Wednesday, June 29, 2011

TSEAC JUNE 2, 1999 Welcome to the FDA traveling road show

From: TSS

Subject: TSEAC JUNE 2, 1999 Welcome to the FDA traveling road show

Date: October 15, 2007 at 3:18 pm PST


CHAIRMAN BROWN: My name is Dr. Paul Brown. Welcome to the FDA traveling road show. We are asked yet once more by the FDA to consider a question of theoretical risk in the absence of sufficient knowledge on which to base any firm conclusion.

The issue before us today is that of excluding categories of American blood donors who have either visited or resided for longer periods of time in Great Britain. The issue is sufficiently delicate, as you see that we have been moved outside the Beltway. (Laughter.)


"Dr. Alan Williams is employed by the American Red Cross, Holland Labs, and is Scientific Adviser for the Florida Blood Services and Canadian Blood Services. In addition, he has financial interests in firms that could be affected by the general discussions.

"Dr. Richard Race has financial interests in firms that could be affected by the general discussions and is a public health science researcher. "In the event that the discussions involve specific products or specific firms for which FDA participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement. And their exclusion will be noted for the public record. A copy of the waivers is available by written request under the Freedom of Information Act. "With respect to all other meeting participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon."

So ends the reading of the conflict of interest statement. Dr. Brown, I turn the meeting over to you.


DR. JACOBS: Thank you, Dr. Brown, and welcome to members of the Committee. Today we are again bringing the question of deferral from blood donation of persons with possible foodborne exposure to bovine spongiform encephalopathy, BSE, as a precautionary measure to reduce the risk of blood transmission of new variant Creutzfeldt Jakob disease. And we are asking the Committee at this time, as we did in December, to consider this in the light of possible shortages.

Next, the current status. So far there have been no cases of either BSE or new variant CJD reported in the U.S. We're aware and we discussed in December the precautionary measures which have been taken in the U.K. First, they are not using U.K.?sourced plasma; and, secondly, they are implementing universal leukoreduction.


Next. In December, we asked the Committee to vote on two votes. I'm going to go through what those votes were. The first one is: Should FDA recommend new deferral criteria for blood donors to attempt to reduce a theoretical risk for transmitting new variant Creutzfeldt Jakob disease be excluding donors potentially exposed to the agent of bovine spongiform encephalopathy? The Committee voted nine yes and six no.

Next overhead. Should FDA recommend excluding donors who have resided in the United Kingdom or other BSE countries? The Committee voted 15 yes, unanimous, to remove "or other BSE countries."


I want to just put on the record and mention the other votes which were taken in December. Should FDA recommend withdrawal for blood components based on these donor deferral criteria? The vote was seven yes, five no. And should FDA recommend withdrawal for plasma derivatives based on these donor deferral criteria? Voted eleven no, one yes.

Next one, please. In addition to these questions on deferral of donors, in December we also asked the Committee to consider the actions that FDA would take if there were a report of a possible case of new variant CJD. We're going to refer those to CDC, but considering our precautionary withdrawal policy for new variant CJD, we asked: Should FDA recommend precautionary quarantine or withdrawal for plasma derivatives to which a possible new variant CJD donor contributed pending confirmation of the clinical diagnosis?

The Committee voted eight yes, one no, one abstained, but they asked us to revisit this question of our operational definition of a possible new variant CJD case. And in the second part of today's deliberations, after the vote on deferral, we will go back to that question.

The Committee also voted that a tonsil biopsy negative for protease?resistant prion would not be sufficient to make product withdrawals unnecessary.


We now have a presentation by Dr. Philip Comer, who will give us the Det Norsk Veritas risk assessment. Dr. Comer?

MR. COMER: Thank you very much, Chairman, and thank you for the opportunity to come and talk about the study that we were asked to do by the Department of Health in the United Kingdom as a result of a recommendation from the United Kingdom's Spongiform Encephalopathy Advisory Committee.


I am just going to go very quickly over the evidence for infectivity in blood. I think probably that will have already been looked at significantly by this Committee, but it was very much part of the background for what we were doing in the study that we did.

If we look at blood transfusions, we know that all attempts to transmit infectivity of blood, blood transfusion, so across a species barrier, have failed and that within animal models, as far as I am aware, the one case which has been reported by Bob Rohwer is still the only case that I have heard of in which there has been a positive transmission by the i/v route within an animal model.

Epidemiology studies have shown that's from sporadic CJD. There is no evidence that there has been any transmission through the blood route. And when we look at blood from human CJD cases, primarily sporadic CJD cases and certainly no variant CJD cases, and look at that, their infectivity through the i/c route into animal models, there have been a few experiments which have shown positive infectivity into rodents but negative results from a significant number of studies into primates and other species. And there have been some questions asked about ?? these cases, these experiments all involve very small numbers of animals and some sort of significant questions asked about those and, in particular, the fact that it is a bit odd that we have got no positive infections in the primates, which you might have expected would be more susceptible than the rodents. Then when we look at actually within animal models themselves, there have been quite a number of cases, experiments where positive infections have been reported from animals infected with some form of TSE and have been through the i/c route infected in the same species, so again with no species barrier. 89

CHAIRMAN BROWN: A couple of points just to bring your experimental data up to speed. Unpublished further experiments on the mouse model have produced good news and bad news.

