P R O C E E D I N G S (8:30 a.m.)

Agenda Item: Administrative Remarks.

DR. FREAS: Good morning, and welcome to the 19th session of the transmissible spongiform encephalopathy advisory committee. I am Bill Freas. I am the executive secretary for today's meeting.

As announced in the Federal Register, and amended in the Federal Register, today's meeting and tomorrow's meeting are open to the public and the public is welcome to attend both days.

At this time, I would like to go around the head table and introduce the committee members to the public. Would the members please raise their hand when I call their name. I will be starting at the right side of the room at the audience's right.

In the first chair is Dr. Sue Priola, senior investigator, laboratory of persistent and viral diseases, Rocky Mountain Laboratories.

The next chair is empty right now, but it will soon be occupied by Dr. Michael Geschwind, assistant professor of neurology, University of California, San Francisco Medical Center.

The next chair is our consumer representative, Ms. Florence Kranitz, president of the CJD Foundation, Akron, Ohio.

The next chair is empty and that will be soon occupied by a new committee member, Dr. Laura Manuelidis, professor and head of neuropathology, Yale University School of Medicine.

Next we have David Gaylor, president of Gaylor Associates, Eureka Springs, Arkansas.

Next we have our industry representative, Dr. Taryn Rogalski-Salter. director of U.S. regulatory policy, Merck Research Laboratories.

Next we have Dr. Nick Hogan, associate professor of ophthalmology, University of Texas Southwestern Medical School.

Next we have Dr. Mo Salman, professor and director, animal population health institute, Colorado State University.

Around at the head of he table is our chair, Dr. Glenn Telling, associate professor, department of microbiology, immunology and molecular genetics, University of Kentucky.

Next we have Ms. Jan Hamilton, advocacy director, Hemophilia Foundation of America.

Next is another new member to this committee, Dr. Mark Powell, risk scientist, office of risk assessment and cost benefit analysis, U.S. Department of Agriculture.

Around he corner of the table we have Dr. James Lillard, associate professor of microbiology, Morehouse School of Medicine.

In the next chair we have Dr. lynn Creekmore, regional epidemiologist, AFIS veterinary services, U.S. Department of Agriculture.

Next we have Dr. James Sejvar, neuroepidemiologist, division of viral and rickettsial diseases, Centers for Disease Control and Prevention.

Next we have Mr. Val Bias, co-chairman, blood safety working group, National Hemophilia Foundation, Oakland, California.

Next we have another new member, Dr. Ronald Brookmeyer, professor, department of biostatistics, Bloomberg School of Public Health, Johns Hopkins University.

Next, Dr. Susan Leitman, chief, blood services section, department of transfusion medicine, National Institutes of Health.

Next is another new member, Dr. James Mastrianni, assistant professor of neurology, University of Chicago.

Next we have Dr. Richard Colvin, center for immunology and inflammatory diseases, Massachusetts General Hospital.

The empty chair will soon be filled by Dr. Richard Johnson, professor of neurology, Johns Hopkins University.

Dr. Bernardino Ghetti could not be with us at today's meeting. I would like to welcome everyone else and thank you for coming.

Now I would like to read the conflict of interest statement into the record. The Food and Drug Administration is convening today's meeting of the transmissible spongiform encephalopathies advisory committee under the Federal Advisory Committee Act of 1972.

All members of the committee are special government employees or regular federal employees from other agencies, and are subject to federal conflict of interest laws and regulations.

The following information on the status of the committee's compliance with the federal conflict of interest laws, including but not limited to, 18 US Code 208 and 21 US Code Section 355(n)(4) is being announced in today's meeting and will be part of a public record.

FDA has determined that members of the committee are in compliance with the federal ethics and conflict of interest laws, including but not limited to 18 US Code section 208, and 21 US Code section 355(n)(4).

Under 18 US Code 208, applicable to all government agencies, and 21 US Code 355(n)(4), applicable to certain FDA committees, congress has authorized FDA to grant waivers to special government employees who have financial conflicts when determined by the agency's need for that particular individual's services outweighs his or her potential conflict of interest, section 208, and where participation is necessary to afford essential expertise, section 355.

Members of the committee, including consultants, appointed as temporary voting members, appointed as temporary voting members, are special government employees or regular federal employees.

