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Blood Safety Transcripts - April 1997

MEETING OF THE ADVISORY COMMITTEE ON
BLOOD SAFETY AND AVAILABILITY

Day 2 - APRIL 25, 1997

P R O C E E D I N G S

PARTICIPANT: For those who weren't here yesterday, we began an exploration of some of the issues involving hepatitis-C and look-back issues, and talked quite a bit about the charge and mandate of the committee.

Today we are going to have a discussion in just a minute with Dr. Thomas Zuck, who is going to tell us a bit more about the infrastructure of blood banking in this country. We'll have some questions from the panel. I don't think we'll go to the floor for these; this is more an overview to make sure that we have a common background as a basis for discussion on blood banking.

Then we're going to move to a discussion in open committee about the issues that have been put on the table with respect to hepatitis-C. As you recall, members of the committee, last night I was suggesting that we have some things to discuss about mission, about how we want to respond to the things we have been asked to do, say something about the ideas we might have for how our response might be crafted that would be most useful to the agencies that have asked us for opinion and advice. So I would like to continue that discussion.

Again, I would urge all of you to be thinking about what approaches, what methods, what type of product you think would be most useful for us to provide. I said last night, and I will repeat it again, if you think we're not ready to offer a specific answer to the questions that we have been asked, we can for further meetings, further input, further information if we're going to do that. It will be important that we be very specific about what it is we need and want to hear about, and if you think there are other issues looming up that have been triggered by discussions that we are going to hear either this morning or yesterday, it would be very useful to have some comments about that. So I think that will be a very lively session, in trying to get our feet on the ground about what it is we want to do next. Then we will move to consideration of another emerging issue with Kreutzfeld-Jacob disease, and have a number of informational presentations about that, and then swing back after lunch to further discussion amongst ourselves about future activities.

A couple of you had asked me about what time do I really think we're going to get done. This is a terrible question to ask me. I told some folks in Philadelphia that I would be there by five today, because we are having a big festival of volunteerism, some of you may have noticed. We're all going to learn how to volunteer, and of course, they have to have someone from ethics there to make sure they do it right.

But that was lined up for me a long time ago, so I asked Dr. Penner if he would step in and chair the meeting this afternoon, should we still be going, if I have to leave, although I know a number of you have said that you have to perhaps leave a little bit on the early side. So I'm going to try and move us along. That means watch the lunch break, because we are going to start at 1:30 on the button. Please be back so we can get going, and if we can finish up a little bit earlier, that would be great.

Any questions or comments about today's plan? Okay, without further ado then, Tom, why don't you enlighten us about blood banking?

PARTICIPANT: Thank you, Arthur. It is a real pleasure to be here. In a sense, it is kind of symptomatic of the times. This is the third time that I have done this in North America, once for the Canadian Commission, the so-called Priever Commission, once for one of the IOM fora, the one that did not issue a report that you have in your packets, and this will be the third time. I think it is emblematic of the intense public interest in the issues that this committee and the other fora have been dealing with.

I am pleased to be able to do it again. It was a bit of a squeak. Things are kind of busy at the New York Blood Center.

I apologize for these slides. They were made in New York. This slide was made in Cincinnati. The purpose of this is to present, principally for the non-blood bankers, and I didn't make a new slide: not the forum, but the committee, and familiarize members with blood centers, their commission and purpose, their operations, the regulatory environment. I know you heard some of that yesterday from Mary Pendergast and Mary Gustavson. And an introduction to process controls.

Now, I come to this talk with a bias. The bias is that we often focus on things that are solutions through testing, through some kind of new additional thing to do, when sometimes what we are doing now, the investment might be relevant to do it better. This issue will come up in several different arenas as we go.

The introduction to process controls is to make the non-blood bankers understand the complexity of what it is we do, and how a recommendation can have a profound effect on work force, on work flow, on quality of product, on timeliness of product. These issues are extraordinarily complicated in the manufacturing arena.

To the blood bankers, many of you my peers and friends, I apologize for putting you through this. If any of you want to take a long bladder break, that is fine with me.

Another New York slide. Types of blood establishments. The U.S. regional blood centers supply the vast majority of the blood in the United States, about 90 percent. Historically, there is one on the geographic region, but this historical orientation is starting to crumble. There are competing blood centers that are starting to be organized in certain communities in the United States. In a sense, this is in response to managed care, enormous pressures to contain costs, and in some cases just hospitals wanting to have a more active role in the management of centers.

So these regional blood center concept is changing not only in the historically one in a geographic region, but also they are starting to form combines, complexes and joint ventures to do testing and other kinds of activities that can be put together to save at reduced costs. Classic examples of that are the San Francisco Bay Area, the Tampa Bay Area, Southern California, and others are soon to follow.

The balance of the blood supply is collected in medical center, hospital or medical center blood banks historically supply their own needs only and are not exporters to other hospitals and/or regional centers. This pattern may also break down as hospitals form regional joint ventures and start to try to reduce the costs of transfusion services by doing and managing their own blood supply. About ten percent of the blood supply in the United States is collected by medical centers and hospitals.

Now, United States blood banking organizations, most of you probably know all of this, is the American Association of Blood Banks, whose principal audience and membership are composed of individual professionals in blood banking and hospital blood banks, the type that I just talked about, and their transfusion services. Most hospitals have a transfusion service which matches the blood they get from a regional center or their own sources to assure that it goes to the right patient.

America's Blood Centers, or ABC, is formerly the Council of Community Blood Centers, which was CCBC. It has about 85 members now of independent, free-standing, non-affiliated blood centers. The only criteria for membership is that you must have a U.S. license from the Food and Drug Administration.

American Blood Resources Association concerns itself with the plasma supply, and as such we will not be talking about the plasma supply today, except very tangentially, and the American Red Cross, which manages about 45 percent of the blood supply in the United States and 100 percent in Canada.

Whole blood collections in the United States are about 13 million. Distribution of collections for organizations are about 45 percent by the American Red Cross, about 45 percent by ABC, and about ten percent is collected by hospitals.

In addition, about 200,000 red cells are imported from Europe in a program started in the early '70s, because the use of plasma in Europe far exceeds what they can collect from volunteers, and so they collect an excess of red cells, and these red cells are exported to the United States, principally through the New York Blood Center.

Now, these patterns may change. These patterns may change as health care continues to change. As we see health alliances forming, you may see these patterns somewhat changing, particularly among the ABC, the independent blood centers.

The ARC blood program is managed centrally as a single program, single sets of SOPs, a target for a single computer system, a single audit system, a single license for all the Red Cross, which I think as of today there are about 45.

For management reasons, these have been divided into regions, and they have senior vice presidents in the regions, and starting to delegate responsibility down to the regional vice president. They are currently emerging from operating under a consent decree. The Red Cross had 12 different areas of concern to the agency -- 13, pardon me, and 12 of these have apparently been resolved.

I think Mary Pendergast gave you a number yesterday that a significant portion of blood in the United States was under a consent degree. The centers are operating in a consent decree. My number is 65, her number was 85, I am wondering who is next.

The total recruitment philosophies in the United States were historically very important in terms of how certain alliances were built up in the United States, and how certain practices were built up. This is not so much an issue anymore, but it is something to think about when we start to talk about availability.

Community responsibility is based on the premise that the donation is the responsibility of everyone, and that the donations are given for the community, not for a specific patient, not for self, but for the community to be used as the community needs.

Individual responsibility, on the other hand, the donation is to receive credits for self or some kind of benefit for self. It is interesting, because as we have more and more difficulty collecting donors, as more and more donors are reluctant to volunteer, whether due to fear or whether due to just the word AIDS, whether because it is very difficult to find time to donate, or for multifactorial reasons, the red cell collections in this country are becoming increasingly difficult, and in many centers are continuing to decline.

Most of the United States is on the community responsibility system. The average donor in those kinds of regions will donate 1.6 to 1.8 times a year.

Individual responsibility is in one particular blood center. There are other vestiges of it, but the one that really comes to the fore is the Delaware Blood Bank, Blood Bank of Delaware. The citizens of Delaware join the blood bank program, they get credits, they or their company get credits for donating blood, and the average person donates blood in Delaware once every three years.

So as we have increasing difficulties, it may be as we get in the age of individualism, a what's in it for me kind of approach from the baby boomers, maybe Delaware may have it right after all.

The blood center mission and purpose statement is pretty much the same for every blood center. It is in one way or another phrased this way: it is our mission to provide the safest possible blood components and related transfusion medicine services to any patient in need in a timely manner and at a fair price. So if we are going to be talking about what a blood center does, this is pretty much everybody's mission statement.

Now, this is where it all starts. We end up in some form or another having a donor, a volunteer in all cases for whole blood in this country, or virtually all, a volunteer that comes and is willing to put their arm out and have a relatively large needle thrust into their arms. This is the bottom line, is getting these volunteer donors to come and be willing to put that on there.

Now, there is a donor base in the community that breaks down into very different kinds of segments that you recruit and you have to manage in one way or another. On the far left is the neighborhood donor centers. That is what we call them in Cincinnati. They are called fix sites or satellites, or they have a variety of names. We call them neighborhood donor centers because we try to staff them with people who live in the neighborhood, and we try to get the donors to relate to a donor center in the neighborhood.

We tele-recruit small organizations. We can't afford, as we say, to have the off-loads, but we'll start to have small organization sponsored drives, and we tele-recruit into these neighborhood donor centers, hopefully getting a steady flow of donors.

On the other side, we have what we call mobiles. In Cincinnati, for example, there are seven of these neighborhood donor centers, one in Kentucky and six in Ohio. The mobiles are two kinds. One is self contained and one is what we call an in house. These are pretty much restricted to large organizations, because of their cost.

The large organization has to make a major commitment. It is expensive for them to have a drive, particularly the in house, because they have to create the space, the logistics of having their own staff help us in setting this up.

We like to have a minimum of 50 donations to go into a company and set up an in house drive. More and more, it is increasingly difficult to get 50 to show up, although we may schedule 70 or 80, because again, the problem with volunteerism is plaguing the blood bank as well as the American Red Cross and the Salvation Army.

This is what a neighborhood donor center looks like. This one is my personal favorite, because it was my first when I came. It used to be a chili company, and we still call it the chili company. This is where donors live, where donors work, and we place them by doing density plots of these donors, and where the density plots of the donors give by zip code is where we located the neighborhood donor centers.

This is what an off-load looks like. You would think that we could do better than these chaise lounges that we use, but indeed, no one has come up with anything better. It is easy to move. This one happens to be set up in the auditorium of a company, and this is self contained in a truck when they set it up, and have whatever space the company makes available to us.

This is a bus. Increasingly difficult for busses and other kinds of mobiles is an adequate water supply, to be able to assure the cleansing of hands and the appropriate universal precautions used by nurses that handle the donors.

The busses are very expensive to operate, but increasingly, companies are saying we can't let you come in, it is too expensive, but you can park the bus in front and we'll support that. So the busses are becoming increasingly important for blood centers to be able to use them.

This is one of the more important -- the namesake of the hospital was a surgeon of somewhat irascible temperament and somewhat flamboyant lifestyle. He had a Gull Wing Benz, and it was widely reputed that he had thousands of speeding tickets when he died, but the Cincinnati Police, because he was such a legend, just kind of ignored it.

This is one of the most important aspects of blood donation, and one that is rarely focused on. This is the health history. This is where the blood centers have the opportunity not only to educate people about HIV and other infectious disease risks, but to assure that a donor is truthful.

This is probably one of the weakest links. We are looking at other systems, such as interactive video, in terms of trying to improve the veracity of our donors. We know from the RED study that a significant number of donors ignore or forget or for some other reason do not reveal to the health historian the fact that they have had many, many -- many of them have had risky behavior encounters which they did not report.

This particular donor is a hero among heroes. He has given hundreds of aphoresis units of platelets. His name is Paul Michaels. He is head of our advisory committee for aphoresis. He is one of the donors that is justa true all-American hero.

This is a picture of what a donor room inside Hocksworth looks like. This is a retractable couch, a little better than the ones that go out into the off-loads. This is an environment that you try to make quiet, sedate, and have the donors at comfort.

Now, when we draw the blood, the blood has to be in some way preserved. You just can't take blood, put it in a bottle or do something else with it without a preservative solution. It is amazing that donors don't understand what we do with blood. I once had a donor stop me and ask me if we freeze-dried it, like coffee. It was not a trivial question; she didn't know.

So we draw it in what we call (word lost) preserves. They are either entrants into the bag or we add additional later. Citrate helates or binds the calcium, and calcium is needed to make the blood clot. So if we bind all the calcium, the blood will stay liquid during its storage. Nutrients are used to maintain its metabolism. ATP is a high energy phosphate that is responsible for all the high energy bonds in our body that enable muscles to work. It also makes red cells able to sustain themselves and metabolize glucose during the time we have it in storage.

The water diluate maintains fluidity, so that the cells can have a liquid medium, because we take most of the plasma off.

This is a unit, what it looks like when it is drawn. It is drawn in multiple packs in which we will maybe add an additional anticoagulate or nutrient. But we have multiple bags that we draw the blood in, so that we can process the blood for multiple different purposes into recipients.

We start with another whole blood, and from the whole blood we can make a red cell concentrate. That is what you think of when you think of a blood transfusion, you think of the red stuff as vital, and it is, for oxygen carrying capacity. We also can make platelet rich plasma, which is rarely used, but on some occasions is useful. Then we can make a platelet concentrate. We take the platelets, which are little cellular bits that make blood clot or facilitate blood clotting, that float with the red cells in the blood, and we can from the platelet rich plasma we can make a concentrate. We are going to go through and show you how some of this is done.

This is -- in our jargon, we call this the sticky stuff. We will in a minute talk about shifting usages for the various kinds of products, but the platelet concentrates are starting to drive the entire system.

We can make fresh frozen plasma, which has all the soluble pro-coagulants. These are the enzyme and substrates that make blood clot, so that when you cut yourself, you stop bleeding and then form a scab from the fibrin mesh that is built from the soluble pro-coagulants. We can also split off cryoprecipitate, which is rich in some of these pro-coagulants, fibrinogen eight and factor 13. This was first described by Dr. Poole in 1964 when she noted this fluffy stuff floating in plasma. It turns out that if we spun that out, we ended up with cryoprecipitate.

It was a major advance in the treatment of hemophilia. For the first time in 1965, she described it in December of '64, for the first time we had something to give hemophiliacs other than fresh frozen plasma, which if we got them hemostatic for severe hemorrhage, it threw them into pulmonary edema, which is excess fluid, which makes their lung non-functioning.

In some centers, modified plasma is used, in which the cryoprecipitate has been removed and the modified plasma is used for people who don't need these coagulation factors, but may need some of these.

Today, fibrinogen was formerly available commercially, because of its high hepatitis risk is no longer available commercially. This is the sole source for fibrinogen that we use for patients in many different situations, from transplantation to sealing the ossicles of the ear, et cetera.

So when we take that single unit of blood, these are what we can get. This is the cryoprecipitate, we get this fluffy stuff. These are the platelets, fresh frozen plasma. These are the pack cells. All of this came from a single draw from a donor. Each of these goes a different manufacturing route. Each of these goes a different computer tracking route. Each of these have different storage conditions. Each of these have different release conditions, each of these have different transfusion conditions. So it isn't just as though we are giving someone a unit of packed cells from that donation. A complex chain of manufacturing events occurs which results in the availability of these components.

So let's look at packed red blood cells first, and look at their manufacture. Now, unfortunately I couldn't find a picture of a spinning centrifuge. The rotor is in a blur, it is kind of neat. I somehow couldn't find it, I apologize.

The basic process in which we separate the different components is based on buoyancy. The oldest cellular components have a slightly different buoyancy, so by spinning them in a centrifuge we can separate them, in this case, plasma from red cells, making packed red cells.

The centrifuge has buckets and it spins at various speeds to take advantage of the different density buoyancy of the various cell components or liquid components. As you see, this is this multi-bag system. These are all hooked together and they are pre-sterilized at the manufacturer, so that you insure the sterile integrity when you move components through these tubings from one bag to another. No bag is ever used twice. It is important that the public as well as the blood donors understand that no bag is ever used twice.

This is what is called plasma expression. Phyllis has gone from the centrifuge back over to an extractor, which has a spring which presses the liquid plasma over into a separate bag that is integrally attached, until she gets to the point that she has only packed cells, and this unit of platelet rich plasma, which will be subjected to further manufacture.

Now, red cells come in different flavors. They are called ABO groups. What you see now is a smooth suspension of red cells. Almost all of the serology that we use in blood banks to find out what blood group a donor may be or a patient may be are all based on mixing reagents and/or samples from a potential recipient and getting a smooth reaction, so that the antibodies that are present in the recipient are not aggregating this smooth suspension.

If there is an antibody in the recipient, or if we have added a specific typing reagent, we can get this, which is an agglutination reaction, which is easily discerned from this. But in some reactions, it is not quite that clear-cut, because this is essentially a three to four plus aggregation.

So I just wanted to say, this is a fundamental -- primitive, perhaps, but fundamental series of reactions that are used to type donors into their subtypes, and to match donors to recipients. A very fundamental process in all of blood banking.

We have the various groups, O, AB and AB. By reagents we add, group O, not a glutinate, either A or B, anti-A will agglutinate an A and a B a B, and group AB was agglutinated by both anti-A and anti-B reagents. These are reagents that we buy commercially and are licensed by the Food and Drug Administration to assure their potency. We also what we call back type, because O has both anti-A and anti-B, A has anti-B, B has anti-A and AB has anti-nothing, or no antibodies. We can back type to confirm the front type. If they are not concordant, we have what we call a discordant typing, and it has to be resolved in some way.

This is a machine which we use currently. This is an Olympus, which types automatically. You can see multi-channels in which it does multiple series of steps to assure do the ABO grouping and our H grouping. We are also able to do some tests for infectious disease, by using that same agglutination principle, by red cells that have been coated by specific antigens that we are hunting for, that is, antigens related to syphilis or CMV.

The reason I wanted you to see the machine is, it is complicated. In the current version, the 2200, is about $622,000. So lest you think that these expenses are trivial to automate this -- but it is absolutely vital to automate it, because as ugly as this picture is sideways -- the reason this machine is so important is a principle I want you to take away, if nothing else from this 101. Everything that we can automate, we automate.

The reason it is so important is, these machines are hard wired to a data handling system. Everything that we can do in a blood center or hospital blood bank to take a person out of the loop, we should do. We are going to come back to process controls. Please take away with you that any time you interject a person to do a step, to read a reaction, to write down a result, you induce error into the system, because people make mistakes. These suckers make mistakes too, but hopefully we have ways of catching them, and we do.

Now, the ABO frequency is here. Notice there are some differences among ethnic backgrounds. That becomes very, very important, particularly in group O, because the usage patterns do not necessarily match the donation patterns. The blacks are under represented in the donor population. The NRAP and other types of NIH sponsored programs are trying very hard to improve and increase participation of blacks, but with relatively modest success. The national marrow donor program is also working to increase the participation, but the disparity between donation and usage is a difficult problem. It is also true in the RH, which is another group other than the ABO of antigens on the red cell.

Then we have a whole bunch of minor blood groups which can create serious problems in multi-transfusion, because all of these have ethnic differences. So in matching certain kinds of donors with certain kinds of recipients, the presence of these MNS (words lost) can be very difficult and problematic in finding an appropriate match for a given person.

This is what a community blood supply looks like. This happens to be the front row -- there is a back row -- the front row of the reefers in Cincinnati. Most blood centers send the blood to the hospital. This is just red cells on consignment. That is, if the hospital transfuses it, it gets billed, if it does not transfuse it, the blood center takes the hit, in terms of out dating.

Out dating in an efficiently run blood center is much less than one percent for red cells. Platelets are a little bit higher because you over manufacture. But that is -- if you walk into a blood center around the country, this is largely what you will see in a walk-in reefer.

But the ABO mismatch problem is a significant one. Medical practice dictates some high usage. Trauma; often the patient comes in, there is not time to find out whether it is an A or a B, so the trauma patient gets group O, which is the universal donor.

ECMO is an extra-corporeal circulation for children in severe pulmonary difficulties, in which you actually rest the lungs by setting up extra-corporeal circulation. It is all done with group O and a fair amount is used. Most of the rare recipients historically in those MNS, Lewis, Duffy, those subgroups, sickle cell patient, for example, they have multiple antibodies, and so it may be only rare donors that can match this rare recipient. Most of those are grouped though so they can be used for any patient, although that practice is changing.

For example, in our center, if you're A, you get A, if you're not, you get O. So we have been able to take some of the pressure off (word lost) usage. I mention the racial distribution and their efforts to increase O collections. But the O donors are getting tired of being tele-recruited all the time, so it is a continuing problem, not just red cells, but group O as well.

So let's take a look at platelets. This is our multi components coming off of many different slides. Let's focus just a little bit on platelets. Platelets, as I said, are this little bit of cellular material. They do not have nuclei; they break off from cells in a bone marrow called megakaryocutes, or megakaryocytes may be released into the bloodstream and break off there.

They are supporters of clotting. Those other soluble pro-coagulants use a platelet plug and form a stable clot. Without platelets, these stable clots are not formed, and you get diffuse and very specific kinds of bleeding related to platelet deficiency.

This is what a platelet concentrate looks like. It will have about .5 times ten to the 11th platelets, so there are a lot of platelets in here.

This is a healthy platelet. You see this swirl, this shimmer? That is a healthy platelet concentrate. There has been some effort to relate the extent of shimmering to yield, but not particularly good correlation.

This as we will see is -- these little cellular bits drive recruitment, drive the practices in the blood centers because of the enormous use, particularly in tertiary care units.

This is the platelet supply. We have five of these, but this is part of the platelet supply at Hocksworth on a given day. They have to be agitated constantly, these machines, rotated around and around and around. The platelets continue to metabolize sugar, and it will make an acid environment if not rotated. So we have to keep freshening the plasma membrane around the platelets so it doesn't kill itself by making acid as a result of metabolizing sugar.

Now, platelet usage patterns are changing dramatically in the United States. As I indicated, red cell usage is declining, and platelet usage is increasing, in large part due to more aggressive and ablative chemotherapy, often with an end to stem cell transplantation or cord cell transplantation or other kinds of rescue strategies from very aggressive chemotherapy. So the patient may be without platelets for several weeks and have to be totally supported by the regional blood supply.

Similarly for organ transplantation, not only during the procedure, dilutional coagulapathy, that is, the platelets are diluted out by massive amounts of transfusion due to difficult breaking, particularly on a re-transplantation. So usage as organ transplantation continues to increase.

Probably the biggest in our area is marrow transplantation for a whole variety. We have three different hospitals doing marrow transplantation in the Cincinnati area. This requires a significant commitment on the part of the blood bank, to be able to support the needs.

We can't draw enough red cells to meet the platelet requirements, so we have in most regional centers to go to a different strategy. In Cincinnati, we will transfuse somewhere between 80,000 and 90,000 red cells this year, but we will transfuse about 125,000 platelet equivalents, which means we have to get the platelets other than that combination of components made from a single donation of whole blood.

So what we have done is gone to what we call phoresis machines. These are machines that have a bowl that continuously separates cellular material from the plasma, much as our single centrifuge did that we showed. In this, the patient is put on line and continuously processed. This is a Phenmole CS-3000 machine.

This shows a patient where he is on the machine, and the blood has been processed. He gets everything back, the platelets and some plasma, and he ends up with a product that looks like this. You can't tumble these, you have to put these on a rotor that makes them rattle back and forth, or they don't maintain their pH, or they get too acid and the cells die.

This is an extraordinarily important part of what we do now. Some physicians advocate their use for safety, because there are fewer exposures. Most of these have six to eight single donor equivalents, i.e., the amount of platelets we can strip from a single blood donation. This will have six to eight of those, so rather than get exposure to six or eight donors, if you get one of these, you have exposure from one donor. Now, if that donor happens to have a virus, you get eight times the dose, but that is another issue. Whether these are truly safer or not, they may be safer because of the immune response to transfuse cellular products, but that is a lengthy discussion for another day.

So let's go to the fresh rows in plasma. This is our unit again. We have discussed the red cells a little bit, discussed the platelets a little bit, and one of the products that we got was plasma. Few indications for clinical medicine use.

In this auditorium, a consensus conference was held several years ago, about ten years ago now, for the indications in clinical medicine. It was pretty much concluded that there was very, very use for fresh frozen plasma in clinical medicine, except for certain coagulopathies and certain other unusual incidence. Nevertheless, it continues to be used, particularly in transplantation in those areas where there is dilutional coagulopathy.

Much of that, about 70 percent, is prepared from recovered plasma. Recovered plasma is that plasma not used by a blood center, and is shipped to manufacturers' fractionators to make the commercial products, the commercial factor concentrates, factor eight, factor 9, immunoglobulin and the like.

Most of the fresh frozen plasma in the United States is shipped to the manufacturers' fractionators under what is called a short supply agreement, which has enormous implications for the safety of the blood supply. It is a provision of the Code of Federal Regulations, which says, we can't inspect every little hospital that has recovered plasma, we just don't have the resources. So we are going to make the manufacturer responsible for assuring that the blood centers and the people that ship the fresh frozen plasma comply with good manufacturing practices.

Actually, in our blood center, we ship to several places, and they will come in every year and inspect us. In terms of the smaller hospital, that may be the only inspection they have, is from the contractor with whom they have the short supply agreement. I am not indicating this is not a safe practice; I'm just saying it is different in the inspection of this particular product for putting it in interstate commerce than it is for almost everything else under licenses.

The recombinant products may change the market for recovered plasma and for the need to fractionate plasma, as we currently do. The practices in that regard are evolving. The difficulty is, these products are more expensive than those that are plasma derived.

Let's go to cryoprecipitate a minute. This is this fuzzy stuff that is floating around in here. If you (word lost) this in four degree Centigrade and if you centrifuge it off, you get this kind of slurry, which contains the coagulation factors that I described.

This is not very, shall we say, orderly, but this is the way it is done. The plasma -- we open these bags, and they will be dripped back down into the receptacle bag. This is in a cold room, and this will happen over the course of a night, because it is best if the plasma is dripped through ice crystals in the neck of the bag. You get the highest yield of factor eight.

So this is made daily in large walk-in reefers, in blood centers, and it is a major source of factor eight, fibrinogen, the sole source of fibrinogen in the United States. It is widely used in transplantation when mixed with thrombin, which is a clotting enzyme, factor two. It will immediately make the fibrinogen polymerize and seal a wound. It is also used as a cast for the middle ear bones. After they do the middle ear surgery, they will put the fibrinogen and thrombin in and it will form a cast to let whatever was done at the surgery heal.

It is a very important component. We don't use enormous amounts of it, but when you need it, it is all there is to do what you want to do.