The bad news is that we have a disappointingly large number of transmissions following intravenous inoculation of either plasma or Buffy coat. We also have a transmission using whole blood as a transfusion into these mice. So that's not good news.

The other thing that is not too good is that we have now got in this particular model a ratio of five to one, as opposed to ten to one, which was also disappointing.

The only piece of good news in that in terms of experimental data is that we found that, again, in this model, the level of infectivity during the entire incubation period is almost negligible compared to the level of infectivity during the clinical phase of illness. And that is very good news indeed. So these are data that are not yet published but ?? 105

CHAIRMAN BROWN: Right, right. And, as I say, if it turns out to be the case with the human disease, ?? and I'm guessing it probably will be ?? with you, I think the likelihood of disease, natural disease, whether it be scrapie in sheep, BSE in cattle, or CJD in humans, is going to be quite a lot less virulent than the experimentally induced disease.

Even under the experimental conditions I mentioned, however, infectivity in all components of the blood during the incubation period is so low that it virtually poses I think no risk, at least in terms of plasma derivatives. 106

Dr. Chan


So the issue that we dealt with in early May was "do variants of CJD pose a risk to blood safety?" And we sort of divided it into the classic variant and others. The others came out of, I'm sure you're all aware, of the scare that we all had over the Utah donor was this a possible chronic wasting disease, etc.

So we just put that issue on the table and let's see where it went. Our process -- we circulated a notice widely to all associations, consumer groups. We've sort of got a mailing list that's growing. 129

And thirdly, the question was: What is the biological plausibility, from our experimental data, that there will be other variants of CJD? I won't go into the attempts of answering these. 135

The rest of the recommendations I'll go through very briefly. Health Canada had not standardized its -- not finalized its policy on classic CJD, and we advised that they do so.

The blood services should provide clear statements about the reasons for believing that there are no longer concerns regarding the classic sporadic CJD; that Health Canada and the blood services provide communication regarding all aspects of product quarantine.

And that was because there's considerable confusion over the Utah donor case. Health Canada identify and provide information that all products that contain trace amounts of blood products -- this was interesting. Many of the physicians did not even know which products that were being distributed contained blood products. We thought this was an important issue. All products can be tracked in the event of an infected donor. And that they take steps to discourage manufacturers from using blood products in the production or formulation of other products.

That mechanisms are developed to ensure that -- oh, this is the surveillance for CJD. That criteria have to be established to determine between classic and variant forms, which I know is the topic that you are going to be discussing this afternoon. 138

CHAIRMAN BROWN: This afternoon's program will begin with several presentations as a part of the open public hearing. 145


The Department of Defense would like to thank you for allowing us to offer public comment.

I am Captain Bruce D. Rutherford, Medical Service Corps, United States Navy, the present Director of the Armed Services Blood Program. On 5 February, 1999, Dr. Sue Bailey, the Assistant Secretary of Defense for Health Affairs, forwarded a letter to Vice Admiral David Satcher, Public Health Service, the Surgeon General of the United States.

In that letter, Dr. Bailey expressed her opposition and the opposition of the Surgeon Generals of the Army, Navy and Air Force on deferring individuals as blood donors based on "perception" of a "possible" risk of transfusion transmission of the agent for "new variant" CJD. There has not been a single case, repeat, single case of transfusion transmitted new variant CJD or classical CJD reported in the world in more than 55 years since transfusion of blood products became widely accepted as a treatment regime.

In November of 1991, the Department of Defense issued an advisory recommending that individuals participating in Operation Desert Storm be deferred as blood donors after a number of Desert Storm troops were identified with cutaneous and visceral Leishmania tropica. Knowing that Leishmania donavani was transfusion transmissible, and now knowing the extent of infection rate of the "at risk" population, the DOD decided to defer those individuals as blood donors who participated in country in the Persian Gulf.

It was not until December of 1993, or two years later, that the DOD stopped asking leishmaniasis related questions of its blood donors. The cessation was due to a concentrated effort by the military health system in identifying an extremely small number of infected individuals and the follow-on screening questions' ability in identifying an extremely small number of donors with symptoms where leishmaniasis could have been a possibility.

However, a study in the survivability and infectivity of viscerotropic Leishmania tropica in human blood donors from ODS participants was later shown to support our concern and was published in the American Journal of Tropical Medicine and Hygiene in 1993.

Transfusion transmission by Leishmania species was a known, not theoretical. We know the calculatable risk of being injured in a car accident, yet millions of individuals a day drive their cars with hundreds of thousands being injured per year and tends of thousands killed each year. It is the same with airplanes, lightening and other activities.

In theory, anything is possible. I remember back a few years ago when the Institutes of Medicine came out with this HIV report. Yes, hindsight was better, but that has always been true.