They have been screened for potential conflicts of interest of their own as well as those imputed to them including those of their employer, their spouse, minor child.

For the discussion topics, topic one, which is experimental clearance of transmissible spongiform encephalopathy infectivity in the plasma derived factor VIII products, and topic two, which is possible criteria for approval of donor screening tests for vCJD, these interests may include consulting, expert witness, testimony, contracts, grants, CRADAs, teaching, speaking, writing, patents and royalties and primary employment.

Today's agenda topics are considered general matters discussions. In accordance with 18 US Code Section 208(b)(3), general matters waivers have been granted to the following:

Drs. Ronald Brookmeyer, Michael Geschwind, Bernardino Ghetti, James Lillard, Laura Manuelidis, and James Mastrianni.

Previously approved waivers for Mr. Val Bias, Dr. Lynn Creekmore, Dr. Nick Hogan, Ms.Florence Kranitz, Dr. Glenn Telling, Dr. Mo Salman, are in effect for this meeting.

A copy of the written waiver statement may be obtained by submitting a written request to the agency's freedom of information office, Room 12-A-30, of the Parklawn Building.

Dr. Taryn Rogalski-Salter is serving as the industry representative acting on behalf of all related industries and is employed by Merck Laboratories. Industry representatives are not special government employees and they do not vote.

With regard to the FDA's guest speakers, the agency has determined that information provided by these speakers is essential.

The following information is made public to allow the audience to objectively evaluate any presentations and comments made by the speakers for topic one:

Dr. Lisa Ferguson is employed by USDA in Hyattsville, Maryland. Dr. Jiri Safar is associate professor, University of California, San Francisco. He has a financial interest in a company that is developing prion diagnostic products. As guest speakers, they will not participate in the committee deliberations, nor will they vote.

In addition, there are regulated industry and outside organization speakers at today's meeting making presentations.

These speakers may have financial conflicts of interest associated with their employer and with other regulated firms.

These individuals who were invited here to represent their companies, these individuals were not screened by FDA for their conflicts of interest, since they are representing regulated industry.

This conflict of interest statement will be available for review at the registration table. We would like to remind members that, if discussions involve any products or firms not already on the agenda, for which they have a personal or imputed financial interest, they need to exclude themselves from such involvement, and their exclusion will be noted for the record.

FDA encourages all meeting participants to advise the committee of any financial relationships that they may have with firms that could be affected by the committee discussions.

So ends the reading of the conflict of interest statement. Before I turn the microphone over to the chair, I would like to ask, if you have a cell phone, please put it in the silent mode, so that you won't disrupt those sitting next to you. Dr. Telling, I turn the meeting over to you.

Agenda Item: Opening Remarks.

DR. TELLING: Thank you, Bill. I would like to also welcome everybody here today. We have a full agenda so, without further ado, I think we will get on to the committee updates. The first speaker is going to be Dr. Ferguson, who will update us on U.S. and worldwide BSE.

Agenda Item: Committee Updates. US and Worldwide BSE.

DR. FERGUSON: I am just going to go through. If you have my handout, you see I have a whole bunch of slides, but I am going to rip through things pretty fast.

They are pretty straightforward slides, just to update what is happening in regard to BSE around the world, and then finally, in the United States.

Just a reminder for everybody, total cases worldwide still is greater than 189,000 cases. Again, most of those, actually greater than 96 percent, have still occurred within the United Kingdom and more than 89 percent of them occurred before 1996 and before.

So, when you still see all these numbers of cases, the vast majority of that reflects what happened in the United Kingdom in the late 1980s, early 1990s.

If you are interested in current totals, the OIE's web site actually has fairly good numbers, fairly updated numbers, about all countries that report cases.

Let's start off and talk about what has happened in the European Union. EU monitoring, since 2001, they have done very intensive surveillance, mandated by legislation.

In 2005, they have recently released their compiled report on all of the monitoring that went on in 2005, greater than 10 million tests in all the 25 member countries, in cattle.

Of those, about 1.5 million are what they call risk animals, which would be the same as our targeted population in the United States, and 8.6 million approximately are animals either 24 or 30 months old at slaughter.

Of that, 561 positive cases, 448 of those are in their risk or suspect animals, and 113 in the healthy slaughter population.