So that is how we manufacture stuff. There are a lot of other steps, there is a lot of more complicated issues that go on, but that is essentially how we manufacture, and how we match ABO grouping to recipient.

Much of the concern of this committee is the adverse reactions of transfusion and the safety part of the charge, and adequacy, is also part of the charge. Adverse reactions are immediate, that is, some kind of serological misadventure. We have given, let's say, an A to an O, and the O is anti-A, will react and cause serious or potential problems in the recipient. Those immediate reactions still account for a significant number of mortality in the United States, principally because of clerical error.

You go back to the principle I said before. If we can take a person out of the loop, we will, or try to, because clerical error still remains the number one risk of blood transfusions, pending some other investigations about infectious disease risks.

There are also delayed reactions, the serologic reactions, in which a recipient will react to one of the less common antigens that we don't screen for, build an antibody and start to destroy red cells, some five to six days after.

A relative common event, they are rarely of serious consequence, and very difficult to prevent if the antibody is undetectable in the recipient at the time of a cross match. This is the one of course that everyone is concerned about, not only immediate transfusion reaction infectious risk, in terms of bacterial contamination of either red cells or platelets, platelet being the biggest concern because they are stored at room temperature rather than four degrees, and relatively few bacterial, so-called psychophilic bacteria enjoy the environment of four degrees.

But platelets are a big concern and increasing concern, through some studies coming out of Canada and some northern cities in the United States.

So the immediate risk of a bacterial transmission is increasingly drawing our attention. But of course, the delayed, which is the hepatitis transmission -- CMV may be relatively rapid in this manifestation in immunosuppressed patients. And of course, the retroviruses, particular HIV, which is of enormous public concern, has resulted in all strategies being used -- multiple strategies, not all, multiple strategies being used to avoid transfusion.

That in part is reflected in a decreased usage of red cells throughout the United States, significant decline since 1986, and it continues to decline in most regions.

But let's look at the levels of protection against infectious disease risks. The general health history, which we know needs attention now after we have done the work with the RED study, the paper was published very recently about the veracity of donors at the time of donation. Self exclusion strategies, which are invariably used throughout the United States, and the confidentiality invariably used, some do not use it, self exclusion, just say, I'm not going to give, and HIV antibody testing, which is what everybody focuses on, because it is a tangible thing we can get our arms around, if you will, to screen out unsuitable units.

We do a lot of tests for infectious disease. We do the one that is of most concern to the general public, HIV 1 and 2. We do hepatitis surface antigen. We do anti-HTLV 1 and 2, anti-core, which is a related hepatitis surface and is a surrogate test for other things, particularly lifestyle issues, ALT, which is an enzyme elevated in some patients with liver disease before they have antibody, hepatitis-C virus. We are doing some form of RPR, some form of syphilis testing. We recently about a year ago introduced p24 antigen, which is the antigen that belongs in the core of HIV. And most blood centers are screening at least part of their blood supply for CMV, some blood centers don't screen at all.

So all of these are being currently done in every blood center licensed in the United States.

How is the screening done? This is a cartoon, which is a kind of a general all-purpose cartoon, if you will. This happens to be for HIV, but it goes for the general principle of how the immunoassays are done. They are the same for all of the assays.

The sample is added. The well has been coated prior to adding with the antigen of interest, or sometimes the antibody of interest. If you are looking for antigen, you coat the well with antibody. If you are looking for antibody, you coat the well with antigen. Then the antibody and the antigen bind. Then you add a detector or a conjugate, which will detect the antibody bound to the antigen, and a color will develop roughly in proportion to the number of antibody binding sites that were found by the conjugate.

(End of Tape 5, Side 1.)

-- the well we just saw. If it is not reactive, the unit is considered safe. There has been some criticism of this practice, but that is the algorithm currently in place.

We test it then in duplicate a second time, if it is initially reactive, and if either of the second two tubes are reactive, the unit is considered unsuitable for transfusion and passed on to additional, more specific tests. That is needed to do medical evaluation and counselling of the donor.

This is an extraordinarily important step, which we will come back to a little later in terms of the contributions of the blood banks.

This is a typical EIA testing laboratory. It happens to be the one in Cincinnati. You can see that the equipment that we use, not unlike the Olympus, this is the PPC or pipetting center, in which the tubes are racked up, and this will pipette the reagents automatically, with no person involved. This is one of the more important devices.

Note there is a positive identification of the tube in the computer. We're going to come back to the importance of computers in a minute.

This is an incubator, in which Marlene is incubating the plates after they have been put in the flexible pipetting center. They have a very precise duration that they are incubated. Then she is putting it in what we call the PPC, the parallel processing center, which will actually read the color and density that is developed in these little ells, and tell us yay or nay whether the unit is reactive.

Now, that machine that you just saw, the PPC, this machine is hard wired into the computer. There are no data transmitted by people in this whole process for any of the tests.

The role of computers in blood establishments, I would like to leave with you, may be one of the single most important parts of a blood establishment. It is vital to process controls, which we're going to talk a little bit at the end, for donor interception and product release at multiple levels.

FDA has a keen interest in computer systems and blood banks. They three and a half years ago proposed validation guidelines, how you validate that your computer does what you say it does. Does it in fact make mistakes, does it let you release unsuitable units for transfusion, or do you through extensive validation procedures have a high degree of confidence that the computer will do what it is supposed to do every time it has a task to do.

Certain systems, those that either move data or themselves in interstate commerce require a 5-10-K, which is a chapter of the code under which medical devices can be approved. It is one of the most critical vulnerabilities of our interest. If our computer is down, we have to lease product. When the computer is down is when almost all the mistakes, at least in our blood center, are made.

We'll come back to computers again and again. You think of infectious disease testing, you think of all the things blood centers do. This is the absolutely nerve center of the blood center.

What is happening here? These are a series of platelets. She is going to be labelling these platelets. What has happened? When she bar codes in the bar code of this unit by number, on the screen will tell her two things. One, is this donor suitable? Do we have something in this donor's history that says this donor is not suitable? Secondly, we have done all the testing, and all that we know about this unit; is there anything wrong with the unit? Is there a positive syphilis test? Is there something wrong?

If either of those conditions occurs, the computer sets a flag, and the computer locks up, and she cannot put a label on it. We'll show in a minute, if you can't put a label on it, it can't get out of the center.

So this is one of the most vital parts again involving the computer. Remember, all the test results, all the information we know got fed into the computer. It got correlated for this unit number, and at the time she tries to put an ABO label on it, it will check the donor and the unit history.

Before she puts it in inventory, there is what we call the final check. This is all done again. The unit is brought out. She will code in the unit number, and she will then -- the computer does exactly the same thing, goes back and checks the unit, checks the donor to be sure there isn't something untoward about either. It is done for a final time, when we make the packing slip. The computer does exactly the same thing. The distribution texts do what this labelling text is doing, and will send it out only after it has had a final check and made the packing slip. The computer will not send a packing slip if the units is flawed in some way.

This is another use of computers to try to improve the safety of the blood supply. These are laptops, which are downloaded every night with all the deferred donors in our system. When you come in to donate blood, you are called up on the computer, and if you're in the DDR, you are told, we are very sorry, you may not give blood because you are in the donor registry.

Some donors are shocked, but most shouldn't be, because most are notified that they are in it and should know they are not supposed to give. But we intercept a great number of donors every day on the mobiles, in the fixed sites, by looking them up on the laptops.

This is kind of a clunky system, but currently on mobiles it is very difficult to do it any other way. So for now, we're stuck with that. I'm sure somebody is going to find out a better way than downloading the donor base every night.

Blood banks are involved with a great many things in the community. There is a little section in the middle here which is kind of a potpourri of messages I want to leave to the committee, and perhaps the audience as well.

Blood banks do a whole lot of stuff other than supply blood and blood products. They run reference laboratories, serologic and chemistry to solve problems for other blood centers and for their customer hospitals. They do therapeutic procedures. We use those same machines that we made the platelets on to do exchange transfusion on patients for a variety of diseases. In some cases it seems like witchcraft, but in some cases it is clearly beneficial to the patient.

We do tissue matching for transplantation. We conduct education seminars, both for customer hospitals and for our internal customers, our personnel. Many, many blood centers are heavily committed to research programs.

We also provide donor recruitment. We provide stem cell collection, we provide purging of T-cells, which is a subset of lymphocytes that you frequently like to get rid of on transplantation, provide frozen storage of autologous sperm and other kind of core bloods and other kinds of components that can be stored. We of course provide blood component support, and in our center we do re-infusion technology, where we are the ones that do re-infusion and blood salvage.

So a lot is done by blood centers. Blood centers have taken a big hit, and blood banking has taken a big hit by the electronic media and the press. But there are a lot of things that blood centers have done that have been very, very salubrious for the American people. Just so we don't get wrapped up in what went wrong, we voluntarily initiated HIV antibody testing. We tested two or three years before there was regulation, because that is what everybody knew. It was yes, of course we have to do that.

We also assumed the resulting burdens. They are essentially public health burdens, which we really hadn't done before. We counsel donors about positive tests and now that has expanded into other positive tests. We manage problems which positive tests create, and those that are not involved with this. Some donors get extraordinarily distraught. There are extraordinary problems dealing with in some cases the problems that the knowledge of a positive test result creates.

This is not a major problem anymore, because virtually everybody that tests positive knew they had a risk factor, which goes back to the REDS data that the history system isn't always reliable.

We initiated community education of donors, of physicians, of the public. This was all done as a public health obligation that blood centers felt they had. Not every blood center director agreed with this, but I think the vast majority did it, and in fact, it was done.

This is a slide to try to add perspective. When I entered blood banking about this time, actually a little before, of the patients that got transfused, -- and I borrowed this slide from Paul Holland, actually, I stole it from him, he willingly gave it to me. When you transfuse multiple units into a recipient, the hepatitis risk was between 25 and 30 percent. Now, that is just in 1965. That is in my professional life in blood banking.

In 1995, with HCV testing, this risk had been brought down to a very, very modest risk. Today, I'm sure the experts that are with you, like Mike Busch, who will be sharing with you the risks of all infectious diseases over your deliberations, but it is absolutely astounding, perhaps one in 100,000 from 25 percent.

Look at this one. This was the biggie. When we first started all-volunteer donors, that was the biggie, and reduced it, cut it more than in half. Then these exclusions in other testing procedures. I only show this slide because I want to leave the committee with the impression that sometimes, when you read things that have been written about the blood industry, if you wish to call it that, I prefer the word blood service complex, if you choose to read and believe everything that is written, it is a total disaster of how the blood banks have responded; not exactly correct.

Now, blood centers operate by certain standards of care. The AABB standards are voluntary. A blood center or transfusion service agrees to be inspected, and they comply with certain kinds of requirements that are put out in the standards for blood banking.

The Clinical Laboratory Improvement Act is a federal statute which governs the conduct of clinical laboratories. In most states, it is administered by the states and delegated by the federal government, but it has certain mandatory requirements that a laboratory must do, among them proficiency testing. And it must have qualified personnel. The requirements for who can work in a laboratory and perform tests at multiple complexity levels is relatively stringent.

Then we have our friend the Food and Drug Administration, which has put an ever more watchful eye on us since 1985. Also, many of us have state and local requirements. Some cities have licensing requirements. Cincinnati happens to be one. Many states have requirements, Ohio happens to be one. So we are burdened, or have to comply with many, many different kinds of requirements. And if we do transfusion service work in many blood centers, and more and more regional blood centers are doing centralized cross matches for multiple hospitals in the region, then you have to be concerned about the hospital accreditation requirements, JCHO, College of American Pathologists, and the like.

Many of these requirements are identical. They overlap and are not -- I was told I had more. No? I had to stop now? I was told I had an hour and a half. Okay, we're going to go fast, folks.

These are the federal instruments. 351 is the basic Public Health Service Act that governs blood centers. The 200 and 600 series of the Code of Federal Regulations on the specific implementations of 351. Quality assurance guidelines flesh out the 600 and 200 series for blood establishments. FDA computer validation guidelines, I mentioned. Then there are various other miscellaneous guidelines.

The reason there are guidelines is that the Code of Federal Regulations takes several years to amend. Sometimes when something becomes a problem, as the problems this committee is going to discuss, the guidelines are due to be put out quickly. We can't wait for the federal industry and procedures act to be able to amend Title 21. So many of the requirements are in blood establishments.

The FDA has now said that any private sector documents that establish standards may be used as a basis of inspection by the Food and Drug Administration.

These are the basic pocket codes. We provide these to every employee. This is the Bible under which blood centers are controlled. It is a New York slide, again.

The regulatory actions, civil in contradistinction to criminal, that the FDA has, jawboning. This is when somebody is not in compliance, usually a larger company of biologics. They say, come on it, we've got a problem, can we solve it without any kind of official regulatory action. Form 43 is left with a blood center, looking at the observations the inspectors have made during their inspection. Warning letters are less and less used, and there is a notice of intent to revoke. Injunctions are more and more common, and earlier in the phase rather than later, these usually preceded this, but not necessarily now.

Lastly, the FDA can recall and seize product that it feels puts the public health at risk.

FDA looks at essentially one critical feature. I don't know how much time I have, but manufacturing processes are in control. To go into a blood center and say, are these manufacturing processes in control. These are measured against what we call current good manufacturing requirements.

I'm going to skip through this rather fast, because I thought I had until 10 o'clock. I want to leave you with the fact that although we get hung up on testing, we get hung up on things that can be done that will improve the safety of the blood supply, nothing maintains it more importantly than making a blood center compliant with current good manufacturing practices.

These are simple elements. Personnel training, are the records accurate, is the equipment calibrated, have the processes been validated, such as computers, are the process controls in place to insure when something goes wrong, it will be detected by some kind of audit process. Auditing and quality assurance on a regular basis is error management, but is the making of a mistake in a blood center used to continuously improve it. Are the SOPs and written procedures in place? Is the labelling accurate in a facility, and is the equipment adequate.

These elements apply to everything we do, every skill box in a blood center that take an activity and a process, it applies. It is based on a prevention model called a control which the auto industry has now embraced, in which rather than detect the bad product and shelve it, you improve your processes to the point that you have a high degree of confidence that your processes will turn out a product of suitable quality and that the public expects.

Basically, it just says a production process is used to make blood components. We can ship without counting, because the statistical process controls, and error management and process modification have been used to insure production. This is a vital aspect of the internal management of a blood center.

It takes a process to make anything. It doesn't make any difference what, there are processes to make components in blood centers. If you take each of these skill boxes, a process to its simplest task, and apply each of these current good manufacturing practices, you will have process control and you will have a compliant organization.

These are the steps to make a platelet concentrate. You saw the platelet with the swirl. These are the skill boxes it takes to make one platelet concentrate. Each of these skill boxes has to be audited, has to be controlled in an SOP, in order to insure that what is infused out here, is at the highest possible quality. This is one component, one part of the laboratory, and this is what it takes to make a unit of platelets with process control.

But it is an industrial concept, process control, as I have outlined it briefly. FDA is treating blood centers as manufacturers, and blood centers have had trouble with it. Blood centers have been run by physicians and medical professionals, and they don't think they are manufacturers. But we are manufacturers. Increasingly, our culture has changed to say, yes, we are manufacturers, and yes, we have to have process controls, and yes, we are held to different standards than other kinds of medical practices because of the public expectations and the risks involved.

But there are some uniqueness to the blood establishment. We have no control or little control over raw materials. If a gay man tells us he is not gay, we have no control over that raw material. If a young lady has gotten a tattoo on her arm and hasn't told her parents or anybody else, and she tells us she was not tattooed, we have lost control over the raw material.

Each component of the various components you saw is a lot or a batch. It isn't like a pharmaceutical that makes 100,000 vials or capsules, tests one or two vials, and says, yes, these meet specs. We cannot do that. We don't have the opportunity to do that. So the classical lot release of a blood product is not possible, at least from blood centers.

FDA reagent lot release is of limited value to us, although we have a certain confidence that the tests, whether it be for HCV or HIV or anti-A or anti-B, in fact meet the minimum standards to be acceptable to use in the blood center.

Please be aware that the requirements of a quality control unit, the training resources, have cost an enormous amount. The budget at Hocksworth is about $20 million a year. Last year, we spent $850,000 on just this issue of quality control, training and record keeping. So it is an enormously costly endeavor, but it is one of the most important endeavors that blood centers can undertake. That is why I wanted to share it with you.

The public expectations of transfusion safety drives a lot of what we do. Zero risk is expected of the United States, and some public statements have been made that that is what we were trying to achieve. Many chilling effects in the legal environment, worldwide lawsuits, the French episode, Canadian episode now, the German episode, and many, many others influence the public's opinion of what we are.

But I would like to leave you with this quote: in view of the inevitability of risk, there is an increasing awareness of the futility of demanding zero risks in matters of public policy. This is all you can get from donating blood. Donating blood is absolutely safe, so all you will get is orange juice.

Thank you very much.

PARTICIPANT: I'm going to see if we have any questions from the committee members from that wonderful overview.

PARTICIPANT: You mentioned the recently published data showing the extent to which donor health histories cannot absolutely be regarded as truthful. However, would you compare and contrast for the committee, for example, the HIV seropositivity rate in the general population as opposed to the blood center population?

PARTICIPANT: No, clearly the blood donor is a much safer person, particularly the repeat donor. That is an important perspective to have on that particular article from the REDS group.

I think the concern is that if you really are striving for a zero risk, -- and I think everybody that knows me knows that I hold the feeling (word lost) on that particular issue -- but I think the concern is that if the public policy is zero risk, as has been enunciated by FDA officials, then the fact that we are not doing as good a job as we might do, and you might have a window case, is of concern. But compared to the general population, you're absolutely correct, there is no comparison.

Yes, sir.

PARTICIPANT: (Inaudible.)

PARTICIPANT: Let me be sure I understand the question. If we issue a unit of fibrin blue, which is for two syringes, one of which has a thrombin solution, which is the enzyme that makes fibrinogen make a matrix, and the other is the cryoprecipitate itself, and they blend and they make this ceiling. Your question is, if that goes to the operating room, do we know it has been used?

PARTICIPANT: Yes.

PARTICIPANT: No.

PARTICIPANT: Tom, is there any blood component now in the United States, whether it be commercial or from a blood bank, that comes from paid donors? For example, plasmaphoresis units, et cetera. Is all of our blood from volunteers, or are there paid donors in certain segments of the whole industry?

PARTICIPANT: Let's divide the industry into two different groupings. One is the fresh blood and blood components, which is all I talked about today. The other is the fractionated plasma industry. Most of those donors are paid. About 30 percent of the blood comes from recovered plasma described under short supply agreements or some other manufacturing arrangement. But all of that is virally inactivated, at least for lipid envelope viruses at this point. There are a couple of specialty products that are not, but the vast majority have been inactivated by solid detergent.

Now, that will kill, as you are well aware, the envelop viruses. It will not kill some of the other viruses of concern, like parvo, et cetera. So yes, there are still paid donors, but the inactivation procedure has changed the risk from those donors significantly.

PARTICIPANT: (Inaudible.)

PARTICIPANT: The question was, would I comment on the shelf life of the various products. Fresh frozen plasma is a year, cryoprecipitate is a year, red cells are 42 days if drawn on ad cell, 21 days if drawn on CPD. Platelets have a five-day shelf life if stored at 22 degrees. Is that it? Did I get it? Okay.

Thank you for your attention and the opportunity to be here.

PARTICIPANT: Thanks. Oh, sorry. Don't leave yet.

PARTICIPANT: (Inaudible.)

PARTICIPANT: Jane, I'm sorry, I can't understand. Could you speak --

PARTICIPANT: I thought I was talking right into the mike. Maybe there is something wrong with the mike.

PARTICIPANT: Perhaps.

PARTICIPANT: I guess not.

PARTICIPANT: Maybe I'm getting old.

PARTICIPANT: My sense is that volunteerism is increasing rather than decreasing. My sense is that the baby boomers are children of the '60s, and there is some evidence that they are doing more in the way of voluntary action.

I don't see any evidence for decreases in volunteerism. I am wondering, are you just taking that from what you see as increasing difficulty in obtaining donors? Or is there some other more -- is there some hard data on this?

PARTICIPANT: No, Jane, I don't have any hard data. I have three pieces of data, or four pieces of data. I have the age distribution of the blood donors in our system, which is kind of moving along. They are getting older and older and older. The second, it is harder and harder to get them, even if they are old.

Then I have two other anecdotal bits of data which are perhaps worthless, but I will share them with you. My wife is president of the League of Volunteers for the Salvation Army in the Cincinnati area, and she said it is like pulling molars to get young people involved. Her committee structure is largely women in their 60s and 70s, and very hard to get 40s and 50s people involved in that arena.

The chairman of the Red Cross chapter in Cincinnati, which is unaffiliated with the blood center, but that person -- the president of that chapter is on our board of the blood bank, and we have talked a lot about this. At least in her experience as a Red Cross chapter, she is having increasing difficulty getting younger people involved.

So it is all anecdotal.

PARTICIPANT: What is the median age of your population at this time?

PARTICIPANT: Of the population of the United States? I don't know.

PARTICIPANT: No, of the population of donors.

PARTICIPANT: It is about 52. I have your name, I'm going to check it on the computer when I get home. I think it is about 50, but I haven't looked in a couple of years. If Jane is right, maybe it has gotten younger.

Thank you again.

PARTICIPANT: (Inaudible.)

PARTICIPANT: I'm sorry?

PARTICIPANT: (Inaudible.)

PARTICIPANT: Thanks for that excellent overview. We'll ask the committee members to come back up, and we'll move to discussion of one of the things we have been asked to offer advice and opinion and comment on by the various agencies.

While we're doing that, I had revelation in my slumbers last night, which normally I wouldn't announce such things here, but this was is probably worth comment. I would like to see who is up on the dias who is a non-voting member of this committee. Put your hand up? We do have some people up here who are acting as -- Dr. McDonald and Mary over here, another Mary over here. They are either here ex officio or consultants from some of the agencies that asked us to exist and give them advice.

I just wanted you to know that there are some members of the committee who have input, but technically can't participate in decisions, so you are clear about that. Not everybody is a voting member. On your participants list, they are either consultants or ex officio folks, and that is what that means.

The reason I went into this is, if you will now read behind door number one, the questions for the committee. When we were constituted, we had a broad mandate, but it is also the case that different agencies affiliated or under the auspices of the Public Health Service have some questions before them that they are seeking advice, comment or input on.

Paul has been nice enough to get the latest phrasing of those questions on the overhead for us here, and we might just take a moment and look at them. They concern the issue of look-back for hepatitis-C, and issues about how well we are doing in outreach to appropriate communities, about testing and medical care for those who are infected with hepatitis-C.

What I thought I would do is ask the committee, since we are now in a better arrangement to talk to one another a little bit, to open discussion of how you would like to respond to those two questions.

We have heard a variety of opinion yesterday about some of the technical information on testing and screening and the epidemiology of hepatitis-C, and we did an overview now of how blood banking works. Certainly, there was some comment that some people felt they would like to have more information. I noted some comments particularly about cost issues, what the cost would be for doing look-back. We had some comments yesterday too concerning the effectiveness of different types of look-back campaigns, both for blood and just generally looking back for other purposes in public health or health care. So there has already been some input for the committee, but you may want to have more information.

Just to remind you, I think given the nature of our charter, given the nature of what we have been asked to do, we may decide to hold off on the answer to these questions. We may decide that we want to answer those questions not with an up-down vote or a yes or a no, but something a little more prose like. We can decide to answer in sentences rather than single utterances. You can decide to answer in sentences that are supported by other comments, either in the length of paragraphs or pages. I suppose we could get into a kind of monograph.

But what I thought we could do is open the floor for discussion specifically, since we have been asked about these two questions, how we would like to respond to them. So let me just begin with that specific question of dealing with these issues that are put to us that our advice and opinions are being sought.

PARTICIPANT: Before we start, I understand that these proceedings are being recorded, but that we will not get copies of what is being discussed. As we get into the critical questions of what we want to evaluate and how, we do need to have a record that we can compare. Could we request that be done, starting immediately?

PARTICIPANT: Is that possible?

PARTICIPANT: The plan is to record and to transcribe. No decision has been made that I know of about what to do with the transitions, but it certainly could be made available, I would think, to the members of the committee without any question.

PARTICIPANT: I think I would like to amplify and support the comments that you just made regarding the committee to give some serious consideration to the product, if you will, or the outcome of its deliberations.

There is really a spectrum of products or outcomes, if you will, that might be considered. At one end of that spectrum is something that I think the committee that have sat on or attended BPAC meetings are very familiar with, which is a yay or nay vote in response to a series of questions or a selection of various options.

The other end of that spectrum is a product that I am more familiar with, having worked at CDC. CDC also has advisory committees which serve it, particularly in the areas of immunization practices, hospital infection control issues.

The advisory committee's products that advice CDC really come out in the form of guidance documents, documents that contain background information about particular issues, a summary of the available data, its strengths, its weaknesses, limitations, et cetera. They actually provide some context for the actual recommendations, not simply a yay or nay vote, do you think that childhood immunization for hepatitis-B should be done.

I think it is important to thank about this, because yesterday, a couple of folks here on the committee talked about what this committee is doing as being precedent setting. I think that that really bears some serious thought. The issue of the day is certainly hepatitis-C. But it is very obvious that this is going to be a recurring theme. There will be new pathogens that confront the blood supply. There will be new tests that emerge that have different sensitivities and specificities. So we are really going to be facing down this issue continually for the foreseeable future.

So it might be -- I'm not at all suggesting that the committee forego its charge. The committee has been asked to address very specifically the issue of how recipients might be notified about receipt of blood from donors who may have been infected with hepatitis-C. But it might be of some use to do that in a context that had some more generalizability, some longevity to it, so that it would be of help as we face these additional issues down the road.

PARTICIPANT: I would agree with what you have said, and I suppose follow it up with a question relative to procedures that are occurring relative to the charge. Are we viewing ourselves as responding in principle, or in context?

If one just deals with question one there, if we are expecting that we will respond in principle, that might require (words lost) in more depth of the programs that exist, and then to know whether or not (words lost) to look at methodologies that are being used and to speak to the content, and to the issues related to the dissemination of those materials.

I'm not sure that I am quite clear on how we should view the charge for answering the questions.

PARTICIPANT: Other comments?

PARTICIPANT: I believe our charge really relates to the policy, as I understand it. That is the situation that we are in at this point, that is, evaluate the policy or setting the policy, or responding by providing some form of policy. I think answering questions is not really what we should be doing here, but perhaps it would be better to consider at least affirming principles that we think policies should be based upon, in which case then I think a premise or principle should be initiated for us to at least get behind and decide if we favor or support. Then from there, decide how it applies to some of the specifics that are being mentioned here in the questions.

