
	4	microbiologist and also serve as the lead for TSE issues in 
	5	FDA's Center for Food Safety and Applied Nutrition, or 

	6	CFSAN.  CFSAN is responsible for regulating cosmetics, 
	7	dietary supplements and most food products other than most 
	8	meats and poultries.  These last two products are regulated 
	9	by the United States Department of Agriculture. 
10		This morning, we are going to be discussing 
11	issue 3 which is chronic wasting disease, which is a TSE of 
12	elk and deer primarily in the western states.  But, before 
13	we actually hear some of the more detailed discussions by 
14	the following speakers on this issues, I wanted to provide 
15	you with a brief background of why FDA and CFSAN, in 
16	particular, is concerned about chronic wasting disease and 
17	how this issue came to be a subject for discussion at this 
18	meeting. 
19		Although I may touch upon some of the points that 

20	will later be discussed by the speakers following me, I will 
21	leave the details up to them.  My goal this morning, really, 
22	is to put the subject into perspective. 
23		The first point I would like to address is the 
24	question why is FDA even involved in chronic wasting disease 
25	issues.  After all, I mentioned only a moment ago that it 

				56 
	1	was UDSA who was responsible for regulating meats, and this 
	2	is true. 
	3		[Slide.] 
	4		USDA's Food Safety and Inspection Service has 
	5	regulatory authority over most meats.  However, the meat 
	6	products for which they have authority are very specific and 
	7	are listed under the Federal Meat Inspection Act.  These 
	8	animals include cattle, sheep, swine, goats, horses, mules 
	9	and reindeer. 
10		[Slide.] 
11		All other meat products, particular game meats 
12	such as elk and deer that are traded in interstate commerce 
13	fall under the regulatory authority of FDA. 
14		[Slide.] 
15		The legal framework under which FDA regulates deer 
16	and elk is the same as with all other foods that it 
17	regulates; namely, the Federal Food, Drug and Cosmetic Act 
18	and the Public Health Service Act.  Although deer and elk 

19	are not major food products in terms of production volume, 
20	FDA is, nevertheless, committed to assuring the safety of 
21	these products as well as the other products it regulates. 
22		I would like to also point out that animals that 

23	are harvested by hunters for their own use are not regulated 
24	by FDA and this is under the purview of the states. 
25		[Slide.] 

				57 
	1		The primary reason why FDA has focused on chronic 
	2	wasting disease at this time is really an indirect result of 
	3	the growth of the elk and deer industry in the recent years. 
	4	The breeding and raising of captive elk and deer is a small 
	5	but growing industry primarily in the West and in the 
	6	Midwest although it does occur in other states as well. 
	7		These animals are raised for a number of different 
	8	reasons including hunting stock, breeding stock for other 
	9	ranches, antler velvet or sometimes referred to as velvet 
10	antlers and, of course, meat. 
11		[Slide.] 
12		As you will probably hear from the speakers that 
13	will follow, chronic wasting disease was first identified in 
14	captive deer herd about thirty years ago.  Since that time, 
15	the disease has also been identified in wild dear and elk in 
16	Colorado and Wyoming and, just recently, in Nebraska as well 
17	as in captive herds in about five US states and at least one 
18	province in Canada. 
19		Chronic wasting disease has been primarily treated 
20	as an animal disease and has been addressed by state 
21	authorities, primarily state veterinarians.  At present, 
22	each state decides how best to handle cases of chronic 
23	wasting disease.  The actions could vary from something like 
24	destroying an entire herd in which chronic wasting disease 
25	was confirmed to simply quarantining suspect animals. 

				58 
	1		Most importantly, from FDA's food safety 
	2	perspective, however, is what happens to the products of 
	3	these animals. 
	4		[Slide.] 
	5		The possibility that deer and elk infected with a 
	6	TSE could be used for human food or cosmetic products put 
	7	this issue squarely into the responsibility of FDA.  It is, 
	8	in fact, this possibility that has prompted FDA to take a 
	9	closer look at this issue from the food-safety perspective. 
10	A more difficult related question concerns that of deer and 
11	elk that have been exposed to infected animals; that is, do 
12	exposed animals, but not necessarily clinically or 
13	pathologically positive, represent a risk for spreading a 
14	TSE to humans. 
15		[Slide.] 
16		Although no human illnesses have yet been traced 
17	to chronic wasting disease, at least one report, which was 
18	provided in the committee's packet, has been used as 
19	evidence to suggest that the question as to whether chronic 
20	wasting disease could be transmitted to humans is still 
21	valid. 
22		We are aware that there is research going on in 

23	this area that could support or refute this notion and we 
24	would hope that the committee members who are closer to the 
25	research would be able to provide us with some insight. 

				59 
	1		So, in closing, FDA questions whether or not 
	2	either deer or elk actually infected with chronic wasting 
	3	disease or those animals exposed to chronic wasting disease 
	4	could transmit a TSE to humans.  FDA will weigh the evidence 
	5	used to answer these questions in formulating policy and 
	6	deciding on actions in dealing with products of infected or 
	7	exposed animals. 
	8		With that, I will quickly read through the 
	9	questions. 
10		[Slide.] 
11		Question 1; are there scientific data or other 
12	scientific evidence for transmission of a TSE from an 
13	infected elk or deer to an uninfected elk or deer and, if 
14	so, how strong are these data or evidence. 
15		[Slide.] 
16		Are there scientific data or other scientific 
17	evidence for transmission of a TSE to people consuming or 
18	using products from deer and elk with chronic wasting 
19	disease.  If so, how strong are these data or evidence? 
20		[Slide.] 
21		Question 3, are there scientific data or other 
22	scientific evidence for a transmission of a TSE to people 
23	consuming or using products made from deer or elk exposed to 
24	chronic wasting disease.  If so, how strong are these data 
25	or evidence? 

				60 
	1		Then, a subpart of question 3, is the potential, 
	2	if any, for transmission to humans different depending on 
	3	the types of exposure; for example, the offspring of chronic 
	4	wasting disease-infected elk or deer, a pen mate of those 
	5	deer, animals that are in close proximity but not 
	6	necessarily in the same pen as the infected deer, animals 
	7	exposed to equipment used in the transportation or 
	8	slaughtering of these animals, or animals on the same ranch 
	9	with no direct contact with the infected deer. 
10		[Slide.] 
11		Question 4, are there scientific data or other 
12	scientific information assessing the potential or actual 
13	infectivity of different tissues or other animal parts from 
14	chronic wasting disease-infected deer or elk.  An example of 
15	these parts might include bone meat versus meat on the bone, 
16	neurological tissues, velvet antler, organs or glands, or 
17	byproducts of slaughtering such as gelatin. 
18		[Slide.] 
19		Question 5, if there is a potential for 
20	transmission of TSE from infected or exposed animals or 
21	animal parts to humans, what is the likelihood of 
22	transmission. 
23		Again, here is a subpart, is the potential, if 

24	any, for transmission to humans different depending on the 
25	route of administration to the tissue; for example, oral, 

				61 
	1	transdermal, inhalation or injection or other. 
	2		With that, we will go on with the speakers. 
	3		[Applause.] 
	4		DR. BROWN:  Thank you, Dr. Brackett.  A very clear 
	5	charge.  I think, for a change, we will be able to make some 
	6	recommendations based on science for topic 3. 
	7		We are going to have a discussion of background 
	8	information on chronic wasting disease presented by Dr. 
	9	Miller from the Colorado Division of Wildlife. 

10		 Background on Chronic Wasting Disease 
11		DR. MILLER:  Good morning. 
12		[Slide.] 
13		I have been asked to provide the committee with 
14	some background information on chronic wasting disease of 
15	deer and elk as a foundation for the rest of today's 
16	discussions.  I am sure that all of you, as members of this 

17	advisory committee, are at least somewhat familiar with this 
18	disease so much of this is probably going to be review for 
19	you. 
20		In the next twenty minutes or so, I plan to 
21	briefly review some of the key features of chronic wasting 
22	disease, its history, our approaches to understanding its 
23	distribution and occurrence and what we currently know about 
24	its status in both free-ranging and farm cervids. 
25		The information I am going to provide is a 

				62 
	1	synthesis of data, much of it previously published--it has 
	2	been generated by a number of very talented scientists who 
	3	have been collectively and collaboratively working on 
	4	chronic wasting disease for over two decades. 
	5		In particular, please recognize the contributions 
	6	of Drs. Beth Williams, Terry Spraker, Katherine O'Rourke, 
	7	Tom Thorne and Stuart Young who have all made substantial 
	8	contributions to our collective understanding of chronic 
	9	wasting disease in deer and elk. 
10		[Slide.] 
11		Chronic wasting disease, or CWD, as most folks 
12	prefer to refer to it, is a naturally occurring 
13	transmissible spongiform encephalopathy affecting native 
14	North American cervids.  It is believed to be caused by one 
15	or more unique strains of infectious self-replicating prion 
16	protein. 
17		The strain of prion that causes CWD is 
18	demonstrably different from the strain that causes BSE and 
19	also appears different from at least U.K. scrapie strains. 
20	The true origin of CWD remains unknown despite what you may 
21	read on the web or in the newspaper.  Whether it began in 
22	scrapie or as a sporadic disease of deer or elk is, and 
23	probably always will be, a mystery. 
24		The known natural host range for CWD is limited to 
25	three cervid species from two genera; mule deer and white- 

			63 
	1	tail deer from the genus Odocoileus and elk from the genus 
	2	Cervus.  All three species show comparable susceptibility to 
	3	CWD but there do appear to be some species or genus-specific 
	4	differences that may influence tissue distribution and 
	5	transmission. 
	6	          The hallmark clinical signs of chronic wasting 
	7	disease are emaciation and abnormal behavior.  In practice, 
	8	subtle changes in behavior attentiveness and locomotion can 
	9	be detected in most infected animals some months prior to 
10	the development of end-state clinical disease.  Intercurrent 
11	infections, particularly aspiration pneumonia and trauma, 
12	can confound both clinical and post-mortem diagnoses and, 
13	consequently, as with the other animal TSEs, laboratory 
14	diagnosis is necessary to confirm infections. 
15	          Important epidemiological features of CWD include 
16	a prolonged incubation period that averages somewhere in the 
17	range of twenty to thirty months with natural infections. 
18	Susceptibility to infection appears to be relatively uniform 
19	among species, between sexes and across age classes.  There 
20	is evidence for genetic influence on susceptibility in elk 
21	but not deer. 
22	          CWD appears to be maintained naturally in both 

23	captive and free-ranging cervid populations in the absence 
24	of exposure to contaminated feeds or other likely outside 
25	sources of infection.  Direct or indirect animal-to-animal 

				64 
	1	transmission, not necessarily along maternal lines, drives 
	2	epidemic dynamics.  In addition, contaminated environments 
	3	is likely play a role in epidemic dynamics and the 
	4	recurrence of disease in some situations. 
	5		[Slide.] 
	6		Chronic wasting disease is not a new prion 
	7	disease.  The clinical syndrome of chronic wasting was first 
	8	recognized in captive mule deer in Colorado in the late 
	9	1960s but actually tying the first recognition of a disease 
10	like this to its first occurrence seems like a substantial 
11	leap of faith. 
12		Based on what we know about its distribution and 
13	occurrence, it is quite plausible that CWD actually arose in 
14	captive and/or free-ranging cervids forty or more years ago. 
15	In 1977, Dr. Williams and Young recognized CWD as a TSE and, 
16	within a few years of finally having a clear-cut diagnostic 
17	criterion, chronic wasting disease was first detected in 

18	free-ranging elk and deer in Northeastern Colorado and 
19	Southeastern Wyoming. 
20		However, there almost certainly were cases prior 
21	to these first cases being detected in the early '80's. 
22	Similarly, the first diagnosis of CWD in a farmed elk was 
23	made in Saskatchewan in 1996.  In retrospect, this most 

24	assuredly was not the first case to occur in the elk 
25	industry in either Canada or the U.S.  So, although there 

				65 
	1	may be some value in recognizing these milestones in the 
	2	history of chronic wasting disease, it is important not to 
	3	interpret these as absolute time lines for the emergence of 
	4	this disease. 
	5		[Slide.] 
	6		Before proceeding into what we know about the 
	7	status of CWD in both free-ranging and farm cervids, I want 
	8	to provide a bit of context on how we have come to know what 
	9	we know.  To truly appreciate how much we know about chronic 
10	wasting disease, it is important to compare approaches for 
11	detecting CWD with traditional approaches for detecting TSEs 
12	in other animal species. 
13		Dr. O'Rourke is going to be talking about 
14	diagnostics in much greater detail so all I am going to 

15	offer for now is kind of a conceptual overview.  For both 
16	scrapie and BSE, there has tended to be a focus on clinical 
17	cases as a means of detecting new infections.  This is 

18	clearly an effective approach, particularly when such 
19	diseases are reportable, but there are biases and 
20	limitations inherent in this strategy. 
21		These surveillance programs are often conducted in 
22	an atmosphere of adversity where there may be substantial 

23	economic penalties for owners of infected animals or herds. 
24	The end result of all this is a strong tendency for 
25	underreporting of these diseases and, consequently, for 

				66 
	1	underestimating their severity. 
	2		[Slide.] 
	3		I hope all of you realize that animals showing 

	4	end-stage clinical disease represent just the tip of the 
	5	iceberg with respect to the overall infection rate in a 

	6	population of interest.  Those of us working with CWD also 
	7	recognized this some time ago and have modified our 
	8	surveillance programs accordingly. 
	9		[Slide.] 
10		Initially, we used histopathology, brain-stem 

11	samples, as an adjunct to surveilling populations for 
12	wasting disease and actually gained a much better 

13	appreciation of the size and shape of that iceberg. 
14		[Slide.] 
15		Beginning in 1996, we adopted immunohistochemistry 
16	of brain stem as our screening tool and, again, improved our 
17	appreciation of the iceberg's depth and magnitude. 
18		[Slide.] 
19		Since last year, thanks largely to the efforts of 
20	Drs. O'Rourke and Spraker, we have been able to use IHC of 
21	tonsillar tissues to gain an almost, but probably not 
22	entirely complete, picture of the CWD iceberg. 
23		[Slide.] 
24		We know even these IHC-based estimates of wasting 
25	disease prevalence are a little low, but, in fact, they are 

				67 
	1	much closer to truth than data that may be generated by 
	2	other means. 
	3		[Slide.] 
	4		Based on pathogenesis data from both experimental 
	5	and natural CWD infections in mule deer and assuming at 24- 
	6	month disease course, tonsillar IHC probably fails to detect 
	7	infections only in the first couple of months after 
	8	infection and is increasingly reliable as the disease 
	9	progresses.  The appearance of IHC staining in brain stem 
10	and subsequently the appearance of spongiform encephalopathy 
11	and clinical signs can also be used to stage disease and to 
12	confirm infections at the population level. 
13		Elk are somewhat more problematic, as Dr. O'Rourke 
14	is undoubtedly going to describe later.  Overall, however, 
15	the approaches currently used to detect wasting disease do 
16	offer a much higher probability of detecting cases than 
17	reliance on clinical disease alone. 
18		[Slide.] 
19		Another important point is that the surveillance 
20	systems for chronic wasting disease in free-ranging wildlife 
21	evolved in the absence of regulatory or economic pressure. 
22	To date, the motivations for reliably estimating the 
23	distribution and prevalence of chronic wasting disease in 
24	native wildlife populations have been two-fold. 
25		One is scientific curiosity.  The second is an 

				68 
	1	accompanying sense of responsibility for both acquiring and 
	2	conveying to the public accurate information about this 
	3	disease and its occurrence in public resources. 
	4		Similarly, the farmed-elk industry recognized 
	5	early on the value of detecting chronic wasting disease in 
	6	their herds as a basis for effective disease management.  In 
	7	this environment, three somewhat distinct approaches to 
	8	surveillance have evolved and are currently in use in 
	9	varying combinations. 
10		Appreciation of the details of these applications 
11	is important, I think, in understanding the data on CWD 
12	status. 
13		[Slide.] 
14		The foregoing caveats not withstanding, 
15	surveillance for clinical suspects remains an effective tool 
16	for detecting new foci of wasting disease infection in both 
17	captive and free-ranging settings.  Under these systems, 
18	clinical suspects are samples whenever they are available. 
19	Histopath of brain stem is usually sufficient to make a 
20	diagnosis that I see as a welcome adjunct.  Data are clearly 
21	biased, though, and consequently of little use in estimating 
22	prevalence. 
23		This approach is actually very similar to 
24	traditional scrapie surveillance in the U.S. 
25		[Slide.] 

				69 
	1		In some captive settings, wasting disease 
	2	surveillance is extending, though, and has been applied to 
	3	all natural mortalities and, in some cases, to all 
	4	mortalities regardless of proximate cause.  Several states 
	5	and the Canadian government have adopted this approach in 
	6	rules that regulate their elk industries. 
	7		Mortality-based surveillance is also an effective 
	8	tool for detecting new foci of infection and has resulted in 
	9	the disclosure of several infected elk farms over the last 
10	three years.  Here, again, histopath of brain stem is 
11	usually sufficient but IHC is also a useful tool. 
12		Inherent biases in these data limit their uses in, 
13	again, estimating prevalence.  This approach is considerably 
14	more aggressive than traditional scrapie surveillance in the 
15	U.S. and has facilitated CWD detection in the elk industry. 
16		[Slide.] 
17		Finally, those of us investigating wasting disease 
18	in free-ranging populations over the last decade have 
19	developed efficient techniques for conducting geographically 
20	targeted random sampling of harvested deer and elk to 
21	estimate prevalence and monitor trends.  In these surveys, 
22	sections of obex and, more recently, tonsillar collected and 
23	examined via immunohistochemical.  Infections can be staged 
24	further by histopath. 
25		Data from these samples represent relatively 

				70 
	1	unbiased point estimates of CWD prevalence.  Unfortunately, 
	2	comparable slaughter-survey data for scrapie and BSE have 
	3	not been reported formally confounding comparisons of 
	4	epidemic severity between wasting disease and, for example, 
	5	scrapie in the U.S. 
	6		This lack of comparable data has perhaps fostered 
	7	some of the popular misconceptions of about chronic wasting 
	8	disease. 
	9		[Slide.] 
10		Using various combinations of these three 
11	surveillance approaches, we have developed a good basic 
12	understanding of CWD status in North America.  At present, 
13	there do appear to be two distinct epidemics occurring in 
14	North American cervid populations.  One epidemic focuses 
15	free-ranging cervids in southeastern Wyoming, northeastern 
16	Colorado and extreme southwestern Nebraska. 
17		The other epidemic is occurring in a relatively 
18	small number of farms or elk herds scattered across the U.S. 
19	and Canada.  Although a common source for both epidemics has 
20	been speculated and would certainly be the most parsimonious 
21	way to explain the origins of wasting disease, no common 
22	thread actually linking all of these events has been 
23	demonstrated to date. 
24		[Slide.] 
25		Alternatively, not knowing how or when chronic 

				71 
	1	wasting disease originated in the first place, it is 
	2	conceivable that whatever event gave rise to wasting disease 
	3	once could have occurred again in farmed elk and that the 
	4	two epidemics are, in fact, not directly related. 
	5		Regardless of whether or not they have a common 
	6	route, these epidemics, as well as we understand them today, 
	7	appear to be essentially unrelated epidemiologically and are 
	8	probably best considered independently. 
	9		[Slide.] 
10		What I first want to do is give a quick overview 
11	of the highlights of the wasting-disease epidemic in free- 
12	ranging deer and elk.  Chronic wasting disease has been 

13	recognized in free-ranging deer and elk since the early 
14	1980s.  This epidemic is likely related in some way to the 
15	cases originally reported in captive research animals, but 
16	which came first is truly a chicken or egg question that we 
17	are probably never going to answer. 
18		[Slide.] 
19		Initially, clinical cases were recognized in both 
20	free-ranging deer and elk in northeastern Colorado and 
21	southeastern Wyoming.  Surveillance for clinical suspects 
22	has been ongoing in both states since the first cases were 
23	detected.  Harvest-based surveys were conducted 
24	intermittently beginning in 1983 and annually in some areas 
25	beginning as early as 1990. 

				72 
	1		Since 1996, we have been using IHC to enhance 
	2	detection of infected animals.  In all, about 7,000 deer and 
	3	elk harvested in northeastern Colorado and southeastern 

	4	Wyoming have been sampled.  Ongoing random surveys have 
	5	revealed a single endemic focus of chronic wasting disease 
	6	that primarily involves mule deer but also includes white- 
	7	tail deer and elk where they occur in that area. 
	8		That is the area in orange in the slide here.  We 
	9	are going to zoom into that, now. 
10		[Slide.] 

11		As described in our publication from last year, we 
12	know from these survey data that chronic wasting disease is 
13	endemic across about 40,000 square kilometers of contiguous 
14	mixed native habitats that spans portions of northeastern 
15	Colorado and southeastern Wyoming.  New data from Nebraska 
16	Game Fish and Parks Department and USDA Vet Services extends 
17	this area just slightly into the extreme southwestern corner 
18	of Nebraska. 
19		They recently reported a case just right there. 

20	It is about as close to Colorado and Wyoming as you can and 
21	still stay in Nebraska, but it does extend that into 
22	Nebraska. 
23		The most intensively infected area that is shown 
24	here in these darker red shades extends from the Laramie 
25	Mountains south into the northern front range of Colorado.  

				73 
	1	In this area, average wasting disease prevalence exceeds 
	2	10 percent in sampled mule deer. 
	3		This high-prevalence ridge is surrounded by areas 
	4	of successfully lower prevalence, as you see with the 
	5	lighter orange areas going to yellow.  On the fringes of the 
	6	endemic area, prevalence is actually 1 percent or less in 
	7	deer.  Elk reside in the western half of this area where the 
	8	mountains start, right along here, and, throughout the area 
	9	where they occur, prevalence is 1 percent or less in that 
10	species. 
11		Where white-tail deer ranges overlap with mule 
12	deer, wasting disease prevalence is similar in both species. 
13	The spatial pattern of relative prevalence of this disease 
14	strongly suggests that what we are seeing is actually an 

15	epidemic occurring in slow motion extending geographically 
16	through natural animal movements. 
17		Our computer models suggest that chronic wasting 
18	disease has likely been present in some of these more 

19	heavily infected areas for thirty-five years or more. 
20		[Slide.] 
21		The good news is that, at present, chronic wasting 
22	disease in free-ranging deer and elk appears to be confined 
23	to this single endemic focus, right here.  Surveys have been 
24	conducted over the last four years in other parts of 
25	Colorado and Wyoming as well as in portions of a number of 

				74 
	1	nearby and distant states and provinces by responsible 
	2	wildlife management and animal-health agencies. 
	3		These are the states and provinces that are shown 
	4	in green on the slide.  None of the areas surveyed, the 

	5	shown-in-green surveyed areas, have shown any hint that 
	6	other foci of chronic wasting disease presently exists in 
	7	free-ranging cervids.  In all, over 7500 deer and elk from 
	8	these areas have tested negative through the 1999 sampling 
	9	season and about another 5200 samples are in the process of 
10	being examined. 
11		At the very least, I think these data clearly 
12	demonstrate the chronic wasting disease is not uniformly 

13	prevalent across all of our native cervid populations in the 
14	U.S. and Canada. 
15		[Slide.] 
16		So, to summarize kind of the highlights of wasting 
17	disease in free-ranging cervids, it does appear to occur as 
18	a single epidemic focus in the wild to primarily involve 
19	mule deer, that it has been ongoing for several decades and 
20	to show some evidence of slow natural spread. 
21		[Slide.] 
22		I want to briefly comment on approaches for 
23	managing chronic wasting disease in free-ranging cervids.  I 
24	know there is going to be a lot more discussion later about 
25	the elk industry and what it is doing, but we are not, as 

				75 
	1	wildlife managers, entirely clear on how to best manage this 
	2	problem. 
	3		Despite that, a number of actions are ongoing. 
	4	First and foremost, public information and education 
	5	regarding this problem has been ongoing since the mid-1990s, 
	6	well before April of 1996.  Since CWD was first recognized 
	7	as something more than just a handful of interesting 
	8	diagnostic cases, our strong desire has always been to 
	9	insure that the public is aware of this problem, where it is 
10	and is not, and what is being done. 
11		Those who suggest anything to the contrary are 
12	simply wrong.  Our surveillance and research has been 
13	important in improving our understanding of the magnitude of 
14	this program.  Until very recently, there have been no large 
15	infusions of funding to study chronic wasting disease and 
16	much of the work has actually been supported by state 
17	wildlife management agencies, intramural university funds, 
18	and in-kind contributions made by the very fine folks who 

19	are collaborating in this work. 
20		Despite the lack of funding or broad interest 
21	until fairly recently, I hope that you can all appreciate 
22	the contributions to understanding that all these things 
23	have brought. 

24		One of the tools for managing wasting disease has 
25	been, and continues to be, selective culling of clinical 

				76 
	1	suspects throughout the endemic area.  It has been ongoing 
	2	for some time, but we have intensified our efforts over the 
	3	last ten years. 
	4		We also have a self-imposed moratorium on 
	5	translocating free-ranging deer and elk from populations 
	6	where wasting disease is endemic as well as from populations 
	7	adjacent to those endemic areas.  Finally, we continue to 
	8	control chronic wasting disease-infected populations through 
	9	annual harvest to either maintain or reduce population size. 
10	We believe allowing these herds to expand unchecked is 
11	likely to exacerbate both the severity and spread of this 
12	problem. 
13		[Slide.] 
14		Turning now to the disease as we understand it in 
15	farmed elk; as is the case with chronic wasting disease in 
16	free-ranging cervids, chronic wasting disease in farmed elk 
17	has likely been present for quite some time.  The first 
18	report of the farmed elk with chronic wasting disease came 
19	from Saskatchewan in 1996.  It was a routine submission of 
20	an animal with a chronic pneumonia that was refractory to 

21	treatment. 
22		Nearly two years later, a similar case was 
23	submitted from a South Dakota elk farm.  Subsequently, 

24	epidemiological investigations as well as submissions made 
25	voluntarily or in compliance with mandatory surveillance 

				77 
	1	rules have led to disclosure of infections in eighteen game 
	2	farms in five western states and one Canadian province. 

	3	There are a few others that remain under investigation. 
	4		To date, all the cases in privately owned cervids 
	5	have occurred in elk.  The apparently intensity of 
	6	infections in herds studied to date has varied widely and 
	7	probably reflects influences of husbandry as well as the 
	8	duration of infected in particular herds. 
	9		There are epidemiological connections documented 
10	through animal movements among some but not all of the 
11	infected herds.  You can see some of those lines here shown 
12	on the slide.  Although there is geographic overlap between 
13	the location of one infected Colorado farm and the endemic 
14	focus in free-ranging deer, epidemiological investigations 
15	really don't support free-ranging deer as the most likely 
16	source of infection in this particular case. 
17		[Slide.] 
18		The elk industry, in conjunction with responsible 

19	animal-health agencies, has been quite aggressive in dealing 
20	with chronic wasting disease.  You will hear more about this 
21	from Drs. Zebarth and Creekmore later today, but I want to 
22	highlight a few important points here. 
23		Of the infected elk farms identified to date, only 
24	three remain under some form of quarantine and negotiated- 
25	disease management.  The remaining herds, all of these in 

				78 
	1	black--I switched from red in the last slide to black here-- 
	2	have been depopulated or are in the process of being 
	3	depopulated. 
	4		In the absence of a national chronic wasting 
	5	disease-program for captive elk in the U.S., many herds were 
	6	depopulated voluntarily or with the help of industry 
	7	funding.  At the urging of industry, Canada adopted a 
	8	national CWD program last year and its implementation is 
	9	under way. 
10		Here in the U.S., several states, shown in purple, 
11	have developed regulations and programs for wasting disease 
12	that are in various stages of, actually, development or 
13	implementation.  Plans for a national program are well under 
14	way. 
15		[Slide.] 
16		So, to summarize the disease in farmed elk, 
17	epidemiological investigations indicate that wasting disease 
18	has been in captive-elk industry for at least eleven years 
19	and probably much longer.  Epidemics in captive elk herds 

20	are apparently self-sustaining, as they are in free-ranging 
21	animals and confinement may actually provide conditions 
22	allowing high incidence to develop in chronically infected 
23	herds similar to what has been described for scrapie. 

24		There is a much wider and less predictable 
25	geographic distribution of chronic wasting disease in farmed 

				79 
	1	elk.  This pattern has been shaped by extensive market- 
	2	related animal movements in an industry that has expanded 
	3	rapidly over the last decade. 
	4		[Slide.] 
	5		So, although chronic wasting disease is of 
	6	understandable concern to a variety of interests, there is a 
	7	considerable amount of information available to help us 
	8	assess the risk and guide policy decisions.  In the U.S., 
	9	chronic wasting disease is probably best viewed as two 
10	separate epidemics, one involving free-ranging cervids and 
11	the other involving captive elk. 
12		Neither of these epidemics are particularly new. 
13	Both epidemics are relatively well described, particularly 
14	in comparison to scrapie in the U.S.  CWD is naturally 
15	maintained in both free-ranging and captive cervid 
16	populations and thus management will be challenging in both 
17	settings. 
18		In the short term, CWD in captive elk is much more 
19	likely to be manageable than CWD in free-ranging cervids.  I 
20	have no doubt, however, that new knowledge on chronic 
21	wasting disease and other TSEs will factor into future plans 
22	for further understanding and managing of both problems. 
23		Thank you. 
24		[Applause.] 
25		DR. BROWN:  Thank you very much, Dr. Miller, for a 

					80 
	1	very clear presentation.  I have one question.  I had 
	2	thought, or my recollection was, that the first intimation 
	3	about chronic wasting disease came in what were called semi- 
	4	captive deer.  We always used to talk about deer that were 
	5	free-ranging and then came in and were fed and so forth. 
	6		DR. MILLER:  That is correct.  That is why the 
	7	chicken-and-egg issue with respect to where this started. 
	8	The animals that were used in those research facilities 
	9	where chronic wasting disease was originally seen and 
10	described, many of those came from the wild.  So it really 
11	is not known whether an animal brought the disease in with 
12	it, and certainly, in a captive confinement setting, it is 
13	going to take off.  We have seen that in any number of 
14	cases, both in the industry and in our research facilities, 
15	or whether it started in one of the facilities and, somehow, 
16	spilled back out into the wild.  We just really don't know 
17	and aren't going to anytime soon. 
18		DR. BOLTON:  I have a question.  Could you tell me 
19	what percentage of the captive elk herds are actually 
20	infected? 
21		DR. MILLER:  Dr. Zebarth or Dr. Creekmore--it 
22	would be low, but, as a percentage--how many elk herds are 
23	there in the U.S., Glen?  Do you have an idea? 
24		DR. ZEBARTH:  2,000. 
25		DR. MILLER:  2,000.  So, right now, what, three 

					81 
	1	out of 2,000 are known to be infected.  It is pretty small. 
	2		DR. LURIE:  If I understood correctly, there was a 
	3	slide there that showed what the particular states had done 
	4	with regard to management, particularly of the elk program 
	5	with the states that had taken action in purple.  Two 
	6	questions; one, what is that action, typically, and, 
	7	secondly, I noticed that there was hole in the middle of the 
	8	purple which looked to me like Wyoming. 
	9		DR. BROWN:  It was. 
10		DR. LURIE:  Can you speak to that, please? 
11		DR. MILLER:  I can speak to Wyoming.  I think Dr. 
12	Zebarth actually has a much more complete discussion of what 
13	is being done in the industry and so I am going to defer to 
14	him on that.  With respect to Wyoming, there is only one 
15	captive elk herd in Wyoming.  Game farming, otherwise, is 
16	not allowed in the State of Wyoming and, consequently, they 
17	really haven't had to do anything regulationwise. 
18		I am not sure.  Beth, maybe you know what they are 
19	doing with that one farm. 
20		DR. WILLIAMS:  They have talked to the managers of 
21	that farm.  They are under the oversight of the Wyoming Game 
22	and Fish Department, but there is no formal program in 
23	place. 
24		DR. BURKE:  Are there any other foci anywhere in 
25	the world of similar chronic wasting disease among elk, deer 

				82 
	1	or related species? 
	2		DR. MILLER:  Not that I am aware of and certainly 
	3	not that have been reported. 
	4		DR. BURKE:  Is there any reasonable surveillance 

	5	or any efforts to identify that anywhere else in the world? 
	6		DR. MILLER:  I know that the folks in New Zealand 
	7	have done considerable surveillance in their red-deer 
	8	industry.  As far as other free-ranging populations, I am 
	9	truly not sure. 
10		DR. DETWILER:  I can address that just a little 
11	bit.  I think that is a valid assessment, that there really 
12	has not been much surveillance done.  New Zealand is doing 
13	captive.  I know Argentina is doing some captive but, to my 
14	knowledge, none in the free-ranging and very, very limited 
15	even in the captive. 
16		DR. ROOS:  How many animals are infected or 
17	diseased or die from the disease per year and has that been 
18	stable over the last five to ten? 
19		DR. MILLER:  In the wild, it is extremely 
20	difficult to gauge how many animals are dying out there. 
21	These are free-ranging animals that live in sparsely 
22	populated or unpopulated areas with respect to human 
23	presence.  It is kind of like a tree falling in the forest 
24	when no one is around in terms of knowing whether or not 

25	they truly die. 

					83 
	1		What I can tell you is that the number of clinical 
	2	submissions that we get from the public has increased in the 
	3	last few years but so has our publicity campaign for getting 
	4	folks to help us report this.  Prevalence, which is probably 
	5	a better gauge of what is going on in the populations, has 
	6	remained stable over the last four or five years that we 
	7	have good data for documenting that. 
	8		My gut feeling is that it is probably increasing 
	9	slightly in some of these areas but it is not an explosive 
10	kind of an epidemic.  Like I say, it is on a fairly 
11	protracted time scale. 
12		DR. BROWN:  Why is prevalence more easy to 
13	document?  Your figure of 10 percent, was that free-ranging? 
14		DR. MILLER:  That is free-ranging prevalence based 
15	on random sampling of populations in conjunction with 

16	harvest.  That is just in that one fairly narrow strip 
17	through there.  The problem is getting a handle on clinical 
18	cases in the wild is almost impossible.  We know what we 

19	get, but there are so many reporting biases and so many 
20	other problems inherent in those kinds of data that tracking 
21	them is-- 
22		DR. BROWN:  So your prevalence figures are you go 
23	out and capture free-ranging animals? 
24		DR. MILLER:  No. 

