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Blood Safety Transcripts

DEPARTMENT OF HEALTH AND HUMAN SERVICES
ADVISORY COMMITTEE ON BLOOD SAFETY AND AVAILABILITY

NINTH MEETING

Volume I

Thursday, August 26, 1999

9:08 a.m.

Hyatt Regency Capitol Hill

400 New Jersey Avenue, N.W.

Washington, D.C. 20001

P A RTICIPANTS

Members

Arthur Caplan, Ph.D.

Stephen D. Nightingale, M.D., Executive Secretary

Janice K. Albrecht, Ph.D.

Larry Allen

James P. AuBuchon, M.D.

Ronald Gilcher, M.D.

Edward D. Gomperts, M.D.

Jessie Goodman, M.D.

Fernando Guerra, M.D.

Paul F. Haas, Ph.D.

William Hoots, M.D.

Carolyn D. Jones, J.D., M.P.H.

Dana Kuhn, Ph.D.

Tricia O'Connor

Jane A. Piliavin, Ph.D.

John Walsh

Consultants

Richard J. Davey, M.D.

Ex Officio Members

Mary E. Chamberland, M.D.

Colonel Fitzpatrick

Paul R. McCurdy, M.D.

David Snyder, R.Ph., D.D.S.

Also Present:

Capt. McMurtry

C O NTENTS

AGENDA ITEMPAGE

Welcome, Roll Call, Conflict of Interest Announcement 3

Address by David Satcher, M.D., Ph.D.,

Assistant Secretary for Health and

Surgeon General 9

I. Deferral of blood donors who have resided or traveled in the United Kingdom for a cumulative six months or more between 1980 and 1996

Status of Issue 44

Strategies for monitoring the blood supply 70

Blood donations by individuals with hemochromatosis 100

Recommendations for increasing blood donations 253

Advisory Committee discussion and recommendations 272

II. Current Availability of Blood Products

Advisory Committee disucssion and

recommendations 329

Adjournment 363

P R OCEEDINGS

DR. NIGHTINGALE: My name is Stephen Nightingale. I am the Executive Secretary of the committee, and I'd like to begin the meeting by calling the roll.

Dr. Caplan?

CHAIRMAN CAPLAN: Here.

DR. NIGHTINGALE: Dr. Albrecht?

DR. ALBRECHT: Here.

DR. NIGHTINGALE: Mr. Allen?

MR. ALLEN: Here.

DR. NIGHTINGALE: Dr. AuBuchon?

DR. AuBUCHON: Here.

DR. NIGHTINGALE: Dr. Busch will be absent today. Dr. Gilcher?

DR. GILCHER: Here.

DR. NIGHTINGALE: Dr. Gomperts?

DR. GOMPERTS: Yes.

DR. NIGHTINGALE: Dr. Guerra?

DR. GUERRA: Here.

DR. NIGHTINGALE: Dr. Haas?

DR. HAAS: Here.

DR. NIGHTINGALE: Dr. Hoots?

DR. HOOTS: Here.

DR. NIGHTINGALE: Ms. Jones?

MS. JONES: Here.

DR. NIGHTINGALE: Dr. Kuhn?

DR. KUHN: Here.

DR. NIGHTINGALE: Ms. O'Connor?

MS. O'CONNOR: Here.

DR. NIGHTINGALE: Dr. Penner will be absent today. Dr. Piliavin?

DR. PILIAVIN: Here.

DR. NIGHTINGALE: Dr. Schiff will be absent today. Dr. Secundy will be absent today. Mr. Walsh?

MR. WALSH: Here.

DR. NIGHTINGALE: Dr. Chamberland?

DR. CHAMBERLAND: Here.

DR. NIGHTINGALE: Dr. Goodman, who will be here on behalf of Dr. Epstein.

DR. GOODMAN: Here.

DR. NIGHTINGALE: Colonel Fitzpatrick?

COL. FITZPATRICK: Here.

DR. NIGHTINGALE: Dr. Goosby is unavoidably absent today. Dr. McCurdy?

DR. McCURDY: Here.

DR. NIGHTINGALE: Dr. Snyder?

DR. SNYDER: Here.

DR. NIGHTINGALE: Dr. Davey?

DR. DAVEY: Yes.

DR. NIGHTINGALE: And Captain McMurtry, for the record, I believe is here also.

Very briefly, before we begin the meeting, it is a matter of federal regulation to read the following statement:

The following announcement is made as a part of the public record to preclude even the appearance of a conflict of interest at this meeting. General applicability has been approved for all committee members. This means that unless a particular matter is brought before this committee that deals with a specific product or firm, it has been determined that all interests reported by the committee members present no potential conflict of interest when evaluated against the agenda.

In particular, as specified in Title 18 of the U.S. Code 208(b)(2), a special government employee, which all committee members are, may participate in a matter of general applicability, for example, advising the government about its policies relating to the hepatitis C epidemic, even if they are presently employed or have the prospect of being employed by an entity, including themselves if they are self-employed, that might be affected by a decision of the committee, provided that the matter will not have a special or distinct effect on the employee or the employer other than as a part of a class.

The example given in 5 CFR 2640.203 which implements the code is as follows: A chemist employed by a major pharmaceutical company has been appointed to serve on an advisory committee established to develop recommendations for new standards for AIDS vaccine trials involving human subjects. Even though the chemist's employer is in the process of developing an experimental AIDS vaccine and, therefore, will be affected by the new standards, the chemist may participate in formulating an advisory committee's recommendations. The chemist's employer will be affected by the new standards only as part of the class of all pharmaceutical companies and other research entities that are attempting to develop an AIDS vaccine.

In the event the discussions involve a specific product or a specific firm for which a member has a financial interest, that member should exclude him- or herself from the discussion, and that exclusion will be noted for the public record. With respect to the other meeting participants, we ask in the interest of fairness that they disclose any current or previous financial arrangements with any specific product or specific firm upon which they plan to comment.

At this point, I would like to turn over the microphone to our Chairman, Dr. Caplan, and suggest that since Dr. Satcher is here that we might proceed to his comments.

CHAIRMAN CAPLAN: In fact, I want to welcome committee members back. I want to suggest, Stephen, it is time to change the identity of that case example from that chemist.

[Laughter.]

CHAIRMAN CAPLAN: Anyway, okay. We had a response from Secretary Shalala to our advisory committee meeting of last April in which she noted our concerns about blood supply, our suggestions about hemochromatosis, and the contextual issue of deferrals of people who have spent extended periods of time in England. And Assistant Secretary Satcher has been kind enough to come and comment on both that response and I guess those emerging issues. And since his time is tight, I'm simply going to turn the floor to him and let him do so.

DR. SATCHER: Thank you very much, Mr. Chairman. Again, I appreciate your respecting my time. I want you to know how much I appreciate the time that you and members of this committee are dedicating to these very important issues that relate to blood safety and availability, and I'm very pleased to be able to join you today.

The first item on your agenda today is guidance to industry that the FDA issued on August 17th. That guidance relates to deferral of blood donors who have resided or traveled in the United Kingdom for a cumulative six months or more between January 1980 and December 1996. I want to address some of the concerns that this action has raised.

We are deferring blood donors who lived in the United Kingdom around the time of the mad cow epidemic. Mad cow disease, as you know, first appeared there in 1985, a few years after a change had occurred in how cow feed was prepared. In 1988, the use of certain animal products in cow feed was banned, and the mad cow epidemic subsequently receded.

It now seems clear that mad cow disease was transmitted by contaminated feed, but there may have been other ways it was transmitted as well. A new variant CJD appeared in the United Kingdom in 1995, ten years after the appearance of mad cow disease. New variant CJD is the human counterpart of mad cow disease. Forty-one of the 43 victims of new variant CJD, which is the total so far, 43, have lived in the United Kingdom for at least ten years between 1980 and 1996. One other victim lived in France, and the last, an Irish citizen, appears to have spent substantial time in the United Kingdom.

It therefore seems likely that the agent that causes mad cow disease crossed the species barrier from cow to human in food, but, again, there may have been other ways it was transmitted as well.

I think the greatest uncertainty at present is the number of United Kingdom residents who will eventually develop new variant CJD. A cow will develop symptoms about five years after exposure. If the incubation period in humans is also five years and no further transmission takes place, there could be at least--I should say there should be less than 500 cases, according to our calculation. However, if the incubation period is much longer, far more could be affected.

A test to detect individuals at risk for developing new variant CJD might settle this issue, but that test, as you know, is not yet available.

There are some other uncertainties that we're concerned about. The new variant prion, for example, has been detected in the tonsils and appendix of individuals before any symptoms of new variant CJD had developed. So the question is: Can pre-symptomatic individuals transmit the disease?

In the case of classic CJD, we have extensive epidemiological evidence for over at least three decades that would conclusively demonstrate that this does not occur. In the case of new variant CJD, however, we do not have a corresponding assurance.

At present, the only way to reduce the possibility that the agent that causes new variant CJD might be transmitted in blood transfusions is to defer any blood donor who might be capable of transmitting this agent. This action was first proposed by the FDA Transmissible Spongiform Encephalopathy Advisory Committee, or TSEAC, on December 18, 1998. At that time the committee recommended that this action not be implemented until its impact had been thoroughly assessed, and we agree with that decision.

On June 2, 1999, the committee reviewed detailed estimates from the blood industry on the impact that this recommendation would have. Essentially, these estimates were that a one-year-residence-based deferral would eliminate about 1.5 percent of donations and that a six-month-residence-based deferral would eliminate 2.2 percent of donations.

So TSEAC then reaffirmed its prior recommendations to defer and polled its members individually on the duration of residence that would trigger denial.

Because of the obvious urgency of this issue, the department moved rapidly to consider it. The Blood Safety Committee, which I chair, met on June 8, 1999, to consider the committee's recommendation and they unanimously supported it. The Blood Safety Committee also unanimously voted in favor of the six-months-residence trigger.

I accepted the Blood Safety Committee recommendation and communicated my support of it to the FDA. The FDA in turn announced its plans to implement this recommendation on June 17th, and their guidance to industry was issued on August 17th.

Now, we plan to monitor the impact of this policy very carefully, and I want to really make that point. We plan to revisit this decision to monitor impact, and you will hear a more detailed description of our monitoring plans later this morning.

We remain committed to regular review of the policy and to updating it as soon as new scientific information becomes available. We will also continue our support of research into the cause, transmission, and treatment of all the transmissible spongiform encephalopathies, including, but not limited to, new variant CJD.

We will also continue our support of research into the most effective means of promoting blood donations, another issue of concern which you have begun to discuss. Furthermore, the senior managers of the department, certainly including myself, are willing and, in fact, eager to participate in appropriate industry-sponsored programs to increase blood donation.

I certainly appreciate the efforts that you made last August to examine the reserve capacity of the blood supply. We have acted on the recommendation that you made. I also appreciate the effort of the Public Health Service Working Group which I commissioned to investigate this matter, and we will act promptly on their recommendations as well. And as you will see, they made recommendations in areas related to better monitoring of the blood supply, promoting donations by eligible donors, removing barriers to safe donation of blood, and along that line that you will hear more about.

I look forward to receiving any additional suggestions that may arise from your deliberations this morning or in the future.

This afternoon you will receive an update on the availability of plasma derivatives, another issue that you have been concerned with and have made recommendations about, and the steps that have been taken to improve this situation will be discussed. We remain concerned about the quantity of these products that is available, and we would like to consider carefully how this situation could be further improved.

You will also hear an update on the progress of the hepatitis C lookback. This update will include the revised guidance to industry by the FDA which was issued on June 17th and CDC's plans for general notifications, tracking the progress of direct notification and evaluating the success of these efforts. And I must say, within the department we are very pleased with how this process is evolving.

Tomorrow morning you will consider the issue of how federally mandated blood safety measures should be financed, and I'm sure this discussion will be lively and constructive.

As you engage in this discussion, I'm sure you will remember that the blood supply is safe and is as safe as it is because we have worked very hard to make it safe and you have worked very hard. We also need to remember that there is no guarantee that it will remain safe unless we maintain our vigilance. So, again, we appreciate the outstanding contributions which you have made to that vigilance.

I'd be happy to answer any questions about these comments if there are any.

CHAIRMAN CAPLAN: Thank you very much, Dr. Satcher.

Let's open the floor to the committee. You have a question, Jim?

DR. AuBUCHON: The scientific imperative for a geographic deferral for new variant CJD, at least based on my understanding of the Transmissible Spongiform Encephalopathy Advisory Committee deliberations, was far from clear; that this group made their recommendation based on the best available evidence and they certainly had an eye towards safety, which was appropriate. Nevertheless, this was not an epidemic that was clearly present upon us. It was a potential threat.

It surprised me greatly that after this committee had discussed at our last meeting the concerns about the availability of the blood supply, that the decision about the safety of the blood supply, which would impact greatly on availability, was not brought to this committee for resolution since our name seems to imply that we consider both safety and availability, and those were the two issues in this case.

Why was the decision made without the input from this committee?

DR. SATCHER: Well, I guess in a sense we thought we had general input from this committee that if we're going to err when it comes to the safety of the blood supply, that we certainly err on the side of being too cautious.

Here we had facing us a decision that would potentially impact 2 percent, 2.2 percent of the blood supply, and could cause in the minds of lot of Americans a lot of concerns about the safety of the supply. So we made a decision that we thought said that we clearly want to take every precaution to protect the safety of the blood supply, and I believe that that's in the spirit of this committee.

We also at the same time, as you imply, took on the issue of the availability and started immediately to develop strategies, including appointing a committee throughout the department to look at strategies for increasing the supply. As members of this committee have pointed out, if you just look at eligible donors, people who are donating, an average of 1 to 1.5 active donors who are donating maybe once or less than twice a year, if we could increase those donations just slightly, we could significantly increase the blood supply. And, of course, there's the hemochromatosis issue that you're going to discuss more today. And as you have said here in this committee, we have the opportunity.

So I think even though we didn't bring this issue to us in the interest of time--and we thought that time was critical--we certainly were listening to you when we had that discussion because of what you had said about opportunities for increasing the availability of the blood supply and the general principle that the concern of the American people about the safety of the blood supply is something that we should keep in mind. That's how we dealt with this issue.

DR. AuBUCHON: Thank you.

CHAIRMAN CAPLAN: Larry?

MR. ALLEN: Good morning, Dr. Satcher.

DR. SATCHER: Good morning.

MR. ALLEN: Each time I attend these meetings I am hopeful that in the few moments that we all share here that we can gain a greater understanding of each other's various views. But there are some things that I'm a bit concerned about, and I know that throwing all these at you at this point not only isn't fair, but I know you don't have the answers to all of these questions.

DR. SATCHER: But feel free.

[Laughter.]

DR. SATCHER: Why should you be any different?

MR. ALLEN: I could give you personal details of what my life and my family's life has been like for the last 20 years just dealing with the issue of sickle cell, but there are greater issues that we see as a problem. Some of them just maybe things aren't being communicated properly, and that is the issue of the lookback--not the targeted lookback but the other lookback--from 1980 to '92, I believe. Dr. Margolis from the CDC had designed a project, and there were going to be two piloted cities, Chicago and D.C.

My understanding, however, is that beyond funding for those two targeted cities, HHS has never asked for funding beyond these two targeted cities. And I'm curious if that is the case, and if so, why?

Secondly, we've been hearing a lot about the hep C and the testing and availability of testing and when testing became available. We've been getting information lately that shows that as far back as 1989, 1990, there have been interferon tests that proved that there were some positive outlooks for hepatitis. It was published in the New England Journal of Medicine back in '89, '90, and since attending these meetings, we've been hearing that up until a certain date, I think late or mid-nineties, there wasn't an accurate form of treatment. And we feel that, you know, if there was at some point a determination that interferon was a possible treatment, that we should have been told about this and something should have been done a lot earlier.

So these are just things that I'm hearing and would like at some point to get some clarification on. Besides that--

CHAIRMAN CAPLAN: Larry, do you want to see if he wants to comment on those two first?

DR. SATCHER: Well, let me just say I know that you're going to have an extensive discussion about the hepatitis C lookback this afternoon. I don't know. Is Dr. Margolis going to be here? You're going to lead the discussion?

DR. CHAMBERLAND: I'm going to give the update.

DR. SATCHER: Okay, Dr. Chamberland. So you're in good hands on that one, and I don't know if you want to comment on the budget thing.

I assume that CDC feels that the program that is proposed to carry out, it can carry it out. I think we're all struggling with resources. There's no question about the fact that in our department we're trying to make the best of the resources we can get from Congress and otherwise. So we believe that we can carry out the program that we have proposed to you. Let me put it like that.

We have not gotten all of the funding that we would have liked to have received to support this effort, but we believe that we can carry out the program that we've proposed.

You will hear more about that in detail this afternoon when you hear about the lookback, unless Mary wants to say something now. But I know you're going to have an extensive discussion this afternoon.

I'm not sure I can comment on the interferon. There have been so many discussions about interferon and its potential, whether it's hepatitis C or AIDS or what have you. And I can only say that I think we have handled that appropriately in terms of how we've evolved the treatment of hepatitis C. And, obviously, the most important thing is that we've developed some new agents in recent years--and we continue research in that area--that are making a significant difference for hepatitis C and will continue to.

I think one of the strengths of our system--and we have a lot of weaknesses--is that we have a very strong system for approving drugs for treatment. And I think the American people have grown to appreciate that over the years as we have benefited tremendously. I don't need to go back and tell stories like thalidomide and things like that to point out the danger of not having that kind of system in place.

So we don't take lightly decisions to say that a drug is effective for treating any particular condition. But that does mean delay sometimes.

CHAIRMAN CAPLAN: Want to do one more?

MR. ALLEN: One other thing. I talked to Mary and other members of the CDC regarding an issue of determining how many people with sickle cell throughout the early eighties, or whenever, came down with HIV as a result of blood transfusions. And what I've gotten back is that there's been no tracking whatsoever on this issue.

I need to know personally what can we do about this.

DR. SATCHER: That's a good question. I'm sure you know my history. I started out in the early seventies as the director of one of the ten national sickle cell research centers, and I would think that it would be easier in that population to answer that question because of the numbers.

Now, the sickle cell disease branch--Paul?

DR. McCURDY: Dr. Nemo just reminded me that the transfusion safety study from the National Heart, Lung, and Blood Institute that was in the middle eighties--'83, '84, or thereabouts--found in a sample of sickle cell patients that 12 percent were infected with HIV. And that's a ballpark figure, but it was in several major cities and is probably accurate.

DR. SATCHER: Yes, I would think that would be reasonable. We know that about 50 percent of the hemophiliac population became infected with HIV during those early years when we were not able to screen the blood supply. So I think--so we do have some information, and the question is whether we're continuing to monitor that for the sickle cell population.

CHAIRMAN CAPLAN: Ron?

DR. GILCHER: I'd like to emphasize one of the points that you made, Dr. Satcher, which I think is extremely important. As a blood center director, I am very concerned about the availability of the blood supply with having imposed the deferral on donors who have been in England. And I think the point that you made that we must have a lot of attention paid to is that this is a deferral that can be lifted in time once more data is available and that we don't shut the door on these donors. And I think that's a very important point for all of us to understand.

DR. SATCHER: I appreciate your point, and that was a very important part of our discussion. We understand the limitation of the information that we have and, therefore, we will monitor the impact of this decision very carefully and any new science that is developed, and we will revisit this issue rapidly.

CHAIRMAN CAPLAN: I had a question; then we'll go over to Dana and Keith.

One of the things I noticed in the written materials that we go--and it relates to the question about tracking infection rates in sickle cell--is that we don't seem to have still a good handle on monitoring the overall situation with respect to blood availability, that data is not readily available about this. And I think the committee--I'll go out on a limb here and say that one of the things that has been flagged for us since our last meeting was this problem of impeding shortage. So I'm hopeful--and it's not so much a question as a comment. I think it's going to be very important over the next year to make sure we establish good tracking of the blood supply when we get into issues about the impact of deferrals or the input from hemochromatosis and so on. It's going to be very important to reassure, I think, the American people that we have good numbers on what's going on with respect to the total blood supply.

DR. SATCHER: I think that's a very important point. As I pointed out, the Public Health Service committee that we set up to look at this issue, the first recommendation was that we do a better job of monitoring the availability of the blood supply. But since that time--I think I'm right about this--the National Heart, Lung, and Blood Institute has committed funds to begin a process of much better monitoring of the blood supply. So we hear you.

I don't know if anybody else wants to comment on that.

DR. NIGHTINGALE: That is on the agenda.

DR. SATCHER: Okay.

CHAIRMAN CAPLAN: Dana?

DR. KUHN: Yes, Dr. Satcher, I'm really pleased that this committee has had the privilege of being able to look into the hepatitis C epidemic and am pleased that we have had the opportunity to make some very important decisions which would affect this nation as well as the decisions that HHS has made regarding hepatitis C and this epidemic.