PARTICIPANT: That leads into something I wanted to raise. We discussed a little bit last night about the development of principles. I spent some time thinking about that this morning, and came up with what I think are four principles that may be applicable to this discussion, and it could carry over into others just as well.

The first principle I think is consistency when we are looking at development. A little bit of background; I work at the Minnesota Department of Health as the medical director for disease prevention and control, and I work with a variety of infectious disease policy issues (words lost). So coming from that background, my experience has clearly demonstrated that policy needs to be consistent with other policies we have.

For example, if we have an HIV look-back policy, it is hard to not have some kind of look-back policy for HCV. The second principle is that of maintaining public trust. If you develop a policy where the public feels that information is being withheld and this gets to the right to know issue as well, I think you've got a real problem.

So I think that when we look at developing our policies here, trying to maintain public trust with efforts to notify if you have been exposed to infectious agents is a very critical issue. I think that when we look at this, I know it isn't something we have strictly looked at, but I think it can also be incorporated with some of there other strategies that have been suggested by CDC in order to accomplish notification and to maintain public trust.

The third principle that I think is important, and one that we really need to keep in mind, particularly given the excellent presentation that we had this morning, was the risk of acquiring an infectious agent through blood transfusion is extremely low. It is not zero, but I think we need to continue to reinforce the safety of the blood supply, and that any policy we develop needs to have -- it needs to be consistent with that message.

The fourth one is I think our policies need to also be consistent with the principle of wise stewardship or both public and medical resources. Even though I think the right to know is a very critical one, I don't think that we can support decisions that don't use resources wisely. I think that that is very applicable to this issue.

For example, I think if we look at trying to do a look-back on persons who were transfused prior to 1990, I don't think that is a wise use of resources. I think that that return on that is extremely limited. I would actually favor a policy that just recommends a blanket, if you were transfused before 1990, you should have a test for HCV. That by the way is also consistent with what we have done in the past with HIV, where we recommended transfusion before 1985 (words lost).

Also related to public resources, I think it is very important that we ask for additional information or studies to be conducted by this federal agency, such as CDC. I think we need to be careful that what we ask for is something we really need. Collecting information, doing studies requires a great deal of resources, and I don't think we should try to embark on collecting additional information unless we believe that information is really valuable.

So it is those principles that I was thinking about. I actually think that we can maybe rephrase some of these questions and can move forward, maybe not asking quite this way, but I think we can move forward with our discussion if we (words lost).

PARTICIPANT: Thanks. When we were talking about what the committee might be doing in terms of product and trying to answer the specific issue on the table, trying to respond to the request for advice, I do feel some obligation to say, I think the committee should think about the range of responses that it believes would be most fruitful, to capture its expertise, that discharge our responsibility to the agencies, but also to the American people through Congress, which wants us to exercise good advice and opinion here.

That all said, I also think we have to keep in mind, we have to answer some questions. So if we are going to come up with a strategy about products, I don't want to say sometime in our lifetimes, but there are issues out there we have to address with a certain kind of urgency, so that if someone solicits an opinion, I think they have a right to expect a timely answer. So let's keep that in mind as we think about what we might be doing, too. We don't want to come out with a report that falls in deaf ears because it is three or four years after when the question got put.

So there is tension, and we just have to be alert to that, in terms of how we shape our mode of thinking about product.

PARTICIPANT: In follow-up to what Chris just said, I think one of the things that falls out of both consistency and public trust is the concept that no matter how low the risk, there is a need for people who are at risk to have some knowledge, if there is any way to access that knowledge about risk, so they can continue to be partners in the management of their own risk and also society's risk as well.

I think that was obviously always (words lost). But I think one of the reasons that I agree with what Chris just said is that it is very important that we do more than just take folks along to where our natural alliances were when we arrived. One of the things that any policy organization, and particularly one as visible as ours, has to do -- unless we give them the opportunity to do, is consensus building. If we can't rely on (words lost) both principles and practices, then it is very unlikely that what is carried away from our output will have very much profound influence on the overall blood supply and its use in the United States. However, if we are permitted to that, if we insist that that be done, I think that we can have the kind of focus advisory capacity the Secretary develops, but also to the broader reaches of public health, in terms of the types of issues that are being raised and need to be raised with regards to blood supply.

PARTICIPANT: I think perhaps at this time it would be worthwhile to offer a general premise or principle for the committee to evaluate, to start with or whatever, so there is something to work with.

PARTICIPANT: I'm sure we would be happy to hear that.

PARTICIPANT: I'll read it out and see how you might want to transform it. The committee affirms the concept that the blood recipients have a right to know risks associated with transfusion of blood and blood products, specifically any unique risks related to blood and blood products they receive.

Now, that covers the general aspects of what we want to address, as well as specifics (words lost), as a working concept. I don't know if that fits or if that is in agreement with other peoples' ideas that that is something that should happen, but I'll pass it on to you.

PARTICIPANT: Unburdened as I am with the high degree of medical knowledge that my colleagues have, I am framed it similarly to Dr. Penner, but in a little broader context: does the patient have the right to know, and if so, is the patient defined as only those who have received transfusions or those who do to medical conditions and lifestyle choices or transfusion --

(End of Tape 5, Side 2.)

PARTICIPANT: The next step here would be what is the best way to communicate, but maybe you should concentrate on the first part first.

PARTICIPANT: We have got two issues up on the table for the Committee to think about, and we can respond to either one. One is what sort of product, what sort of statement, guideline, criteria, generalizable principles, points to consider could we offer that we think would be useful and then specifically on the questions have we got the ability to generate a beginning principle or beginning premise that would then guide either us to a comment on that today or guide us, perhaps to know exactly what else we would need to know before we might affirm the principle at some future date. How is that for backward prose?

Both issues are up on the table. What does the product look like, and are there points of consensus even just on what we have heard like, let us call it the patient's right to know phraseology that is beginning to emerge here from this twin proposal, and I would just like to keep the floor open for comment on the issue of the kind of product that we are aiming for, too, because then we can jump right toward the discussion of that first phrasing of one particular principle.

Dr.AuBuchon, and we will go to Dr. Garrett.

Dr. AuBuchon: I would favor the Committee developing a series of points that need to be considered when a decision to implement lookback is being considered. HTB lookback is the question that we have been asked to address now, but there are other tests for which lookback might be utilized either currently or in the future, and at least for no other reason than explaining the rationale for any decision we make, it would be useful for us to set out as a preamble of our final resolution that the key point of a lookback decision, a patient's right to now is part of that. It is not the only factor that I think should be considered in a final decision, but I think maybe the Committee is beginning to enumerate the points that need to be considered in that kind of analysis.

I think it would be most useful if we set out a framework as well as a final decision.

PARTICIPANT: Dr. Garrett?

Dr. GARRETT: My concern is that as we open up the issue of lookback or the specifics of hepatitis C that it is also going to perhaps create some concern and apprehension in those that are looking forward or prospective recipients, and I think we probably also have to think in terms of how to build that in for the recipients or the prospective recipients, and I think the other concern relates to the issue of those that perhaps serve as representatives for the recipient. In the instance of children, it is the interested third party, a parent or caretaker that has to be the one to know rather than the individual patient.

PARTICIPANT: Paul?

PARTICIPANT: I think maybe we are starting to move in a direction that is following on the ideas of principles of framework. The two questions that are in front of us I see very closely linked together, and now as I look at the first question by itself, do we favor getting information out there, I, personally, would have trouble saying, "No," to that. On the other hand, I look at that question, and I don't know what the question says to me because the information, if I can be really kind of negative is that a letter goes out somewhere, and that is it. We say that we gave the information. I don't think that is the intent at all, but yet that is what the question basically allows us to read into that.

So, if we start setting up some concept of framework within the principles that were mentioned as to what this type of public information may be, that would, in my mind, at least have some influence to the next question of dealing with the lookback, and we need to look at these two things in concert as opposed to individual issues.

PARTICIPANT: I want to say before I go to this, Paul, that I am hearing some consensus. I want to make sure I read this right, that the Committee believes it would be most helpful to come up with responses to these sets of questions that are more of a framework, more of principles, more of points to consider, statements that might be supported by some rationale or explanation as part of how it thinks it can be most useful. Is that a fair consensus about product so far?

Let me ask you to think about something before I turn the floor over to Paul. I am going to ask you really for maybe the only vote of this meeting, but is that something that you feel prepared to do today or is it something that you think you are going to need some more information and input to do it so we don't get our agency friends upset soon, but perhaps not today?

Paul?

PARTICIPANT: I wanted to say that from the standpoint of the department I think I can say that what we want is something that either is policy or can be readily turned into a policy on this issue of notifying patients of certain information that may be available.

I think I would also like to ask Mary Pendergrass if she would like to comment on both my comments and maybe add to them? It might be most useful from the standpoint of the various agencies involved.

DR. PENDERGRASS: Thank you, Paul. I was hesitant to speak. This is a committee for the Secretary but as evident from the history, the issues pertaining to things that we looked at have (inaudible) looked at (inaudible) in a series of forums since 1989. The policy today has been not to engage in retrospective lookback, and I think what this, but that is a very charged decision, but if that is the decision, but if that is the decision today, and I think that the agencies were hoping that we would get very clear guidance from this Committee as to whether or not the course should be changed, and if so, exactly what one would expect from us.

I think we have, over the years, heard and discussed many principles and many other different points of view presented, and many things that need to be taken into account, such as not unduly scaring the American public, not decreasing the number of people who are willing to become blood donors, etc. Those issues have been put on the table and I think debated in the past, but the problem we have is that it is very difficult to come to a decision as to what to do with all those tough and competing vectors, and I think we were hoping that perhaps we could get fairly explicit items on that, but again, it is your advice to the Secretary.

PARTICIPANT: Dr. Penner?

DR. PENNER: I think if we accept the principle of the right to know, then there are corollaries that will follow and will be easy to dictate, and then in support of the patient's right to know, I would like to offer a couple of anecdotes.

One, we ran through the situation where we decided not to let patients know that they had the hepatitis core(?) antibody positivity, and many of you will recall that. That policy was finally reversed. The reason for not letting individuals know that they were positive for hepatitis core antibody was that we need the core antibody to be able to be used in some blood products, the fractions. So, therefore, telling individuals that they were positive meant that those individuals would not continue to come back and donate blood.

Those individuals did come back to donate blood. We discarded their red blood cells. We took the plasma and we sent it off, and we never told them that they had any abnormality when tested.

Now, I ran into one problem with that, and this is an anecdote and that is one of my physicians in the city had to have some surgery and asked his wife to donate for him as a direct donor. She donated and then was told that she couldn't give blood to him because she had an abnormality in her testing, and she said that she had been giving blood every 2 months for the past, 10 gallons worth; what happened; why isn't she a good donor, and then we had to tell her. Well, she is hepatitis core antibody positive, and he was furious, which I think any of you would be, and she was as well, of course, because no one had told her that she was positive.

So, we went through that. That was not a horrible story, but I have another story, and that was last week when we had the patient who was in the hospital and was in because of a serious infection and bleeding; blood cell values were very low; the patient was going to have a splenectomy in the hope of improving his blood condition simply because the spleen was enlarged and then it was suddenly found out that he was hepatitis C positive. He did not know about this and was transfused 10 years before, and at this point he was now cirrhotic, and we found out by looking at the biopsy.

Now, this individual could have been told or perhaps could have found out that he was hepatitis C positive, might have been offered at least a different or an alternative mode of life style or even therapy at that point, but at this point he is now ready for a liver transplant.

Now, this is what I think we are offering individuals by not pursuing as aggressively as possible this know-how and letting individual know that they have been exposed to an increased risk.

PARTICIPANT: Let me just run down a couple of other issues, items, areas, points to consider that I have heard, not to get you all to agree to them but because I think if we are trying to move this forward and coming up with some useful advice, practical advice, some help to the agencies who want to know about their course and whether they should continue to sail where they have been sailing, the patient's right to now issues, that the default mechanism should be to try to inform as much as possible, raise some other similar sorts of principles, other similar sorts of points to consider that I might lay in front of you, and I have a motive in doing this because if you buy into some of these or have others, that also might tell us what else we do or don't need to find out about, hear about, find out what is known or not known or whatever will be known about at another occasion or to decide that maybe you do have enough information to say something today, either tentatively or by way of a final statement on these particular questions, and here is what I have in mind.

We heard, for example, that lookback or patient's right to know has to be linked up to an informed physician population so that they know what to do if people come back with questions or have concerns, so that part of the right to know is not simply telling somebody something; it is preparing physicians and health providers to answer questions or concerns that come up. Is this a right of disclosing something to a person? We heard that the linkage has to be there in terms of being able to pay for testing and have costs covered if you come in and say, "Something may have happened, and you may want a test done," that there is an issue potentially about what will happen if many people come in and transfused before 1990 or 1988 or some cutoff date and all demand or seek testing services. We heard some comment that we have to set the hepatitis C risk in context, that we don't want people believing just because they were transfused and they have hepatitis C that we can draw a conclusion about cause and effect out of that. That is an issue that we have to grapple with about right to know and what are we saying substantively when we ask somebody who knows something.

Many were concerned about the cost of doing this, that it not be unduly burdensome. There was a hint of discussion yesterday about liability and how that would play out into a campaign to inform people.

We heard, I will just mention two other things that we have to use effective and efficient means to lookback. We may not even be sure about what that is in terms of sending out information by letter, by advertisement, by hotline, by Web site or roadway billboards or whatever it is going to be or maybe it is all of those, and if we don't know what works, then we will have to say something about recruiting or notifying in a comprehensive fashion.

We also said yesterday that it might be nice to make some comments about looking proactively at establishing baselines and looking forward is part of the advice we want to give on this, so that while the agencies may be concerned about sailing a course, we might also want to say something about new oceans to go towards to grind this metaphor into the ground.

So, those are other things that I heard, and I heard different people comment and say, "Well, I might have some consensus about this," or "These are areas which concern me." They don't necessarily lead us to a conclusion at the moment about the wisdom of any of those, but they might point us in the direction of saying that if we were to have another meeting, we would like to hear somebody address costs. We would like to hear somebody address outreach. We would like to hear somebody address legal liability and so forth and so on or maybe not. Maybe the Committee can think of better things than I have just run through and say, "No, we can at least leave here today with six statements that we think ought to be considered," and that is going to be satisfactory to you all.

So, I am just tossing that out by way of saying, "So, what else do we need to know? How might we move on this?" I see Ron, and I see Jane down there, and then we will -- okay, Dr. Yochelson?

DR. YOCHELSON: I need to add my comments at this point. Again, I feel very strongly about the right to know, but what? I think the accuracy of the information is critical. I am not sure how often all of the information which we currently have is in fact accurate, talking about false-positive information and the dissemination of that information which could create more problems than it solves.

Then the process of how to do it, if we believe we want to impart that right to know and how aggressively. For example, what if records are no longer available to do the tracking and we propose that that should be done? Then another approach will have to be made.

The intensity of the lookback will determine its effectiveness, but that will obviously also increase its costs.

I think these are considerations that this Committee must clearly look at, and I am not sure that we can solve those issues today.

PARTICIPANT: Dr. Fisipul?

DR. FISIPUL: I have a sort of disconnected set of things I would like to say. First of all, I really liked Christine's principles, and then I wanted to reinforce the idea that it would be good if we could come to create some general principles such as, for example, the patient's right to know as long as that is put in some larger context. There is also the public's right to know, and maybe that is the context in which the patient's right to know needs to be placed.

The second thing I would like to say proceeds to this issue of what it is that patient is going to know, and it seems to me in that connection we would simply have to start (inaudible) and we had some discussion yesterday about difficult it is these days for the physicians being as busy as they are and changes in medical care, how (inaudible). If we cannot get physicians to listen, how would we possibly hope to get the (inaudible) to less well-informed, in fact, the misinformed (inaudible.) So, in terms of things that we have been asked to think about specifically, I would like to propose that we seriously consider supporting the idea of some sort of physician education status as the first thing that we propose and this all has to be put into the context of resources and what is the best place for resources.

It seems to me that to have this in mind (inaudible).

PARTICIPANT: Dr. -- sorry, keep going.

PARTICIPANT: (Inaudible) just finally, I really think that we need to seriously professionalize this and with the statistics we saw yesterday that possibly is going to (inaudible).

I cannot imagine objecting to a prospective proposal of prospective lookback with what we know now including how the (inaudible). I guess I just want to say two things. I know that, I, personally, would be able to support (inaudible) put in the context of Christine's principles and (inaudible) aggressive campaign in educating doctors and (inaudible.)

PARTICIPANT: Dr. Alberts?

DR. ALBERTS: Following up on the (inaudible) issue, I believe that this is a particularly important one, and if effective this certainly would be (inaudible) not only from the point of view of hepatitis C but for other (inaudible) awaiting blood transfusion (inaudible). So, the question that is in my mind that I need reassurances on is what would be done; what is the time line; how would it be measured; and what would be (inaudible) compounds because if a decision is made today and on one or another particular point instead of being said that a decision cannot be changed, a recommendation and perhaps in some respects we are looking at a moving target; so, I think the issue of (inaudible) patient and a professional, I think the patient is really a key one (inaudible).

PARTICIPANT: There is a possibility that the Committee might want to keep in mind just to follow this point that you could make recommendations, offer suggestions and points to consider, and you could ask that you hear something back at some future time about what is being done.

I want to keep it in the mind that you can lay out as we sometimes say in ethics aspirations and leave it to some extent to others to implement those aspirations and then ask for some feedback about how well are we doing in reaching ideal goals.

I have Dr. Chamberlain and I see Mr. Allen, and then we will start moving down that way.

DR. CHAMBERLAIN: Just to follow up on a couple of comments that stressed the importance of physician education, yesterday we did hear about a plan that has been developed and is being implemented by Dr. Margolis from CDC, and it may be given time constraints and whatever, the lateness in the afternoon, it may be that the Committee may want to hear additional information about the plan, its components, its time line, what thoughts have been given to measuring the outcome, the success of such a plan. Particularly a couple of things have already happened. One that you heard about was the NIH Consensus Conference which I think was a very important first step to address Dr.Gilcher's and others' concerns about what we tell people has to be the right information, and this Consensus Conference, you know, really did make a very good effort at putting together what is very current and what was felt by consensus to be the best approach to management and follow-up of patients.

So, that really was an important first thing to do to know what to say to people and then, also, in terms of mechanisms and again, if the Committee wishes to hear about this more from folks at CDC, that might be helpful. There are lots of different mechanisms that are planned to get these information messages delivered to physicians, such as this national teleconference that will be held later this fall, electronic medium written materials, etc. So, just to assure the Committee that there are efforts that are being made. We may need to hear more about them, and there may be more questions that the committee has.

PARTICIPANT: Mr. Allen?

MR. ALLEN: I agree with some of the comments and the question about (inaudible). What I want to talk about is the fact that we need to reconsider first about the patient's right to know and then from there we can talk about how far back to go with the lookback or what diseases or whatever. It seems to me that we have to make decisions on (inaudible) and then start talking about costs versus how many people can pop out after you go, and then we can make some decision about (inaudible) and clearinghouse and something where all this information is under one roof, and that will cut the cost down instead of having a state-by-state doing this on their own. I think the first decision you have to make is about the patient's right to know.

PARTICIPANT: I think that the question before us is a difficult one and also paramount, but I do know that we probably also need to satisfy another section of this government which would be Congress in the decisions that we will be making, and I think we wouldn't be wise if we did not take into serious consideration some of the recommendations that have been made by the Committee on Government Reform or Oversight and especially recommendation No. 3 and No. 4, and those seem to be pretty strong directives of first when notifying, in short notifying 300,000 recipients of blood and blood products who were infected with hepatitis C virus before 1990, and the fourth one says, "HHS should send any more clinically useful information to providers of care to the public regarding blood safety issues."

I think that what I know of Congress in the dealings that I have had with them, especially as this Chaise(?) Committee report came out they were very adamant about these two points, and I think that we need to deal with these effectively to the satisfaction of Congress. Otherwise, I know I think I know Congress well enough, it will be revisited and you will have to deal with these issues again.

PARTICIPANT: Just let me make a very quick comment related to the issue of provider education, and I think it is really essential to keep state health departments and mobile health departments (inaudible) because a lot of times if people in the public get information about an infectious disease condition they will call their health department oftentimes before they will call the provider, particularly if they are not connected with the provider at that time.

The other thing is I think that state health departments and local health departments can serve as a very valuable resource in disseminating information to providers and to the public. So, I just wanted to mention that fact.

PARTICIPANT: Yes, I think we all agree that we would like to be able to identify those people who do have chronic hepatitis C as a result of blood products and certainly even far beyond that, but our charge is really in regard to the blood arena, and I would like to stay focused and to try to resolve that problem. How do we do that, identify these people so they can be counseled, and when they can be treated, they can be treated without doing something negative, without destroying the blood banking system, etc., which we are not going to do, and I would like to beg the issue? I kind of liked the first thing you said from a practical standpoint. In other words, what is the most practical way to get at these people who were transfused before 1990? It doesn't sound like that worked well there from what we have heard, but even though it is far from ideal, that sending out some letter to all blood recipients, period, and giving a relative risk if you were transfused during this period of time your risk of getting hepatitis, something like that, and I don't want to go into details. That could be worked out, and then at the same time put in place something for right now which sounds like a lookback might be easy to do, relatively easy to do, and we are not going to have too many cases of C right now.

So, in other words, I would like to get at all these people who have C in the past from blood in the best way we can do it without hurting a system that is critical for the welfare of our country and our people, and I think we have to stay focused on C, on blood relating to C and try to come up with something, and I think we could do that.

As far as implementing it, that is something else, but I think in terms of policy what you heard, I think Dana just outlined some of this, that we ought to just grapple with it and not try to be, as far as the right to know, that sounds very good. The right to know could be dangerous with certain things. They might want to know did my donor, is he left-handed or right-handed. I am being sarcastic, but that can get way out of hand. Let us stay focused on C, and if the donor was at risk to transplant C, well, then you have a right to know that and to try to act appropriately.

PARTICIPANT: I first would totally concur that we need to make a very strong statement with respect to education and the importance of education, not only at the physician level and the transfusion center level, but if we have 27 million transfusions a year as Captain Rutherford has suggested, that is 27 million contacts we are of aware of. It is going to go forward as well as back. I just did a very simple polling. The hemophilia community is very much aware of the blood contamination, the blood issue, specifically HCV. In our (inaudible) community we have a research network of 35 centers across the country, and I called two principal investigators last night one of which has 70 (inaudible) that they see on an annual basis that do test for HCV of which seven in that group tested positive for HCV.

Now, whether that is life style or whether it is blood supply or the blood products that we take every week or not, who knows, but that is important.

I polled 12 fellow (inaudible) that infuse like I do weekly, and two indicated that they knew they were tested. Eight indicated that they were not aware that they were specifically tested for HCV, the average of which has been infusing with a blood product for the last 5 years and two indicated that they were absolutely certain that they were not tested or had been screened for HCV.

So, I think the communities that use blood products would be an automatic, it is a small community but nevertheless an important and exposed community, and I think that the education has to be directed towards them as well.

PARTICIPANT: Let me just say something about education. There are many projects under way now that are coming from various spheres that are directed toward patient education, primary care education, the specialist doctor, the public at large, and I think you are going to see that all come to fruition in the next year.

One of the reasons for the delay was the NIH Consensus Conference on Hepatitis C. The people doing this did not want to come out with things that conflicted with the Consensus Conference. Everybody wanted to be on the same page here. So, there was a delay until we had the Consensus Conference.

So, I think you are going to see much more physician education, patient education that will come from various ways. It will come from the media. It will come from slide sets, for lectures to go to talk to primary care physicians. It will come from monographs to physicians. It is going to come from various avenues, but there is going to be an intense effort to educate about hepatitis C. I think you should be reassured about that because it is going to happen.

PARTICIPANT: I think we have sort of come to a consensus that there should be some kind of education. I think, also, we have come to a consensus about (inaudible). I think what we need to do now is define what we mean by lookback. Do we mean a traditional lookback, in that case (inaudible)? Do we mean some focus on lookback or a general lookback where we just blanket the transfused community with information, saying that if they have had transfusions they want to consider an HCV test? We need some (inaudible) to get to the point of deciding what we mean by lookback. I think all the other issues we have sort of come to some sort of consensus. There is a need for some kind of educational program, physicians, patients, across the board. Whether it is the one that PHS put together, who knows? We need to decide that today. We need to ask for additional information on what (inaudible) but I think there is sufficient information in the packet that they provided us on what they instituted and a time line for which to institute that. Whether these proposals will be successful or whether they have data on previous educational programs focused like this, I don't know whether that is necessary or (inaudible). I know that is something we need to grapple with, but I think we need to define terms because at this point we have all said that lookback and patient's right to know is important.

PARTICIPANT: I think it is also reasonably clear that in terms of traditional lookback, that is knowing that someone was transfused with a product that is from someone we now know to have subsequently been at risk essentially cannot be done for any transfused before (inaudible) because we didn't have the measurement, and these are the 300,000 people that are (inaudible). So, the question is what to do about those. I think that we really cannot go ahead and do the focus on (inaudible) and so the question in my mind is what could we do other than one, in terms of educational things, starting with the listing of physicians who (inaudible) and actually trying to reach those people. I must have missed an issue here. I am somewhat dubious of the effectiveness (inaudible). That doesn't mean we should (inaudible.) The problem, of course, is where would the money come from for particularly these kinds of educational programs we are talking about. (Inaudible) back to HHS and saying, "Okay, this is what the Committee says we need to do as two first steps."

Who is going to take responsibility for that? HHS is very (inaudible) and I am just worried that (inaudible) some sort of platitude will come out of it and then will fall into a hole.

PARTICIPANT: I am going to take three more comments. Then what I would like to do is put two proposals on the table for you to consider, and then we will take break. So, we will go to Dr. McDonald, Dr. Guerra and then I have got Mary back there.

DR. MC DONALD: I think that the best way to look at this is rather than the way the question has been worded up there is to look at the 1990 and prior time period, the 1990 to 1997 time period and then prospectively, and I think that I very much agree with the comments about prior to 1990, and again, (inaudible) HIV policy when we recommended Christmas before 1985 was or (inaudible) transfused, see if we can come up with something like that for that group.

In the 1990 to 1997 group it is a little trickier in terms of resources, and one of the things I think that we need to consider, and this was brought up a little bit earlier is the issue of persons who, donors who tested positive by BIA or who got a supplemental test. I am very concerned about sending out notifications to recipients of blood products from those donors because of a very high false positive rate and, also, the sort of low effectiveness of doing that. I think that we need to consider for the lookback issue to focus on situations where there has been a confirmatory or supplemental test performed where we have a pretty good positive evaluative test, and I hope that the Committee will consider that.

Then I think for the future we can look at a prospective (inaudible) type of situation.