25		DR. BROWN:  What? 

					84 
	1		DR. MILLER:  We are sampling animals in 
	2	conjunction with harvest.  So it is a essentially a 
	3	slaughter survey is what it is. 
	4		DR. CLIVER:  This seems to be one of the few TSEs 
	5	where there is some potential for antemortem sampling if the 
	6	tonsil collection could be done in that way.  Is there any 
	7	thought being given to darting some of these animals and 
	8	letting them loose after you have taken the samples? 
	9		DR. MILLER:  We have actually been doing a little 
10	of that this last winter, or this current winter.  It is 
11	easier said than done.  It would be an interesting exercise 
12	but, in terms of applying that on large-scale depopulations, 
13	we are talking about, literally, 40,000 square kilometers or 
14	more of native habitat, tens of thousands of deer and 
15	thousands of elk in that area.  The logistics of it would 
16	not be particularly pleasant to think about. 
17		DR. DeARMOND:  A question from Dr. Priola's 
18	presentation.  Could lateral spread, in this disorder, by 
19	through the placenta and what is their behavior in dealing 
20	with placenta?  A second one is, are the farm-raised animals 
21	exposed to meat-bonemeal products? 
22		DR. MILLER:  With respect to the first question 

23	regarding transmission, certainly it is conceivable that 
24	placental tissue would be involved.  The cervids are very 

25	different in terms of the way they behave.  They tend to go, 

				85 
	1	particularly in the wild, and fawn or calve in a very 
	2	isolated setting.  They almost immediately consume the 
	3	placenta and as much of the fetal fluids and other things as 
	4	they can because of the predator-avoidance strategy. 
	5		So, in terms of the agent being particularly 
	6	effectively spread that way, probably not.  It certainly 
	7	could contribute, but there are other things that are 
	8	contributing to its spread. 
	9		DR. DeARMOND:  So only the mother eats that or do 
10	other deer come in and help? 
11		DR. MILLER:  Typically, when they are fawning of 
12	calving in natural settings, they are by themselves so they 
13	are the only one around.  We have tried to collect placental 
14	tissue in our captive-deer herd, our research herd.  You 
15	have to be sitting right there when it hits the ground or it 
16	is gone.  They don't share. 
17		Again, there are millennia of evolutionary 
18	pressure for them to do that because that is how they avoid 
19	having the little ones eaten. 
20		DR. DeARMOND:  And then, for artificial feed-- 

21		DR. MILLER:  As far as the artificial feed, Glen 
22	could probably address that.  It is banned.  Certainly, in 
23	practice, in our research facility, we have had chronic 

24	wasting disease for decades and we don't use, and to my 
25	knowledge never have used, meat and bonemeal.  Certainly, in 

				86 
	1	the free-ranging animals, meat and bonemeal is not being 
	2	used and certainly does not seem to part of what is 
	3	perpetuating the problem. 
	4		DR. BROWN:  Actually, the more interesting 
	5	question is the converse; do they ever wind up as meat and 
	6	bonemeal? 
	7		DR. PRUSINER:  This number of 10 percent 
	8	prevalence in this slaughter sample, where is this 
	9	published?  In all of the materials we have, I can't find 
10	it.  I ask people this and when I quote this figure, 
11	everyone is absolutely astounded.  I would like to see the 
12	published data. 
13		DR. MILLER:  I will hand you a reprint when we get 
14	done. 
15		DR. PRUSINER:  Okay. 
16		DR. MILLER:  It is in the journal Wildlife 
17	Diseases, October of this last year. 
18		DR. PRUSINER:  Great.  Thank you. 
19		DR. DAVEY:  Dr. Miller, could you just enlighten 
20	us a little bit in terms of venison and gelatin, what other 
21	products, byproducts, meat products, from these animals get 
22	into the human food chain? 
23		DR. MILLER:  Again, I am thinking Glen is probably 
24	going to hit on some of this stuff later on.  With respect 
25	to the free-ranging animals we harvested, virtually none.  

				87 
	1	Those were essentially animals that are taken in to private 
	2	possession and processed for meat, muscle tissue. 
	3		As far as rendering and things, I would think--the 
	4	industry is so small right now, and there are so few animals 
	5	that go to slaughter, it is mostly custom slaughter, is it 
	6	not--Glen, very little, if any, of that, would be going into 
	7	rendered product or into those other products. 
	8		DR. DeARMOND:  What happens to road kill, when a 
	9	deer is run down in the road? 
10		DR. MILLER:  It depends on where it gets hit.  In 
11	some places, the coyotes and the magpies and the other 
12	scavengers clean it up.  In other places, it is allowed for 
13	people to pick those road kills up as long as they get the 
14	proper permits. 
15		DR. MILLER:  In California, I think you have to 

16	report it and I think they take it and they grind it up and 
17	make it into feed for other animals; is that not right? 
18		DR. MILLER:  We don't do that; no. 
19		DR. MANUELIDIS:  You mentioned something very 

20	interesting.  You said that this was not like scrapie in 
21	Europe.  Maybe you could sort of expand and update us a 
22	little bit on what the sort of experimental models of this 
23	are currently going on and if it is related, you think, to 
24	scrapie in the United States that began not to be under 
25	surveillance? 

				88 
	1		DR. BROWN:  Dr. Miller, any questions that you get 
	2	which you know are going to be covered subsequently by other 
	3	people, you can defer. 
	4		DR. MILLER:  I am not sure on that one.  Dr. Bruce 
	5	and her colleagues over in Edinburgh have actually put 
	6	wasting disease into their mouse pathogenesis profile.  I 
	7	don't believe those data have been published yet. 
	8		DR. WILLIAMS:  Only mentioned in Dr. Bruce's 
	9	Nature article in 1997.  So it was a mention, not really a 
10	documentation of that transmission. 
11		DR. MILLER:  In terms of other studies, Linda, did 
12	she have a comment about--in terms of looking at the 
13	relationships between wasting disease and scrapie, there is 
14	obviously a lot of fertile ground there.  I think the folks 
15	at Ames, at ARS, have done some work putting scrapie into 

16	elk.  There are other cross-species transmission studies 
17	underway.  But scrapie into deer; I don't know whether 
18	anybody has started that one yet. 
19		DR. DETWILER:  That has been talked about but I 
20	don't know.  There are a lot of things that are ongoing. 
21	Since you referred to me, I just want to go back and, lest 

22	we go down the path of the sampling of live animals through 
23	tonsil, I will just really reiterate what Mike said.  You 
24	heard the human community saying about doing the testing on 
25	cadavers, that that is logistically a nightmare. 

					89 
	1		To us, that is not a logistical nightmare. 
	2	However, catching and using general anesthesia, because 
	3	taking a tonsil--they don't lay down and say, "ahh," just at 
	4	your command. 
	5		DR. PRUSINER:  They don't stand up and say "ahh." 
	6		DR. DETWILER:  Right; they don't stand up.  We 
	7	have done it in sheep, tried to do it in sheep, and they are 
	8	captive.  We have them in flocks and it is very difficult. 
	9	Dr. O'Rourke is developing for the third-eyelid biopsy. 
10	That is much more logistically feasible--but even in sheep, 
11	where you have them in confinement, unless under general 
12	anesthesia. 
13		DR. GAMBETTI:  Dr. Miller, if I understand 
14	correctly, the assessment is made by immunostaining of the 
15	obex and/or the tonsils.  If we had to use, really, that 

16	approach to human prion disease, we would miss some of the 
17	cases simply because there are varieties, there is change 
18	and diversity in the distribution of the PrP-sc.  That may 
19	occur also in chronic wasting disease. 
20		So I understand that it may be more taxing on the 
21	resources, but I would recommend that other parts of the 
22	brain be tested as well because, as I said, the 
23	distribution, not necessarily, is the same in all the 
24	animals. 
25		DR. WILLIAMS:  I would just like to say that we 

				90 
	1	have looked at quite a number of deer and elk including mule 
	2	deer and white-tail deer, looked at the whole brains and 

	3	find that the disease is very stereotyped in the lesion 
	4	distribution of spongiform encephalopathy, in particular, 
	5	and also in terms of the PrP deposition. 
	6		The dorsal motor nucleus of the vagus is, in all 
	7	cases, where the first deposition occurs and it is very 

	8	stereotyped, although I completely agree that you can't 
	9	assume that every single case is going to be exactly the 

10	same.  So we do look at whole-brains, and not just the obex, 
11	on many of them. 
12		DR. BROWN:  It is rather more like BSE in scrapie 
13	in the sense that it tends to be distributed in the 
14	midbrain. 
15		Don, and then we are going to go on to the next 
16	speaker. 
17		DR. BURKE:  I didn't understand the answer to the 
18	question about whether or not these had been examined by the 
19	mouse pathogenesis biotype.  They have or have not and, if 
20	they have, what do the results show? 
21		DR. WILLIAMS:  One mule-deer brain has been 
22	examined through the mouse-strain typing system and the 
23	results from Dr. Bruce's work and Dr. Frazier's work was 
24	that the CWD is not like BSE.  It is not like CJD or variant 
25	CJD.  It is not like any of the strains of scrapie that they 

				91 
	1	have worked with.  So it is basically unusual. 
	2		DR. BURKE:  But it fits in the general profile of- 
	3	-scrapie is all over the place and so it doesn't mean, just 
	4	because it is not the same, it couldn't be the same. 
	5		DR. WILLIAMS:  Exactly. 
	6		DR. BROWN:  Thank you very much, Dr. Miller. 
	7		The next presentation is by Dr. Ermias Belay from 
	8	the CDC.  He will be presenting information on the 
	9	epidemiologic investigations of a group of young cases of 
10	Creutzfeld-Jakob disease who have a history of exposure to 
11	venison. 
12	     Epidemiological Investigations of Young CJD Cases 
13		           Exposed to Venison 
14		DR. BELAY:  This one is my presentation so you can 
15	ask me questions. 
16		[Slide.] 
17		I will summarize the findings of our investigation 
18	of unusually young CJD patients who were reported to have 
19	consumed deer and elk meat. 
20		[Slide.] 
21		The occurrence of CJD in two deer hunters and a 
22	third patient who consumed venison created a concern about 
23	possible transmission of CWD to humans.  The occurrence of 
24	these cases created a concern primarily because of the 
25	unusually young age of the patients. 

				92 
	1		The occurrence of CJD in patients or person thirty 
	2	years of age and under is extremely rare in the United 
	3	States.  The majority of the cases in this age group have 
	4	been associated with either receipt of human growth hormone 
	5	or dura mater grafts. 
	6		[Slide.] 
	7		This slide shows CJD cases thirty years of age and 
	8	under reported to CDC during 1979 through 2000.  Cases that 
	9	have been associated with human growth hormone, in red or 
10	purple, and dura mater grafts are shown here.  The three 
11	cases that reported consumption of venison are shown here. 
12	These other cases are sporadic CJD cases.  As you can see, 
13	the occurrence of sporadic CJD, in this young age group, is 
14	extremely rare in the United States. 
15		[Slide.] 
16		The concern about possible transmission of CWD to 
17	humans was also raised because of the endemic occurrence of 
18	chronic wasting disease is deer and elk in the United 
19	States, as we heard from Dr. Miller today and the potential 
20	of these TSE agents, as evidenced by the new-variant CJD 
21	outbreak in the United Kingdom. 
22		But, fortunately, as Dr. Miller told us today, the 
23	endemic occurrence of chronic wasting disease is limited to 
24	localized areas in the states. 
25		[Slide.] 

				93 
	1		This map shows the distribution of the three cases 
	2	in relation to CWD endemic areas.  The cases occurred in 
	3	Florida, Utah and Oklahoma. 
	4		[Slide.] 
	5		Our investigation involved reviewing the clinical 
	6	records and conducting pathologic studies of all the three 
	7	cases.  The pathologic specimens were evaluated by Dr. 

	8	Gambetti, Dr. Pierluigi Gambetti, and colleagues at the 
	9	National Prion Disease Pathology Surveillance Center in 
10	Cleveland, Ohio.  So all of the data that I will be 

11	presenting relating to the pathologic specimens was 
12	performed by this center, the national center. 
13		[Slide.] 
14		In addition, we interviewed close family members 
15	of the patients to determine receipt of human growth 
16	hormone, or human tissue grafts, in the presence of any 
17	neurosurgical procedures.  We obtained dietary habits and 
18	travel history and determined their hunting practices.  We 
19	specifically looked for evidence of possible exposure to 
20	venison obtained from the known CWD endemic areas. 
21		[Slide.] 
22		Finally, we compared the key evidence that 
23	supported a causal link between BSE and new-variant CJD in 
24	the United Kingdom to that of CWD and CJD in the three 
25	patients in the United States.  This key evidence that we 

				94 
	1	used in our comparison included an increasing incidence of 
	2	the disease among young cases, which was true in the United 
	3	Kingdom in the new-variant CJD, recognizable exposure of the 
	4	patients to the infective agent-- 
	5		[Slide.] 
	6		The presence or absence of a unique characteristic 
	7	pathology, and a phenotypical homogeneity among the patients 
	8	and different immunoblood characteristics of the protease- 
	9	resistant prion protein and a uniformity in the codon 129 of 
10	the prion-protein gene in the patients; so we used all these 
11	parameters to compare the possible lines of evidence that 
12	were generated in the United Kingdom for the new-variant CJD 
13	to that of chronic wasting disease and CJD in these 
14	patients. 
15		[Slide.] 
16		Case 1 was a twenty-eight-year-old woman who 
17	presented in early 1997 with the characteristic CJD signs 
18	and symptoms.  The EEG was reported as abnormal.  It was not 
19	classic for CJD. 

20		[Slide.] 
21		This patient died four months after illness onset 
22	and analysis of the prion-protein gene indicated a 
23	methionine-methionine homozygosity at codon 129 and the 
24	absence of genetic mutations. 
25		[Slide.] 

				95 
	1		The immunohistochemical analysis showed a punctate 
	2	or synaptic pattern of immunostaining with no plaques.  The 
	3	immunoblood analysis was not performed in this patient 
	4	because of lack of frozen brain tissues. 
	5		[Slide.] 
	6		This patient was reported to have consumed deer 
	7	meat during her childhood when the patient was one to six 
	8	years of age.  The deer that this patient consumed were 

	9	mainly harvested by the patient's father in the State of 
10	Maine.  In addition, this patient was reported to have 
11	consumed elk meat provided to the family as a gift during 
12	two occasions when the patient was about six years of age. 
13		Although the exact origin of the elk consumed by 
14	this patient could not be determined, the family member 

15	indicated that the elk meat may have been obtained from 
16	Wyoming.  There was no history of consumption of organ meat 
17	either from deer or elk. 
18		[Slide.] 
19		The second patient was a twenty-nine-year-old 
20	patient who presented with dementia beginning in May,	1998. 
21	This patient also had other neurologic signs that are 
22	compatible with CJD. 
23		DR. PRUSINER:  Was this a man or a woman? 
24		DR. BELAY:  This was a man. 
25		[Slide.] 

				96 
	1		His initial two EEGs were reported to be normal 
	2	and the CSF 14.3.3 test was negative.  The evaluation of a 
	3	brain biopsy specimen confirmed the CJD diagnosis. 
	4		[Slide.] 
	5		Analysis of the prion-protein gene showed valine- 
	6	valine homozygosity and absence of genetic mutations. 
	7		[Slide.] 
	8		The immunohistochemical analysis showed a punctate 
	9	immunostaining with no plaques.  The immunoblood analysis of 
10	protease-resistant prion protein showed the type 1 pattern 
11	with a molecular mass of about 21 kiloDalton.  This patient 
12	was recorded to have hunted deer almost every year since 
13	1985 in many non-CWD-endemic areas, mainly in Utah. 
14		[Slide.] 
15		In addition, the patient's family reported that 

16	the patient had eaten elk meat which the patient, himself, 
17	harvested in 1995 from a non-CWD-endemic area of Wyoming 
18	which is very close to the border of Utah.  The patient was 
19	reported to have regularly consumed the liver from deer and 
20	elk but not the brain or any other organ meat. 
21		[Slide.] 
22		The third patient was a twenty-seven-year-old man 
23	who presented with memory loss in December, 1998.  This 

24	patient also developed other neurologic signs compatible 
25	with CJD. 

				97 
	1		[Slide.] 
	2		The EEG was reported as abnormal but non- 
	3	diagnostic for CJD.  The CSF 14.3.3 test was positive.  The 
	4	evaluation of his brain biopsy confirmed the CJD diagnosis 

	5	in this patient.  No autopsy was performed on this case. 
	6		[Slide.] 
	7		Analysis of the prion-protein gene showed a 
	8	methionine/valine heterozygosity and the absence of genetic 
	9	mutations.  The immunoblood analysis of PrP-res showed the 
10	same type 1 pattern with a molecular mass of 21 kilodalton. 
11		[Slide.] 
12		This patient hunted exclusively--he hunted deer 
13	almost every year and exclusively hunted in two areas close 
14	to his hometown.  He was born and grew up in that area and 
15	specifically hunted in two geographically limited areas 
16	close to his hometown. 
17		There is no history of consumption of deer or elk 

18	meat obtained from the known endemic states in this patient. 
19	However, the plant that the patient took his deer carcasses 
20	for custom processing has also been processing about twenty 
21	elk from Colorado every year.  So he used to take his deer 
22	carcasses for custom processing to a specific plant and that 
23	plant regularly processed about twenty elk every year 
24	obtained from Colorado. 
25		However, the origin within Colorado of this elk 

				98 
	1	could not be determined.  As I say, there was no consumption 
	2	of deer or elk meat obtained from the known endemic areas 
	3	directly by the patient. 
	4		[Slide.] 
	5		In summary, all three cases had confirmed CJD with 
	6	no iatrogenic exposure or genetic mutations and none of the 
	7	patients had a history of travel outside of the United 
	8	States or a clinical pathologic profile consistent with the 
	9	new-variant CJD.  All three cases were reported to have 
10	regularly consumed deer or elk meat but none were reported 
11	to have consumed deer obtained from the known endemic areas. 
12		[Slide.] 
13		In addition, none of the patients reported 
14	consumption of brain or spinal cord either from deer or elk. 
15	There is some possibility that cases 1 and 2 may have eaten 
16	elk meat obtained from Wyoming.  However, there are some 
17	uncertainties regarding their exposure to elk.  In case 1, 
18	for example, the Wyoming origin of the elk was not 
19	absolutely certain.  The patient's family indicated that 
20	they were not sure about the exact origin of the elk that 
21	they received as a gift from their family friend. 
22		[Slide.] 
23		In case 2, the Wyoming elk was harvested by the 
24	patient, himself, outside of the known endemic areas in 1995 
25	which is about three years before the onset of CJD in the 

				99 
	1	patient.  In case 3, as I said, there was no consumption of 
	2	deer or elk meat obtained from the known endemic areas.  The 
	3	contamination of his deer meat by elk meat obtained from 
	4	Colorado at the processing plant was possible.  But it 
	5	remains uncertain whether or not the elk processed in the 
	6	same plant were actually infected with CWD or originated 
	7	from the known endemic counties from Colorado. 
	8		[Slide.] 
	9		No unique pathology or clinical pathologic 
10	homogeneity was detected among the three cases.  Based on a 
11	classification scheme developed by Parchi and colleagues, 
12	case 2 was classified as a VV1 variant and, in case 3, as an 
13	MM1/MV1 variant.  The MM1/MV1 variant is the most common 

14	variant described by Parchi and colleagues and represented 
15	about 70 percent of sporadic CJD patients. 
16		The immunoblot characteristics of case 1 were 
17	unknown, but the clinical pathologic profile suggested the 
18	MM1/MV1 variant which, as I said, the most common variant 
19	seen in about 70 percent of sporadic CJD patients. 
20		[Slide.] 
21		The VV1 variant, to which case 2 was classified, 
22	was described by Parchi and colleagues to constitute an 
23	estimated 10 percent of sporadic CJD patients. 
24		[Slide.] 

25		Because of the similarity, the clinical pathologic 

				100 
	1	similarity, of cases classified in the VV1 variant with that 
	2	of case 2, we determined the hunting practices and venison- 
	3	consumption histories of other members of the VV1 variant. 
	4		In none of the other four cases classified in this 
	5	variant where hunters in at least two of the four cases were 
	6	reported not to have consumed deer or elk meat indicating 
	7	that this clinical pathologic picture could actually occur 
	8	in the absence of venison consumption. 
	9		[Slide.] 
10		This table shows the comparison of the key 
11	evidence that supported a causal link between BSE and new- 
12	variant CJD to that of a possible link between CWD and CJD 
13	in the unusually young patients.  In the new-variant CJD, 

14	there was a definite increase in the incidence of the 
15	disease among young cases which was not the case in the 
16	United States.  We only had three patients during 1997 
17	through 2000. 

18		A unique characteristic pathology was described in 
19	the new-variant CJD where the pathology in the three 
20	patients was not different from that normally seen in other 
21	sporadic CJD patients.  Clearly, there was a clinical 
22	pathologic homogeneity among the new new-variant CJD 
23	patients which was not the case among the three cases, among 
24	the three patients in the United States. 
25		The protease-resistant prion protein in the new- 

				101 
	1	variant CJD was reported to be different from the classic 
	2	forms whereas, in at least two of the three patients, the 
	3	PrP-res was similar to that in the majority of sporadic CJD 
	4	patients. 
	5		Exposure of the patients in the new-variant CJD to 
	6	the BSE agent was highly plausible because of the widespread 
	7	occurrence of BSE in the United Kingdom whereas exposure to 
	8	chronic-wasting-disease-infected venison in our three cases 
	9	was not so clear. 
10		Finally, all the reported new-variant CJD cases 
11	had a methionine-methionine homozygosity on codon 129 
12	whereas each of our three patients had different 
13	polymorphisms at codon 129 of the prion-protein gene, in 
14	case 1 with methionine-methionine, in case 2, valine-valine. 
15	Case 3 was methionine/valine. 
16		[Slide.] 
17		In addition, in collaboration with state wildlife 
18	and agriculture representatives, Dr. Linda Detwiler's group 
19	at USDA collected and tested over 1,000 hunter-harvested 
20	deer and elk brain samples from the areas where the venison 
21	consumed by the patients originated.  All these deer and elk 
22	brain samples tested negative for chronic wasting disease by 
23	immunohistochemical.  All the samples were obtained from the 
24	areas where these patients actually collected their venison. 
25		[Slide.] 

				102 
	1		In conclusion, although the occurrence of three 
	2	unusually young CJD patients who were reported to have 
	3	regularly consumed deer and elk meat suggested a possible 
	4	relationship of their illness with CWD, our follow-up 
	5	investigation found no strong evidence for a causal link 
	6	between CWD and CJD in the three patients. 
	7		However, our conclusions are limited to the three 
	8	patients and continued surveillance remains very critical to 
	9	continue to monitor the possible transmission of chronic 
10	wasting disease to humans. 
11		Thank you. 
12		[Applause.] 
13		DR. BROWN:  I have one question for you, Ermias. 
14	By analogy to the BSE situation in variant CJD, are there 

15	any characteristic or distinctive glygotyping patterns in 
16	deer or elk that might also have been seen in any of the 
17	patients glycotyped?  That seems to me to be, by analogy, 
18	probably the single most important phenomenon that might 
19	totally blow away the straw man that you have constructed. 
20		DR. BELAY:  We have considered that possibility. 
21	Dr. Pierluigi Gambetti has been involved in studying the 
22	glycoform ratios of PrP obtained from chronic-wasting- 

23	disease-infected animals.  I will give Dr. Gambetti a chance 
24	to comment on that. 
25		DR. GAMBETTI:  These studies are very preliminary 

					103 
	1	but, in our hands, the protein, the scrapie prion protein 
	2	from the chronic wasting disease is what we call type 1.  It 
	3	is the unglycosylated isoform migrates at 21 kilodalton. 
	4	The ratio of the glycoforms, as I said, we haven't examined 
	5	a sufficient number of cases, but, so far, it looks like it 
	6	is not remarkable.  It looks certainly not like one of the 
	7	new variants. 
	8		So, in terms of proteins, scrapie prion protein, 
	9	the chronic wasting disease does not seem to offer very much 
10	help in being very typical and, therefore, from this area, 
11	we cannot draw any conclusions. 
12		DR. BELAY:  Can I add some comments? 
13		DR. BROWN:  Sure. 
14		DR. BELAY:  I think what is also relevant is what 
15	Beth mentioned in terms of the strain typing that was 
16	performed by Dr. Moore.  Although it was limited to just one 
17	animal, that investigation actually suggested that the PrP 
18	scrapie or PrP-res in CWD-infected animals is actually 

19	different from any other PrP-res that we are aware of. 
20		DR. BROWN:  Right; but to make sense of that, you 
21	would need-- 
22		DR. BELAY:  With the limitations of the study. 
23		DR. BROWN:  That's fine, even one.  But to make 
24	any interpretation of that, you would need to do one of the 
25	cases similarly.  In other words, you want to see some 

					104 
	1	correlation between the human and the elk.  I gather that 
	2	was not possible. 
	3		DR. BELAY:  We have not done any strain typing in 
	4	the patients and also in the chronic-wasting-disease- 
	5	infected animals. 
	6		DR. LURIE:  I just want to understand how you 
	7	chose these three cases.  Obviously, one criteria was their 
	8	age.  But were they selected because you knew ahead of time 
	9	that they had some kind of exposure to deer or elk, or did 
10	that only turn out in the course of your questionnaire? 
11		DR. BELAY:  No.  We selected these patients 
12	because they were reported to us specifically these are 
13	patients who have been regularly consuming venison. 
14		DR. LURIE:  The point I want to make is you have a 
15	summary slide sort of comparing the causality elements of 

16	BSE and this.  Really, two of them were vaguely positive. 
17	One was, perhaps, increasing incidence.  The other was 
18	exposure to the meat in question.  Really, those were the 
19	entrance criteria into the study. 
20		DR. BELAY:  We looked into CJD cases in that age 
21	group reported to CDC even in the past.  The three patients 
22	stand out because of their venison consumption. 
23		DR. BROWN:  It is the age that entered them into 
24	the study. 
25		DR. LURIE:  That is not quite what he-- 

					105 
	1		DR. BELAY:  That's right.  What Dr. Brown is 
	2	saying is correct. 
	3		DR. LURIE:  So it is only the age. 
	4		DR. BELAY:  The age and because they also reported 
	5	venison consumption, then that triggered our investigation. 
	6		DR. BROWN:  Peter, this is not a systematic study. 
	7		DR. LURIE:  No; I understand that. 
	8		DR. KATZ:  Do you have the venison consumption 
	9	data on the earlier young cases? 
10		DR. BELAY:  Almost all of them except one.  That 
11	one was a patient who died in 1981 and we were not able to 
12	trace the-- 
13		DR. KATZ:  And? 
14		DR. BELAY:  None of them had venison consumption. 
15		DR. KATZ:  Ever. 
16		DR. BELAY:  That's correct. 
17		DR. BURKE:  I was going to extend that question in 
18	terms of were any kind of case-control studies done.  I 
19	don't have any sense of what the U.S.-based age consumption 
20	of deer and elk is across that region of the country.  Do 
21	you have any data on that at all? 
22		DR. BELAY:  Can you rephrase the question again, 
23	please? 
24		DR. BURKE:  Is there some way to do a proper case- 
25	control study with whether or not ingestion of deer or elk 

				106 
	1	is a risk factor for the development of chronic wasting or 
	2	new variant or whatever at this point? 
	3		DR. BROWN:  Young CJD. 
	4		DR. BURKE:  Young different CJD. 
	5		DR. BELAY:  As you can imagine, a case-control 
	6	study in this group of diseases is extremely difficult 
	7	because, by the time the patients die, you would be 
	8	eliciting information that took place pretty much for a 
	9	lifetime period.  So you would asking questions like, "Did 
10	you ever eat venison?" and that information would have to be 
11	obtained from family members. 
12		The bottom line is case-control studies would be 
13	complicated.  But I agree that case-control studies have 

14	some value at the same time.  In addition to the limitation 
15	of getting the information from the family members, case- 
16	control studies are also limited by their ability to detect 
17	a low level of transmission. 
18		In other words, if there was a low level of 
19	transmission, you may not see any difference between the 

20	cases and the controls that you would be investigating.  But 
21	such a case-control study is underway in Canada that I am 
22	aware of.  They have included questions like consumption of 
23	venison and we are awaiting that study to see if that would 
24	warrant a larger-scale case-control study in the United 
25	States. 

					107 
	1		DR. BROWN:  Don, the short answer is no.  The CDC 
	2	and Dr. Belay and Dr. Gambetti really are to be 
	3	congratulated because this could have been like the 
	4	anecdotal stories about squirrel meat that just hang in the 
	5	breeze without anybody ever really looking into it. 
	6		I give them all the credit in the world for 
	7	actually driving these as far as they can.  But they are 
	8	still anecdotal. 
	9		DR. PICCARDO:  Case no. 1, there is no immunoblood 
10	analysis.  In case 2 and 3, there are immunoblood analyses. 
11	Extensive immunoblood analyses from different areas was done 
12	or from a single area? 
13		DR. BELAY:  Do you want to comment on that, Dr. 
14	Gambetti? 
15		DR. GAMBETTI:  Could you say the question again? 
16		DR. PICCARDO:  On cases 2 and 3, the immunoblood 
17	was from a single area or were multiple areas analyzed by 
18	Western blot? 
19		DR. GAMBETTI:  In case 2, several areas.  The 
20	diagnosis was initially established from a biopsy and, when 
21	the autopsy tissue was obtained, it was confirmed, the 
22	result was confirmed with samples from different areas. 
23	Case no. 3, I don't remember specifically whether it was 
24	several areas, but, generally, that is our rule.  We perform 
25	a Western blot on multiple samples. 

					108 
	1		DR. PICCARDO:  In all cases, you saw type 1, you 
	2	never saw a mixture of type 1 and 2, or a weird pattern in 
	3	any of the-- 
	4		DR. GAMBETTI:  Case 1, we did not receive frozen 
	5	tissue. 
	6		DR. PICCARDO:  No, no; from cases 2 and 3, all the 
	7	Western blots show a type 1 PrP. 
	8		DR. GAMBETTI:  Exactly.  Correct. 
	9		DR. BROWN:  Just in closing this presentation, the 
10	other interesting interface that one of these patients had 
11	for this group was that he was a professional blood donor 
12	and had donated multiple, multiple, multiple units of blood 
13	even into his early clinical phase. 
14		Now, on to the next presentation, diagnostics by 
15	Dr. Kathy O'Rourke. 
16	      Diagnosis of Elk-Associated and Deer-Associated 
17		        Chronic Wasting Disease 
18		DR. O'ROURKE:  Good morning.  Thank you.  I would 
19	like to assure you that I am not here under false presences. 
20	I am not a veterinarian nor a pathologist and there are 

21	those people representing those disciplines here, both on 
22	your committee and available for questioning that can help 
23	you. 
24		[Slide.] 
25		I am a research microbiologist with U.S. 

				109 
	1	Department of Agriculture with adjunct appointments at 
	2	Washington State University and Colorado State University. 
	3	I was asked to talk to you about the types of diagnostic 
	4	techniques that are in use and that are being developed for 
	5	chronic wasting disease, both in free-ranging and in captive 
	6	animals. 
	7		As you will see from the title of this 
	8	presentation, I consider that elk-associated chronic wasting 
	9	disease and deer-associated chronic wasting disease are 
10	separate diagnostic entities.  I will try to make clear 
11	during the presentation why that is so. 
12		[Slide.] 
13		As you will see, the number of participants is 
14	beginning to outstrip the capability of an overhead 
15	transparency.  Dr. Spraker and Dr. Williams, and Dr. Jenny 
16	and Gidlewsky, represent the states of Wyoming, Colorado and 
17	the last two the federal government.  These are the 
18	pathologists that bring you the work that I will be talking 
19	about today. 
20		Dr. Balachandran does the equivalent work in 

21	Canada currently.  Dr. Creekmore, who you will have an 
22	opportunity to meet later today, perhaps, and Dr. Rhyan 
23	operate the administrative aspects of the APHIS CWD Program 
24	at this present time.  We are grateful to the area 
25	veterinarians in charge and the veterinary medical officers 

				110 
	1	of APHIS who have provided us samples from captive animals. 
	2		The state agriculture departments in South Dakota, 
	3	Oklahoma, Colorado, Nebraska and Montana provided samples 

	4	and, in particular, Dr. Sam Holland and Dr. Tom Klein have 
	5	provided extensive samples as well as detailed epidemiology 
	6	of a very serious outbreak of chronic wasting disease in a 
	7	captive herd in South Dakota. 
	8		The North American Elk Breeders Association are 

	9	represented here today and Dr. Zebarth will be talking to 
10	you.  There are others, but they don't fit on the 
11	transparency and I know your time is limited. 
12		[Slide.] 
13		The diagnostic marker that I will be discussing is 
14	termed PrP-scrapie by convention and by analogy to sheep 

15	scrapie.  There is no implication here that it is same 
16	protein that is associated with scrapie in sheep. 
17		The areas of interest based on our previous 
18	results and those from around the world in sheep are to 

19	focus on the brain, the tonsil and other lymphoid organs of 
20	the head as well as lymphoid tissue in the third eyelid, in 
21	particular reference to the sheep live animal test that is 
22	being investigated currently.  These are the target tissues. 
23		Extensive surveys were made in other tissues. 

24	These remain the best candidates and I will show you why 
25	that is as we proceed. 

				111 
	1		[Slide.] 
	2		The assay that I will discussing is a 
	3	immunohistochemical assay.  It is done on a single piece of 
	4	equipment at this point, or rather a single model of 
	5	equipment, in Canada at our research lab in Pullman, in 

	6	Colorado State University, University of Wyoming and at 
	7	NVSL.  We have available to us two different monoclonal 
	8	antibodies.  Again, the characteristics of these antibodies 
	9	are different.  I will try to point out the differences as 
10	we proceed because the use of the antibodies is critical to 
11	both the sensitivity and the specificity of these assays. 
12		Neither of these antibodies is specific for the 
13	pathologic form of the prion protein.  The tissues that I 
14	will be discussing are fixed in formaldehyde and paraffin 
15	imbedded for routine histologic diagnosis. 
16		The pretreatments that typically reduce 
17	substantial PrP cellular reactivity are primarily the 

18	formalin fixation.  However, this is variable among the 
19	different species as well as between the antibodies.  Formic 
20	acid is used partly to reduce the cellular reactivity and 
21	also to increase the PrP scrapie reactivity. 
22		Proteinase K is used in some laboratories.  I have 
23	to caution you, however, that the proteinase K resistance of 
24	the prion protein is a diagnostic characteristics in the 

25	fluid phase; that is, in terms of ELISA testing or Western 

				112 
	1	blotting.  PK alone does not distinguish this PrP cellular 
	2	from the PrP scrapie in formalin-fixed tissues in chronic 
	3	wasting disease. 
	4		[Slide.] 
	5		The sample populations that were available to us 

	6	were not selected ahead of time for an optimal situation. 
	7	As you know, these are free-ranging animals.  So we are 
	8	grateful to get the samples that we get and we work on what 
	9	is available to us. 
10		We have several different types of populations 

11	beginning, originally, or course with the free-ranging 
12	clinically affected cases in which spongiform lesions were 
13	predominant.  Those, of course, were the earliest cases 

14	diagnosed before the development of immunohistochemistry. 
15	Later, we were able to extend the studies to free-ranging 
16	clinically normal deer and elk. 

17		Because of the extensive surveillance that is done 
18	in Colorado and Wyoming and because of the participation of 
19	APHIS and the state veterinarians in other areas, we are 
20	able to group tissues depending on whether they come from 
21	the endemic area or from well outside the endemic area. 
22		Third, we have access to captive deer and research 
23	facilities and to game-raised elk.  These are the study 
24	populations that were available to us. 
25		[Slide.] 