But I would like to just continue to encourage whatever we can do to quickly, as soon as possible, continue with the targeted lookback as well as the national media campaign to inform the American public, because as yet I still don't think the American public is aware and is going to--is not going to be able to take any kind of actions to either make some lifestyle changes or to pursue treatment until they are really made aware of what's going on on a national, broad-based view of this.

DR. SATCHER: Well, I think you're right, and I would say when you discuss this issue this afternoon, I think if you feel that, you know, the plans we have in place and the way it's progressing are not adequate, then we would expect you to say that and to make some recommendations as to how to strengthen it.

I agree. I think it's really critical that we move fast, and we've got to move faster than we're moving. It's not easy to educate, motivate, and mobilize the American people on an issue like this, but I think the strategy here is one that will work.

CHAIRMAN CAPLAN: Keith?

DR. HOOTS: Just to follow up on what Dr. AuBuchon and Dr. Gilcher said on the TSE deferral issue, after having reviewed the whole summary of the meeting of TSEAC as well as the BPAC, it still wasn't clear to me. I know that qualitative risks were determined in terms of loss of repeat donors by the impact of this deferral and loss of repeat donors. But I never saw and I don't think this committee has seen a very accurate curve and the slope of the curve where repeat donors cross into single donors and how that curve crosses the theoretical risk curve of one year versus six months versus three months in terms of deferral for UK residency.

Those are the kinds of issues, coupled with other theoretical issues like who's met/met, codon 129 positive, is that a theoretical higher risk factor--all those things I haven't seen factored into a complex algorithm. I understand that the Blood Safety Committee was under some exigency to make a recommendation. But in light of Dr. Gilcher's comment about the fact that there's a continual effort to relook at this issue, I'd like to urge that either this committee, the Blood Safety Committee, the TSEAC, and perhaps all of the above put together all the modeling capacity that might be out there, both from the UK, from all the EU, and from the United States, of how these risk curves cross each other and where the paramount points are reached. Because I think if we're going to come up against a supply shortage at some point, it would be nice to know who we're going to back off on first so that we can reassure the public that we're not just waffling in the wind because yesterday we had enough blood but today we don't and, therefore, we're going to back down on our recommendations; but, rather, we have a prospective algorithm that says we can increase the blood supply by 100,000 units per year by saying that we've looked at the numbers and we think the risk of deferring repeat donors because we're replacing them with single donors is actually higher to the public than deferring them because they happen to live in the UK or resided in the UK for six months.

DR. NIGHTINGALE: Dr. Satcher, if I could answer that on your behalf, I would be glad to provide Dr. Hoots and the rest of the members of the committee with the final version of the briefing paper that was provided to the committee on the 8th. The committee will recall that I gave you 20-odd handouts the first time. The data is in there, and I apologize for the fact that it is not highlighted. I will be glad to provide that to you.

DR. HOOTS: Okay. Thank you.

DR. SATCHER: And if you want more discussion of it--we do want to make decisions on the best available science at any given time, and sometimes, you know, we have to balance that. But we try to find the best available science and use that as the basis for our decisions. So we accept that challenge. But I think you will find that it was.

CHAIRMAN CAPLAN: Fernando?

DR. GUERRA: Dr. Satcher, as you well know, there have been some recent important recommendations that have been offered along the lines of important public health preventive efforts with the discussions around the thimerosal issue as it obviously relates to the use of hepatitis B vaccine.

I guess, you know, the concern relates very much to some of what we're discussing this morning and at any of our other meetings related to theoretical risk and how one conveys theoretical risk to the public and to the practitioners of health care and those who provide the different services.

And in this instance where we have, I think, had the occurrence of several instances, whether it's with vaccines or with the safety of a variety of blood and blood products, where we're making certain very important decisions and offering some recommendations based on theoretical risk, that certainly put up some warning signs to the public at a time when we obviously need to maintain a level of confidence and trust in those important programs and services.

At times we fall short in terms of how we can best communicate that so that hopefully we don't lose too much of that trust, but you'd perhaps offer some comments about that.

DR. SATCHER: Yes, because, as you know, I was involved in the decision that we made about thimerosal and to try to limit thimerosal vaccines and move toward thimerosal-free vaccines. And you're right, that was based on the fact that given the increase in the number of vaccines that children receive by the age of two, I guess first in Europe, concern was expressed about the amount of mercury--and this is the ethyl form of mercury, but the amount of mercury that children are getting in these schedules.

Then FDA did a very thorough investigation in this country, had manufacturers to report on their vaccines and thimerosal content. And on the basis of that, we thought that while we felt that we still had a safety cushion, if you will, in terms of the amount of mercury any child would receive, theoretically it was above what we consider acceptable. And, therefore, we made the decision to start by deferring vaccines that could be deferred--for example, the first dose of hepatitis B--and then to move toward thimerosal-free vaccines over a period of time.

So your point is well taken. Again, we made a decision because we think as long as the safety of any child is in question based on the vaccines that we provide, and we can do something about it without hurting children in terms of vaccinations, we try to do that. And I know and share your concerns that the real issue here is that we have saved millions of lives through our immunization program, and the worst thing that could happen would be to allow a situation to develop where, based on some theoretical risk that was not realistic, that we had people backing away from child immunizations.

So we're struggling with that. As you know, we had a major congressional hearing two or three weeks ago on that issue, not just thimerosal but concerns that parents have about things like autism and the relation of the vaccine, even though we have no evidence--and the Institute of Medicine has participated in studies, and certainly in England there have been studies. Certainly there is no evidence of the relationship. But parents are concerned.

So our response has to be we will continue to research these issues, we will continue to do everything that we can to make vaccines as safe as we can make them and to deal with concerns that parent have, very similar to what we say about the blood supply. So you're right, it's a very similar situation that we're dealing with.

Jessie, I don't know if you want to comment on that, but basically that's where we are.

DR. GOODMAN: No, other than to say that there's clearly this fine balance, and part of preserving public trust is how you communicate when something--one way I like to think of this is that we have to communicate differently about what is a potential public health risk versus what's a public health emergency or crisis. And because of the way the media and the complexity of that distinction is handled, they're often handled the same, and everything becomes a crisis. And we have to struggle in our communications about these potential risks to be sure we communicate that that's what they are.

On the other hand, if we don't face up to these potential risks and they become crises that weren't dealt with, the damage to the trust is much, much greater. But I agree there's a problem in risk communication, and the government does not have control--the government could do better at risk communication, but ultimately that's a public and democratic process.

CHAIRMAN CAPLAN: Jane?

DR. PILIAVIN: This is one more question about the CJD situation.

First, I want to say that if I had still been a member of the BPAC, as I once was, there would have been one more vote against this deferral of people who had lived In Great Britain, and it's not just because our family lived there for the year 1983-84, although you are losing a very remarkably good blood donor in my daughter. She's got that kind of blood that only 10 percent of people have that they can give to preemies.

DR. SATCHER: We hope to regain her.

[Laughter.]

DR. PILIAVIN: Well, you can't have her now. She's pregnant.

Seriously, my understanding of the science--and I'm not a medical scientist--is that if there is any potential risk, it lies in the white blood cell component of the blood. And I'm wondering--and this also is partly a cost question. We're struggling with the issue of how we're going to pay to leukoreduce the whole American blood system, and this is being proposed since other countries are doing it--whether anyone has actually thought of the trade-off on how much it's going to cost to get all these new blood donors in relationship to the cost of the leukoreduction, and, you know, that we wouldn't have to get the new blood donors if we could leukoreduce, if that's what everybody's worried about, if this question makes any sense at all.

DR. SATCHER: I'm going to ask Steve to answer that.

DR. NIGHTINGALE: I think given the time constraints that is not the case, that the concern is limited to the white blood cells. We could talk more about that later, but not now.

CHAIRMAN CAPLAN: Well, if I don't see any other questions, I'll offer the thanks of the committee for Dr. Satcher coming here and spending time with us. And I appreciate the fact that you are being attentive to the committee's deliberations and thinking hard about our recommendations, and I have a feeling that you'll have that opportunity again after we're done over the next two days. Thank you.

DR. SATCHER: Thank you.

CHAIRMAN CAPLAN: I think we're going to go--

DR. NIGHTINGALE: Do you want to go over the letter and then go to--

CHAIRMAN CAPLAN: Sure. You can actually do the letter. That's fine.

This is a letter that was sent to me that you received, but I think it's important that we put it on the record, so to speak.

DR. NIGHTINGALE: This is a letter from the Secretary to Dr. Caplan dated July 15, '99. It says:

"Dear Dr. Caplan: Thank you for your thoughtful letter summarizing the deliberations of the Advisory Committee on Blood Safety and Availability on April 29-30, 1999. These deliberations concerned the reserve capacity of the United States blood supply and what steps could be taken to strengthen it. In view of our recent decision to defer blood donations from individuals who have resided in the United Kingdom for more than six months, your discussions were particularly timely.

"I appreciate your concerns regarding the current trends in blood donation and demand. Your committee should monitor this situation closely, just as you are monitoring the supply of plasma derivatives and the progress of the hepatitis C lookback effort. The additional resources needed to accomplish this task should be addressed with the operating divisions that sponsor your committee.

"I also appreciate Dr. Schreiber's analysis of how we might correct the decline in blood donations by focusing additional efforts on retention of first-time donors. At the same time, it would be premature to depend on a single strategy to increase donations, so I also concur with your recommendation regarding blood donations by individuals with hemochromatosis. I am directing the Health Care Financing Administration and the Food and Drug Administration to identify strategies that would implement this recommendation.

"I am sensitive to the issues you raise in your letter regarding the potential impact of the current economic transformation of medicine on the safety and availability of the blood supply. These issues are currently under review within the Health Care Financing Administration, and you should anticipate a presentation of these issues from Medicare's perspective at your next advisory committee meeting.

"Sincerely, Donna E. Shalala, Secretary."

CHAIRMAN CAPLAN: I suspect, based on the fact that we have the Secretary's attention and the Assistant Secretary of Health's attention on these matters, that Steve keeps turning to me quietly and saying, "It should be lively the next two days," because we have the deferral issue to go to, an assessment of how we're doing on the supply of blood products, a review of how we're doing on hepatitis C lookback, and then the opportunity to culminate the whole thing with a discussion of money and reimbursement issues.

I think that that's a pretty rich diet, and I'm hoping that we can actually come away understanding both what's happened with respect to some of our recommendations and how things are moving, and get into some of these financial issues. Jane opened the door a little bit on that with some of the questions about the cost of hunting new donors down as you try to pursue safety, and there are obviously some reimbursement questions and other issues around that we have to think about if we're going to be fair to the mission that Jim pointed out of thinking about supply as well as safety.

I've been struck by the fact that the FDA moved fast on this deferral issue. I think that that's the one we're going to go to first. There are certainly a lot of questions and issues that come up there, and I think we've got--is Dorothy here? Dr. Scott? Oh, there she is. We've got Dorothy Scott to present to us, and I think we've given you two and a half hours to do this.

[Laughter.]

CHAIRMAN CAPLAN: The guidance. Dorothy?

DR. SCOTT: Well, I won't take two and a half hours of your time, but what I want to do is summarize the new recommendations contained in the newly published guidance from August 17, 1999, the guidance entitled "Revised Precautionary Measures to Reduce the Possible Risk of Transmission of CJD and New Variant CJD by Blood and Blood Products."

Could I have the first slide? Maybe you can turn the lights down in the front a little bit.

This is a summary of the points that I just wanted to bring up that are contained in this new guidance. The first and obviously one of the most important points that's going to be discussed today is the indefinite deferral of donors who have traveled or lived in the UK for six months or more between 1980 and 1996, and I think the rationale has already been summarized for you thoroughly this morning.

Secondly, it contains the indefinite deferral of donors who have received injectable bovine material from BSE-endemic countries between 1980 and 1996.

In addition, there is the new recommendation not to withdraw plasma derivatives from donors with CJD or CJD risk factors. There's also the new withdrawal of blood components and plasma derivatives from donors with new variant CJD or possible new variant CJD. And, finally, this document contains recommended labeling for non-implicated materials which mention CJD.

Next slide, please?

As you know, our prior recommendations, which were published on December 11, 1996, did not address the issue of BSE exposure. The new recommendations are to defer donors who've lived in the United Kingdom or traveled there for a cumulative time of six months or more, and the United Kingdom is defined as England, Northern Ireland, Scotland, Wales, the Isle of Man, or the Channel Islands.

Next slide, please?

It's also recommended to defer donors who received injectable products made from cattle in BSE-endemic countries since 1980. This obviously was a late addition to the guidance, and it was in response to new information that we received that diabetics are importing or are expected to import bovine insulin from Europe since this is no longer going to be available in the U.S. It has been the FDA policy since 1993 not to source bovine materials for drugs from BSE-endemic countries.

The rationale for this has already been described this morning, but clearly we don't know enough about the number of people who are incubating new variant CJD. People living in the UK seem to be at particular risk of this, and we don't know enough about the likelihood of transmission by blood of new variant CJD. And, therefore, donors who may be at potential risk of developing new variant CJD are indefinitely deferred as a precaution, and this recommendation will be frequently re-examined because of concerns about the shortage, and hopefully new scientific information will be available soon.

We are aware that several experiments are underway looking at the ability of blood and plasma from new variant CJD patients to transmit the disease to animals.

The guidance also provides recommended questions for donor deferral, and it specifies withdrawal of endate(?) components for these risk factors.

Next slide, please?

This is, I think, more obvious and probably less of a difficult issue, and that is the disposition of plasma derivatives if a donor is discovered who has new variant CJD. And, of course, the prior recommendations from 1996 did not address this issue.

The new recommendation is to withdraw all material collected from a donor who develops new variant CJD or from a donor with a clinical presentation that's highly suspicious for new variant CJD in the absence of confirmatory neuropathology.

The current way of making a diagnosis of new variant CJD relies upon a neuropathological specimen, and, of course, these may not be available in a timely fashion. And I think the rationale is the same in a sense, scientifically, for deferring UK donors, and that is that we don't have any epidemiological lab data telling us whether or not the new variant CJD agent is transmitted by blood. However, we do know that it's biologically different from classical CJD, and, therefore, we do not think that CJD data concerning blood can be extrapolated to new variant CJD.

Next slide, please?

We anticipated a problem which may occur, and that is that we would have report of a possible new variant CJD case where the neuropathology is unavailable. For example, this might be a donor with a CJD-like illness at a young age. However, decisions about blood products from that donor ought to be made in a timely fashion, perhaps not--and perhaps we should not wait to find out whether the diagnosis is confirmed or ruled out.

Next slide, please?

We have recommended that FDA and CDC both be immediately notified in case of a donor with a physician's clinical or pathological diagnosis of CJD, that is, classical CJD, or CJD-like illness and age less than 55. And it is hoped that this kind of reporting would capture any CJD-like illness in a young person, which is a potential new variant CJD case. And I think people from the CDC can tell you that they do receive reports of possible new variant CJD cases which have to be investigated.

The actions that are planned in such cases are that there would be an expeditious CDC and FDA investigation and decision about what to do with blood products. We anticipate that if a new variant CJD diagnosis cannot be ruled out, it's likely we would ask for withdrawal of all components and derivatives from such a subject. So this would be decided on a case-by-case basis.

Next slide, please?

I want to switch a little bit to another important aspect of this guidance, and that is the disposition of plasma derivatives when a donor has classical CJD or risk factors for classical CJD. The prior recommendation in December was to withdraw plasma derivatives from donors with CJD or CJD risk factors, blood components as well. And the CJD risk factors were defined as receipt of human pituitary growth hormone, a dura mater transplant, or two or more family members with CJD, which would suggest the presence of inherited CJD.

The new recommendation is not to withdraw plasma derivatives if the donor has CJD or CJD risk factors. The rationale for this has already been gone over, I think, in this committee and in others. There's a vast amount of epidemiological data which indicates that transmission of classical CJD by blood and derivatives is unlikely, and, secondly, laboratory studies have been published which show removal of the CJD agent in experimental models by manufacturing processes which are used for plasma derivatives.

Now I want to switch to another topic in the guidance which is covered that is new. Next slide, please? And that is the labeling of non-implicated blood products for the theoretical risk of CJD transmission.

Prior recommendations did not address this issue, but the new recommendations are to label all blood products, including those used as additives or excipients for other products, to indicate a theoretical risk of CJD transmission and also to state the potential risks of viral transmission.

Next slide, please?

The rationale for this is that although CJD transmission has not been documented by blood or blood products, the labeling of non-implicated products will provide information to the public about potential or theoretical risks. And just very briefly, I'm going to go over the wording of this labeling, which was worked out in conjunction with the CDC, some vaccine groups, the Office of Vaccines, and, of course, the Office of Blood.

Next slide, please?

The recommended labeling for all blood products except for albumin is as follows: Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically the CJD agent. The labeling for albumin is slightly different, and it actually provides enhanced reassurance, and the reason for that is that albumin has never been known to transmit any viral disease. And we know that experimentally albumin has the greatest removal in model systems of CJD-like agents.

So the recommended labeling for albumin is somewhat longer and is as follows: Albumin is a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of CJD is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

That's the end of the slides.

The implementation of this guidance is recommended to be as soon as feasible and not later than six months after publication. We're right now in the 60-day comment period, and I should tell you that we've already received a number of comments both through official and unofficial channels, and these comments concern the recommended donor questions, the shortage concerns, the potential shortage concerns and how to address them, and also aspects of consigning notification.

A working group has been formed within the FDA to address these many useful comments expeditiously, and we are hoping to be able to report on some or many of those at the upcoming Blood Products Advisory Committee meeting in September.

Thank you.

DR. NIGHTINGALE: Thank you very much, Dr. Scott.

Would any member of the committee like to add to the comments that the FDA has already received?

Dr. Davey?

DR. DAVEY: Dorothy, I'm sure you've received comments about the question about the deferral for injectable bovine materials from BSE countries since 1980.

To my knowledge, that particular issue has not been discussed in any detail with any of the Advisory Committees to my knowledge. So that question appeared in the guidance, at least to my perspective, somewhat surprisingly. And I wonder if the FDA has considered how blood centers will manage donors when they are asked if they have ever received injectable bovine material from BSE countries since 1980. I think very few people will have any idea whether they have or not, and we are going to get a lot of answers, "I don't know."

What are we going to do with those donors? This question is very problematic, and I hope there will be a consideration for withdrawing it.

DR. SCOTT: Well, I think this is a useful aspect of the 60-day comment period. The intention of having the comment period is possibly to make changes. And you are quite correct, and this was late-breaking news to us as well. During the finalization of this document, it was brought to our attention that these bovine materials were being imported by diabetics.

And so the amount of discussion that has occurred for all of these other issues did not occur here. And I think that rewording of this question or reconsideration of this question is definitely a major issue.

DR. DAVEY: Thank you.

DR. NIGHTINGALE: Dr. Gilcher?

DR. GILCHER: A comment to Dr. Davey. At least in our blood center, we currently defer all donors with diabetes who are on insulin. So, in effect, by asking that question, we do ask that it will negate a lot of explanation with respect to bovine insulin.

DR. NIGHTINGALE: Colonel Fitzpatrick?

COL FITZPATRICK: I just have one comment. We've heard from everyone about the intent to review the policy. But on the first page, the sentence says, "Is continuing in event that there may be a need for future updating and further relevant guidance." I think a more positive statement would be helpful there.

And one other, if I could.

DR. NIGHTINGALE: Yes.

COL FITZPATRICK: On page 10, it talks about post-donation reports. And it says, "The establishment..." immediately under 2A "The establishment to immediately retrieve and quarantine for subsequent destruction pooled plasma, intermediates and derivatives and any other materials containing plasma from the nvCJD donor."

Previously, in the guidance, you had qualified an immediate retrieval and quarantine by saying "products under the control of the establishment." And it might be appropriate to use that same qualifier in that paragraph, as the next paragraph talks about notifying consignees.

DR. SCOTT: I think we can coordinate those statements.

DR. NIGHTINGALE: Other committee members have any comments?

Dr. Hoots?

DR. HOOTS: It's a question actually of Colonel Fitzpatrick.

In our previous discussions Captain Rutherford was on record as saying the Department of Defense was very much against deferral of U.K. residents. Have they, in the context of the new recommendations, have they relooked at this or is it still pretty much their stand?

COL FITZPATRICK: We have continued to state our opposition to the deferral with a letter to Dr. Henney and a letter to Dr. Satcher. However, we will comply with the guidelines as published when they become final.

DR. NIGHTINGALE: Oh, Fernando?

DR. GUERRA: Just for clarification, do albumin products use something like vimaerosol as a preservative?