PARTICIPANT: Dr. Guerra?

PARTICIPANT: Which is also very (inaudible) what we have done with (inaudible.)

PARTICIPANT: I am reminded of some of the very complex and extended deliberations of the Advisory Committee on Immunization Practices when we were dealing with quite recently the issues surrounding the change in the dosage of polio vaccine schedule going from the oral polio vaccine to the sequential or the inactivated enhanced poliovirus (inaudible) polio. As we went through that process that extended over more than a year, it was very clear that it had to be a work in progress because there was so much information that had to come together that ultimately has such a profound impact on a country and on the health care systems.

I think that this is one of those situations where this Committee has enormous responsibility that extends beyond just hepatitis C and Creutzfeldt-Jakob disease and the concern with the nation's blood supply, and I think we have to maybe at the end of this meeting perhaps develop an interim statement and recommendation that we do have concern for hepatitis C virus as an infectious agent in the nation's blood supply. A concern certainly is one that has some very significant consequences though our initial impression is that it probably is not in such proportions that we have to put out an immediate alert and what have you but that we need to begin to engage in a discussion that is going to extend over several meetings to cover or to try to generate additional information we are presently lacking.

Some things I think we probably need to get a better handle on are the following: One is we need to have some more information on some of the statistics, especially as they are distributed across the country and by age distribution and populations.

I think we have to better understand and bring in the outside experts to tell us how we can communicate risk in an effective and caring and concerned way to the general public and, also, to the professional community.

I think there are some important ethical considerations that we haven't always really gotten a good handle on as it relates to something that is for the common good and that puts ultimately a lot of people at risk and in some instances that the proportions are so small, but nonetheless the consequences extend beyond that.

I think there have to be perhaps specific considerations related to prior to the nineties and then currently and then for the future. I think we need to more clearly establish some time lines for what it is that we want to accomplish and by when, and begin to develop some terms of reference around that, and I think we also have to consider how the responsibility for this information should be shared across the public and the private sectors; who is going to help underwrite the cost of this that I think is going to require a considerable allocation of resources which presently are in short supply, and I think that once we get into it is going to become a very costly venture and is one that really to maximize this opportunity we have to do the cost/benefit analysis and see what other benefits beyond just the hepatitis C so that we can really make it an even greater benefit.

PARTICIPANT: Mary?

PARTICIPANT: I still believe that we have not clarified a critical issue, and that has to do with whether we are recommending policy and/or program and specific implementation of program. I do not believe that we are here to tell (inaudible) Public Health Service, CDC, or HHS how to do any of this but rather to affirm in general terms that A ought to be done; B ought to be done; C ought to be done and one should consider A, B and C in doing it, but if we are about program and implementation then we perhaps need to be allowed to look at those as two separate agendas. I think we need to work on policy first and if we are expected to come back and look at program and implementation, some of the very specific comments that have been made relative to those issues might be appropriate at that time and again, at that time in very specific dialogue with the programmatic officials from those agencies.

PARTICIPANT: What I was going to do is ask the group to consider, and it is right in the spirit of Marion's comment; it seems to me as if from this morning's discussion we were moving toward a consensus that we would like to focus our recommendations in a format that goes beyond answers to questions in short form to attempts to show policy, that we may have things to say, a bit about program, but our primary thrust is policy, and in terms of implementation where we have degenerated to it on occasion; it is inevitable; we don't really need it, and that is going to be the headache of agencies and Congress and others to figure out.

Do we have, is that a consensus that we can agree to?

Okay. Secondly, then, that is how we will vote, people nodding. The second thing I hear us saying is that we are in strong agreement to answer a comment that one of our friends from a significant agency said that it is time to change course, that we do hear, we believe that there is a strong obligation to inform people about risks, that that has not been done adequately, that while we are tempted to answer the question two, we don't have quite enough information yet to comment on policy. There are different groups, the pre-1990, the 1990 to 1997 folks, the high users. We may have policy things you want to say about that, but we feel we need more information about basic statistics, economics, law, precis of what others have said. We do have information. It is probably not in the most usable form quite yet about our predecessors on that matter and that we would like to hear some more, too, about how risk is communicated, what options are out there so that while we are tempted to say something about question two in terms of the looking forward, looking back and how that might go, we are not quite ready to say that yet. We would like another meeting to hear from a few more individuals, some more information, some more time to read through and digest what was sent to you before this.

Is that a point of consensus?

The reason I put it that way is I want to give the agencies optimism that if we hold another meeting relatively soon, July, August, September, somewhere in there that we will try to frame a policy response in the spirit of Marion's division between policy, program and implementation that really does go to these questions but that we also want to reserve the right to try to come up with generalizable principles in the spirit of Chris' comment about consistency, about under burden, about protecting the safety of the blood supply and that we may have things to say at the high level of principle in the context of policy so that we may say things that are to come back to Dr. Berra's comment generalizable out to other issues about blood safety. Is that a third area where we can agree?

All right, we will look at that much agreement, unless there are people waiting to go to the bathroom. So, what I would propose now is that we take a break; however, that is the good news. The bad news is 15 minutes, and I mean 15 minutes on this one, and I am going to respectfully ask that our visitors who are coming to talk to us about CJD disease try to keep their remarks individually to 20 minutes each because I want to keep us right on schedule, and I want to make sure they have time to talk to the panel and to the audience.

So, if you could work on that during the break, maybe pare it down a bit, that would be very helpful. So, we will get back at eleven-fifteen.

(Brief recess.)

PARTICIPANT: CJD disease that has newly emerged is a problem perhaps with the blood supply and some of the issues that come up around that. We are going to hear a bit about that from two speakers who, again, I will remind I have asked to try to shorten their remarks a little bit so we can be done on the button in this session by twelve, and I want to remind the Committee --

PARTICIPANT: Could I have a little more flexibility in my talk?

PARTICIPANT: Okay. We will try to eat lunch today in the same conference room at the cafeteria. What is the name of that room, Paul, do you remember?

PARTICIPANT: Yes, Bethesda.

PARTICIPANT: Bethesda?

PARTICIPANT: Bethesda Room.

PARTICIPANT: That is pleasant.

PARTICIPANT: It is. We go in the same door and it is sort of slightly to the left.

PARTICIPANT: In the door, kind of off to -- in the main door of the cafeteria where we were yesterday down in the basement, the front door. You will see it is a little bit off to the left. There is a room back there, and we are headed there.

One other thing I asked Paul to do which he will be sending around is just a piece of paper, if you can write legibly if you have e-mail. I think we have asked you for your phone numbers, but I would like to have Committee members supply us with e-mail if they have that. It is not inconceivable as a gift to the government of the United States that the University of Pennsylvania could create a list of Committee members, and so, if you have e-mail or have home e-mail, if you could write that very legibly on the piece of paper that will come around, I would really like to see --

(End Tape 6, Side A.)

-- everybody because one way to try to put the transcripts of this meeting in your hands is to put it up on a Web site, and that might be something we could do in the modern era, inspired by Dr. Zuck's talk on computers.

So, I will talk with Paul about whether that is possible. We can get information out pretty fast and then if anybody else wants to see it, go to the Web site and see it there.

Without further ado, Dr. Brown?

DR. BROWN: Thank you very much. Is there some hidden reason why the members of the Committee have backed off from the podium?

(Laughter.)

PARTICIPANT: They don't know about CJD that much.

DR. BROWN: Creutzfeldt-Jakob disease is a fatal, subacute neurologic degenerative disease. It usually runs its clinical course in about 4 to 6 months, unlike Alzheimer's disease which is a several-year course. Creutzfeldt-Jakob disease really does have a much more vicious clinical evolution, and so, a person who becomes sick today is usually dead within 3 or 4 months. There are no recoveries.

The reason we include Creutzfeldt-Jakob disease i what we call the transmissible spongiform encephalopathies is shown on the first slide.

Do I govern that?

PARTICIPANT: Yes.

DR. BROWN: This is an H&E section of the brain from a patient with Creutzfeldt-Jakob disease and if that is not persuasive enough I think you can clearly see the vacuolization and spongy look but some patients with this disease go on to this stage in which there is essentially no brain left.

So, this is why it is called spongiform encephalopathy. We don't yet know precisely what causes this group of diseases. By that I mean we have not defined a physical particle with certainty in this as one might have, for example, defined a physical particle of polio, but for purposes of this meeting, you may still consider Creutzfeldt-Jakob disease as a virus disease, even if the causative agent turns out to be the evil prion protein.

We know a great deal about what kills these agents or this agent. We know a great deal about what does not, but the causative agent behaves in many, many ways like a virus, and again, in the context of this conference that includes a viremia or it probably includes a viremia, that is to elaborate on that the target organ which as you see is the brain of this disease is not the only organ that contains infectivity.

Infectivity in patients who die from this disease can be found in various parts of the body, the spleen, the liver, the kidney, the lung, the heart and notably in the blood.

A number of efforts over the past 20 years have been directed towards determining how often the infectious agent can be recovered from blood, and to some degree at what level of magnitude.

About 15 different experiments have been conducted on animal models of one or another spongiform encephalopathy, sometimes Creutzfeldt-Jakob disease adapted to a rodent, such as a mouse, more often an analogous disease called scrapie, a natural disease of sheep and goats, also, which is adapted to rodents and the most widely used model is a hamster adapted rodent model.

The efforts to detect infectivity in blood can be divided into two areas. One is the experimental models as I have just mentioned, but the second area is the effort to isolate infectivity or detect infectivity in the blood of humans themselves.

Over the past, as I say, 20 years about 15 different experiments have been conducted on experimental models, and a fair number of those have been successful in the sense that infectivity was detected in the blood.

In the aggregate those experiments suggest two or three important things. One, infectivity can be found in the blood irregularly; two, the level of infectivity found in the blood is very low, vis-a-vis brain, for example, in which the level of infectivity may be 100 to 100 million. Well, let us go into logs, 10 to the 8th to 10 to the 9th infectious units per gram of tissue. Blood from the same animal might have a level of infectivity of less than 10 infectious units or 1 log of infectivity.

So, like other peripheral organs in the body, blood when it does contain infectivity contains only very low levels.

The third important feature is that infectivity has been detected in blood not only during the clinical phase of disease in these experimental animals but during the incubation period. The exact timing of that infectivity and its occurrence during the incubation period is not consistent.

In one experiment it began fairly early on, and then decreased. In another experiment it was found at irregular intervals throughout the incubation period and in one study which I think is probably the best study it appeared about halfway through the incubation period with increasing titers to the clinical phase.

We are talking incubation periods here of somewhere between 3 months and 6 months usually. So, there are long incubation periods. To give you an illustration in the mouse infected with Creutzfeldt-Jakob disease the incubation period when you inoculate the mouse intracerebrally which is the optimal method of inoculation the incubation period from the point of inoculation to the onset of clinical disease is about 115 days, about 4 months.

The final point that has come out of the animal studies is that it appears that this infectious agent is associated with the buffy coat component of the blood. That remains to be absolute verified but in most of the studies that have been done when infectivity has been detected, it has been detected in the buffy coat.

Far fewer studies have been done in humans with Creutzfeldt-Jakob disease. There are four experiments in which infectivity was detected. Dr. Rohrer I think will probably give you a few details about that. Each of these studies has some caveats attached to it and if there were only one such study we would probably say that we are not really very sure that this is correct.

Four studies give it a little more weight. They were done in four independent laboratories, but nonetheless you should not, I think, accept just as given wisdom that infectivity has been shown conclusively to be present in the blood of humans with these diseases.

One reason for saying that is in our own laboratory at the National Institutes of Health here using primates as the assay animal, that is to say inoculating blood from humans clinically ill with Creutzfeldt-Jakob disease into the brains of either monkeys or chimpanzees, and I add here that in the only experiment that has ever been done in animals using the intravenous route rather that the intracerebral route the results were negative.

We, here in our laboratory have never succeeded in isolating the infectious agent of any of these diseases from humans, and that, as I say includes three patients with CJD whose blood was transfused into three different chimpanzees, and these chimpanzees have been followed for 15 years. So, if the titer is low as we would expect that still is sufficient time for these chimpanzees to have died from the disease.

What I want to, I guess emphasize here is that we are still not certain, in fact, that there is infectivity in the blood of humans with CJD. It will not be a surprise one way or the other. I rather personally imagine that from time to time there is infectivity in the blood and if that is correct, of course, that is the reason we are here. If that is incorrect, then we need no longer discuss the issue.

What then is the interest? The interest is twofold or I can say that we should approach this in two different ways. First, is there any evidence that this disease has ever been transmitted in fact in humans through blood or blood products, and that is a subject that Dr. Shermberger will address a little bit later on.

The other question is forget whether it ever has been transmitted, is there any potential for its being transmitted and for this we go to the laboratory.

Rather than simply repeat what has been done in the past, a couple of years ago we decided to try to push forward just a bit and examine the infectivity in blood, its distribution in blood when we put into it a very high dose of infectivity, in other words, to conduct a validation study, spiking human blood with a high dose of infectivity; where does it go, and for that we used the scrapie hamster model because we wanted as high a dose input as we could get, and the highest level of infectivity in any of the diseases that we know of is in this model.

So, we were able to put into the blood a sufficient amount of infectivity in a sufficiently small volume to achieve an input of whole blood at the level of about 7 logs of infectivity per ml of blood. That is a lot of infectivity, and what we actually did was to take the blood of a healthy normal Red Cross donor, 50 ml of it and add to it 1 ml that contained this amount of infectivity and then the blood was separated according to standard commercial protocol and following that the plasma or a portion of the plasma was fractionated according to the currently-used modification of the cone(?) technique into fractions that are the cryoprecipitate, fraction 123, fraction 41, 44 and finally fraction 5.

The results of that experiment are shown in the next slide.

That came to us as a bit of a rude surprise because using under the conditions of this experiment, and I should add here that you might well ask, "Well, in what form did you add this infectivity? Is it brain homogenate?" No, we didn't. We tried to imitate as much as possible or approach the idea that this infectivity is, in fact cell associated. So, what was put into the blood in this particular experiment was a trypsinized washed suspension of brain cells from the infected hamster, hoping that intact cells which they were at the level of 99 plus percent would partition much the way the cellular element in normal blood does.

That is arguable. As you will see from our second experiment, it probably was a correct assumption. So, we were surprised that there was so much infectivity spilling over into the red cell component and the plasma component. In fact, there is no significant difference in the level of infectivity here between the white cell and the red cell component. There is a significant level of difference between plasma and white cell, red cell whole blood, but it is not as you can see a very major drop.

Yes?

PARTICIPANT: (Inaudible) element in this, is that --

DR. BROWN: In the sense that if we subjected plasma to dialysis we might get rid of it?

PARTICIPANT: Is the infectivity changed?

DR. BROWN: We did not dialyze the blood because of course that is not done in practice. These kinds of experiments now lead us to envision further experiments in an effort to see the level in plasma drop to nothing ideally, and there are a number of approaches we might use on that. In any case in this experiment there was a very high contamination of plasma at the level close to 10 to the 6th, somewhere between 10 to the 5 and 10 to the 6. Given that much infectivity in plasma, the first two cone fractionation steps were almost as, well, exactly at the same level of infectivity as plasma, substantial drops down in the 41, 44 specimen and in the 5 specimen, and you know better than I, but in case anyone in the audience does not, cryoprecipitate is the major or has been the major source of Factor 8. Fraction 1, plus 2, plus 3 is the major source of immunoglobulins. Fraction 41 and 44 have several components in them, none of which is perhaps as important from a numerical point of view as the prion 123, and fraction 5 is the major source of albumin.

Yes?

PARTICIPANT: Infectivity was demonstrating by injecting with fractions into the brains of the test animals?

DR. BROWN: That is correct. Again, this is an effort to get the optimal number of transmissions. All of this was done; the assay was conducted, the specimens in the following way. Each specimen was inoculated intracerebrally into healthy hamsters. So, we have no species barrier nor do we have what you would call a real-life situation because of course, no therapeutic product is administered in this way.

We did this experiment in spite of hoots of disbelief in its validity because we did want to see where the distribution was, and we didn't want to start with a very low dose only to discover that we didn't have anything in any of the fractions opening us to criticism that we hadn't proved anything. We haven't certainly proved anything with respect to the human real-life situation in this. What we have shown is that under conditions in which severation and fractionation were done like it is done in commerce that this is what you would get, if you put in 7 logs of infectivity.

So, what is the, not alternative but the next step? And the second experiment we did was to try to get that much closer to a real-life situation and because we are open to criticism or the experiment, I think is open to criticism that what we put in, namely a suspension of cells that were not white cells, that is to say it was an extraneous spike, instead of trying to bracket the underside or low dose of input and infectivity by simply diluting this brain material and doing the same experiment with a very dilute input suspension which would have given us perhaps a level of one to two, we really wanted endogenous infectivity, inherent infectivity because that is what the situation is in humans, and so, we chose not to do that.

We chose to take a mouse model of Creutzfeldt-Jakob disease. We inoculated several hundred mice with Creutzfeldt-Jakob disease agent intracerebrally and at the point when the mice became ill, about 115 days later we exsanguinated them and pooled their blood and then we did exactly the same thing we did in this experiment.

We separated and fractionated according to commercial protocols. The basis for doing this is an experiment conducted in our laboratory many years ago by a visiting fellow in which using exactly the same mouse model he was interested in a different goal but in the course of the experiment he did take serial specimens of blood, spleen and brain and blood actually in this case was not whole blood. It was buffy coat, and here is the number of weeks after his inoculation, and this is the infectivity of each specimen, and as is generally true with these diseases in the experimental situation, the earliest rise occurs peripherally in spleen in spite of the fact, interestingly enough that the inoculation is done intracerebrally.

The brain infectivity rises more or less linearly, well, in a log order until the death of the animal, and here as I mentioned there is no infectivity at 6 or 9, but it begins to appear somewhere in this area about halfway through the incubation period with on at least two points increasing titers such that by 18 weeks the infectivity was about 1-1/2 logs. Again, I will remind you that in this experiment it is not whole blood that was being looked at but buffy coat.

Based on this we decided to do this second experiment that we did by sacrificing the mice right at about this point here. This represents letting the mice get ill and die. This is basically there. The mice usually stay alive for 2 or 3 weeks following the onset of illness in this model.

To show you that it was fairly comparable the estimated titers in brain, spleen and buffy coat at 16 weeks from the first experiment were 5-1/2 logs, 1-1/2 logs in spleen and about 1 log in buffy coat. Our figures equally estimated are about 5 logs, 2 logs and 1 log. So, we did duplicate Curoto's(?) work, and this is very nice because assuming that this experimental model will be useful, it looks like it is very reproducible for future experiments.

Based on the hamster experiment we would have expected to find, if we found infectivity in plasma, we would also have expected to find it in the cryoprecipitate and in fraction 123 and probably not in fraction 41, 44 or 5, and that in fact is precisely what happened.

I give this busy table because this is an experiment which is not quite complete, and we are dealing with very low titers, and if I had had time to simplify this, I would have done so.

Here are the specimens that were assayed, whole blood, red cells, white cell platelet fraction or component, plasma, cryoprecipitate 123, 44, 41, 44 and fraction 5. We used 75 mice for this particular experiment. We had three pools of blood and we retained two of them without having used them, but one we chose to use, and the amount of blood that we pooled was 45 ml. Of this we had about 19 ml red cells, 3-1/2 of white cell platelets, and this is considerably more than you would ordinarily have you bagged it, but we wanted to get out on either side of the buffy coat to a substantial degree so that we didn't run the risk of missing any, and so, more importantly because we didn't want to contaminate the plasma with the buffy coat and what you see here is the proportion of the specimen inoculated. We may or may not get back to that when questions arise.

We had to dilute these specimens because there was a fair amount of toxicity of undiluted specimens, but we generally did not have to dilute them more than 1 to 5. Where you see higher dilutions it was where we were expecting possibly higher titers and we wanted to be sure that we didn't miss them, and as you can see here in total we inoculated a lot of animals. We inoculated far more animals than you would usually use in a virus experiment because our purpose, we knew we were going to have very low levels, and we knew therefore, if we had a level and in fact it turned out to be correct; let us just this. Plasma, 4 positive animals amongst over 130 inoculated. Well, if we had only inoculated what is usually done, six animals we might very well have had no positives and missed the whole show. So, the setup of this kind of an experiment really does require large numbers of animals to demonstrate any infectivity, and what you see is that the white cell platelet component did have a transmission. Plasma had several transmissions. Cryoprecipitate had several transmissions, and even one transmission at a 1-to-10 dilution, that is, or a 1-to-40 dilution and fraction 123 had two transmissions.

I have not put percentages up here because they are really kind of meaningless and I also want to point out to you that these untested or negative animals I haven't broken that down, but many, in many cases these are untested animals, untested in the sense that we are not satisfied just that the animal died with something that looked like spongiform encephalopathy.

In the mouse that has this disease you cannot count on that. So, every animal that has died has been or will be examined by using Western blot analyses of brain tissue which will either be positive or negative for the presence of the evil protein, and that is pathognomonic. If it is there, the animal has died from CJD. If it is not there, he died from something else.

Most of these animals are still alive or were alive until they were sacrificed. We ran this experiment for 14 months at which time we decided that it was time to conclude the experiment, and we sacrificed all the animals that were still alive and healthy.

We will also look at them for the presence or absence of protein. In one case we would have an LD titer, lethal dose titer. In the case where we look at everything we could expand it to an infectious dose titer, but the results will be the same.

Yes?

PARTICIPANT: How do you demonstrate the prion protein presence?

DR. BROWN: The protein is extracted from brain tissue as it has been for, oh, I guess 10 years now. It is a series of, often it is a series of centrifugations, exposure to high-salt detergents and finally, some proteinase K which digests everything except this proteinase resistant protein. That is then put through an electrophoretic gel and transferred to nitrocellulose paper and an antibody to that protein is used to detect it. In this case, it is an antibody against mouse prion protein. It is a very sensitive test. It is nowhere near as sensitive as a bioassay, but if it is there, there is no question about what the animal has died from.

If you do a little arithmetic, well, first of all, I guess this pair of experiments is rather nice because the results really converge. They are consistent with each other, and it tells us that even when the infectivity is endogenous using currently-practiced method of blood separation and plasma fractionation that there is some residual infectivity in the first two cone fractions, very little but some, and if you do a little arithmetic which I won't do here but based on the amount of the specimen, on a proportion of the specimen inoculated, on the dilution you can come up with a final little note that in the circulating blood about one in six mice if everything were distributed at random independently, about one mouse in six that had been infected had a single infectious unit circulating in their blood. So, this is the kind of level of infectivity we are talking about right at the threshold of detection.

However, an infectious unit is defined functionally. It is whatever number of particles or whatever it takes to cause an infection, and one infectious unit is going to cause an infection, and so, it is something that we need to continue I think to be aware of. It is not a problem that is going to go away, and these experiments tell us that there is the potential for infectivity to be present in not only whole blood but in plasma fractions as you see.

We are not saying from these experiments that that happens. We are saying that there is a potential.

Thank you.

PARTICIPANT: Let us go quickly just to see if there are any questions for Dr. Brown from the Committee members?

DR. BROWN: It was either very boring or very lucid.

PARTICIPANT: It was terrific. My question is you said that you know what things kill and what things don't kill the infectious agent. What are they, and do any of them pertain to effects of viral inactivation that is done for some (inaudible).

DR. BROWN: Alas, no. If we are talking about things that are highly destructive, this is an extraordinarily resistant infectious agent, and the kinds of things that are most effective to inactivate it are things like one normal sodium hydroxide, undiluted bleach, autoclaving, saturated urea. Aren't you sorry you asked? It is, most of the things that inactivate these agents are incompatible with biological activity of a healthy sort.

PARTICIPANT: Dr. Brown, you said that the agent was in the buffy coat. Is it free or is there evidence that it is actually phagocytized by some mononuclear cells for example?

DR. BROWN: I think these experiments, and Dr. Rohrer is going to show you some experiments next that open the question that casts some doubt on the idea that they are in fact linked to white cells. Even if they were, I don't think I could answer your question. We haven't done enough. The conditions of this experiment were designed to imitate the commercial situation. There are much more precise ways that we can get at the question of exactly where this is. If it is in plasma, is it because it is in fragments or is it soluble? We can do sizing experiments, all kinds of things. As I said, this mouse experiment which is a reproducible model now allows us to really examine in detail some of the questions that obviously are occurring to you and certainly occurred to us, things like white cell exclusion methods, filtration, higher centrifugation methods.

I mean if these really are white-cell associated, then we are going to have to step up the centrifugation speeds and maybe put a white cell exclusion step in there. I mean if we can eliminate risks just by simply raising the centrifugation speed from 6000 to 12,000 I cannot think of a more wonderful, simple way to just pack up and go home and say that we don't have to worry about it anymore.

PARTICIPANT: Let us do two more.

Dr. Chamberlain?

DR. CHAMBERLAIN: The tables you just presented represented the results of intracerebral inoculation?

DR. BROWN: In both cases.

DR. CHAMBERLAIN: In both cases? Can you tell us if there are any data (inaudible) that inoculation would occur or (inaudible) intravenously injected?

DR. BROWN: Sure, we expect to do that as one of, God, I guess 20 different kinds of things we are going to do, but one of them would certainly be parallel, duplicate experiments using some sort of parenteral route and hopefully it would be a transfusion route. Dr.Rohrer has already established the feasibility of using hamsters in transfusion experiments. So, we absolutely want to do that.

PARTICIPANT: Dr. Brown, the epidemiology of the patients suggests that we are looking at issues, that there is an oral route. Do you think --

DR. BROWN: You are referring to the possibility that the new variant that has been described is because of ingestion? Right, okay. Crewell also suggests that even more, didn't prove it, though.

PARTICIPANT: If this particular material were to be fed to animals would the infection (inaudible)?

DR. BROWN: That is to say --

PARTICIPANT: Rather than the intracellular route or --

DR. BROWN: Right. I don't know if Bob is going to show this. There is a whole hierarchy of efficacy, and if -- are you going to show that slide, Bob? Did you bring that?

PARTICIPANT: No.

DR. BROWN: But if you have got --

PARTICIPANT: We are supposed to keep (inaudible).

(Laughter.)

DR. BROWN: Right. Oral is the least efficient route, so that if you can, for example, detect by intracerebral inoculation 10, 100 or maybe even 1000 infectious units, you might not detect any by the oral route.

PARTICIPANT: All right, let me thank Dr. Brown for sharing his enthusiasm for the exploration of this dread agent with us and we will ask Dr. Rohrer to come right up and we will continue on.

DR. ROHRER: There is one more experiment in this complex of experiments to be discussed, and we will get to that in a moment and that is an attempt to look at whether or not there is any risk of actually transfusing this infectivity causing disease by the transfusion route, if in fact there was infectivity associated with blood, but to introduce this subject I want to address that topic first in some detail because it is not clear to me that we really have truly established that there is infectivity in blood, and I think that is still one of the most important issues before us, and it needs to be investigated in a more comprehensive way than it has been done so far.