				113 
	1		In terms of the use of the brain in diagnostic 
	2	analysis, the question has already been well raised.  We 
	3	needed to know for sure that we were looking at the 
	4	appropriate part of the brain.  Dr. Williams had originally 
	5	looked at many parts of the brain.  Dr. Spraker extended 
	6	that work by doing very detailed anatomical mapping of the 
	7	prion-protein deposition in the brains of free-ranging deer 
	8	and elk.  Those findings will be published later this year. 
	9		We had to answer some important questions.  First 
10	of all, certainly, in advanced disease, where is the prion 
11	deposited?  Secondly, in animals that don't have 
12	histologically evident lesions, is there a particular place 
13	in the brain that is always invariably involved.  And, if 
14	prions are found in only one area immunohistochemically, 
15	where would that be? 
16		The answer continues to be the dorsal motor 
17	nucleus of the vagus which, as you know, is the medulla at 
18	the level of obex.  These are small paired tissues on either 
19	side of the midline.  With careful trimming and embedding, 
20	our ability to visualize both of the nuclei is very powerful 
21	because the staining is almost always bilateral. 
22		[Slide.] 
23		The tonsil was the next best place to go because 
24	we have extensive data from sheep demonstrating that, in 

25	about 97 percent of the scrapie-infected sheep, 

				114 
	1	immunostaining in the tonsil will proceed that in the brain. 
	2	We were looking for an early diagnostic test.  What is the 
	3	first place we can look? 
	4		So we asked the same types of questions; where is 
	5	the prion found in the animals with advanced disease.  Now, 
	6	it gets harder after this.  Where is it found in animals 
	7	that don't show evidence of disease.  Again, our ability to 
	8	work from sample sizes in the thousands rather than the 
	9	dozens and to separate those animals based on the geographic 
10	origin of the samples was crucial to our ability to work 
11	through this. 
12		[Slide.] 
13		Here is where things begin to differentiate.  In 
14	mule deer, in the CWD-endemic area, every deer that has been 
15	reported back to us by Dr. Williams and Dr. Spraker in which 
16	staining is in the brain, there was also immunostaining in 
17	the tonsil if that tissue was available. 
18		Some deer in the endemic area have no detectable 
19	staining in the brain but they do have detectable staining 
20	in the tonsil.  PrP-scrapie is abundant when it is detected 
21	in the tonsil, particularly when compared to sheep scrapie. 
22	No deer outside the endemic area have PrP-scrapie in the 
23	tonsil. 
24		These findings were developed over a number of 
25	years and the tests did need to have some developmental work 

			115 
	1	done on it.  We initially pooled the two monoclonal 
	2	antibodies.  They bind different parts of the prion protein 
	3	and we had only limited information about the genetic 
	4	variability within the animals, and we wanted to be able to 
	5	maximize our chances of finding every single animal, so we 
	6	pooled the two monoclonal antibodies. 
	7	          However, it became clear, over time, that, as the 
	8	sensitivity of the assay was increased by certain 
	9	pretreatments, particular proteinase-K pretreatment, we were 
10	beginning to see an odd sort of staining in areas outside 
11	the endemic area that did not look the same way that we saw 
12	staining from animals in the endemic area, but it couldn't 
13	be disregarded. 
14	          We found that only one of the monoclonal 
15	antibodies retains its tight specificity for PrP-scrapie in 
16	these fixed tissues.  So, at this point, prion staining of 
17	the tonsil in preclinical deer is done with only one of the 
18	two monoclonal antibodies. 
19	          The take-home message here is that very large 
20	samples sizes are needed and the point about test validation 
21	is very well taken.  At this point, these data are now based 
22	on a retrospective look at a hundred samples of deer with 

23	known CWD; that is, the most conservative definition which 
24	is spongiform lesions in the brain.  The negative control 

25	sample is 300 samples of deer from outside the endemic area. 

				116 
	1		[Slide.] 
	2		In sharp contrast, elk have been tremendously 
	3	difficult to work on.  Some elk with prion staining in the 
	4	brain, particularly those animals with histologic lesions 
	5	and widespread immunostaining do, in fact, have prion 
	6	detectable in the tonsil.  However, this staining is not at 
	7	all abundant and three years ago we were still feeling that 
	8	we might not see prion staining in the extraneural tissue of 
	9	elk. 
10		We are able to see it.  It is not abundant.  The 
11	cellular form of the protein keeps its reactivity to one of 
12	the monoclonal antibodies, even after formic-acid 
13	pretreatment and even after formalin fixation; that is, the 
14	cellular prion protein is readily detectable in elk samples 
15	using antibody 89 but not antibody 99.  So, again, careful 
16	choice of the primary antibody was critical here.  We also 
17	need to use the most sensitive assays available to us at 
18	this point to even see something. 
19		We only see it when we see advanced disease.  So 
20	we have to caution you here that we see staining in the 
21	brain of elk when we don't see it in the tonsil, exactly the 
22	opposite of what we see with deer and opposite of what we 
23	see with the majority of sheep with scrapie. 
24		[Slide.] 
25		Therefore, in summary, earliest detection of CWD- 

				117 
	1	positive animals, based on the immunohistochemistry 
	2	techniques available to us today and in use, in deer, the 
	3	earliest site for diagnosis is the tonsil or the other 
	4	lymphoid tissues of the head.  In elk, the earliest 
	5	diagnostic site remains the obex carefully collected and 
	6	trimmed so that the dorsal motor nucleus of the vagus can be 
	7	detected optimally bilaterally. 
	8		[Slide.] 
	9		These techniques are really terrific.  However, 
10	they don't address the essential question; how early in 
11	disease can an animal be diagnosed.  As you already know, in 
12	any infectious disease, there is a lag time between 
13	infection and the appearance of the diagnostic marker at 
14	detectable levels. 
15		In the TSEs, this lag time can range from weeks in 
16	experimental mice to months in sheep and years, perhaps, in 
17	some of the other TSEs.  In the sheep studies that we are 

18	conducting, we have a little bit of an advantage since most 
19	sheep are infected soon after birth and we are able to make 
20	some guesses based on the age of the sheep about whether it 
21	is an appropriate animal to sample or not. 
22		However, in chronic wasting disease, this studies 
23	done by Drs. Miller and Williams suggest that the disease 
24	might be transmitted to animals outside that perinatal 
25	period.  Therefore, we are not able to take an animal, look 

				118 
	1	at its age and make a guess about whether we might find 
	2	detectable staining or not. 
	3		Therefore, I can tell you where the earliest place 
	4	is that we can find prions.  I am not able to tell you what 
	5	a period of time is in which that animal cannot be diagnosed 
	6	because of the limitations of our testing and because of the 
	7	biology of these diseases. 
	8		[Slide.] 
	9		The diagnostic site that certainly does not appear 
10	to be useful right now in cervids is the third eyelid. 
11	Lymphoid tissue accumulates in the third eyelid of sheep. 
12	This is the bulbar surface of the nictitating membrane in 
13	sheep.  That lymphoid tissue is abundant in lambs and can be 
14	sampled in animals up until about age 4 or 5 when it is 
15	difficult to find adequate tissue. 
16		Our studies to date on sheep have indicated that 
17	that tissue accumulates prions in roughly the same kinetics 
18	as the tonsil, although at a slightly lower rate.  Estimated 
19	sensitivity of a third eyelid immunohistochemistry test 

20	using our current techniques is about 85 percent when 
21	animals over 14 months of age are tested. 
22		The specificity of the test is greater than 
23	98 percent.  We applied this test to mule deer, first of 
24	all, and found out that the bulbar surface of the 

25	nictitating membrane of deer is highly enriched in 

				119 
	1	lymphocytes.  However, these appear to be solid sheets of T- 
	2	lymphocytes.  They are not the secondary germinal centers 
	3	which are round, discrete areas, easy to recognize 
	4	microscopically. 
	5		They primarily consisted of a stroma of follicular 
	6	dendritic cells in which macrophages and B-cells 
	7	predominate.  These are the antigen-presenting sites in the 
	8	lymphoid tissue.  They are abundant in sheep and they are 
	9	almost nonexistent in most of the deer that we looked at. 
10	Therefore, we have stopped looking at third eyelid on deer. 
11		[Slide.] 
12		In contrast, in elk, these are huge animals 
13	compared to the sheep that we have looked at.  They have 
14	really big eyelids.  Dr. Zebarth will talk to you next as an 
15	expert in collecting these third eyelid biopsies, where we 
16	are able to sample animals exposed to chronic wasting 
17	disease on a facility in South Dakota, animals that were 
18	housed in quarantine by the Elk Research Council. 
19		The animals were sampled over time and followed 
20	through profession to chronic wasting disease.  As with the 
21	tonsil, however, even when we do see staining, it is not 
22	abundant.  We did not see immunostaining in the animals 
23	until probably six weeks or so before the animals went on to 
24	die. 
25		The animals were sampled only every four to six 

				120 
	1	months so we don't have tight time curves on this.  However, 
	2	right now, our working conclusion is that while PrP-scrapie 
	3	could be detected in the third eyelid of elk, it would only 
	4	be useful as an immediate test preslaughter and only to 

	5	indicate that the prion may be distributed outside the 
	6	brain.  It is not the earliest diagnostic site. 
	7		We predict that there would be many animals 
	8	infected with chronic wasting disease--elk, that is--with 
	9	staining in the brain but not in any of the lymphoid tissue 
10	including the third eyelid. 
11		[Slide.] 
12		Our conclusions, therefore, based on the findings 
13	of today is that deer-associated chronic wasting disease 
14	could be detected best by analysis of the tonsil, compared 
15	with the brain for confirmation and realizing that the 
16	tonsil-positives will outweigh the brain positives. 
17		The tonsil contains relatively large amounts of 
18	PrP-scrapie and their paired tissues.  Therefore, they lend 
19	themselves well to adaption to other test methodologies; 

20	that is, one tonsil can easily be formalin-fixed as a gold 
21	standard for reference and the other tonsil could be used in 
22	other types of assays. 
23		There is tremendous interest, of course, out there 
24	in the world to make better, faster, cheaper, more high- 
25	volume TSE surveillance testing and we are working with all 

				121 
	1	laboratories requesting assistance using large tissue banks 
	2	submitted by the Colorado Division of Wildlife.  So the 
	3	tonsil down the road in deer lends itself to larger-scale 
	4	surveillance. 
	5		[Slide.] 
	6		In elk, we don't have that advantage.  Right now, 
	7	the staining of the brain is critical.  The safest technique 
	8	is to take an entire cross-section through the medulla at 

	9	the level of the obex.  Therefore, we don't have a paired 
10	tissue to use for other types of test methodologies.  The 
11	immunostaining, however, is very, very sensitive. 
12		In the hands of trained pathologists, we can 
13	detect two or three infected neurons.  The fact that they 
14	are usually staining bilaterally lends an extra confidence 
15	to this.  So the staining here, if the samples are taken 
16	correctly, is very, very sensitive and specific.  However, 
17	it is time-intensive.  It takes several days for these 

18	tissues to be processed and, in terms of slaughter samples, 
19	Dr. Spraker has worked with us on animals that need to have 
20	results back again with five days.  That can be met, but 

21	only with the willingness of the pathologists and their 
22	technicians to work through weekends since we have been 
23	unable, so far, to convince people to work only on Monday 
24	mornings with tissue collection. 

25		There is no other tissue in the elk that we have 

				122 
	1	yet identified that has the diagnostic significance of the 
	2	brain but I must add a caution here.  We have looked, not as 
	3	extensively, at tissues in the gut as we have in the tonsil. 
	4	We don't yet see any evidence that we have a huge buildup 
	5	for prion in the gut that would precede that in the other 
	6	lymphoid tissues in elk, but those studies are ongoing right 
	7	now. 
	8		[Slide.] 
	9		Work in progress, then; we are working on 
10	development of rapid diagnostic tests for deer-associated 
11	chronic wasting disease so that, optimally, someone who 
12	harvests an animal in an area that is endemic or may be on 
13	the fringes of the endemic area would be able to know within 
14	a matter of a day or two whether that was an infected animal 
15	or not. 
16		We certainly are looking at more cost-effective 
17	large-scale surveillance tests so that, as the United States 
18	moves towards scrapie eradication, they will be able to do 
19	very effective, large-scale ongoing surveillance for chronic 
20	wasting disease to try to bring that disease under control 
21	next. 
22		[Slide.] 
23		We are looking at improved methods for detection 
24	of lymphoid-associated PrP-scrapie in elk.  However, we can 
25	only detect what is there.  Bioassay will be needed to 

				123 
	1	decide whether our biochemical means are underestimating the 
	2	true amount of infectious tissue there. 
	3		There are certainly people out there that are 
	4	developing transgenic mice that have an elk or a deer gene. 
	5	Our ability to do in vivo testing on animals in a timely, 

	6	efficient manner will be critical to our understanding of 
	7	the distribution of infectivity in these animals. 
	8		We are also looking at the relative genetic 
	9	susceptibility to elk-associated chronic wasting disease. 

10	Elk, but not deer, have a reported polymorphism at codon 132 
11	which corresponds to codon 129 in humans.  There are some 
12	changes upstream that change the numbering, but this is the 
13	corresponding codon to codon 129. 
14		In elk, the animal can have either a methionine or 
15	a leucine or both, and we are looking at genetic 
16	susceptibility.  Elk with the methionine-methionine 
17	homozygous state appear to be predisposed.  However, 
18	heterozygous animals have certainly been diagnosed.  The 

19	prevalence of leucine-leucine homozygous animals is so low 
20	that it will take a challenged study to determine if there 
21	is any resistance there. 
22		Thank you. 

23		[Applause.] 
24		DR. BROWN:  Dr. O'Rourke, I had one or two 
25	questions.  Did I infer correctly from your presentation 

					124 
	1	that there is, at the moment, no data on the infectivity 
	2	distribution in the tissues of either elk or deer with 
	3	chronic wasting disease, apart-- 
	4		DR. O'ROURKE:  Beth can address this. 
	5		DR. WILLIAMS:  I would say that the only ones that 
	6	we have true infectivity studies on would be brain, and not 
	7	for the other tissues.  We do have evidence of PrP 
	8	deposition in other tissues, but not in terms of bioassay. 

	9		DR. BROWN:  The PrP--I was going to say, barring 
10	infectivity assays, does the PrP distribution resemble that 
11	seen in other TSEs? 
12		DR. WILLIAMS:  Scrapie would be the best analogy. 
13		DR. O'ROURKE:  In mule deer. 
14		DR. WILLIAMS:  In mule deer; that's correct.  In 
15	elk it may not be quite as much involved in the lymphoid 

16	tissue. 
17		DR. O'ROURKE:  That's correct.  Elk seem to be 
18	intermediate between the TSEs in which only the brain is 

19	involved versus the models like sheep in which the lymphoid 
20	tissue is heavily involved.  Elk are a new diagnostic 
21	challenge because they fall in the middle there. 
22		The difficulty with doing infectivity studies on 
23	chronic wasting disease is that there is not currently a 

24	useful mouse model.  The disease doesn't go readily into the 
25	mice that are used in conventional bioassays, so we are 

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	1	waiting for a transgenic mouse to be available.  It is not 
	2	just that it will make it faster.  I will even make it 
	3	feasible to do those studies. 
	4		DR. BROWN:  The second question is, in those 
	5	animals, the deer, in which tonsil had PrP and brain did not 
	6	have PrP--in those animals, were different areas of the 
	7	brain sampled?  I find it very difficult to believe that 
	8	there are animals with positive tonsils and negative brains. 
	9		DR. O'ROURKE:  Oh, no; that is not surprising. 
10	This is what happens in sheep scrapie, for a period of time. 
11	These are hunter-harvested animals of all different ages, 
12	probably suggest that these animals were in the first year 
13	to year and a half of infection. 
14		DR. BROWN:  Okay.  So these are early-incubation- 
15	period animals. 
16		DR. O'ROURKE:  I'm sorry.  These are what we have 
17	presumed to be early-incubation animals, clinically normal, 
18	hunter harvested.  I apologize for not making that clear. 
19	In the animals that are clinically affected or that have 
20	staining in the brain, tonsil and brain always correlate.  A 
21	small percentage of sheep are brain only.  Mule deer, tonsil 
22	and brain, but tonsil first. 
23		Beth? 
24		DR. WILLIAMS:  I would say one other thing in 
25	terms of pathogenesis work that we have done.  It certainly 

				126 
	1	indicates that in animals that are slaughtered post 
	2	inoculation that the lymphoid tissues do become positive 
	3	before the brain does, which is to be expected. 
	4		DR. BROWN:  As usual; right. 
	5		DR. O'ROURKE:  I'm sorry; as usual for mule deer 
	6	and sheep, not as usual in elk.  That is why my initial 
	7	title slide urges you to consider elk-associated diagnostics 
	8	different from deer-associated diagnostics because the 
	9	distribution of the prion is profoundly different in 
10	extraneural tissues. 
11		DR. BROWN:  Thank you very much, Dr. O'Rourke. 
12		The final presentation of this morning is an 
13	industry perspective presented by Dr. Zebarth of the 
14	American Elk Breeders Association. 
15		          Industry Perspective 
16		DR. ZEBARTH:  My name is Glen Zebarth.  I am a 
17	practicing veterinarian, do commercial practice primarily on 
18	cervids and elk.  I have been involved with a group called 
19	the Elk Research Council and we have maintained a herd of 

20	infected animals and submitted tissues to Dr. O'Rourke and 
21	Dr. Williams and Dr. Spraker. 
22		[Slide.] 
23		I have been asked to present the industry 
24	perspective on chronic wasting disease.  The North American 
25	Elk Breeder's Association has taken an active and leading 

				127 
	1	role in developing and implementing a control program with 
	2	the goal of eventual eradication of CWD in farmed elk.  The 
	3	program includes a certification of a herd's CWD status. 
	4		I would, at this time, go down to item no. 2, the 
	5	scientific evidence that the industry is aware of would 
	6	indicate a lack of evidence of transmission of CWD to humans 
	7	or cattle and most of these items have been covered earlier, 
	8	the species-barrier evidence from Rocky Mountain lab, the 
	9	oral-transmission study that is underway by Dr. Beth 
10	Williams.  There is an interim report on that on twelve 
11	cattle that were exposed orally and are presently free at 
12	three years post-exposure. 
13		Correct me if I am wrong, Beth, somewhere. 
14		There was a cross-species transmission study done 
15	by Dr. Gould at Colorado State University and was conducted 
16	in the geographically targeted survey area of Colorado and 
17	Wyoming.  It involved twenty-two ranches where cattle were 
18	commingling with free-roaming deer in the endemic area.  262 
19	cattle brains were followed through slaughter, collected and 
20	analyzed and were negative for the demonstration of prion. 
21		[Slide.] 
22		Item d, on the next sheet, is the only data that I 
23	am aware of in regard to velvet antler and is very limited. 
24	So I would not propose to interpret that for any more other 
25	than exactly Dr. Rubenstein's comments contained here. 

				128 
	1		From South Dakota, Dr. Holland, the state 
	2	veterinarian, had submitted to Dr. Rubenstein eleven 
	3	antlers.  Three of those were from animals that were brain- 
	4	positive on slaughter.  Three were unknown status and the 
	5	rest were negative on brain examination.  A detectable prion 
	6	was not found at the log infectivity of three logs of 
	7	infectivity. 
	8		In real-life experiences, as Dr. Miller reported 
	9	earlier, free-ranging elk have a documentation of being in 
10	the endemic area from 1981 and in b, under there, I would 
11	say that there is a misprint and it should be, "hunters have 
12	been exposed to and consuming animals from CWD-endemic areas 
13	for at least twenty years with no apparent variant CJD 
14	occurring," apparent to us.  We need to add that, please. 

15		The take-home message that I would like to leave 
16	with the committee today is that the North American Elk 
17	Breeders Association, as an industry, has been active in 
18	trying to responsibly deal with this occurrence and has 

19	worked in developing proposed regulations, has provided 
20	financial support of ongoing scientific research, has 
21	supported the search for better diagnostic tools, has, 

22	through the Association and an organization called the Elk 
23	Products Board, developed quality processing and 
24	manufacturing standards for elk products. 
25		When CDW was first diagnosed in a commercial 

				129 
	1	farmed operation in December of 1996 and January of 1997, in 
	2	the farm facility in South Dakota, the elk breeders of South 
	3	Dakota voted unanimously to support emergency legislation 
	4	through the State of South Dakota that had the goal of 
	5	banning the sale of products from any of those herds.  Those 
	6	herds were quarantined. 
	7		Subsequently, seven herds were identified in South 
	8	Dakota.  Six of those have been depopulated and the final 
	9	herd has a few remaining animals that have been identified 
10	as genetic LLs and are scheduled to be moved to NADL at 
11	Ames, Iowa for an LL-challenge study. 
12		[Slide.] 
13		The North American Elk Breeder's Association, in 
14	August of 1998, convened a symposium in Kansas City at which 
15	time a model program for the control and surveillance of CWD 
16	was formulated.  That problem was taken and submitted to the 
17	United States Animal Health Association in October of 1998 
18	and was passed through the Alternative Agricultural 
19	Committee and the Wildlife Diseases Committee and was 
20	published and put out to state veterinarians, to the state 
21	agencies, as a model control program to use for a template. 
22		As of this date, eighteen states have adopted and 
23	are in some varying stages of a control program. 
24		[Slide.] 
25		On the very last sheet, this is basically somewhat 

				130 
	1	similar to what Mike had on his map.  There actually are 
	2	some more states that are included in here than I think your 
	3	map shows.  These states are the primary states that have 

	4	farmed animals and the estimate is that 80 percent of the 
	5	farmed animals are contained in these states.  As you can 
	6	see, it is a variety of a mix of different programs. 
	7		You can go back to the first page, please. 
	8		[Slide.] 
	9		The main component of the CWD model control and 

10	the goal for eradication program is really two factors.  One 
11	is a verified inventory.  The elk industry is already one of 
12	the most regulated farmed-animal industries in the United 
13	States.  This means that we already have excellent inventory 
14	records on herds and animals. 
15		In most of the states where farmed elk are raised, 
16	by law, the owner is required to have a license with the 
17	Board of Animal Health in that state and is required to 
18	submit an annual inventory.  Some of those states, that 
19	inventory is verified by a third party and some not.  Anyone 
20	who is on a CWD eradication, on this program, has to have a 
21	third-party-verified inventory. 
22		The second major component of the program, then, 
23	is that the brain is examined on every animal that dies, 
24	regardless of the cause, that is in excess of sixteen months 
25	of age.  So the two components of the program are a verified 

			131 
	1	inventory so that we can verify that we know we looked at 
	2	the brain of every animal that expires, regardless of the 
	3	cause, and then the diagnostic tests that we have used, 
	4	examination of the brain, as a follow-up to the information 
	5	Dr. O'Rourke just gave us. 
	6	          This also, then, has the process of--we have in 
	7	the states of North Dakota, South Dakota and Colorado, the 
	8	entire states are--by law, all of the herds are mandatorily 
	9	required to be in this program.  Those states are going on 
10	thirty months.  So we have three states with a fairly large 
11	number of herds that we have thirty months of a certified 
12	status. 
13	          In other words, the brains have been examined 
14	systematically from all of the animals that have died that 
15	were in excess of sixteen months for thirty months in those 
16	three states.  We think that is a very critical fact in that 
17	we are starting to accumulate some herds that we have 
18	verified status and we can have some comfort that these are 
19	herds that not only do we say they have not had an 
20	occurrence of the disease, but we have looked and we have 
21	some proof of examination that there isn't something going 
22	on there. 
23	          At the present time, and with the state programs, 
24	it varies with different states as to whether there has been 
25	a ban of products out of those herds.  We have checked, and 

				132 
	1	all of the herds that have been infected, the seventeen 
	2	herds that Dr. Miller spoke about, none of those herds say 
	3	that they have sold elk velvet antler into the trade since 
	4	they were diagnosed. 
	5		[Slide.] 
	6		The industry supports ongoing research and a 
	7	dialogue.  This basically just underlines some of the facts 
	8	of the research that Dr. O'Rourke is doing.  As she 
	9	mentioned, we did maintain a herd of fifty-two elk that were 
10	obtained from infected herds in a biosecure facility and did 
11	serial sampling.  We maintained those animals for four years 
12	and subsequently they all went to slaughter. 
13		Out of that, we also sampled, and have worked with 
14	Dr. O'Rourke, on the LL-genetic screening.  We are taking 
15	some of those animals now for an LL-challenge at Ames. 
16		One other study that is being done is on of the 
17	infected facilities has been depopulated and we are now in 
18	the process, with the South Dakota Board of Animal Industry 
19	and with the Colorado Division of Wildlife in a project and 
20	model study and reintroducing some animals in an 
21	environmental contamination study there. 
22		[Slide.] 
23		NEABA supports, requests and urgently needs 
24	indemnity.  The importance of an indemnity and the 

25	importance of the industry to work with USDA APHIS 

				133 
	1	Veterinary Services is that if we can obtain indemnity, then 
	2	we will obtain a lot greater compliance from the herd owners 
	3	to be in the program. 
	4		If we do not have any indemnity and we are 

	5	requesting people to be in the program, and they are 
	6	diagnosed and we put them on a permanent quarantine, we 
	7	basically, financially, have ruined them.  So what the goal 
	8	is of the industry is to survey and monitor every herd in 

	9	the industry and to then, as soon as a herd is identified, 
10	to depopulate that. 
11		That is the model that has been accepted and is in 
12	place now in Canada.  The benefits of indemnity would be for 
13	a fair-market value.  Indemnity would increase the market 

14	value of certified products and the market value, then, 
15	would be an incentive for the breeders to comply with the 
16	program. 
17		The value of breeding stock gives meaning to 
18	federal requirements for monitoring interstate movement and 

19	the indemnity will enable more states to implement mandatory 
20	participation and immediate depopulation of any herds. 
21		The elk industry not only has state regulations 
22	but it has a breed registry program where the value of the 
23	animals has made it economically advantageous that these 

24	animals, basically, are all registered and have a DNA 
25	profile, or record.  So these animals can be tracked.  If a 

				134 
	1	positive case is--they have a unique ID and they have a DNA 
	2	profile and they can be tracked back to their origin. 
	3		[Slide.] 
	4		Many states have controlled licensing and 
	5	inventory programs and especially the states that have had 
	6	some cases and especially the states of North Dakota, South 
	7	Dakota and especially the state of Colorado. 
	8		The elk industry is basically--the estimate I have 
	9	is approximately a $1 billion industry in the United States, 
10	the farmed-elk industry, with gross sales of elk farm and 
11	velvet antler estimated at $150 million.  The elk industry 
12	has a track record of aggressively addressing disease issues 
13	in that the same general format that we are proposing to 

14	address CWD was used for brucellosis and tuberculosis and 
15	that a model program was formulated, adopted by some states 
16	that have gone and approached USDA APHIS Veterinary 
17	Services. 
18		UNMRs were written.  Indemnity was created.  That 
19	resulted in brucellosis--there has not been a case of 
20	brucellosis in a farm cervid herd for seven years.  So we 
21	can, with some confidence, say that is eradicated in the 
22	farm population.  There has not been a case of tuberculosis 
23	for two years, a newly discovered case. 
24		That was done after nine years from the initial 
25	outbreak as far as t.b. and six years after a federal 

				135 
	1	program.  The CWD program, then, that we are proposing or 
	2	requested in the process of working with USDA APHIS, follows 
	3	these same general guidelines of a control program that 
	4	would be enforced by interstate movement, would be 
	5	supplemented by indemnity so the producers have an incentive 
	6	to rapidly and quickly dispose of and totally depopulate any 
	7	identified herd. 
	8		We see this as the best guarantee we can give the 
	9	public that no products from these herds that are either 
10	from infected animals or animals that have been in contact 
11	with infected animals, would enter commerce or get into the 
12	food chain.  So the goal is to look at, aggressively, and 
13	identify every herd that is positive and immediately 
14	depopulate that herd. 
15		We are confident that, with diligence and with the 
16	assistance of USDA APHIS Veterinary Services, that that is 
17	not easy but is doable. 
18		Thank you. 
19		[Applause.] 
20		DR. BROWN:  Thank you very much, Dr. Zebarth.  Why 
21	is Pennsylvania still asking for elk to be sent to their 
22	state? 
23		DR. ZEBARTH:  I would refer that to Dr. Miller. 
24	That is free-ranging. 
25		DR. BROWN:  I don't know.  Pennsylvanians 

				136 
	1	apparently think that it was wonderful in Colonial days to 
	2	have elk ranging around the state.  They have initiated a 
	3	program to bring elk from the west. 
	4		DR. ZEBARTH:  Mike, would you care to address 
	5	that?  There are a number of eastern states that have been 

	6	involved in reintroduction of free-ranging animals; is that 
	7	correct? 
	8		DR. MILLER:  Exactly.  I am sure it is part of a 
	9	national species expansion program that the state is 
10	involved in.  You would really need to get the folks from 
11	Pennsylvania to speak specifically to why they are doing 
12	that. 
13		DR. BROWN:  Is there any awareness--I am sure 
14	there is, but let me ask a different thing.  Are they aware 

15	of the potential problem in this kind of interstate commerce 
16	of elk? 
17		DR. MILLER:  Certainly.  As I mentioned, we won't 
18	allow animals to be taken from places where we know chronic 
19	wasting disease occurs.  I think the states right now that 
20	are receiving animals are well-aware of the problems and 
21	trying to do what they can do insure that animals don't come 
22	from populations that are likely to be infected. 
23		The same way with the elk industry. 
24		DR. ZEBARTH:  The elk industry proposes to do that 
25	but proposes, also, to do one step further because we have 

				137 
	1	the ability to identify and control these animals, we would 
	2	propose, eventually, to only move animals that would have a 
	3	certified status. 
	4		DR. MILLER:  There are plans, I think, underway 
	5	and desire, certainly, to try to identify free-ranging 

	6	populations of animals that can be, to the best of our 
	7	technical ability, certified as free.  Certainly, there are 
	8	places in the country that they could get animals from. 

	9		DR. BROWN:  Would that certification include a 
10	third-eyelid test? 
11		DR. MILLER:  It wouldn't do a whole lot of good, 
12	it doesn't sound like. 
13		DR. WILLIAMS:  It wouldn't be third eyelid.  It 
14	most likely would be a brain test on harvested animals to 
15	certify the free-ranging herd as being a negative herd. 

16		DR. O'ROURKE:  I have been asked to provide third- 
17	eyelid tests on animals that are intended to be reintroduced 
18	into the Great Smokey Mountain Park.  Those animals are 

19	being sourced from a place in Canada in which the animals 
20	are free-ranging but protected from ingress and egress by 
21	free-ranging animals. 
22		I have told them that if they choose to archive 
23	those tissues, they could feel free to do so.  But, because 
24	the test right now does not have very much value, I didn't 
25	want to give them a false sense that they were, in fact, 

				138 
	1	guaranteeing the CWD-free status. 
	2		The geographic source of the animals is the key 
	3	issue for them. 
	4		DR. BOLTON:  How are the carcasses from the 
	5	depopulated herds disposed of? 
	6		DR. ZEBARTH:  The carcasses, primarily, have been 
	7	incinerated and then, in a biosecure, land-fill facility. 
	8		DR. BOLTON:  I have another question.  Do you have 
	9	an idea of prevalence of CWD is within an infected herd, a 
10	farmed herd? 
11		DR. ZEBARTH:  We have seen two different scenarios 
12	in the farm population, one in the index herd, the original 
13	index herd in South Dakota.  Correct me, Beth and Katherine, 
14	if I am wrong on this.  It was a concentrated feed-lot 
15	situation and there ended up being a high rate of incidence 
16	in a group of bulls, 125 bulls, that had a high incidence, 
17	in the neighborhood of 36 percent. 
18		The other farm situations we have seen have 
19	generally been much, much lower incidence than that, at 1 or 
20	2 percent.  The industry is taking the position and the 
21	desirability, one case and it is out.  That has been our 
22	experience. 
23		DR. BOLTON:  One final question for me.  In the 
24	depopulated farms, have any of them been repopulated and, if 
25	so, how long ago has that occurred? 

				139 
	1		DR. ZEBARTH:  So far, no.  The owners have 
	2	voluntarily or in conjunction with--most of those have set 
	3	up a herd plan with the state veterinarian and there has not 
	4	been any depopulation in any of those facilities.  We are 
	5	proposing, under environmental contamination, to repopulate 
	6	with a controlled number of animals from a certified-free 
	7	herd into one small area in one of those facilities. 
	8		DR. BURKE:  Don, do you know what percentage of 
	9	your captive animal herds in this country are operating 
10	under your aegis? 
11		DR. ZEBARTH:  Dr. Creekmore might have that.  I 
12	would say 50 percent and that is an estimate.  But that 

13	would be my estimate at this time.  The states that I 
14	maintained are 100 percent.  The two largest states for 
15	farmed elk are Colorado and Minnesota.  Minnesota is a 

16	voluntary program.  There are 204 herds in Minnesota.  137 
17	of them voluntarily are in the problem. 
18		DR. PRUSINER:  Could you give me a little idea of 
19	the elk-farming industry relative to the deer-farming 
20	industry that produces venison?  This is a billion dollar 
21	industry with $150 million in sales annually?  How many 
22	animals does that equate to and then could you give us the 
23	same numbers for deer, or do you know them? 
24		DR. ZEBARTH:  I do not know for deer.  For elk, 
25	the number is approximately 110,000 farmed-elk in North 

						140 
	1	America of which approximately half of that would be in 
	2	Canada and half in the United States.  Canada is 52,000 and 
	3	some. 
	4		DR. PRUSINER:  How many are killed each year? 
	5		DR. ZEBARTH:  I do not know that.  I do know that 
	6	in our looking and monitoring levels, checking the normal 
	7	mortality of animals sixteen months of age and over is 
	8	1 percent.  The number of animals slaughtered in the United 
	9	States this year, there are a couple of individuals in the 
10	audience that are in the meat industry.  My estimate would 
11	be a total of 800 to 1,000 head. 
12		DR. PRUSINER:  1 percent? 
13		DR. ZEBARTH:  No, no; two different things. 
14	1 percent death loss in a herd, and then the animals that 
15	were taken to slaughter, healthy animals taken to slaughter- 
16	- 
17		DR. PRUSINER:  10 percent. 
18		DR. ZEBARTH:  The previous year was about 800 
19	animals. 
20		DR. PRUSINER:  So that is 1 percent.  1,000 
21	animals slaughtered out of a herd of 110,000 is 1 percent 
22	are slaughtered in a year. 
23		DR. ZEBARTH:  Okay.  There are not very many of 
24	them slaughtered. 
25		DR. PRUSINER:  So how do you make money?  How do 

						141 
	1	you make $150 million a year out of this? 
	2		DR. ZEBARTH:  Sale of breeding stock. 
	3		DR. BROWN:  Velvet antlers. 
	4		DR. PRUSINER:  Wow.  What an industry. 
	5		DR. ZEBARTH:  There are several components. 
	6	Velvet antler is one economic proponent.  There are a lot of 
	7	people that own and have elk just because the regality of 
	8	the animal and that is especially true of deer, but a lot 
	9	people have elk just for the sake of having them and seeing 
10	them. 
11		DR. PRUSINER:  Wow.  Okay. 
12		DR. BOLTON:  Are game preserves included in your 
13	grouping? 
14		DR. ZEBARTH:  In the surveillance, yes.  Their 
15	heads are examined in hunter operations.  Yes. 
16		DR. BELAY:  How widespread is the use of antlers? 
17	It is from every dead animal?  Is it 50 percent?  Can you 
18	give us an estimate? 
19		DR. ZEBARTH:  Please repeat the question.  I'm 
20	sorry. 
21		DR. BELAY:  How widespread is the use of antlers? 
22	Is it from every dead animal that antlers would be used? 
23		DR. ZEBARTH:  No.  The velvet antler is a 
24	traditional product.  It is harvested at a very specific 
25	stage of growth which is about a four- or five-day period of 

				142 
	1	time.  It is harvested with an anesthesia of the antler, 
	2	sawed off and immediately frozen.  It is harvested above the 
	3	growth line so that is an annual removable product. 
	4		DR. BROWN:  Most of that is probably exported; is 
	5	that true? 
	6		DR. ZEBARTH:  Exported.  70 percent of the world's 
	7	supply goes to South Korea. 
	8		DR. LURIE:  You said in your comments that the elk 
	9	industry is one of the most regulated farm-animal industries 
10	in the country.  What I mostly hear is a voluntary program 
11	to which 50 percent of elk herds do not belong, some state 
12	laws, not in every state, half of which are voluntary, and 
13	no federal requirement that should an animal come down with 
14	CWD that the entire herd be depopulated. 
15		I don't know, but that-- 
16		DR. ZEBARTH:  Those are all excellent arguments 
17	that we have proposed that we need indemnity to facilitate 
18	and then we need this to be made a program disease.  The 

19	industry has requested to USDA APHIS that this would become 
20	a program disease and then the things you mentioned would 
21	logically follow, follow in that interstate movements 
22	requirements, depopulation of infected herds and indemnity 
23	for-- 
24		DR. LURIE:  But those things are not in place 
25	right now in a widespread way. 