DR. SCOTT: I believe they can, but I can't answer that question for you definitely.

DR. GUERRA: Because I think then that obviously has been one of those tremendously effective agents; that is, anti-viral or a virucide

and bacteriostatic, bacteriocidal, and fungicide. And I see in the one statement here that they give the greatest level of reassurance for a very remote risk for transmission of viral diseases. That possibly could change if that is eliminated.

DR. SCOTT: That's possible, but we were actually referring to all of the data that we have concerning albumin given by itself.

CHAIRMAN CAPLAN: Go ahead.

MS. JONES: I just have a question that is not just specifically related to the CJD, but when you look at your labeling change that you are recommending, is it going to be FDA's position now that anything else that comes along that's a theoretical risk you are going to add to the labeling to say this is a theoretical risk?

I mean, are you setting a precedent here by expanding the labeling? I could see that in the circulars that are distributed to patients. But is that a really bad precedent for the Agency to be setting, to put that on the blood product bag or--it's just a question.

DR. SCOTT: Right. We did try to word it to cover everything. So what we wrote is: "May carry a risk of transmitting infectious agents," and then, "e.g., viruses." So, for example, viruses.

So the intent was to broadly cover possibilities and not to have to add anything else.

MS. JONES: I could see future discussion if you'd added a theoretical risk of CJD on there, that an argument could be made for other things that come along to be called out like that. And I'm just, even if you broaden the statement, doesn't CJD fit under--do you understand where I'm going with that?

DR. SCOTT: Yes, I do. And I think the way we stated it, what we intended was to cover all infectious agents, period. And then to give examples of two that particularly concern people; viruses, because they have been transmitted, and CJD because it's a current concern. It's not a virus, but it does fall under infectious agents.

I do understand what you are saying.

MS. JONES: As new concerns come along--

DR. SCOTT: Right. Will we add new examples, and that has not been discussed or planned.

DR. GOODMAN: I could comment. I don't think the intent is that all theoretical risks for any products should be on product labels. So I don't think we should interpret it that way.

CHAIRMAN CAPLAN: I'm not sure you can answer this question, and anybody who wants to from FDA is welcome to do so. But I was thinking about the conversation that we had with Dr. Satcher about risk communication. And we are now trying to run two policies on CJD and new variant CJD. And I'm looking forward with keen anticipation to the ability of the media and other organizations to get the difference across.

I am particularly concerned about one aspect of the policy now, though, and that is the idea of trying to figure out whether someone is in a new variant CJD situation based upon a clinical profile. And what it looks to me like is happening is that we're going to go with age plus a clinical presentation to put somebody into nCJD, as opposed to just CJD.

But this is all by way of saying: Educate me first, if you can, about how we're going to actually implement that so that the committee is in a position, when it's asked by others, to explain what the difference is between CJD product that stays out and labeled and new variant CJD, where we have a suspicion that we're going to do a recall based upon a profile.

DR. GILCHER: Dr. Caplan, your point is extremely well taken. Because if you go back to the AIDS era, originally HIV was HTLV-3, and we had an HTLV-1 and 2. And even physicians could not get that straight. So we had to rename HTLV-3 HIV-1, to really clarify that.

DR. NIGHTINGALE: There is a very sophisticated surveillance section at the Centers for Disease Control. Dr. Schoenberger, who leads it, is not here to explain it in detail at this time.

Dr. Chamberland, would you like to review that briefly or do you think that's already on the public record?

DR. CHAMBERLAND: Maybe what I can just do is just briefly--I think this has been previously described by Dr. Schoenberger and others at previous meetings. But CDC does have in place a number of overlapping systems of surveillance to try and detect cases of CJD, be it sporadic, classic or new variant.

And with the announcement of the new variant in the U.K. back in 1996, we undertook a very intense period of active surveillance--it was short-term--to try and very actively look for any cases of new variant that might have been in this country that have gone undetected. And this involved, in several sites in the United States, active calling of thousands of neurologists, pathologists, et cetera, people that might likely see these cases.

No cases of new variant were detected. We felt that, by review of death certificates, that that instrument, in and of itself, detected about 86 percent of the classic CJD in this country, which, as a means of validating surveillance, is a pretty good measure.

Since that active period of surveillance was very short term, you can't continue to call physicians like that around the country every month or so, we have put into place--tried to increase awareness, I guess is a better way of putting it, with the physician groups that are likely to see these unusual cases, to increase their awareness of this clinical syndrome.

And in point of fact, long before this guidance was published, we had, through the American Association of Neuropathologists--I believe that's the organization's name--put out mailers to these physicians alerting them that we want to hear about cases of "CJD" that are less than 55 years of age.

Furthermore, we systematically review every year--the National Center for Health Statistics' mortality is available to us--and we review all cases of "CJD less than 55 years of age," go back with the assistance of state and local health departments to learn further information about these cases; again, trying to reassure ourselves or, I guess, just trying to be very vigilant about trying to ferret out any of these cases that may be there.

We're also working with Case Western Reserve to serve as an important resource for clinicians to send materials for further examination, to, again, make a pathologic diagnosis. So, just very briefly, some of the activities.

DR. HOOTS: To follow up your comment, and the question I asked Dr. Satcher, I just can't help or let them all pass without commenting about the irony of how our discussion, just this committee's, has evolved over time in terms of relative risk--we started with sporadic and now to variant--in terms of just the age issue, for instance.

The first discussions, obviously, with sporadic CJD, we were concerned about older populations and that they may be higher risk for transmission. Now we've almost come full circle. If you accept even a moment of the premise about the lymphatic theory and the fact that younger patients may be higher risk for variant because of their lymphatic hyperactivity relative to older populations, it's come full circle. And obviously, in terms of the surveillance, it's come full circle already because you are looking at under 55 now.

It adds, obviously, to the whole issue of availability because older donors, as we have been told time and again, are more frequently repeat donors, and, therefore, we're much more dependent on them in 1999 for our blood supply than we are for the 20-year-old. So the impact of them, I mean, in the good sense, we at least have gotten past that part.

But in terms of how we have to approach this problem--and perhaps in commenting about what Art was saying--is that maybe we have to spend a little more time convincing society of how dynamic this process is by exactly telling them a little bit about how these machinations have gone. And that, indeed, we learn something every quarter, if not every year, that will impact what these recommendations are. Because, generally, what happens is an announcement comes out, "These are new things," and people then process the fact that this must be a new perception of risk when, in fact, it's an evolution of a risk, of our understanding about the risk. And maybe part of our job is to say that this is going to be dynamic forever; that we will probably never arrive at a point where we can say, "We know exactly this is the right thing to do forever."

But we just think, at this moment in time, this is the right thing to do. But we are continuously processing all of the new information over, and over, and over again. And we will change the moment we have perception that the risk has tilted in one direction or the other.

DR. DAVEY: Just one question and one comment. A question, Dorothy, just about the mechanism that the guidance was issued. It's highly unusual that guidance of this nature be issued in final form without a draft copy being available and an official period of public comment before the final document is issued.

So I would like to hear your comments on why this unusual mechanism was employed in this case. And also just a comment, following up on Dr. AuBuchon's comments with Dr. Satcher, that I also found it unusual that a decision of this magnitude that impacts so importantly on safety, and especially on availability, was not fully vetted and discussed by this committee.

DR. SCOTT: I want to address that very last comment. However, there are a couple of reasons that this document was issued in this fashion, and these are legally justified reasons according to the regs.

But the first is that it was felt, since a decision had been made about deferring people with the possible risk of exposure to BSE, it was felt that we should implement this for reasons of public health as soon as possible. Although you will say to me that it's a theoretical risk. However, it was felt that it should be issued expeditiously with regard to the donor deferral.

The second point is that it actually provides a relief in the case of nonwithdrawal of plasma derivatives for subjects with CJD or risk factors for CJD. And on this basis it was also felt that this should be released expeditiously.

COL FITZPATRICK: On the confusing over naming, I just had a question. One of the recent articles suggests that it be called variant CJD, as opposed to new variant CJD. Is there going to be a convention for that?

DR. SCOTT: Well, in my survey of the literature, there are an equal number of important articles that call it new variant or variant CJD. But it does seem that variant CJD in the last six months has become more prevalent.

COL FITZPATRICK: But is there going to be a convention established? Because now you have two names, and we are going to confuse people even more.

CHAIRMAN CAPLAN: Right.

DR. NIGHTINGALE: We anticipate that parsimony will take precedence, certainly among journal reviewers and their editors. We anticipate it will be "v" rather than "nv."

CHAIRMAN CAPLAN: It's always delightful when philosophy rears its head to clarify concepts. But, I mean, it's going to be really crucial here. And we may even think, as a committee, about whether you want to say something about this naming issue because I, personally, think it's going to be very tough to explain to people the dynamic policy risk shift without being clear about what's targeted, what isn't targeted; why, on the one hand, something is still out there, and on the other hand, something isn't out there; and why that something that isn't out there right now might come back.

So having clear names is not the worst thing we could suggest. And I might flag for us to think about during the next two days even commenting the importance of some education, again to really try and drive, as Keith says, a dynamic, evolving policy situation in response to a theoretical problem so that people understand, as best we can make them, what's going on.

Steve, you wanted to read a memo in there on the blood supply thing?

DR. NIGHTINGALE: What I wanted to move on to was the next topic and make two comments about what Dr. Hoots had said.

First of all, I wanted to advise the committee and the public that Dr. Hoots' capsule of the thought process a moment ago came as close to anything as I could personally come up with to representing the thought process that went on in the mind of senior management and the government at the time this policy was formulated; in particular, the statement about making the best policy decision that was possible at the time the decision was made and the understanding that that policy decision was only as good as the data that was available to it, and for that reason, the commitment of the government to review the policy as new information becomes available, and also, of course, Dr. Hoots' comment about how dynamic the process is. That's clearly reflected in the modifications of the agenda of this meeting as we are making as we go on, because things have happened since then.

In your packet that you received on Tuesday, the committee members had a memorandum of August 10th to Dr. Kirschstein from Dr. L'Enfant, the director of the National Heart, Lung and Blood Institute. The brief background you need to know is that, following Dr. Shalala's letter to Dr. Caplan, Dr. Satcher, as the assistant secretary of Health and Surgeon General, who was also the Blood Safety director, sent letters to the agencies asking them to initiate the process of implementing the Secretary's directives in her July the 15th letter. And what you have in your packet is part of the process of the response to that letter, and I will read it into the record because that is where we are.

On August 10th, Subject: Monitoring the U.S. Blood Supply, Dr. L'Enfant writes:

"First, in follow-up to Dr. Satcher's memorandum of July 22nd, the National Heart, Lung and blood Institute concurs with the importance assigned to monitoring the adequacy of the U.S. blood supply, especially in view of the imminent deferral of potential donors who have spent time in the United Kingdom.

"The Institute is prepared to respond by arranging for monthly data collection from a sample of blood collection centers, with analysis focusing on trends and possible seasonal shortages. If feasible, data will also be collected from transfusion services, emphasizing the detection of shortages, if they occur, and their adverse effects, if any, on patient care. The mechanisms by which this data collection will be supported are under review, but the cost seems unlikely to exceed $300,000 annually and may be somewhat less.

"Other public health service agencies and parts of the private sector will be involved to ensure that the data meet the needs of the government and of the blood collectors and that there is a smooth transition between procedures used to satisfy immediate requirements and a long-term solution to providing necessary blood data."

Signed, "Claude L'Enfant, M.D."

Obviously, this process is still evolving. But what I would like to do is ask Dr. McCurdy, Dr. Nemo or both if they would like to make any comment.

Paul?

DR. McCURDY: I have one overhead, and I will make a couple of comments. It is accurate that the Heart, Lung and Blood Institute is devoting resources to developing and using procedures to monitor the blood supply, and we are considering it both a short-term and at least an intermediate-term solution, and probably would be prepared to continue it indefinitely if that's the best way to go.

Adequacy is not quite like beauty, in the eyes of the beholder, but it does mean different things to different people. For example, if a blood center gets an order for a large number of O negatives, and they respond, "You've got to be kidding" and supply half of it, is that a shortage or is it not a shortage? And I was never able to figure that out when I was a blood center director.

I think it is, however, very certain that adequacy is blood group specific. It's been commented a number of times that blood is administered blood group specific most of the time. Group O is often, if not usually, in short supply, at least in some parts of the country, and A and AB are often in excess. AB, for the nonblood bankers, could be considered a universal recipient, and there are some hospitals who simplify their inventory management by not stocking any AB units at all.

Monitoring the adequacy of the blood supply is also rather difficult. We propose or we plan to start out by monitoring collections. We also will move to monitoring usage in transfusion centers as quickly as we can do that. That's a much more complicated issue than monitoring collections in regional blood centers.

Of particular interest in determining the adequacy, however, is getting information on whether surgery is delayed or if it is delayed. And I would hope that we could get information on the blood group involved with the patient who has the delay because I suspect that it's going to be primarily in Group O patients. It may also be occasionally in Group B patients. I would expect the A's and ABs would rarely be postponed.

The National Blood Data Resource Center, which you will hear from soon, noted, somewhat to my surprise, that nonsurgical use of blood, uses of blood, were also deferred or not completely covered during their last survey year, which I think was 1997. So we expect to get that information.

Inventory analysis is greatly complicated by the continuous flow in and out. So if you take an inventory at 8 o'clock in the morning, it may be more adequate or less adequate than one at 5 o'clock in the afternoon, after the day's shipments have gone out. We hope to begin to look at that by taking several spot checks each month, at a given time of day, of inventory and see if we can begin to make sense out of that.

The National Blood Data Resource Center has told us that there are more than 150 collecting centers and more than 2,000 transfusion services. Getting information monthly would be an exercise in futility trying to get all of those. So we are planning to do some sampling. We will work out with the Data Center how we are going to sample. My guess is it will be a modified probability sample that we can extrapolate to the entire country.

I just mentioned monthly collection of data from this sample. We plan to do that because there is a clear seasonality in both utilization and collection of blood. I collected a fair amount of information on this years ago when I was a blood center director. Recent data from the Red Centers confirms that there still is a degree of seasonality. And Jeff McCullough, at an Institute of Medicine presentation a few years ago, pointed out seasonality in both utilization and in collections in his experience.

So to summarize, the NHLBI will be working with the private sector. And the private sector in this instance, at least initially, will be the National Blood Data Resource Center. They, clearly, have the capability of working with us on this idea, and so we will utilize their expertise.

I might add, and I think it was in Dr. L'Enfant's letter, that we will be involving other PHS agencies in developing and monitoring the blood supply. So if at any time it's determined that it would be better for another agency to do it, whatever transition is necessary, would be done very smoothly.

Thank you.

DR. GOMPERTS: Dr. McCurdy, in this brief summary, the events that are being put in place, I think it's important to focus on the patient rather than the actual blood center and the distribution centers. You certainly mentioned surgeries and delays of surgery or cancellation of surgeries, but there are other important stress foci, such as transplantation units, critical care, the utilization of platelets, the availability of platelets. These are important stress issues that would need to be covered and hard data available on that.

DR. McCURDY: I emphasized the blood group specificity, and that obviously is more important for red cells. But we do plan to monitor platelets, both random donor platelets and apheresis platelets.

It's been said, for example, that the supply of apheresis platelets being more adversely affected than the supply of whole blood because there's a reliance on a fewer number of donors in that area. That remains to be seen. There aren't a lot of data on how frequently donors are pheresed. I have my own personal experience which is in one direction, I have observations that are another direction and then there's a publication out of the RED study that's sort of halfway in between. So we'll see.

DR. GOMPERTS: And I think also focus on the consequences. So where there is a shortage, what actually are the consequences on the patient.

DR. McCURDY: I think that one of the reasons we are starting with blood centers is that they are more likely to have data systems that can provide data relatively quickly, and the small amount of data that we want and in a format that we can use.

We do plan to move into transfusion services as quickly as we can. My impression, which has been confirmed by at least a few others, is that monitoring transfusion services is going to be at least an order of magnitude more complex and will probably take more time to develop.

On the other hand, I'm not sure that other than for postponed or delayed surgery, we'll need to do the blood group specific monitoring in hospitals that we would do in blood centers.

CHAIRMAN CAPLAN: Do you want to follow up?

DR. GUERRA: A couple of questions, Dr. McCurdy.

In the equation for looking at the supply, and the demand and the balance of all of that, is some of this being done by specific ICDM-9 diagnoses in terms of what I think was referred to, you know, beyond just surgery and trauma, there are so many other conditions, including, you know, very small increments of packed red cells that are given to very small and prematurely born infants.

But I think the other issue is what is the ratio--and acceptable ratio--that is maintained in terms of stockpiling, to try to keep some reserve within the nation's blood supply? And then, I guess, how do you assess wastage? Is that also built into the equation?

DR. McCURDY: I think that one of the things that I've tried to do is to make this as simple and direct as possible. There have been several other attempts through the years at monitoring the blood supply, in one form or another. The American Blood Commission in the '70s had a data unit that, from my perception, was trying to be all things to all people, and got so complex and complicated in their data collection and analysis that by the time it was out, it was not much use because it was several years old. I'd like to avoid that.

Dr. Doug Sojourner, with Institute support, for a number of years has done some studies and reported--has serial papers, some of which did look at ICD-9 diagnoses. This would be very desirable, I think. There have been several attempts at doing this, including one using, I think, a now defunct quality assurance system in hospitals. But I think that would add a level of complexity that would make it very difficult for us to get timely information.

I think I commented that we will develop and use, and I'd like to emphasize the develop as well as the use, because I think, as time goes on, we will modify the data we collect and how it's analyzed, hopefully not to negate what's gone before, but to build upon it if it seems to be both feasible and desirable.

CHAIRMAN CAPLAN: One of the things that's undoubtedly going to come up as we look at this deferral issue, and then relate it to the impact of hemochromatosis-derived blood coming into the system, is shortages, what are they caused by, what are they due to. A reasonable estimate of how long that system is going to take to set up?

DR. McCURDY: Well, I'm a bit, by nature, impatient, and we would like to start collecting data as soon as possible, maybe next week or following that. That becomes a little absurd when you get to it. But in our discussions with the potential source, the National Blood Data Resource Center, there has arisen the possibility of beginning collections, say, in June or July or something like that, this collection of data going back a little bit so that we will cover some of the time period before the introduction of the deferral of U.K. donors, as well as afterwards.

It's very difficult to look at the whys. We have asked several experienced blood bankers to look at the data that we now propose to collect and make suggestions. And Dr. Gilcher is one of those and has made a suggestion that may address some of the issues you just mentioned.

CHAIRMAN CAPLAN: The reason I'm flagging this is I think, just taking the prerogative of the Chair, that the committee may want to think about a recommendation here to urge some collaboration immediately to get data up and running, both backwards and current, until other information and surveillance on the supply side can be introduced, although we'll hold Paul to next week. I like that.

[Laughter.]

CHAIRMAN CAPLAN: But it's going to be important because, as some of us have commented, there are cost issues here, and there are going to be political issues in the face of scarcity and shortage, and it's going to be important to know what patterns of supply and shortage are, as best we can know them. So we may need to recommend some private-public collaboration about data and what's out there, to make sure that we have a handle on what's going on. We're kind of on this little seesaw of what do we increase, what do we decrease, were there shortages anyway, are they exacerbated, are they not? And there are going to be all kinds of claims flying around. So we may need to try and get the best data possible, given the circumstances.

DR. McCURDY: I might comment that we hope to do that. One of the issues that has been discussed is the question of whether individual blood center's data should be exposed to public gaze. And it is our plan to do this on a macro basis, without identifying individual cooperating blood centers or hospital transfusion services.

There has been widely reported, without any explanation, other than guesses, that the utilization of blood is different in New England than it is in the West, and we may stratify, if it seems to be feasible, with sections of the country. It would be my hope that somebody would try to explain this rather than just count the beans.

DR. GILCHER: In support of what Dr. McCurdy has said, almost all blood centers collect certain data all of the time. For example--and I had discussed this with Dr. McCurdy earlier--we know exactly the number of donors that come into the center, and we know how many products come out. But if we were to monitor, because this data is already available from our center, and I believe from probably almost every large blood center, we know the deferrals, therefore we know the number of donors who were accepted. We know how many complete and incomplete units there were. So now we know how many products reach the laboratory. We know what the losses are from testing or anything else. So we know how many labeled products reach the door.

Where we cannot add the final pieces is what happens to it after it goes out the door. We would know what we would outdate within our own blood center. But what happens to it at the transfusion level is clearly going to be more difficult, as Dr. McCurdy has said. We could start next week. The truth is that data is already there, from the blood center standpoint. We have it.

DR. HOOTS: Ron, do you know or do you keep records on, if you get a request from a transfusion service for 14 units, and you say, "Well, at the moment we have..." 14 units of O "...and right now we have 12, and we'll have to wait for--" do you have that kind of information as well?