If I can have the first overhead?

The evidence for infectivity in human blood comes from these four papers, and that is it, and as you can see in each case it involves transmitting human blood by the IC route into a rodent of one sort or another, the guinea pig and hamsters by the Manulides(?) and mice here, mice here and hamsters down here.

This is a very, very surprising result even if there was infectivity in the blood, and I want to share with you why some of us are so incredulous about these claims.

Next?

There is a well-known phenomenon in the TSE experimental work of the species barrier and what that consists of is that when you try to go from one species to another, humans, for example, into rodents the efficiency of the transmission is reduced, typically by at least 10 to the 3rd or more reduction in titer, i.e., if you took a hamster-adapted scrapie model and inoculated it into a mouse you would find that the titer had been reduced by a factor of 1000 between doing the same inoculation in the hamster.

Actually I picked a poor choice there. It is much higher than that in the hamster, but between say mouse and hamster it is 1000-fold reduction, and when you consider humans, CJD is barely transmissible to rodents even when the highest titer tissue, i.e., brain tissue is what is being inoculated, and the titer in CJD brains are probably 10 to the 7th or thereabouts, more or less. We don't have a very accurate titer because, of course, we could never do this experiment in humans, but such as we know it from primate transmissions it is in this range of thereabouts.

TSE blood titers on the other hand as Paul Brown has just told you are very, very low, less than one infectious dose, 50 per 50 microliters of inoculum. That comes out to 20 infectious doses per ml of blood.

So, blood should be about 10-million-fold less transmissible than brain. If brain is barely transmissible into rodents and when those types of experiments are done you can inoculate 10 hamsters with an undiluted or a 10 percent brain homogenate and only a few of them will get it; so you are working at the limits of transmissibility, how can blood be transmissible when its titer is so much lower?

Next?

Moreover this is a brief summary of the work that has been done at NIH trying to transmit sporadic CJD into primates which should be the most susceptible host for the human disease, and there has been no instance of a transmission including these transfusion-type experiments which Dr. Brown mentioned a moment ago.

Next?

Then what --

PARTICIPANT: What is the observation period for those?

DR. ROHRER: It varies, but I think Dr. Brown just mentioned that some of those chimps have been around for 15 years, and I don't know about the monkey experiments. Actually, we would have to ask him, and he would probably have to look it up.

Then there is one more control on this family of attempts, and these are experiments that I have just talked about. Let us look down here. It turns out that the Manulides, at least have done another series of experiments attempting to demonstrate because it is their hypothesis that Alzheimer's disease may be a transmissible disease, and when they have done these types of experiments using buffy coat from familiar Alzheimer's disease, relatives of these patients and even normal patients, normal people from their own laboratory and others they are getting transmission rates of a Creutzfeldt-Jakob-like disease into the hamster of 26 out of 30 in this publication right here.

From my point of view that is a control on their methods, and there is something wrong in their laboratory if they are getting this kind of background for normal transmissions.

Here is an attempt by Godek at the NIH Laboratory to reproduce this work with zero transmissions, the same type of experiment.

This calls into question in my mind the validity of the transmissions that have been claimed so far from humans to rodents.

Yes?

PARTICIPANT: If you inject human autopsy brain into these rodents do they claim that they are getting infection that way from Alzheimer's disease patients?

DR. ROHRER: Actually they have not done that experiment. Their idea is that this is in the blood, and they have pursued that avenue, but the important control here is that if you put Creutzfeldt-Jakob disease brain into rodents, yes, you can get transmission, but it is a very, very inefficient process.

PARTICIPANT: Was the question have Alzheimer's brains transmitted disease?

DR. ROHRER: He said, "Have the Manulides looked at Alzheimer's in brains?"

PARTICIPANT: The Manulides people have not, but we have to the tune of about 110 attempts. Zero results.

DR. ROHRER: I am sorry. I should have added that, that lots of other people have looked, the NIH Lab in particular, but others as well have tried the brain to monkeys, brain-to-rodent route and there has never been a credible transmission.

So the conclusion is that it has yet to be established that there is, in fact, a viremia in Creutzfeldt-Jakob disease, with the caveat that we do not have a very sensitive method for looking for it.

Next?

It is still not proven, however. Now, let us look at the rodent experiments from the same perspective. This is a summary which I thought Dr. Brown was going to present. So, I can cover it quickly, but let me just make a couple of points. Natural scrapie up here, the few times that that has been looked at, 0 out of 18, 0 out of 3. Experimental scrapie, this was a goat-to-goat transmission, for example, sheep-to-mouse transmissions here, rat-to-rat transmissions, and this is the route. This is blood or serum or blood clot, for example, in this case has been taken and inoculated intracerebrally. The goal here is to see is there any infectivity in these materials. So, you take the most efficient route of inoculation which is intracerebral to look, and the thing to keep in mind there is you can only put about 30 microliters of sample into the brains of these small rodents, but here you can see that in the natural disease zero and variable results here. The most important experiments are these here and here which are summarized a little more thoroughly on the next slide where we have seen some very definite evidence of viremia, and these are important because it was a consistent finding.

It occurred, this is the duration of the infection here, clinical disease here. This is one of the models which is CJD adapted to guinea pigs and you can see it occurred where it was looked at. The solid circles represent positive transmissions where an inoculation took place. This is a negative where an inoculation took place.

So, looking over this period of time it looks as if there has been a viremia throughout the preclinical as well as the clinical period of the disease. This is also seen in the mouse experiment with CJD-adapted mouse that Dr. Brown just mentioned.

These were the actual time points that were looked at, and there is another measure of potential titer here which the incubation time, and the incubation time slowly went down here. It was very, very long in all of these transmissions, very, very long here, very, very long here. That indicates that the titer was very, very low.

Here in contrast though is an experiment from Ecklund in which this actually represents two experiments of this size in which they found nothing over the whole clinical period of analysis after scrapie in their laboratory, but here is the hamster model again. These were after IP inoculations, and we see a fairly consistent finding of viremia in the hamster though here it seems to be dying off towards clinical disease and here the experiments were not carried all the way out to this period.

These experiments, all the experimental viremias where positive transmissions have occurred have one thing in common which makes me nervous about them. Very high titers of inoculum were used to induce the infection in the donor animals and very small amounts of infectivity were recovered later in the blood.

Next?

To summarize, very low titers when it is found. It is present throughout the infection, however, and it has been seen in several host agent strain combinations, and there is this possibility that it may be enriched in the buffy coat because the buffy coat was isolated. There is a practical reason for doing that. You can take 2 mls of blood equivalent concentrated into a buffy coat and inoculate that into one animal. To inoculate those whole 2 mls would require 40 or more animals.

Next?

But there is this potential artefact. High-titer inoculum, very low-titer recovery from the blood, parts per 100,000, parts per 10 million in some of these experiments, and what concerns me is that because these agents are so extremely stable there is the potential that what is being done here is that people are re-isolating the inoculum in blood, and that leaves the question, does the viremia actually occur in natural disease?

Next?

I think that is just restated there. So, let us go on.

So, with these caveats in mind --

(End Tape 6, Side B.)

-- these in an indisputable way, nevertheless, we decided to go on and do what we could in terms of an experiment and by way of background interest in this subject increased dramatically about a year and 4 or 5 months ago when people began to realize that Creutzfeldt donors were present in the donor community, Creutzfeldt-affected people were present in the donor community, and those of us who had an opportunity to respond to those concerns did what we could at that time.

These are experiments. The experiments, I am going to describe right here are opportunistic in the sense that we had a bunch of animals that were coming down at that moment which we could use as donors. We used them. We developed this transfusion model. We used them. The numbers are very limited. That is because it takes a long time for this disease to develop when we are working at these low titers, and this is what I can offer you right now.

Other experiments are in progress and hopefully we will know more in the ensuing years, but I do have to warn you that generating data in this system is slow because we are pushing it to the limits of its ability to measure.

Transfusion of TSE-infected blood. Infectivity is spread neurally. So, this is a disease like rabies. There is no reason to expect that blood plays any role in the pathogenesis of this disease. There is no reason to -- if there is infectivity in the blood it may be there in some dead-end way, and one of the things that occurred to me that if there is infectivity in the blood it may be infectivity that is in the process of being cleared and eliminated in some way or it is sequestered there, and it is relatively inactive, and if you move it from one animal to another nothing really will happen.

On the other hand, the IV route of inoculation of rodents anyway is one of the most efficient routes. It is only 10-fold less efficient than the IC route and that is not so reassuring.

Next?

That is inoculating brain homogenate, not inoculating blood. So, these are the experiments we did. We wanted to use the hamster, if possible. The hamster is the highest titer model known for these agents. So, it is kind of a worst-case situation. We have the best possibility of seeing something in it.

The measurements can be made faster than they can be made in the mouse or any other animal, and so there are lots of advantages. One of the disadvantages of the hamster is it does not have a tail.

That is a disadvantage for blood work. Nevertheless, this is the way we did these experiments. We collected the blood under metathane(?) anesthesia from the open chest by cardiac puncture into citrate, and we have gotten quite good at this and basically, and we have gotten a lot better since the experiments that I am going to show you here. Our goal currently is we throw away the animal if we cannot get 5 mls of blood because we want to use 2 mls for transfusion, 2 mls for buffy coat using a dextran method and for an IC inoculation and then 1 ml for whole blood inoculation.

This has to happen immediately after inoculation. This can happen later, and this can happen later because these are IC inoculations here. This is a live blood inoculation.

Next?

We prepared the recipient under metathane anesthesia with the help of a pediatric surgeon. We developed a surgery. It is essentially bloodless for exposing the carotid. We put ligatures on both sides of a carotid, cannulate it. We removed 2 mls of normal blood, transfuse in 2 mls of the blood from the infected donor that we have just collected. We ligate the carotid on both sides, tie it off, suture and let the animal recover.

Next?

This is the summary of what I can show you right now, and this experiment is still in progress, but we have seen a transfusion transmission. So, you should be aware of it. These animals are divided into two groups. There are animals whom the donors received high-dose inoculum. So, these animals are subject to this caveat that I just mentioned to you about the possibility that we are recovering the inoculum in the blood of these animals.

We only had three of these that ended up surviving, and in this group we had an animal at 261 days come down with scrapie.

Subsequently we inoculated the whole blood which we had stored from this animal and 156 to 160 days later we have seen three cases. This is happening as I speak. I had to change these slides last night, not for this group but on the next table that I will show you.

So, this is quite early in the infection period. So, we may see quite a bit more of this before a year is up.

Down here are the animals, this is another cohort of animals which were given a limiting dose of inoculum. These animals received at most 1 to 10 infectious units of inoculum. They were at the end point of an end-point dilution titration. Therefore we have gotten around this question of contamination by the inoculum with this cohort, and so far we have seen no transmissions in this group. We did see a death here. This animal died without symptoms. We reinoculated the brain of that animal into another because that is a more sensitive test to see whether it was harboring infectivity or not, but that is down the road whether we will know that or not. None of these whole blood inoculations have come down from that animal.

Next?

Paul, could we go back to that? I wanted to make one more point there. This experiment would have told us something about this caveat if all of these animals in this group had come down and none of these animals in this group came down. The fact that we only got one, and we got none here, we don't have a statistic. We are going to have to scale this experiment up in order to answer this question about this potential artefact, and in fact, we have done that. We are in the process now of putting on 50 transfusions from this group, 50 transfusions from that group, doing the buffy coats for each one of those, and we will do a certain number of the whole bloods.

The whole bloods are expensive to do because we can only put in 50 micrometers per animal, and as a consequence to inoculate a milliliter of blood requires 20 animals. That is why we have got 20 animals. That represents a millimeter.

Next?

I am almost done. We weren't sure we would get viremia by the IC route because one of those experiments I showed you earlier indicated that by clinical disease there wasn't any. We saw that we did. There is infectivity in those bloods, and so, it does extend to that period. To cover ourselves, however, we also did a series of IP inoculations and collected preclinical animals at 40 days into the infection. That is because both the Procary(?) and Durnier(?) experiment had seen infectivity at that period and also clinical cases. One of those experiments had not.

Again, we did transfusions. Where we had enough blood left over we did buffy coats, and we inoculated these whole bloods, the ones that are indicated here by the little circles. So far we have seen nothing in the transfusion group. We have had some deaths, however, and again, we are looking at those animals by reinoculation to see whether they actually had any infectivity in them, and we have had one buffy coat come down. That is surprising. I was expecting a lot more than that, and it is especially surprising that we have a whole blood coming down in an instance where the buffy coat didn't.

This inoculation right here represented 2 mls of blood. This inoculation right here represents 50 microliters of blood. Again, this is early in the whole blood inoculations, and we could see more animals come down over the next half year.

Next?

In conclusion here, the TSE diseases can be transmitted by transfusion. We saw one out of 13 animals that had been observed for greater than 400 days. That is more like 430 days now, one of 23 animals observed for, this is the same animal, but this is just putting the incubation time caveat on this. The donor for the animal that transmitted had received a high dose inoculum, and there has been no infection in blood or by transfusion from donors that received limiting dose inoculum, and an instance of transmission from -- this is this case where we got a buffy coat transmission, but didn't see it from blood. That is surprising to us, and we have demonstrated for the purposes of future work that the IC inoculation does result in the viremia and that the viremia extends to the clinical phase even after IP inoculation. That is a practical consideration for designing future experiments.

Next?

And in summary it is not proven that TSE viremias exist in natural disease. If they exist the titers are very low. Nevertheless they are transmissible by transfusion. Low levels of infectivity can be expected in plasma in these fractions. That is the take-home from Dr. Brown's talk, and another way of looking at that data from the experiments that Dr. Brown presented is that if you consider albumin there was a great reduction in the infectivity between what was introduced in the hamster experiment and what was found in albumin, and there is also reassurance in that because if we are talking about these extremely low levels of exposure in the first place it may not take a great deal of reduction to remove this stuff from blood, and let us stop with that.

PARTICIPANT: We have got time for one or two questions for Dr.Rohrer.

PARTICIPANT: Several weeks ago you spoke at the Blood Safety Screening Conference. There was a discussion after that presentation about the theory that --

DR. ROHRER: Maybe you shouldn't go there. Do you want to see the rest of this?

PARTICIPANT: It is interesting, the theory that there was intergenerational expansion of the inoculum with the possibility that --

DR. ROHRER: If I can have another 5 minutes, I will present a couple of issues which I feel like this panel in particular should consider with respect to blood, and I think I can get through that in just a few minutes.

I didn't plant that question, Mr. Chairman. I would just like to say a few remarks which I hope will add some perspective to the issue of Creutzfeldt-Jakob disease and its relationship to blood and blood transfusions.

What is driving concern in this area in my mind is the comparison with AIDS, and these are really very different situations. AIDS was a newly emergent disease in the eighties. It appears in blood in high titers. It is a blood-borne disease. This is part of its pathogenesis, and we do have effective screening methods now for HIV which have been very good at protecting us from it.

In contrast Creutzfeldt-Jakob disease has been around at least 100 years, and it is probably an ancient disease. It has probably been with us forever. It is very low titer by comparison with AIDS. It is a central nervous system disease. There is no role in the pathogenesis, and there is no way to test preclinical individuals for this disease, and the point I want to make is that the blood supply has been exposed to CJD since the very first transfusion was done because we have never -- it has been there, and we have had no way to eliminate it. We still don't have any way to eliminate it.

There is as a consequence an unquantifiable and irreducible risk of exposure, not necessarily infection but exposure to CJD-donated blood through blood and blood products, but there always has been that risk.

Next?

Moreover this exposure is larger than people think it is. The incidence of Creutzfeldt-Jakob disease in our population is about one per million per year. That is worldwide, but the incidence of CJD infection is that incidence rate for clinical disease times the incubation time, and this disease we know that incubation time can be up to 40 years from kuru and some of the human growth hormone transmissions.

Next?

As a consequence, the incidence in a population of 240 million, that should be 270, is one per million, up to 40-year incubation period. There should be 250 cases per year of clinical disease in our population, and that is just about right. That is what we see, but there could be up to 10,000 carriers of this disease. If 10 percent of the population donates blood, there should be out of 24 million donors, we should be seeing 25 clinical cases a year among donors. We are only seeing five or six. There could be as many as 1000 carriers.

Next?

From the standpoint of blood pools it makes sense to throw away components when you have identified a person that you know was a Creutzfeldt donor, but at the level of pools I don't feel that you can differentiate pools on the basis of occasionally identifying CJD.

Most exposures from undiagnosed carriers and virtually all pools must be exposed. If you do the arithmetic, how big the pools are and how many donors, how often they must get exposed, they are all exposed, and this differentiation gives a false sense of security with respect to this disease, and these types of products. The best sense of security that we can get about Creutzfeldt-Jakob disease comes from the epidemiology, and Larry Shermberger is going to talk to us about that in a few minutes, and there is no evidence that there is any problem here.

Next?

This is a reworking of the slide that was just mentioned because when I presented this concept at the CHI conference it got a reaction I was not looking for. What I want is to raise a point of discussion. There is a potential danger from Creutzfeldt. It doesn't come from where people think it comes from, and it has to do with recycling.

We have a number of very scary accidents with TSE disease on the books, okay, epidemic TSE diseases that were caused by intraspecific within-species recycling of these agents by a feed and biologicals. The only example for biologicals is this vaccine, but that vaccine had a lot to do with the high incidence of scrapie in Scotland to this day.

Kuru, that is a feeding case, and TSE is our most dramatic example which is directly traced to feeding, but in each case the problem here is cannibalism basically. This is feeding cows back to cows, feeding humans back to humans, inoculating sheep back into sheep.

The danger from these agents is a similar silent subclincial amplification over many passages through its natural host. In this case we are talking about humans, and the danger is if viremias actually exist, and it is imperative that we find out one way or the other in an irrefutable way, and if CJD can, in fact, be transmitted by transfusion, this disease could be amplified through the transfusion cycle by reinoculation of blood from previous transfusion recipients. It could take generations for this problem to materialize in a way that we would recognize it. The reason for that is that the incubation time is very long, can be very long. It is related to dose. When the dose goes down, the incubation time goes up. A person could be incubating this disease for life and never get the disease before he died from other causes.

We wouldn't know about it, and transfusion provides an avenue for this type of thing to happen. We need to know of this issue about whether or not this is a potential threat or not, but research is what I am calling for, not drastic measures tomorrow with respect to the blood supply.

PARTICIPANT: I am going to exercise a prerogative here and thank Dr. Rohrer for his presentation, and we are going to go right to the lunch break at this point because we are behind.

What I would like to do is have us reassemble here at one-fifteen. We may take a few more minutes for committee discussion of future activities. So, I am going to alert the after-lunch speakers that we may not get them on until about one-twenty-five, so you know, but let us all try to come back at one-fifteen.

(Thereupon, a recess was taken for lunch, to resume at 1:15 p.m.)

AFTERNOON SESSION 1:15 P.M.

PARTICIPANT: If we could get back to our seats, we can get back to work. What I would like to do is alter the schedule of events slightly because we are going to see if we can move toward some consensus on the question that the agencies have asked us and some of the Committee members have been busy during the lunch break trying to phrase some language. We were able to get a couple of versions of some possible points of consensus that we might at least reach tentative agreement on here on wording or it could conceivably get pretty close, and maybe we are fine with a little faxing and communication among Committee members for wordsmithing right after the meeting.

I don't want to discourage the emergence of consensus, and I think if we move on this quickly we may actually be able to find some points of agreement that would be useful to the agencies, at least tentative. I certainly am going to announce that we will do another meeting to carry our policy advice further, since there is interest both in hearing more about program and implementation possibilities, and I know that we may want to say more as a Committee than the points of consensus that are up there already in these draft versions, but nonetheless, it seems to me important that if we can make some progress and solidify our response to the specific questions that we should take advantage of that and so, I would like to do that first and then we will go back to the meeting program, maybe after about 20, 25 minutes of discussion here.

As promised, for those of you looking forward to this, I will hand the mantle of authority to John Penner around two-twenty-five so I can go back and teach Philadelphians to be ethical. That is really the yeoman job of the weekend, and then -- if you have been to Philadelphia, and then the presentations will then just pick up, and we will have a period at the end of the day. I asked Dr. Penner to be sure to leave a little room for public comment about both the consensus and some of the ideas that this Committee has said about its role in terms of offering policy advice in trying to support it with some rationale and explanation.

I also supplied some dates to Dr. Goosby, possible July, August and September dates that would work out for me and we will try to be in touch with you about what specific dates those would be for another meeting to follow on the heels of this one for the Committee.

So, John, do you want to do your version first?

PARTICIPANT: Both Dr. Hoops and I have tried to come up with some general response to a need to get some recognition of the elements of the (inaudible) draft study and (inaudible) for the record how things should be handled, and (inaudible). My thought and suggestion would be that we might want to get these copied or something very similar to them so that all members of the panel will have them and have the comments directed back so that there would be a final version that might be acceptable by all.

PARTICIPANT: Is there a mike over there, John? Is there one near you that reaches?

PARTICIPANT: This will keep Jane from saying too much.

PARTICIPANT: I doubt that, not too much but saying something.

PARTICIPANT: Okay, the Committee confirms the concept that the blood recipients have the right to know of risks associated with transfusion of blood and blood products and specifically any unique risks related to the blood product they receive. The corollary to that principle would be in this respect we would recommend a general approach to educating patients receiving blood (inaudible). In addition, whenever possible we recommend direct notification of individuals who have received any blood product not treated by an effective antiviral process obtained from a donor known to be or subsequently known to be positive for hepatitis C by screening and supplemental testing. So that incorporates some of the things we have been talking about up until this time with the attempts to remove some of the corresponding problem we might have with products that are fractionated and have been tested and requiring that all those products be just disappearing from production.

I will let Pete read off his.

PARTICIPANT: Oh, thanks. Actually I appreciate the input of Mary Chamberlain and Christine McDonald for particularly some of the specifics, but predicated on the premise that a blood recipient has the right to know he or she is at risk for hepatitis C we affirm the following principles: All public health policy should be consistent with the above premise and with prior commitments to individuals who interface with the blood system.

No. 2, this Advisory Committee is dedicated to extending the public trust about the safety and efficacy of the US blood supply.

No. 3, all recommendations made by the Advisory Committee should be ever mindful of wise stewardship of both the public or community moneys and energies. Therefore, we recommend to the US Secretary of Health and Human Services the following: No. 1, a prospective recipient notification program be implemented forthwith whereby a donor of a blood unit who seroconverts to hepatitis C antibody positivity by EIA followed by confirmatory supplemental test be identified and excluded as is the present practice, also, that all recipients of blood components from this donor be notified to facilitate HCV testing for all component units collected, and again, we discussed the last part, collected 12 months, and I just used jargon for the prospective lookback, and this probably needs some work, but anyway, (inaudible) okay?

No. 2, to implement as soon as possible a program to educate providers of medical care to appropriate assessment of individuals at risk for HCV and to therapeutic options as defined by the 1997 National Institutes of Health Consensus Conference on Hepatitis C.

No. 3, other strategies for identifying and notifying individuals at risk for hepatitis C be explored and/or developed out of the future deliberations of this Advisory Committee in collaboration with the US Public Health Service and the wider community of knowledge and expertise.

No. 4, for persons transfused prior to 1990, we recommend that testing for HCV antibody be undertaken and that this be done through education campaigns targeted to the public at large, selected high-risk communities and providers. We do not recommend targeted lookback for individuals transfused prior to 1990. This is consistent with prior HIV policy.

PARTICIPANT: And let me --

PARTICIPANT: The only thing left out was motherhood. You have got it all there.

PARTICIPANT: Let me ask if you would prefer, do you want to start looking at the more complex Hoots' proposal, just looking at that document first or would you like to start with the somewhat simpler but nonetheless insightful and analytically commanding Penner proposal or it may turn out that I think both actually say something a little bit different. They might actually stand together if they get merged with a slight twist. So, what is your preference? Do you want to look at Penner, look at the simpler one first or would you like to look at the longer -- yes, Dr. Alberts?

DR. ALBERTS: Yesterday, there was discussion or mention by several Committee members that they wanted additional information, and is that still the desire of the Committee, and should we possibly get that information before we proceed with discussion of the outcomes? We may want to recraft some of these statements with additional information in our hands.

PARTICIPANT: Just a point of order about that. There is a comment in Dr. Hoots' proposal about getting more information to sort of say more about how to look back, I guess it would be fair to say, but we may propose these as tentative recommendations subject to further comment or revision at the next meeting. We can say that this is where we are at as of today, but we are going to revisit as of X time from now.

PARTICIPANT: The problem I have with the first proposal is the terminology "unique risk associated with the particular unit," and then in the second corollary that these recipients be identified to the extent possible. Implied in that is if it is possible, and the truth is that right now, I forget the numbers, it is in the CDC analysis, the US blood supply has probably identified at least probably 100,000 blood donors who are confirmed positive for HCV of which probably half are multiple-time prior donors, and the blood centers clearly have in their capacity the ability to link that information to the prior issued components and notify hospitals that these units went out, and that can go back for decades. The hospitals will be handcuffed in working through these things. You know, they don't have records dating back further, etc. So, practically that proposal carries with it the burden to do all that, and I think what the Committee may need to understand in much more detail is the actual practical issues implied by that and the burdens and the reality in the current structure of actually accomplishing such a communication of unique risks to each donor.

So, I really have, I think if that is something under consideration that there needs to be a lot more data presented to the Committee to realize the pros and cons. There are data from Europe that, unfortunately is not in the packet, published papers where they have several countries embarked on targeted lookback from seropositive donors found subsequent to screening, and there is no question there is yield. You will find an infected recipient approximately for every positive donor who triggers a lookback out of the 20 or so lookbacks that derive from that, you will find a positive recipient. There is yield, but it is extraordinarily costly and complex, and I just don't think it is viable in the current structure, and it is very low yield relative to the big pool of exposed recipients.

So, if there is consideration still of that option then I think more data need to be brought forward to my mind to convince people that that is really not a worthwhile resource allocation.

PARTICIPANT: How do you feel about doing that from 1990 to (inaudible)?

PARTICIPANT: Right, the problem, the distinction that hasn't been made yet is that of the first generation versus second generation tests.

PARTICIPANT: (Inaudible).

PARTICIPANT: Right, the problem is not so much the supplemental piece although I totally concur with only doing lookback driven from supplemental confirmed donors. The problem is that the first-generation test missed approximately 20 to 25 percent of infected donors, and it translates to about one per 1000 units for first-generation screened blood for transmitting HCV.