Again, in 2005, same as in 2004, both the number of cases and the overall prevalence in tested animals continues to decrease. The number of cases decreased by about 35 percent, overall prevalence by about 29 percent.

These reductions in the number of cases, also the increasing age of positive cases -- if you read their report, there is a lot of very good information about age of cases and how that progresses over the years. I didn't include that there, because that would have made me go on for far too long this morning.

Both of those do indicate success of control measures in Europe. They also provide very good details on analysis by year of birth of positive animals.

The peak of exposure actually appears pretty well defined in a few of the member states. This is the same as it was last year, which is a good indication.

France and Ireland, that peak appears to be about 1995, Germany, Belgium, Italy, The Netherlands, the peak appears to be about 1996. So, that is a good indication that perhaps -- well, it could be one of two things.

Either that is when the control measures really started to kick in or, more important, it could also be an indication of the increased surveillance that began in 2001. It is a little bit early to tell.

They are also doing significant monitoring in small ruminants, 614,000 tests in sheep and goats. Of that, 959 positives. Obviously, most of that is scrapie. They had no confirmed BSE cases in small ruminants this year.

Just to show you what has happened over the past five years within Europe, as you see, total number of positives by year, and that is decreasing every year, the same thing here in the risk or suspect animals versus healthy slaughter.

Those are very good indication that the control measures that they have in place in Europe are working and are doing the job that they are supposed to do.

Let's move to North America and a brief update here on BSE in Canada. As a reminder, Canada has been doing active surveillance, targeted surveillance, in the population where they are most likely to find disease since 1991.

As everybody knows, in 2003, they identified their first native case, in May of 2003. After that period, they significantly increased their surveillance.

So, these are just their numbers, in 2003, about 5,700 samples, two positives. One was the one that we found here in the United States in Washington State in December of 2003. So, increasing their surveillance again, with no cases in 2004, two in 2005, and five to date in 2006.

They did provide a very detailed epidemiological summary that was made public in January of this year. They are continuing that work and hopefully will have some more updates out fairly soon.

What this summary shows, it really talks about their geographic cluster theory, and the idea that the links between rendering, feed production, livestock production, tend to occur in clusters, in a fairly well defined geographic area. It is only logical, then, that that would be where the disease could cycle, would be in that type of a cluster.

What this report shows, which went through the first five cases, I believe, it does define links between most of these cases and links in this cluster.

There are also linkages in the more recent cases, again, to that same cluster and, as I mentioned earlier, hopefully they will be putting out some more updates with as good epi work in the near future.

To focus a bit on Japan, BSE was first identified in Japan in late 2001. Actually, it was September 2001. They imposed a feed ban, than, after that first diagnosis. So, the feed ban has only been in place since 2001.

Here is the number of cases. It stays about the same here until the past two years, where it has jumped up a bit.

One note about Japan. A lot of their surveillance and the testing numbers that you see have been primarily in clinically normal animals, or animals presented at slaughter.

It has only been since about 2004 that they have really increased their focus on the targeted animals or the risk population, as we would define it.

Now, let's move to the United States. As everybody knows, we have been doing active surveillance in the United States since 1990, and we are targeting the population where the disease is most likely to be diagnosed. That is the most efficient way for us to conduct a surveillance system.

The assumption is that if we can't find disease in that population, then it is even more unlikely for us to find it in the non-targeted population.

So, we can use the data that we get from that targeted sampling to extrapolate information to the broader cattle population.

Our targeted population has always been, and continues to be, those animals that have some type of a clinical abnormality that could even remotely be considered consistent with BSE.

So, these would be non-ambulatory animals, dead stock, which are animals that die for some unexplained reason, central nervous system cases, either called to our field people or on farms.

We work with veterinary diagnostic labs, public health labs, for rabies negative animals, and then we also work with our colleagues in FSIS, for those animals that are condemned on ante-mortem inspections when presented to slaughter.

Everybody knows we ran an enhanced BSE surveillance program that began in June 2004. Our initial intention was to run that for 12 to 18 months, with the goal of getting as many samples from the targeted population as we could.

We actually ran on a bit longer than the 18 months and ran through August of 2006, greater than 785,000 tests during that whole enhanced program. During that time frame, there were two positives identified during that effort.

Just to show on a monthly basis what we did in our enhanced program, as you can see, there is a little bit of a cycle.