				143 
	1		DR. DETWILER:  May I comment on that?  That is 
	2	something, actually, the USDA has requested but they have 
	3	2,000 herds.  So you can imagine.  You have to get the 
	4	attention of Congress in order to do that.  So that is why 
	5	even recommendations from this committee carry weight in 
	6	that regard. 
	7		DR. LEITMAN:  I have a question for Linda.  How 
	8	does this compare to scrapie?  In CWD, there is no evidence 
	9	that the disorder has crossed species barriers into humans, 
10	from what we have heard this morning.  That is true for 
11	scrapie in sheep as well.  If a sheep herd, or a member of a 
12	sheep herd, has scrapie, does the herd have to be decimated? 
13		DR. DETWILER:  Have to be?  No, not any longer. 

14	We have had a scrapie program from 1952 to the present. 
15	From 1952 until 1982, 1983, it was complete flock 
16	depopulation.  We found that drove the disease underground, 
17	that you had one animal that might be newly introduced and 
18	all the sheep had to go. 
19		We have actually, now, gone to a process where 
20	high-risk animals are removed.  This is even changing as 
21	these new tests come on board, so high-risk animals are 
22	removed.  Then the flock gets monitored after that with the 
23	certification so that you could--and, sometimes, if it is 
24	heavily infected, the flock is depopulated, but it is not 
25	mandated federally.  In some states, it is.  So there are 

				144 
	1	combinations now. 
	2		DR. ROOS:  Isn't there some evidence of 
	3	interspecies spread of scrapie, for example, TME?  I don't 
	4	know whether the data is that good. 
	5		DR. DETWILER:  To my knowledge, there is no 
	6	association with scrapie and TME.  I think there has been 
	7	speculation in the early literature about sheep.  There has 
	8	been speculation about cattle with TME.  But none of those 
	9	have been, to my knowledge, any conclusive evidence with 
10	TME. 
11		Now, scrapie, with experimental transmission, yes. 
12	It has been transmitted to a number of species but not to my 
13	knowledge in any natural route. 
14		DR. BROWN:  I think, as you have probably noticed, 
15	we are not breaking.  What I would like to do now is hear 
16	the open public hearing presentations and then we shall have 
17	lunch.  Then we shall discuss this issue immediately after 
18	lunch. 
19		          Open Public Hearing 
20		DR. FREAS:  Following our Federal Register 
21	Announcement, I have received four requests to address the 
22	committee during the open public hearing.  The first request 
23	is Mr. Dan Marsh.  Is he present?  The second request I have 
24	seen is from Barbara Fox from the North American Deer 
25	Farmers Association. 

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	1		MS. FOX:  I will pass. 
	2		DR. FREAS:  The third request, Lloyd Riddle from 
	3	Natraflex Brands. 
	4		MR. RIDDLE:  Nobody else wanted to get between the 
	5	crowd and lunch, I see.  I will dispose of this quickly. 
	6	Good morning and thank you for allowing me to share my 
	7	comments with you.  My company, Natraflex Brands, is the 
	8	leading velvet-antler dietary distribution company in the 
	9	United States.  We estimate we have about two-third market 
10	share. 
11		I am here to share with you, and the general 
12	public, some information regarding the safety of our product 
13	and the steps our company takes, as well as the general elk 
14	industry takes, to insure that our products continue to be 
15	safeguarded from CWD. 
16		Let me state from the outset that Natraflex 
17	maintains documentation on the source and the chain of 
18	custody of our velvet-antler material and our records show 
19	that we have not purchased velvet antler from any ranch or 
20	any farm that has had a CWD-positive case diagnosis at the 
21	time of the purchase nor have we made a purchase from any 
22	farm or ranch that has had a subsequent CWD-positive case 
23	diagnosis. 
24		Product safety is paramount to us at our company 
25	and the following are just some of the steps we take to 

				146 
	1	insure that our products are safe.  Number one, Natraflex 
	2	limits our velvet antler purchases to growers and states 
	3	that are enrolled in state- or provincial-run CWD 
	4	surveillance and eradication programs. 
	5		This means that those growers must submit the 
	6	brains of required animals that perish or that are 
	7	slaughtered to the state veterinarian for CWD testing.  You 
	8	can't find what you are not looking for.  All of our 
	9	suppliers are--in most cases, required by law--looking for 
10	CWD.  In fact, our principal supplier of velvet antler is 
11	also used as the negative-index herd, if you will, for CWD 
12	live-animal testing. 
13		This herd is subject to extensive veterinary and 
14	health review by some of the world's leading TSE scientists. 
15		Number two, as a matter of policy, public 
16	perspective and common sense, we do not, and have not, 
17	sourced any products of any kind from any ranch that is or 
18	has ever been under CWD quarantine. 
19		Number three, notably, and from a statistical 
20	management perspective, to date, Natraflex has sourced fresh 
21	velvet antler from only fifteen growers.  As a consequence, 
22	we know exactly where our product comes from and we 
23	continually monitor these sources for quality and safety 
24	issues. 
25		In fact, as you have heard from earlier speakers, 

			147 
	1	although CWD has been known to exist in the wild population 
	2	for several decades, the elk and deer industry responded 
	3	very proactively when CWD first appeared in farm stock 
	4	several years ago and have worked with various state 
	5	agencies to adopt state-run CWD surveillance programs.  Some 
	6	of these programs have been in place for as long as thirty 
	7	months. 
	8	          These programs are beginning to approach, or 
	9	exceed, the generally accepted CWD incubation period and, as 
10	a consequence, several states are considering issuing CWD 
11	status certification similar to the accreditation you heard 
12	received for t.b.  As you heard from Dr. Zebarth, there is a 
13	proposal to USDA to make this a national program.  Natraflex 
14	welcomes these programs as a double check and as a 
15	validation on our own existing standards as well as 
16	providing confidence to the consuming public. 
17	          Number four, Natraflex supports USDA, American Elk 
18	Products Board, and North American Elk Breeders Association 
19	quality control and feed standards.  These standards 
20	mandate, among other things, that farmed elk and deer feed 
21	not contain prohibited mammalian proteins, unlike the former 
22	European practice of feeding TSE-infected animal protein to 
23	cattle. 
24	          Natraflex also strongly supports the national 

25	model CWD eradication program developed by these same 

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	1	agencies provided that the program included herd indemnity 
	2	to maximize surveillance results and for basic fairness 
	3	reasons. 
	4		Five, each batch of velvet antler we produce is 
	5	thoroughly tested in an independently licensed laboratory 
	6	not only for compositional conformity to our standards but, 
	7	also, for food-borne pathogens and other contaminants such 
	8	as heavy metals.  When a live animal test for CWD is 
	9	validated, we will require that test as well. 
10		Six, Natraflex maintains comprehensive, chain-of- 
11	custody records that trace each bottle's lot number back to 
12	the ranches that produced that antlers.  Each bottle of our 
13	product can be traced back to the farms that produced it and 
14	none of our supplying farms has ever had a CWD-positive 
15	case. 
16		Seven, finally, all of our products are packaged 
17	at an FDA-licensed and inspected facility and are labeled in 
18	compliance with FDA regulations.  CWD is rare among farmed 
19	elk and deer and complete eradication measures are advancing 
20	rapidly.  Further, we have seen no scientific evidence that 
21	shows CWD can be transmitted to humans.  Centuries of elk, 
22	venison and velvet antler consumption by humans would seem 
23	to bear this out. 
24		The bottom line is that there is no evidence that 
25	velvet antler poses a public-health risk.  However, and let 

				149 
	1	me be very clear on this point, Natraflex does not rely on 
	2	centuries of empirical evidence or the science alone.  We 
	3	share the commitment of the elk and deer industry, USDA and 
	4	the FDA to have safe and effective products.  We will 
	5	continue to take whatever steps are necessary to insure that 
	6	our products are guarded against CWD. 
	7		Given the science and the information presented, 
	8	and given the comprehensive array of Natraflex quality 
	9	control and chain-of-custody procedures, we believe that you 
10	can be confident the our velvet-antler supplements are safe. 
11		Thank you for the opportunity to share my comments 
12	this morning. 
13		DR. FREAS:  Thank you, Mr. Riddle. 
14		Our next speaker is Dr. Michael McDonnell from the 
15	North American Elk, LLC. 
16		DR. McDONNELL:  Thank you.  I am Dr. Michael 
17	McDonnell.  I am a researcher in the beef industry but I 

18	also happen to be part owner in a slaughter facility and 
19	meat-distribution facility for elk. 
20		In general, you have had specialists here today 
21	that describe CWD in great detail.  I am going to try and 
22	give a quick overview and also a view from the meat 
23	industry.  One thing, or two things, that we all agree with 
24	is we want to have a safe food supply and, really, we wish 
25	that we could control and eradicate this problem so that we 

				150 
	1	didn't have to have this type of discussion. 
	2		The first question that I look at from the meat 
	3	industry is the question of is CWD directly transmissible to 
	4	humans.  I think, from what we have seen here, we have not 

	5	seen direct data but it may be premature to call it that it 
	6	is not a risk.  But it is also premature to declare it a 
	7	risk.  We need to work on it more.  My desire would be to 

	8	try to eradicate it so that we don't have to discuss that 
	9	particular part of it. 
10		As a meat company, and there were some questions 
11	asked of other producers and I was glad to be able to come 
12	up here and make some statements.  Whenever we have a highly 
13	suspect herd, or a herd that has had a positive animal in 
14	it, all the meat, all the internal organs, from that herd 
15	will be destroyed at the direction of the state in which we 
16	are, whether it is burned, whether it goes to a landfill or 
17	whatever.  We try to be as safe as we can. 
18		Any positive animals that come back will be 
19	destroyed.  Only animals that test negative will be allowed 
20	into the human food chain.  The elk industry has done a very 
21	good job of self-policing itself in that 80 percent of the 
22	elk herds that have had an initial positive have voluntarily 
23	depopulated their herd.  By the end of this year, the 
24	remaining herds will be depopulated. 
25		Some data that I will share with you in the herds 

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	1	that we have been involved with the depopulation, if the 
	2	herd was depopulated within six months of the initial 
	3	positive sighting, we have had zero incidence of positive 
	4	animals.  If the time frame goes to one year to two years 
	5	after the initial observation, we have a 7 percent infection 
	6	rate in those herds. 
	7		If we go to the third year and on out, the 
	8	infection rate goes up to 30 percent.  Therefore, we would 
	9	like to get indemnity so that we can eradicate this earlier 
10	because the quicker we break that chain, the less problems 
11	we will have in the long run. 
12		We have had some discussion of elk being a 
13	nonamenable animal, which means it falls in a grey area and 
14	is really under FDA control because it is not under USDA.  I 
15	would ask that the FDA consider putting it under their 

16	umbrella with USDA like they do FSIS and allow the APHIS 
17	program to be used in both the domestic and the wildlife, 
18	similar to what meat inspection is done by FSIS so that we 
19	could have a uniform program and could work to the 
20	eradication of this problem. 
21		Thank you, sir. 
22		DR. FREAS:  Thank you, Dr. McDonnell.  Could you 
23	stay for a question? 

24		DR. McDONNELL:  If you word it that way, yes, sir. 
25		DR. BURKE:  The question is if a herd is 

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	1	depopulated and then they restart a new herd there that 
	2	there is a progressive increase in the-- 
	3		DR. McDONNELL:  No; I'm sorry.  If we have an 
	4	initial animal diagnosed positive, and then we depopulate 
	5	the herd within six months of finding the initial animal, we 
	6	find no other positives in the herd.  If we wait a year to 
	7	find that, then we find 7 percent.  The longer you wait, the 
	8	more it builds up and, if we can do it quickly, we can nip 
	9	it in the bud and stop it. 
10		DR. NELSON:  What do you mean by "depopulate?" 
11		DR. McDONNELL:  Kill everything. 
12		DR. NELSON:  All the animals are killed? 
13		DR. BROWN:  Does that square with what we heard 
14	from Katherine and you, that is there was one 35 percent 
15	bull herd and the rest of them were flat-out said to be 1 to 
16	2 percent.  This sounds like it is a different set of data. 
17		DR. McDONNELL:  Those are the ones that I have 
18	been personally involved with.  There have been three herds 
19	or four herds that I have not personally been involved with. 
20	I am just going on the data that I have been involved with. 
21		DR. WILLIAMS:  There is a situation with some of 
22	our experimental herds within the endemic research 
23	facilities where we do have cases where animals have been 

24	removed from particular paddocks and then animals from CWD- 
25	negative herds reintroduced into those facilities.  Under 

				153 
	1	those circumstances, with environmental contamination and 
	2	potentially fence-line contamination, we have had prevalence 
	3	in those herds up to 50 or 60 percent. 
	4		DR. BROWN:  So this is an extraordinarily 
	5	contagious disease, relative to something like scrapie which 
	6	is 1 to 2 percent, BSE which maybe doesn't get horizontally 
	7	transmitted at all.  But, certainly, by comparison with 
	8	scrapie, in terms of the data such as it is, this is 
	9	explosive. 
10		DR. WILLIAMS:  Linda, do you want to comment on 
11	the occurrence or the prevalence of scrapie within endemic 
12	flocks? 
13		DR. DETWILER:  At least in things that are 
14	monitored--again, whenever you have controlled programs, I 
15	just have to caution you, you skew your data because if you 
16	get the first one, or what not, and the flock is 
17	depopulated, then you eliminate this finding.  So scrapie is 
18	usually reported a little bit higher, Paul, 2 to 5 percent 
19	in most flocks.  But you can have up to 10 to 20 percent 
20	infection. 
21		Now, in retrospect, that is work done in the '80's 
22	prior to the genotyping.  Probably now, if you went back and 
23	genotyped those, probably ones with higher prevalence, you 
24	would probably see some genetic differences in there.  That 
25	is my own guesstimation. 

				154 
	1		DR. BOLTON:  I have a question, again, going back 
	2	to the disposal of the animals, when the herd is 
	3	depopulated, all of animals' carcasses are burned or 
	4	incinerated or are they retested and only the positive 
	5	animals are incinerated and the other animals are butchered 
	6	and the meat used? 
	7		DR. McDONNELL:  Using the data that we collected 

	8	earlier, depending on how long we have for the infection to 
	9	progress, if it is a short-term--you know, immediately or 
10	soon after we get the original where we do not anticipate 
11	any positives, those animals are held under a retaining 
12	order.  Usually, the samples are sent to Terry Spraker at 
13	Colorado State.  Those animals that test positive are all 
14	destroyed.  Those animals that test negative would be 
15	allowed into the food chain. 
16		DR. BROWN:  One other question.  In the herds of 
17	animals which you have allowed to progress over time up to 

18	several years, what happens to the placentas in these herds; 
19	that is to say, you have got a herd.  You know there is an 
20	infected animal.  You let the herd continue to exist. 
21		I am looking for a method of transmission.  In 
22	this kind of a herd, would the placenta be source of cross- 
23	contamination because it would be fed on by a number of 
24	animals? 
25		DR. McDONNELL:  I am going to pass on that 

					155 
	1	question because that is not my area of expertise but I will 
	2	answer it in a different way.  We have had it in herds that 
	3	are all male and we have transmission in velveting herds 
	4	where there is no placenta present. 
	5		DR. BROWN:  At the same kind of rate; that is, 7 
	6	to 30 to-- 
	7		DR. McDONNELL:  We don't have enough of those 
	8	herds to establish a real positive number there.  I was 
	9	throwing those numbers out with the idea of saying we need-- 
10	the earlier we get on it, the better control we have. 
11		DR. BROWN:  And, at a minimum, you have got some 
12	transmission in all-male herds. 
13		DR. McDONNELL:  Yes. 
14		DR. BOLTON:  What is the density of the animals in 
15	these meat farms?  Is this like a feed-lot situation or is 
16	the more like a wild-- 
17		DR. McDONNELL:  No; they would be dispersed enough 
18	that grass still grows in the pasture, if you want to say 
19	that. 
20		DR. BOLTON:  How many animals per acre, for 
21	example? 
22		DR. McDONNELL:  Five animals per acre?  Four to 
23	ten?  It kind of depends on what part of the country you are 
24	in, what the grass-carrying capacity is. 
25		DR. ZEBARTH:  The one herd that I spoke of that 

				156 
	1	had the high incidence was a feed-lot situation.  There was 
	2	no vegetation in there.  We are talking about 125 animals in 
	3	a very, very small area.  That is the only herd that we know 
	4	of that had the real high incidence.  The other herd, of 
	5	which he speaks, that was maintained for a long time was the 
	6	herd that we were maintaining and doing the serial sampling 
	7	on.  So that is why that herd was maintained and that is 

	8	why, when that herd was killed, there was a fairly high 
	9	infection rate. 
10		DR. BOLTON:  I am just asking the question in 
11	general, in the elk that are bred and kept for meat 
12	production, what would be the general density of the-- 
13		DR. ZEBARTH:  It would vary according different 
14	parts of the country or vegetation, but a rule of thumb 
15	would be no denser than one animal per acre and, as a 

16	general rule, probably one animal per three acres. 
17		DR. McDONNELL:  In general, about twice the number 
18	of elk stocking rate than you would for cattle would be the 
19	normal.  And that varies all over. 
20		DR. PICCARDO:  I need some clarification.  Let me 
21	see if I understood correctly.  If an animal is infected in 
22	a flock, then the whole flock goes through testing at the 
23	state; is that what you said? 
24		DR. McDONNELL:  If they are depopulated; yes.  My 
25	company's standpoint is that we test everything that we 

						157 
	1	slaughter whether they are suspect or not as a monitoring 
	2	program. 
	3		DR. PICCARDO:  Right; but the ones that test 
	4	negative, that means, by immunohistochemistry? 
	5		DR. McDONNELL:  Yes. 
	6		DR. PICCARDO:  Go back to the food chain? 
	7		DR. McDONNELL:  They can go back. 
	8		DR. PICCARDO:  They can go back?  What do you mean 
	9	by "they can go back?"  There is no rule? 
10		DR. McDONNELL:  Some herds choose not to have them 
11	go back.  There was a herd that was slaughtered two weeks 
12	ago and we passed on it because I thought it would have a 

13	higher infection rate than it actually did.  We passed on 
14	that herd.  So they were all destroyed even though they 
15	tested negative. 

16		DR. PICCARDO:  So there is nothing legal.  It is 
17	your decision, basically?  It is not like you are enforced 
18	to do one way or the other. 
19		DR. McDONNELL:  That is correct.  Unfortunately, 
20	being a nonamenable animal, there are a lot of grey areas. 
21	I have had a number of requests, with both USDA and FDA, for 
22	further guidance to narrow up a lot of those loopholes.  I 
23	have got to say the regulatory people look at me and say 

24	that I am a little bit odd to be asking for more 
25	restrictions but I feel it is appropriate in this area. 

				158 
	1		DR. PICCARDO:  I don't follow very well the logic 
	2	on this because if this is a highly infectious disease, and 
	3	then the animals that tested negative are allowed, at least 
	4	in this grey area, to go back to the food chain-- 
	5		DR. McDONNELL:  The human food chain. 
	6		DR. PICCARDO:  Right; even worse. 
	7		DR. McDONNELL:  But we have not seen it be 
	8	infective yet into the human side. 
	9		DR. PICCARDO:  No, no; I understand.  But the 
10	issue of the negative is, of course, we know nothing about 
11	the preclinical stage, et cetera, et cetera.  So we are in a 
12	grey area where we don't know enough.  You have a positive 
13	animal.  You have some negative animals.  And then the 
14	decision is in a grey zone of what is going to happen with 
15	that and there is no regulation. 
16		DR. McDONNELL:  There is no regulation. 
17	Unfortunately, we have no test--if we can not find the 
18	presence of a compound, the general process is we assume it 
19	is not there.  If we take a stand to remove all animals from 
20	the food chain, then we run into difficulties in the beef 

21	and the swine industry because it is a difficult question. 
22		DR. BROWN:  I think what you are getting at, the 
23	answer, it seems to me, is that there is a decent 
24	possibility, under these conditions, for animals that are 
25	undetected but infected to enter the human food chain.  I 

				159 
	1	think you both agree about that. 
	2		DR. PICCARDO:  You are absolutely right, Paul. 
	3	But, then, I have another question maybe for Beth or Linda. 
	4	For the ones that tested negative on immunohistochemistry in 
	5	humans--in humans where it is supposed to be more ideal 

	6	conditions, if you wait long enough, or the material is 
	7	fixed long enough, sometimes you might have a negative by 
	8	immunohistochemistry due to the long fixation or the not- 
	9	ideal condition of the material. 
10		How ideal is the material that you test? 
11		DR. WILLIAMS:  It is variable.  But, in general, 

12	especially the plants that have been used to doing this, we 
13	get good samples from them.  We get the right part.  And 

14	they are typically only fixed for a short period of time 
15	because the carcasses are hanging and, obviously, they don't 
16	want to leave them hanging for very long if they are going 
17	to move on into the food chain. 
18		So they do send us pretty good samples.  I will 
19	say that we have a little bit of information in terms of 
20	experimentally infected elk looking at the time at which we 
21	can detect PrP in the brain.  This would be for elk.  It is 
22	a little bit different than deer, as has been mentioned.  By 
23	six months, post oral inoculation, we can detect it at the 
24	obex. 
25		In those two cases, the staining was relatively 

					160 
	1	strong suggesting that it could have been picked up even 
	2	prior to six months.  But, again, experimental or 
	3	inoculation. 
	4		DR. BELAY:  Dr. Brown, it was my understanding 
	5	that there is actually a proposal to change what we are 
	6	discussing in terms of whether or not a test-negative animal 
	7	from an infected herd should be allowed to go into the human 
	8	food chain.  My understanding was there is a proposal to 
	9	change that.  Is that true?  I am asking this question to 
10	Lynn.  Dr. Creekmore? 
11		DR. DETWILER:  Isn't that what the committee is 
12	supposed to be discussing? 
13		DR. BROWN:  No; it is not.  No; we have to decide 
14	whether or not residence in northern Colorado for six months 
15	is a deferral criterion. 
16		DR. NELSON:  If you are an elk. 
17		DR. BELAY:  Let me rephrase my question.  We have 
18	heard about a national plan to eliminate or eradicate 
19	chronic wasting disease from farmed elk.  My understanding 
20	was, as part of that national plan, any animal that tests 
21	negative, as long as that animal is coming from a CWD- 
22	infected herd, it would not be allowed to go into the human 
23	food chain regardless of whether or not the animal was 
24	positive or negative. 
25		DR. BROWN:  This is for your own curiosity; right, 

					161 
	1	Ermias? 
	2		DR. BELAY:  Right. 
	3		DR. BROWN:  Because it has nothing to do with the 
	4	issue. 
	5		DR. BELAY:  Correct. 
	6		DR. BROWN:  Linda, can you answer that, or can 
	7	anybody? 
	8		DR. CREEKMORE:  My name is Lynn Creekmore.  I am 
	9	with USDA APHIS Veterinary Services, the National Animal 
10	Health Program staff, and I am the staff veterinarian 
11	working on the chronic wasting disease proposed program. 
12	Right now, the proposed program isn't dealing with that 
13	issue of whether or not test-negative animals from a 
14	positive or exposed herd should or should not enter the food 
15	chain. 
16		The thrust of the program, as Glen described, is 
17	to have a herd-certification-intensive surveillance program 
18	with the primary response to a positive herd being that of 
19	depopulation with payment of indemnity.  There is another 

20	option within our program also of a long quarantine period. 
21	The question of what can or cannot happen to the animals 
22	while they are under that quarantine period in terms of 
23	products or slaughter is something that we are looking to 
24	the food-safety and public-health agencies to give guidance 
25	on. 

					162 
	1		DR. BROWN:  We are closing, now, the public 
	2	hearing.  There may be further discussion on various points 
	3	that were raised, both by our formal presentations and the 
	4	public speakers.  We will now adjourn for lunch. 
	5		DR. FREAS:  Was there anyone else in the audience 
	6	who wanted to address the committee in this open public 
	7	hearing? 
	8		DR. BRACKETT:  I just wanted one clarification 
	9	both from what Linda said as well as what Ermias said.  It 
10	goes back, and I would like to direct the committee back, to 
11	the questions that were asked which is we are really looking 
12	at the science available to look at the questions so that we 
13	can make some decisions.  So that is really what the basis 
14	is for infectivity. 
15		DR. FREAS:  If there is no one else in the 
16	audience at this time wishing to address the commission, 
17	then I guess we are going to go for lunch. 
18		DR. BROWN:  We will reassemble here at 1 o'clock. 
19	It is now 12:20. 
20		[Whereupon, at 12:20 p.m., the proceedings were 
21	recessed to be resumed at 1:00 p.m., this same day.] 

				163 
	1		           AFTERNOON  SESSION 
	2		                                       [1:10 p.m.] 
	3		                Topic 3 
	4		          Committee Discussion 
	5		DR. BROWN:  We will have committee discussion. 
	6	For the members of the committee, I have an option from the 
	7	FDA.  We do not need formally to vote on each of the ten 
	8	questions--actually, five questions and five subquestions-- 
	9	on this particular issue.  But they would like a sense of 
10	what the committee is thinking about each of these 

11	questions.  It seems to me that two or three of the 
12	questions are extremely easy and they really didn't need to 
13	ask our advice at all. 
14		Such as the first question; are there scientific 
15	data or other scientific evidence for transmission of TSE 
16	from an infected elk or deer to uninfected deer or elk.  It 
17	is an interesting transposition, actually, isn't it; elk to 
18	deer, deer to deer--okay; elk or deer to uninfected elk or 
19	deer and, if so, how strong are these data? 
20		DR. BOLTON:  Strong enough to have an epidemic? 
21		DR. BROWN:  Strong enough to have an epidemic; 

22	exactly.  So I don't think we really need to spend much time 
23	on that.  Of all the things we heard this morning, that is 
24	probably the most secure. 
25		DR. BOLTON:  Could they give us more questions 

					164 
	1	like that? 
	2		DR. BROWN:  Yes; I was going to say, we would love 
	3	to have more questions on which we had some scientific 
	4	observations on which to base our responses.  The second one 
	5	is not bad either; are there scientific data or other 
	6	evidence for transmission of a TSE to people consuming or 
	7	using products made from deer or elk with chronic wasting 
	8	disease. 
	9		Remember to keep your focus on the things that FDA 
10	has some control over; namely, foods and cosmetics.  We are 
11	not talking, for example, about an elk rancher who might, 
12	through contact, develop the disease.  We are really talking 
13	about products.  So the question, again, is are there 
14	scientific data that consuming or using products made from 
15	deer or elk with CWD are transmissible to humans. 
16		Anyone who might have a comment on that? 
17		DR. BURKE:  Before we left the first one, I wanted 
18	to be sure that I understood.  It appears, for chronic 
19	wasting disease, there is more evidence for horizontal 
20	transfer than there is in BSE.  In BSE, there is relatively 
21	little evidence for sustained-- 
22		DR. BROWN:  That is absolutely correct. 
23		DR. BURKE:  Just to make sure.  So that the reason 
24	for the question here is largely to differentiate between 
25	the epidemiologies of these two types of diseases. 

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	1		DR. BROWN:  That is a good point.  I guess so. 
	2	That is very acute.  I couldn't see the reason for the 
	3	question, but I think you have hit on it. 
	4		DR. BURKE:  I will try to interpret the next one, 
	5	too. 
	6		DR. BRACKETT:  Actually, the reason we wanted to 
	7	know that is if you have an exposed or an unexposed group of 
	8	animals and they were moved in with exposed, are they, now, 
	9	at risk, horizontal transmission. 
10		DR. BROWN:  And the answer, based on what we heard 
11	today, is certainly yes.  Is there any disagreement on that? 
12	What about people?  I would have said no, not on the basis 
13	of the data we have now.  But I wouldn't cross off the 
14	possibility; right? 
15		DR. PICCARDO:  Right; so there should be further 
16	investigation.  There should be a clause there. 
17		DR. ROOS:  I don't think we have any data to 
18	support transmission of CWD to humans.  The issue, really, 
19	is how good is the surveillance system and what are we 
20	really looking for and, if it is a very atypical 
21	presentation and case, as it might be, would we miss it 
22	altogether.  So I think it is open-ended. 
23		DR. BROWN:  I think that is a good point that I 

24	was going to make, also, Beth.  I should know this because 
25	our laboratory conceivably has done it, but I am not aware 

						166 
	1	of it or I can't remember.  Has CWD been put into any 
	2	primate? 
	3		DR. WILLIAMS:  It has been put into squirrel 
	4	monkeys and it was positive in one case. 
	5		DR. BROWN:  Out of-- 
	6		DR. WILLIAMS:  I don't even know how many--Dick 
	7	Marsh did the work and I don't know how many squirrel 
	8	monkeys he inoculated. 
	9		DR. BROWN:  It was intracerebral inoculation? 
10		DR. WILLIAMS:  Intracerebral inoculation; yes. 
11		DR. BROWN:  It looked rather like TSE? 
12		DR. WILLIAMS:  Yes; it was a spongiform 
13	encephalopathy. 
14		DR. BROWN:  Because there is no reason--in spite 
15	of what you heard this morning, or you might have taken away 
16	from this morning, a priori, there is no reason to equate a 
17	syndrome due to CWD in a primate with the syndrome of 
18	variant CJD.  It might look like blue-bottle fever.  We have 
19	no idea.  But it is not likely and, from what you say, it is 
20	very unlikely that it would turn up as a very unusual 
21	unrecognizable syndrome in humans. 
22		So if it looks like a TSE--and I won't go through 
23	the rest of it. 
24		DR. ROOS:  I wanted to note that the pathology is 
25	very different.  I wondered whether there was data about the 

					167 
	1	subhuman primate transmission and its pathology. 
	2		DR. BROWN:  That is a good point, also, about the 
	3	primate neuropathology. 
	4		DR. WILLIAMS:  Unfortunately, that was not well 
	5	examined and the slides are gone.  I have not been able to 
	6	retrieve those slides.  I, personally, haven't looked at 
	7	them so I can't comment on how the spongiform encephalopathy 
	8	in that squirrel monkey might compare with other 
	9	intracerebral inoculations of other TSEs.  I can't comment 
10	on that.  I know it was a spongiform encephalopathy but that 
11	is not based on my personal examination and the slides 
12	appear, and the blocks appear, to be gone. 
13		DR. BROWN:  It is particularly interesting because 
14	mule deer have the nicest daisy plaques of any species 
15	outside humans. 
16		DR. WILLIAMS:  Actually, white tails have it even 
17	better.  But that is right. 
18		DR. ASHER:  The neuropathology of TSEs 
19	experimentally transmitted have frequently not closely 
20	resembled those from the original host.  That is true of 
21	kuru and it is even true of new-variant CJD and BSE. 
22		DR. BROWN:  It may be a question of degree.  Let's 
23	just take kuru.  The plaques don't transmit but the 
24	spongiform change certainly does. 
25		DR. ASHER:  Right, but the pathology is very 

						168 
	1	strikingly cerebellar in humans-- 
	2		DR. BROWN:  Yes; the topography is different but 
	3	no neuropathologist would miss the diagnosis on that 
	4	account. 
	5		DR. ASHER:  But one distribution was not 
	6	predictive-- 
	7		DR. BROWN:  Yes; you can't predict an identical 
	8	neuropathology.  But it is recognizable. 
	9		DR. PICCARDO:  As long as it is with spongiform 

10	changes because when you move into plaques, then you have a 
11	big problem. 
12		DR. BROWN:  Yes; unless they are immunopositive. 
13		DR. PICCARDO:  Yes, of course.  But what I am 
14	saying is that the experience in the transmission 
15	experiences show that the spongiform changes, although the 
16	topography might be different, are easy to transmit but the 
17	plaques are very hard to transmit. 
18		DR. BROWN:  Or they don't.  They are simply not a 
19	part of the species reaction.  Look at BSE in cattle.  They 
20	don't have daisy plaques. 
21		DR. PICCARDO:  Right. 
22		DR. BROWN:  Not a plaque in a cow.  But it is the 
23	pathogenic marker of the neuropathology in humans.  So you 
24	can't predict. 
25		DR. PICCARDO:  I guess my point has to be 

			169 
	1	broadened not only to the neuropathology but also to the 
	2	neurologists.  There are prominent neurologists here.  In 
	3	order to look for these weird cases, other neurologies, the 
	4	Academy of Neurology, or whatever, doing an active 
	5	surveillance, looking for unusual cases of CJD, et cetera. 
	6	          DR. BROWN:  I think Pierluigi probably, and maybe 
	7	other people--yes; you are certainly accumulating, 
	8	increasing numbers of cases of CJD both typical and atypical 
	9	such that there is an increasingly good chance that these 
10	atypical cases will be brought to your attention.  I mean, 
11	you are actively searching them out and you are becoming 
12	known as the place to which such brains would be sent, not 
13	the only place, necessarily, but a major place. 
14	          So I think, Beth, it would be a very useful thing 
15	now to initiate an experiment of CWD in primates fed to 
16	squirrel monkeys and really look that in not necessarily a 
17	big, systematic way, but if you had three or four squirrel 
18	monkeys infected with a strain from, for example, an elk and 
19	three or four with a strain from a deer, you could sample. 
20	You could even take a brain biopsy.  You could do all kinds 
21	of things now instead of ten years ago when there was much 
22	less interest. 
23	          DR. WILLIAMS:  There are lots of projects to do. 
24	Funding, and all these kinds of things, obviously, come into 
25	play but I agree.  It would be very interesting. 

				170 
	1		DR. ROOS:  I don't think that the CJD surveillance 
	2	program is well advertised in the general neurology 
	3	community.  Maybe I am mistaken about that, but in journals 
	4	and at meetings, at least up until this point.  Ermias, 
	5	maybe you have some idea about how many cases do you think 

	6	you are missing in your registry?  What percent of general 
	7	neurologists know about your registry? 
	8		DR. BELAY:  Which registry are you talking about? 
	9	We have several mechanisms for CJD surveillance.  The one 
10	you are referring to is probably the national center that 
11	Dr. Gambetti is the head of.  Dr. Gambetti will probably 

12	speak for himself that just recently have gave a talk in the 
13	American Association of Neurology. 
14		I will let Dr. Gambetti speak for that.  He went 
15	to a major neurology association meeting trying to advertise 
16	the system and encourage them to utilize this national 
17	center for diagnostic and surveillance purposes. 
18		Dr. Gambetti? 
19		DR. GAMBETTI:  I agree 100 percent with the 
20	statement that our national surveillance center, that the 
21	National Prion Pathology Surveillance Center, is not really 
22	seeing a representative number of cases.  So I agree with 
23	the statement that it is not really fulfilling his job.  Why 
24	we are not seeing in a year a sufficient number of cases. 

25		I give you some numbers.  In the Year 2000, we 

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	1	have examined or received already examined--for example, 
	2	from Dr. Prusiner and DRM Laboratories, a total of 109 
	3	cases.  Now, these represent the prevalence of CDJ in the 

	4	United States as the same as in Western Europe, just 35 to 
	5	40 percent of the cases suspected. 
	6		Those cases are very thoroughly examined. 
	7	However, as I said, they represent only 35 to 40 percent of 
	8	the cases.  We try very hard to increase this number.  It 
	9	looks like there are at least three problems and all, of 
10	course, are related to the fact that our resources are, at 
11	the time, limited. 
12		One of the problems is exactly as Dr. Roos 
13	indicated.  We have been unable, and maybe Dr. Belay can 
14	explain better-- 
15		DR. BROWN:  I think we don't need or want a long 
16	explanation.  It is a little off focus. 
17		DR. GAMBETTI:  But that was the question. 
18		DR. BROWN:  No, no; the question was would--I 
19	don't mean to be rude, Pierluigi, but we are off the focus. 
20	The question was is there an adequate surveillance, a 

21	systematic adequate surveillance.  The answer is no. 
22		DR. GAMBETTI:  The answer is no. 