DR. GILCHER: We do. We monitor that because, again, as Dr. McCurdy said, about the only blood group that really ends up being in short supply is Group O, especially the O negatives of the Group O's. And, again, we do monitor that, and I'm not saying every blood center would have that piece of data.

DR. HOOTS: Because that might be something good to track. If you started seeing the differential between request and availability from large centers like your own, and use O positive or negative, perhaps, as the surrogate for all because that's the most likely to be impinged, it might be the first indicator until you get to the actual transfusion service that something is changing.

DR. GILCHER: But there's another qualifying factor that's very important and, again, we do it within our blood center, and that is the medical management side. Because it's very clear to us that hospitals, always knowing that they want more O's, will overorder the O's, and so that plays a role. So we have the medical management part, myself and other physicians on our staff, who are always monitoring the orders and what, in fact, the real needs are at the hospital level.

DR. McCURDY: I can say that during most of my tenure as a blood center director, I monitored orders versus actual shipments very closely and found it to be very illuminating, both from the standpoint that Ron said; certain hospitals were more prone to overordering than others and so forth, but it also gave me the best handle that I had on the adequacy of the supply. But I don't think--I'm delighted to hear that Ron is doing that. My inclination is that that's not a common phenomenon.

DR. GUERRA: I guess, Ron, in a way that's sort of stockpiling. Is there some formal way to stockpile or to assure that there are, maybe on a local or regional basis, the available units that one might anticipate, given any number of totally unanticipated events on a population basis?

DR. GILCHER: Again, every blood center monitors the usage by their hospitals. We have that for the last 15 or 20 years, could tell you exactly what the use is of every hospital in our system. So we are monitoring that, Fernando, essentially on a daily basis by our hospitals. So we know what their usage of blood is.

DR. GUERRA: But I guess my question is--and maybe, Paul, you can answer it--is there some formal institutionalized requirement for assuring that we have stockpiled "X" number of units somewhere in the country or on a regional basis, so that if there were a sudden increase in demand that we would be able to respond?

I guess my public health orientation is that we stockpile vaccines, for example, because of the unanticipated outbreak that might happen in a community, and you do that based on some data, et cetera. I guess there isn't a system for blood.

DR. GILCHER: Well, let me attempt--I'm sorry. I should have stated it this way--again, we maintain within the blood center what you would call a stockpile; that is, minimum inventory levels. When we reach that level, then we will increase our telephone recruitment to bring those levels back up, and that allows us to handle, essentially, any kind of emergency that would occur in our system.

And I suspect that every blood center uses some variation on what I'm talking; that is, a minimum inventory level within the blood center, remembering, of course, that each hospital also will have its own minimum inventory level.

DR. DAVEY: I'd just like to comment that we do, in the Red Cross system, we certainly have pretty much an identical system that Ron described. We monitor unfilled orders, what the hospitals order or what blood types are in special demand in certain areas. We do find that academic centers tend to order more O's than smaller hospitals, maybe more immunized patients, I'm not sure, but we see that.

We also, and I know Ron participates, there are systems in the country, the National Blood Exchange and the Red Cross, a hub system, where we can move blood around in case of spot shortages, in case of an emergency or some particular local situation where blood is needed. So there are systems to move blood around. I think that can be always improved and perhaps consolidated, but those systems exist.

DR. McCURDY: I think it's also true that the larger the blood center, within certain limits, or at least up to a point, the less likely you are to have wild fluctuations in demand within that region. Because when Hospital A has a trauma case that's soaking up a lot of blood, Hospitals B and C may not have. And I think the luck of the draw suggests that, with very large regions, that's the case.

There also has been in place, for a long time, and I think it's continually improving, mechanisms for shipping blood from one place to another. And with air transport the way it is now, with the exception of occasional real bad weather, you can restock a center that's in the midst of an emergency. And my guess is that in the emergency you had a few years ago, Ron, you had lots of offers of people willing to ship, if you had the need.

DR. GILCHER: Yeah. Again, a very good point that Paul is making, and that is that the blood center must have an adequate supply to deal, as I said, with the emergency that can occur. And there have been two in Oklahoma City, unfortunately. But from the standpoint of the blood supply, I guess it was fortunate.

When the bombing occurred, a lot of blood was used extremely quickly. Within about four hours, there were about 350 units of blood used in excess of what ordinarily would have been used. The reality is that we did have the blood on the shelf, and that was absolutely critical. And other surgeries were curtailed in the city that day to, in fact, effectively increase the available blood supply. That is how you would handle an emergency. But it really has to be there. So having minimum inventory levels in every blood center is really critical.

DR. GOMPERTS: Perhaps one really important statistic would be how often does the blood center reach that minimum inventory level, how frequently are they calling up donors that are reliable, and to what extent is their donor pool being exhausted; in other words, limited, from the point of view of transfusion?

DR. GILCHER: It happens every week in our center. We are monitoring it that closely, that we will reach a minimum level and telephone recruitment will be revved up. So it's literally an hour or daily basis process.

CHAIRMAN CAPLAN: Let me hold the discussion here for one second because I want to let Ms. Sullivan, who talked to us earlier about blood shortage, have a chance to get into this discussion about how to monitor.

But while she is moving forward, I guess I will rephrase what I said about something we might want to think about and say that if the blood banking community and collection agencies want to see deferral policies affected, it may be important to be able to supply information in a timely way, both historical and current, about what the situation is with respect to donors so that people could see what the impact is of a policy.

So that, it seems to me, I don't know how the burden is going to go on this, but instead of mandating, it might be prudent--and we could say something like this--to have whatever information would be persuasive for those who want to modify a deferral policy, relative to supply availability, to put those numbers out there. Otherwise, what happens is people just say things are short. And I will tell you, personally, you just see statements saying things are short, you see them all of the time, and they are not persuasive.

So the burden is going to be there to come up with something that is persuasive until we get a better sentinel thing going.

MS. SULLIVAN: Good morning. I am pleased to have been invited to speak to you, once again, about the National Blood Data Resource Center.

Today, rather than making a data presentation, I would like to take the opportunity to share with you our plan for monitoring blood supply and demand over the next 16 months. I believe that the variety of upcoming NBDRC blood data collection activities, plus ongoing research projects addressing other issues relating to blood safety and availability, will compliment one another well and provide critical information to meet the needs of this committee, the Public Health Service and other stakeholders in the blood services community.

As most of you know, the National Blood Data Resource Center is an independent, not-for-provide corporation conceived and founded by the American Association of Blood Banks in 1997.

The mission of the NBDRC is to collect, analyze and distribute data on all aspects of blood banking and transfusion medicine. We are proud that in our short 24-month history we have established a reputation as the premier source of reliable national blood data. And we sincerely appreciate the recognition of this committee, the executive secretary and the ad hoc task group convened to strategize ways to increase the blood supply, the NHLBI, the FDA and many others present here today who have assisted the NBDRC in rapidly and successfully establishing itself in this particular niche.

In return, you have our commitment to continue to provide accurate and timely data to meet your needs, both routine and urgent, as long as sufficient financial support is available.

I will now present a quick and rather crude picture of the various methods of data collection that the NBDRC will utilize in the next 16 months. The NBDRC is committed to continuing the biennial Nationwide Blood Collection and Utilization Survey, even if it must be supported entirely by internal funds and report sales, as it was last year. I previously shared with this committee the national estimates from the last survey, which captured total collection and transfusion data for 1997.

I don't have a pointer, but I think that you can clearly see the red and blue lines. The red line indicates that collection data are captured, and the blue line indicates that utilization data are collected as well.

In January of 2000, we will distribute the next nationwide survey to approximately 3,000 hospitals and blood centers, which will again be funded primarily by NBDRC members, including our corporate charter members, and by a contribution from the AABB.

The results of the 2000 survey, which will be available to NBDRC members and customers approximately 12 months from now, will provide data for 1999, as you see on the right side of the overhead, and will extend the historical trends analysis through 1999 as well.

However, in the interim between surveys, there is little information available regarding the adequacy of the blood supply other than anecdotal. Some blood centers have recently reported significant increases in 1998 and 1999 collections, while others have issued repeated appeals for blood, beginning well in advance of the anticipated summer shortages this year. The impact of this on the nationwide supply can't be carefully assessed without current nationwide data for comparable time periods and donation types.

In order to better estimate the adequacy of the recent supply and to enable us to project the available supply for the year 2000, the NBDRC will conduct a QuiKount of U.S. blood center collections next month. The short survey will be distributed to all blood centers immediately after Labor Day and will capture collection data only for all of 1998 and the first six months of 1999 by quarter and by blood group. The QuiKount will be funded internally and the results will be shared with all interested parties beginning in early November.

Last, but not least, I'm very pleased to acknowledge what Dr. McCurdy announced this morning; that we will begin to collect supply data on a monthly basis in the next couple of months under a short-term financial arrangement with NHLBI. Initially, we will enlist the participation of a representative sample of blood centers willing to report their monthly distribution figures very rapidly. Later on next year we hope to bring the corresponding national hospital sample online in order to capture timely and detailed utilization data.

These various methods have the combined advantage of co-validation of data, broader representation, better sample selection and rapid response, to list a few.

I'd like to conclude by leaving you with a list of the major research activities that will be in place at the National Blood Data Resource Center in the year 2000; as I've already covered, the Nationwide Blood Collection and Utilization Survey and the monthly monitoring of the blood supply, in addition, the long-term CJD investigational lookback study, which will be in its sixth year, with 300 recipients investigated and funded by the CDC.

And finally, we will also be conducting an investigation of factors that may influence the blood donation decision. This study represents the second phase of our survey of donation incentives and will also explore the psychosocial and environmental factors, such as competition for donors among blood centers and their impact on the donation decision in current donors, lapsed donors and eligible nondonors.

I hope to be back next year to share some of these exciting results with you.

Thank you.

CHAIRMAN CAPLAN: Questions? Comments?

[No response.]

CHAIRMAN CAPLAN: If not, why don't we take a ten-minute break, and we'll come back to these issues after the break. In fact, if you generate up a question, we can put that back to Ms. Sullivan after the break, too. But let's take ten minutes, and then we'll resume.

[Recess.]

CHAIRMAN CAPLAN: All right. We had a lot of interesting discussion at the break, as often happens, and I hope we come back to some of the issues that I talked about with people or overheard people talking about in our discussion period.

What we're going to do is spend a little bit of time looking at the HCFA response to the Secretary's letter. Steve is going to offer some comments about that. Then we're going to have more of an FDA response to that letter as well. This is the original Shalala letter to me which I carry with me at all times. And then we'll review some of those recommendations about ways to increase the blood supply through trying to encourage donation. Then we'll end with public comment and open up the discussion, if we have to. And we'll watch this for starvation purposes. We might break around 12:45 or something like that, and then pick up our own discussion.

I know there's a lot of interest in many of the issues around the deferral and how they affect supply. We certainly have time to talk about that some. And I think at the same time we're trying to weave together some of the other factors that are playing on supply like reimbursement and strategies to increase donation, anyway, and the hemochromatosis issue because they seem interconnected. So I apologize if there's a lot of balls up in the air, but that's how it goes.

I did have one thing I wanted to get to before going to Steve. I was wondering, we didn't see the letter that DOD sent about deferral. I don't think we ever saw that, and I was curious if there was any comment that you wanted to make about why the department wasn't thrilled with the deferral idea.

COL. FITZPATRICK: The two letters--there was an original letter to Dr. Satcher and then a follow-up letter to Dr. Henney. The discussion between the three Surgeons General was the impact of deferral of a theoretical risk, and it was our position that the impact of the theoretical risk was unknown, that the evidence of one transmission by blood in an animal model that was not injected directly into the brain was very limited evidence of the risk of transfusion, that the follow-up of donors who had been diagnosed with nvCJD and their blood products to recipients has yet to produce a transfusion-transmitted case of nvCJD, and the fact that when we look at our own donor base, there are isolated cases where up to 30 percent of the individuals may be deferred.

The greatest impact is on the Air Force, lower impact on the Army and Navy, and with the realization of it, the largest of our donor centers are at basic training sites where the individuals are new accessions and will not have been stationed in the United Kingdom. And our feeling was that the risk did not warrant the action and that it was not needed to be as quick an action, that it was possible to wait and collect more evidence before you took the action--although it is the most cautious approach possible.

DR. NIGHTINGALE: I might simply add that there was active discussion between the departments during the formulation of the policy.

COL. FITZPATRICK: Right.

CHAIRMAN CAPLAN: I'll bet.

[Laughter.]

COL. FITZPATRICK: And we continue to say that we will comply with the policy.

CHAIRMAN CAPLAN: There's some good opportunity for more humor here, but we'll let that go and maybe return to that.

Why don't we just--Steve, you may be able to say something about the HCFA response?

DR. NIGHTINGALE: Yes. I think we're going to move on to the disposition of the advisory committee's recommendation regarding hemochromatosis, and you'll recall that in the Secretary's letter to Dr. Caplan, she noted that she was directing the Health Care Financing Administration and the Food and Drug Administration to identify strategies that would implement this recommendation.

There also have been ongoing for several months very active discussions between Dr. Satcher's office and the Health Care Financing Administration, or HCFA, about the role that HCFA might take in the implementation of this policy.

There are some constraints that are perhaps more obvious to bureaucrats than to the public at large, and one of those is that the Health Care Financing Administration is not the administrator of a national health insurance. The Health Care Financing Administration does administer Medicare. It participates with the 50 states in the administration of Medicaid, but it is the 50 states that regulate the private insurance industry in each of those states, and it is none of the above that regulate the care of the uninsured.

So in the search for a quick fix to this issue, none was obvious within the mandate of the executive branch, which includes HCFA, and that will be discussed in more detail tomorrow. I simply felt it was important to note for the record that these discussions have taken place and are ongoing.

The more substantive response, however, was from the Food and Drug Administration. That is in the packet of the committee. I apologize. The version you got inadvertently didn't have the date on it. The date is August the 10th. And Captain Gustafson of Food and Drug is going to discuss that, and then she will move on to the discussion of the PHS report on expanding the capacity of the U.S. blood supply.

Captain Gustafson?

CAPT. GUSTAFSON: Thank you.

As has been mentioned, at the last advisory committee, the advisory committee recommended that the Department of Health and Human Services create policies that eliminate incentives to seek donation for purposes of phlebotomy from patients with diagnosed hemochromatosis who require obligate phlebotomy as therapy for their disease. Further, as undue incentives to donate blood for transfusion rather than being therapeutically phlebotomized are removed, the department should create policies that eliminate barriers to using this resource.

We've already mentioned quite a bit about Dr. Caplan's letter to Dr. Shalala and Dr. Shalala's response to Dr. Caplan in which she informed him that she concurred with the committee's recommendations regarding blood donations by individuals with hemochromatosis and that she was directing Health Care Financing Administration and FDA to identify strategies that would implement the recommendation.

In turn, Dr. Satcher sent memos to the agencies with an action item, which was to identify strategies to implement the advisory committee recommendations.

Dr. Henney on August 10th responded to Dr. Satcher with recommendations that were developed within the FDA Center for Biologics Evaluation and Research. We are committed to the following course of action:

For blood establishments that can verify that therapeutic phlebotomy for hemochromatosis is performed at no expense to the patient, FDA will consider case-by-case exemptions to existing regulations. Current regulations require disease state labeling for units from such collections to be released for transfusion and limit the frequency of whole blood collections. FDA has the authority to permit exemptions to the blood regulations under the provisions of Title 21, Code of Federal Regulations 640 120.

Since we are dealing primarily with safety and we want to monitor the situation, as part of any exemption to blood labeling and/or frequency of collection that we approve, we will request that safety data be collected and submitted to the agency. The data to be submitted will include viral marker rates, incidence of transmissible infections based on rates of seroconversion to viral markers, frequency of post-donation reports of undisclosed risks, and reports of donor and recipient adverse events. These data will be compared with comparable data obtained on the general donor pool.

Our next course of action is that we will review any funding plan proposed by Health Care Financing Administration to determine its adequacy in removing the financial incentive for persons with hemochromatosis to donate blood for transfusion. As Dr. Nightingale has mentioned, HCFA is limited in its authority, and within its authority, it's limited in scope. There is still a vast number of persons who are affected that are covered by private insurance or not covered at all. It appears that for the foreseeable future the responsibility to ensure that there is no charge to the patient will lie with the collecting agency.

Upon a finding that undue financial incentives have been removed for therapeutic phlebotomies of hemochromatosis patients and with favorable outcomes of surveillance data obtained under 21 CFR 640 120 exemptions to existing regulations, the agency can propose revisions to the regulations. Such revisions would allow therapeutically obtained blood from hemochromatosis patients to be used without disease state labeling and allow hemochromatosis patients to be phlebotomized for a collection of transfusion products more frequently than once every eight weeks without examination by a physician at each phlebotomy event.

Are there questions?

CHAIRMAN CAPLAN: Just so I understand the legal requirement here, you have to do this surveillance in order to gain the exemption? Is that how that works? On safety.

CAPT. GUSTAFSON: We can grant the exemption as an alternative procedure, but the assumption is that you will ensure that there is a measure of safety, that you're not granting exemptions without there being data to ensure that there's a good reason to grant it.

DR. CHAMBERLAND: I think this is similar to what you were asking, Art, but are the safety data going to be collected concurrently after the exemption has been granted, or does a blood collection agency need to present the FDA with some data it has already collected prior to having been granted the exemption?

CAPT. GUSTAFSON: We are aware--actually, we thought we had a candidate to start this process, and they actually have, you know, data, quite a bit of data. We've hit a snag with that application. But we don't feel that there is an inherent risk with the hemochromatosis patients, and we are willing to look at surveillance data after the exemption during the course of use, because at the present time the blood is not being used because of the restrictive labeling.

DR. CHAMBERLAND: And of the objective measurements that are listed in the memorandum that you reviewed with us that FDA will be examining to assess safety, I mean, I think as we discussed at a previous committee meeting, because viral marker rates are already so low, the population in a statistical sense that would need to be examined to address this with some level of statistical confidence is probably going to be difficult to attain. Some of these other things might be something you feel you have a chance of getting a better handle on, but that's the sort of--the operating premise is that you're already starting with such a low risk population to begin with.

CAPT. GUSTAFSON: And we are very aware of that.

DR. HOOTS: Just down to the practical, you've exempted the less than--the more frequent than every eight weeks limitations, and so as a prescribing physician, if you have a patient with hemochromatosis who's on, say, monthly phlebotomy, your concurrent care of that patient doesn't have to change. You write the order for monthly phlebotomy, and as long as you're following that patient, the blood bank is exempt from any extra administrative responsibilities other than tracking what happens to the recipients. Is that correct?

CAPT. GUSTAFSON: That's right.

DR. HAAS: Maybe Keith has given me a possible answer to my question, but I know that there is a question about how much extra blood we would get using the hemochromatosis patients. But I'm wondering if we're now again running ourselves into another situation. I understand the need for testing and making sure we have safety of the blood. But is the cost and time that we put into making sure these new patients, the hemochromatosis patients, are good donors, is it better--should we be spending our time there, or should we be taking those same resources and spending the time and just bringing in more people to the donor pool?

It seems to me this is an additional cost that we need to think about.

CAPT. GUSTAFSON: I don't know that I can--I can't answer that, but--

DR. NIGHTINGALE: One possible answer is both.

DR. HAAS: We don't have unlimited resources. That's--

DR. GILCHER: I can answer the question because what we have done, as you know, Mary, in our community is there is no charge to the patient who presents with a prescription for a therapeutic phlebotomy. So that cost is now built into our system. And on each of those donations, the individual is tested. They are handled as though they were a donor because it's just simpler to run them through our screening process. So we have the viral marker data on these individuals. So it's already there. We already know who they are. So we would have no recruitment cost. If we were to bring them into our system then at some point, there would be no additional cost to us.

CHAIRMAN CAPLAN: I mean, I guess what I'm hearing from some of the questions here is: Would it be helpful, or are we simply facing regulatory requirement, to urge an expeditious review of the safety question for these donors? Can we speed that process or is it what it is?

CAPT. GUSTAFSON: Well, I think it's--what it is--I mean, because there's certain data that you would monitor over time like seroconversion during the donation interval.

DR. AuBUCHON: I'm just curious, Mary, why the FDA is looking for these data about seroconversion, understanding that the size of the population we're dealing with is not going to give any statistically meaningful results, and we have, at least to my knowledge, in the blood banking community and this committee at its last meeting heard no data to suggest that these individuals were in any way different than any other individual absent the financial incentive, which we're taking care of through a different mechanism.

I'm just wondering if, again, there could be a way that this could be speeded up absent any data that suggests that we need to be cautious.