With the population that we are sampling -- these are animals that are clinically abnormal in some way, and with the facilities where we were collecting, these are animal disposal facilities, rendering facilities, 3D, 4D, salvage slaughter plants.

Animals tend to get sicker, die, be culled in the winter. So, we always had a little peak in the winter. I just wanted to show folks, most folks don't quite understand exactly where we were sampling and why that might occur.

Let me explain a bit about OIE standards. These are the international animal health standards for BSE surveillance.

This reflects changes to those standards in May 2005. This is what we are using as our guidance for how we do surveillance from here on out.

It is a weighted point system. Previously it was a simple table that said if you had cattle population X, you need to get Y number of samples.

Now it is an interesting system where it recognizes that you are more likely to find the disease in certain subpopulations.

So, you get more points for that population where you are most likely to find the disease. We have four surveillance streams.

They are clinical suspect, which would be those animals with really pretty classic clinical signs of BSE, causality slaughter -- these would be those animals -- these are European terms, sometimes they fit with North American terms, sometimes they don't.

Casualty slaughter are those animals that are clinically abnormal. They would be condemned on antemortem inspections.

So, these are those non-ambulatory animals, could be the very weak, emaciated, thin, just some type of a subtle abnormality.

Fallen stock are dead stock, essentially, those animals that die for unknown reasons. Then, healthy slaughter is pretty self explanatory.

I don't know if you can actually read this. Hopefully you can. This shows the point system where it recognizes that you are most likely to find disease here in a clinical suspect.

So, you get 750 points for a clinical suspect between four and seven years old. That subpopulation is where you are really most likely to find disease if it is present.

You get essentially limited points for sampling in routine slaughter. So, what countries can do to use this table, you can access whatever population you like to meet the standards, and then the table says you need to get X number of points for a certain design prevalence, 300,000 points over a seven year period at a design prevalence of one in 100,000.

So, a country can then use this table and figure out what type of samples in what population they want to sample to reach those numbers of points.

So, you could sample a pretty small number of clinical suspects and reach that point value, or design prevalence, or you can sample a much higher number of routine slaughters. It recognizes that you can access both of those populations. It is just how many samples you want to get.

We did a summary of not only our enhanced surveillance program, but also what we have done for surveillance for the past seven years. That was made public in April of this year.

Just to give you kind of a graphic example of how to do this point system, these are the points that we obtained in our surveillance for the past seven years.

So, close to three million OIE points over the past seven years in the different surveillance streams. For those who ask about this healthy slaughter one, knowing that we really are not sampling healthy slaughter animals, this is a function of our data base.

Especially in some of these earlier years, our data might be somewhat limited. If we could not pull out of the data base a specific clinical sign, to assign this to one of the other surveillance streams, by default it would go into the healthy slaughter for this calculation.

So, with that summary of data, not only did we put out there just a raw data summary, we also did an estimate of BSE prevalence in the United States.

We used two methods to do this. One is the BsurvE model, which is a model developed by the Europeans with some input from our colleagues down under in New Zealand.

It looks at what we know from the epidemiology of the disease in Europe and factors in population data when animals are most likely to leave the population.

It can be used to help a country set up a surveillance system, can also be used to estimate prevalence.

We then also tweaked this model a bit and came up with what we call the Baysian birth cohort model, which incorporates what we would expect to see the effects of a feed ban, which the Bsurv doesn't show, and it also sets up some linkages between birth cohorts.

We also did several sensitivity analyses in this report, just to make sure that our assumptions weren't way off base.

The overall conclusion was that the BSE prevalence in the United States is very low, less than one infected animal per one million adult cattle.

If you are interested in most likely values, with the Bsurv model the most likely value was seven infected animals, with the BBC model the most likely value was four.

With the sensitivity analyses, those values ranged from one up to about 40, which all of those then led us to this conclusion, pretty solid, that the prevalence is less than one infected animal per one million cattle.

So, what are we doing now and where are we going from there? We have used these same methods and have moved forward into what we call ongoing surveillance.

We have been transitioning here since the end of August. What we figure is about 40,000 samples per year, again, still from this targeted population.

This will allow us to continue to monitor the status of U.S. cattle and will allow us to detect prevalence if it starts to increase.