So, I would actually recommend both for purposes of capturing those recipients in a more global program and the concern over supplementals not having their license until that point that the retrospective general notification continue through recipients through 1990, through mid-ninety-two and that we retrospectively do the lookback for the seroconverters subsequent to that point.

PARTICIPANT: Could we amend that to put that in? Does everybody agree with Hoots?

PARTICIPANT: If Dr. Hoots can get his Magic Marker out, we could do that.

PARTICIPANT: Actually I --

PARTICIPANT: You can just do it on a separate sheet.

PARTICIPANT: -- more specific because I think it does most of the things we are talking about amending on the first one.

PARTICIPANT: I think the second piece was, I am very comfortable with that one, with these last commentaries.

PARTICIPANT: Yes, Paul?

PARTICIPANT: Might it make sense that if we get the ideas that are coming forward that we not try to rewrite a document on the spot. It seems to me one of the things that this does for us is to give us something to move forward, and we ought to take the promise that we may make note of it and then someone or some group after this could really prepare a little better document to come back and look at.

PARTICIPANT: Well, also, another option would be, of course, to circulate to Committee members for comment these statements. Let me remind you again just as a point of protocol, we could say as a general starting point subject to further emendation we are going to leave here agreeing that we are going to work on either the Hoots or Penner version and then continue to do that, but I think it would give a momentum to our audience to believe that we have started to craft it. That is my point. I don't care if we finalize it right now, but I would like to see us agree that these are starting documents that we are willing to work with further. If they are way off base there is no point in leaving here that way.

Yes, Mary?

PARTICIPANT: I think the other thing that the Committee may wish to consider is a point that I brought up earlier this morning, whether the output of the Committee would simply be these statements or whether they would be put in a little bit more context with supporting documentation, etc., and again, would invite the Committee to discuss that and think of the options that that might be, I think as our Chair said, could be from paragraphs to pages, but I would hope that there would be more discussion on that as well.

PARTICIPANT: On that point we have what I think is quite a good starting document that CDC, I guess the PHS group that we are responding to has developed, and I would wonder if that couldn't serve, that eventually would be an actual publication out of this Committee with recommendations.

PARTICIPANT: Actually in the handouts that the Committee received there are several documents. There is what has been called the White Paper or the Options Paper. There was also a paper that was put together by the FDA that contained basically Paul Meades' presentation and had issues related to lookback, and you know, in CDC lingo we call these, quote, good starts, and so, I don't think when I talk about developing context that we are necessarily reinventing the wheel. We have some documents to work from, published material, unpublished material, and you are right. Some of this could be put out in a stand-alone, based on a lot of work that has been done already, but clearly work that would reflect the Committee's input and opinion and what they want to say.

PARTICIPANT: Other comments?

Would it be reasonable then to offer a proposal just for discussion to start with what Dr. Hoots has presented to us as a set of recommendations, agree that this is a good beginning document, not a final document, try to have it typed up, get it to you by e-mail or fax, let you look at it, offer comments back? I told the winner of this prize that I would make them the point person for collecting feedback documents and then they could come, and if we can do it, maybe we can circulate this and have some emendations that we are all in agreement to approve by the time we reconvene. If not, we can discuss the document further, but we can do a little work in between the meetings. The reason, seriously, that, Keith, I would like you to collect these is that there are some technical and medical points that I think it would be good to have a physician person looking at the documents as they come back.

So, is that a proposal that people are comfortable with, that we will start with a draft that we have reached consensus on as of today, and then we will try to have that typed up promptly, not by you, Keith, in this case, but if you could leave your overheads as a legacy to Paul, and he will get those typed, we will get them out to you all, and then we can begin the process of feedback comments? You and I can talk about how the areas are emerging, and then we can resume a discussion to finalize it at the next meeting.

Comments about that?

PARTICIPANT: I just have one comment that I would like the Committee to consider as we look at this document, and that is we are creating patients. Once we notify these people they are HCV positive, we have in a sense created patients, and those patients need to have some guidance as to where they are going. We need to think about is there going to be availability of counseling; is there going to be availability if you get people with normal ALTs that are anti-HCV positive? They may not be HCV RNA positive. How are these people going to be handled? There needs to be some thought about what happens to the people once we identify them, and I think while that is not an issue with the document we are dealing with, I think that we need to think of that as we review this document and how we might position our response to that.

PARTICIPANT: Along those lines you might want to have nationwide listing of sites to be tested, both for the indigent and the private because the test is not cheap, and if we could do that, I don't know how you pay for that, but if you do that, I think that would be very good so that when they get this you have got some people who are going to have to go to some public facility and get it done, and otherwise they are not going to get it done.

PARTICIPANT: Dr. Hoots?

DR. HOOTS: In that regard I really think that part of our mandate here is to really make suggestions, and I think at our next meeting I would duly propose that we consider recommendations to the Secretary concerning having HCFA and perhaps even congressional consideration be given to say that this is an important issue and it be put high on national levels, excuse me, public health agenda.

PARTICIPANT: And remember, what we are doing here is to try to explore that twisting, turning path from policy to comments on program, to comments on implementation. I think it is not appropriate, personally, that we not pay any attention to costs or how some of these things become implemented but as we sort of go halfway down the, moving from a set of policy recommendations to a set of program recommendations we can certainly cite, flag, urge attention to to some extent some of these issues, but how to implement will be out of our hands, but some of them we can certainly say that these are points of concerns, things we think ought to be high priority and do it that way.

I want to keep us slightly alert to the fact that we don't want to pretend we can implement for four agencies, Congress, and I mean it has been a good 2-day meeting, but not that much consensus, but if we give the general directions, by the time we get back, I think that will be helpful to those folks who do ultimately have to pay for it and implement it that way.

So, we have got to get a balance there. That is my only point.

Did I see Marion's hand up there?

PARTICIPANT: I think you basically have said it. I would just remind us again that it is not our job to do the implementation but on the other hand we might also perhaps at a future meeting that is not too far off invite commentary from the agencies that would be involved in implementing this policy so that they can do the cost analysis, if cost analysis is something that they think might affect their capacity to address the policy issue or to bolster their budgetary requests to the Congress. So, we might invite commentary from Dr. Shalala's office, from CDC and appropriate agencies relative to these policies that we are setting forth.

PARTICIPANT: Yes, I just wanted to add to those comments (inaudible) HCFA. As far as Medicare, this is my understanding, there are only two screening procedures that are actually approved, and there is a special exception for Congress through Medicare, particularly to cover counseling tests, screening tests. It is going to take something by Congress. So, you are talking legislation. It is not a simple thing. It is going to be similar to testing for diabetes. They can do that. For Medicaid, the rules are different, but, Eric, you may know more about that than I do, but I would definitely recommend that you have somebody with HCFA, if you are going to look at this implementation, that HCFA is going to have to be one of the players because if you are talking Medicare and you are talking about a screening test (inaudible) to the best of my knowledge.

PARTICIPANT: Yes, I think that it really would be a combination of HCFA and HRSA discussions around who would really pick up the, as Dr. Albright has identified, the identification, the new identification of a potential patient.

There really are a number of conduits through which patients, especially indigent patients can enter and access appropriate consideration for medical care through the community health centers and migrant farm worker clinics, homeless clinics. Even as points of access we could facilitate a point of access through MCB(?) clinics which might have a higher probability of identifying individuals who are HV positive, as well as TB clinics for that matter, but we could put together a picture of the implementation with that as a component, have HCFA's ability to just do a screening test. You are absolutely right, but in the context of a person who is eligible for Medicaid, being --

PARTICIPANT: That is different.

PARTICIPANT: That is different, and I think that it is in that context that we probably would be able to capture most in terms of indigent care. The people that will be in between are the individuals who don't qualify for -- they are not eligible for Medicaid and don't have private insurance, but I think that is the group we have to strategize around which is what we are concerned about.

PARTICIPANT: (Inaudible).

PARTICIPANT: Yes.

PARTICIPANT: (Inaudible) we are treating somewhere between 8 and 9 million (inaudible) grantees at about 2000 sites, and there are 16 million people that fall between the cracks.

PARTICIPANT: We could prepare information for the Committee to really give you a feel for how that would unroll and what if any holes are in that implementation plan at the next meeting.

PARTICIPANT: Yes?

PARTICIPANT: (Inaudible) how is this going to be perceived by managed care? That is another major question, depending on what area of the country you are from. The infiltration of managed care into that area who are paying for that diagnostic test, that screening test (inaudible). So, I don't know how (inaudible).

PARTICIPANT: I think that you could perceive it as a problem or you could perceive it as an already medically indicated intervention. I mean this is not coming up with a new standard or coming up with even a new test. It is actually trying to heighten the awareness in the patient population that there is indeed a potential that they may be at risk for something, that if they interfaced with their medical delivery system, they would, if they do it right, self-identify with the patient that there is that potential risk and follow through with the appropriate diagnostic test. That is the way I would prefer to perceive this as opposed to a new recommendation.

PARTICIPANT: That is the way I see it.

PARTICIPANT: Let me jump in here and say I am going to take just one or two other comments from the Committee. I am going to see if anyone in the audience would like to offer a comment quickly, maybe one or two people just about where the Committee has moved as a kind of brief interlude to public input from those who have been listening to this in case someone wants to offer a comment on that, and then we will go back to the CJD discussion that we had planned.

The only reason I am saying one or two more comments here is this is like catastrophe theater. We are up on the cusp of consensus, and if we talk longer we will get off it. So, it seems we have consensus. We have got a working document we want to start off with. We are not quite ready to say that the language is such that we are happy with it as recommendations for today, but we are happy with it to work on, and we are going to use Dr. --

(End Tape 7, Side A.)

-- friends in our audience, and they may want to develop comments along the lines that we are now listening to about implementation and what that would actually mean which we would then take up and follow up what many of you have said, other points that we may want to add on at the next meeting in terms of outreach costs, more specifics of a programmatic nature, if not of an implementation nature, and that long-winded sentence, do we have consensus about that strategy for proceeding now?

Okay.

Anyone in the audience want to offer a comment at this point in time? We will try to do this again at the end of the day, but I did want to see if -- they are so astounded that we have actually agreed on something, they are rendered silent.

PARTICIPANT: As I recall when we first got the hepatitis C assay it was adding $1 to the (inaudible) that we were writing off, and I guess the subsequent one is about $1.50, and it may be up to $1.75. That was one that was added onto a panel of the HIV, HITLV-I, II and so forth. So, I am not so sure that if it is batched appropriately and sent through from the blood banking centers that it will not be fairly inexpensive, if done properly.

The other aspect is I think there is some need to consider the fact that the blood banking centers do have some counseling (inaudible) for the HIV patients (inaudible). There may be some basic support available from blood banking centers as well as public health who have been handling the same thing for years anyway. So, I am not so sure that there isn't that availability there, that this may not be a major (inaudible) dollar program.

PARTICIPANT: John, I keep threatening to put you in charge here, and that is going to happen, but why don't we move then if there are no public expressions (inaudible) audience back to the presentations on CJD and I appreciate the patience of our first speaker in allowing us to discuss the specifics of the hepatitis C issue that was before us.

Dr. Shermberger is going to tell us something about the epidemiology of CJD disease. He has slides.

DR. SHERMBERGER: All right, good afternoon. I am a physician-epidemiologist with the Centers for Disease Control and Prevention, CDC. In my role as coordinator of the CDC surveillance activities on Creutzfeldt-Jakob disease, CJD in the United States I, along with my colleague, Dr. Hermius Belay may also provide consultation to some of the increasing numbers of persons affected by the unresolved public health issue of CJD and blood safety.

These persons include many patients who are notified about the receipt of ECOL(?) blood products, their physicians and others involved in implementing the current interim public health policy on this issue.

I am very pleased that this policy is being reviewed by this Committee and that I have the opportunity today to discuss CJD and blood safety focusing primarily on published and ongoing epidemiologic studies.

As we have heard from Drs. Paul Brown and Bob Rohrer there are laboratory and experimental studies that support some concern about the possible risk of CJD transmission by human blood. These studies have demonstrated the probable or possible, as we heard occasional presence of the CJD agent in the blood of CJD patients at low titer.

I say, "Probable or possible," rather than definite because of possible laboratory contamination and artefacts. These studies have also demonstrated the infectivity of blood, most likely primarily the white cell component throughout most of the incubation period in two different rodent models of CJD. They have also demonstrated the infectivity of buffy coat, plasma, of plasma derivative fraction and cryoprecipitate from sick animals in one of these rodent models, including disease transmission by blood from a sick animal when administered intravenously.

A key unanswered question about the results of these studies in rodents, particularly the infectivity of blood throughout most of the incubation period is whether these results apply to CJD infections in humans and indicate a risk to transfusion medicine.

There are several other causes for the concern about CJD and blood safety. Among these are several characteristics of the disease itself. CJD is invariably fatal. It is caused by a non-conventional agent. Disinfection is unusually difficult. Incubation periods are long and variable, and no practical screening test exists to identify those who are incubating the disease.

In addition, since the 1970s iatrogenic cases of CJD have been increasingly recognized, including an ongoing international outbreak of over 90 cases among persons who received pituitary-derived hormones 4 to 30 years before onset of their CJD.

None of the above reasons for concerns about transmission of CJD by blood products, however, establishes the magnitude or even the existence of a possible risk to human recipients.

For this assessment epidemiologic data are useful, including case reports, case-controlled studies, routine surveillance data and special studies of persons with unusually high exposure to blood. Based on the existing epidemiologic data, CDC has concluded that the risk of transmission of CJD by blood products in humans is extremely small and theoretical.

The term "theoretical" is used to describe this risk because we are aware of no compelling evidence that has been reported for any instance of transmission of CJD to a human recipient by a blood product.

Case-controlled studies are often the most practical epidemiologic studies for identifying risk factors for rare diseases such as CJD. The results of five such studies including one large study in Europe that is not yet published support CDC's conclusion that the risk, if any, of CJD transmission by blood must be low.

As shown in this slide, an article published by Dr. Winchens and coworkers in Neurology, 1996, reported that a history of transmission was not a risk factor for CJD. This finding was based on a reanalysis of a combination of three case-controlled studies in Japan, the United States and the United Kingdom.

Only 9.8 percent of 174 patients with CJD compared with 13.7 percent of 328 control subjects had a history of a blood transfusion. The adjusted odds ratio was 0.6 with a 95 percent confidence limit between 0.4 and 1.2.

Control subjects included spouses, neighborhood controls and various hospital controls. In one of the three studies analyzed separately was the proportion of CJD patients with a history of a blood transfusion higher than that for their controls. The CJD cases in the three studies were diagnosed between 1970 and 1984.

A fourth case-controlled study published by Dr. Esmond and colleagues in January 1993, in Lancet included 63 cases of CJD identified between 1990 and 1992, in the United Kingdom.

These 63 cases were not included in the pooled data published by Dr. Winchens and coworkers in 1996. These additional 63 cases of CJD were identified in the United Kingdom through prospective national surveillance begun primarily because of public concerns about the possible spread to humans of bovine spongiform encephalopathy.

As in the other case-controlled studies a history of receiving blood was not a risk factor for CJD. Only 6, 10 percent of the 63 CJD cases compared with 14 percent of the 63 age-sex-matched hospital control subjects had a history of receiving blood.

In the analysis of all 155 CJD cases from the United Kingdom, that is during both the 1980 to 1984 and 1990 and 1992 periods Dr. Esmund and colleagues documented that a similar proportion of CJD patients, 15 percent and controls, 13 percent had a history of donating blood, as well as of receiving blood.

In brief then the published case-controlled studies indicate that a similar proportion of CJD patients and controls donate blood and that having a blood transfusion is not a risk factor for the disease.

With regard to this latter point, current case-controlled data from the European Collaborative Study of CJD Risk Factors are further corroborating these earlier published studies. This information comes from Dr. Robert Will, consultant neurologist, national CJD Surveillance Unit in Edinburgh, Scotland, who reports that Dr. Cornelia Von Dwyne of the Netherlands will be the principal author of this European study which has enrolled over 340 CJD patients.

In addition to case-controlled studies, the risk of transmission of CJD by blood can be assessed through long-term follow-up data on the recipients of blood products derived from an identified CJD donor, that is a donor who subsequently develops CJD.

In 1995, a letter from Germany in the Lancet Journal was the only such published data available. This letter indicated no evidence of transmission of CJD to either 27 patients who definitely or eight who probably received a blood unit from a CJD donor who died in 1991. None of the recipients in either group died of CJD. The transfusions were received between 1971 and 1991. At least 13 patients in the two groups, including at least seven who definitely received a blood unit from the CJD donor survived 10 years or longer after the transfusion. Eight patients in the two groups lived for more than 15 years afterwards.

In 1995, at the request of the Food and Drug Administration CDC and the American Red Cross initiated a long-term follow-up study of recipients of transfusable blood components derived from CJD donors who are reported either to the American Red Cross or to any other blood center that might wish to participate. Mary Ann Sullivan and Dr. Roger Dodd of the Holland Laboratory, American Red Cross serve as the principal investigators.

In addition, key people from the regional centers of the American Red Cross, the New York Blood Center and myself serve as co-investigators. Mary Ann Sullivan will present the methodology and results of this study in more detail to the Advisory Committee in the next presentation.

In brief, the study has determined the vital status and if deceased whether CJD was the cause of death in about 150 recipients of transfusable blood components from 13 donors who subsequently developed CJD.

At last report none of these recipients had died of CJD. These recipients include 26 persons who had lived 5 or more years after their transfusion, including four who had lived as long as 14, 16, 22 and 25 years afterwards.

The number of CJD donors and investigated recipients and the duration of follow-ups after transfusion continue to increase in this study.

Additional epidemiologic evidence on the possible risk of transmission of CJD by blood products is available from other ongoing collaborative CJD surveillance projects at CDC. For national surveillance of CJD -- can you still hear me? Okay, for national surveillance of CJD, 1979 through 1995, for example, we extracted information on the deaths of US residents for whom CJD was coded as one of the causes of death on routine reported national multiple cause of death data.

These data are based on information reported on death certificates. During the 17-year period a total of 3907 cases of CJD were reported to CDC through this national mortality system.

This slide shows the total age adjusted as well as the age specific annual death rates per million population in the United States for these years, 1979 through 1995.

Note particularly that the total age-adjusted annual death rates illustrated by the red line have been relatively stable at about one CJD death per million population.

These relatively stable annual CJD death rates and the previously described evidence that persons with CJD do not differ from control subjects in their history of receiving or donating blood support the conclusion that despite regular blood donations by donors who subsequently develop CJD, blood transfusions do not appear to be amplifying CJD infections in the population.

This next slide shows by age group the number of CJD deaths and the number of these deaths reported with hemophilia A or B, thalassemia or sickle cell disease, diseases associated with increased exposure to blood or blood products. Note by the zeroes in the third column of the slide that none of the 3907 cases of CJD identified in the multiple cause of death data, 1979 to 1995, were reported, also, to have had hemophilia, thalassemia or sickle cell disease. Because many of the patients with these diseases are exposed to blood products at a very early age, it is also noteworthy, as indicated on the bottom of the slide with the asterisk, that no CJD cases were reported in persons 5 to 19 years of age in the United States during the 17-year period.

Clotting factor concentrates used by hemophilia patients to control bleeding are commonly derived from the plasma of between 4000 and 30,000 donors. Since regular recipients of such concentrates can be expected by chance alone to have exposure to CJD donors through these treatments, hemophilia patients constitute an important sentinel group for assessing the possible infectivity of a blood product from such donors.

In addition, recent animal model experiments suggest that cryoprecipitate prepared from the blood of CJD-infected rodents is more infectious than other derivatives.

Since the mid-1960s many hemophilia patients have received cryoprecipitate, particularly patients treated before clotting factor concentrates became widely used in the early 1970s.

A few hemophilia treatment centers such as the Puget Sound Blood Center and Program in Seattle have continued to use cryoprecipitate even after concentrates became available because of concerns about the safety of the concentrates.

Dr. Arthur Thompson, Director of the Hemophilia Program in Seattle estimated that roughly several thousand hemophilia patients nationwide have probably received at least some cryoprecipitate. Thus, in addition to general CJD surveillance through the multiple cause of death data, which indicate the absence of CJD in any hemophilia in the United States between 1979 and 1995, CDC has actively sought cases of CJD specifically among persons with hemophilia.

About 13,000 of the estimated 17,000 hemophilia population in the United States are cared for in hemophilia treatment centers. Despite increased publicity about CJD in this hemophilia community since late 1994, no case of CJD in a hemophilia patient has been confirmed to date.

In addition to alerting over 120 US hemophilia treatment centers in September 1995, about CJD surveillance, CDC has continue to make follow-up inquiries quarterly to the largest of these centers where the majority of the active hemophilia patients are enrolled.

CDC has also obtained brain tissue from 25 of 27 deceased hemophilia patients identified for neuropathologic study to help further assess the possible presence of CJD in hemophilia patients.

As of last week, Ms. Elizabeth Barnhart of Dr. Bruce Evets' Hematologic Diseases Branch, CDC reported that the neuropathologic study results were complete on 22 of these deceased patients. None had evidence of CJD. Causes of death included AIDS, post-hepatitis cirrhosis, liver failure and lymphoma, and this study continues.

At the suggestion of Dr. Paul McCurdy and to assist in a further assessment of the absence of CJD among hemophilia patients who specifically received cryoprecipitate Dr. Arthur Thompson submitted to CDC a recent follow-up report on a cohort of such patients currently under surveillance in Seattle.

This cohort included 101 patients with a blood-clotting disorder who had received at least 100 units of cryoprecipitate between 1979 and 1985. Ninety of these patients had hemophilia A.

Altogether during the 7-year period beginning 1979, this cohort was known to have received just over 238,000 units of cryoprecipitate. Since members of this cohort received additional cryoprecipitate before and/or after the 7-year period, this measured exposure represents only an estimated one-half to two-thirds of their overall exposure.

Each unit of cryoprecipitate comes from an individual donor. Recent follow-up data on this cohort revealed that 76 were alive a minimum of between 11 and 17 years after the receipt of cryoprecipitate and 25 were deceased.

None had developed CJD. The follow-up report specifically indicated the two surviving patients in this cohort had received at least one unit of cryoprecipitate in 1982, from a donor who later developed CJD.

In ending this discussion of CJD and blood safety I emphasize that despite some laboratory experimental evidence suggesting a potential for blood-borne transmission of CJD the accumulating epidemiologic data from both published and ongoing studies have strengthened CDC's conclusion about this risk.

The conclusion is that the risk, if any, for transmission of CJD by blood products is extremely small and at present appropriately regarded as theoretical. Periodic re-evaluation of the accumulating epidemiologic data and more laboratory tests of the infectivity of blood products will undoubtedly provide a stronger scientific basis for modifying as appropriate public health policies on CJD and blood safety.

In addition to deferring donors at high risk of CJD the current interim US policy which I understand you haven't heard about yet, but that current interim US policy provides for, and this is key, for retrieval and quarantining of all licensed blood products derived from donors who subsequently developed CJD or who are subsequently determined to be at increased risk of CJD.

On the one hand this retrieval and quarantining aspect of the current interim policy has helped reassure many concerned persons about the safety of the blood supply. However, there are also some valid concerns about the appropriateness and efficacy of this aspect of the current policy.

It is also costly. As of December 1996, recalls and quarantines of blood products from CJD donors and donors at increased risk of CJD were estimated by a member of the American Red Cross to have cost the agency over $100 million.

In addition, the policy risks creating product shortages, particularly since there is no agreed-upon mechanism in place to use quarantined product to prevent or reduce any shortages that might be created, no agreed-upon mechanism in place to use quarantined product to prevent or reduce any shortages that might be created. This risk of shortages can be expected to increase as awareness of CJD in blood safety increases and as a higher proportion of the CJD donors are identified.

Finally, the policy does not have a clear benefit in terms of preventing CJD based on currently available epidemiologic data.

As final observations, the issue of CJD in blood safety illustrates that even a relatively rare transmissible disease can sometimes create an important evolving complex public health problem. The associated risks deserve ongoing evaluations. Surveillance and other epidemiologic data can be very important for continuing to assess these risks and to help guide public health policy.

Thank you.

PARTICIPANT: Thank you, Dr. Shermberger. Let us take a couple of questions, if there are any. I have one not knowing what our policy is. What are the at-risk screen-outs for CJD on the donor side, criteria used?

DR. SHERMBERGER: Jay, do you want to talk about the policy.

PARTICIPANT: Right, we have a whole presentation prepared. We will review that in detail.

PARTICIPANT: Okay.

PARTICIPANT: Briefly you have persons who have had iatrogenic exposure. You have persons who have a family history suggestive of a genetic-based risk, and you have persons, well, those are at risk.

PARTICIPANT: People may not understand that CJD is in part an inherited disease as well, that there are about I would say on average around 10 percent of the cases that occur have a mutation on Chromosome 20 that they inherit, and they are at increased risk, and so one of the questions that Jay was referring to was to ask whether they have multiple cases in their family, and if they do, then they are screened out from donating, deferred.

PARTICIPANT: Dorothy, you would know in looking at the case-controlled data, one of my concerns is sort of trying to stratify those data, for example, take out cases that you think are familial and looking at different age groups in terms of the risk of transfusion and were any of those kinds of issues considered when those (inaudible.)

PARTICIPANT: She is asking whether in the reports of these case-controlled studies, whether the data was analyzed in subgroups by age --

PARTICIPANT: Also, by --

PARTICIPANT: Or by whether they were known to be familial cases or not familial cases, and I have looked at all those papers and have not seen that. The recent report from Europe where that data is fresh and ongoing, and they haven't published it, those types of analyses are certainly possible to do.

What I was concerned a little bit about those case-controlled studies is the use, the frequent use of hospital controls as opposed to community controls. The hospital controls, to me, would have a slight bias towards an increased possibility of having a history of blood transfusion.

Now, this was recognized, I know at least in one of the studies by Esmund, and he went ahead and tried to correct the data by eliminating any blood transfusions from the control group that were related to the reason for that hospitalization, and he describes that in the paper.

I am also aware that in the European study where they didn't initially correct for that, that if you go, say to 10 years back, that is actually took the date of when the transfusion was given, and if you just look at the data of the transfusions 10 years or further back from the date that the histories were taken that the two groups are very, very similar. The CJD cases and the controls are very similar.

You notice that we were getting a tendency for the CJD cases to almost look like they are protected a little bit by transfusions, but that protection effect seems to go out a little bit, and I think it is related to this business of the hospital control issue.

PARTICIPANT: Thank you. Why don't I ask Dr. Sullivan to come up. I think she is going to give us some information about the Red Cross looking at CJD, and Mark wanted to talk a little bit about policy and criteria (inaudible).

MS. SULLIVAN: Good afternoon. I am Mary Ann Sullivan of the Transmissible Diseases Department of the American Red Cross, Holland Lab. I appreciate the opportunity to present our data to you today, and I also appreciate the honorary doctorate.