23		DR. BROWN:  It is not your fault. 
24		DR. GAMBETTI:  But you have to give me a chance to 
25	explain why.  Yes; you have, because otherwise we are left 

				172 
	1	with the idea that the surveillance is doing nothing and it 
	2	is not true. 
	3		The reason why we cannot see many more cases is 

	4	one, we have been unable, for a question of regulation, to 
	5	contact the neurologists at the national level.  We have 

	6	been able to contact several times neuropathologists and 
	7	pathologists.  I am planning to present, to give a 
	8	presentation, at the American Academy of Neurology, the 
	9	plenary session.  So we try to inform all the neurologists. 
10		Second, and perhaps the major reason, autopsies. 
11	The autopsy rate in the United States is about 20 to 
12	30 percent, no exception for CJD.  So autopsies are not 
13	performed.  If we had more resources, we would reimburse the 
14	institution for performing autopsies.  I am sure that the 
15	autopsy rate will go up. 
16		Third, we have to have a system like the European 
17	surveillance center in which the family of the patient and 
18	the caring physicians are contacted when the patient is 
19	alive and right away a rapport, a relationship is 
20	established, and the patient is followed and, if he expires, 
21	an autopsy is performed regularly. 
22		So these are the thing I am trying very hard to 

23	pursue.  Unfortunately, so far, the resources have not been 
24	sufficient to do all this. 
25		DR. BROWN:  Thank you. 

					173 
	1		Is there more discussion on this question? 
	2		DR. NELSON:  The other issue is do we know the 
	3	extent of exposure of the human population. 
	4		DR. BROWN:  To TSE? 
	5		DR. NELSON:  To potentially infected animals, 
	6	either, because we have heard that animals from a herd that 
	7	may have a case are tested and enter the food chain.  There 
	8	may be other exposures. 
	9		DR. BROWN:  Is the distribution of products, let's 
10	say meat, from elk and deer widely distributed throughout 
11	the country or does it stay more or less closer to home in 
12	the regions where the farms are located?  I am sure somebody 
13	from the industry who is here can answer that question. 
14		DR. ZEBARTH:  The meat primarily would be consumed 
15	in the local area.  It is more of a cottage industry so it 
16	would be consumed in the local area.  The greatest exposure 
17	would be free-ranging animals.  As far as the farmed 
18	industry, they would be primarily locals. 
19		DR. BROWN:  Would you refresh my mind and, 

20	perhaps, that of the committee on what products are in 
21	commerce from deer and elk other than meat and velvet 
22	antlers? 
23		DR. ZEBARTH:  Those would be the products. 
24		DR. BROWN:  Those two. 
25		DR. ZEBARTH:  The meat and the velvet antler. 

					174 
	1		DR. BROWN:  The meat primarily as-- 
	2		DR. ZEBARTH:  Primarily as steaks to local areas 
	3	and upper-scale restaurants.  It is not really a ground meat 
	4	industry such as in bison. 
	5		DR. BOLTON:  Just to add to that, the restaurant-- 
	6	and excellent restaurant, I must admit--that we ate at last 
	7	night, venison was on the menu as was calf brains. 
	8		DR. ZEBARTH:  The venison you ate almost certainly 
	9	was New Zealand red deer, Cervina.  There is a lot of elk, 
10	venison, consumed in restaurants in the United States. 
11	99 percent of that is New Zealand red deer, Cervina.  The 
12	domestic elk industry has very, very low, almost virtually 
13	no penetration into that market. 
14		DR. NELSON:  What about deer?  The white-tail deer 
15	are all over the United States but is it just the localized, 
16	Western deer only? 
17		DR. ZEBARTH:  I would let some of the wildlife 
18	people speak to that.  Primarily, white-tail venison 
19	consumption is hunter consumption.  I don't think there is a 
20	large commercial white tail venison market.  I am not the 
21	one to speak to that. 
22		DR. NELSON:  But it is throughout the United 
23	States, pretty much. 
24		DR. WILLIAMS:  White tails are found throughout 

25	the United States, but the disease is located just in the 

					175 
	1	corners that you saw. 
	2		DR. BROWN:  What we are hearing is that most 
	3	venison consumed in this country doesn't come from this 
	4	country. 
	5		DR. BELAY:  Dr. Brown, I think the question is not 
	6	this exposure to venison but exposure to potentially 
	7	chronic-wasting-disease-infected venison.  I think what we 
	8	can say is if we compare this situation with what happened 
	9	in the United Kingdom, for example, where hundreds of 
10	thousands of infected, BSE-infected, cattle may have 
11	actually been consumed by the population in the U.K., the 
12	possibility that a huge chunk of the population in the 
13	United States would be exposed to chronic-wasting-disease- 
14	infected elk would be very, very minimal, particularly just 
15	because it is limited, geographically limited, to a specific 
16	area. 
17		DR. BROWN:  Probably more importantly, it is 
18	limited by the people who eat venison which is not the 
19	majority of the population. 
20		DR. BELAY:  If we look at Allan Williams' data 
21	from yesterday, the donor survey, the blood donor survey, he 
22	indicated to us that 62 percent of the donors actually 
23	reported venison consumption.  So it is not uncommon. 
24		DR. BROWN:  That seems high.  I stand corrected if 
25	that is true.  Two-thirds of the American public eat 

					176 
	1	venison? 
	2		DR. BOLTON:  They have at some point. 
	3		DR. NELSON:  Ever. 
	4		DR. BROWN:  Oh; ever.  Okay. 
	5		DR. BELAY:  Now, venison consumption obtained from 
	6	the wild was about 40 percent from Allan Williams' data. 
	7		DR. BROWN:  What proportion of the population 
	8	hunts? 
	9		DR. BELAY:  Again, from Allan Williams' data, it 
10	was a little over 13 percent. 
11		DR. WILLIAMS:  I might add, that data matches 
12	reasonably well with the information from game and fish 

13	agencies at around 10, 15 percent depending on the area. 
14		DR. BELAY:  Right.  In fact, we used Allan 
15	Williams' data to our three patients, unusually young CJD 
16	patients, to see if the occurrence of the three unusually 
17	young CJD patients could have actually happened by chance 

18	alone, given the 40 percent or so exposure of the population 
19	to venison potentially coming from the wild. 
20		Our statistical analysis showed that the 
21	occurrence of three cases could actually occur by chance 
22	alone, given that level of exposure in the population. 
23		DR. BROWN:  Right; so we are already working on 

24	question 3; are the scientific data or other evidence for 
25	transmission of the TSE to people consuming or using 

				177 
	1	products made from deer or elk exposed to chronic wasting 
	2	disease, or at least we are leading in this direction. 
	3		I don't think we have any information on that at 
	4	all. 
	5		DR. BOLTON:  I think, as with question 2, there is 
	6	no evidence for transmission but that does not mean that 
	7	transmission could not occur. 
	8		DR. BROWN:  Right.  There are several subquestions 
	9	here, the potential for transmission to humans depending on 
10	the kinds of exposure.  These are hopeless questions even to 
11	address.  The offspring of CWD-infected deer?  I mean, we 
12	haven't heard a shred of evidence all day long bearing on 
13	that question.  We weren't given anything to consider and I 
14	don't think we can consider a response. 
15		DR. CLIVER:  It has got to be moot. 
16		DR. BROWN:  Similarly, pen mates of--I will read 
17	these subset questions.  If anybody on the committee thinks 
18	they have any basis to answer any of them, please speak up. 
19	Pen mate of CWD-exposed deer or elk, animals in close 
20	proximity but not in the same pen with CWD-infected deer or 
21	elk, animals exposed to equipment used in transportation of 
22	slaughtering of CWD-infected deer or elk, elk and animals on 
23	the same ranch but with no direct contact with infected deer 
24	or elk.  That is the set of questions. 
25		DR. BOLTON:  I would propose that they are all the 

				178 
	1	same and that they are all unknown. 
	2		DR. BROWN:  Any disagreement with that? 
	3		DR. KATZ:  I have no vote so what I say can be 
	4	taken any way you want. 
	5		DR. BROWN:  Very, very seriously. 
	6		DR. KATZ:  But I think the answer to 3, are there 
	7	scientific data, the answer is no.  Before we get onto a 

	8	slippery slope about unknown and absence of proof and all 
	9	that--I mean, I think that the answer to question 3 is no 
10	and should be recorded as such.  There are no data, 

11	recognizing it doesn't mean there never will be data. 
12		DR. BROWN:  That's right.  The question is worded 
13	in such a way so that no is the only possible answer. 
14		Question 4, are there scientific data assessing 
15	the potential or actual infectivity of different tissues or 
16	other animal parts from CWD-infected deer or elk.  I was 
17	looking ahead when I was asking about peripheral tissue 

18	infectivity of our speakers and, as you heard, there is none 
19	apart from the tonsil and third eyelid and brain.  So, if 
20	there is no disagreement with that, we can dispense with 
21	that question, too. 
22		DR. WILLIAMS:  I would just say that there is some 
23	evidence from PrP examinations using immunohistochemistry 

24	for some of the nerves and for islet cells in the pancreas 
25	and for lymphoid tissues. 

					179 
	1		DR. BROWN:  Right.  It seems to me that what you 
	2	said was that the PrP distribution was sort of intermediate 
	3	between the very restricted distribution that has been seen 
	4	in cattle and the much more widespread distribution that has 
	5	been seen in scrapie, and CJD, too, for that matter. 
	6		DR. WILLIAMS:  I would just say that a number of 
	7	these other tissues really haven't been examined adequately. 
	8		DR. BROWN:  Right.  But there is probable cause to 
	9	suppose that the distribution will not be markedly different 
10	from scrapie on the one hand and BSE on the other.  It is 

11	somewhere in between.  So there will be peripheral tissue 
12	infectivity here and there. 
13		DR. BOLTON:  Again, the way this question is 
14	worded, the answer has to be yes.  Scientific data or other 
15	scientific information assessing the potential or actual 

16	infectivity.  So PrP distribution clearly indicates that 
17	there are some differences. 
18		DR. BURKE:  Here we take the term infectivity to 
19	mean detectable by any diagnostic technique. 
20		DR. BROWN:  PrP being a surrogate marker and 
21	plausible.  It doesn't distinguish. 
22		DR. BURKE:  But it doesn't say human infectivity 
23	and it doesn't say infectivity for other animals.  It says 
24	infectivity. 
25		DR. BROWN:  The operative word was spotted by 

				180 
	1	Dave, "potential."  It probably is.  I am sure there is. 
	2		DR. BURKE:  We might answer this question if it 
	3	said infectivity for other animals or infectivity for 
	4	humans. 
	5		DR. BOLTON:  If there is infectivity for other 

	6	animals, then there is at least potential infectivity for 
	7	humans since we don't know what the cross-species 
	8	transmission efficiency is from elk or mule deer into 
	9	humans.  So the word "potential" there, I think, is the 
10	catchall. 
11		DR. BROWN:  I think the FDA simply wanted us to 
12	record the fact that there is likely to be infectivity in 
13	various organs, tissues and cells of disease-affected elk 
14	and deer.  We have no basis, really, to predict how that 
15	distribution is going to shake out, but it wouldn't be 

16	shocking if spleens and a heart and sinus and maybe 
17	something else in a bioassay that was sensitive turned out 
18	to have infectivity.  It would be very surprising if they 
19	didn't. 
20		So the potential is there.  That is about all we 
21	can say. 

22		DR. NELSON:  It seems like, from what we were told 
23	today, that the highest human tissue exposure may be to 

24	velvet antlers.  However, we were told that they were not 
25	coming from infected animals but whether or not, in other 

					181 
	1	producers, or--they could be. 
	2		DR. BROWN:  And it is all going to South Korea 
	3	anyway; right? 
	4		DR. NELSON:  I can assure you it is in Thailand as 
	5	well. 
	6		DR. BROWN:  In any experiment that was undertaken, 
	7	pathogenetically, that would certainly be a major tissue to 
	8	assay. 
	9		DR. WILLIAMS:  Those tissues are banked right now 
10	from several different pathogenesis studies and awaiting 
11	work, when and if. 
12		DR. BROWN:  Any other discussion on this aspect? 
13		Question 5 was, if there is a potential for 
14	transmission of a TSE from infected or exposed animals or 
15	animal parts to human, what is the likelihood of 
16	transmission.  If there is no objection, we will go on to 
17	topic 4. 
18		DR. DETWILER:  Should we vote on no. 2? 
19		DR. BROWN:  Would you like to?  We can vote on 

20	anything that you--if the committee would like to register 
21	votes on any of those questions it is perfectly okay. 
22		DR. DETWILER:  I think the vote would go on 
23	record; right?  I think that is important for the industry, 
24	for the FDA.  I don't know how the FDA feels.  I shouldn't 
25	speak for them. 

					182 
	1		DR. BROWN:  Why don't we very quickly, then, 
	2	again, for the record, vote on 1, 2 and 3.  We can run 
	3	through these very quickly.  1 was the transmission animal 
	4	to animal, elk to elk, deer to deer.  Can I have just a show 
	5	of hands?  The hands are up for yes. 
	6		[Show of hands.] 
	7		DR. FREAS:  Thirteen hands are raised. 
	8		DR. BROWN:  Anybody on the committee believe that 
	9	there is no scientific data to support transmission of CWD 
10	from animal to animal. 
11		[One hand raised.] 
12		DR. BROWN:  One negative. 
13		The second question, are there scientific data or 
14	other scientific evidence for transmission of a TSE to 

15	people consuming or using products made from deer or elk 
16	with chronic wasting disease.  Show of hands on this one as 
17	well?  The hands, again, will be for yes, there is such 
18	evidence. 
19		[Show of hands.] 
20		DR. BROWN:  Since there are none, we will just 
21	make it concrete, a show of hands for no. 
22		[No response.] 
23		DR. FREAS:  Fourteen no votes. 
24		DR. BROWN:  3 just extends that.  Do you want to 
25	vote on 3?  Do you think 3 is important, Linda?  We have no 

					183 
	1	idea about exposed to. 
	2		DR. DETWILER:  I throw that back to FDA. 
	3		DR. BROWN:  In this case, instead of saying 
	4	consuming or using products, we are saying consuming and 

	5	using products made from deer or elk exposed to, not even 
	6	necessarily infected, just exposed to the disease.  Show of 
	7	hands for yes, there is such scientific evidence. 
	8		[No response.] 
	9		DR. BROWN:  Show of hands for no, there does not 
10	exist such scientific evidence. 
11		[Show of hands.] 
12		DR. FREAS:  Fourteen. 
13		DR. BROWN:  I guess we can continue on.  Why not? 
14	This is a piece of cake. 
15		DR. PRUSINER:  Wait a minute, Paul.  I have a 

16	question.  Will you explain to us the difference between 
17	scientific data and other scientific evidence? 
18		DR. BROWN:  Well, in some cases, it is other 
19	scientific information. 
20		DR. BOLTON:  That's right.  That is in 4. 

21		DR. BROWN:  That is in 4.  No; I can't-- 
22		DR. BRACKETT:  Data should be numerical. 
23		DR. NELSON:  We are talking about geologic or 
24	astronomical data, I guess. 
25		DR. BROWN:  Yes; that is not bad.  Data requires a 

				184 
	1	number; right? 
	2		DR. CLIVER:  A parameter; yes. 
	3		DR. BRACKETT:  We were interested in any kind of 

	4	scientific inference, even, that would say, one way or the 
	5	other.  For instance, this happened in BSE.  What is the 
	6	likelihood it might happen in chronic wasting disease.  It 
	7	doesn't have to be, necessarily, although we are interested 
	8	mostly in, measurable data. 
	9		DR. CLIVER:  All he is saying is the question 
10	wasn't redundant.  We answered both aspects of it, I think. 
11		DR. ROOS:  So 3a, Paul, is the potential. 
12		DR. BROWN:  It is potential depending on types of 
13	exposure for which we have no information at all.  If so, 
14	how strong are these data or evidence?  We have no data or 
15	evidence. 
16		DR. BOLTON:  The question asks is the potential 
17	different depending on the type of exposure.  We don't know 
18	anything about any of the exposures.  I don't know how you 
19	would tell whether they were different. 
20		DR. BROWN:  Question 4, scientific data or other 
21	scientific information assessing the potential or actual 

22	infectivity of different tissues and other animal parts from 
23	CWD-infected deer or elk. 
24		DR. McCURDY:  Are we talking about infectivity 

25	globally or are we talking about infectivity for the same 

				185 
	1	species or other species or what are we talking about? 
	2		DR. BROWN:  I think my reading of that would be 

	3	simply the demonstration of infectivity in any species.  I 
	4	think what they are trying to get at is not whether or not 
	5	something is infective for monkeys but not mice or for elk 
	6	but not cows.  I think any infectivity measurement, any 
	7	detectable infectivity by any method implies there is 
	8	infectivity.  It doesn't constrain us to talk about species 
	9	barrier or anything else. 
10		What we have heard about infectivity essentially 
11	is zero outside the brain.  There are no infectivity 
12	measurements, as I understand what you said, outside the 
13	central nervous system in this disease in any species under 
14	any circumstances. 
15		DR. WILLIAMS:  If you are just talking about 
16	infectivity, actual transmission, that is correct. 
17		DR. BROWN:  Just infectivity; yes.  On the other 
18	hand, there is this wonderful word "potential," or "actual" 
19	infectivity.  I think probably Dave is right, the use of 

20	that word "potential" is probably meant to grab at PrP which 
21	would be a reasonable correlate. 
22		Under those circumstances, we have heard this is 
23	certainly lots of PrP depending on the species and 
24	circumstances in the third eyelid and tonsil of infected 

25	animals.  So there is definitely evidence of potential 

							186 
	1	infectivity apart from the central nervous system but no 
	2	evidence of real infectivity apart from the central nervous 
	3	system.  Curious phrase. 
	4		So I read question 4 as being a yes answer under 
	5	those circumstances.  But the committee should now vote on 
	6	that, or we have decided we will.  So, on this one, why 
	7	don't we just go around because it is conceivable that there 
	8	may be differences of opinion on that.  Ray? 
	9		DR. ROOS:  Yes. 
10		DR. DETWILER:  Yes. 
11		DR. BURKE:  I vote yes and would like to emphasize 
12	that my concern that, since velvet antlers is so widely used 
13	by so many people, that would be one that should have 
14	special attention paid to it. 

15		DR. McCURDY:  Yes. 
16		DR. PICCARDO:  Yes. 
17		DR. GAYLOR:  Abstain. 
18		DR. NELSON:  Yes. 

19		DR. BOLTON:  Yes. 
20		DR. BROWN:  Yes. 
21		DR. BELAY:  Yes. 
22		DR. CLIVER:  Yes. 
23		DR. LURIE:  Yes. 

24		DR. WILLIAMS:  Yes. 
25		DR. PRUSINER:  Yes. 

					187 
	1		DR. FREAS:  One person abstained.  Thirteen people 
	2	voted yes with one abstention. 
	3		DR. BROWN:  Does the committee agree that, on 
	4	question 5, we can simply say absolutely no data on which to 
	5	base an opinion? 
	6		DR. LURIE:  Can I just make one very brief comment 
	7	which is the fact that committee voted unanimously no to 
	8	both 2 and 3 should not be taken, I don't think, as a 
	9	message that there is inherently no need for government 
10	action in this area. 
11		DR. BROWN:  I agree.  The way the question is 
12	worded, a light reader might say, "Ah; no problem."  And 
13	they may be right, there is no problem but we haven't proved 
14	there isn't. 
15		DR. LURIE:  Right.  There is still place for 
16	action. 
17		DR. DAVEY:  Paul, do you think before we move off 
18	this topic, would the committee like to consider something 
19	about indemnification?  Is that our role?  It might have an 
20	implication, as we have heard, both on reporting, which is 
21	certainly--there is a negative incentive to report.  And 
22	also, on the more uniform depopulation of infected herds. 

23	So indemnification might be something we might want to make 
24	a comment about. 
25		DR. BROWN:  I think it is important that you made 

				188 
	1	the comment, but I don't think, for the purposes for this 
	2	committee that it needs more discussion than that.  The 
	3	point was made in a presentation.  You have made it.  I 
	4	agree, personally.  Dr. Clive has another comment. 
	5		DR. CLIVER:  I was just going to say we are 
	6	advisory to FDA.  If indemnity happens, it is going to be an 
	7	APHIS function, I think.  APHIS didn't ask. 
	8		DR. KATZ:  Having sat on these committees before, 
	9	I, personally, would advise the FDA to communicate that 
10	sentiment to other parts of the regulatory bureaucracy. 
11		DR. LURIE:  It certainly isn't mine.  I can't 
12	really see, firstly, where it is our business.  But, if it 
13	is, getting into the job of indemnifying a company that is 
14	making a product with no provable scientific use for export 
15	to people in South Korea, I can't see where it is at all our 
16	business to recommend any kind of indemnification for a 
17	company like that. 
18		DR. DETWILER:  There has been precedence out of 

19	this committee on recommendations out of the FDA that was 
20	recommended a couple of years ago for APHIS, for USDA to 

21	expand the ban to Europe.  That carried a lot of weight for 
22	us.  So it is appropriate, at least the comments here, to 
23	take back to USDA or FDA to convey to us.  It does carry 

24	some weight. 
25		DR. ROOS:  I guess the real message is our concern 

				189 
	1	about selling some of the herd on the open market despite an 
	2	infection that might have occurred.  The best way to handle 
	3	that situation, I think, has to be considered. 
	4	Indemnification might be one, but there may be other 
	5	solutions to this.  At least, I think the answers to the 
	6	questions here raise concern about the present situation. 
	7		DR. BROWN:  I would finish the issue by repeating 
	8	that, in my view, the most vulnerable point of all is the 
	9	escape of an infected carcass into a rendering plant.  That 
10	depends not just on a regulation but on--not a regulation 
11	but on good care in insuring that that kind of thing doesn't 
12	happen.  Of course, that won't ever be a 100 percent 
13	restriction.  It could happen. 
14		With the elimination of the disease, one wouldn't 
15	have to worry about it.  But, as we have heard, to eliminate 
16	the disease in wildlife is virtually--it is almost 
17	unthinkable in terms of its difficulty.  It could probably 
18	be eliminated, as you say, Beth, in captive animals.  That 
19	would be a goal worth pursuing, but I think the danger, the 
20	prime danger, of CWD is in a cross-contamination species- 
21	jumping leap to an animal species, a livestock species, 
22	rather than a human species. 
23		That has nothing to do with the FDA, but it is 
24	just a personal comment. 
25		DR. BURKE:  Not addressing the mechanism for doing 

				190 
	1	that, but the difference between this and the scrapie is 
	2	this is a new disease.  It is relatively low prevalence.  It 
	3	is relatively well-confined and I am persuaded by the 
	4	argument that you can make a good case for trying hard to 
	5	eradicate it from captive populations now in the United 
	6	States to try to avoid that kind of catastrophic incident in 
	7	the future. 
	8		It wouldn't address the wild herds but at least it 
	9	would address one major potential threat.  I think that 
10	makes sense to me.  That needs to be carefully thought about 
11	and I am persuaded that that is a reasonable strategy.  I am 
12	not sure it is the right one, but it is a reasonable 
13	strategy. 
14		DR. BROWN:  All one would need to get a lot of 
15	money, more money than you ever imagined possible, would be 
16	to mix up the diagnosis on two brains and report out an elk 
17	in place of a cow and find daisy plaques in a cow in 
18	Montana, say  That would be very bad news. 
19		DR. BELAY:  I agree that this situation is 
20	different from the scrapie situation.  It goes back to what 
21	Peter said earlier and that is that government, actually, is 
22	required in this area.  One of the government actions, 

23	potentially, would be a surveillance for chronic wasting 
24	disease and the elimination program that we heard about. 
25		Effective surveillance, I believe, would require 

				191 
	1	some form of indemnity because, other than that, there would 
	2	not be any incentive for the farmed-elk owners to report 
	3	chronic wasting disease if the government is going to jump 
	4	and just depopulate the whole herd without indemnity. 
	5		DR. BROWN:  So we have got two or three people 
	6	thinking that, in the total picture, indemnity is going to 
	7	be a serious consideration of the goal is to eliminate risk, 
	8	potential risk, to any other species. 
	9		We will now move on to issue 4, the final issue of 
10	this meeting.  This is concern a discussion as to whether a 
11	history of possible exposure to various animal TSE agents--- 
12	unspecified, various; it is a mixed bag--whether they should 
13	be considered by the FDA in determining the suitability of 
14	blood donors. 
15		The first presentation will be from Dr. David 
16	Asher from CBER in the FDA. 
17	 Discussion as to whether a history of possible exposure to 
18	various animal TSE agents should be considered by the FDA 
19	         in determining suitability of blood donors 
20		   Introduction, Charge and Questions 
21		DR. ASHER:  Thanks, Paul.  I can't resist putting 
22	in my own two cents on the last issue.  Actually, the 
23	scenario that the chairman outlined is a concern of the FDA 
24	which has responsibility for the regulation of animal feeds. 
25	There is a feed ban that prohibits the feeding of most 

				192 
	1	ruminant proteins to other ruminants. 
	2		[Slide.] 
	3		We are going to address now the suitability of 
	4	blood, plasma and tissue donors exposed to various TSE 
	5	agents of animals.  The accidental infection of blood, 
	6	plasma and tissue donors with animal TSE agents would be of 
	7	special concern because, theoretically, at least, such 
	8	infections might, then, be passed to recipients with greater 
	9	efficiency than the initial infection due to loss of the 
10	species barrier, in jargon, a dead-end host would become an 
11	amplifying host. 
12		In 1996, new-variant CJD was first described in 
13	the medical literature and was clearly linked to exposure to 
14	the BSE agent.  That link increased the concern of 
15	regulators about the possibility that the BSE agent might 

16	accidentally make its way into products containing or made 
17	with ruminant components. 
18		Our concern regarding BSE and vaccines were 

19	discussed by a joint meeting of this committee and the 
20	vaccine and related biological products committee in July of 
21	last year and the theoretical risks associated with blood 
22	products and tissues were discussed yesterday and earlier 
23	today.  Other products will be considered briefly this 
24	afternoon. 
25		The BSE/variant-CJD connection also increased our 

				193 
	1	concern about human exposures to other animal TSE agents 
	2	that will be considered in this session.  Three animal TSE 
	3	agents have been recognized in the USA; chronic wasting 
	4	disease, which has just been discussed and will be 
	5	considered again, briefly, in a short time; transmissible 
	6	mink encephalopathy, which has not been seen in this country 
	7	since	1985.  Opportunities for human exposure to mink 

	8	tissues appear to be limited and I won't mention mink 
	9	encephalopathy any further; and, finally, scrapie of sheep 
10	and goats. 
11		[Slide.] 
12		Implications of the scrapie agent for biologics 
13	and devices were considered nineteen months ago when the 
14	committee reviewed safe sourcing of materials derived from 
15	sheep and goats for the manufacture of FDA-regulated 
16	injectable and implantable products. 
17		Human exposures to scrapie of sheep and goats 

18	historically have not been of concern.  There is a long and 
19	uneventful history of human exposures extending to infected 
20	animals and their products extending back for probably more 
21	than two-hundred years.  There is no convincing anecdotal or 
22	epidemiological evidence of any transmission to humans. 

23		CJD prevalences are similar in countries with 
24	scrapie and those without scrapie and attempts to transmit 
25	scrapie experimentally to chimpanzees have failed. 

				194 
	1		[Slide.] 
	2		However, even for scrapie of sheep and goats, 
	3	there were some uncertainties.  Multiple strains of scrapie 
	4	agent have different biological properties and there is at 
	5	least a suspicion that the BSE agent may have originated as 
	6	a strain of scrapie agent.  Attempts to transmit scrapie to 
	7	chimpanzees were very limited and scrapie was transmitted to 
	8	several species of monkeys so that there cannot be an 
	9	absolute species barrier between scrapie of sheep and 
10	primates. 
11		The committee advised the FDA to continue to avoid 
12	using sheep and goats with scrapie as sources of material to 
13	manufacturer FDA-regulated injectable and implantable 
14	products.  However, no concern was expressed about human 

15	exposures to scrapie agent in food.  We have had a long 
16	experience with that. 
17		[Slide.] 
18		The FDA has received inquiries expressing some 
19	concerns about the potential transmissibility to humans of 

20	various TSEs of animals.  You have heard typical discussions 
21	during the previous hour.  Except for new-variant CJD, of 
22	course, no human TSE has been attributed to infection with 
23	an animal TSE agent and BSE agent, the presumable cause of 
24	new-variant CJD, has never been found in U.S. cattle. 
25		[Slide.] 

				195 
	1		As part of its commitment to insure the safest 
	2	possible supply of blood, blood components, plasma 
	3	derivatives and tissue products, the FDA now asks this 
	4	committee to consider whether exposure to any of the TSE 
	5	agents known to infect animals in the USA or to the BSE 
	6	agent if accidentally introduced into the USA in an imported 
	7	product might pose sufficient risk as to compromise the 
	8	suitability of blood, plasma or tissue donors. 
	9		[Slide.] 
10		The following sources of potential exposure to 
11	animal TSE agents within the USA will be discussed.  First, 
12	products derived from sheep and goats, with goats from BSE 
13	countries including imported sheep and their progeny with an 
14	undifferentiated TSE--that is, the so-called Vermont sheep 
15	which will be described by Linda Detwiler. 
16		Products derived from deer and elk with chronic 
17	wasting disease will be further discussed by Lynn Creekmore 
18	who has already had brief comments.  And, finally, Robert 
19	Moore of our Center for Food Safety and Applied Nutrition 
20	will summarize ruminant-derived materials as components in 
21	dietary supplements. 
22		Let me now read the charge and then the questions. 
23		[Slide.] 
24		Please consider whether the agent of any animal 
25	TSE that occurs in the USA is likely to infect humans 

				196 
	1	exposed to animals or to their products and whether the 
	2	probability that blood, plasma or tissue donors have been 
	3	infected is sufficient to warrant recommending their 
	4	deferral. 
	5		Please consider whether the BSE agent is likely to 
	6	be accidentally imported into the USA in products or 
	7	components of products and whether, without evidence that 
	8	such importation has actually occurred, exposure of donors 
	9	to any products poses sufficient risk to warrant 
10	recommending deferral. 
11		[Slide.] 
12		Should the FDA be sufficiently concerned about the 
13	suitability of any blood, plasma or tissue donors 
14	potentially exposed to TSE agents of animals, both agents 
15	known to infect animals in the USA and agents that might be 
16	accidentally imported to consider recommending deferral.  If 
17	so, which animal TSE agents present in the USA or 
18	accidentally imported, what types of product and what 
19	intensity of exposure should be of concern? 
20		Thank you. 

21		[Applause.] 
22		DR. BROWN:  Thank you, Dave. 
23		The first presentation, then, will be from Linda 
24	Detwiler from the USDA and she will tell us about the flap 
25	in Vermont. 

				197 
	1	     Undifferentiated TSE in Flocks of Sheet in Vermont 
	2		DR. DETWILER:  That is probably an understatement. 
	3		[Slide.] 
	4		I just wanted to at least give a slight overview 
	5	of BSE in sheep just to bring everybody--I have just three 
	6	slides here to bring everyone up--I think we have talked 
	7	enough about scrapie, not only today but in the past, on the 
	8	committee that people understand at least what is known 
	9	about scrapie pathogenesis because, in this case, in these 
10	sheep in Vermont, the disease actually could be scrapie or 
11	BSE. 
12		Just quickly, BSE in sheep, Foster, et al., 1993 
13	and 1996, put BSE orally into sheep.  They had this negative 
14	and positive line sheep.  They are just genetics.  The 

15	negative line are sheep that they normally don't see the 
16	natural scrapie in.  The positive line are genetically the 
17	type of sheep that they normally do see natural scrapie in. 
18		In the negative line of six animals inoculated 

19	with half a gram of brain tissue, one did--one came down 
20	with clinical disease and then, in Bruce's strain typing, it 
21	was identified to be the same strain as BSE.  So BSE-in and 
22	BSE-out identified. 
23		In the positive line, there were five animals 
24	total.  Two came down with clinical disease.  However, when 
25	strain typed, they came down with a more atypical, or 

				198 
	1	something that did not look like BSE in the strain typing or 
	2	other known strains of scrapie.  So they called it atypical 
	3	in the research paper. 
	4		[Slide.] 
	5		So far, research of BSE in sheep, distribution of 
	6	infectivity, brain, spinal cord and spleen, and that is 
	7	actual infectivity by mouse inoculation.  In the intestine, 
	8	most likely the Peyer's patches associated with the 
	9	intestine, it is PrP-res or the abnormal form of the prion 
10	protein. 
11		Yesterday, we heard of the one report of the blood 
12	transfusion, 400 mls from a sheep that was fed BSE in the 
13	incubation stage and a transfusion to another sheep that 
14	developed disease.  This is ongoing research so there will 
15	be new information.  So that is BSE in sheep. 
16		Right now, it looks like it will be very similar 
17	to scrapie in sheep versus BSE in cattle, in oral 
18	experiment. 
19		[Slide.] 
20		So where is Europe on the situation with sheep. 
21	This is all experimental data.  The European Union, in 1998, 
22	issued an opinion paper which stated that it was highly 
23	likely that there was exposure of their sheep and goat 
24	populations to feed contaminated with BSE.  So meat and bone 
25	meal with BSE agent. 

				199 
	1		However, in the diseases, clinically, 
	2	histologically, the tests for PrP to date, and they are 

	3	working on some new tests, that they don't differentiate 
	4	between the two diseases, scrapie and BSE.  Most 
	5	differentiate scrapie from the mouse bioassay system, and 
	6	that can take up to two to three years.  That is Bruce's 
	7	system. 

	8		So, right now, what they are having to do is take 
	9	what they are reported as natural cases of scrapie that 

10	might be high risk or suspect for potential for BSE, put 
11	those in the mouse bioassay systems and wait this long time 
12	to determine what disease it is. 
13		So far, there have been no natural cases of BSE in 
14	sheep detected to date.  However, the numbers assessed are 
15	small, less than 100, that have been completed.  But, in 
16	regards to their public-health protection in the European 
17	Union, they have specified risk material, so the high-risk 
18	tissues from sheep and goat tissues of animals going to 
19	slaughter waiting for other data to come out. 
20		[Slide.] 
21		Where are we in this whole situation?  1947 was 
22	our first case of scrapie.  In 1952, we put a control 
23	program in place.  We then closed the door pretty much, the 
24	imports of sheep and goats, other than from a few countries; 
25	Australia, New Zealand, that are considered free of scrapie, 

				200 
	1	and then Canada with a similar program. 
	2		We didn't want to introduce any new strains of 
	3	scrapie into the United States.  However, the sheep 
	4	industry, goat industry, asked us for new genetics and if 
	5	there was a way to bring those in under a monitoring to 
	6	introduce some new genetics into the country. 
	7		So, in April of 1996, the regulations were changed 
	8	to allow sheep and goats to come in and be monitored under 
	9	the Scrapie Certification Program for five years.  Under 
10	this provision, these two shipments were imported. 
11	Originally, we thought they were from Belgium and we later 
12	found out they were actually from Belgium and The 
13	Netherlands. 
14		They were imported in both August and November in 
15	two different groups.  There were 65 head, total.  The 

16	distribution was 52 went to one of the Vermont farms. 
17	Eleven went to the other Vermont farm.  And then two rams 
18	went to a New York farm. 
19		[Slide.] 
20		They have been monitored since entry.  That was 
21	part of the requirement to come in.  They have been under 
22	actual quarantine since October of '98.  That was right 
23	after the opinion paper came out to give the legality or 
24	basis for an actual full quarantine. 