I think in this case we have hindsight, 55 years of hindsight. We do not need to institute a UK deferral policy which will only lead to further crippling of our nation's blood supply and more product shortages. 148

CHAIRMAN BROWN: Thank you, Captain Rutherford. Are there any questions that any of the panel would wish to address to Captain Rutherford?

The next presentation will be by Kay R. Gregory of the American Association of Blood Banks.

MS. GREGORY: Good afternoon. 148

In conclusion, AABB notes that there is no evidence that nvCJD is transmitted by blood transfusion. There are no cases of nvCJD in the United States. It is unknown whether travel to Great Britain correlates with exposure to or infection with the agent of BSE.

And there is no evidence that any proposed criteria will decrease the theoretical risk of acquiring nvCJD from transfusion. In contrast, there is good evidence that even a one to two percent loss of donors due to new deferral criteria will have a significant impact on blood availability and, hence, on the safety of those transfusion recipients who cannot tolerate a delay in receiving blood products.

The country should contemplate nvCJD deferral criteria only when it is apparent that such a policy would improve blood safety more than the loss of donors and the associated decrease in blood availability would compromise blood safety.

Thank you.

CHAIRMAN BROWN: Thank you, Ms. Gregory.

The word theoretical has been used many, many, many times this morning and will continue to be used, and it's being used correctly. I'd just point out that, for ten years, between 1985 and 1995, the risk of new variant CJD from BSE was also theoretical.

The next speaker is Dave Cavenaugh from the Government Relations Committee of Ten Thousand.

MR. CAVENAUGH: I'm the government relations person at the Committee of Ten Thousand. The organization is the Committee of Ten Thousand. CHAIRMAN BROWN: Yes, that's fine. Thank you.

MR. CAVENAUGH: Okay, COTT, which is the Committee of Ten Thousand, is gravely concerned about the industry logic favoring UK donors over additional U.S. replacement donors even with the survey, and even with the lack of data on paid and unpaid high volume pheresis donors. This morning's discussion showed a glaring omission in the analysis to date of the impact of excluding well paid, highly educated, non-incentive provided pheresis donors in addition to the larger, understood group of paid pheresis donors.

We've heard quite a bit in terms of the studies and in terms of some of the questions about the likely blood borne nature of this never documented entity of prion and its ability to be transmitted by blood.

There's a perceived link between new variant and beef that's been raised based on proximity, but the BSE classical CJD link should not be forgotten. It should be entertained at the minimum. Living in the United Kingdom in the late '80s seemed to be a major factor, for example.

What was it about living there, that's proximity. Both statistic presenters showed clear risk of new variant in the blood, not even enlarging the scope to include classical CJD. There are no nv cases in the U.S., but plenty of classical -- arguably, much more than the one in one million rate alleged.

Just ask CJD Voice, the patient-family support group which spoke before you 18 months ago. Small then, its numbers have mushroomed. Something is getting transmitted. Can it all be through beef? But most disturbing is the recent news confirming a second mutated form of prions also causing death in under a year.

This doubling of the number of ways prions can be malformed with fatal results raises our concern levels considerably. The explanation that it is spontaneous sounds like an early catch all. With an entity so new, so unknown and so dangerous, the committee should be providing every protection possible, not bowing to arguments of relative risk.

Thank you.

CHAIRMAN BROWN: Thank you. 154

CHAIRMAN BROWN: Well, this is exactly why we're here today. Dr. Satcher and the other groups have already decided that this is not worth significant worry with respect to classical CJD, and that new variant was an unknown. And so that's why we're considering specifically new variant because we don't have information specifically on it. I mean, everything we don't have information on becomes a subject for this committee. (Laughter.) 213

DR. LEITMAN: We seem to be extrapolating the partitioning data of classical CJD -- the agent of classical CJD to the agent of new variant CJD. That may or may not be okay.

I'd like to ask Dr. Prusiner if we can at all extrapolate the lack of transmissibility through blood components of classical CJD agent to new variant?

DR. PRUSINER: I don't know that I'm qualified to answer this. I can only tell you that the little bit of work that we've done now on new variant CJD says that it is a dramatically different strain of prion. That means that the confirmation of PRP scrapie is dramatically different than anything else we've studied.

So let me give you an example. We've looked at 40 different cases of sporadic CJD, and we know that there's several different confirmations there at least. And all of these are transmissible in about 200 days to either mice that have a human PRP gene or have a chimeric mouse human PRP gene. If you look at new variant CJD, it takes more than 500 days and only about 60 percent of the animals get sick. Now, as I said before, if we take new variant CJD and we passage it into a mouse that expresses a bovine PRP gene on a null background, then all the mice are getting sick in 240 days. The piece of data I don't have that you want is you want to know if I take sporadic CJD or familial CJD cases and passage those into mice with a bovine PRP gene, do they get sick? And the answer is I don't know yet. 218

MS. HARRELL: Well, I asked him the question, was there a deferral ?? was there deferral criteria for blood donors for classic CJD for people who have either resided or visited the UK.