CAPT. GUSTAFSON: Well, we're willing to grant the exemptions with the commitment that data would be collected on these donors. I mean, it's basically--it's information that you're going to be collecting anyway because they're going to be donors and you're going to do the testing and you're going to have post-donation reports. But it would be to stratify them, to look at them in comparison to the other donors for a period of time, as a "make sure," a belt-suspenders type of activity that we do so often.

DR. AuBUCHON: So you're saying that a plan to collect this information would be acceptable. One would not--

CAPT. GUSTAFSON: That's right.

DR. AuBUCHON: --have to collect that information before applying for the exemption. Okay. Thank you.

DR. HOOTS: I'm going to raise an issue that probably is not fair to ask you, but, nonetheless, it enters into one of our future discussions about expanding the donor supply. But it just struck me--I happened to follow two siblings, sisters, who had homozygous hemochromatosis. Neither has reached majority yet, but they're clearly adult size and they're getting phlebotomized.

Now, under present regs theoretically you couldn't use their blood, but I only raise it because I think we need to consider other options in terms of expanding the blood supply, and this might be a nice, easy entry. There won't be very many of these, but there are some out there, in terms of exemptions for age for donation.

CAPT. GUSTAFSON: We actually don't have age restrictions. American Association of Blood Banks has in their standards age.

DR. HOOTS: Okay. That's good to know.

DR. DAVEY: Mary, am I correct, you in your final conclusion, it's your opinion that blood centers will have to absorb these costs, that HCFA is not prepared to do this? Did I understand that correctly?

CAPT. GUSTAFSON: Well, I think there will be more discussion tomorrow, and I'll defer to Dr. Nightingale on that.

DR. NIGHTINGALE: And I'll defer it to tomorrow, but I think your understanding is basically correct.

DR. McCURDY: I would take issue with one of the comments of Dr. AuBuchon. As far as I've been able to determine, there has been no systematic survey of the frequency of any viral markers in patients with hemochromatosis, most notably hepatitis C. And since that frequently is a silent infection, the data collected as a result of this initiative will tell us whether this is more common or not. There's no necessary reason to say that it's more common. On the other hand, there is reason to suspect that the presence of hemochromatosis and hepatitis C is more likely to lead to liver disease and the detection of the individual, the clinical detection of the individual, than not. So I think the jury is still out on that.

I think the age issue is a consent issue, not an FDA issue.

MR. ALLEN: Getting back to this Code of Federal Regulations, is there a time frame on things like the lookback, the HCV lookback? Is there anything that we can look at and say that we have X amount of months or whatever to get this done, get this started?

CAPT. GUSTAFSON: Well, you'll have more of a detailed discussion on HCV lookback this afternoon. Was your question on lookback or was it on--

MR. ALLEN: The regulations themselves. Do they give any determination of how long this process should take?

CAPT. GUSTAFSON: Are you talking about hemochromatosis or lookback?

MR. ALLEN: Any lookback.

CHAIRMAN CAPLAN: In other words, how much time do the regs say--

CAPT. GUSTAFSON: Oh, it's not. It would be--it's not a regulation now. It would be--what we've set up is our procedures in order to grant exemptions, that we would ask for a collection of data. And like Dr. Gilcher says, he's been collecting it all along, anyway. So, no, I think, you know, that it would be somewhat over time because we would--albeit few seroconversions, we would want to see if we have any.

MR. ALLEN: I guess I'm going beyond this issue of the hemochromatosis. I'm also concerned about the time frame of the HCV lookback.

CHAIRMAN CAPLAN: That one we'll do. We'll come back to that. I understand that part. We'll get to that this afternoon.

I don't see any more questions at this point. Why don't we go to the public comment?

DR. NIGHTINGALE: We have the PHS.

CHAIRMAN CAPLAN: Oh, I'm sorry. The PHS report you were going to comment on. That's all in your packet, by the way, which I had a chance to read beforehand. But in case you didn't, maybe we can just review that. This was the--you might explain what that working group was that Dr. Satcher referred to.

CAPT. GUSTAFSON: I'll read the first part. At the request of the Assistant Secretary for Health and Surgeon General, Dr. David Satcher, who also serves as the blood safety director, the Interagency Working Group on Blood Safety and Availability convened an ad hoc task group representing Public Health Service agencies, Department of Defense, and selected members of the Food and Drug Administration's Blood Products Advisory Committee to advise the PHS Blood Safety Committee on national strategies that may be undertaken to increase the blood supply.

The group met by teleconference five times between June and August, and the group members are on this slide. In addition to the group members, the group also, well, came very early to recognize that the true expertise in blood banking lies in the blood industry, and they're the ones who have the experience and insight in identifying problems in supply and demand for blood. Therefore, representatives of the blood industry were invited on a one-time basis to provide input and comment. These representatives were from the American Association of Blood Banks, the National Blood Data Resource Center, America's Blood Centers, and American Red Cross. And they're listed on this slide.

A variety of problems contributing to blood shortages were identified. The problems include low numbers of people who donate blood on a routine basis, the lack of a national monitoring system for blood collection and usage, and restrictions on donations from some potential donors that may not be necessary to protect the public health.

The group recognized that not all problems can be readily solved and that most resolutions lie with the blood community, but the group has identified some strategies for approaching solutions in which the Federal Government can play a role.

The first recommendation we've talked about extensively, and it's to monitor the blood supply on an ongoing basis. I won't go into detail here. The short-term strategy is that NHLBI will fund the National Blood Data Resource Center and the projects--the monthly monitoring projects that Marian Sullivan discussed this morning.

While the group viewed the support of the ongoing effort as the most expeditious approach, it also concluded that the appropriate long-term strategy would be the use of competitive contracting under the direction of PHS to ensure adequate monitoring of blood supply availability and use.

The next recommendation is to encourage more donations by eligible donors. It has been estimated that nearly half the population over 17 has donated blood at least once; however, only 5 percent of that population donates blood in a given year. Among active donors, the average number of donations per year has been consistent over time at about 1.5 donations per year.

One way to address this issue would be to get as many donors who donate only once or twice a year to give one more time. Also, as a more longer-term strategy, it would be important to encourage a lifetime habit of donating by donors who have given once or twice. NHLBI has some planned studies in this area and will be supporting studies in this area.

Additionally, a long-term strategy would be to encourage childhood education in the public schools in order to develop a positive attitude toward donation, and we are aware that there are some blood centers who have programs currently.

The next strategy would be improved donor relations as part of recruitment and retention. The blood supply is dependent upon the volunteerism of Americans. Strategies that can be undertaken on a long-term basis should address customer service improvements. There are competitive pressures to volunteer for many charitable causes, and Americans demand better customer service than in the past. Information from an earlier era indicates that few donors, maybe only 2 or 3 percent, are lost because of a bad experience at the time of donation; however, those studies are over 20 years old. Much has changed in the past 20 years in terms of donor deferral criteria, increased competition among blood centers for the same donors, and we think it would be good to determine if current donor practices are effective in encouraging and retaining blood donors, recognizing the need to avoid undue incentives to donate.

We think that most of the issues of donor relations lie within the purview of the local blood centers, but there may be more similarities than differences from one region to another. The task group identified areas in which the government can play a role. In the absence of current published studies, the PHS may cosponsor with industry a public workshop for identifying best practices for donor recruitment and retention. The public workshop should also address the need and study design of instruments to evaluate donor interactions since much available donor behavioral information is anecdotal.

We also identified long-term projects that could be undertaken, and key among that is simplifying the donor questionnaire. Dr. Davey I think reported at the last meeting that donors find the current questionnaire extensive, intrusive, and tedious for repeat donors. This is a project that should be shared among the PHS agencies in terms of addressing.

Other longer-term projects would be development of a computer-assisted donor history questionnaire, and the NHLBI is sponsoring a study on the computer-assisted donor questionnaire and its use in blood centers. Additionally, NHLBI has other customer service research that it is planning in the future.

The next item is remove restrictions to safe donations, and I just spoke about the activities that FDA is undertaking in terms of the hemochromatosis patient. In addition, we should review our donor deferral policies and the re-entry algorithms that allow donors who are deferred to re-enter the donor pool.

Donor deferral policies are created with redundancies and the goal of preventing unsafe donors from re-entering the donor pool. However, donors deferred in the past because of false positive viral marker testing can be reinstated after additional testing following a defined testing protocol with interpretive algorithm.

By their conservative nature, donor re-entry algorithms do not allow reinstatement of a proportion of past donors who are healthy but deferred because of viral marker testing results. FDA should review the current donor deferral re-entry algorithms used to reinstate the donors to see if they're still valid and if changes can be made.

Also, there's the issue of males who have sex with other males and their deferral. Currently, a male who has had sex with another male even once since 1977 is deferred for life. At recent BPAC meetings and a public workshop, FDA has discussed whether the current deferral policy for males who have had sex with other males should be relaxed by some degree. The Blood Products Advisory Committee did not make a decision on this issue, but encouraged FDA to continue to gather information to address the question, and FDA should continue in those efforts to review the issue and modify the deferral policy, if warranted.

Another issue which there's less data on and less far along is whether or not donors who are positive to the antibody for hepatitis B core should be able to donate blood safely, and the group recommends further studies in this area to see if these donors could re-enter the donor pool.

The last issue is that the PHS should address economic issues facing the blood industry, and the first step in this is to provide a public forum which is the discussion that will be held tomorrow with the advisory committee, and a more long-term basis is to review government policies affecting reimbursement in more detail.

Any questions?

CHAIRMAN CAPLAN: Can you tell us what--these are the recommendations they came up with. What are the steps to go forward in terms of timeline?

CAPT. GUSTAFSON: Okay. I think we have already started some of the initiatives, definitely in terms of hemochromatosis, in terms of monitoring. Like Dr. McCurdy said, we'd be happy if data could be collected tomorrow. So I think that we are moving ahead on most of the issues, and NHLBI is shouldering quite a lot of the burden in terms of supporting the research in the donor behavior issues.

DR. HOOTS: Just a follow-up on my previous question to you, but more focused now on the child or adolescent donor potential. Has any thought been given to putting out RFPs from PHS to blood centers, universities, to work with high school pilot projects? Because, obviously, issues come up when you talk about not only consent issues, but there may be--we probably would want to have more data about seroprevalence in 16- to 18-year-olds than perhaps we have from--you know, if we were going to entertain even implementing that, but there could be a tiered process where you could start with 10th graders on education and move them to 11th graders where they get their blood drawn with, obviously, their parents' permission to test seroprevalence of everything we mark for, and then by the time they are seniors, if the project were successful, they would move into potential donors, at least even before they reached 18 since there is not a federal mandate against that and since it would be a research project to begin with. And if that data were supportive and it were successful and the media were to pick it up as a successful project, that could train the next generation of blood donors in a way we've never undertaken, at least since the Second World War, in this country to replete our vanishing older-age donor supply.

CAPT. GUSTAFSON: I don't think there's any existing RFPs in the area, but, you know, we've had discussions--I think Dr. Piliavin at the last Blood Products Advisory Committee gave an eloquent extemporaneous talk on the need for childhood education, even starting in grammar schools, on public responsibility to donate blood.

There are successful high school donor programs, and I don't know whether any of the committee members have those programs. I know that they do--I don't know how early they start. The donations are generally not until 17, the senior year. But I think that some of them do have some educational information that's given out, I don't know, at 10th grade, but at a period of time before they actually go in to donate.

DR. AuBUCHON: I'm not sure how deeply you will have to gaze into your crystal ball to answer this question, Mary, but will the availability of licensed, more sensitive infectious disease marker tests, specifically nucleic acid testing, allow the agency to more rapidly consider removing the requirements for other tests or relaxing donor question requirements, specifically the anti-core testing and men having sex with men?

CAPT. GUSTAFSON: My crystal ball, I can't tell you what the outcome will be, but I think that that's a consideration. And having more sensitive testing is then the value-added to some of the questions that we have right now, and I think that all needs to be considered as a total package.

DR. GOMPERTS: I have one question. Has the working group considered evaluating the long-term health consequences on the relatively small donor pool who are long-term donors? In other words, what is the impact on giving blood over a long-term period, a long period of time on these particular donors? Because there are hypotheses that there are health benefits to these particular donors. Is there a consideration to evaluate this particular group?

CAPT. GUSTAFSON: We haven't discussed that. I know that the commercial plasma industry has done lookback--I mean, not lookback in the term of lookback, but they've done a retrospective study in terms of looking at long-term plasma donors and found that they stay healthy over time. I don't know that we have long-term blood donor studies that I'm aware of.

DR. McCURDY: I think what you're referring to probably is the effect of iron depletion or partial iron depletion, which has been postulated to be beneficial for heart disease.

The Institute has both looked at that a bit in the Heart Division. I don't know what their recent thinking is, but the data were quite limited and didn't really prove the issue, although there are some believers out there.

I think that there also have been some attempts to set up studies in one sort of another. This would be an extremely difficult thing to study, and the issue is probably iron, quantitative body iron, rather than blood donation. Blood donation does result in some limitation in total body iron stores, as you're aware.

There also have been some suggestions that removing lymphocytes at blood donation or early on apheresis donation might reduce surveyance or infection or malignancy or something like that. Again, there have been a few attempts that I'm aware of to study this. It's so difficult to study that I don't think there have been any real prospective studies. I believe there was one attempt to match up multi-gallon donors with a statewide cancer registry that showed no correlation, that there was no relationship there. That's the best I can do.

I think that I could say one more thing, and that is that the NHLBI would be happy to talk to people who have a particular interest in studying this, who might have an interest in developing some additional demonstration or education programs focusing on high school students and so forth. I don't think we have any plans at present to put out an RFP in this area, but we're always open to investigator-initiated awards in this and, of course, any other area.

DR. DAVEY: Mary, thanks for reviewing the task force recommendations. I believe we also considered whether there could be some government-sponsored attention to creative uses of education material, like PSAs, media appeals that are new and creative to the public about blood donation, and maybe even some way to enlist prominent celebrities, officials, people that might appeal to the young people to donate blood and donate in a visible way so that people can see that that's a process that people should participate in. Is that part of the recommendation?

CAPT. GUSTAFSON: I skipped right over that, and I was hoping that you wouldn't point to that.

We came to--I think the recommendation is actually that we would support industry-sponsored PSAs in terms of volunteering, like high government officials to give statements on the public health benefits of donating blood. So that's what the recommendation actually states.

DR. NIGHTINGALE: May I remind you that in Dr. Satcher's presentation this morning, he stated that the high government officials were willing and, in fact, eager to participate in appropriate industry-sponsored public service campaigns.

DR. GUERRA: I guess given the tremendous advances that have taken place in recent years and months for screening for so many infectious diseases and that give us a fairly precise assessment of risk in terms of some of these diseases, has any discussion or consideration been given to the possible use of inmates from either state or federal institutions to perhaps be brought into the donor pool?

CAPT. GUSTAFSON: No.

[Laughter.]

DR. GUERRA: Thank you. Is it something that perhaps could generate some interest in an RFP to--no?

CHAIRMAN CAPLAN: That was pretty resounding we reject it. The last time I heard that proposal come up was from Dr. Kevorkian.

[Laughter.]

DR. PILIAVIN: This is just a point of information regarding the use of celebrities. When Donna Shalala was chancellor at the University of Wisconsin, her picture was frequently in the student paper, at the time when they were trying to encourage blood donations, giving blood at the local university donation center. I have no idea whether it worked.

DR. NIGHTINGALE: Public comment?

CHAIRMAN CAPLAN: I was just tempted to see if that was the kind of person that would motivate youth, but all right. Anyway, it seems to me the other issue that's up on the table here, before we turn to the public comment period, I was telling Rick that from the last meeting that we held, I had some comments in the papers and media about blood shortages and wrote a little thing for a website about where things were with hemochromatosis and got about 50 e-mails from people complaining bitterly about red tape at donation. I mean, people have told me about it, not the least of which Rick, and others from the blood collection agencies.

But these were people who at least said that they were donors or had been frequent donors, and I worry about where we're headed with our British blood deferral questions and so forth. One of the costs on the safety end is obviously to increase the length of the questionnaire, and that does seem to be a real concern, at least from this screwy sample that I got back. So it might be important for us to be thinking about encouraging ways to get efficient screening done without making it seem either a hassle to the people who want to, or the other fear is intrusion on privacy. There's a lot of distrust about maintaining privacy of records, even if there's an assurance that it's there, but that's an important issue in terms of communicating to the public that privacy can be protected from what's picked up on these screens.

I got a dose of that concern firsthand, and I hope the committee can work on that. We may want to say something about that further.

Okay. Thank you.

I don't have the list. Do you have that?

DR. NIGHTINGALE: It is our practice in the committee to welcome public comment from all who wish to comment and try to give people as much time as possible to deliver their comments. Our other practice is to do it in alphabetical order for no particular other reason than it is self-correcting and self-demonstrable whether or not everybody gets in line where they should be. I do know that the American Association of Blood Banks, America's Blood Centers, and the American Red Cross, along with Dr. Paul Cummings, are interested, and Jan Hamilton-H, Hamilton--of the Hemophilia Federation of America will wish to comment at this point, without wishing to exclude anyone from comment, if you could order yourselves alphabetically, we would appreciate it.

We'd also ask the commenters to limit their discussion to this first agenda topic, which is the deferral of blood donors and the government's response to it. There will be ample opportunity for the public to comment at each agenda item.

So if I could begin--I know Ms. Gregory, I know it begins with a G, but your organization begins with two A's. Welcome.

MS. GREGORY: Thank you. I'm pleased to be here today on behalf of the American Association of Blood Banks, and I'll just quickly remind you that this is a professional society, and we represent 9,000 individual members and 2,200 institutional members, and hopefully the overhead will warm up in a minute, which means that we represent virtually all of the blood collecting agencies in the country and over 80 percent of the blood that is transfused in the country.

Like this committee, we are concerned not only with the safety of the blood supply, but obviously with the adequacy and the availability of the supply. And I believe each of you have already received a copy of our written comments, so I'm just going to highlight some things and then spend most of my time on a couple of initiatives which you may not have heard of yet.

Next slide, please?

First of all, you've already heard this morning about this wonderful new variant CJD question, which we believe is probably impractical and most donors will be unable to answer with any degree of accuracy. So in answer to that, I should tell you that the American Association of Blood Banks, America's Blood Centers, and the American Red Cross have sent a joint letter of comment to the docket about this particular question and some wording in some of the others, and we expect that the FDA will act on our request to consider this expeditiously.

Next slide?

I want to talk for just a minute about strategies for monitoring adequacy of the blood supply. You've already heard about the NBDRC efforts, and this is a program which is supported by the AABB, and we certainly encourage funding to allow this activity to continue.

In regard to blood donations by individuals with hemochromatosis, our position has always been that we need to remove the financial incentive, and we also agree that we need to remove the labeling restrictions. And we certainly would support the FDA approach that they've outlined in their letter.

I should tell you that the AABB standards currently would prevent anyone with hemochromatosis from donating, but there is a mechanism for obtaining a variance from that standard as well, so that those facilities that apply to the FDA for a variance from their requirements should probably apply to the FDA for a variance from our standards at the same time, and I would certainly expect that that would be granted.

Next slide?

In terms of recommendations for increasing blood donations, you've already heard a lot of these from Mary. Not surprising. She's heard a lot of it from us. We would support a national meeting, and we particularly would be concerned that the recruitment professionals be included in this meeting. They may have lots of insights as to what works and what doesn't work, and we could have a lot to learn from such a meeting.

Secondly, we've also always said we believe there needs to be more research into the behavioral science aspect. We don't have a lot of information about why people do things the way they do, and we think it would be helpful to have that.

Thirdly, as Mary said, and you heard Dr. Caplan say as well, we think we should look at how we can streamline the donation process, and we need help from the FDA to do that because many of the requirements that we follow come from them. But we think that particularly the donor questionnaire is an area that's ripe for being looked at and being worked on. We need to collect essential information. We want to ask essential information. But as you've heard, many of the questions are viewed as intrusive and perhaps aren't necessary any longer in the light of some recent developments in testing, et cetera.

Then, finally, as Mary has also mentioned, review donor suitability criteria, not only from how they answer the questions but the test results that we get, and being able to re-enter some of these people, particularly from older tests where we know we had some problems with the way the tests were constructed.

Next slide?

I'd like to spend a little bit more time on some of the AABB long-term initiatives that are generally not well known. The first one is an educational initiative which is going to be launched sometime in the year 2000 under the auspices of the National Blood Foundation, which is a program of the American Association of Blood Banks. And they have already formed a partnership with MetLife to launch a large-scale program to develop and implement a nationwide educational program about blood donation.