25		They were allowed to sell, from premise, progeny.  

				201 
	1	They had to be sold into other scrapie-monitored flocks. 
	2	That was the thing.  They could not sell any of the original 
	3	imports.  They could sell progeny into other scrapie- 
	4	certification flocks.  So there were nine sold. 
	5		Of these nine animals sold, there were seven ram 
	6	lambs.  We did go out and contact the owners and purchase 
	7	all those and destroyed all those animals, took samples. 
	8	There were two ewe lambs and another ram lamb sold to 
	9	another premise.  Because there were ewe lambs that lambed 
10	in this flock, we asked the owner and purchased this entire 
11	flock as well, again with the transmission of scrapie. 
12		These samples have been tested from this flock and 
13	there was no evidence of disease.  But there were three 
14	actual progeny into this third flock. 
15		[Slide.] 
16		Other product, cheese, was sold throughout the 
17	United States.  These were predominantly East Frisian milk 
18	sheep.  They were manufacturing cheese, especially the 
19	larger farm, and selling throughout the United States. 
20	Then, prior to the quarantine, there were 45 carcasses that 
21	went for human consumption.  I will talk more about those. 
22		[Slide.] 
23		This is just to show you the breakdown.  They came 
24	in in 1996 but didn't start lambing until '97 because they 
25	were young when they came in.  This is a breakdown of how 

				202 
	1	many lambs, when they went and the poundage.  The poundage I 
	2	put on here just to give you an idea of the age.  So they 
	3	would be six months or less. 
	4		The last two shipments that went for slaughter, we 
	5	were able to bring the carcasses back after the European 
	6	Union opinion and then we destroyed those, or the last two 
	7	shipments. 
	8		So where did they go?  Where did these go?  They 
	9	were sold at two local stores, like mom-and-pop outlets. 
10	They were sold off-farm.  None were sold through the 
11	internet.  10 percent of the sales off the farm went to 
12	friends, acquaintances and tourists, and the family and 
13	their attorney consumed the product.  They are in court with 
14	us, now, too. 
15		[Slide.] 
16		What happened after the quarantine?  We bought 
17	all, then, the culled, sick, picked up the deads.  In these 
18	situations, in order to milk sheep, I just want to explain, 
19	you have to keep breeding them.  So they produce young and 
20	then they produce the milk.  So we did get a lot of 

21	offspring in the meantime from when they went under 
22	quarantine; in fact, over 300. 
23		But what the USDA did with those is we purchased 
24	them like we were the slaughter outlet because you cannot 
25	have a quarantine--that, by the way, was applied by the 

			203 
	1	State of Vermont--unless you give an outlet.  So we 
	2	purchased them like a slaughter outlet and incinerated the 
	3	carcasses.  So we have been doing that ever since.  Anything 
	4	that was older, that was culled, sick or died, we sampled it 
	5	and then incinerated the carcasses. 
	6	          The results?  On histology, we found in some of 
	7	these vacuolated neurons, astrocytosis and neuronal 
	8	degeneration.  By regulation, in the USDA, we have to have, 
	9	for TSE, scrapie diagnosis, four confirmed lesions for 
10	histology.  Most of the sheep had one of the lesions, two of 
11	the lesions.  One had three, but none had all four.  So 
12	there was no regulatory basis that we could act upon these 
13	sheep. 
14	          There was capillary electrophoresis, again, I just 
15	want to emphasize.  But this has been talked about publicly 
16	and, also, in court.  There were blood-positives on some of 
17	these sheep and that was done, even though the test is under 
18	development, at the request of one of the owners who said, 
19	"Test my sheep because I think it will clear them." 
20	          Lo and behold, we did have six sheep that came 
21	back blood-positive.  We took brains, then, from those sheep 
22	that were positive by the CE and tested those under our 
23	regime of testing, and four of those tested positive by the 
24	Western blot analysis.  That was done by Dr. Richard 
25	Rubenstein, with whom we have a cooperative agreement, at 

				204 
	1	the Institute for Basic Research in Staten Island, New York. 
	2		The Western blot done by actually had a little 
	3	hearing of its own.  Would you like to see the Western blot, 
	4	the committee?  You have to click in the middle.  I couldn't 
	5	figure out how to cut and paste this on. 
	6		Why don't we go on.  Then I will come back and try 
	7	and get it up there for you to take a look at. 
	8		[Slide.] 
	9		So what happened? This happened in July of this 
10	past summer, the Year 2000.  We approached the owners--at 
11	that time, there were the three flocks in existence, the one 
12	with the ewe lambs and these other two--to ask them to 
13	voluntarily depopulate the flock. 
14		By the way, the entire time from when they started 
15	to be under quarantine and even prior to that, we had asked 
16	them if they wanted to sell the flocks to us and that we 
17	would pay for the flocks, just to remove the risk.  They 
18	chose, at that time, not to do that.  So, even up to before 
19	this, they were asked if they would depopulate those flocks. 
20		Then, after the positive diagnosis with the 
21	Western blot, because that is, for us, a legally binding 
22	test, the owners were asked one more time to voluntarily 
23	depopulate.  The small flock, the one with the progeny, did 
24	agree, so those sheep were removed, as I told you earlier. 
25		Then, on July 14, the Secretary of Agriculture 

				205 
	1	declared an extraordinary emergency.  That is what we need, 
	2	in the USDA, in order to seize property.  So an emergency 

	3	order had to be declared for us to obtain money.  Orders 
	4	were then issued by the Department to seize the flocks, the 
	5	two flocks. 
	6		[Slide.] 
	7		One of the things here, now, I will talk to about 
	8	is what it is we found.  The tests that we have run, so the 
	9	histology, the immunohistochemistry and the Western blot, 
10	they don't differentiate between different strains or 
11	variants of scrapie from BSE.  So these tissues would, too, 
12	then have to go in mouse bioassay.  So we don't really know 
13	what disease we are dealing with here. 
14		It was named this atypical, because of the 
15	histology.  We had Gerald Wells from the U.K. look at the 
16	histology and that is one of the ways he described it, "TSE 
17	of foreign origin."  The foreign origin came into play 

18	because these sheep came in as groups and there was no 
19	exposure to U.S. animals or U.S. product. 
20		[Slide.] 
21		What happened next is really history because it 
22	really played in the media.  The two owners went to court 
23	for a temporary restraining order.  The judge denied the 
24	temporary restraining order, as I said.  There was even a 
25	hearing on the Western blot test.  He did not grant the 

				206 
	1	temporary restraining order. 
	2		However, he asked them to voluntarily comply. 
	3	They did not.  So then we had to go back to court and ask 
	4	for a motion for an order to comply and for the judge to 
	5	rule on the merits.  So we filed final briefs at the end of 
	6	December and we are waiting on a court decision. 
	7		By the way, they have been maintained, again under 
	8	quarantine and under surveillance, with the same protocols 
	9	in place, that anything that dies, anything is removed, we 
10	get and sample. 
11		How about if I try and bring that Western blot up? 
12		That is all I have. 
13		[Applause.] 
14		DR. BROWN:  Thank you, Linda.  We will look for 
15	the Western.  One question, Linda, and that is in the 
16	history, had there ever been a prior case of scrapie on 
17	those farms, ever, before the imported sheep came? 
18		DR. DETWILER:  I should have probably talked about 
19	the history of the flocks.  They came out of about ten 
20	different flocks in Belgium and the Netherlands. 
21		DR. BROWN:  No; I am more interested, actually, in 
22	the U.S. 
23		DR. DETWILER:  Oh.  No, no.  They were brought in 
24	for different premises where we had no reports of ever 
25	having sheep there, nor were they commingled with anything 

				207 
	1	here.  They were brought in as separate groups for this 
	2	purpose. 
	3		DR. BROWN:  So, essentially, it is virgin pasture. 
	4		DR. DETWILER:  Correct; at least to the best of 
	5	our knowledge. 
	6		DR. BURKE:  What is the reluctance on the part of 
	7	owners to voluntarily depopulate? 
	8		DR. DETWILER:  They do not believe, and I am just 
	9	paraphrasing so--they do not believe that there is a problem 
10	in these flocks.  I will give you a history--I think that 
11	might help, too--on the situation in Europe.  We did go back 
12	and try and get a lot of information.  We haven't been that 
13	successful of getting information from the government.  We 
14	have requested it, but they have said they have got their 

15	hands full with other things right now. 
16		One of the things that we did find from just 
17	getting other data from sources like the veterinarian that 
18	signed the health certificates, that they were fed 

19	concentrate.  So we do know that, that they were fed 
20	concentrate made in local mills that did produce both 
21	ruminant and non-ruminant feed, although we have 

22	certifications that said they didn't include ruminant meat 
23	and bonemeal in the feeds at least since certain amounts of 
24	times when the feed bans went into place. 
25		So we have those, but there is a likelihood, in 

				208 
	1	Europe, of cross-contamination.  They did come in with 
	2	scrapie certification statements, that they had been 
	3	monitored.  But even now, since that time, we have found 

	4	that some of them have not been monitored as long as they 
	5	may have seemed to have been.  So there is some question, 
	6	even on exposure to scrapie. 
	7		[Slide.] 
	8		This is the Western blot.  I couldn't get the 

	9	other block.  He had that on a separate one, the fourth 
10	sample, on a different one.  I'm sorry.  I got one to go but 
11	I couldn't get the other one, to bring it with me. 
12		DR. PRUSINER:  Could you explain-- 
13		DR. DETWILER:  I can only explain the three 
14	positives because this is Rich's stuff.  These, I think, are 
15	two sheep from there that he did call no--these three, he 

16	caused positive.  And then, over to the side, are some of 
17	the controls. 
18		So these three, at least what Rich explained in 
19	court, were the three that he called positive.  These two 
20	were also sheep, as I recall, from the flocks.  You know 

21	what?  I don't know much about Western blot.  Bob Roher, he 
22	helped with the thing and the Western, so he probably could 
23	answer more, or you can talk to-- 
24		These, I believe, are controls. 
25		Any other questions? 

					209 
	1		DR. ROOS:  Two questions.  First, how many other 
	2	flocks were imported during this window. 
	3		DR. DETWILER:  That's it. 

	4		DR. ROOS:  Oh; this is it? 
	5		DR. DETWILER:  This is it. 

	6		DR. ROOS:  The second is how did these come to 
	7	your attention?  Were there sick animals or you pursued them 
	8	because you know them came in? 
	9		DR. DETWILER:  When things change, one of our jobs 
10	is to monitor what is changing in science and what is 
11	changing in the world.  One of the things we noticed, as the 
12	science changed in '96--oh, by the way.  That is a good 
13	point you bring up.  At the end of '96, when the publication 
14	of Foster's paper that showed that it was not only in brain 
15	and spinal cord, when it was in spleen, then we thought, 

16	"Oh, oh; it might be--" and the paper suggests that maybe, 
17	if BSE became natural in sheep, that it could spread like 
18	scrapie and then feed bans wouldn't control it. 
19		So we, again, shut the door at the end of '96 to 
20	all sheep and goat imports with the exception of going back 
21	to the same countries, Canada, Australia and New Zealand. 
22		DR. BROWN:  Thanks very much, Linda. 
23		The next presentation is entitled, efforts to 

24	contain and eliminate chronic wasting disease from farmed 
25	cervids given by Dr. Creekmore of the APHIS staff, USDA. 

				210 
	1	      Efforts to Eliminate a Program to Eliminate CWD 
	2		            from Farmed Elk 

	3		DR. CREEKMORE:  Thank you. 
	4		[Slide.] 
	5		I am really not going to be able to talk too much 
	6	to you about products, so, in terms of products and 
	7	distribution and where they have gone, what we have 
	8	discussed this morning is the best information that we have 
	9	right now.  But I was asked to give a USDA APHIS Veterinary 
10	Services overview of our efforts to initiate the program to 
11	eliminate CWD from the farmed-elk industry. 
12		I will probably go really quickly through these 
13	first few slides because much of this was covered already 

14	this morning and I don't want to belabor things that we have 
15	already been through.  But I would like to give you a little 
16	bit more information on our surveillance efforts to date in 
17	the farmed-elk industry as well as where we are with this 
18	development of a program. 
19		[Slide.] 
20		Dr. Miller summarized what we know about the 
21	distribution of this disease in free-ranging deer and elk 
22	and the fact that we have an endemic area that is fairly 

23	well defined.  However, what I want to move on to is how 
24	recently we have found CWD in farmed-elk herds in multiple 
25	states in the U.S. and Canada.  He also depicted that but I 

				211 
	1	maybe will show it to you in a bit different way. 
	2		[Slide.] 
	3		CWD was first detected in the farmed-elk industry 
	4	in the U.S. in South Dakota in 1997.  Since then, the 
	5	disease has been identified in thirteen farmed-elk herds in 
	6	five different states.  The last positive farmed-elk herd 
	7	was identified in late April of this year in Colorado.  At 
	8	this point, nine of these elk herds--or, actually, excuse 
	9	me; of last year, April of last year in Colorado. 
10		At this point, nine of these elk herds have been 
11	depopulated or have gone to slaughter in testing.. 
12		[Slide.] 
13		Six were from South Dakota, one in Montana, one in 
14	Colorado and one in Nebraska.  That leaves four herds that 
15	are remaining, one in South Dakota, one in Colorado, one in 
16	Nebraska and one in Oklahoma.  Also, as was mentioned this 
17	morning, the one herd that is left in South Dakota is slated 
18	to be depopulated. 

19		[Slide.] 
20		USDA's support of surveillance has included both 
21	farmed and free-ranging cervids.  Dr. Miller included our 
22	efforts to support farmed-elk surveillance in his summary 
23	this morning.  In terms of farmed cervids, we, USDA APHIS, 
24	have tested about 2,500 animals since the latter part of 
25	1997, so starting with our fiscal year '98, which would be 

				212 
	1	starting in October of '97. 
	2		As you can see, surveillance numbers have 
	3	increased each year.  The 339 figure represents from October 
	4	through December of this year. 
	5		[Slide.] 
	6		Many of the submissions have been from the North 
	7	Central states and most have been from farmed-elk 
	8	operations.  The numbers of submissions are somewhat 
	9	reflective of states that have initiated surveillance or 
10	certification programs.  So far, there has been very little 
11	surveillance in the farmed-deer industry.  CWD has not been 
12	identified in deer from the farmed-deer industry yet but we 
13	really need to be doing surveillance to have assurance that 
14	it is not there. 
15		We are trying to encourage increased surveillance 
16	in both the farmed-elk and deer industries and surveillance 
17	will be a key component of the proposed herd certification 
18	program.  However, efforts have been hampered by the absence 
19	of a national program as well as the lack of indemnity. 
20		[Slide.] 
21		Key areas of USDA APHIS Veterinary Services focus 
22	and response regarding program development have been 
23	prioritized based on resolutions from the U.S. Animal Health 
24	Association or the USAHA.  This association has requested 

25	action from federal and state agencies to address the CWD 

				213 
	1	issue. 
	2		In 1998, USAHA recommended a model program for 
	3	surveillance control and eradication of CWD in domestic elk. 
	4	This model was for use by the states as a template for their 
	5	CWD programs and it was a model that was developed by the 
	6	North American Elk Breeders Association.  It is what Dr. 
	7	Zebarth described to you this morning. 
	8		They created this model in association with the 
	9	states and others including some state wildlife agencies and 
10	USDA representatives.  Then, in 1999, USAHA requested that 
11	USDA and the states develop a CWD herd-certified status 
12	program for farmed-elk based on this NAEBA model. 
13		[Slide.] 
14		In response to the 1999 USAHA resolution, USDA 
15	APHIS has begun to develop such a program.  In the past 
16	year, we have submitted a budget for a CWD program as a new 
17	line item for FY 2002, so that would be starting in October 
18	of 2001.  At this point in the process, the submitted budget 
19	will be enough to establish a framework to support a CWD 

20	program for captive elk but won't be adequate to cover 
21	indemnity. 
22		Then, in terms of program development, itself, in 
23	March of last year, we brought together a Veterinary 
24	Services CWD study group.  This group took the NAEBA model 
25	and revised it.  Like the original model, our VS revision 

				214 
	1	included certification with increase in status based on 
	2	surveillance as the basis for the program. 
	3		However, the revision encouraged the more 
	4	aggressive approach of depopulation of positive herds rather 
	5	than quarantine as the primary response.  This revised 
	6	program developed by the VS study group was then taken to a 
	7	group we called the National CWD Working Group for input. 
	8	That was in June of last year. 
	9		This group was composed of stakeholders including 
10	representatives of the farmed-cervid industry as well as the 
11	exotic wildlife industry, state agriculture and wildlife 
12	agencies, university and USDA ARS representatives.  The 
13	objective of this meeting was to obtain input on the 
14	framework of the certification plan that we had adapted from 
15	the NAEBA model. 
16		That objective was met and a revised plan was 
17	produced.  We took this most current draft back to the 
18	original VS study group, back to the national working group, 
19	circulated it to federal and state veterinarians, industry 
20	associations and representatives, producers as well as to 

21	others and asked for input which we have received. 
22		What I would like to do now is briefly summarize 
23	the framework of the proposed program. 
24		[Slide.] 
25		The APHIS proposed program is designed to address 

			215 
	1	the farmed-elk industry and it will use a herd certification 
	2	program as its basis.  The basic requirements for 
	3	participation in the herd certification program will include 
	4	fencing to enforce separation from free-ranging cervids, 
	5	animal identification and herd inventory with annual 
	6	verification, diagnostic surveillance of all deaths of 
	7	animals over sixteen months of age. 
	8	          Herd status would be based on the number of years 
	9	of such surveillance with no evidence of CWD.  Herd 
10	additions would be allowed from herds with the same or 
11	greater status and a positive herd diagnosis would be based 
12	on post-mortem brain testing performed by the National 
13	Veterinary Services Laboratory or NVSL-approved 
14	laboratories. 
15	          [Slide.] 
16	          If a positive herd is detected, the preferred 
17	option in the proposed program is depopulation of the herd 
18	with payment of indemnity.  An alternative option is a five- 
19	year quarantine with selective depopulation of high-risk 
20	animals if they are able to be identified.  In the case of a 
21	quarantine, it would be required for a herd plan to be 
22	developed.  This herd plan would include inspection with 

23	removal and testing of any clinical suspects, surveillance 
24	of all deaths that occur in the herd, animal ID and 
25	inventory and additional fencing requirements. 

				216 
	1		If a herd is a traced-forward or traced-back herd, 
	2	there are also requirements.  For a traced-forward herd, the 
	3	preferred option is removal of the trace animal with 
	4	testing.  If that traced-forward animal is negative, then 
	5	the herd enters the certification program for further 
	6	surveillance.  If the animal is positive, that herd is 
	7	treated as a positive herd. 
	8		Then, also, an option for a quarantine, as I 
	9	described, for a positive herd is possible.  Then, for a 
10	traced-back herd, a five-year quarantine with a herd plan as 
11	I described above. 
12		The industry, at this point, has requested that, 
13	as we continue to develop the federal CWD program that we 

14	build into the program a prohibition on the sale of velvet, 
15	meat or other food products from quarantined herds. 
16		[Slide.] 
17		In terms of interstate movements, within this 

18	plan, we want the states to be able to have the disease 
19	legally reportable and have ability to quarantine for the 

20	disease if it is detected.  With this particular program, as 
21	proposed, the producer will have to be a participant in the 
22	herd certification program to be able to move his or her 
23	animals interstate. 
24		In lieu of a national program, a number of states 
25	have instituted CWD programs and many others are in the 

				217 
	1	process of developing programs similar to that I just 
	2	described--in other words, based on the NAEBA model or on 

	3	the USDA proposed program model.  Dr. Miller also covered 
	4	that a bit this morning. 
	5		So, various levels of surveillance and 
	6	certification of herds currently exist in some states. 
	7	There is basic underlying support for the USDA CWD program 
	8	from the industry and others and, for the most part, there 
	9	seems to be basic agreement that a program is badly needed 
10	and that this proposed program provides a good framework to 
11	take further in the process. 
12		[Slide.] 
13		USDA APHIS will continue to support surveillance 
14	of farmed and free-ranging cervids.  We plan to continue to 
15	support development of improved diagnostic tests and other 
16	research.  We plan to continue the process of developing a 
17	mutual framework for CWD epidemiological data-collection 
18	needs on a national and international basis and, in 

19	September of this last year, we began this process by 
20	convening state, federal and Canadian epidemiologists and 
21	veterinarians working on CWD epidemiology to share 
22	information on current CWD work and information needs. 
23		In addition, we will continue the development of 
24	the national CWD program. 
25		[Slide.] 

				218 
	1		At the USAHA meeting this past year, in October, 
	2	we presented the proposed program in a resolution requesting 
	3	that USDA APHIS continue to develop and implement a federal 
	4	program for the eradication of CWD in farmed-elk with the 
	5	provision of indemnity was passed.  In response to this 2000 
	6	USAHA resolution, the VS CWD study group will be meeting 
	7	again in February of this year to create a final draft of 

	8	the proposed program taking into account and incorporating 
	9	input as appropriate so that the process of drafting 
10	regulations may begin. 
11		We plan to implement this program in FY 2002 or 
12	starting October of 2001. 
13		I would be happy to answer any questions. 
14		[Applause.] 
15		DR. FREAS:  Since our chair is out of the room, 
16	can we hold the questions and go on to the next speaker. 
17	There is one more speaker.  When our chair is back, he will 
18	lead the discussion of the questions, if you are going to 
19	stick around, Dr. Creekmore. 
20		Our next speaker is Dr. Robert Moore speaking on 
21	regulation of ruminant materials in U.S. dietary 
22	supplements. 

23	Regulation of Ruminant Materials in U.S. Dietary Supplements 
24		DR. MOORE:  My name is Robert Moore.  I am Chief 
25	of the Dietary Supplements Branch in the Division of 

				219 
	1	Compliance and Enforcement in the Center for Foods at FDA. 
	2		[Slide.] 
	3		I have been asked to summarize the current 
	4	information that we have concerning the status and the use 
	5	of animal-derived ingredients including those of bovine 
	6	origin in dietary supplements. 
	7		I have several take-away points that I want to 

	8	just communicate up front.  First, FDA is the responsible 
	9	federal agency for regulating the safety of dietary 
10	supplements and the agency has the regulatory and legal 
11	authority and tools to act against unsafe products. 
12		Dietary supplements may lawfully contain some 
13	animal-derived tissues and such products, both of domestic 
14	and foreign origin, are known to be marketed in the United 
15	States.  The information that we have from domestic and 
16	import inspectional activities indicates that most bovine- 
17	derived ingredients do not originate in areas in which BSE 
18	has been identified. 
19		Fourth, FDA recognizes that there are emerging 
20	public-health issues that it may need to consider with 

21	respect to the use of these both bovine and other animal- 
22	derived ingredients in dietary supplements. 
23		[Slide.] 
24		I first want to talk about some of the basic legal 
25	definitions and the framework that applies to dietary 

				220 
	1	supplements since the 1994 amendments.  There are many 
	2	dietary supplements being marketed in the United States that 
	3	contain animal-derived ingredients.  With some exceptions, 
	4	most of these products appear to be lawful in that they 
	5	appear to contain dietary ingredients that are defined in 

	6	Section 201(ff)(1) of the Food, Drug and Cosmetic Act as 
	7	amended by the 1994 Dietary Supplement Health and Education 
	8	Act. 
	9		DSHEA, which I will simply refer to as DSHEA, 

10	rather than saying it each time, defined the term "dietary 
11	supplement" to mean, in part, that it is a product that 
12	would contain several named ingredients; a vitamin, a 
13	mineral, an amino acid, an herb.  But the definition also 
14	states that legitimate dietary ingredients include "a 
15	dietary substance for use by man to supplement the diet by 
16	increasing the total dietary intake of that substance." 
17		[Slide.] 
18		Finally, it also defined dietary ingredient to 
19	include a concentrate metabolite constituent extract or 

20	combination of anything previously named in that section of 
21	the statute.  What the term "dietary substance" means, 
22	however, is not addressed directly in the statute or in the 
23	legislative history that accompanies it. 
24		Therefore, the term must be defined in accordance 
25	with its common, usual meaning.  We have tentatively 

				221 
	1	interpreted that term in the statute using an understanding 
	2	of the ordinary meaning of the words that were included by 

	3	Congress in the definition; namely, that dietary means if 
	4	you go to a Webster's, or a Random House, or pick a source, 
	5	dietary means "of or relating to the diet." 
	6		The term "diet" means an organism's usual food or 
	7	drink.  The word "substance" generically refers to, "that 

	8	which has mass, occupies space and can be perceived."  So, 
	9	when you take that in the context of the statute, the term, 
10	from a legal point of view, a dietary substance simply means 
11	the common-sense understanding of the term. 
12		It means substances customarily used as human food 
13	or drink.  Many animal-derived tissues and substances, 
14	therefore, arguable fit within that common meaning. 
15		[Slide.] 
16		I would like to take a few minutes to briefly 
17	summarize the general regulatory framework that exists for 
18	supplements.  But, first, I want to dispense with one 

19	misconception.  FDA has ample statutory authority to 
20	regulate supplements.  DSHEA did not free dietary 
21	supplements from federal oversight.  The 1994 law did amend 
22	the act such that supplements are subject to a regulatory 
23	framework that is different from that which existed before 
24	the 1994 amendments and is somewhat different than the 
25	regulatory framework that applies to other foods, which I 

				222 
	1	will simply refer to as conventional foods, for lack of a 
	2	better term. 
	3		In a general sense, the current regulatory 
	4	framework is based on postmarketing oversight by the agency. 
	5	There is generally no premarket review or approval by FDA 
	6	needed before any dietary supplement may be marketed in the 
	7	United States unless the product contains what the statute 
	8	defines as a "new dietary ingredient" or it makes a claim 
	9	that causes it to be subject to regulatory as a new drug or 
10	under the new-drug or under the health-claim provisions of 
11	the act. 
12		[Slide.] 
13		Products enter the marketplace based on a 
14	manufacturer's determination that its products are safe. 
15	Additionally, nothing in the statute requires that the firm 
16	share with us the information that is the basis upon which 
17	it has concluded that its product is safe.  While the 
18	government does not have to determine that a product or an 
19	ingredient is safe prior to it being marketed, except for a 
20	new dietary ingredient, we have the responsibility to 
21	monitor the marketplace and develop evidence and information 
22	that would enable us to act against unsafe products that are 
23	identified postmarketing. 
24		[Slide.] 
25		So, to market a dietary supplement that includes 

				223 
	1	an animal-derived ingredient, a firm simply must comply with 
	2	the basic rules that apply to marketing any other dietary 
	3	supplement.  First, it must insure that the product actually 
	4	is a dietary supplement legally as defined in the act. 
	5		This means that, among other things, it must 
	6	contain a "dietary ingredient" as I defined earlier, that it 
	7	does not contain substances that are prohibited by other 
	8	sections of the act--for example, products that have 
	9	previously been authorized for investigation as drugs or 
10	substances that have already been approved as drugs--and 
11	that it doesn't violate certain other exculsionary criteria- 
12	--for example, that it is represented as a conventional 
13	food. 
14		Second, the firm must insure that the product is 
15	safe, not only that it is safe within the meaning that it 

16	isn't inherently harmful but that it also is safe in other 
17	ways, that it is not contaminated with adulterants, it 

18	doesn't contain pathogenic microorganisms, and so on. 
19		Third, it must label the product properly.  The 
20	labeling, at a minimum, must include the disclosure of each 
21	ingredient in the product by its common or usual name 
22	meaning the dietary ingredient must be identified in terms 
23	that a typical consumer would immediately be able to figure 
24	out what the dietary ingredient is. 
25		In practical terms, a minimum requirement for 

				224 
	1	animal-derived ingredients would be to identify the species 
	2	of origin in the layman's term for the tissue being used. 
	3	For example, one example--and I am not saying that everyone 
	4	in the marketplace, by the way, is doing this to our 
	5	satisfaction, but the term "bovine products" that use bovine 
	6	testicular tissues, that would be the appropriate term 
	7	rather than making up a name like orchic. 
	8		You can go down every tissue in the animal body 
	9	and there is a sort of made-up name that has meaning to some 
10	part of the consuming public but perhaps not all. 
11		[Slide.] 
12		It is within this regulatory framework that 
13	dietary supplements may contain dietary ingredients that 
14	originate in animals.  In general, there are four broad 
15	categories of animal-derived dietary ingredients that we are 
16	aware of in the marketplace, ingredients that simply are 
17	animal tissue, substances that have been extracted from an 
18	animal tissue of some type, ingredients that are not tissues 
19	but are from animals, things such as eggs, milk, colostrum, 
20	things of that nature. 
21		Then, of course, there are ingredients from other 
22	animals.  Bovine-derived ingredients are certainly not the 
23	only non-plant materials used in supplements.  We are aware 
24	of everything from fish incrustation, birds, reptiles, fish, 
25	insects and everything else.  So the issue of the risks 

				225 
	1	associated with animal-derived ingredients perhaps are not 
	2	solely limited to those of bovine origin. 
	3		Keep in mind, however, that these are broad 
	4	categories.  Not everything in each of them would be 
	5	eligible to be a dietary supplement, remembering that one of 
	6	the defining requirements is, is an article that is the 
	7	usual food or drink of man.  So not everything that is of or 
	8	comes out of an animal necessarily is part of the usual food 
	9	or drink of man. 

10		[Slide.] 
11		A wide variety of animal tissues is used in 
12	supplements.  These include glands such as the adrenal or 
13	pituitary.  They can be organs, liver, brain, lung, what 
14	have you, and various other tissues such as velvet antler 
15	which we have heard about and blood. 
16		As I have mentioned, animal-derived ingredients 
17	are not limited to bovine sources only.  Supplements 

18	typically contain tissues from sheep, pigs and other 
19	mammals.  Finally, as I also said, they also contain things 
20	such as milk, colostrum, eggs and their constituents and 
21	constituents that have been manipulated in the production so 
22	that the typical composition of those things has been 
23	manipulated, such as by vaccination or immunization of the 
24	animal it is coming from. 
25		[Slide.] 

				226 
	1		Dietary supplements may also contain substances 
	2	that were derived from an animal-sourced raw material.  Some 
	3	examples of these include glucosamine, which is typically 

	4	obtained from bovine trachea, sphingolipids that have been 
	5	isolated from animal neural tissue, and isolated proteins 

	6	obtained from bovine spinal tissue and other substances and 
	7	an array of metabolite from other tissues. 
	8		They also include specific proteins that have been 
	9	isolated from bovine blood. 
10		[Slide.] 
11		As of this date, FDA has not promulgated 
12	regulations governing the use of animal-derived ingredients 
13	in dietary supplements.  However, we have taken several 

14	actions intended to minimize the potential that bovine- 
15	derived ingredients from animals from BSE countries do not 
16	find their way into supplements. 
17		First, FDA, since BSE was identified in Britain 
18	and the issue came to the forefront, has issued several 

19	letters to the industry on the topic.  The letters explain 
20	the agency's policy on the use of bovine-derived ingredients 
21	originating in BSE-positive countries; namely, that no such 
22	tissue may be used lawfully in a dietary supplement because 
23	tissues that may contain the causative agent of BSE in 

24	cattle presents a significant or unreasonable risk to 
25	consumers of the product and the product is, therefore, 

				227 
	1	adulterated within the meaning of the act. 
	2		The letter strongly advised firms using such 
	3	ingredients that they should develop plans or processes that 
	4	will insure that such tissues are not used.  FDA has 
	5	reissued those letters periodically as new developments have 
	6	arisen and to keep the industry aware and focused on the 
	7	issue. 
	8		The issue is specifically addressed also, the use 
	9	of bovine-derived materials, in our compliance program that 
10	serves as the guidance to our inspectional components in the 
11	field offices.  The compliance program contains guidance on 
12	priority issues that the agency wants addressed by its 
13	inspectors and requires inspectors to investigate, during 
14	routine inspections of supplement manufacturers, if they use 
15	bovine-derived ingredients, to identify the types of 
16	ingredients and to determine whether management has 
17	developed a program to insure that such ingredients don't 
18	derive from a BSE-positive country. 
19		FDA has also issued an import alert that provides 
20	for the automatic detention and refusal of entry of any bulk 
21	material, bulk bovine-derived material, from any BSE country 
22	which, at this time, consists of all of the countries in 

23	Europe and then a few other countries scattered around the 
24	world in which BSE has been identified. 
25		It also provides for the automatic detention, 

			228 
	1	without physical examination, of any shipment of any 
	2	finished product, dietary supplement or other food, that 

	3	contains a bovine-derived ingredient that originates in a 
	4	BSE-positive country.  Those finished products are refused 
	5	entry unless the firm can provide documentary evidence that 
	6	the tissues were sourced from animals that did not 
	7	originate, reside or were slaughtered in a BSE-positive 
	8	country. 
	9	          [Slide.] 

10	          The information that we have on the use of animal- 
11	derived ingredients comes mainly from our import and 
12	domestic inspectional activities.  First, the information 
13	from our domestic establishment inspection program suggests 
14	that the bulk of the bovine-derived material currently 
15	marketed in the U.S. is sourced either from the U.S. sources 
16	or from New Zealand, Australia and Argentina. 
17	          We are not aware of any sources of original 
18	material being originated from Europe.  We also know that 
19	there is some export of U.S.-sourced materials abroad where 
20	it is processed and returned or is used as the raw material 
21	for the manufacturer of constituents; for example, U.S. beef 
22	tracheas exported to Spain and other countries in Europe 
23	where, then, the glucosamine or chondroitin is extracted out 
24	and then reexported to the United States for incorporation 
25	into foods. 

				229 
	1		The information we have, while limited, seems to 
	2	indicate that most firms have a plan or a process in place 

	3	to provide some degree of assurance that their ingredients 
	4	are not originating in BSE countries. 
	5		[Slide.] 
	6		As I mentioned at the outset, the question, can 
	7	FDA act against products, is yes.  The statute provides a 
	8	variety of means that the agency can act depending on the 
	9	circumstances and the scientific information we have at 

10	hand.  First, we can use our authority to refuse entry to 
11	imported products that are adulterated or that appear to be 
12	adulterated. 
13		Second, the act provides for direct action against 
14	a particular product or class of products if it is 
15	adulterated within the meaning of one of the provisions of 
16	the acts that we enforce.  Third, the statute provides FDA 
17	the authority to promulgate regulations to insure that 
18	products are safe or that they are manufactured in 
19	accordance with practices that would minimize the risks that 
20	they would pose. 
21		That authority to issue good manufacturing 
22	practices was specifically conferred by DSHEA.  The agency 
23	is developing proposed rules for that that, depending, may 
24	or may not be published soon--I mean, depending on what the 
25	incoming administration decides what is a priority. 

					230 
	1		Finally, the agency can always issue guidance--in 
	2	the absence of regulations, can issue guidance and conduct 

	3	manufacturer or consumer outreach to respond to particular 
	4	safety issues in the interim while it undertakes either 

	5	enforcement or rulemaking to put regulations in place. 
	6		Thank you. 
	7		[Applause.] 
	8		DR. BROWN:  Thank you very much, Dr. Moore.  Would 
	9	you be able to stay for a little bit? 
10		DR. MOORE:  Yes. 
11		DR. BROWN:  I would like Dr. Moore to stay and not 
12	ask him questions now, but have what I believe is a single 
13	presentation from the floor.  Then we will open the issue to 
14	discussion. 
15		          Open Public Hearing 
16		DR. FREAS:  We are opening the open public hearing 
17	now.  We have received one response to speak in this 
18	afternoon's open public hearing.  That is from Dr. Scott 
19	Norton.  If Dr. Norton is here, would you please come 
20	forward.  You can either use the podium or the microphone, 
21	whichever is your choice. 
22		DR. NORTON:  I am Scott Norton and I am a 
23	physician in the Washington D.C. area.  I am here speaking 
24	as a private citizen today. 
25		I first became concerned about the presence of 

			231 
	1	tissues from ruminant animals in dietary supplements about 
	2	six months ago and expressed my concern in a letter that was 
	3	published in New England Journal of Medicine in July of Year 
	4	2000. 
	5	          A couple of the products that I had looked at, and 
	6	examined their labels, that raised these concerns I brought 
	7	in right here.  I will just read some of the organs that are 
	8	found in one that is called Male Power.  Deer antler, 
	9	pancreas, orchic--despite what we just heard that the FDA 
10	prefers the term "testicular tissue" to be written on the 
11	labels, I have never seen a dietary supplement say 
12	"testicle."  They always say "orchis" or "orchic" which may 
13	sound rather flowery to the etymologically impaired--thymus, 
14	adrenal, heart, lymph node, prostate, spleen and pituitary. 
15	There are actually seventeen organs in that particular 
16	product. 
17	          There is another product that is called Brain 
18	Nutrition that tells us that it is vitamins and minerals 
19	essential for important brain function.  It does not mention 
20	that there is any glandulars on at least the bold print. 