In October 1994, it was learned that a frequent US blood donor had been diagnosed with CJD. The FDA Office of Blood Research and Review subsequently called for an assessment of the risk of CJD transmission to recipients of donated blood and blood products.

As Dr. Shermberger has indicated, we immediately initiated an investigational lookback study to collect recipient outcome data for recipients of prior donations from donors who subsequently developed CJD which we hope will allow for a more accurate estimate of the risk, if any, of transmission of CJD by blood components.

In the next few minutes I would like to share with you the data which were collected in the first 2 years of this long-term study.

The participants in this collaborative study are investigators at the Red Cross Holland Lab, the CDC, the New York Blood Center and numerous medical and regulatory personnel at Red Cross Blood Services Regions throughout the country.

A lookback of newly identified donor cases is initiated on a continuing basis. In the interests of time I am not going to go into detail regarding our study methods, but I will be happy to entertain any questions afterwards.

However, there are two important procedural points that I would like to emphasize. First, only donors with diagnosed CJD are included in this study. We feel that it would not be productive to include donors with a family history of CJD or history of HGH or dura mater transplant, and secondly, no recipient notification occurs in the context of this study directly.

Lookback data have been received thus far for 14 donor CJD cases which occurred between 1975 and 1996. The location of the blood center reporting the case and the year of diagnosis are indicated on this map. As you can see, three blood centers have provided data for multiple cases.

This table indicates for each of the 14 cases represented by our study data the date of onset of CJD in the donor, the date of death, the total number of donations and the dates of the first and last donations and the status of the diagnosis.

It is important to note that in five of these cases it was a matter of 1 month or less between the date of the final donation and the onset of disease.

This table indicates for each of the 14 donor cases the number of recipient reports that we have received and the vital status of those recipients.

Of 291 prior donations investigated a total of 175 recipient reports have been collected. Eighty-seven of these recipients are known to be deceased and 88 were alive at last report.

Of the 87 deceased recipients cause of death has thus far been obtained for 70, and none were due to CJD or noted any undiagnosed neurological disorder. Death certificates have been requested from the appropriate states for the remaining 17 deceased recipients.

The deceased group has a median survival of only 3 months, and these data are consistent with those of other lookback studies and reflect the general experience of relatively high mortality in a selected transfused patient population due to underlying disease.

The 88 recipients alive at last report have a median survival of 4-1/4 years. The total person years of survival for all 175 recipients identified by the study thus far is 325, with a median of 1 year. However, this number is expected to increase substantially when the next annual search of the national death index is completed, and this search is expected to be completed at NCHS within the next few days.

Our current search involves 89 of the 175 recipients included in the study. The minimum number of recipients who survive for 5 years or more post-transfusion is 26 as Dr. Shermberger mentioned.

These relatively long-term survivors are summarized on this slide by length of survival. Columns 2 and 3 illustrate the difference in the total number of recipients in each group versus the number of surviving recipients whom we continue to follow, and there are actually in this group only three individuals who are deceased and the longest deceased survivor was the one at 14 years.

CJD was not the cause of death for any of the deceased. I have also indicated the components received by each group or individual and the time elapsed between the transfusion and the onset of disease in the donor. The two longest-surviving subjects at 22 and 25 years post-transfusion are both currently in their fifties and healthy. Each received a unit of whole blood from the same donor within 5 years of the donor's CJD diagnosis.

The distribution of blood components to all the study subjects is shown here. Although the current number of identified recipients is 175, one deceased individual actually received three separate components from the same donor on two different occasions, donation occasions which resulted in a total of 177 components here.

Sixty-one percent of the recipients that we are following received red cells; 20 percent platelets; 12 percent FFP and less than 5 percent each for cryoprecipitate and whole blood.

We have received recipient data in response to nearly 70 percent of all the requests that were sent out to consignees. However, the efficacy was actually less than 50 percent for records for transfusions prior to 1985.

This indicates the generally poor availability of transfusion records after 10 to 15 years and unfortunately illustrates a major weakness of the lookback study design when applied to a disease with a potentially long incubation period.

In conclusion no cases of CJD have occurred in 158 recipients of blood components from 14 donors who subsequently developed CJD. Long-term follow-up of survivors will help to provide an estimate of the risk of transmission by blood components and in closing I would like to say that we invite any other blood centers who may be unfortunate enough to have a CJD case in a donor to participate with us in this important research effort.

Thank you.

(Applause.)

PARTICIPANT: Thank you. Are there any questions of the former Dr. Sullivan?

(Laughter.)

PARTICIPANT: (Inaudible) rate of diagnosis of CJD (inaudible.)

PARTICIPANT: The rate of diagnosis is increasing?

MS. SULLIVAN: There certainly aren't any data to suggest that. Rather it is more likely that the reporting has gotten better. Also, the awareness in family members and awareness of the need to contact the blood center and notify the blood center if their family member died of CJD has gotten higher probably because of media exposure and the BSE situation.

PARTICIPANT: I think that is a key point that we are probably still only getting a small proportion of what is out there, and I think that was one of the points that was being made, I think, by Dr. Rohrer in his calculations in the beginning when he thought there might be 25 or so in one year of people who had a history of donating. Now, not all of them would be so recent. Only a portion of the 25 is going to be relatively recent donors, and that is more likely to get into our system.

PARTICIPANT: Let me rephrase my question. Is it likely that you will learn about the (inaudible) cases (inaudible) as the years progress because of (inaudible) of awareness?

MS. SULLIVAN: I think that is certainly likely and if you look at the dates of death or the dates of diagnosis of cases in our study there are only a few, very few, one from the 1970s, two from the 1980s and then a whole little bolus of cases from 1994, 1995 and 1996.

PARTICIPANT: Thank you. Dr. Weinstein will conclude this segment.

DR. WEINSTEIN: Well, you have heard the biology and epidemiology of CJD, and I would now like to review the FDA's response to this disease and describe some of the very difficult challenges that we have before us in handling it.

May I have the next overhead, please?

The topics that I will discuss here include a brief history of FDA's response here, the scope of the problem, the initiatives that we have undertaken regarding CJD, a description of our current recommendations and I will describe some of our challenges in the form of case studies.

May I have the next?

Now, as we have all heard here, CJD is a rare, fortunately, a rare but invariably fatal neurodegenerative disease. We have no plasma screening test. We have no way of clearing the infectious agent from blood or blood products that won't end up denaturing the products. The disease has a very long incubation period, and it occurs in a sporadic form, a familial form and in iatrogenic form.

Although we have heard that there are no transmissions of CJD to humans through blood or blood products, nevertheless, because there is a theoretical risk for transmission and the fact that we have no serum test for the disease, FDA has taken a very aggressive action to mitigate the potential risk for transmission.

I would like to briefly review the history of FDA's actions with regard to the disease. Throughout the period of 1983 to 1994, there were reports of about six donors diagnosed with CJD who contributed to the blood supply who reported to have contributed to pools, and these materials were withdrawn by the blood establishments and the blood manufacturers, and the effect on the supply was very minimal.

In 1987, in November, the FDA issued a memorandum to blood establishments calling for the deferral of recipients of pituitary-derived growth hormone. This was initiated because of reports that people who had received this pituitary-derived material had developed CJD.

Later on in December 1993, the FDA issued a guidance regarding post-donation information reports, and this activity, this memorandum increased the reporting of diseases in general to the FDA. The request emphasized post-donation reporting. It asked for more documentation. It asked for further investigation, and a further description of withdrawals. Also, the FDA received a greater notification about withdrawals as did consignees.

Now, the impact of this was to increase the degree of reporting and we will see this later on in a graph here that shows the number of people who, the increase in reports of CJD.

Go on to the next overhead?

Throughout the period of late 1994, 1995, there were a number of public discussions that occurred with the Blood Products Advisory Committee, and in June 1995, a special advisory committee on CJD was formed to give the agency more advice about this disease.

The agency took the recommendations of these groups and formed an interim policy decision memorandum that was delivered in August 1995.

There were actually two memorandums here. One was disposition of products derived from donors diagnosed with or at known high risk for CJD and the second memo to blood and plasma establishments, precautionary measures to further reduce the possible risk of transmission of CJD by blood and blood products.

The memos made recommendations for deferral, donor deferral, product disposition and recipient notification. The recommendations were developed based on consideration of the risk to the donor, the risk from the product and potential impact on the blood product availability, and our attempt, again is to maintain a balance here between the need for the products and the risk of using the products.

The memoranda were updated in the --

(End Tape 7, Side B.)

-- revised memorandum. You asked before about the definition of donors at risk. This memorandum outlined the way that that information would be provided, donors questioned about CJD to assess the potential of risk; is there a family history of CJD; has the individual received pituitary human growth hormone; has the individual had a dura mater transplant?

As far as the definition of familial risk, has the donor been told that a family member or his family is at risk or does the donor have two or more family members with CJD? Donors with relatives with iatrogenic CJD are not considered to be at increased risk, and there is also this category of possible family risk. Donors with one affected family member or a donor may resume donations if genetic testing is negative for CJD risk, and this has an effect on the product that that donor might have contributed to that, as we will see later on in product disposition.

Next?

As far as what happens to products that have received donations from the individuals, for products that have received donations with CJD, all products for injection should be destroyed and consignees notified in order that they retrieve and destroy the product.

Regarding products that are made from material from donors at risk for CJD and those were outlined before, the human growth pituitary hormone recipients, people with CJD in a family member, dura mater recipients, the policy or the recommendations call for quarantine or destruction of plasma derivatives in all cases of increased risk of donors unless the donor has one family member with CJD.

Regarding the plasma derivatives from at-risk donors, they may be used for further manufacturing into non-injectable products if labeled with cautionary statements, such as biohazard, collected from a donor determined to be at risk for CJD, for laboratory use only or intended only for further manufacture into non-injectable products.

May we have the next?

Now, regarding the notification procedures, the memorandum recommends that consignees of these products receive notification unless the donor has only one family member with CJD. Also, the recipient of counseling decisions should be based upon risk/benefit decisions by physicians and caretakers.

So, in other words the recipient of the product here should be counseled by a health care intermediary.

Now, let me see, I think we will turn it the other way here. This shows the effect of these recommendations and sort of the historical context of what these recommendations affected.

We see here from 1993 to 1994, that there were relatively few individuals who were reported to have contributed to these blood pools here. These are donations from individuals with CJD who were subsequently found to have CJD or at risk for CJD.

From 1995 and 1996, you see that there is a considerable increase in the number of individuals reported. It is also very interesting, and we should note here the low numbers of individuals that comprise this graph here. We are talking on the order of maybe 35 or 40 people. This has had, however, an incredible effect on blood supply and the availability of materials, and this is what we will see in the next few overheads.

There is a very broad range of products that are affected by this CJD disease. It includes not only the blood and blood components, albumin immune globulins, clotting factors, protease inhibitors, excipients for drugs, talking about pharmaceuticals, talking about vaccines. These are all products where these blood components are used. Albumin is used as a filler for recombinant proteins. So, even recombinant clotting factors are not immune from being affected by the withdrawal of these products.

They are used in in vitro supplements. They are used in growth factors, and as we will see later on, they are used in products which are surprisingly affected, products that come in contact with blood that perhaps many of us don't usually think of being involved in this situation such as embryonic tissue and materials that are used in fertility clinics.

May I have the next slide?

PARTICIPANT: What is an excipient?

DR. WEINSTEIN: An excipient can be considered as a filler, such as in a final vial.

Now, as far as the number of lots withdrawn, between 1983 and 1997, we have a listing here of lots. You see that for albumin there were approximately 500 lots of material withdrawn. However, it is notable here that in 1996, we have 87 lots. So, in this 1-year period we have increased the number of products, the number of lots withdrawn considerably. This amounts to on the order of 20 percent of the total, and as you can see there is a similar ratio with many of these other products.

Also, if you are perhaps not familiar with the term "paste" here, these are intermediates that are used to produce these other protein fractions.

There is sort of a subtle element here though that you should also be aware of, that when we say, "withdrawn," at times many of these products have already been used by the time the withdrawal notice goes up. So, it is not always true that all of this material is removed from the market directly. There may be material that has already been consumed, and I am sure that this will be discussed later on by Peter Page.

Okay, we will go on to the next.

Now, I will discuss here a number of case studies so you can get a further handle on the degree of magnitude of this problem here.

We have a situation that is as yet unresolved where a number of cases have been reported to us of donors who have received a dura mater transplant and who contributed to pools from which products were made. This is the American Red Cross situation. We will, as I say, hear more of that later from Peter Page.

There is prediction of shortages by the manufacturer because of the removal of products that were made from the pools to which these donors contributed. The questions that we are confronted with, should risk assessment be made based on documentation of draft sources; should donor stratification be used regarding draft pooling and availability; and what clinical information is needed to help us make some of these decisions?

These are the questions before us, but let us look at the effect that this recall or withdrawal will cause regarding the availability of blood products.

May I have the next one?

It has been determined here that we will have on the order of 2 million units of albumin, 2 million vials of albumin withdrawn, 144 million units of factor 8 withdrawn, 40 batches of alpha-1 protease, unknown amounts of stabilizers that are used for biotech products, and so, it is worth considering here that the entire number of units used in the United States for the AHF, for example, is on the order of approximately 500 million units per year, and so, we are talking about a considerable amount of material that might be withdrawn from the market because of this one situation.

PARTICIPANT: Did you ever estimate the cost of this?

DR. WEINSTEIN: If we estimate, if we say here that the cost of a single unit is on the order maybe of 70 cents, something like that of AHF alone, we are talking about something in the millions, hundreds of millions of dollars for this situation.

Now, this is another situation which we were confronted with earlier this year that gives you a sense of the indirect nature of this problem, situations that were simply unanticipated when the memorandum was originally formulated and decisions about risks that we had to make that would help us to decide what to do in this situation that were not originally formulated in the original memorandum.

In this particular case transferrin protein was made from a batch of material that a single CJD donor had contributed to. The transferrin was purified from that batch of material. It was used in cell culture in a very low concentration, the order of a few microgram per ml to grow cells.

These cells produced monoclonal antibodies. These monoclonal antibodies were purified and attached to an immunoaffinity column covalently. The antibodies were then used to make, to purify antihemophilic factor, and so, if we use the recommendations strictly as they are seen from this memo of 1996, we are confronted with the problem that here was a product, that is the factor 8 product here, was this factor 8 product in fact, contaminated with CJD material.

We did a very careful risk assessment in cooperation with the CDC and with outside consultants, with the NIH and we also made our decision policy very clear to concerned public consumer groups, the National Hemophilia Foundation and the Committee of Ten Thousand, and our decision based on our risk assessment was that the chance of contamination of this product was very remote, negligible and that a shortage would occur potentially if the product were withdrawn, and we felt that the product could be released, and that is what in fact happened.

The last case study here is one in which these blood products are used indirectly here in washing of embryonic tissue and sperm. This was a case in which we had the in vitro exposure of tissues to implicated lots of material. There was a postdonation discovery of two donors at risk for CJD, one possibly with human growth hormone 30 years ago and one with a dura mater transplant.

In this case, we recommended that material that was easily disposed of be disposed of, such as sperm and that materials saved and that are not easily replaced, such as embryos could be used but that there should be prospective recipient notification and retrospective notification.

So, I hope I have given you sort of a sense here of the magnitude of the problem, some of our recommendations and I leave with the hope that we will be able to apply the better biological and epidemiological information here to help us in making future decisions and risk assessments based on the science of the issue.

(Applause.)

PARTICIPANT: Thank you. I think we are going to have two discussants. Maybe we can hold the questions until the discussants present their material.

Next, Dr. Glen Pearce will be our patient issues discussant.

DR. PEARCE: Thanks, Dr. McCurdy. I would like to briefly go through in the next few minutes the patient perspective on CJD and some of the issues that have emerged since 1994. Before I do that, I would like to just orient everyone a little bit to hemophilia, hemophilia care and to put the CJD problem in the context of blood safety in general as it relates not only to blood products but specifically to hemophilia products.

This is a tricky one. This doesn't work, does it? Okay, I will try to take you through it. Briefly the available plasma products that have been used for hemophilia treatment over the past 30 years or so have been products for coagulation factor 8 deficiency, factor 9 deficiency.

Thanks. And coagulation factors containing von Willebrand's factor, and this is to treat the three major forms of hemophilia that are encompassed in this community, factor 8 deficiency, factor 9 deficiency and von Willebrand's disease.

More recently recombinant DNA produced synthetic clotting factors have emerged on the market since late 1992, early 1993. There are two manufacturers producing coagulation factor 8. Over the past 2 months one manufacturer is making factor 9 and in development other factors to treat bleeding disorders are also making their way through the regulatory pathway.

All of these products offer new opportunities for improved treatment, and really the bottom line here in the use of these products is to prevent, not treat bleeding episodes.

Over the years hemophilia has been treated after bleeding starts and over the past few years as incrementally safer recombinant-derived products have emerged on the market, the goal is to use primary prophylaxis. That is something that has been advocated by the medical experts within the hemophilia community for young children and is something that a number of older children, as well as adults are beginning to do, so that the morbidity and mortality associated with trying to deal with a bleeding episode is eliminated.

The lesson that we learned in terms of blood safety is really from the 1970s and 1980s, and what we have concentrated on yesterday and today. Treat until we know whether or not the material is safe. That is exactly what we all did, and that is exactly what is not acceptable here in the 1990s, and as a manifestation of that policy, CJD comes in and the risk of CJD comes in.

We need to know the risk before we use these products. No more can we treat until we find out after a period of scientific study whether or not the products are safe, and of course, this principle applies not only to the coagulation factor products but to all blood products.

An overview of the agents that could be transmitted, we have had a little bit of discussion on this, but just to put it in perspective, HIV-I and II, hepatitis B, hepatitis C. The safety record over the past 10 years or so has been outstanding for these products. They are inactivated by solvent detergent treatment and heat and each of these viruses is killed in a very substantial way by these kinds of inactivation processes.

On the other hand, non-lipid envelope viruses which include parvovirus B19 and hepatitis A virus are not inactivated by these kinds of processes and do remain in plasma-derived concentrate on occasion. HAV has been shown to be transmitted this past year, I will cover that in a moment, in a couple of instances, but parvovirus really has not been investigated other than looking at a number of different vials of different kinds of plasma-derived concentrate, finding parvovirus in there and then looking at recipients and finding evidence that a very high proportion of recipients have been exposed to parvovirus over the normal population.

Creutzfeldt-Jakob disease, we will cover that in just a minute, but all of these agents are really markers of other undiscovered agents. So, there are concerns about these agents being transmitted, but in addition what other agents that may have the characteristics of these agents that may be more lethal than these agents are being transmitted, and to put that in perspective, 16 years ago we were not aware of any of these agents at all. Yet all of these have been shown to be transmitted by blood products. So, it is probably naive to think that the list won't be expanded somewhat over the next 16 years.

It includes not only undiscovered agents but agents that can newly emerge as threats to the blood supply like HIV did.

There has been an unprecedented loss of human life and that is really why viral elimination is important and why we are here.

The mortality from HIV, hepatitis B and hepatitis C is approaching 50 percent in the hemophilia community. In addition there are viral synergies that work in patients with bleeding disorders that make HCV an even more lethal infection.

This population is really at the front end of the blood supply and has been over the past 30 years, 25 years since concentrates have been widely used.

Currently there is an average of 15 to 80 thousand donors that go into a single lot of clotting factor. I am speaking of factor 8 in this case and the average patient would use about 10 lots a year. So, you can extrapolate the numbers and see the number of different people that that patient will be exposed to.

This exposure is made all the worse because this treatment is lifelong, and the infection certainly in the case of HCF and HIV begins in infancy, and if one is fortunate enough to live 70 years it is not clear what the natural history of HCV would be but the evidence so far is that it is a pretty significant disease in this population.

We also have absolutely no knowledge of the impact of parvovirus B19 or CJD or any other undiscovered agent on this population yet, agents which may have very long incubation times.

I should mention parvovirus B19 is something that is endemic or epidemic within the United States and in the world and generally is a self-limited infection, but about one in 3000 donors has an active infection, and they have very high levels when you have an active infection. You have got 1 trillion virus particles per ml. So it is difficult to dilute that out, and at least in the immunodeficient population of which people in the hemophilia community, half of them fall into that category, it can cause a chronic, profound morbidity. So, this is not a benign disease in the hemophilia population; yet it has been ignored.

To put this into more practical terms, what has occurred over the past year, and where does CJD relate to the various kinds of problems that have emerged over this past year? I alluded to the hepatitis A transmission that occurred about a year and one-half ago, multiple CJD market withdrawals that we have heard about from Mark Weinstein. There was possible bacterial contamination. There was bacterial contamination in albumin and possible contamination of a factor 8 product that resulted in the evaluation of a lot of plant GMP, good manufacturing practices and the shutdown of this plant for a period of 5 or 6 months, and then there was a case of porcine factor 8, factor 8 that comes from pigs that is used to treat patients who have inhibitors and cannot use the regular human factor 8 where porcine parvovirus was detected, and it wasn't clear as to whether or not that could cause disease, and so, that product has been on hold until one can figure out if that causes disease.

There are other potential threats to clotting factors and other blood products, the presence of HIV group O which is not fully detected by screening tests. I referred to parvovirus, B19 and then the transferrin issue which Mark talked about that I will come back to in a couple of moments as an illustrative case.

With regard to CJD then you heard some of the history already, and things really precipitated after that late 1993 memorandum. By fall of 1994, donors with CJD were found. It resulted in market withdrawals of not only factor 8 but a number of other products, and we were made aware then that between 1983 and 1994, there were six other cases reported were products were removed from the market but no announcements had been made.

The BPAC(?) in December 1994, had voted to destroy single units that had been contaminated with CJD but to re-release the pooled products and to the National Hemophilia Foundation as well as others in the hemophilia community this really seemed to be a binary equation. Either the material was safe or it wasn't safe, and if it wasn't safe because single units were being destroyed, then it shouldn't be safe for the release of pooled products.

Those products were not released. A CJD panel was convened in June 1995, that did elect to withdraw and quarantine and reverse that decision, and that is the state that we are in today, and then as we have heard over these past 2 years numerous other market withdrawals have occurred.

So, the position is really very simple, and it is know before we treat. We asked 2-1/2 years ago for a series of questions to be answered, and we heard this morning that there are some answers to some of these questions, and the answers are perhaps not particularly encouraging.

Is CJD transmitted by plasma? Are purified plasma products infectious in experimental models of CJD? And can CJD be inactivated without destroying clotting factor, and we didn't see data to that effect, but we have heard how resistant the agent is, and at this point there does not appear to be anything promising that can inactivate that agent without destroying any of the biological material that you would like to preserve.

So, this position has led to a heightened awareness of risk and benefit ratios, many discussions between physicians and patients on the risk to the use of plasma-derived products, new research initiatives that we have heard about and some initial discussions on pool sizes and patient notification that are moving along relatively slowly at this point.

So, what is the risk? I think it is useful to talk about transferrin where Mark described an indirect exposure of CJD in the product, and to talk about how that occurred and what the implications of that are now that we are several months out from that decision.

What you heard was that the transferrin is used as a growth supplement for the cells that make a monoclonal antibody that is used to purify factor 8. Sorry, this is fairly complicated. Fortunately, Mark went through it first. This product interestingly came from an American Red Cross donor. The fraction 4 plasma was sold to a buyer who used it to make alpha 1 anti-trypsin and they also made transferrin from it which they sold to Baxter for use in the cell culture.

So, the route of transmission that would have to occur would be in the starting plasma, partitioning to the fraction 4 which at least from the animal studies looks as if that could occur. Then it would need to co-purify with the transferrin that came out of that fraction. That transferrin is added to the cells in cell culture. Those cells are secreting or spitting out monoclonal antibody. So that agent has to then bind to that monoclonal antibody. Monoclonal antibody is hooked up to a column and then plasma containing factor 8 is passed through.

So, that CJD agent then has to come off the factor 8 antibody, go with the factor 8 and then co-purify with it.

So, the risk assessment from Baxter as well as the one that Mark told you about between the FDA, other experts and the CDC was that there was negligible incremental risk. This conclusion was accepted by those two federal agencies. As Mark said, consumers were involved in reviewing that decision, and the agency decided to release those lots without labeling.

The after word that I would like to mention here is what were the consequences of that then? Did that just happen quietly or were there things that occurred in the community that would cause us to wonder if that was the correct decision, and the answer to that is that there were groups; there were local community organizations out there that objected to this. They objected to the release of those lots without labeling.

Now, you might say, "Why on earth would they do that when the risk assessment was such that everyone agreed that there was negligible incremental risk?" The reason that they did that at least in my opinion is because there is really no trust. There is no trust because of what happened in the seventies and the eighties, and many individuals are very suspicious of what the FDA decides to do, what industry does. They are suspicious of the National Hemophilia Foundation, the CDC because of everything that happened. So, despite the fact that this may be a rational conclusion, I think it is important to point out that there are those in the community that don't agree that this was a rational conclusion and that those lots should have been labeled.

So, there is a much deeper problem here than simply looking at the science and evaluating the science on the basis of its own merits, and that is probably the most important message to convey.

The kinds of questions that need to be answered are in the process of being answered. We have asked whether or not it is transmissible by blood or plasma, by fractionated plasma, by purified components. At least in the experimental model that answer is yes. Does it cause disease in humans via this route? We have heard that it does not appear to cause disease in humans. I would take that news that was presented as relatively good news with the caveat that those are very small numbers, and I would be very interested in seeing a power test on those numbers to know what that false negative rate might be.

If you look at the transmission of human growth hormone recipients, the CJD transmission in human growth hormone recipients, I think the last I heard it was just under 2 percent of all those who had received human growth hormone.

What that means is that if you look at 100 patients you may miss it, and if that is the case, what kind of modeling can be done to determine what the total number of at-risk patients are that need to be looked at in order to have some assurance in the human system that CJD is not transmitted? My guess is that that number is substantially larger than the small numbers that we have heard already, but I would like to see the statistics on that. I think that would be an important follow-up point as these studies continue.

These animal models for better or worse, they are what we had. They are what was used, and the question would be whether or not they are predictive of the human experience. That is a very tough one at this point, but unfortunately they are all that we have at this point, and there are other questions.

If more could be understood about the etiology of CJD maybe the at-risk individuals could be identified, but unfortunately, nothing is really understood about that.

Then the answer of whether or not it is inactivated has not really been established. It is probably not inactivated by current techniques. For experimental methods, though there is much more work and much more research that could be done.

So, to conclude, in looking at potential solutions to this problem, it is a question of safety or even the perception of safety, getting back to that trust issue versus cost and supply. A position of the NHF is to continue to quarantine CJD contaminated units. We have suggested that smaller pools would decrease that impact on supply. We may be hearing from Dr. Page that they have taken some steps in that direction to minimize the impact to the American Red Cross.