We want to create public awareness about the need to donate blood. This initiative will target the secondary schools and has already been endorsed by the National Association of Secondary School Principals, and that's an organization that has 40,000 members, and they looked very carefully at the program that we were proposing.

Next slide?

The goals of this program are not simply to collect blood. You know, we're all out there trying to collect blood, but the goals are really broader than that. We know that younger donors make decisions for reasons that are different from their parents, and we also believe that young adults want to volunteer, but they need to be convinced to devote time and effort to any particular cause. So we want to work on developing a long-term sensitivity to the need for blood donation and to begin to establish a lifelong pattern of blood donation.

Next slide?

Now, the way we will go about implementing this program is to try to demonstrate the inherent value of blood donation, among other things. First of all, there is an arm that is interested in blood education awareness, and you've already mentioned things like health and science classes and getting more information out there that way.

Secondly, of course, we're going to promote blood drives, but we want to do it using more of the high school, the secondary school resources. Things like marketing and advertising clubs can have projects to work along with this. They have community service organizations like Key Clubs, and those things can be used not only as class projects but, you know, they're always looking for things to do, so helping to promote a blood drive would be one way to involve those people.

And, lastly, and most importantly, is coordination with local blood facilities so that this is viewed as a local activity, although it will be helping to provide nationally information and materials for how to go about doing this.

Now, the problem, of course, is that this is a costly venture. We know it's going to cost more than a million dollars to do this. We're prepared to undertake this project, but, of course, we're interested in any funding from any government agency or any funding from anyone else who might like to join in this activity. And we would be happy to provide additional information more specific about the program in other meetings with other individuals if you're interested in that.

Next slide?

And, lastly, I want to address an ongoing, again, nationwide campaign, and although I'm speaking for the AABB, this is a campaign which really involves the AABB, the ABC, and the Red Cross. It is really a joint activity. It's a nationwide campaign. Over 2,000 facilities in every one of the 50 states participate in National Volunteer Blood Donor Month. And this month is January because that's a month when we historically know that we tend to have a shortage of blood.

It begins with a presidential proclamation in January, and it includes a congressional blood drive. I know you've heard at this meeting mentioned that Congress needs to be more involved and more aware about blood donation. Well, we're trying to make that happen. And the theme for the campaign is "Fight for Life," and we asked the Democrats and the Republicans to challenge each other and see who can come up with the most donations.

So Capitol Hill plays an important part, and in 1999--

CHAIRMAN CAPLAN: I can't help but interrupt to say that may be the connection to the prisoner proposal.

[Laughter.]

MS. GREGORY: I would agree, but you need to remember that Congress has a lot of staff people as well.

In 1999, we're happy that they had the largest blood drive ever, and we collected over 400 units of blood from our congressional blood drive. We're already busily working on National Volunteer Blood Donor Month for this year, hoping that it will be an even bigger success.

It's amazing, when you have the same kinds of advertising campaigns, the same kinds of incentives, you have T shirts, buttons, calendars, all kinds of things that appear all over the nation, you really do get a lot of attention, and we've put a lot of effort into doing this.

I would like to thank you for this opportunity to comment. We've sort of brushed over a lot of very important issues that you've dealt with this morning. But we'd like to assure you that we stand ready to assist the committee in any way possible because we believe that we'll be most successful attaining the goal of a safe and adequate blood supply for the nation if we all work together in a partnership to reach that objective.

Thank you.

CHAIRMAN CAPLAN: While our next speaker is coming forward, it also occurred to me, more seriously than impugning our poor congressional representatives, we might see if we could get a campaign started to ask presidential contenders if they've donated blood.

[Laughter.]

CHAIRMAN CAPLAN: All right.

DR. NIGHTINGALE: On that note, we welcome America'S Blood Centers to the podium.

MS. SMITH: My name is Kristin Smith, and I'm here on behalf of America's Blood Centers, whose members provide nearly half of the nation's volunteer donor blood supply. I would like to thank this committee for the opportunity to present our views on the new variant CJD deferral guidance that has been issued by FDA.

While we have previously stated our concern that the principles of science-based medicine are questioned by this recommendation to address a theoretical risk, we understand that public officials need to reassure the public that they are committed to a safe blood supply. However, a very basic component of a safe blood supply--namely, its adequacy--will be threatened by this deferral.

At a time when shortages are widespread and predicted to increase, the new variant CJD deferrals will reduce the blood supply by an estimated 2.2 percent. Prompt action must be taken to make sure blood is there when it is needed.

In 1997, the General Accounting Office reported that nearly half of all blood transfusions are life-saving and immediate. When blood supplies become critically low, the first line of defense is emergency recruitment of donors and efforts to locate surplus blood among all hospitals on an as-needed basis. If these efforts fail, our next step is to ask physicians to cancel elective surgery. Elective surgeries are not just plastic and orthopedic surgeries, but also critical cancer, heart, and transplant surgeries. Our fear is to be faced with a tragedy--a school bus hit by a train, a mass shooting in a school, a terrorist bombing of a public building, and a critically low blood supply.

Members of America's Blood Centers are prepared to implement any deferral policies that HHS feels are required in the name of blood safety. While we have the expertise required to mobilize donors, we do not have all the resources necessary to recruit new replacement donors. The nation's blood providers urgently request the department's assistance and support. How can HHS help?

First, we request that HHS develop--I think you've got them in reverse order. The first one, national campaign to increase blood donation.

First, we request that HHS develop a national campaign to increase blood donation. This campaign can have two parts: one for the short term and one to address longer-term issues.

For the short term, that is, the next six months, a steady stream of messages from high-ranking government officials and other respected public figures communicating the crucial need for blood donations would help alleviate and prevent shortages that will put patients at risk. In addition, and for the longer term, HHS should provide local grants and national funding that support proven techniques for increasing blood donations. This campaign should be planned in conjunction with national blood organizations that have developed a number of successful national and local recruitment programs.

ABC launched one such program last November. To prevent holiday shortages, ABC, in conjunction with the health care industry of New Jersey and four local blood centers, launched the RX Partners for Life campaign. This corporate blood drive campaign increased donations among 17 drug and medical device companies by more than 15 percent. Resources are needed to roll out this program to other industries, such as oil companies and banks.

Another example is Pints for Half-Pints: Giving Kids Another Chance, which ABC will launch this fall. By sharing the stories of children who have received life-saving blood transfusions, this campaign puts a young face on the need for blood donation. The long-term goal is to cultivate a new, enthusiastic young generation of donors to replace an aging donor population and those lost by existing deferral policies.

Along these lines, we applaud a recent initiative from Dr. Barbara Alving, head of the Blood Diseases and Resources Division of the National Heart, Lung, and Blood Institute, that would bring the independent members of America'S Blood Centers and the Red Cross under one umbrella for national recruitment efforts. Unfortunately, no money has been allocated for this activity. We ask for an immediate appropriation to help Dr. Alving in this national effort to increase blood donations.

Next slide, please?

Secondly, we ask HHS to remedy the lag between when an FDA-recommended blood safety measures is implemented and when hospitals receive proportionate reimbursement increases from third-party payers such as Medicare and Medicaid. This lag, which can be as long as three years, makes it difficult for blood centers to pass along their added costs of recruiting new blood donations or other blood safety measures. HHS can easily remedy this situation. We understand the committee will address this reimbursement issue tomorrow.

Third, we ask that HHS develop a professional education program on blood usage. It is unlikely that blood is heavily overused in this post-AIDS era that also sees frequent blood shortages. However, physicians need to understand they should be conservative in blood usage where possible and coordinate elective blood-intensive patient procedures with the hospital transfusion service and/or community blood centers. The department should assist blood centers in informing physicians about current actions and any new deferrals. These messages should be developed through multimedia tools that can be distributed locally through national and state professional organizations. These tools should be planned in cooperation with national blood organizations and organizations like the American Medical Association and the American Hospital Association.

Fourth, HHS should develop educational materials for deferred donors. The new variant CJD deferral criteria will alarm many affected individuals as to the reason for the deferrals and the implications for their health. Official HHS multimedia tools should be developed for such donors and health care professionals to provide information and advice. We note that CDC has offered to help develop a Q and A on the deferrals, and this should be very useful. HHS should also consider sponsoring a toll-free hotline and website with medical support that donors and professionals can use to get information and counseling on this important deferral.

Finally, we ask that HHS publish the circumstances in which the UK deferrals will be allowed to lapse; that is, what would the department consider adequate evidence that new variant CJD is not a threat to the U.S. blood supply? This not only sets a trigger for re-evaluation of this deferral, but also holds out hope to deferred individuals that they may once again be welcomed back as the heroic blood donors they have been.

The last slide, please?

By developing a national campaign to increase blood donations, a professional education program on blood usage and educational materials for deferred donors, and by setting a sunset criteria for the deferral, the department would greatly assist blood organizations in protecting the adequacy of the blood supply.

Thank you.

CHAIRMAN CAPLAN: Comments?

[No response.]

CHAIRMAN CAPLAN: Okay. Thank you.

DR. NIGHTINGALE: I think the American Red Cross is--Dr. Davey?

DR. DAVEY: Steve, we don't have a formal comment. I'd just like to say that our position on the new variant CJD deferral is in the public record and has been very clearly stated to the TSE committee. And as you've heard earlier today, we hope the FDA will seriously reconsider the question on the BSE injectibles, and we concur with the comments of my professional colleagues about very precise periodic re-evaluation of this deferral criteria.

Also, in terms of increasing blood donation, we concur with Mary Gustafson's task force recommendations and support them and participated in them, and as members of AABB, we support and concur with Kay Gregory's presentation on this topic.

CHAIRMAN CAPLAN: Yes, Dr. McCurdy?

DR. McCURDY: Art, I'd like to make one quick comment, and that is that approximately 1987, I think, or very shortly thereafter, the NHLBI implemented a National Blood Resource Education Program. This was stimulated by the blood banking organizations. Sometimes in the early 1990s, about probably '92, '93, it was discontinued, and it was discontinued because the blood banking organizations didn't think that it was particularly useful. It had two prongs. It had a professional education aspect, which I thought was very good. I'm not sure how effective it was, but it was very good. And it had a number of public service announcements that were put together over the years based on advice from the blood banking community. And apparently they didn't do the trick or at least the blood donors weren't knocking down doors to donate. So as I said, the institute discontinued it as not being appropriate.

I think it might be wise to look at what would be different now if there were to be a broad-based effort in education for public donation and then professional use of blood.

DR. NIGHTINGALE: I know that Dr. Paul Cummings and Ms. Jan Hamilton wish to address the committee. Is there anyone else who wishes to address the committee? Could they raise their hands, please? Mr. Cowles, National Hemophilia Foundation--and ABC continues.

DR. HOLLAND: Actually, I'm Paul Holland.

DR. NIGHTINGALE: I'm sorry, Paul.

DR. HOLLAND: I'm the medical director of the Sacramento Medical Foundation Blood Center in Northern California. It's an independent, not-for-profit community blood center. But for the FDA's notice, I'm speaking here as an individual, not as a representative of my center.

To reduce the theoretical risk, we are being told to adopt what I consider illogical, inconsistent, unwarranted, and unproven approaches which are not supported by any credible scientific evidence to date. In fact, these recommendations are not only not based upon scientific evidence, they fly in the face of what evidence we have. These recommendations should not be accepted by the blood banking community in the United States or in any other country. I think they should be repudiated.

If implemented, I think there is more likelihood that we will increase this theoretical risk or trying to prevent a variant Creutzfeldt-Jakob disease. I think we will increase real risk of what we already know to be transfusion-transmitted infections and will have started on a very slippery slope of donor deferrals which will be hard to get off of.

I want to make four points. You've already heard some of them, but I think they're worth emphasizing.

We already have shortages in this country. Those shortages will be exacerbated of blood, blood components, and blood derivatives. If one patient suffers or dies because of this, this would outweigh the theoretical benefit you're trying to accomplish.

Second, the replacement of these deferred but otherwise qualified and primarily repeat donors that we're going to lose with new donors or even with some who may qualify with the diagnosis of hemochromatosis, presuming we can get by all the hurdles, will more likely increase real risk for recipients of known transfusion-transmitted infections such as hepatitis and retroviruses.

Third, I remind you that America is not now and has never been self-sufficient in blood. We continue to import hundreds of thousands of units from Europe. We will have to import even more. And unless those European countries from which we import blood follow the same guidelines, practices, procedures, we'll be bringing in blood which, in my view, has even more of a theoretical risk of new variant or variant Creutzfeldt-Jakob disease than it's intended to replace. If countries, like Germany is proposing, decide to adopt similar measures and lose many of their donors, they may not even have as much excess blood to export to us as they do now.

Fourth, you already know that one case of variant Creutzfeldt-Jakob disease has occurred outside the UK in France. If another case occurs there, will we start banning people who have gone to France? Many other countries in Europe besides the UK and France have had BSE reported in their cattle. If a case or two occurs in those countries--Belgium, Switzerland, Ireland, Luxembourg, the Netherlands, Portugal--do we start banning people who have spent time there?

We have TSE in American elk and deer populations. We have mad deer disease. If someone in this country develops CJD after ingesting meat from such animals, do we start deferring hunters, their families, people who eat venison? It seems to me once you make these illogical decisions, you will have to continue down this same path.

I really urge the Department of Health Services to reconsider, and this committee also, this decision to ban individuals who have lived in the UK for more than six months during this period of time as blood and plasma donors. I really think this will cause more harm than you hope to prevent.

Now, I know that I am blowing in the wind in this, but I wanted to put it on the record, anyway.

The current recommendations to reduce the risk of transmission of CJD by blood and plasma products have at least some basis in fact. I for one think that they are more than adequate to protect the blood supply from the theoretical transmission of these agents. I will recommend to my blood center, and any others that will listen to reason, that they retain those and not accept the new recommendations. I really think they are unwarranted.

Now, if the FDA and the Department of Health Services really want to make some useful recommendations, which are based upon some scientific data, I can give them at least two.

First, they should recommend that patients not be transfused with blood or blood components into their brains.

Second, if we really believe that all of these people, all these blood donors and plasma donors are at risk of transmitting this disease, why don't we survey the entire American population about who has been at risk by being in the UK for more than six months, identify them, and make sure when they go to their surgeons for operations that their surgeons either use disposable instruments or throw them away after they have operated on them?

Finally, there's a children's fairy tale called "The Emperor's New Clothes." I think it's time to say that, despite what our advisers are telling us, the new recommendations have no merit, just as the emperor had no clothes.

Thank you.

CHAIRMAN CAPLAN: Comments? Go ahead.

DR. GOMPERTS: Dr. Holland raises a relevant point that I'm not aware has been considered by the TSE Advisory Committee or even BPAC, and that is the issue of importation of blood and blood components, et cetera, and how relevant is this from the point of view of what is trying to be achieved.

CAPT. GUSTAFSON: Blood that is imported into the U.S. has to be licensed by the Food and Drug Administration, and the current blood for transfusion that's imported from the European countries is under U.S. license. So they would be expected to follow the same recommendations as a U.S. facility.

DR. GOMPERTS: Thank you.

DR. AuBUCHON: However, there is BSE, as Dr. Holland noted, in numerous herds of cattle in Western Europe, not just in the United Kingdom. I do not believe there is BSE that's widely prevalent in this country, or no BSE, I forget which one of those--

DR. CHAMBERLAND: No BSE.

DR. AuBUCHON: There's no BSE in this country. Thank you. So, therefore, even by following the FDA guidelines as now published, we'd still have entry into this country blood from donors who had been exposed to BSE beef presumably at a much higher rate than individuals who had traveled from this country to the United Kingdom.

COL. FITZPATRICK: For Dr. Holland, I just had a question. My understanding of your recommendation would be that a blood center operate in violation of the license or drop their license.

DR. HOLLAND: No. I think you have to make it clear--I have to make clear that these are recommendations, these are guidelines. My understanding is they are put out there for comment, they're put out there for acceptance or not. Until they are regulation--and we do have a democratic process which takes about three to five years to make them regulations. Until they're regulations, I don't think we have to accept them. And I'm recommending that we not accept them because, in fact, they are recommendations or guidelines.

Now, I guess someone could tell me otherwise, but my compliance officer tells me these are recommendations, they're guidelines suggested by the FDA. You can accept them or not accept them. I do not want to accept them, and I am recommending that nobody accept them. But I'm sure most people will. A number of you have said you will. In my view, you don't have to.

Once you accept them, however, you must follow them, and you can be cited for failing to follow them, and you can be cited in your 483. But if you don't accept them, they don't exist--for you.

[Laughter.]

CAPT. GUSTAFSON: You are right that guidance documents do not have the effect of law like a regulation does. And so, therefore, they're not enforceable on their face. There is the issue, though, of guidances are based on regulations in terms of donor deferral and donors being in good health on the day of donation and preventing risk to the blood supply.

So although they are recommendations, they are not regulations, and they are not directly enforceable, you can get into an issue of expert testimony and having enforceability in that way.

DR. HOLLAND: But you agree they're not regulations?

CAPT. GUSTAFSON: They're not regulations. They're not enforceable on their face. You are right.

DR. HOLLAND: Thank you.

CHAIRMAN CAPLAN: Well, thank you. We'll look forward to that legal fight and hearing more about it.

[Laughter.]

CHAIRMAN CAPLAN: ABC?

MS. McMILLAIN: Yes, I'm Melissa McMillain. I'm America's Blood Center's public relations director, and I just wanted to comment in response to a couple things that Captain Gustafson had said and some other people had said about young children programs and that there weren't any.

In fact, there are a couple. One of our blood centers actually has a program that starts at kindergarten with puppet shows. It goes through kindergarten through sixth grade. The first year that this blood center implemented this policy was the '94-95 school year, so that the first group of kids who graduated from this program were eighth graders when they started the program, the first year that they were able to donate, the first-time donor rate increased 23 percent. It's a proven program. It continues to grow in its success.

These are the types of programs that perhaps we can talk about in conjunction with HHS and other national blood organizations to make them work across the country.

Secondly, there's another program by another one of our blood centers called My Blood, Your Blood. Again, it's a youth-oriented program targeting elementary school kids with an animated, cartoon series with platelets and white blood cells and red blood cells, all computer graphics, very interesting. Again, it's a program that may unroll. These are the types of programs, again, that may be supported by HHS and the other agencies and in conjunction with other national blood organizations.

I just wanted to put that on the table to let people know that these were programs that are available. We can talk--you know, we'll be happy to answer any questions about them and talk to you about how to unroll them further.

Thanks.

DR. NIGHTINGALE: Why don't we move to--Dr. Cummings and Ms. Hamilton will return to the alphabetical order. If there's anyone else--Dr. Cummings, would you approach the podium, please? Is there anyone else in the room who wishes to address the committee at this time? Sorry, Patrick Collins of the National Hemophilia Foundation. That will conclude the morning session.

Dr. Cummings?

DR. CUMMINGS: Thank you. I'm Paul Cummings. I'm here to talk about computer-assisted, interactive video donor screening. An embodiment of that technology that we have trademarked, the Hoxworth Quality Donor System. In simpler terms, it's multimedia donor screening, a technology which Dr. Piliavin, among others, advocated in 1991, and it's been referred to as computerized screening in earlier presentations here.

I have an MBA in marketing, a Ph.D. in systems, and several--many relevant blood publications, and about 30 years of experience, or 20, at least, in the blood industry.

Next slide, please?

This is a project supported by, in part, the National Heart, Lung, and Blood Institute via a small business innovation research Phase 1 grant. I'll be presenting the preliminary results from sample sizes of 277 donor surveys and 395 disks of the--or records captured on the computer disks during the process of processing the donors. Its work is conducted in conjunction with Dr. Zuck of the Hoxworth Blood Center and Dr. Wallace of the Center for Management Systems. And in our Phase 2 application, where we hope to expand what we have done now and the software that we are currently using, Dr. Gilcher, a member of your group, and the Oklahoma Blood Center have agreed to join us, as well as Dr. Miller and the Blood Center of Southeastern Wisconsin.

Next slide, please?

We addressed two problems or two kinds of problems in addition to those normally addressed by a computer system. One is clarity in recall, and the other is truthfulness. Our measure of clarity and recall, and improvement therein, is FDA-reportable errors and accidents. Seventy-two percent of those are classified as donor suitability. Of those, 53 percentage points are post-donation information which was known or should have been known at the time of donation by the donor. They're such things as visits to malarial areas, tattoos, histories of cancer, surgery, et cetera. Another two percentage points is simply incomplete donor history forms, which we directly address. A total of 55 percent of all errors and accidents we're addressing with the Hoxworth Quality Donor System.

Next slide?

Truthfulness problems. We know they're a problem via the red studies of NHLBI. Roughly 2.2 percent of the donors are reporting incompletely or inaccurately or dishonestly, depending on whose definition of the term you want to use. We know that it requires audio privacy, usually via earphones, for socially sensitive and stigmatizing, as opposed to other kinds of questions. The past studies that have been done of computerized donor screening in the industry have all used incomparable questionnaires--that is, they have had a different questionnaire for the computerized screening than was used in the routine manual donor screening process.