We did this calculation, again, based on our analysis of the enhanced surveillance data and using the Bsurv model.

We first of all looked at OIE recommendations, which are at a design prevalence of one in 100,000. We wanted to make that a bit more sensitive. We wanted to stick with one per one million. So, we used the Bsurv model to estimate sample numbers and points.

Again, think of that basic premise that I described for the OIE, with a different number of points for different subpopulations.

With this, we need to get three million analytical points over a seven year time frame. When we look at what we did in enhanced, we averaged about 9.5 points per sample. So, we just divided and that gets you to about 40,000 samples per year, assuming we will get the same average points over a seven year time frame.

That is a very quick run through of both an update of what is going on in the world, what the international standards are, and where we are headed in the future. I think I have time for questions.

DR. TELLING: Yes, you do. Thank you, Dr. Ferguson. Are there any questions?

DR. GESCHWIND: Dr. Ferguson, when you were talking about the Japanese cases, could you comment about the ages of the animals?

Before 2004, I believe they were testing every cattle within a certain age range, and that they did find BSE cattle among those that would not be identified with the current methods in the United States. Can you comment on that?

DR. FERGUSON: I am not quite sure what you expect me to comment on. I think as we all know Japan, in 2001, by their regulations, required that every animal slaughtered, regardless of age, be tested for BSE.

They have recently changed that reg slightly, and it is only animals 20 months of age and older be tested at slaughter.

They did find two animals, a 21 month old and a 23 month old -- unless my memory escapes me at this point in time -- young animals, apparently normal at slaughter.

They were positive on the screening tests, negative on IHC, and then positive again with the way Japan has done the western blot.

They have put those into mice to see if there is transmission. To the best of my knowledge, those results aren't out there yet, but there is no indication that they have gotten any signs of disease in those mice.

Perhaps some of the researchers in this group can clarify that, if I am mistaken on that point. That is the situation in Japan.

DR. EPSTEIN: Lisa, my question is, does USDA have information about food chain controls in non-U.S. countries? Are we in a position to comment how adequate the food chain controls are from country to country?

DR. FERGUSON: I can speak for AFIS per se, since we are not the food safety group. That is really not part of the information that we have.

Our colleagues in FSIS, through their equivalency evaluations, work with certain countries, will have some information on essentially the red meat inspection and control, similar to what they would do in the United States. They would have that type of information. I am not sure how much further in the food chain you need to go beyond that.

MS. KRANITZ: Dr. Ferguson, in the United Kingdom and Japan they have found cases of BSE in animals that are not symptomatic. So, I would like to know why the USDA doesn't consider random sampling of healthy stock.

DR. FERGUSON: I think it is shown in that OIE table. We all recognize that you can pick up disease in animals before they begin to show clinical signs.

It all comes down to what is the purpose of your surveillance program and how do you best accomplish that purpose.

In the United States, the purpose of our surveillance program is animal health monitoring, to help us define either the presence or the absence of disease in the U.S. cattle population.

The purpose is not to identify each and every individual case of BSE that might be out there. In fact, that is an impossibility to do with current test methods that are there.

So, we have chosen the most efficient way by targeting that population where we are most likely to find disease if it is present, to give us sufficient information to help us define the status of the U.S. cattle population.

DR. MANUELIDIS: As a point of information, how many cows, adult cows, are there in the United States, so that the 459,000 that were tested is what percentage of the population versus Japan.

Then the second question is, the Japanese found more cases. Would you sort of compare a little bit or say something about the method of testing and the adequacy of the American testing method in its generality as compared to the more extensive Japanese testing and European testing.

DR. FERGUSON: Let me make sure I remember it. The first question was about adult cattle populations. We estimate adult cattle populations to be about 42 million currently.

I haven't done those numbers. I am not going to stand up here and do math in my had and divide 759,000 over 42 million. I will let you guys do that, if you so choose.

As far as the adequacy of our surveillance efforts in the United States compared to other countries, we feel very comfortable and very solid with the information that we have obtained, both over our enhanced efforts for the past two years, and all of the surveillance that we have done prior to that.

The prevalence estimates that we have done uses some very solid analytical methods, we believe, to come to the conclusions that we have.

So, we feel like the surveillance that we have done, targeted in the population that we have, is sufficient to help us define what is going on in the United States.