Develop methods to inactivate this agent. This is an area where the NHLBI, the NIH could be very instrumental in doing more basic research in this area, continuing to try to identify the cause and predisposing risk factors. I understand these are long-term questions, but this is really what needs to be done in order to have some assurance that we are on the horizontal part of a very low-incidence rate as opposed to the vertical part of a problem that has a very long incubation period.

Then in a practical sense for members of the hemophilia community to decrease reliance upon plasma-derived products and move more towards recombinant which is what the medical and scientific advisory council of the National Hemophilia Foundation has been moving toward over these last few years.

So, I would leave you with questions about the lessons learned from the experiences in the seventies and eighties. I recognize that CJD is not the same as HIV but there are lessons to be learned from how those kinds of things are handled that do have consequences on this agent and how this agent is being seen by consumers, providers and I hope by industry and the FDA, and I would ask whether or not the current criticisms of this kind of position really reflect those lessons and take into account the lack of trust that there is within members of this community.

Thank you.

(Applause.)

PARTICIPANT: Thank you. We will hold comments until afterwards.

Dr. Page will be discussing derivative cost availability issues.

DR. PAGE: Thank you very much. I appreciate the opportunity to respond to the request to provide information that we have regarding availability and cost of derivatives secondary to CJ policies of the Food and Drug Administration.

I appreciate Tom Zuck's giving the blood banking 101. I wish he had covered some of the plasma fractionation issues as well, and I will give you a little more blood banking 101 and lead up to cost information.

The American Red Cross last fiscal year collected almost 5.8 million units of whole blood from volunteer donors in the United States which as was said earlier is about 45 percent of the whole blood donations collected from volunteers in the United States. About 80 percent of these whole blood donations have their plasma separated and used as recovered plasma which means that it is pooled and fractionated into plasma derivatives.

In addition to the 12 or 13 million volunteer whole blood donations there are probably around 12 million or so source plasma donations primarily from paid donors. Most of Red Cross' donors are repeat donors. Our figures from a year or 2 ago show that they donate about one and one-half times per year on the average. Fifteen percent are first-time donors. The large majority of our donors come from community groups and the workplace or businesses where we go to them to collect blood. We get a fair amount of blood from students and a small amount from the military.

Many but not all, most of our first-time donors are from the high school and college student populations.

In response to Dr. Gompert's question and Dr. Puliavan's comment this is the age profile of Red Cross volunteer whole blood donors of at least a couple of years ago.

This contrasts to the distribution of CJ that Dr. Shermberger showed you, but you can see that there is some overlap, inasmuch as we do collect a fair amount of blood from people over the age of 50, and certainly over the age of 60, and I will come back to this in a while. About 10 percent of our blood comes from people who are 60 years of age or older.

Dr. Weinstein mentioned that in 1993, the FDA required procedures be put in place to track and act upon post-donation information, information we receive from a donor, a relative or another reliable third party after the donation that indicates that the donor developed symptoms after the donation or information is provided to us about the possibility of a risk factor prior to the donation.

In the American Red Cross we have between 200 and 400 reports per month of post-donation information which results in withdrawal of the components. This is out of about 500,000 units collected each month or a rate of about one in 2000.

This is a quote from the recent GAO report of earlier this year on blood supply safety. Licensed facilities and American Red Cross and most regional blood centers or licensed facilities reported post-donation error and accident reports or post-donation information resulting in withdrawal at a rate about 3000 times higher than that of unlicensed facilities which would be typified perhaps by hospitals that collect blood and about 135 times higher than that of plasma centers. So, I would also just add that we have been receiving post-donation information from donors spontaneously for decades even before the FDA required procedures be developed.

You have heard that we had a few reports from family members of CJ in the eighties, and ever since I have been in blood banking it has been common for donors who donate to help others to call us and say that they developed a fever the day after they donated or they just learned that they had been exposed to somebody prior to donation that now has hepatitis.

Of the post-donation information reports Red Cross has received I just listed those in the donors that developed CJ and those that had family history, and you can see that we have had on the average a report a quarter and no more than two reports a quarter for those two instances.

The left half is the three cases back in the eighties and the others start in the fall of 1994, when we had a large case, a donor who had donated about 10 gallons including recently and quite frequently, and it implicated a large amount of plasma, and after that there was a lot of attention which I think just increased people's awareness or our interest in hearing this information.

Relating to post-donation information related to CJ, the first column means the donor developed CJ, and we heard about it from a concerned family member. GH reflects the fact that the donor told us often after checking with his family or parents later on that he thinks he may have gotten growth hormone earlier in life and dura mater reflects information that we receive later that they may have received a dura mater transplant and family history, FH, means that there are two or more family members.

Of those initial reports, the CJs were all confirmed clinically or by histology. Of the growth hormones only 20 of the 39 or excuse me, 20 of the 39 upon further investigation were documented not to be growth hormone, and I will give you examples of that in the next slide, and for dura mater six we could document that it wasn't dura mater. One it wasn't even brain surgery. It was a scalp laceration that was sewn up in the emergency room.

(Laughter.)

DR. PAGE: But growth and hormone are relatively common words and adults don't have a good recollection for what they were treated with as a child and often the pediatrician or family physicians' records are no longer available. The physician is dead or they cannot remember his name and have moved.

Upon further investigation which has taken some effort, we have been able to document an example of at least one of each, one that wasn't growth hormone, that was testosterone, one that was steroids, one that was chorionic gonadotropin, one thyroid extract. One actually was bovine pituitary extract, but it was back in the forties, and a few had human growth hormone but they only had recombinant, and it was difficult for us to show that they hadn't really received it, but we could do that, and then a number of people said that they took it orally which to us means that it couldn't have been human pituitary derived growth hormone.

We are stuck, however, with a number of people who say that they got growth hormone once or twice or they cannot remember if it was a shot or a pill and were not able to obtain documentation, and we have recently had several such cases that have resulted in withdrawals of 500 to 550 thousand dollars worth of derivatives each.

The number of CJ-related withdrawals as of earlier this month is listed there, totaling 13. We have some cases when we get a report of CJ that the last donation was more than several years ago. So, there was no end-dated(?) product available to withdraw or since we make recovered plasma out of 80 percent of our collections, 20 percent do not result in recovered plasma. So, sometimes we are lucky, and there is not a plasma pool affected.

Now, I will start talking about the effect on supply of final products. AHFM is anti-hemophiliac factor or the factor 8 concentrate. Albumin and polygam is the Red Cross brand name for intravenous immune globulin.

The first line is the amount of each product where it was quarantined that either our fractionate or had as final product in-house not yet released or not yet shipped or that Red Cross had in its warehouse, not yet shipped or Red Cross regions still had on their shelves and not yet distributed.

The units are in international activity units for AHF. Equivalent units are basically the usual vial size for albumin and in polygam it is in grams.

Now, when we do a withdrawal of end-dated product, and we have shipped it out, we never know whether what has been shipped has yet been infused or remains on a hospital pharmacy shelf or in a patient's refrigerator. We recently reviewed our experience, and while we find that large amounts of end-dated product have been shipped for AHF only 3 percent of it is returned to us in our experience with these recalls or withdrawals and for albumin only 1 percent is returned and for polygam only 4 percent is returned.

So, these numbers for estimated returns have multiplied the 3, 1 and 4 percent times the total composition of that lot that was previously distributed, and you have the total effect on supply of these final products.

What is not included in the slide which I will mention later when I talk about cost is the plasma that is in process that is already pooled and includes a unit from one of these donors where it is in the process of fractionation at a stage and that processing has stopped. It is pulled off the line and final product is not manufactured. So, it never made it to a measurable number of units or grams.

We did a survey of 142 of our customers which would be primarily hospitals, also, some home care companies to find out if for some reason withdrawals or if a particular lot was to be withdrawn how much would they have on their shelves, and they said on the average that they have 2 to 3 days' worth of their use supply on their shelves. For gamma globulin they may have 10 to 14 days on the average and for AHF it was highly variable since it is in hospitals and hemophilia comprehensive care centers and in patients' homes, but a number of hospitals ordered it for just-in-time use only, and if there were a shortage they wouldn't have any on hand to keep them going for a while.

On the last slide, I also forgot to mention something else that was not included. In addition to the in-process plasma not being included as was alluded to earlier, Red Cross will occasionally sell paste to another manufacturer to manufacture into other products, and not included in this is another manufacturer of intravenous gamma globulin that had almost 1 million grams of IV gamma globulin affected by this which includes an amount not known to me that may have been distributed, but we believe that a fair amount was returned and, also, some product used to make albumin in another country as well as was alluded to earlier prolastin(?) alpha-1 prolastin which is used, excuse me, prolastin has a sole supplier and it is an orphan drug and a fair amount of that was withdrawn, and that is not incorporated in this slide nor in my further slides about cost effects on the Red Cross.

I could just point out here that 100 million units of AHF final product, assuming that an average patient with hemophilia might use 50,000 units per year would be enough AHF to treat 2000 patients with hemophilia for 1 year or enough to treat 50 patients for 40 years.

Without surveying we have received spontaneous comments from the consignees, hospitals or customers to whom we have attempted to ship derivatives. We have a number of orders that are back ordered. As was mentioned the relative shortage has been compounded by other recalls and other quarantines. (End Tape 8, Side A.)

So, we are spending an inordinate amount of time chasing inventories to fulfill patient care obligations resulting in less than optimal care and another supplier said that customers cannot find product at any price.

Now, the financial effect on derivatives for the American Red Cross alone has been calculated to be $106,300,000 as of the beginning of this month. You will note that I am using the same figures for quarantined and the estimated return which are totaled again which I have valued and then I have added in what the value of the in-process plasma in the process of fractionation would have been expected to result in as value when finally fractionated.

So, that is $75 million worth of AHF, $12 million worth of albumin and $18 million worth of polygam. This does not include other manufacturers' products that were affected by parts of this plasma.

I am going to mention the relationship of CJ withdrawals to the kind or the origin of the plasma. Tom Zuck said that of the plasma fractionated in the United States, he said that 30 percent comes from recovered plasma or volunteer donors. I used a figure of 20 percent, but I think the point is still clear. A large majority of plasma volume fractionated comes from paid-source plasma donors. However, looking at a summary that the FDA provided in July last year that was as of June 1996, they had a series of 23 withdrawals related to CJ, of which nine were Red Cross, nine were non-Red Cross volunteer collectors and five were paid plasma centers.

So, 78 percent of the withdrawals were related to 20 to 30 percent of the recovered plasma. One initiative Red Cross has taken to try to protect the adequacy of supply is to exclude from fractionation plasma units derived from blood donors aged 60 or older. It is anticipated that the frequency of withdrawals of end-dated derivatives would be significantly reduced, thereby protecting the supply for patient needs. This relates to the fact that substantially fewer persons less than 60 years of age would develop CJD in the next 2 to 5 years than persons would who are already over 60 years of age, 2 to 5 years being the maximum dating period for plasma derivatives.

So, this business practice which Red Cross initiated earlier this calendar year is not expected to have any effect on the safety of derivatives but is being taken to protect the reliability of a continuously adequate supply of all types.

As an aside I might just mention because the question has come up, a logical and necessary outcome of this initiative is that more single donor fresh frozen plasma for transfusion will come from donors 60 years of age or older. While plasma derivatives are heat or solvent-detergent treated to preclude transmission of HBV, HCV and HIV and maybe other as yet unidentified lipid envelope viruses, single donor FFP in the United States does not undergo any such treatment at the present time but since seroconverters from negative to positive for HIV and HBV are more frequent in a younger population it can be expected that while still rare, fewer blood donations would be collected during the window period for these viruses would be used as single donor FFP for transfusions since they come from older individuals.

We hope that this will reduce the frequency or number of withdrawals related to donors developing CJ by perhaps 75 percent, but the issue of donors developing older family members who have CJ such that there would be two CJ members in a family will continue, and we find that our donors are now reading the information and listening to the questions more carefully and they will go home and ask their family or others about therapy long ago, and we continue to get a small level but with significant effect reports of dura mater or growth hormone treatment in the past, sometimes which we can document and sometimes we cannot.

Thank you very much.

(Applause.)

PARTICIPANT: Thank you. We have time for comments and I will ask that we keep things fairly brief (inaudible.)

First would be Dr. Bianco from the American Blood Centers.

DR. BIANCO: Thank you. (Inaudible) as you remember America's Blood Centers or ABC is an organization that includes 72 independent community-based blood centers.

ABC thanks the Committee for the opportunity to discuss issues related to the potential for the transmission of CJD agent by transfusion. ABC members recognize the complexity of the problem, and the numbers (inaudible) philosophical questions that it raises. However, ABC members also recognize that there must be a rational way to draw the line on the extent of market withdrawals because we see the notifications both in cases of CJD and in case of other diseases for which transmission by transfusion has not yet been documented.

We are dealing with ethical and medical issues that are much bigger than CJD, and they are undeniable facts of life, and we must find ways to deal with these issues in an ethical and realistic way. Unfortunately, these facts are painful but important. The first is that all blood donors are going to become sick and die at some point in their lives, and in many instances the cause will be identifiable.

The second is that relatives of all blood donors are going to become sick and die at some point in their lives, and in many instances the cause will be identifiable.

The third is that recipients of blood and blood products, and I am a recipient of large amounts of red blood cells in plasma are also going to become sick and die at some point in their lives. Depending on our age and luck this may happen before or after those that helped us with their donation get sick and die.

These facts raise a critical question. When is it ethical and appropriate to notify recipients about diseases of the donor? One approach is to pursue product withdrawals because notifications when donors are found to have recognized blood transmissible diseases and to use information about other donor ailments to prospectively defer such donors from blood donation but to take no action regarding past donations.

This, in effect, was the practice until CJD became an issue and FDA issued its first memorandum in August 1995.

We then started notifying recipients of blood and blood products that there was a theoretical possibility of transmission of prion diseases and that they may acquire this horrible disease at some undefined point in their lives.

ABC members feel that the current practice should be revisited and is very pleased to see it brought up before this Committee. ABC members feel that an alternative strategy would be to attempt to define disease states which may be transmissible by blood for which no data exist to substantiate the hypothesis.

A surveillance system for the handling of reports of diseases for which transmission by blood and blood products has not been documented could be created and could operate as follows: For instance, and I will try to shorten my presentation, but my presentation has been distributed to the Committee, there are diseases with etiology unknown or poorly understood, no clear evidence of transmission by blood, low prevalence among recipients of large amounts of blood and blood products and no evidence of separate transmission.

Diseases that could currently be classified under that category are CJD, malignancies, autoimmune disorders, multiple sclerosis, Alzheimer's and other degenerative diseases. CJD is definitely the agent that is controversial. There is no documented transmission. There is no epidemiological evidence of CJD transmission to hemophiliacs and other blood recipients. There is no documented evidence of transmission of CJD by sexual contact, casual contact or from mother to child.

Under the surveillance system blood establishments would place a donor in a deferral file if appropriate, would retrieve (inaudible) products, retrieve unpooled plasma products collected in the prior 6 months and place these cases in a surveillance file available for FDA inspection. They could also file a report with FDA. Fractionators would proceed in the same way but would also maybe create a repository of samples from plasma pools and fractions for future studies.

FDA or CDC or some other public health organization could compile a list of those diseases that were reported by blood establishments and present each one of them for which reports have been filed to the Blood Products Advisory Committee, to other public health agencies like CDC and NIH and ultimately to this Committee for discussion and recommendations regarding the following question. Does newly acquired information suggest that notification about disease of the donor would be useful or beneficial to recipients of specific or all blood products from these donors, their families or their physicians? If the answer is yes, FDA could recommend studies to be performed on repositories of samples from donors, plasma pools, plasma fractions, could recommend notification of recipients of specific products and could institute notification of newly reported cases.

If the answer is no, no action would be taken by the blood establishment until the next review session for this disease. This proposal tries to balance the recognized obligation for notification felt by blood establishment and regulators with the recognized benefit of disclosure to recipients of blood and blood products. Disclosure of currently available information about CJD to a recipient does not carry recognizable benefits, does not help the recipient to make decisions about health, behavior, family life, finances and so on. However, the proposal also recognizes that scientific progress may in the future change this premise.

The proposed mechanism would then trigger recipient notification.

Thank you for considering this proposal.

PARTICIPANT: Thank you, Dr. Bianco.

We will proceed to, I think, discuss and present a little bit more of this at the next meeting. We are also interested in the inevitability of more mortality but we will accept that.

Dr. Bell now had some comments, and Dr. Bell is from the International Plasma Products Industry Association, IPPIA.

MR. BELL: I am now the second person to receive an honorary degree. Thank you. The International Plasma Products Industry Association is the international trade association representing the commercial producers of plasma-based therapies, nearly 80 percent of the plasma products industry. Our members include ALFA, Baxter, Bayer, Cention(?) and Immuno.

Every year approximately 4 million people rely on therapies to treat serious and life-threatening diseases, to provide passive immunity to disease or to sustain patients who are being treated for severe trauma or burns.

The recent outbreak of hepatitis A linked to frozen strawberries illustrates the role of plasma-based therapies in people's lives. To provide temporary immunity to the hepatitis A virus tens of thousands of schoolchildren were given immune globulin, a plasma-based therapy.

The need for plasma-based therapies is obvious. The safety and efficacy of these therapies are then of paramount concern.

A critical component of blood product safety lies within the policy development process where government, industry and consumers and other interested parties have the opportunity to participate and debate public policy.

Here at this meeting you have discussed Creutzfeldt-Jakob disease and hepatitis C and their respective impact on blood product safety. There is an obvious need for leadership to confront these threats, both real and theoretical to blood product safety.

IPPIA is here today to introduce ourselves, to offer our expertise on behalf of the industry. In our efforts to lead by example, the association has promulgated a series of voluntary standards as part of a continuing effort to raise the bar for the quality and safety of our therapies.

Additionally, industry has established a research consortium to investigate new opportunities to enhance the safety of plasma derivatives. Let me quickly provide you an overview of these two initiatives. First, the voluntary standards; there are a number of opportunities from the beginning of the collection process all the way to the end point of manufacturing to interdict and cull out otherwise unidentifiable potentially infectious units. Through center management, donor management, unit management and testing technologies our program seeks to systematically confront each of these opportunities.

The first step is in reducing the risk of undetected pathogens entering the manufacturing process, is to manage the quality, the recruitment and the retention of the donor population. Our voluntary standards establish a maximum allowable viral marker rate based on the incidence of HBSHE, HCV and HIV.

The next opportunity to interdict is through donor management. Approximately 5 to 10 percent of all individuals who walk into a donation center are doing so for the first time. It is this group of individual prospective donors that are widely acknowledged as the group most likely to be at risk to carry virus.

Under our voluntary standards plasma from one-time plasma donors will not be used to make plasma-based therapies. Only donations from those individuals who test negative on two separate occasions and on each and every subsequent occasion will be used to manufacture plasma-based therapies.

The next opportunity to interdict is through unit management. Our voluntary standards require all donations to be held in inventory for a period of not less than 60 days. During this time if the donor seroconverts and subsequent donations test positive, the earlier donation can be retrieved from inventory and destroyed.

Beyond our efforts to select a quality donor population using only previously tested repeat donors and managing units through inventory hold and retrieval there must be an effort to use cutting-edge, state-of-the-art testing technology to identify and exclude potentially infectious units.

In 1997, voluntary association standards will require that all plasma used in the manufacturing process will have tested negative through genome amplification testing for HIV and hepatitis C. The adoption of this testing will ultimately require regulatory approval, and we are working closely with the FDA to achieve that end.

As you can see the voluntary standards are comprehensive. Yet, they cannot be measured in their effectiveness by any one of these standards. These standards must be viewed as a whole.

Another voluntary initiative undertaken by the industry is the Consortium for Plasma Science formed this past January by five leading plasma fractionation companies.

The aim of this research consortium is to develop broadly applicable technologies or methods that inactivate or remove pathogens in plasma or plasma derivatives.

Approximately $4 million will be available in research grants from 1997 to 1999. The primary emphasis will be on non-envelope viruses referred to earlier. That may include parvovirus, hepatitis A virus, vaccinia and SV40. Specifically with respect to CJD, IPPIA encourages high priority on research toward resolution of the theoretical risks of CJD.

We look forward to the development of scientific evidence that will provide the basis for definitive public policy, hopefully resolving the theoretical concern of transmission of CJD through blood.

It is encouraging to note that the World Health Organization in March concluded that, quote, studies have yet to identify a single instance in which the disease has actually been transmitted by blood.

We welcome the Federal Government's leadership in organizing a workshop sponsored by the NIH that will focus on epidemiological studies of CJD and its theoretical transmission risks through blood.

Finally, we at IPPIA believe that through our own voluntary initiatives to address both real and theoretical risks and through cooperative dialogue such as this meeting here today we will make strides to our mutual goal, a safe and adequate supply of plasma-based therapies.

Thank you.

PARTICIPANT: Thank you.

One last comment then very briefly by from Dr. Kleinman from AABB so that we have not missed anyone, and then we will try to close out the panel.

DR. KLEINMAN: Thank you. I think you all had a chance to pick up this statement which is in the back. So, I think I will just read it from the midpoint to save some time.

In the case of CJD, well, as a follow-up procedure donors, as we have heard sometimes provide both post-donation information about their medical condition or their risk factors to the blood bank. Should this occur, measures are in place to notify consignees and to retrieve and quarantine any implicated end-dated blood products intended for use in transfusion or further manufacturing into injectable products.

The dilemma in the case of CJD is to identify what truly is an implicated unit. For donors subsequently diagnosed with CJD, FDA has recommended that all implicated blood components and plasma derivatives should be destroyed. To protect against the possibility of not having product to treat patients the FDA has indicated that in the event of documented shortage affected plasma derivatives could be labeled to indicate the presence of implicated units and could be issued.

Previously donated units are also withdrawn when the donor is know to have a history of multiple blood relatives with CJD or if the donor has now informed the blood bank that he has received human pituitary-derived growth hormone or a dura mater transplant.

Use of finished plasma derivatives found to contain a unit from a donor with a history of only one known family member with CJD is permitted given that over 85 percent of cases of CJD are sporadic.

Consignee notification for the purpose of retrieving end-dated components is necessary and may prevent the use of an implicated unit. However, in the event that the unit has already been used, the value of recipient tracing and notification is less clear. The FDA has suggested that when considering counseling of recipients of implicated blood products the magnitude of the risks associated with informing patients that they have received such products should be weighed against the magnitude of the risk that CJD is transmitted by transfusion from these products, and the ABB currently recommends that blood collection facilities notify transfusion facilities of any units theoretically at higher risk for transmitting CJD.

In Association Bulletin No. 96-4 there is information about CJD and about suggested procedures and materials to facilitate a decision on the part of a recipient's physician as to whether or not to notify the recipient.

Under the bulletin's recommendations the medical director of the blood bank would initiate deliberations by an appropriate body at that institution. This could be an institutional review board, an ethics committee, medical staff executive committee, etc.

That group can then deliberate and develop criteria for informing patients that they have received a component or derivative from a donor with a CJD risk as well as the Committee could develop criteria for electing to withhold such information.

These criteria would allow physicians to individualize decisions and to make those notification decisions that are best applicable to individual patients. The result would be an institutional policy and procedure that would be distributed to the medical staff in that facility, and this policy would ideally be in place before any such notifications are actually received by the hospital.

The ABB continues to monitor research on CJD and to inform its membership of ongoing developments. The ABB places the highest priority on the safety of the blood supply and will develop standards as consensus on scientific data and medical practice regarding CJD is reached.

Interim guidance to members will be published as information becomes available.

Thank you.

PARTICIPANT: Thank you, Steve.

There is a lady in the back who has a really concerned comment. I will let her proceed to bring it to our attention.

Mrs. Hendrickson?

MRS. HENDRICKSON: Yes. My name is Angie Hendrickson, and I am one of those untrusting people. I am a consumer. I have an almost 14-year-old son who is a patient here at the NIH. He has severe hemophilia A. He has full-blown AIDS. He was also infected with hepatitis C. He has parvovirus B19 and I have been receiving withdrawal notifications for CJD since 1994. Since I received my first notification I have been looking at CJD. I attended the Center for Biologics Meeting on TS Use earlier this week, and something that I think has been missed here with the issue of CJD and the blood supply is despite that we saw in the graphs with the years when we are seeing the rise in CJD cases, I think that we are overlooking the outbreak of BSE in England. There has been new evidence of a new strain, a new variant of CJD called VCJD, and the World Health Organization since last year has been looking into the potential that BSE is linked to CJD. Now, I am concerned about this, and I think that there are too many things to just let this thing dangle for a long time.

My son has been exposed to a lot of diseases. I have him on videotape sticking an IV needle into his arm looking into a camera saying, "You mean now I might get mad cow disease?" That is what I want to say. We are blood safety here, and I went and heard Mr. Rohrer yesterday and the day before talking about the transmissible spongiform encephalopathies. They have seen a porcine transmission. There was a forum held right here at the NIH in February about the evolution of primate lentiviruses.

We are hearing that there are no cross transmissions, and I am seeing different things. I am hearing different things. I am concerned, and I bring you my concerns here today. I have a lot of documents. I am going to make copies, and I am going to send them to this Council, and I hope that you will look at them.

Thank you.

PARTICIPANT: Thank you. You represent the bottom line for the Committee. I think we are all in favor of listening to those comments. We will continue on with at least a few questions, but Eric Goosby, do you have anything to bring to the attention of the panel? (Inaudible) Dr. Eric Goosby.

DR. GOOSBY: Yes, it has been there for a while. I just want to express our commitment to be responsive to the issues that the panel has raised over the last 2 days in the discussions that have occurred and the concerns that have been presented, the requests, etc. We will convene a work group after this toward the end of this week, this week coming up and look at the issues that were brought up by the Committee and respond to them with a time frame that will be somewhere around 2 to 3 weeks.

A number of the requests that came up yesterday, a couple of them we were able to turn around and put back to you today, but the majority of them will come back to you over the course of the 3-to-4-week period.

Issues in your deliberations that occur in preparation for the next meeting we will also make sure that there is an attempt and ability to transmit that information throughout the Committee membership and the ex officio members. So, the next meeting will be a little bit more in tune with the specific needs that you identify over these next few weeks. So, let me just make that commitment to you.

PARTICIPANT: Now, for the panel, do you wish to go into a little question and answer or (inaudible) review this material at the next meeting? Do we have some burning questions?

It doesn't look like it. I would like to thank all the panelists and, also, the commentators we have had. In addition, Mrs. Hendrickson we will be very glad to get the material that you send forth. Many of us have been taking care of patients similar to your son, and we hope (inaudible).

At this point the meeting is adjourned.

(End of recording.)