The closest study to anything in blood that we're aware of to try and determine the advanced impact it will have--one, we provide privacy on a comparable questionnaire basis--is a study that was reported in Science about a year ago by Turner and some associates. What you can do there is look at the last column, you'll see the paper survey rate divided into the audio computer-assisted survey rate, and you get the multiplier of the percentage reported for audio CAS. That is roughly anywhere from 2 to 14 times as much reported.

Next slide?

This is the initial introductory screen on the system of which there are a total of 60 in it. The audio goes off after the second repeat of it. If there's no donor present to start the system, they press the start button, and the audio picks up again and advises the donor to put on the headphones for the privacy. And pressing the continue button then starts the process up where some basic descriptive information is asked for tailoring the interview and questions are asked.

Next, please?

This is a typical question screen, of which there are 45. The only thing atypical about this is the picture. The pictures are custom tailored as well as the text of the question. It is custom tailored to every question, designed to get at the essence of the question and deal with some issues that are difficult to deal with with words.

The buttons on all of the screens are the same so the donor gets to know them. The voice in the audio is that of Dr. Carey. It may look like a simple screen, but it took us eight tests to get that one that would satisfy the donors most.

By the way, the unique part of this technology, as far as we know, is that as simple as it seems, it's the only system that we know of that uses a picture to draw attention to and describe the question better.

Next, please?

This is the survey information that we have focusing on the four variables of most interest to the committee, I believe. If you look, the left-most bar in all cases or the--what color is it? I guess it's blue. The blue bar is the donors that are neutral, have no preference for either the computer or the nurse. The green bar is the ones that prefer the computer, and the right bar is the ones that prefer the nurse.

As you can see, the green bar is always substantially larger than the white bar--a pleasant surprise to us--and this, by the way, was with a ten-minute computer interview in place against the five-minute manual interview. So I was quite surprised.

You can see the clarity. The nurse doesn't come close to the computer. With understanding, the majority of the donors say it doesn't make any difference. But among those who say it does make a difference, eight times as many say the computer generates a better understanding.

On truthfulness, as you can see, the majority of the donors, two out of every three, say they'll be more truthful with a computer than with a nurse.

The one perhaps of most interest is the higher repeat likelihood. We ask a question on how likely--whether or not the nurse or the system would make donors more likely to repeat donate, and these were, by the way, almost all repeat donors. They had been through the other system previously.

As you can see, 68 percent said it didn't make any difference to them. However, among those that it did make a difference, four times as many said that they were more likely to repeat donate using the system than a nurse. You may recall a presentation Dr. Schreiber made to this group where he indicated that if we could increase the new donor repeat rate by 15 percent, it would generate a 10 percent increase in the supply of blood. You may also recall a presentation by Dr. Wilkinson, who noted that it cost $10 to $30 more per unit to recruit a new donor as it does a repeat donor. The implications, in other words, of that, as well as the repeat donors generally, are considered safer. If that holds up, if people honor their intention, and the system gets widely adopted, it could have major implications for both the safety and the cost of the blood supply.

Next, please?

This is what we call a summary of the Phase 1 results, benefits hierarchy for additional testing and development during Phase 2. At the very bottom level, the centers achieve that upon implementation of this system, the reliability level, that is, they get the standardization of a computer system, which is nothing more than an extension of FDA's good manufacturing practices and blood center SOP processes. Additionally, however, with our system, they're guaranteed complete medical history forms, no blank spaces, and we eliminate all transposition and typo errors by virtue of the donor entering the data on the touch screen directly.

At the next level, we believe we will achieve a substantial reduction, probably something in the range of 50 to 80 percent of that 55 percent, in the reportable errors via more truthful and more accurate reporting. However, we have yet to prove that. That's one of the reasons we need a Phase 2 grant.

On the top level, there is no question at this point--we have additional measures--but that the system satisfies donors more than nurses do in the traditional processes. Moreover, all of the evidence we have is that it substantially will lower the cost. In addition to the implications of safety and quality generally and the positive impacts on cost, we did a time study, a small one, and the indications are that we will save 30 percent on the direct labor involved in interviewing donors for the most common form, the community blood donor, and more labor on apheresis and autologous donations.

That's it. Thank you for your time.

By the way, there are copies for the committee.

CHAIRMAN CAPLAN: Thank you. Do you have a question?

DR. GOODMAN: I missed the beginning, but you asked people about their understanding, but did you test their understanding?

My question was: You asked people about their understanding. They say they understand this better than your traditional oral questionnaire. But did you also test whether, in fact, that's true, that they did understand the material better?

DR. CUMMINGS: We have a way of testing, which every--the entire process is recorded to the hard disk of the computer at every step in the way. So we know what questions the donors questioned, what they didn't question, in terms of when they took it up with the nurse. We know if they dilly-dallied, if they put one answer down and then changed their mind and put another answer down. We did not do--and there was no indication--there wasn't any indications of as much confusion as people say there are with the questions, actually.

But we did not do a direct test against another set, nothing like randomized trials. However, all of these donors, or all but 17 of 18 of them were repeat donors, so they had been through the previous process. I mean, they said their understanding was better. So is there a better way?

DR. GOODMAN: Yes, well, I guess it just might be important--I mean, it's very encouraging results. It might be important as you move it forward to--you know, when you do have a controlled trial with different donors to actually assess their actual understanding, and the understanding may be easier in this repeat donor population also than in a new donor population. I just am struck by one of the nice things that makes a system like this so easy and user-friendly is kind of reminiscent of the Internet, and we all know how people use that and click on this and that without necessarily understanding what they're doing.

DR. CUMMINGS: Though it has tremendous potential for experimental work because we can change a question very readily to validate a question, for example, which is a historic FDA problem.

DR. GOODMAN: Right.

DR. CUMMINGS: We can readily find out the differences we're getting.

DR. GOODMAN: That would be great.

CHAIRMAN CAPLAN: Yes?

DR. SNYDER: I've got one quick question for you or for anybody from the blood banking community. How many of the centers have computers that could be used for these purposes?

DR. CUMMINGS: This is the standard PC set-up.

DR. SNYDER: I understand that, but I'm just asking about the start-up costs for the centers to install these things. Am I making sense with that?

COL. FITZPATRICK: There would be substantial start-up costs--

DR. SNYDER: That's what I figured.

COL. FITZPATRICK: --to purchase all the PCs, stations for interviews, yes.

DR. SNYDER: Is anybody doing it now out of your project?

DR. CUMMINGS: Hoxworth is the only place doing it, and it was the only place willing to do it when we entered into the project. Now we have--Dr. Gilcher is joining us, as is Miller. The costs, I don't see them as substantial. You start dividing them over the number of donations, I mean, you're talking something less than 25 cents a donation, and you're talking potential labor savings if those repeat donors follow through of $3 to $6 a unit.

DR. SNYDER: The costs of computers have dropped like a rock.

DR. CUMMINGS: The most expensive piece is a $400--

DR. SNYDER: You don't need--yeah.

DR. PILIAVIN: You don't need all the bells and whistles.

DR. SNYDER: You don't need the bells and whistles. You need a CD-ROM--

DR. CUMMINGS: This runs--basically it will run on a 486 DX2 or anything larger.

DR. SNYDER: You're in the $500 range or less.

DR. CUMMINGS: Yes, and the most expensive thing is the touch screen, and that's not as necessary as it was, but it totally gets around the problem of user keyboard aversions when you use that. It tends to increase the satisfaction and increase the--you're talking $400. You're talking five years, probably, on the life of one. So how much is that per donation? I mean, you're down into pennies.

CHAIRMAN CAPLAN: Jane?

DR. PILIAVIN: I would just like to point out, if we are indeed starting to go after the younger donors, as has been repeatedly emphasized, this is the computer generation, and you would expect that the satisfaction among them would be even greater.

DR. CUMMINGS: One of the somewhat interesting things is it seems that in some cases it's the older--we have not had time to stratify the data. We just pulled it all together for the Phase 2 application. But there's some indications actually that the older people like the technology better, that it gives them a feeling of being able to keep up with the youth.

[Laughter.]

CHAIRMAN CAPLAN: All right. Let's move on to the final presenter before the break.

MS. HAMILTON: I'll be brief. First of all, I'd just like to say before I get into my prepared comments that if any of you are interested in why several of us were very vocal about prison populations and donations, ask anybody here with the hemophilia community. We'll give you statistics that will curl your hair.

Thank you for the opportunity to speak to this group again. Yesterday's edition of USAToday featured an op-ed piece raising concerns about guidelines for deferring British donors that spells doom and gloom for the availability of an adequate blood supply in America. We've all asked for more stringent requirements and erring on the side of safety to screen out possible contaminants. We've cried foul because prior administrations weren't cautious enough and allowed the HIV/AIDS disaster to occur. Now that guidelines have been issued to be proactive in preventing another disaster, we must do our parts to help increase the donor pool.

The Hemophilia Federation of America is taking steps to help that issue. After more than a year of planning and think tanks, next month we are launching a pilot project that we hope will be copied across the nation. We're inviting people from every corner of society to take part in a massive effort to increase public awareness and donor participation, encourage improvement in continuing education and donor screening and blood processing techniques, encourage further education and quality improvement at the hospital level for safety techniques and proper storage and administration of blood and blood products, to encourage further continuing education on the part of the nursing and medical staffs of hospitals on blood utilization with emphasis on making the available supply go as far as possible, and to encourage increased awareness and education at the level of nursing and medical schools on the proper utilization of blood and blood products.

Invitations are going out as we speak to educators, college organizations, civic groups, clergy, athletic organizations, government officials, blood banks, industry, nursing and medical schools, and civic leaders to join together and form a task force to address the issue of safety and availability at the local level.

Dr. Satcher stated a few months ago that the safety of the blood supply begins at home, and we hope to help make this happen. We hope to be able to spread the pilot project across the country as another grass-roots effort to address the issue. We welcome any of you who care to join us in this effort with your individual participation, your organization's participation at all levels, including any pots of gold you wish to share.

All of this said, we feel it necessary to stress that we are at the same time very concerned about the impact from deferred donors on product availability, not only for our own community but for others that rely upon blood products for their very lives, especially the alpha one and immune deficient and sickle cell communities.

These concerns are heightened severely by the announcement of the alpha closure. We are very disappointed that alpha had not complied with such important remedies and applaud the FDA for rising to the occasion and putting some teeth into their demands for a safe manufacturing environment. This action, added to already existing restraints in the marketplace, leave us with big question marks regarding what happens now. We would appreciate any rays of hope that can be shared on this subject.

Once again, we must emphasize that we asked for stricter guidelines, we got stricter guidelines, and we must stand behind them and do our part to see that the 2.2 percent decline in donations is overcome.

Thank you.

MR. COLLINS: Good afternoon. My name is Patrick Collins. I'm with the National Hemophilia Foundation. I will be very brief in my remarks this afternoon.

First, the National Hemophilia Foundation does endorse the decision on deferring donors who resided for a cumulative period of six months or more in the United Kingdom. In fact, the co-chair of our Blood Safety Working Group, Dr. Bruce Ewenstein (ph), serves on the TSE Committee and was one of the 12 who did vote in favor of the deferral.

We'd also like to praise the leadership of the TSE Committee as well as Dr. Satcher and the HHS Blood Safety Committee for making the decision. It's not an easy decision. You're questioning whether or not to defer donors and 2.2 percent of your donations to the American blood supply or considering the risk of new variant CJD. It's not an easy decision either way and it defines leadership, and we praise Dr. Satcher and the TSE Committee for doing that.

Moreover, we agree with Dr. Satcher in stating that if there is to be an error, let it be an error on the side of safety.

Dr. Holland brings up a good point, that 2.2 percent of donors to the American blood supply will be deferred and that will raise issues of people not being able to get needed transfusions. Let me play devil's advocate. If the deferral is not made, what happens if five years down the road it is determined that new variant CJD is, in fact, transmissible in the blood supply? Lord knows that is not a good question to answer either. So "if" can be used in either situation, and both situations are, in fact, quite difficult.

The National Hemophilia Foundation would support the continued review of this deferral policy, and as more data becomes apparent, if data does show that new variant CJD is not transmissible, then obviously the deferral policy should be lifted. But until we know for certain that new variant is, in fact, not transmissible, to err on the side of safety or to be correct on the side of safety, more important, is the way that the Public Health Service should proceed.

And, lastly, obviously NHF, as Jan Hamilton stated with the Hemophilia Federation, and I think every consumer group, we obviously support initiatives to work on increasing blood donations to the American blood supply, as were stated this morning by several members, including the American Blood Centers as well.

Thank you.

CHAIRMAN CAPLAN: Thank you. Well, let me suggest that we reassemble at 2:00. We'll go right into a discussion of what we've heard this morning by the committee. Then we'll break into a discussion of availability of blood products, somewhat shorter, and somewhat shorter for the rest of the afternoon on hepatitis C lookback, where things stand.

So let's reassemble here at 2:00.

[Whereupon, at 1:04 p.m., the committee recessed, to reconvene at 2:00 p.m.]

A F T E R N O O N S E S S I O N

2:12 p.m.

DR. NIGHTINGALE: Could I ask the committee members to take their seats, please.

CHAIRMAN CAPLAN: I feel some duty to disclose that there are some cookies behind me, which I am ingesting at a high rate. So you might want to go up there if you want one.

I was trying to think over lunch how to have our discussion of what we've heard this morning a little bit. We've got some issues of availability of blood products to revisit and some discussion of the status of hepatitis C to go this afternoon, but we obviously have to spend a little time talking here.

And what I told Steve, which he didn't want to hear, but I told him anyway, was that it does seem to me that, in one sense, when we look at the deferral issue and the related questions of donor availability, we are advisory. In that sense, agencies move, they do what they feel they have to do in the face of challenges or risks and so forth. They are not duty bound to bring every question they have to us. When they want our advice, they ask for it.

On the other hand, we clearly are trying to wrestle with broader questions of availability that we've been asked to deliberate about. So some of you have said to me, "Well, what's to talk about? Of there is an FDA recommendation here, then it's done, and we're moving on."

I think we can discuss what we would like to see happen in terms of how that regulation goes, what we think about availability based upon what we've heard about the deferral policy. We may want to recommend certain actions about reporting back to us or collecting information and so on. And I don't have much more of an agenda to present to you than that. I'm going to just open the floor to see where the committee wants to take those issues. But maybe that's good for a preamble.

Jane?

DR. PILIAVIN: I have a more radical proposal. I would like to make a motion that we vote, after our discussion, on whether we agree with this policy or whether we believe that it should be rescinded.

CHAIRMAN CAPLAN: We can leave that--I've got to get my procedural thing for a motion.

DR. PILIAVIN: It was a motion. It needs a second.

MS. O'CONNOR: I'll second.

CHAIRMAN CAPLAN: I suspect that motion will let us discuss for a while. So let's discuss. It's real funny for me to be--most of these motions, as you've come to understand over the years, I have my driving ambition and personal wish to exercise it, but I don't here. So the floor is open. If anybody wants to get into the discussion about that motion, please do.

DR. HOOTS: I know Steve offered to provide more of the discussion materials. But I really would like to see a lot of introspection on behalf of all of the people who are advising on this issue with regards to the available scientific data and bringing into the equation analysis by people who are very, very expert in the field of risk analysis. Because, obviously, there are always countercurrent, as we've said before, countercurrent risks to any action. And it's very important, I think, that we have as close an approximation, based on the available knowledge and theory on both sides of the argument, of the impact of this, even if we don't change a thing, even if this recommendation changes for an "X" period of time.

It's those sorts of analyses that will give us the kind of information we absolutely require to determine if this is the right direction to go, at least retroactively, if not prospectively.

And I think all of the preliminary material that we have been provided over the last two years, plus what was provided of the updates that Steve so kindly provided us, suggests that this not only is a rapidly evolving field of knowledge, but that we probably will have some more information almost at every meeting. And at least for the committee's own self-interests in this, to have that relooked at would be worthwhile.

But I think, in the broader sense, for the nation's blood supply, on both the safety and the availability side, I just would like to see a little more data than what we've seen so far. I mean, it's still going to come down to theories, but we have to make sure that we've balanced the "countervaillant" theories on risk appropriately or else we may look back and say, "Well, yeah, we did the right thing because theoretically we always err on the side of safety," but, in fact, find that we didn't necessarily totally err on the side of safety. We may be safe for variant CJD, but we may be less safe for other things. And that's what I'm still not--I still don't think I have enough information, even based on what we should be able to get right now, to really--where to draw the line.

I mean, six months, it seems to me, I'd be interested, and I kind of raised this question with Dr. Satcher this morning, but six months seems to be kind of a practical, rather than a scientific, line in the sand. Because when you get to three months, the percentage of the donor population gets so significant that we would really have to live very on the edge. But is that enough of a reason to draw it there or is there other information that could be brought to bear to determine if it needs to be drawn at all, and if it does, is that where it needs to be drawn.

DR. AuBUCHON: I recognize the applicability of the argument that was offered by one of the speakers in the public comment section that if five years from now or ten years from now we find that variant CJD is transmissible by transfusion, that failure to enact some type of safety measure at this point would have seemed foolhardy. This is part of the lesson from the HIV situation from 15 years ago. And I recognize the residual concerns about that kind of situation repeating itself.

On the other hand, I'm also very concerned medically that if variant CJD is transmissible by transfusion, that what we are doing today is woefully inadequate. And, in fact, if it's transmissible via this route, it's probably already been transmitted and is being transmitted, and weeding out those 2.2 percent of the donors who have spent more than six months in the U.K. will do probably nothing. And it also means that having only spent probably about four months in the U.K. in the time period, I'm at great risk and may start doing strange things at any moment.

[Laughter.]

DR. AuBUCHON: So I'm concerned that--

CHAIRMAN CAPLAN: That answers my clinical retrospective.

DR. AuBUCHON: It answers a lot of questions, I am sure, for those around the table.

So I'm concerned on one hand that we've done way too much, and on the other hand, we're not doing nearly enough. And just because there are arguments on both sides of the issue, doesn't mean that some compromise at six months, as Keith pointed out, is necessarily the right point to draw that line in the sand.

DR. PILIAVIN: I want to say something I think a little stronger than that; that is, I think the evidence that there is any danger whatsoever is essentially nonexistent, that this isn't indeed a decision that's been made mainly on political grounds of the sort that if in five years there is something that happens and we don't do anything, we're going to look really awful.

And I think we have now reached the point at which the definition of safety has become something transmissible in the blood like viruses or anything else that we can possibly think of that might harm a human recipient. Nobody is thinking about the safety that comes, for example, or the lack of safety, that comes from human error in the screening process from human error in the matching process or from what is facing us right now, the lack of safety that comes from the nonavailability of blood.

Now, we keep talking about data. The data do not exist and will not exist probably ever to allow us to say that we could rescind this on the basis of data. Okay? You cannot prove the null hypothesis. We cannot demonstrate that there is never going to be any possibility of this, even if nothing ever happens. Okay? That's not proof that nothing could happen. So when they say this can be reviewed every six months, on what basis could it possibly be reviewed? On the other hand, we can get really good evidence about operations that are not being done, the postponing of things like cancer surgery, on the basis of not having enough blood.

And I just think our whole definition of what we mean by safety in the blood supply has gotten totally skewed, and we just really need to refocus on what we mean by safety.

CHAIRMAN CAPLAN: One thing that occurs to me, listening to these presentations, is that I feel like our committee has been in the position, on this FDA position, of being notified, rather than being asked. So that some of the information that Keith is talking about we don't have.

And I'm not sure how I would respond to Jane's request or if someone made a motion to, say, endorse it, I don't know what I would say about that either. Because a lot of the information is in the material that we looked at, but a lot of the discussion from the TSE Committee or in their BPAC deliberations and other places, the kind of thing we'd normally have heard here, which we did hear on hepatitis C lookback in arriving at a formula, we don't have.

So in one sense I feel like it's tough to know which way to go with respect to the policy decision in terms of saying good or bad, on the other hand, it's a situation where we could ask for more information. And I hear what Jane says about, at the same time, you have to understand you are always going to have some risk, and you are not going to ever prove a negative in that sense, too.

But I find myself inadequately informed, in a way, about the notification that a decision has been made. So it's hard to know which direction to go, say yea, say nay, without that.

DR. AuBUCHON: I've done some work in cost effectiveness analysis in the last few years, and I'm not going to attempt to apply those techniques to CJD deferral criteria. However, one thing I have learned from doing these analyses is that putting a dollar sign in front of a particular intervention or showing exactly what the return is doesn't attract a whole lot of attention outside of the field of people who are interested in doing those kind of academic pursuits.