21	But if you look at the small print on the back, we learn 
22	that it has brain extract and pituitary extract, raw, in 
23	there. 
24	          We know that many of the organs that can be found 
25	in the dietary supplements do fall in that list of organs 

				232 
	1	that are suspect for contamination with TSEs, the labels, in 
	2	nearly all cases, identify neither the animal source nor the 
	3	geographic location from which the organs were derived.  I 
	4	have seen one line that did specify from New Zealand cattle 
	5	but no other manufacturer will list either the species or 
	6	the geographic location. 
	7		The FDA's and the USDA's import alerts that we 
	8	just learned about prohibit the use of these organs in 
	9	foods, medicines and medical devices.  But my reading of the 
10	alert, 17-04, suggests that DSHEA does allow some loopholes 
11	for these tissues to possible slip in. 
12		I will just read from 17-04 that we heard.  On the 
13	first page, it says that, "This alert does not establish any 
14	obligations on regulated entities."  I love seeing 
15	legislation that starts out with that caveat. 
16		Then it says, further, "The USDA regulations do 
17	not apply to bovine-derived materials intended for human 
18	consumption as finished dietary supplements."  We also learn 
19	that the prohibition, or the import alert, is limited to 
20	bulk lots of these tissues, completed tissues, from BSE- 
21	derived countries.  It does not mention if it is not a bulk 
22	import or if it is raw materials rather than finished 
23	materials. 
24		Further, we know that it is strongly recommended 
25	but not actually prohibited in the language here.  So I have 

				233 
	1	not taken the assurances from that import alert that Dr. 
	2	Moore was trying to convey to us. 
	3		So, in sum, dietary supplements sold in the United 
	4	States often contain ruminant tissues from undisclosed 
	5	sources.  Personally, I am rather squeamish and I don't 
	6	think I would be eating prostate or testicle or pituitary, 
	7	but I am also a little bit wary of consuming products with 
	8	those glands, not just out of personal repugnance but simply 
	9	out of a health concern. 
10		So my question to the advisory committee is this; 
11	is my caution reasonable and, if it is, should we take 
12	further efforts to inform, or even protect, the American 
13	public from such exposure. 
14		I was curious about Dr. Moore's remarks.  I sensed 
15	two messages.  One was the initial reassurance that FDA has 
16	the regulatory authority but then I also learned that it is 
17	the manufacturer's responsibility to provide those 

18	assurances, that the FDA doesn't actually inspect. 
19		I think that the FDA commissioners from Harvey 
20	Wylie to David Kessler would say that that track record has 
21	proven itself. 
22		Thank you very much. 
23		[Applause.] 
24		DR. BROWN:  Thanks, Dr. Norton. 

25		          Committee Discussion 

				234 
	1		DR. BROWN:  We now open a discussion, if there are 
	2	no other public declarations, comments.  We open the 
	3	committee discussion.  Before you go, Dr. Lurie, I wanted to 
	4	ask, since Dr. Norton brought up three specific points on 
	5	the--was it a legislative--was it 17-04?  It had a number on 
	6	it, whatever, the document from which he quoted. 
	7		The quotes seem to be in flat contradiction to 
	8	what Dr. Moore suggested and I would like that ironed out in 
	9	public.  Somebody has misinterpreted or not interpreted far 
10	enough and I don't know who that is. 
11		So, Dr. Moore, could you possibly respond to the 
12	specific sentences that were read?  Thank you. 
13		DR. MOORE:  The import alert contains a guidance 
14	to FDA field personnel.  It does not establish any 
15	requirements or create any rights or obligation.  Those are 
16	standard disclaimers required under other administrative 
17	acts that govern the agency's regulatory thing.  That is 
18	simply the agency cannot impose binding things on a 

19	regulated entity without doing notice and comment 
20	rulemaking. 
21		Import alerts are not done under notice and 
22	comment rulemaking.  So that is why that disclaimer is in 
23	there, to make that explicit.  One has to read any legal 
24	document in its entirety.  While the initial part, the 

25	charges, apply to bulk ingredients, when one goes to the 

				235 
	1	guidance section, it is explicit to the inspectional 
	2	agencies that this applies also to finished products that 
	3	contain specified risk material. 
	4		So it applies to bulk and finished even if the 
	5	charges, as they are written on the opening page, use the 
	6	word "bulk." 
	7		What was the third?  You said there were three? 
	8		DR. NORTON:  The wording that you quoted, and that 
	9	I read also, just uses the phrases "recommended" and 
10	"strongly recommends," but it does not seem to have any 
11	absolute binding. 
12		DR. MOORE:  It doesn't because it is guidance.  As 
13	I said, it is a guidance.  For FDA to impose binding 
14	requirements on the industry, one must do notice and comment 
15	rulemaking.  This is not notice and comment rulemaking. 

16	Therefore, it is a guidance.  One cannot order someone to 
17	do--that is the very nature of the word "guidance." 
18		DR. NORTON:  I think it is that prospect of a 
19	loophole which we see, for example, just in the labeling of 
20	the testicle versus orchic, whether companies can, perhaps, 
21	use their own preferences for the labeling where they might 
22	be able to use their own preferences for the purchasing, 
23	again, in sort of contradistinction to the guidance. 
24		DR. MOORE:  A firm can always choose to ignore a 
25	law, a regulation or a guidance.  It is a matter of FDA, 

				236 
	1	with the resources available to it, to pick and choose those 
	2	things it is going to act on based on what poses, at that 
	3	moment, the greatest public-health safety threats. 
	4		To the extent that firms are using labeling, 
	5	identity statements to identify products that maybe wouldn't 
	6	be the common or usual name the agency would prefer probably 
	7	is not the type of violation of a regulation or act that the 
	8	agency is going to devote resources to given that there are 
	9	other issues that we would devote those resources to that 
10	have a direct public-health threat at that time. 
11		So we are going to focus on safety, our resources 
12	on safety issues first.  These more technical violations of 
13	the act are going to be dealt with on a somewhat lower 
14	priority. 
15		DR. BROWN:  I think, in general, what Dr. Norton 
16	is saying is what the committee has been aware of about 
17	other products, too.  Guidance is the preferred, it would 
18	seem, mechanism or means by which the FDA seeks to insure 
19	safety.  While it is true that one flaunts something that is 
20	suggested as opposed to something which is a law, at their 
21	own peril, I suggest that the peril to flaunt a law is 
22	substantially greater than the peril to flaunt a 
23	recommendation. 
24		So I don't think there is an argument there.  I 

25	have quite a lot to say about this subject, but, Dr. Lurie, 

				237 
	1	go ahead. 
	2		DR. LURIE:  The debate, actually, reminds me a 
	3	little bit of what the singer Tom Waits said about religion 
	4	which was, "There are a lot of religions and they can't all 
	5	be right.  But they might just all be wrong." 
	6		I would like to thank Dr. Norton for what he has 
	7	done here.  I think it was extraordinarily brave of him to 

	8	write this letter and I think that the interaction we have 
	9	just seen is that, in fact, in this case, one religion is 
10	right.  Dr. Norton is right here. 
11		In fact, there is no teeth, whatsoever, to what 
12	the FDA can do in this area.  He is absolutely right that 
13	guidances are liable to be flaunted and the experience of 

14	this very committee at our last, or next-to-last, meeting is 
15	that some of the regulated industries have done just that. 
16		When the FDA passed its guidance with regard to 
17	sourcing of materials for injection, implantation and the 
18	like, to not source them from BSE countries in '93, we 
19	discovered that the regulated industries spent about seven 
20	years flaunting precisely that. 
21		So there is no assurance here.  I find, frankly, 
22	the assertion by FDA that they have "adequate regulatory 
23	authority" in this area is incredible. 
24		It is incredible because there is no guarantee of 
25	safety except that which the self-interested manufacturer 

				238 
	1	might, itself, provide.  There are no regulations on good 
	2	manufacturing practices and there is certainly nothing on 
	3	efficacy. 
	4		If that is what we call adequate regulatory 
	5	authority, I just don't understand.  Furthermore, if the 
	6	issue is safety, the FDA knows well that it lost a case out 
	7	west someplace of 34 people killed by Ephedra.  Even 34 
	8	bodies, let alone the potential for illness about which Dr. 
	9	Norton is concerned, were not enough to result in the change 
10	of the regulation of Ephedra. 
11		So this is a tremendously worrying area.  I agree 
12	that, at present, there may be no evidence of harm, but Dr. 
13	Norton has well indicated a real hole in the regulation not 
14	only here with respect to BSE but with regard to dietary 
15	supplements more generally. 
16		DR. DETWILER:  May I just, at least, correct one 
17	thing, and then I will tell you how you can--Dr. Norton 
18	mentioned about the USDA.  There is no exemption for dietary 
19	supplements.  There is for cosmetics.  There is for gelatin. 
20	But there is no exemption for dietary supplements. 
21		I will tell you one thing, though.  In importation 
22	and what happens with importation, USDA, if it is bulk 
23	product, our regulations can keep out organs and tissues of 
24	ruminant origin.  That is a given.  If it is labeled with 

25	products of ruminant origin, we don't regulate end use.  We 

				239 
	1	don't regulate end use. 
	2		Our regs is the material coming in.  If it is 
	3	labeled as ruminant-origin coming in, then our system can 

	4	pick it up and keep it out, with the exemptions of certain 
	5	tissues going for cosmetics, but then CFSAN has a system in 
	6	place there for cosmetics.  Then gelatin, as this committee 
	7	has looked at the issue of gelatin, those are our two 
	8	exemptions. 
	9		The dietary supplements, since they are labeled 

10	with certain tissues, we can keep them out.  However, if the 
11	labeling is such where that is not apparent--that is what 
12	happened in the vaccine issue--we don't know--there is no 
13	way in our system, and maybe this is what you are alluding 
14	to--there is no way in our system to pick that up.  We have 
15	no mechanism that says we know, the USDA knows, what is in 
16	there. 
17		But there is no exemption in the 9 CFR for dietary 
18	supplements. 
19		DR. NORTON:  That's wonderful.  I feel good to 
20	hear that but I just know that what I can obtain from the 
21	USDA's website it says, for example, since 1991, the USDA 
22	has prohibited the importation in the U.S. of certain 
23	tissues and organs from ruminants from countries where BSE 
24	exists. 
25		Then it goes on to that 9 CFR 94.18.  But then, at 

				240 
	1	the end of the paragraph, it says, "The USDA regulations do 
	2	not apply to imports of bovine-derived materials intended 
	3	for human consumption as either finished dietary-supplement 
	4	products or for use as ingredients in dietary supplements." 
	5		DR. BROWN:  The other point that could be made 
	6	here is that something which-- 
	7		DR. DETWILER:  This is not the USDA's; is it? 
	8		DR. NORTON:  That is the FDA's import alert 17-04 
	9	that cites the USDA. 
10		DR. DETWILER:  I just want to correct--this is not 
11	the USDA's. 
12		DR. BROWN:  Let me say something here and that is 
13	that it strikes me that if the FDA is depending on the USDA 
14	to be the primary stop gap, then that is punting the ball. 
15	If it is a question of the port authority stopping material 
16	that might be a risk in terms of its presence in dietary 
17	supplements, that is probably not the ideal solution. 
18		It is nice that the USDA gets in on the act.  It 
19	is a little disquieting to think that the USDA has the 

20	primary role in the act.  I bring to the committee's 
21	attention just a case that we published as part of our 
22	iatrogenic disease paper a few months ago.  I thought it 
23	would be instructive. 
24		It is an anecdote, but it was the case of a woman 
25	in Massachusetts, several years ago, who died from CJD.  

				241 
	1	After the fact, it was discovered that she had been taking a 
	2	dietary supplement for a year or two or three before--more 
	3	than that, actually.  She had been taking dietary 
	4	supplements for years. 
	5		That is probably not uncommon either.  I think 
	6	probably it was, in fact, a case of sporadic CJD but it was 
	7	a little worrisome to learn the ingredients of what she was 
	8	taking.  She was taking a half a gram of brain, of bovine 
	9	origin, which, on the label, said was "imported," as though 
10	this was a merit. 
11		It was not specified from what country it was 
12	imported but it was specified that it had been specially 
13	processed to retain all its natural purity and its potency. 
14	Here is a lady who is taking half a gram of brain for years, 
15	not knowing the origin of the brain, at a time when BSE was 
16	rampant. 
17		As I say, there is no indication that the two were 
18	related.  But it was a little troubling to realize that this 
19	had occurred.  Brain is a favorite substance in many dietary 
20	supplements.  And pituitary is a favorite substance in many 
21	dietary supplements.  God knows what they do, in terms of 
22	improving human health.  But I think there is a real 
23	consideration that they might do the reverse. 
24		That is one of the reasons why I hoped, and now 

25	have gotten the opportunity, at least to bring into the 

				242 
	1	public domain certain concerns about these supplements. 
	2		MS. OLIVER:  My name is Janice Oliver.  I am from 
	3	FDA's Center for Food Safety.  I would just like to comment 
	4	on a couple of things and a couple of comments that have 
	5	been made. 
	6		When Bob was commenting on dietary-supplement 
	7	regulation in terms of BSE coming in from countries and how 
	8	we regulate it coming from other countries, he was not 
	9	commenting on DSHEA and its regulatory authority all the way 
10	across the board.  That would have taken much longer.  He 
11	had a very small presentation on it. 
12		The import alerts that we have are guidances to 

13	our field.  The primary focus, because it is easier to do, 
14	is looking at bovine ingredients that might be coming in 
15	from BSE countries.  That is in the bulk. 
16		There are two ways for doing that.  One is USDA, 
17	and some of it is done through USDA.  The other is that 
18	companies, through Customs, have to notify FDA of any food 

19	products or other products that are coming in, and so we get 
20	notified.  Our inspectors, then, are notified of those 
21	things and automatically detain them.  They are not allowed 
22	into the country. 
23		That is what the import alert does.  It is 
24	automatic for notifying the investigators and inspectors. 

25	The products are also included in there that are dietary 

				243 
	1	supplements if they come from BSE-originated countries and 
	2	have bovine ingredients. 
	3		As you said, there are a number of products that 
	4	are on the market, and I think two were pointed out, that 
	5	don't have the source.  They should have the source on them. 
	6	They are not required to have the country of origin for 
	7	bovine ingredients or for any ingredients on the list.  It 
	8	is only when they come in that they know that or when we go 
	9	to the inspections of establishments to find out where do 
10	they get their ingredients and what do they get. 
11		I just wanted to clarify those things that you 
12	were talking about before.  That is an import alert which is 
13	not a regulation.  There are two parts to it.  The first 

14	part you read was very clear.  I looked at it again this 
15	morning and it is very clear dealing with the bulk 
16	ingredients. 
17		The second part is, basically, saying, if you get 
18	dietary ingredients in, or a dietary supplement from, a 
19	country that has BSE, then you are to call the Center for 
20	Foods.  There is a contact in there.  It basically ends up 
21	being an automatic detention.  That is what happens.  They 
22	are detained. 
23		DR. NELSON:  But the number of countries that are 
24	endemic for BSE are changing. 

25		MS. OLIVER:  Yes. 

					244 
	1		DR. NELSON:  How quickly--I mean, you must always 
	2	be behind the risk, given the BSE situation? 
	3		MS. OLIVER:  It originally said U.K.  It has been 
	4	updated several times as it has been--I don't have the list 
	5	of countries.  Bob has it.  It includes all of Europe and it 
	6	includes a number of other countries, so it has been updated 
	7	since additional information has come in.  That is what has 
	8	happened.  It includes the new BSE countries as the 
	9	information comes from USDA. 
10		DR. NELSON:  Why is there no requirement that it 
11	is on the label?  That doesn't make sense--where it comes 
12	from? 
13		MS. OLIVER:  There isn't any.  I can't answer why, 
14	but there is no requirement that it be on the label where 
15	the specific ingredients come from. 
16		DR. BROWN:  Linda, would it be okay to share a 
17	couple of--information about possible loopholes to this from 
18	last week's meeting, or not? 
19		DR. DETWILER:  The one thing that I do--there are 
20	loopholes.  I am not going to say that--but I don't want 
21	people to be misled.  If it is brought to our attention, we 
22	do have the regulatory authority to keep it out, other than 
23	the exemptions that I said.  So that is where I really 
24	wanted to make it clear.  I'm sorry.  I get defensive about 
25	that. 

				245 
	1		But there is nothing in our regs that exempts 
	2	dietary supplements per se, if it has those.  But, again, we 
	3	have to know about it.  See; we have to know what is on 
	4	there in order to prevent that.  I think that is where we 
	5	don't have--like, for animal vaccines; that is one thing 
	6	that comes under our jurisdiction.  So we do require, just 
	7	like the FDA, for human vaccines, the list of things and 
	8	what is in there. 
	9		DR. BROWN:  Maybe I could just ask you what is the 
10	way station for determining what, in fact, is in a package 
11	or a bulk or anything.  The first people that see it, when 
12	it comes into this country, I think you said were the 
13	Customs and Immigration people.  They are responsible for 

14	categorizing it according to what documentation they have. 
15		DR. DETWILER:  That's correct; yes. 
16		DR. BROWN:  One of the categories is 
17	miscellaneous. 
18		DR. DETWILER:  This was something Bob probably 
19	could address because that is something that he brought up 
20	yesterday.  I am not sure if that applied just to the 
21	products.  Maybe he could clarify that. 

22		DR. BROWN:  Even before he does, you remember the 
23	wonderful story that was told about a bulk shipment of a 

24	material that was labeled pesticide.  I am just recounting 
25	this to indicate what can happen.  An alert Customs and 

				246 
	1	Immigration officer looked at the size of this thing and 
	2	said, "That is an awful big package for pesticide." 
	3		He opened it and it turned out to be meat and 
	4	bonemeal.  It was meat and bonemeal because it was going to 
	5	be spread on ground to prevent grazing by deer who hate the 
	6	smell of meat and bonemeal.  That is the kind of thing that 
	7	probably doesn't happen but very rarely, but it can happen. 
	8		If we are depending on savvy Customs and 
	9	Immigration officers as our first line of defense, it is a 
10	very nice line of defense to have but it seems to me there 
11	ought to be one or two closer to the FDA. 
12		DR. DETWILER:  That was a combination of Customs 
13	and USDA.  Just to give our guy credit. 
14		MS. OLIVER:  May I say one more thing--Janice 
15	Oliver--on the closer--and on the thing that you were 
16	talking about where something is brought in under another 
17	name.  Over this past year, there was a initiative, a 
18	presidential initiative, in which FDA and Customs basically 
19	put into place a plan and the development of additional 
20	rules and additional safeguards really to target bad actors, 
21	which is really what you are targeting about. 
22		There has been additional surveillance.  There is 
23	additional secured storage, additional civil money 
24	penalties.  There are a number of things to go with that.  I 
25	am just acknowledging that that can happen and we are 

				247 
	1	putting into place, as has Customs, additional things to try 
	2	to have that not happen.  That is different than when things 
	3	are identified when they came in and they are identified to 
	4	customs and rightly identified and we do something with 
	5	them.  That is a second part of the story. 
	6		DR. BROWN:  The use of blocking imports is 
	7	certainly one approach to maintaining the safety of the 
	8	product.  But another approach, of course, is requiring the 
	9	producers of the product to document, in a satisfactory way, 
10	the authenticity of what they are telling you. 
11		My understanding is that the FDA really cannot do 
12	that under the present law, not in the way they can do it 

13	with other products including other food products; that is, 
14	you ask a manufacturer, you suggest it to a manufacturer, 
15	you guide the manufacturer, say, "It would be awfully good 
16	if you did this and we certainly recommend that you do do 
17	it; do you do it?" and the manufacturer sends back a letter 
18	and says, "Yes." 
19		You put the letter in a file.  I would be much 
20	more assured if I knew that there was some mechanism in 
21	place that was actually used by the FDA to authenticate and 
22	document the truthfulness of this industry's response to 
23	your guidance. 
24		It just seems to me that you ought to hold--I 

25	can't say that you ought to hold, because maybe you don't 

				248 
	1	have the authority to hold, but it just seems to me a 
	2	logical thing to hold this industry to the same standards of 
	3	safety that you hold every other industry to. 
	4		DR. CLIVER:  A couple of impressions.  First of 
	5	all, it was clear to me when the dietary supplements law was 
	6	passed that it was the intent of Congress to make it as 
	7	difficult as possible for FDA to do the things that they had 
	8	always done with drugs, for example; no proof of efficacy, 
	9	safety is sort an ephemeral concept there.  Beyond that, 

10	though, as far as division of responsibilities among the 
11	various agencies is concerned, it gets very difficult, at 
12	the federal level especially, to build in redundancy. 
13		The fact that USDA APHIS has a specific 
14	responsibility for what comes in at a port that may be of 
15	animal origin or that might have agents of animal or plant 

16	disease, yeah; we could look for backups on that.  But it is 
17	not our place to reinvent government.  This is the way 
18	government works. 
19		There is an inauguration going to happen tomorrow. 
20	We may find government being reinvented on very short notice 
21	here but I bet that some of the things we would most like to 
22	see happen are not going to. 
23		So we are in a situation where we are working 
24	within a system and we need to provide as good guidance that 
25	may have some scientific basis, as we can.  I think that is 

			249 
	1	what we are being asked to do.  Personally, I wonder about 
	2	calling something an herbal supplement that has all these 
	3	animal products in it.  That strikes me as clearly 
	4	mislabeling.  But, beyond that, just the fact that we don't 
	5	explicitly outlaw--including eye of newt or wing of bat 
	6	doesn't necessarily mean that the public isn't being 
	7	protected with reasonable certainty. 
	8	          DR. BROWN:  You can.  I would add only to that--I 
	9	think you are absolutely right--that we also have a little 
10	part in reinventing government.  And that is what we are 
11	doing. 
12	          DR. MOORE:  I would address two issues.  What we 
13	can do is to limit the availability or to take action 
14	against a substance.  We can do--with the authority that 
15	Congress has given us in the statute.  If the statutory 
16	authority doesn't exist, FDA, as a regulatory agency, can't 
17	dub itself with that authority.  That is a legislative fix 
18	to the extent that you may not be perfectly satisfied with 
19	some of the elements in our statutes.  It is Congress that 
20	is the appropriate part of the federal government that can 
21	change that law, not FDA. 
22	          The second is regarding the authority for identity 
23	and to document source.  Clearly, our view is that authority 
24	exists.  It is authority that exists probably in the parts 
25	of the statute that gives us the legal authority to impose 

				250 
	1	good manufacturing practices. 
	2		To the extent of what types of records we can 
	3	require the industry to keep, whether or not we have access 
	4	to those records, are legal questions that are way beyond 
	5	the time we have here. 
	6		We have been working on good manufacturing 
	7	practices.  They are written.  They are at the Office of 
	8	Management and Budget.  When, if or what they do with them 
	9	is out of our hands.  We have gone as far, under the 
10	Administrative Procedures Act, as we can go at this point to 
11	address these issues.  It is a matter, now, of, once that 
12	proposal is released for publication in the Federal Register 
13	and the rulemaking process moving on. 
14		DR. BROWN:  I don't want anybody in the room to 
15	think that I, personally, am putting the FDA on the 
16	defensive.  I think the FDA, as you say, is doing about as 
17	much as it can.  What I had hoped would be to put on the 

18	public record a sentiment which desires more.  I think 
19	probably the FDA feels the same way. 
20		DR. PRUSINER:  I wonder if we could just take a 
21	few minutes--I don't want to drag this out because it is 
22	probably not--it may not be what you think is appropriate 

23	but I think it is appropriate in the sense that it is really 
24	illustrative.  I would like to see the FDA comment on this. 
25		If we take a specific dietary supplement that is 

			251 
	1	sold.  Let's just take one.  What we have heard about are 
	2	these sort of lots of stuff in one.  Let's talk about 
	3	melatonin for a moment because here is something that large 
	4	numbers of people are taking.  There are books that are 
	5	written about this.  This is a real fad. 
	6	          In many European countries, you can't even buy it, 
	7	for whatever reasons; it is not clear to me.  In the United 
	8	States, it is freely available.  I can tell you that I think 
	9	the stuff works.  It does good things for jet lag and, after 
10	trying it a few times and becoming convinced it works, then 
11	someone says to me one day, "You know, this stuff is all 
12	extracted from bovine pituitaries." 
13	          I threw it all out.  So the next thing I do is I 
14	start to investigate where does the stuff come from.  Then I 
15	am told by the manufacturers in the United States, at least 
16	one of them, that it is all synthetic.  Then, if you look on 
17	the labels, it says, "HPLC-analyzed," whatever this means. 
18	          I would like to know if we have any information 
19	about something like this as a specific instance of 
20	something where we--everyone on this committee, I am sure, 
21	would not want to have melatonin extracted from bovine 
22	pituitaries whether it is in the United States or whether it 
23	is from Europe, especially from Europe, flowing into the 
24	consumer market.  Tons of this stuff is being purchased and 
25	used. 

				252 
	1		DR. BROWN:  Let's follow up with that specific 
	2	example.  You say the label or the manufacturers say it is 
	3	synthetic.  I suppose a synthetic substance could be 
	4	imported from Europe.  So suppose we have this example, 
	5	melatonin, said to be synthetic, imported from Europe.  Is 
	6	there any documentation to indicate that the synthetic is 
	7	really synthetic?  Is it manufactured somewhere in a 
	8	factory? 
	9		Is there any validation of what is on a label or 
10	do you simply trust what is on the label and what the 
11	manufacturer says. 
12		DR. BOLTON:  I think that is an excellent 
13	question.  I think a recent example of that goes back the 
14	term "organic" in terms of organic foods.  Is there a 
15	definition of synthetic or natural that is used and accepted 
16	by the FDA or any regulatory agency that has actual meaning? 
17		DR. PRUSINER:  This gets amplified in Dr. Moore's 
18	presentation about, let's say, glucosamine.  We have U.S. 

19	materials going to Spain, being extracted in Spain, maybe 
20	extracted in a plant that is extracting glucosamine from 
21	European animals.  Then it is cleaned by whatever process 
22	they decide to clean it by and then they start extracting 

23	materials from the U.S., and they return these to the U.S., 
24		Especially in the case of the prions which are so 
25	difficult to inactivate, how good is the cleaning process? 

				253 
	1		DR. BOLTON:  I have an additional question about 
	2	that.  What is the assurance that additional locally sourced 
	3	tracheas are not added into that manufacturing process, thus 
	4	boosting the yield, if you will, but being returned to the 
	5	U.S. as being produced from U.S.-sourced raw material? 
	6		DR. McCURDY:  Are there data to indicate how many 
	7	grams, or whatever, of infected brain are likely to infect 
	8	an organism, either animal or man, when taken orally? 
	9		DR. BROWN:  If I am not mistaken, and I can be 
10	corrected, I think a half a gram is enough in a cow, orally; 
11	in other words, one good dietary-supplement pill. 
12		DR. McCURDY:  What I am driving at is the question 
13	we are asked is really not do we wish to regulate these 
14	things coming in.  I think the statements about difficulties 
15	in regulating things in the future or near future for new 
16	regulations were probably accurate. 
17		But I think that we could exhibit some quite 
18	reasonable concern about blood donors who are taking dietary 
19	supplements that contain a certain amount of unspecified- 
20	origin brain, brain-related, brain and pituitary material. 
21	If they have done this for more than a sniff or something 
22	like that, then, perhaps, they should be deferred as blood 
23	donors. 
24		That is probably worse than spending six months in 
25	the U.K. 

				254 
	1		DR. BROWN:  That is exactly right.  I think that 
	2	is why the discussion has apparently been on things that are 
	3	not directly related to these questions because, in order to 
	4	think about deferrals for blood donors who are taking 
	5	dietary supplements with things like bovine brain in them, 
	6	it is very important that we know that those products are 
	7	safe. 
	8		I think we have heard enough to suggest that they 
	9	may not be. 
10		DR. McCURDY:  There is one other item that needs 
11	to be considered and that is what proportion of blood donors 
12	are doing this; that is, how many blood donors would you 

13	lose, and I don't know what the demographics--there is 
14	fairly good information on the demography of blood donors. 
15	I have no idea what the demography of people who take these 
16	supplements is.  Maybe they are old men like me and aren't 
17	going to be blood donors anymore. 
18		DR. BROWN:  The wording of the question is not as 
19	demanding as the wording of other deferral questions; that 
20	is, the question here is "consider recommending."  We are 
21	not even recommending at this point.  We are saying to the 
22	FDA, please think about this.  It is worth thinking about. 
23		DR. DETWILER:  One point about brain from Europe, 
24	and Jean Philippe is still here, those are considered 

25	specified risk material and it is not correct to be 

				255 
	1	incinerated; correct?  Or destroyed?  Brain and spinal cord 
	2	and other high-risk tissues in Europe? 
	3		DR. NORTON:  In tomorrow morning's British Medical 
	4	Journal, which has appeared on-line today, there is an 
	5	article called "U.S. Takes Precautions against BSE."  One 

	6	paragraph says, "Even though the U.S. and U.K. governments 
	7	ban the practice of feeding cattle products to cows, in the 
	8	early 1990s, some U.K. renderers continued to manufacture 
	9	and ship contaminated meat and bonemeal around the world. 
10	British export statistics show that thirty-seven tons of 
11	meal made from offal was sent to the United States in 1997, 
12	well after the U.S. government banned imports of such risky 
13	meat.  The ultimate use of these imports has not been 
14	identified." 
15		That will appear tomorrow morning. 
16		DR. DETWILER:  That actually was in The New York 
17	Times.  That is a direct quote out of The New York Times 
18	article.  We called the reporter on that.  That statement, 
19	the thirty-seven tons, was taken out of the U.S. 
20	Geographical BSE Risk Assessment.  What they didn't put in 
21	there, in the statement, was the remainder of the GBR is at 
22	that time, the big labeling for that category in the U.K., 
23	because it was illegal for them to ship it to us from their 
24	own regs.  It is illegal for us to get that. 
25		We did go and try and trace that so that wasn't 

				256 
	1	correct on there.  But we did import feather meal out of the 
	2	U.K. at that time, but the big labeling, and it is right in 
	3	the GBR, says that there was a big catch-all category from 

	4	that. 
	5		DR. PRUSINER:  Can you translate that? 
	6		DR. DETWILER:  I'm sorry; it has been a long two 
	7	days.  They have a category--this is from their export 
	8	statistics.  It is flowers, meals, and what not.  The notes 
	9	on there to say that it was illegal there.  Britain was not 
10	shipping that product out.  It was illegal to send it into 
11	the U.S., however, it could contain--that category was 
12	other; flowers and poultry and non-mammalian protein. 
13		At that time, it was still okay to import to the 
14	United States poultry and feather meal which we had done. 
15	We had some shipments. 
16		DR. ROOS:  I guess we have heard about the legal 
17	aspects of this from the FDA and the ingredients of two 
18	products which were vaguely noted and concern about 
19	melatonin, and your anecdotal report, Paul.  But all of 
20	these are anecdotal.  I would like to say what we really 
21	need is data, if we can get it. 
22		In other words, how often has bovine central- 
23	nervous-system product come in or how often is it coming in 
24	now.  Is that able to be identified or known even by 
25	figuring out what is bovine product by analysis and then, 

				257 
	1	dealing with that data and these issues and the concern in a 
	2	more dedicated fashion. 
	3		I think what we know now is that we are concerned 
	4	about this, that we don't think it is as regulated as it 
	5	should be but what I am not sure about is, in fact, how much 
	6	bovine central-nervous-system product really is on the 
	7	shelves at the moment or has been over the last five years. 
	8		I think we need to know that.  Now, maybe we can't 
	9	figure it out exactly, but I think we could change the 
10	anecdote.  We could figure out where melatonin comes from 
11	and get that data and have it returned to committee because 
12	I think that is a very important piece of information in 
13	order to guide us in our actions and the level of our 
14	concern. 
15		DR. BROWN:  I can tell you from having visited a 
16	shop locally that sells nutritional supplements that about a 
17	quarter of the nutritional supplements on the shelves 
18	contained brain or pituitary.  There is a lot of brain out 
19	there, number one. 
20		The other matter is that we do already ban the 
21	importation, for example, of brain.  And brain is being 
22	ingested. 
23		DR. ROOS:  But remember, Paul, there are plenty of 
24	people in the United States who have brain regularly and 
25	want to do that. 

				258 
	1		DR. BROWN:  But we don't import it.  We can't 
	2	import it from Europe. 
	3		DR. ROOS:  The importation is, yes, to me, the 

	4	issue.  How much of what you see on the shelf is imported 
	5	central nervous system. 
	6		DR. BROWN:  What I am trying to say, Ray, is that 
	7	we did not require a systematic epidemiologic study of CJD 
	8	in people who eat imported brain from Europe before banning 
	9	its import.  We just didn't do it.  To require that would 

10	set a different standard for nutritional supplements than it 
11	does for brain--and I use brain because it is orally 
12	ingested.  We obviously don't do it for blood. 
13		I am not arguing with you in terms of yes, it 
14	would be nice to have this data, but we have certainly acted 
15	without-- 
16		DR. ROOS:  No; there are two issues.  One is 
17	whether one should ban it, and I agree with it.  And the 
18	other is should one be concerned about individuals who have 
19	ingested it and who have known dietary histories that might 
20	be more worrisome than spending six months in U.K.  It is 

21	that issue which really relates to deferral practices here 
22	by the FDA that I think we need a little bit more data on. 
23		I agree with the ban. 
24		DR. BROWN:  One source of that data, and I don't 
25	think anybody is here from the European CJD Surveillance-- 

				259 
	1	they have about, I don't know, 500, 600, 700, maybe 1000 
	2	cases of CJD for which extensive dietary histories were 
	3	taken throughout Europe.  I am pretty sure one of the 
	4	questions was dietary supplements. 
	5		That would just be one source of information.  It 
	6	wouldn't be definitive but at least it might give an idea of 
	7	what you are talking about; that is, is there any 
	8	relationship between dietary supplements--on the other hand, 
	9	they probably couldn't ask if the people knew what the 
10	dietary supplements contained. 
11		They might have been arrow root instead of brain. 
12	So it probably is not information that is available anywhere 
13	in the world. 
14		DR. BURKE:  I don't know what the word "banned" 

15	means yet because we have heard several interpretations of 
16	what a ban is.  If we knew today that somebody was 
17	importing, still, from the United Kingdom brain that was 
18	going into nutritional supplements and it wasn't being 

19	picked up at importation, do either the FDA or the USDA have 
20	any powers to do anything about that? 
21		DR. DETWILER:  Yes.  If you found something that 
22	came in, we would have the power to go back, if we had found 
23	something on the shelf, to go back.  The cosmetics or the 

24	gelatin; those are the only ones we don't--to go back and 
25	trace that back, to take action. 