CHAIRMAN BROWN: I'm sorry. Repeat that, the question.

MS. HARRELL: Is there a deferral policy for blood donors to attempt to reduce the risk of transmitting classic CJD for people who either resided or visited the UK?

DR. SCHONBERGER: The answer is no.

MS. HARRELL: And if there is no risk, if we think that there is no risk of transmitting the whatever to ?? for CJD, what makes this different, for new variant CJD much different?

CHAIRMAN BROWN: That's the first time, Stan, you'll ever hear of prion referred to as a whatever. (Laughter.)

CHAIRMAN BROWN: I mean, I've heard it referred to as a lot of different things. I'm ??

DR. PRUSINER: You've said that many times, Paul. (Laughter.)

CHAIRMAN BROWN: It may be that ??

DR. PRUSINER: Is that in the Congressional Record?

CHAIRMAN BROWN: The issue is not about sporadic CJD. That is the issue we can sort of generically say CJD. Presumably, if the blood from a patient with new variant CJD were infectious, the disease that it would transmit would be new variant CJD. So it's not ??

MS. HARRELL: Okay. So CJD is not transmitted through the blood is what you're saying?

CHAIRMAN BROWN: We have no evidence from looking at populations that that has ever happened. The question is: since we know it can happen when we use experimental models of CJD, we can take CJD blood from one animal and produce the disease in another animal.

So there is the "theoretical possibility" that this might also happen in humans, particularly with a different strain of the disease, which new variant is, about which we don't know a whole lot. That's the question. DR. SCHONBERGER: Isn't the answer to her question that the incidence of CJD, REDS, classic CJD, is not influenced by whether or not you've lived in the UK between 1980 and 1996 ??


DR. SCHONBERGER: ?? but the incidence of new variant CJD is?

CHAIRMAN BROWN: Yes, 40-love. (Laughter.) 240

CHAIRMAN BROWN: I agree. We're starting to vote, and we'll start with Larry. Hold on. All right. The question is: should FDA recommend new deferral criteria for donors of transfusable components, to attempt to reduce the theoretical risk of transmitting new variant CJD from transfusions based on donor exposure to BSE in the UK?


CHAIRMAN BROWN: Incidentally, just to remind the committee, it is possible to vote punt; that is to say, you can vote yes, no, or no vote ?? abstain.

DR. HUESTON: Well, for my own benefit, I suppose, to walk through the logic ?? and maybe for the benefit of Barbara because I think she raises a good point about how we proceed ?? we have a situation with a small number of known cases of variant Creutzfeldt Jakob, all but one of which are in the UK.

However, we know there is a potential for widespread exposure to BSE that has already occurred. Therefore, we expect more cases, but we really don't have a good idea of the magnitude of the epidemic that we're going to expect.

Part number 2 says, "While there is no known whole blood or blood product transmission of classical CJD in humans, variant Creutzfeldt Jakob differs substantially from classical CJD." So we recognize that there is the potential for transmission of some of the transmissible spongiform encephalopathies via blood, albeit controversial We have an animal model, and we can identify infectivity in lymphoid tissues with variant Creutzfeldt Jakob, which is different from classical Creutzfeldt Jakob.

At the same time, it has been pointed out many times by a number of people that there have been no observed risk ?? or no observed cases at this point of transfusion or blood product related variant Creutzfeldt Jakob cases in the UK. I think that's a little premature. One might say the absence of evidence is not evidence of absence.


At the same time, there are look-back studies in place in the UK, and there is a natural experiment ?? a huge natural experiment ongoing in the United Kingdom, where if, in fact, there is a risk, I believe that the risk will first be apparent in the United Kingdom far before we would see it anywhere else.

At the same time, in looking at the precautionary principle ??

CHAIRMAN BROWN: Is this the preamble for a vote?

DR. HUESTON: Yes, sir. You got it. (Laughter.)

DR. HUESTON: If our goal is to be precautionary, but at the same time we have to preclude having more negative impacts for any action that we take, then positive ?? in other words, impacts on the blood supply. And I have struggled through the whole time, but I'm going to vote no at this time.

CHAIRMAN BROWN: Could I urge the remaining members of the committee ?? (Laughter.)

CHAIRMAN BROWN: ?? to vote rather than ?? I appreciate it, and I let Will, you know, chatter on because he hasn't said a whole lot, and I wanted to hear what he had to say. And so thank you, but we'll never get through if we continue to explain the reasons for our votes, each one and all. So, Susan?

DR. LEITMAN: I take the opportunity to disagree with what you just said. I think the vote at this table is so critical, it will have such a huge impact potentially on the way America collects its blood, that if we go beyond our designated time it's worth it.

And I was influenced, and it was helpful to hear the last speaker's discussion. So I think if any of us have discussions or points to mention now, they might be valuable.

The deliberations of this committee are among the most difficult of any advisory committee I've ever been on because there are simply inadequate data upon which to base a decision. For myself, in the absence of data suggesting or, rather, documenting risk, I cannot vote yes based on assumptions, perceptions, possibilities, uncertainties, theoretical risks, and potential risks.

On the other hand, there are tangible measurable data that deferral of any percentage of donors, whether it's half, one and a half, two percent, will lead to replacement by donors by a small proportion of donors that are at increased risk for measurable diseases such as hepatitis B and C. So I vote no.

CHAIRMAN BROWN: Dr. Leitman votes no.

Dr. Prusiner?

DR. PRUSINER: I would like to vote yes, and I would like to say I have 23 points that I want to go through. (Laughter.)

DR. PRUSINER: I only want to say very quickly that I don't think that economics and the availability of donors is a reason to vote yes or no in this. I think that the economy has a way of solving these problems, and I think that will happen. I think the real problem here lies that we have a very imperfect data set, and we're dealing with a disease which is universally fatal. This is really the problem that we face.

CHAIRMAN BROWN: Dr. Prusiner votes yes. Dr. Roos?

DR. ROOS: I think we're dealing with a situation in which we have no evidence of any transfusion that has transmitted either classical or new variant Creutzfeldt. And we have a situation where there are risks involved with blood transfusions that the donors accept at this point.

That is, we were informed about ?? I guess about 14 percent of individuals do donate blood that have I guess the recipients. About 14 percent of individuals that donate blood have some risky behavior. And maybe I might include living in UK part of that risky behavior.

And so I kind of accept this as, at the moment, acceptable risk for donated blood and I am awaiting evidence to prove that there is more danger involved. So I'm voting no here.

CHAIRMAN BROWN: Dr. Roos votes no. Dr. Belay?

DR. BELAY: I'm concerned about two issues. The first one is the studies that showed the presence of the new variant CJD agent in lymphoreticular tissues. And the second concern I have is the absence of evidence against blood-borne transmission of new variant CJD. The kind of data that's available for classic CJD is not available for new variant CJD, so I vote yes.

CHAIRMAN BROWN: Dr. Belay votes yes. Dr. Lurie?

DR. LURIE: Really, what we're doing is balancing one risk against two others. The two risks are the problem of the replacement donor, which is not zero but it is probably very small, given that we're only talking about one, two perhaps, percent replacement of donors here, depending on what happens in B if we get that far.

The second has to do with the diminution in the blood supply itself. And, again, there are scenarios available to us under B that allow us to minimize that. So we really have, on the one hand, two small risks that can more or less be quantified, and on the other hand we have another risk, which may itself be small, but if we are wrong could be very, very large. And that's really the benefit ?? the risk benefit calculation that we're making. For me, there remain too many uncertainties, and so I vote yes.

CHAIRMAN BROWN: Dr. Lurie votes yes. Dr. Hoel?

DR. HOEL: Yes. I'm changing my vote from last time, and I'm going to vote yes, mainly because of what I see in the epidemiology data of the cases in England and the modeling work. I think this needs to be monitored further to see how it comes in because the risks could be quite large, and so I would vote yes.

CHAIRMAN BROWN: Dr. Hoel votes yes. Dr. Bolton?

DR. BOLTON: I believe that there is insufficient documentation of the risk at this time. And in light of that, I can't ?? I don't think that the information warrants changing the current policy. I vote no.

CHAIRMAN BROWN: Dr. Bolton votes no. Dr. Nelson?

DR. NELSON: Well, this is a pretty difficult vote. Last time I voted no, and I'm going to vote no again, although I am ?? really, it's disturbing that there is no really good data at this point.

And I am impressed with a comment that was made earlier, and that is that there is an experiment in the UK of many people who have been exposed to UK donors over a period of many years. And I am somewhat reassured that there have been no cases, and I'm also reassured with the quality of the epidemiologic surveillance and data from the UK.

I think that that has been well done, carefully done, and presumably it will continue to be closely monitored. You know, if a single case had occurred, we would really need to change our policy immediately. That's number one.

But the other problem I have is if I voted yes, then I would have to make a decision on 1B. And the only ?? (Laughter.)

DR. NELSON: ?? the only reasonable decision on 1B would be to remove ?? to exclude all donors who had lived in the UK. I see no basis for any arbitrary decision. Once you go down that route, then you have to exclude anybody from the UK or who visited the UK or Ireland during this period. I don't see any alternative.

CHAIRMAN BROWN: Dr. Nelson votes no. Dr. McCullough?

DR. McCULLOUGH: I agree with Susan. This is one of the most difficult groups I have had to deal with. I'm impressed by the epidemiologic data. I'm also impressed by having sat through in 1983 and 1984 discussions of there ain't been a case reported yet, and also that we are concerned about the impact on the blood supply.



And possibly also, I'm influenced by having been the fodder for congressional hearings and 60-minute expose on things that might have been done differently at some of those times. So I'm going to vote yes. I have tremendous confidence in the blood systems of this country that they will be able to ?? not easily ?? respond if changes are made.

CHAIRMAN BROWN: Dr. McCullough votes yes. Dr. Brown votes yes. Dr. Ewenstein?