					260 
	1		DR. BURKE:  What would be the actions that would 
	2	be possible? 
	3		DR. DETWILER:  It depends on the circumstance.  If 
	4	it was brought in versus administrative, and that is the 
	5	most likely action, versus a criminal action. 
	6		DR. BURKE:  So there is some authority there in 
	7	existence today. 
	8		DR. LURIE:  That is if you knew. 
	9		DR. BROWN:  But it is interesting that it is USDA 
10	authority. 
11		DR. DETWILER:  Right.  That is it exactly, if you 
12	knew.  But that was the point.  You said if we found it; 
13	right? 
14		DR. BURKE:  That was the question 
15		DR. LURIE:  But the point is you might not know. 
16		DR. DETWILER:  Absolutely. 
17		MS. OLIVER:  FDA has authority, too, to take it 
18	off the market.  We have it on an import alert which, 
19	basically says we deny entry on certain charges.  If it came 
20	into the country, we would--we would have to know about it, 
21	obviously.  We would seize it.  We would ask for it to be 
22	recalled.  We would do those things.  We are talking about 
23	the BSE. 
24		DR. BOLTON:  What obligation is there of the 
25	manufacturer to document and inform the FDA or the USDA of 

				261 
	1	the source of the raw materials in these products?  Is there 
	2	any obligation? 
	3		DR. DETWILER:  That is where I said before, those 
	4	things for human use, other than meat which comes under the 
	5	meat inspection, but for human use, those things don't come 
	6	under our authority to document what is in them. 
	7		DR. BOLTON:  So if I am a manufacturer of a 
	8	supplement and I have a bottle on the shelf that does not 
	9	say where the raw materials come from, and I don't have to 
10	document that and I don't have to inform anybody, how will 
11	you find out? 
12		MS. OLIVER:  There are two things that we do.  It 
13	is not foolproof, but I can answer that question for how we 
14	find out.  One is on imported products that come in, if it 
15	has a bovine ingredient, we will, from a BSE country--it is 
16	coming from a BSE country--we will detain it and we will 
17	require that they provide us the source of that information, 
18	as long as we know about it. 
19		If we go on inspections and it is one of the 
20	things that Bob was saying, one of the things that we have 
21	our inspectors do during inspections of dietary-supplement 
22	manufacturers is, if a bovine ingredient is being used by 
23	the firm, we ask that they find out the source of the bovine 
24	ingredient and where it is coming from. 
25		So they determine that.  But the manufacturer 

				262 
	1	does-- 
	2		DR. BROWN:  Would you run that by again, please, 
	3	one more time? 
	4		MS. OLIVER:  Yes.  The manufacturer-- 
	5		DR. BROWN:  The whole of that sentence. 
	6		MS. OLIVER:  Okay.  Going from the imports.  On 
	7	the imported products, we have a directive, an import alert, 
	8	to our field that when the product comes in, and we have to 
	9	be notified of entry of dietary supplements, whether it be 
10	in bulk or whether it be as a finished product.  If we are 
11	notified of it, and USDA is also one criteria for the bulk 
12	ingredients--if we are notified, we are to detain them which 
13	is denying entry.  We do not allow it entry from a BSE 
14	country. 
15		If it is an importer and it is from a BSE country 
16	and it has multiple ingredients on it, some of which are 
17	bovine origins, we will ask the importer to determine for us 
18	where that has come from or we will deny it entry until 
19	then. 
20		If, during an inspection, and I say during an 
21	inspection because we do not require it of everybody, during 
22	our inspections of dietary-supplement manufacturers, one of 
23	the items that we have for the inspectors to check during 
24	the inspections is if bovine ingredients are used in the 
25	dietary supplements, to check the source.  They are checking 

				263 
	1	to see if it has come from a BSE country.  That is what they 
	2	are doing. 
	3		Now, we do not inspect every country regularly, if 
	4	you come back to ask what we do.  But that is what we do 
	5	during the inspection. 
	6		DR. BROWN:  What if Spain, or let's say what if a 
	7	manufacturer in this country using bovine brains, say, has 
	8	it processed in Spain.  Perhaps it comes from Spain.  And 
	9	then they send it to Canada.  And then Canada runs it across 
10	the country on a train? 
11		MS. OLIVER:  That was one of the things that Bob 
12	Moore talked about earlier.  He had a number of things that 
13	he talked about in the slides and what we have found out in 
14	inspecting dietary-supplement manufacturers is that some 
15	products are shipped either from the United States, from 
16	Canada, somewhere else to be further processed and that we 
17	need to further look into what controls are needed and do 
18	some additional work in that. 
19		DR. BROWN:  I agree, but--go ahead. 
20		DR. BOLTON:  So, for example, if a company was 
21	using a bovine brain extract that was imported from Morocco, 
22	say, there is no guarantee that that material might not have 
23	actually originated in the United Kingdom, the brains being 
24	sent to Morocco, ground into a paste, bottled and shipped 

25	from Morocco.  Here it would look like they came from 

					264 
	1	Morocco. 
	2		MS. OLIVER:  The information we would have is the 
	3	source information that was either provided by the importer 
	4	or was provided by the processor. 
	5		DR. BROWN:  I don't think the committee is 
	6	expecting the FDA to act as policemen and to detect out-and- 
	7	out fraud, dishonesty. 
	8		MS. OLIVER:  Right. 
	9		DR. BROWN:  We know that, but what I am getting at 
10	and what I think some of the other members of the committee 
11	are getting at, is that there is a spongy quality to the 
12	precautions. 
13		MS. OLIVER:  All I am trying to do is clarify what 
14	we have and what we don't have.  I am not trying to say it 
15	is a fail-safe thing.  We did not bring everyone here from 
16	the Office of Dietary Supplements or otherwise to provide 
17	all the information for some of the questions that you are 
18	asking. 
19		We provided information on looking at the controls 
20	for BSE that are coming into the country.  We did go 
21	further.  One of the things we are going to do after this 
22	committee is go back and look at, again, what additional 
23	things besides what we are doing do we need to do 
24		DR. LURIE:  The two kinds of authority you 
25	mentioned were, one, in effect, the labeling which you have 

				265 
	1	already shown can be eluded, at least in principle, by 
	2	transshipment.  The second was inspection.  I guess my 
	3	question to you is how many of these dietary-supplement 
	4	manufacturer plants have you actually inspected? 
	5		What I am struck by is we are worried about the 
	6	definition of organic--was that the expression?  I am 
	7	worried about the definition of the word "milligram" because 
	8	the variation in the amount of these substances from drug to 
	9	drug, from batch to batch, is enormous as it is. 
10		So what kinds of inspections, really, are you 

11	doing and what fraction of places have been inspected? 
12		MS. OLIVER:  I can't give you that.  The people 
13	who would give you that information are not here with me 
14	today, that would have the information.  We can certain 
15	provide that later.  I just don't have it offhand. 

16		DR. DETWILER:  I think one of the points here, and 
17	I heard it a little from FDA, but just from the government 
18	agencies, I think it is really important to take away--as 

19	Dr. Cliver said, we can only do what the authority of 
20	Congress gives us to do.  You can even see with the Vermont 
21	sheep, that is exactly why we are in court because someone 
22	is challenging that we don't have the authority to do it. 
23		I think we are all facing that, that we get 
24	challenged more and more.  And so that is one thing that I 
25	think is important take-home for the committee. 

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	1		DR. BROWN:  I don't think anybody disagrees with 
	2	that. 
	3		DR. CLIVER:  I was just going to say, apropos of 
	4	reinventing government, though, it is all a matter of rigor. 
	5	Some years ago, I wrote a piece proposing that FDA and USDA 
	6	get together and ban ingredients from the U.S. food supply. 
	7	You may have missed it.  It was published in the Journal of 
	8	Irreproducible Results.  But, all the same, I think that 
	9	would get the job done. 
10		DR. BROWN:  Shucks. 
11		DR. ROOS:  I think one aspect that will fuel FDA's 
12	ability to act and give it authority is if we know how well, 
13	or poorly, things presently ran.  In other words, for 
14	something like Stan's melatonin, or some of the drugs we 
15	saw--in other words, if, in fact, we could demonstrate that 
16	bovine central nervous system was, in fact, on the shelf, 
17	perhaps that would drive home the message here and the 

18	concern and also provide some of the authority as well. 
19		DR. BROWN:  You have seen two bottles.  It is out 
20	there, Ray.  I don't know how many bottles we have to bring 
21	in. 
22		DR. ROOS:  We know that it is central-nervous- 
23	system tissue.  But is that from U.K. or local? 
24		DR. BROWN:  Ah; from the U.K.  That is another 
25	issue. 

				267 
	1		DR. ROOS:  Anybody can get central nervous system 
	2	locally here and it is up to people if they want to take it 
	3	or not. 
	4		DR. BROWN:  Right; but a lot of the discussion 
	5	surrounded the idea that it is labeled bovine.  Maybe the 
	6	country of origin isn't specified and maybe it could come 
	7	from the U.K. and it is a hell of a thing to try and figure 
	8	out, under present law and authority, what the truth of 
	9	those statements is. 
10		DR. ROOS:  I think it is a good epidemiological 
11	study. 
12		DR. BROWN:  I would also respond to Linda, just as 
13	I responded to Dr. Cliver, if somebody doesn't make a noise, 
14	nothing happens.  So just to say we can only do what we can 
15	do and not try to do more doesn't fly with me. 
16		DR. DETWILER:  That was not my point I was making. 
17	It was the point to get that on the record again as the 
18	emphasis here that that is some of the-- 
19		DR. BROWN:  Right. 
20		DR. DETWILER:  That was not my point to give that 
21	as an excuse to all of us.  I have actually come here and 
22	asked the committee to make recommendations to help us get 
23	support. 
24		DR. BOLTON:  I think it is worth putting on the 

25	record that at least I, personally, as a committee member, 

				268 
	1	believe that the USDA and the FDA do need the authority to 
	2	do more.  If it is Congress that needs to act, then they 
	3	should look into it. 
	4		DR. NELSON:  If we voted yes to this question, 
	5	wouldn't that send a message that this is an area that has 

	6	been neglected or not adequately dealt with, or spongy or 
	7	whatever, that the FDA needs to look into without saying-- 
	8		DR. BROWN:  Certainly together with the 
	9	transcript, I think that is true. 
10		DR. NELSON:  I think the Congress might get the 
11	message if we found out that half of our blood donors are 
12	taking dietary supplements and we don't know where the hell 
13	we are coming from. 
14		DR. McCURDY:  That was going to be my point.  I 
15	think we could probably bring this to closure by simply 

16	making a recommendation or indicating that we are deeply 
17	concerned about the likelihood that blood donors would be 
18	taking orally sufficient brain-derived material to be of 
19	potential risk for CJD. 
20		DR. BROWN:  One way to begin to bring it to 

21	closure is to go ahead and vote on question 1, which we can 
22	do, now, I think. 
23		DR. DAVEY:  Just one last comment, along with what 
24	Paul has said, I think that I would agree with Dr. Roos that 
25	we need to get data on the supplements.  Whatever we can get 

					269 
	1	that makes sense at this point would be useful for 
	2	committee, I think. 
	3		We also need data on blood donors in terms of what 
	4	they are taking and how much of it before we can even begin 
	5	to address the problem because it is going to be a huge 
	6	percentage of donors.  Before we move on to that, which we 
	7	are not, we have to have those data in hand. 
	8		DR. BROWN:  Right.  I want to remind the committee 
	9	and reread the question; should the FDA be sufficiently 
10	concerned about the suitability of any blood donors 
11	potentially exposed to TSE agents of animals to consider 
12	recommending deferral.  We are not voting on recommending 
13	deferral.  We are voting on considering it. 
14		DR. BELAY:  Why don't we take out that last part 
15	of the sentence? 
16		DR. BROWN:  Because I think it is an important 
17	part of the sentence to leave in.  That's why. 
18		DR. BELAY:  I agree with what Dr. Roos is saying. 
19	This is because we don't know how many donors-- 
20		DR. BROWN:  How much of the sentence do you want 
21	to take out? 
22		DR. BELAY:  Just the last part. 
23		DR. BROWN:  That could be two-thirds, or two 
24	words. 
25		DR. BELAY:  No, no; the part which starts with "to 

					270 
	1	consider recommending deferral." 
	2		DR. BROWN:  Should the FDA be sufficiently 
	3	concerned about the suitability of any blood donors 
	4	potentially exposed to TSE agents of animals? 
	5		DR. BELAY:  Yes. 
	6		DR. BROWN:  Sufficiently concerned to do what?  To 
	7	consider recommending deferral. 
	8		DR. McCURDY:  I think that is accurate. 
	9		DR. BROWN:  I think we are going to vote on the 
10	question as written. 
11		DR. McCURDY:  Yes. 
12		DR. ROOS:  It is not recommending deferral.  It is 
13	just considering it.  So I think it is a little spongy. 
14		DR. BROWN:  Ray? 
15		DR. ROOS:  I will give it a yes. 
16		DR. DETWILER:  I just want this broad thing 
17	because sheep scrapie is not known to--I don't know; would 
18	that--I guess the FDA can sort that out; right?  Because we 
19	have already had that. 
20		DR. FREAS:  Is that a yes or a no? 
21		DR. DETWILER:  That is a yes. 
22		DR. EWENSTEIN:  Yes. 
23		DR. BURKE:  Yes, but it seems that the FDA is 
24	already considering it. 
25		DR. McCURDY:  Yes. 

					271 
	1		DR. FREAS:  Is Dr. Gaylor here?  No? 
	2		DR. NELSON:  Yes. 

	3		DR. BOLTON:  Yes. 
	4		DR. BROWN:  Yes. 
	5		DR. BELAY:  Yes. 
	6		DR. CLIVER:  Yes. 
	7		DR. LURIE:  Yes. 

	8		DR. WILLIAMS:  Yes, but with the same caveats 
	9	about U.S.-derived TSEs. 
10		DR. PRUSINER:  Yes. 
11		DR. FREAS:  That was thirteen yes votes. 
12		DR. BROWN:  Thirteen to zero.  The second 
13	question; if so, which animal TSE agents present or imported 
14	into the USA, what types of product and intensity--has that 
15	been crossed out of the final--should be or imported into. 
16	Is that right, Dave?  Is Dave still here?  That didn't get 
17	revised in time? 
18		DR. ASHER:  Give us a second here. 
19		DR. BROWN:  Or accidentally imported; right?  If 
20	so, which animal TSE agents present in the U.S.A, or 
21	accidentally imported, what types of product and what 
22	intensity of the exposure should be of concern? 
23		I don't know if any of us can talk about intensity 
24	of exposure, but we could probably make some comment about 
25	what types of product, which animal TSE agents present in 

					272 
	1	what types of product. 
	2		Beth, you were concerned about that and so were 
	3	you, Linda.  You were saying that you don't think scrapie is 
	4	one such TSE.  We would all agree about that. 
	5		DR. DETWILER:  Yes; it is thinking this whole big 
	6	thing, with the thing of possible exposure if you eat sheep 
	7	or what not, here, that you have a huge-- 
	8		DR. BROWN:  No, no; I agree.  There is 250 years, 
	9	at least, of epidemiologic evidence that scrapie does not 
10	pose a direct human pathogenic risk.  There is direct 
11	evidence in spades that BSE does, and there is the potential 
12	for something like elk velvet antlers, too.  We just have no 
13	idea.  We don't know. 
14		But if the committee has any other suggestions 
15	about--those are the only animal TSEs I am aware of.  Mink 
16	don't seem to be present in nutritional supplements--that I 
17	know of. 
18		DR. BELAY:  Dr. Brown, the only animal TSE that I 
19	would be concerned about under question 2 would be BSE. 
20		DR. BROWN:  That is, obviously, the major concern. 
21		DR. BELAY:  I would say the only concern that I 
22	would have. 
23		DR. NELSON:  But, actually, which countries are at 
24	risk is changing and I am not sure how well even regulations 
25	are keeping up with the change. 

					273 
	1		DR. ROOS:  Why shouldn't we be concerned about 
	2	chronic wasting disease?  We basically discussed that we had 
	3	very little information about it, so it is certainly of 
	4	potential concern. 
	5		DR. BROWN:  I agree.  For the present, we have no 
	6	idea if it is a concern or not, but we all know that BSE is 
	7	a concern.  So it seems to me a logical answer to question 2 
	8	would be BSE in BSE countries.  That is the agent and that 
	9	is the area. 
10		DR. NELSON:  In neural tissue?  Which tissue? 
11		DR. BROWN:  It doesn't say which tissue.  Is that 
12	a new one? 
13		DR. BOLTON:  It says what types of product.  I 
14	heard the thinking on scrapie.  I, personally, would not eat 
15	sheep brain. 
16		DR. NELSON:  No; I wouldn't either. 
17		DR. BOLTON:  Even if it was from the U.S. in a 

18	scrapie-free flock, I probably would not.  I would be a 
19	little concerned about a dietary supplement that was made 
20	from CNS tissue of sheep or bovines, even if they were 
21	sourced in the U.S. 
22		DR. BELAY:  But the question doesn't address 
23	whether or not we should consume--or consumption of brain. 
24	The question specifically mentions whether or not we should 
25	consider deferring donors who have consumed this product. 

					274 
	1		DR. BOLTON:  I think this question asks which 
	2	animal TSE agents present in the U.S. or accidentally 

	3	imported into the U.S., what types of product and what 
	4	intensity of exposure should be of concern. 
	5		DR. BELAY:  It is related to question No. 1.  It 
	6	cannot be taken without question 1. 
	7		DR. BROWN:  So what we are mainly concerned about 
	8	is BSE brain. 
	9		DR. BELAY:  That's correct. 
10		DR. BROWN:  That would be at the top of the list. 
11	And possibly brain, period, as a kind of unattractive 
12	nutrient. 
13		DR. LURIE:  Paul, maybe I am, again, confused 

14	about these questions, but I understood, when I looked at 
15	these questions, that 1 and 2 actually applied to these 
16	three specific products that were identified for us under 

17	issue 4 which were products derived from deer and elk, the 
18	Vermont sheep and the dietary supplements. 
19		DR. BROWN:  No, no; my reading is that this is a 
20	strictly independent issue.  Issue 4 has nothing to do with 
21	issue 3. 
22		DR. LURIE:  No, no, no; that was issue 4.  That is 
23	issue 4.  It says, "the following will be discussed." 
24		DR. BROWN:  Oh; the TSE agents.  Right 
25		DR. LURIE:  Yes. 

					275 
	1		DR. BROWN:  So we have the full basket of agents 
	2	to think about but we don't have to make it global; that is, 
	3	we don't have to say, "Yes; it has to be mink 
	4	encephalopathy, BSE and scrapie."  We can pick and choose. 

	5		DR. LURIE:  My point is I thought we only had to 
	6	choose from these three.  That is the way I understood it. 
	7		DR. BROWN:  It is animal TSE agents.  That is 
	8	global, any animal TSE agent.  But there are not many. 
	9		DR. NELSON:  Three is ruminant-derived tissues. 
10	So that would be the BSE. 
11		DR. EWENSTEIN:  I take the point that is being 
12	made.  I think the FDA is directing us at a couple of very 
13	specific points.  I think it is fair to include, as our 

14	chief concern, these dietary supplements which I find 
15	astounding in terms of their risk given the fact that we 
16	saw, even the data that Linda presented, if you want to give 
17	a sheep BSE, you give them a half a gram.  That is what you 
18	were giving every day to that patient you took a look at. 
19		DR. BROWN:  No; I did not give that.  No, no. 
20		DR. EWENSTEIN:  That is what "one" was giving to 
21	that patient that you were asked to look at.  But I think 
22	there are specific questions.  In other words, if someone is 
23	heavily involved in this industry, if they eat deer or elk 
24	meat, if they had cheese made from these Vermont sheep, I 

25	think those are questions that we should address, even if 

				276 
	1	the answer is we don't want to have an answer right now to 
	2	the FDA. 
	3		I think the FDA is asking us to address those 
	4	specific risks. 
	5		DR. ASHER:  Yes; it would be helpful if you would 
	6	address exposures to chronic wasting disease, the Vermont 
	7	sheep and dietary supplements.  You already know that we are 
	8	concerned about all exposures to BSE agent.  The only 
	9	concern is whether there are ways in which it can enter the 
10	United States through these products. 
11		You would be welcome to address scrapie but that 
12	was already addressed a year and a half ago at some length 
13	and no concern was expressed about dietary exposures, of 
14	which we have a very long and reassuring experience. 
15		DR. BROWN:  Is the committee agreed that BSE is 
16	the prime villain as a potential danger? 
17		DR. BOLTON:  Can we include in that the 
18	possibility that undifferentiated scrapie in sheep, at this 
19	time, may be BSE?  It is going to take some time, I guess, 
20	to document whether that is, in fact, scrapie in those sheep 
21	or whether that is BSE in sheep. 
22		At that time, does that become BSE in sheep or 
23	does it become some other nomenclature? 
24		DR. DETWILER:  I think only time will tell.  I 
25	don't think we can predict that. 

					277 
	1		DR. BROWN:  But, happily, there is no demonstrable 
	2	infectivity in any dairy product in any TSE.  So that is a 
	3	good thing. 
	4		DR. DETWILER:  That was the product--the broad 
	5	distribution was the cheese. 
	6		DR. EWENSTEIN:  I think, to try to come to 
	7	closure, on the Vermont flap, as you called it, I think that 
	8	we can try to be reassuring in that the products that came 
	9	out probably are very low risk products even though we don't 
10	fully understand the nature of the infection, itself. 
11		So I think the part that I am struggling with, 
12	because I don't know enough about it, is the sort of deer- 
13	and-elk-meat exposure.  Do we consider, at this point, that 
14	is sufficient enough if somebody has consumed large amounts 
15	or is in that industry to worry about them being potential-- 
16		DR. BROWN:  It wouldn't be the meat.  It would be 
17	the velvet antlers because that is what would be in the 
18	supplements.  Just substitute "velvet antlers" for "meat." 
19		DR. EWENSTEIN:  Okay, but are we-- 
20		DR. BROWN:  We are just talking about dietary 
21	supplements.  Therefore, deer and elk meat would not be at 
22	issue. 
23		DR. EWENSTEIN:  Why are we just talking about 

24	dietary supplements?  Point 1 deals with all deer and elk 
25	issues. 

					278 
	1		DR. BROWN:  I may be wrong. 
	2		DR. ASHER:  Please address all exposures to 
	3	chronic wasting disease, potential exposures. 
	4		DR. EWENSTEIN:  Paul, point 3 was then focussing 

	5	on the dietary supplements, but I think the issue had to do 
	6	with the CDC's presentation on the young CJD exposures and 
	7	whether there was any possible connection.  I think that is 
	8	the point that the committee should address one way or the 
	9	other. 

10		DR. BELAY:  The BSE situation is different because 
11	we have enough ample evidence that BSE is actually a human 
12	pathogen whereas, in chronic wasting disease, we do not have 
13	any evidence that chronic wasting disease is a human 
14	pathogen. 
15		It does not necessarily mean that there will never 
16	be a human pathogen, or it will never be transmitted to 
17	humans, but we do not have enough evidence to start 
18	formulating policies. 
19		DR. BROWN:  That brings us back to the original 
20	idea that we don't have any indication that blood is 
21	infectious either but we are deferring for six months.  It 
22	gets back to the deferral, if you have stayed in Colorado 
23	for six months.  If you follow logical consistency long 
24	enough, you get very illogical. 
25		DR. LEITMAN:  But we do have new variant.  We know 

				279 
	1	that it has crossed the species barrier in the case of BSE. 
	2	And we have no data to support that CWD will cross the 

	3	species barrier.  In fact, the little data we have from 
	4	Cohee's study suggests that it is unlikely to do so.  So I 
	5	think it is a different group with respect to individuals 
	6	who have been exposed to CWD and eaten elk meat and our 
	7	level of concern at present. 

	8		DR. BROWN:  I agree.  And, incidently, we need, I 
	9	think, unless the FDA stipulates that we have to, I think 
10	this part of the question--that is, so-called question 2, 
11	does not merit a vote.  It merits discussion which is what 
12	is happening.  Otherwise, we have to vote on every tissue, 
13	each disease, and I don't think we are capable of doing 
14	that. 
15		DR. McCURDY:  It seems to me that we have 
16	indicated that the Vermont sheep tissues and material that 
17	have been consumed are low risk.  It seems to me that, with 
18	CWD, most of the meat is low risk.  I think I would be 

19	unhappy at encouraging, or not discouraging, people from 
20	eating brain of brain products from CWD animals.  I just 
21	don't know how to deal with antlers.  I guess the antlers 

22	may be dealt with on the basis of the number of individuals 
23	that might be exposed and express some concern about that. 
24		But I don't know-- 
25		DR. BROWN:  And that is going to take an extended 

				280 
	1	trip to South Korea. 
	2		DR. McCURDY:  No, thanks. 
	3		DR. DAVEY:  Paul, I think we just want to make 
	4	sure the committee has the direction we are going clearly in 
	5	mind.  I am concerned about what I have heard today.  This 

	6	is disturbing about the supplements, for sure.  I took my 
	7	glucosamine this morning. 
	8		I think to tie this all the way down to deferring 
	9	blood donors is getting a little bit ahead of the game. 
10	What we need to be focussing on is regulating dietary 
11	supplements and the concerns we have about that instead of 
12	jumping ahead and saying we are going to have to consider 
13	deferring blood donors at this point. 
14		That is a huge step and I think we ought to be 

15	very cautious before we make that--even a consideration of 
16	that.  Our consideration, now, should be getting data about 
17	regulating these supplements. 
18		DR. BROWN:  I agree, but that was not, 
19	unfortunately, what we were asked to do.  I have no input in 
20	terms of what we are being asked to do, but I think the gist 
21	of using blood donors, in a sense, was a mechanism to open 
22	up the entire issue to public discussion. 
23		Therefore, we are not asked to do what most of us 
24	would really like to do which is to get the dietary- 
25	supplement people to get their act together and tell us 

					281 
	1	exactly what is going on.  Rather, the window into that area 
	2	is blood donors.  I think that is the rationale. 
	3		DR. DAVEY:  I am not sure that is the right window 
	4	to be looking through right now. 
	5		DR. BROWN:  But it is the only one we have. 
	6		DR. ASHER:  It might be helpful if you attempted 
	7	to keep the discussion of the various exposures separate. 
	8	It would make it easier for us to intuit your opinions on 
	9	them.  There is no reason why a conclusion has to be drawn. 
10	I think that the agency now appreciates the level of concern 
11	and also appreciates the level of uncertainty.  That might 
12	be sufficient for our needs. 
13		DR. BROWN:  Do you want us to consider each of the 
14	diseases now? 
15		DR. ASHER:  Yes. 
16		DR. BROWN:  Paul--was it Paul or Linda--there were 
17	two expressions that chronic wasting disease, per se, was-- 
18	no; excuse me--the Vermont sheep issue, that anything having 
19	to do with Vermont sheep was extremely low--well, low risk 
20	and not to worry, no matter what the products.  The products 
21	that were widespread were cheese. 
22		DR. BOLTON:  What about the animals, themselves? 
23		DR. DETWILER:  I'm sorry? 
24		DR. BOLTON:  Eventually, the animals will either 
25	die or be destroyed.  Products derived from their eventual 

					282 
	1	demise, are we considering those as well? 
	2		DR. DETWILER:  Oh; you mean the eventual demise? 
	3		DR. BOLTON:  Yes. 
	4		DR. DETWILER:  Oh; the eventual demise, they will 
	5	either go up some chimney or through a sodium-hydroxide 
	6	digester. 
	7		DR. EWENSTEIN:  So if we are going to run through 
	8	three questions, then the first one, which seems the 
	9	easiest, is a decision that folks who have been exposed to 
10	these Vermont products do not have to be deferred.  That 
11	seems to be the black-and-white question.  That would be my 
12	opinion. 
13		DR. BROWN:  While we are at that, does anyone 
14	disagree with that?  Are there any dissenting ideas?  All 
15	right; we have disposed to Vermont sheep 
16		DR. LURIE:  I want to add something to Vermont 
17	sheep.  I think that the scenario laid out by Linda is very 
18	worrisome.  I think as long as we have been using this 
19	committee as a sort of the bully pulpit to make our concerns 
20	clear, I think it would be helpful to have the committee on 
21	record as fully supporting what the USDA has been trying to 
22	do in this area. 
23		DR. FREAS:  If I could add to that, our charge and 
24	mission, as this committee, is to make recommendations to 

25	FDA on FDA policies.  We really are stepping outside of our 

				283 
	1	bounds of the mission of this committee.  Advice is very 
	2	good.  Even good advice is very welcome to the right place. 
	3		I honestly think, in light of the mission and the 
	4	charge of this committee, for us to make recommendations 
	5	other than to the Commissioner of FDA, we are stepping out 
	6	of our bounds. 
	7		DR. BROWN:  The jury will disregard the last 
	8	declaration.  We have dispensed with the Vermont sheep and 
	9	now we are on to--we haven't dispensed with the Vermont 
10	sheep? 
11		DR. BURKE:  I am afraid we haven't.  The rationale 
12	might be this way.  The Vermont sheep are the closest thing 
13	that we have.  If we were to make a hierarchy of all of the 
14	other agents available to us, the Vermont sheep appear to be 
15	as close, perhaps, to BSE as another agent. 
16		Thus far, we have said that the BSE agent is the 
17	one that we know has gone cross-species and, therefore, the 
18	one that would be most closely related to that, meaning 
19	sheep that might be infected with a BSE-like agent, would 
20	logically be the next most worrisome thing. 
21		I am not saying that that is sufficient grounds 
22	for deferral from donation, but just as a logical tree, that 
23	would make the most sense to me. 
24		DR. BROWN:  I think the point is well taken.  I 

25	think the only thing that really tempers it is the products 

				284 
	1	that were distributed. 
	2		DR. ROOS:  There were forty-five carcasses that 
	3	were sold for human consumption but, as I heard, some of it 
	4	went to the attorney. 
	5		DR. DETWILER:  Just to put perspective, it was 
	6	muscle meat that was sold and it was of lambs. 
	7		DR. BELAY:  I would like, also, to bring to your 
	8	attention that we are allowing people who have spent less 
	9	than six months in the U.K. to continue to donate blood.  So 
10	the question would be is the risk coming from people who 
11	have eaten the Vermont-sheep product a higher risk than what 
12	we have been allowing from the U.K.? 
13		DR. McCURDY:  Paul, I think, again, trying to put 
14	it in perspective, I wouldn't recommend anybody who had been 
15	eating brains from these sheep donate blood.  I think they 
16	should worry, but my information is that nobody has eaten 
17	any brains. 
18		DR. DETWILER:  No brains. 
19		DR. BROWN:  That is what Linda said.  It was 
20	strictly meat.  Not only strictly meat, it was young meat. 
21		DR. McCURDY:  Strictly meat and cheese.  Young 
22	meat and cheese.  Those are low risk. 
23		DR. BROWN:  Right. 
24		DR. EWENSTEIN:  I understand, at best, these risk 
25	assessments are semi-quantitative.  They are probably just 

				285 
	1	qualitative, but I think if you look at what Dr. Belay was 
	2	saying, just taking everything together, the total amount of 
	3	exposure to any one donor in the U.S., the kind of product 
	4	that was consumed, et cetera, I think that this falls below, 
	5	and if we are using six months in the U.K. as some 
	6	threshold, and I know it is sort of an arbitrary threshold-- 
	7	but, if we are using that, this seems to be falling below 
	8	that level, at least from what we know right now. 
	9		We have to make some sort of decision.  Either we 
10	are going to start tracking these people down who had some 
11	of this cheese and say, you can't donate, or they can 
12	donate.  I think we have, probably by consensus, agreed that 
13	they can.  It seems like you can justify that on these sort 
14	of qualitative grounds. 
15		DR. DETWILER:  One other issue on the cheese, just 
16	because I know CDC, when they were requested for assistance 
17	here on milk and cheese, is that milk and cheese, by WHO or 
18	any milk and milk-products for known TSEs are not know to be 
19	associated with infectivity.  So this would open this whole 
20	ball of wax on milk and cheese from Europe, actually, which 
21	does freely move in and is consumed. 
22		DR. BROWN:  Dispense with Vermont. 
23		DR. BURKE:  With logical consistency; thank you. 
24		DR. BROWN:  The next issue, then, is chronic 
25	wasting disease.  I think everybody would agree that that is 

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	1	in the middle of this triplet of hierarchies. 
	2		DR. WILLIAMS:  I would just to say, and the 
	3	committee has already said, that there is no scientific 
	4	evidence that CWD is recognized as a human pathogen.  Then, 
	5	to make the jump, that, then, people will get it and then 
	6	transmit it via blood, I think, going a little bit too far. 
	7		DR. BROWN:  Is there a sentiment to put chronic 
	8	wasting disease in the same low-risk category, then, as the 
	9	Vermont sheep?  Are they similarly unrisky?  You are you 
10	think it probably is. 
11		DR. McCURDY:  Except for neural tissue. 
12		DR. PRUSINER:  I just think we know so little 

13	about chronic wasting disease that we don't know how to 
14	think about it.  I think that is really what we ought to 
15	say. 

16		DR. BROWN:  Except we could probably say it is not 
17	a good idea to eat brain, I would imagine, from, say, an elk 
18	that died with chronic wasting disease. 
19		DR. PRUSINER:  I wouldn't disagree. 
20		DR. WILLIAMS:  And those are the recommendations 
21	that are given. 
22		DR. BROWN:  Right. 
23		DR. BOLTON:  Just to echo, I guess, what I said 

24	earlier, the fact that we voted that there is no evidence 
25	that it is a human pathogen does not mean that there is 

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	1	evidence that it is not a human pathogen.  So it is still an 
	2	open question. 
	3		DR. EWENSTEIN:  Excepting that, I think, we then 
	4	still have to assign a risk.  We have to, at least, 
	5	determine that the risk is sufficiently high that we would 

	6	want to defer donors.  I don't think, speaking for myself, 
	7	that we have crossed that threshold at this point. 
	8		DR. BROWN:  What it seems to me we are saying is 
	9	that the risk in chronic wasting disease and the products 

10	there from, the risk in Vermont sheep and the products there 
11	from, both are likely to be small, but they are absolutely 
12	indeterminate on present knowledge whereas, the risk of BSE 
13	products is both demonstrable and finite. 
14		Does that give the FDA enough guidance? 
15		DR. ASHER:  Yes. 
16		DR. BROWN:  Does anyone on the committee have any 
17	further remarks to make? 
18		DR. EWENSTEIN:  The only thing is--well, I guess 
19	we have all said it before, but I would really urge the FDA 
20	to prioritize these products--and I know that they don't get 
21	to approve them ahead of time so that they, then, have to 
22	prioritize what supplements to go after. 
23		I don't suggest that they haven't already done 

24	this, but I would certainly think that the sense of this 
25	advisory committee is to prioritize those products that we 

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	1	know have brain and neuronal tissue coming from cows of 
	2	unknown origin as high on the list of those that should be 
	3	inspected carefully. 
	4		DR. BROWN:  Dave? 
	5		DR. ASHER:  That answered it part of the way.  It 
	6	is our take, then, that you are encouraging us to collect 
	7	more information because of the concern that the BSE agent 
	8	could be entering the United States in dietary supplements 
	9	containing ruminant materials of unknown origin. 
10		DR. BROWN:  That comes to the end of a very packed 
11	two days of meetings.  I think I can speak for Ray and for 
12	Stan.  I certainly speak for myself that, after five years 
13	as chairman of the this committee, I want to thank every 

14	member here present and past for their intelligence, their 
15	patience, their common sense and they have made my 
16	chairmanship a pleasure. 
17		Thank you. 
18		DR. FREAS:  Thank you, Dr. Brown. 
19		[Applause.] 
20		[Whereupon, at 4:25 p.m., the meeting was 
21	adjourned.]