DR. EWENSTEIN: Yes. I'm impressed by the modeling data. I believe that we have biologic data as well as at least the potential epidemiology coming out of England to suggest that this is a new disease and on that basis should be handled with a lot more caution, because we don't have the comfort that we have with the long-standing classical CJD. And so I'm going to vote yes.

CHAIRMAN BROWN: Dr. Ewenstein votes yes. Dr. Detwiler?

ORY COMMITTEE MEETING Thursday, June 3, 1999??????? DR.

DETWILER: I'm going to vote yes, because with these diseases, a long incubation and the lack of a pre-clinical screening test, that the day you find out there is transmission you're already years too late, and you can't easily clean up the problem. And I think they found out that even with the human transmission because that was based on there is no theoretical ?? or it's only a theoretical risk until 1996.

CHAIRMAN BROWN: Dr. Detwiler votes yes. Dr. Piccardo?

DR. PICCARDO: I would vote yes because all of the data from classical CJD cannot be extrapolated into the new variant.

CHAIRMAN BROWN: Dr. Piccardo votes yes. Dr. Williams?

DR. WILLIAMS: I'm going to vote no. I think that this is truly a balancing act, and it's a tradeoff between a known problem, I believe related to the blood supply, and the problems that may follow from a reduced supply and the perception of a risk of new variant CJD.

And I completely agree that an experiment is going on right now. Those data are going to come in, and, obviously, there is going to be close attention paid to those data, and that surely this committee and FDA will respond should information indicate that we need to take another look at the issue.

CHAIRMAN BROWN: Dr. Williams votes no. Dr. Hollinger?

DR. HOLLINGER: I'm voting no also, for the same reasons that have been addressed. I think there is ?? by doing something now doesn't mean that everything is going to be turned around and you don't have to worry about it, if you do have a long incubation situation and one can wait to see if there is some risk down the line, and I think we do have those things going on ?? natural and experimental ?? in England. So I'm voting no. CHAIRMAN BROWN: Dr. Hollinger votes no. Ms. Harrell?


Case Report of V MS. HARRELL: Okay. Sitting next to my ex-learned colleague ?? (Laughter.)

MS. HARRELL: Okay. I'm voting to be prudent, and I think that this will buy us time to get the data in and have it analyzed from the UK. But right now, we don't have time, and so I vote yes.

CHAIRMAN BROWN: Ms. Harrell votes yes. Dr. Cliver?


CHAIRMAN BROWN: Dr. Cliver votes no. Dr. Burke?

DR. BURKE: This is a balancing act, and I can ?? there are measurable negatives here. In the face of a theoretical, I vote no.

CHAIRMAN BROWN: Dr. Burke votes no. Dr. Tramont?

DR. TRAMONT: I vote yes.

CHAIRMAN BROWN: Dr. Tramont votes yes. Twelve yes. Nine no. Well, at the least, Dr. Epstein can come away from the day with the understanding that he has not been given a mandate. (Laughter.)

DR. FREAS: Can I just make a comment? I did verify the count. There are 21 voting people at the table. Dr. Roos is a non-voting participant. And the total does add up to 21.

Excuse me. I apologize. Dr. Rohwer is ??

CHAIRMAN BROWN: I don't have to ask Bob what he would have voted, had he been allowed to vote. (Laughter.)

CHAIRMAN BROWN: But I will if you'd like to put it on the record. This is simply a question to Bob, since he's at the table. Were his vote to be counted, what would it have been?

DR. ROHWER: I'll use this soapbox opportunity.

CHAIRMAN BROWN: Uh-oh. (Laughter.)

DR. ROHWER: I am very concerned that we may be facing the grave possibility of an epidemic of new variant CJD, an epidemic that, if it occurs, could be made much worse through the mechanism of interspecies transmission, such as would occur through blood products. But I recognize the real risks of insufficient supply.

However, I am impressed by Dr. Donnelly's warning that if the feed ban in the case of BSE had been delayed just one year, the epidemic would have been vastly worse than it was. And, therefore, I feel we should take whatever opportunities for implementing mitigating measures that we can that do not simultaneously jeopardize the supply unduly.

So I recognize that what we have ?? the opportunity we have here is very, very imperfect, but I feel like it is possible to do something, and we should do it.

CHAIRMAN BROWN: Jay, you wanted a recount, or just a reexpression? DR. EPSTEIN: Just a reexpression.

CHAIRMAN BROWN: Okay. The vote on question 1A is 12 votes yes, nine votes no. Therefore, the committee is obliged now to consider what deferral criteria might be recommended. And presumably, based on the evidence, the only deferral criteria that are offered us that make any sense are duration of residence in the UK.


Dr. Scott


In addition, we do know, as Dr. Prusiner has pointed out several times, that the new variant agent is biologically different from the classical CJD agent, so we can't necessarily extrapolate all of the information that we have on classical CJD to new variant.

For example, he talked about the differences in the protein and its behavior, and we also know that there is enhanced expression of the new variant agent in lymphoid tissues compared with CJD. And we don't know much about its virulence or infectivity compared with the classical CJD. And, of course, we haven't had time to get or enough patients or subjects or transfused people to get the kind of epidemiologic data that we have which tells us that transmission of classical CJD by blood or blood products at worst is rare and may not occur.

So, currently, the diagnosis of new variant CJD is based upon neuropathology, and these are the three most characteristic features ?? numerous widespread kuru type amyloid plaques, which obviously can occur in a few other kinds of CJD but are quite common in new variant CJD; spongiform change, which is predominant in certain areas of the brain; and a high density prion protein accumulation, especially the cerebrum and the cerebellum by immunohistochemistry, and tonsillar biopsy may ultimately play a role in this diagnosis as well as analysis of prion glycoforms.

Current age, if alive, or age at death, less than 55. Since the typical age of a new variant patient is about late 20s, and the typical age of a classical CJD patient is about 65, this is one criteria that is useful. And new variant patients tend to have persistent painful sensory symptoms early in presentation and/or psychiatric symptoms.

I can go into this further if people want to know about it. But there were a couple of articles published in the Lancet from the CJD surveillance unit in September 1997, which goes into this in great detail.

In addition, the patient must have dementia and a delayed development of neurologic symptoms, particularly movement disorders, about a four-month delay. And, again, this is somewhat different from classical CJD in its course. They may have a normal or abnormal EEG, but not the diagnostic EEG, which is a pseudo periodic sharp wave that's often seen in classical CJD. The duration of illness should be greater than six months. Again, this is in marked distinction to most cases of classical CJD which average four to four and a half months of duration. Whereas, the new variant case typically is around 14 months duration, although there is a spread.

In addition, routine investigations will not suggest an alternate diagnosis. And this is a criteria, really, for the U.S. There should be history of possible exposure to BSE; that is, consumption of local beef products as resident or traveler to a BSE-affected country.

And there is only two more. No history of iatrogenic exposures that are related to development of classical CJD, and, finally, of course, such a patient, if they had a prion protein gene mutation, it was associated with familiar CJD. That would not fall under ?? that would not be a patient that we would worry about new variant CJD in.


DR. ROOS: Thanks, Dr. Scott. So we're not asked to take a vote, but just to discuss these issues. Yes?

DR. NELSON: I'm concerned a little bit about the explanation for the age criteria, and I can see that this is very useful because the one thing you do know, when somebody gets sick, you can estimate what their age is. And so that's an easy ?? you know, an easy early marker for a possible case that's not classical.

And I assume that probably the reason for the classical CJD patients being much older is that the incubation period is so long that they probably had an exposure much longer. But as this epidemic ?? or as the ?? if it's exposure to the BSE agent from the epidemic, it seems like over time this age criteria will probably change, and that the under 55 may no longer be a useful criteria 10 years from now or 40 years from now.

And I just wonder if Larry or anybody could comment on that.

DR. SCHONBERGER: We definitely agree, and it underscores the evolving nature of these diagnoses. All I can say is the age is an excellent and easy criteria for us to use now. All cases, as you know, in the world of new variant CJD have been under age 55. In fact, I think the oldest was ?? I think the median age is like 29 or so, 28 at onset and 29 at death. So that's why that particular criteria came into existence.

However, obviously, if the epidemic should change and we should start seeing older cases, then, obviously, we would have to change.

There is some semantic problems. We actually investigate every case under 55. So, in a sense, all cases under 55 in the United States could be regarded as under investigation or possible. We have not used the word "probable," in part because that's the word they use in the United Kingdom, and they count those cases as amongst the cases of new variant CJD that we count.

The 40 cases in the UK, I think, includes one, is it? One probable? That was a case in a teenager whose brain tissue was unavailable for study. And they indicate that it's too early in the epidemic. Their experience is too small for them to be absolutely sure about that, but they're willing to ?? at this point to call it a case.

And I've been told that with these new MRI criteria, and so on, that maybe we'll be able to call cases without necessarily having the tissue, depending on what they find the specificity and sensitivity of those to be. So all cases essentially under 55 right now are under investigation.

Plus, we have established amongst pathologists the concept that any case that has the pathology of new variant CJD, regardless of age, or even regardless of whether they've diagnosed it as CJD, should be reported. And those two would count as new variant even though they are not under 55. DR. ROOS: Just a quick question, Larry. What is your timeframe of reporting, or what is the goal here? Obviously, with respect to these new guidelines, you want to identify these cases fairly quickly and make some disposition as far as blood products.

DR. SCHONBERGER: Precisely because we are looking at all cases under 55, I was encouraging FDA to encourage the blood establishments ?? or the first to identify these cases at least, and that has been the history ?? to report to us any case of CJD under 55.

Once we get that report, it may be very easy for us and very quickly making it ?? to very quickly make a determination that we're dealing with, say, a dura mater case or a human growth hormone case. But then, another part of FDA will probably become interested in that.

So we think it's worth the blood establishments reporting all of their cases in donors. There just are not that many CJD cases that are going to occur among donors that the blood establishment is going to be able to identify that quickly. But if they do, we want it reported right away. DR. ROOS: Just a quick question. So, I mean, how about if this patient donates to some large blood pool or has donated whole blood? It doesn't go back to the blood establishment. It goes to a neurologist, gets diagnosed, etcetera. What's the timeframe then?

DR. SCHONBERGER: Well, frequently, our experience with the withdrawals ?? and I'll use the Utah case as an example as that came out ?? we handled that very, very rapidly. But even handling it very, very rapidly, you'll find that huge, huge numbers of recipients were exposed to this donor's blood products.

So the withdrawal program is relatively inefficient, compared to what we just did, which was to get deferral criteria. And I think that's why it was important to try to be preemptive in a sense and have the deferral criteria up front.

The withdrawal procedure, even when you do it very quickly as in the Utah case, I would not encourage people to depend on that for considerable safety. What we will do is we will modify and ameliorate the situation. But it certainly won't eliminate even the majority of the risk.

DR. ROOS: I just think it might be good to publicize these new policies widely to the neurological community, so that they alert you, Larry, or the FDA quickly. The Utah case, in fact, was kind of a very aberrant case. It could be that there are other cases that get less sophisticated care. And if you really want to identify things in a timely manner, you obviously have to publicize the program and new policies to the neurological community. DR. SCHONBERGER: Well, let me clarify that the primary group doing the surveillance on this are blood establishments. And if this group wants to recommend that blood establishments, you know, provide blood donors with cards or something that would, you know, speed up any type of reporting, that's possible.

The surveillance that CDC is conducting is not designed for that type of rapid turnaround or rapid identification in reporting. That's another weakness of the system and relying on this withdrawal system for tremendous protection of the population.

DR. ROOS: Peter?

DR. LURIE: My question/concern is whether or not requiring all nine of these criteria is too restrictive a set of criterion. I guess the data question that I have is: of the 30-odd new variant CJD cases in Britain, how many of them have met all nine of these criteria?

DR. SCOTT: Well, could I also respond to that question?

DR. LURIE: Yes, please do.

DR. SCOTT; I don't know the answer to how many have had all nine of those criteria, but most. However, the CJD surveillance unit has somewhat altered their criteria with time such that the current organization is similar to this but not the same. And most critically, they have gotten rid of the age criteria and added an MRI criteria. But this is not yet published material, and it's very recent. We just got that information on May 31st. And I think the other thing to mention is that we weren't considering only using all nine criteria. But, really, that's the purpose of the third way, if I can say it, which is to have a very low threshold for identifying even potential cases and then to make a rapid decision on a case-by-case basis. But what we're anticipating is probably what you're thinking, that not all of those criteria are going to be met, just due to a lack of information, time hasn't passed, we don't have material to analyze. And so I think what we're anticipating is that we would be ?? we would err on the side of caution unless investigation showed us that it was most unlikely that this was a new variant case. 292

DR. HUESTON: You don't know to what you've been exposed. So it's ?? the second thing is it draws ?? I think it gives a false sense of security and directs, potentially, attention to the wrong products, because the average person thinks of beef as primal cuts of beef. And that's, at this point, the least likely of the sources of exposure, given meat products. The third comment is that I personally am very concerned about the proposed ?? this criteria of possible new variant CJD by FDA. And I have two major reasons for that. The first is that I see the potential for conflict arising between FDA and CDC, where FDA is stepping forward or making a pronouncement of possible new variant CJD, and at the same time CDC says, "We're still investigating; you know, it's premature." And I think that puts the FDA in a very awkward position, and I think an inappropriate ?? Larry is telling me that they are investigating 25 ?? DR. SCHONBERGER: There's about 25 cases under 55 a year. DR. HUESTON: So my fear ?? here is my fear based on my experience. Item number 2 says, "Donor has physician's clinical or pathologic diagnosis of CJD."

DR. SCHONBERGER: They're not all donors, by the way. Very few of them are donors. Okay?

DR. HUESTON: Okay. Fair enough. But once you get a terminology like this established, my concern is that it's going to spread further, that people are going to say, "Well, the FDA would have called this a possible case." Number 2 says, "Has a physician's clinical or pathologic diagnosis," it doesn't say anything about the physician. And no offense to my distinguished colleagues, but there are a number of physicians that are simply not in the position to make a clinical diagnosis or a pathologic diagnosis of Creutzfeldt Jakob. That has not precluded some of these same physicians from making a proclamation.

Third, I think that the public health and the risk communication implications of this are potentially massive. And having been on the firing ?? you know, on the other end of trying to deal with these, you know, the press grabbing hold of a case and blowing it totally out of proportion and creating a great deal of concern, I don't see why you need another term. I think you coordinate with the CDC, you coordinate your investigation when it comes back from a blood collection center that you have a donor less than 55 years of age, where you have some suspicion of Creutzfeldt Jakob Disease. You go through the same CDC workup, and you base ?? on a case-by-case basis, you base your decision on that coordination with CDC. 296

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