But one thing that I have found useful is to use these techniques to stratify what the yield is, what the risk is from different threats and different interventions. It strikes me as peculiar--I guess is the appropriate word--that this committee has spent so much time and effort, the Federal Government has spent so much time and effort investigating this potential risk, when there are other risks that are currently existing in the blood supply that we know about, that are currently killing people, that neither the FDA nor even the industry are spending that much time trying to eradicate.

Chagas' disease is transmitted by blood transfusion. We know that. It has been documented. But we see no FDA guidance on that. Parvovirus and other viruses are transmissible by blood, and yet there are no steps along those lines that I'm aware of. And the one soapbox that I continually climb on, and I will do so again briefly, and that is that from the FDA's own records we know that at least about two dozen people every year are killed in this country, killed, by getting the wrong unit of blood, and it's been that way for 50 years, and it will be the same way next year because no one is doing anything about it. But we have no FDA guidance on that.

Why not focus our attention on those things where we know that there are large risks, relatively large risks, and try to eradicate the risks that are real rather than spending our time and effort on potential threats?

DR. NIGHTINGALE: Dr. Caplan, I would make one comment that we did discuss future topics for the Advisory Committee with Dr. Satcher a couple of weeks ago, and the issue that you brought up about donor risk actually was one that he approved of for the next future meeting. It's a little early to talk about the next agenda, but we are actually addressing, internally at least, the issues that you just raised.

CHAIRMAN CAPLAN: Larry?

MR. ALLEN: Quite honestly, I'm not really sure where to begin here. When I hear us talk about maybe rescinding some of the things that we've been discussing for quite a long time, it concerns me because I listened to some of the other consumers that I've met in the last year or so, and I hear some of the stories about the pathogens that have gotten into their communities, and I'm trying to learn from that, and I think everyone here is trying to do the same. But I'm concerned that we're missing out on something here, and that's just overall safety, and the public's perception of what the government is doing about it.

I can't speak for all of the families that have issues with chronic illnesses, but I can certainly speak for a few and say that our plates are full right now, and the last thing we need is another issue to be fearful about. Whether or not that seems realistic to some of you or not is really not the issue. If you are not living with these problems, then it's hard to relate.

I just don't understand, unless we have data one way or the other to prove this, then we have to err on the side of caution. And to me that means dealing with CJD the way we've been doing it. Let's be conservative. FDA--we've gone through this before--everyone has taken a conservative approach. I think we should continue along that line until we hear something different.

There are certainly other issues for blood safety that we need to move on to, I agree with that. But one of the main things that really concerns me is the public's perception of what's going on. And there's not a lot of trust here, not at all, and we need to do something about that. We need to address that. We're talking about cost, we're talking all of these other issues, let's deal with that, too.

DR. HAAS: A couple of observations. One, just following from Larry's comment, very definitely implied in his comment, there are at least two blood recipient populations out there; the population that we hope rarely needs blood products and then the other segment, which is a relatively small segment, that uses blood products on a highly continuous basis. The probabilities of potential problems are different in those two populations, and we need to try and separate that out and figure out how to deal with it. I don't have an answer to that, but I want to make sure we always keep in mind there are at least two different populations.

The second thing is that our last meeting we had a lot of information about several problems contributing to the problem of supply. Might it not be helpful, now that we're a few months past that, to find out if we have companies coming back on line--because they were put off-line because of manufacturing practices or some of the other problems that we heard about that were keeping the supply low--now back in the swing of things?

If the other problems are taken care of and maybe improved upon, then the loss of blood products, because of our concern about CJD, become less important. If, however, those are ongoing problems, and we have to expect them to be ongoing problems, then this 2 percent figure that we throw around takes on a different significance.

CHAIRMAN CAPLAN: Dana?

DR. KUHN: I think Jane's motion brings up, for me at least, an issue of process. I recall about a year ago, when we were dealing with the FDA guidance for quarantine and relaxing the quarantine, it was kind of brought up to us and said, "Here. This is what you are going to do," in other words. And, again, I think I had to identify with Richard and also with James this morning when they were addressing the Surgeon General in saying it was kind of like deja vu again, you know, saying that here is a guidance.

Now, whether or not these are good guidances, I'm like you, Art, I'm not sure. I haven't been privileged to the information. But once again, I'm going on the information that the TSE and the Blood Safety Council have had the privilege of looking at and coming up with this guidance. I would have to have a tendency to go along with them. However, I sure would like to know where this committee stands in light of this new variant Creutzfeldt-Jakob disease issue, and especially this guidance issue.

So I think it's a matter, to me, of process. Where are we in this process? Where does this committee stand? Is this something that we are supposed to deal with or is this something that we're supposed to get and just take our rubber stamp and stamp it? You know, I think this is--to me, the issue is process.

CHAIRMAN CAPLAN: Trish?

MS. O'CONNOR: I think one thing to point out, although TSEAC Committee did vote to defer, it was far from a unanimous decision. Twelve voted for and nine voted against. So it may be that it's not as clear as we would be led to believe by the decision that was made.

CHAIRMAN CAPLAN: Let me offer an incoherent answer to Dana about procedure on this one. I don't know what I'm talking about. But I think we haven't been asked whether we like the deferral decision or not. That's why I said I think we've been notified that they did something. And the mandate that we have to keep on safety and availability, that decision impacts availability. So indirectly we might choose to say something like what Jane offered or we might choose to say we're going to be attentive here, and we want to get more, and we want to revisit or what else. But I think our mandate, procedurally, is from the broader scope of you think about safety and availability and advise us about that. Now something has been done that affects both. We weren't asked by anybody to offer an opinion, but we have a broader charge to keep an eye and offer opinion about safety and availability. So that's a little bit inchoate, but I think that's why we can talk about it in the distance.

And remember, too, one other fascinating fact, which we sometimes forget--I do--they don't have to listen to our advice.

Paul?

DR. McCURDY: A couple of comments I'd like to make, a bit from the perspective of a gray beard, since I've been involved in this for a fairly long period of time, more than 20 years in regional blood banking in one way or another.

Virtually every change in blood banking, particularly with regard to donor management in the last 20 years, that has come done the pike has been greeted with cries of shortages. Those shortages, by and large, have not materialized. That doesn't mean there aren't spot shortages and individual blood group shortages. There are, and there very likely always will be, although they can be minimized. So I don't know that it's necessarily a given that there will be shortages as a result of losing these donors.

It also has been apparently assumed that these lost donors will be replaced by first-time donors, which is not necessarily a given. It's also been said that first-time donors are less safe than repeat donors. And there are things in the literature, papers in the literature, that attest to this.

But I believe it was this committee, it could have been the BPAC, had a presentation within the last six months from the RED study that indicated that first-time donors and repeat donors were indistinguishable, as far as risk, when you looked at seroconversion rates rather than looking at seropositive rates. The first-time donors have had "X" number of years to become positive. The repeat donors have had since the last donation to be positive.

I think there are many things, as Steve alluded to, that have been under discussion in one place or another. Human error is one of them. There is a research project underway, supported by the Institute, looking at human error and attempts to change it that have not necessarily been presented to this committee because, well, there are only so many hours in a meeting.

CHAIRMAN CAPLAN: Rick?

DR. DAVEY: Yes. Just following up on Paul's comment. While, Paul, I take your point that we're not entirely sure on what the impact of this deferral might be on shortage, I think it's going to have an impact, but we're not sure.

But I think we can look at this really in two ways: Does this policy make sense on its own merits? I mean, is there the science to support it? Is this a precedent that we want to establish to make a major move to defer blood donors based on poor science or at least inadequate science--not poor science, inadequate science--and on a theoretical risk only? I think that's a separate question.

And then the next question is, if we're going to do this, what kind of an impact it's going to have on the blood supply. So I think we ought to look at this separately and not just say, Well, if it may not affect supply, let's do it anyway. I don't think that's the right way. We need to look at it two ways.

Another point, just maybe commenting a little bit on what Larry was saying earlier. There is an issue certainly of trust that we're doing the right thing, as representatives and advisors to the government. But I think we also have to be concerned about our actions in terms of the public perception of the safety of the blood supply. I mean, I think two issues recently, HCV lookback and now CJD, the public has gotten very strong messages about blood safety.

I think the public education effort, actually, that's been suggested and mounted informing the public about HCV is focused entirely on blood transfusion. The other 93 percent, or people who have HCV by other causes, as far as I can see, that's just not being addressed. The public is hearing blood transfusion and HCV are closely linked, and you better worry about it.

And now we have the headlines about mad cow disease in the blood supply. The confidence of the public in the American blood supply is shaken by our actions, and we have to be very careful of that. We need to have people willing to accept blood transfusion when it's medically necessary and not be so afraid of it that they are refusing it when they really need it.

CHAIRMAN CAPLAN: Yes?

DR. GUERRA: I would take it a few steps further. I think that, you know, it has to do with trust in not just the blood supply and the safety of the blood supply, but the food chain, the vaccine supply, some environmental type of concerns that I think cumulatively are really putting a tremendous burden on the public in terms of how to interpret theoretical risk, in many instances, in a way that affects them personally or collectively in communities.

So I think that we have to be very careful, if, in fact, we are going to move to affirm the recommendation that was made. It probably is going to add another layer of complexity to perceived or theoretical risk across other very important areas of concern.

CHAIRMAN CAPLAN: Let me suggest maybe that we let Steve offer a comment about the policy, and then if people think we've had adequate discussion, we can consider the motion that's been seconded.

DR. NIGHTINGALE: I think my comments will be fairly brief.

I would say, on behalf of the Department, that we are very comfortable with the decision that we have made, we are very comfortable with the process by which it was made, and we are very comfortable with the time frame in which it was accomplished.

Having said that, we understand, perhaps better than we may have been given credit for in the previous discussion, the uncertainties and the limitations of current knowledge. The government has made a commitment to review the decision as frequently as warranted, and certainly on a regular basis, to ensure that that commitment to review the decision, as soon as it was warranted, is made.

One of the realizations that we have in the government is that communicating a complex decision, such as we perceive this to be, to the public is itself a very complex task. And the primary reason for putting this topic on the agenda of the committee this morning, and for this afternoon as well, was to initiate that process of communication. That process will continue, and we expect that public response to the government's policy will evolve as its understanding of it does.

Having said that, I would make two other comments. As Dr. Caplan said, the government does not always take the advice of its advisory committees. At the same time, we value the advice. We very definitely value the advice of this committee. This has been a good committee, and it remains a good committee. It's a good committee because we don't always agree with it. If the committee simply rubber stamped, I think the phrase was earlier, the decisions we'd already made, we could save a little bit over $300,000 a year by putting our energies elsewhere. That's not the purpose of having it.

I think the value of an open and free discussion is apparent not only at the time that it's made, but subsequent to the time that it's made. I think if you retrace the transcripts of this advisory committee, its understanding and its recommendations on the hepatitis C lookback have evolved over time. In a public committee like this, where we intentionally have individuals with diverse backgrounds, part of our obligation is to assist all of the members with those diverse backgrounds to complete their understanding of an issue.

So I personally feel that this has been a very successful meeting of the committee, both for the committee itself and for attempts to communicate our decision and the reasons for it to the public. I think it goes without saying, but I do wish to say it anyway, that the administration, that this government takes its obligations to preserve the safety of the blood supply, and enhance it whenever possible, very seriously. We do understand the balance between those two often conflicting obligations.

We permitted the discussion to proceed for six months, from the time that the TSE Advisory Committee initially made its recommendation until the time the TSE Advisory Committee conformed its recommendation. I think many of the people in this room were involved in that discussion, although in a slightly different administrative framework.

I should say that there are many advisory committees to the government. Some have even suggested that there might be too many. I am not one of them, being an employee of an advisory committee.

[Laughter.]

DR. NIGHTINGALE: But I was asked, when I talked to the TSE Advisory Committee, to acknowledge that there were overlapping spheres of authority. I think that we felt that the committee structure, regardless of which committee it is, is the appropriate way to seek input into a decision. And we sought input into this decision very hard. And that is why I said that we were comfortable with the process by which the decision was achieved.

We have not stopped the process of seeking input into our decisions as new information becomes available. And that perhaps is, in the long run, the reason why we value the comments that have been made at this meeting, even when certainly some of them would not coincide at least with my own views on the issues.

So I would encourage this committee to continue to offer us its best advice. If we don't want your advice, we won't put the topic on the agenda. We anticipate that your advice, at one point in time, may not be the same as it would be at a future point in time. And while we might point out that the advice we get from newspapers might change from time to time, we would not make the same point to you because we expect that not only your understanding of this issue will evolve, but ours will as well.

CHAIRMAN CAPLAN: Any other comment?

DR. GILCHER: I think the decision to defer is not one that we're going to get an answer to because there are a lot of diverse opinions in this room. But the criteria for the selection of people to be deferred has really got to be looked at very carefully.

I, myself, am not sure if the criteria are the right ones. I don't know that they are, I don't know that they are not. But that has to be, I think, intensively looked at.

The last point that I want to make is that we've already heard about what else we can do, which is to really enhance the additional recruitment or, in fact, to allow donors in the system to donate on a more regular or frequent basis. And I proposed some things off-line here to the FDA that could enhance the flexibility of collection of donors more frequently.

And I think these are things that we can impact and should look at.

CHAIRMAN CAPLAN: Yes?

MS. O'CONNOR: I have a question. Once guidelines are in, what are the chances of saying, "Oh, I guess we don't need to do that"? I mean, does it just become sort of self-perpetuating, once you've made the decision, since both Jane and Keith have made the point you can't prove a negative? So does that mean it's just going to be forever? Realistically, not theoretically, but realistically.

DR. NIGHTINGALE: No. Art, if I could answer that question, I would reiterate what has been said repeatedly, is that we plan to revisit this issue on a regular basis.

MS. O'CONNOR: I understand. But I mean in practice, what really happens with these things.

CHAIRMAN CAPLAN: We're still in a formal comment period on these, right?

MS. O'CONNOR: Okay.

DR. NIGHTINGALE: I mean in practice, also.

MS. O'CONNOR: Historically, Steve--I'm not casting aspersions on this--what happens with guidelines, generally? Do they just become regulations and then they don't get rescinded or is there any history that you could--

DR. NIGHTINGALE: There is not a simple answer to that question. If you go to the Web page of any of the centers of the Food and Drug Administration, you will find a lot of them. And if you trace their histories back, you will find those histories are complex. And I think you will also find that the histories of those guidelines are guided by the available evidence, both at the time they were enacted and supplementary. Just go back, for example, and look at the history of the guidelines on hepatitis C lookback, for instance.

CHAIRMAN CAPLAN: Jane, could you, within some semblance of reason, restate that motion?

DR. PILIAVIN: I stated it in an either/or fashion, which is not the way a motion should be phrased. It should be phrased one way or the other.

I guess it could be phrased as that the Blood Safety and Availability Committee concurs with the guidelines that have been put forth regarding the new variant CJD exclusion. We can vote on whether we concur or whether we don't concur. Does that sound reasonable, Steve?

CHAIRMAN CAPLAN: Okay.

DR. ALBRECHT: I have to agree with what other people have said. I just don't have enough information to make a decision.

DR. PILIAVIN: Then abstain.

DR. ALBRECHT: The committees that had the data had more information. I think a good point was made about the BSE and other countries. I don't know if that was addressed at the committee. Perhaps it was, and there was data that said this is not a major issue. I simply am unprepared to vote on a motion like that.

CHAIRMAN CAPLAN: I think that--oh, go ahead.

MR. WALSH: I just have one point of clarification that I would like to ask DOD. It's my understanding from Bruce Rutherford that a one-year residency in the U.K. might have been acceptable to DOD and would have a fractional impact, as opposed to the one-third of the impact to your blood supply now, in the event of a mobilization. Is DOD uncomfortable with this recommendation?

COL FITZPATRICK: Are we uncomfortable with the guidelines? I would have to say we are uncomfortable with the guidelines, and we've expressed that opinion. The impact of six months versus one year would, of course, help us.

Now, to address the mobilization piece, I've been in DOD for 24 years and a blood banker for 23 of those 24 years. If another Desert Shield/Desert Storm were to occur tomorrow, I have full confidence that the population of this country would respond, as they did the last time, and we had more than enough donors to meet what we projected to be the need during that conflict. And we used far less than what we projected. So in the event of a true mobilization, I personally am not concerned about the ability of the nation to respond.

However, currently, we are deployed in numerous sites. We have transfused already in Kosovo more blood than we have transfused in Bosnia since the first time we went in there. Now, that's only 86 units, which doesn't sound like a whole lot to a nation that collects over a million, but it is a significant amount of blood to us. And to continue to respond on a continual basis to deployments and meet that need, plus meet the normal routine need of the nation, without the added impact of a full-blown war, will become more difficult as we do more things to reduce the donor population. And this is just one of more that undoubtedly will occur.

So, yes, we opposed the ban from the U.K. deferrals for a number of reasons. And I'll try and be brief because I'm taking too long here. But if I take off my DOD hat for a minute and I put on my blood banker hat, we have a great deal of lack of knowledge about CJD and new variant CJD. And I have watched the TSE Committee struggle with that lack of knowledge and the BPAC struggle with that lack of knowledge, and now I get to watch us struggle with that lack of knowledge.

To err on the cautious side is the most prudent thing to do in some people's opinion. And if five years from now we find our first case of transfusion-transmitted new variant CJD, then of course we've done the wrong thing, and we can have no impact on that. So I struggle with those choices because there is no evidence to support, in my opinion, doing this ban, and there are a lot of conflicting things. And I keep hearing HHS say we are going to review it. But what I don't hear is some criteria for that review.

It is now 1999. In 1989, the U.K. felt fairly confident that they had taken steps to eradicate BSE. So we are ten years out from what was probably the prime risk period for contracting new variant CJD or transmitting it. The incubation periods are estimated from four years to a lifetime, depending on which one you want to pick. So HHS and, to be more cautious, we could say, well, we have to wait several lifetimes before we will know that nothing has been transmitted. Well, that's not acceptable.

So I think maybe the onus or the charge back to HHS and the FDA should be to establish some criteria for this review that allows them to negate the ban and actually puts that onus and that charge to them. If these criteria are met, then the ban should be taken away. If the criteria are not met, the ban remains in place. And I think that, given our great lack of knowledge about this subject and all of the forces affecting it, might be one of the better positions.

DR. NIGHTINGALE: I have heard several times, actually, today the question about what is the criteria for review of the decision, and fortunately there's a very simple answer to that. The simple answer to that is new scientific knowledge. And that's not a trivial answer at all because there is a substantial amount of research going on, both in the states and elsewhere, by well-recognized, quite productive people with long-established track records.

We are hopeful that there will be progress in identifying those who are susceptible to the disease and those who might be at risk of transmitting the disease within the next two years. I think it is presumptuous to go any further than that. But those of who have attended the Holland Lecture series in May recently heard the state of the art, and we cannot predict whether or not--I'm not going to name a name, but any one of several names are going to get there before the rest of them. But there's a race going on, and there's a big prize that starts with "N" for the person who gets there first.

We will review that data certainly before it becomes available for publication. We do believe that we have excellent communication throughout the scientific community right now, and this is a good opportunity for me to acknowledge that there are people in this room, and there are a lot more people not in this room who have been very, very helpful to the government in helping them understand the current state of knowledge.

Six months is not just an arbitrary figure. It's there because, when you are talking to people every couple of weeks, it is worthwhile to require a regular review of the status of progress in the medical field. You can get too comfortable in a laboratory. And there will be regular review of this issue, but there will also be extraordinary review whenever the telephone rings. And if the telephone rings, we are committed to pick up the telephone and seeing why it didn't ring.

CHAIRMAN CAPLAN: Well, I still think there's a motion on the floor, which is we concur with the regulatory advisory of the FDA. I guess we can all vote yes, no, abstain.

So let's do one more comment, and then I guess we'll up-down the motion and then see if we want to say anything else about this.

MR. ALLEN: My question is this: We are all agreeing that we are suffering from a lack of knowledge here. My questions are these: Is it true that for 20 to 30 years it was known that there was a non-A, non-B form of hepatitis in the blood supply? Is it true that for the last seven years, at least seven years ago, there was a potential treatment for HCV that was known by some, but not by most? Can we agree that if a pathogen is dangerous enough to screen for, that we should be taking other steps to do something about it?

It's just the issue I brought up earlier about the sickle cell patients and the community itself not knowing that some of them were at risk for HIV during the '80s and now to find out that, within a few seconds of bringing it up, that it's 12 percent. None of these communities knew this. None of them know that to this day, for the most part.

So it comes down to who knows what, who is consistently going to tell us what they know, who is not going to tell us what they know and what do we do about it and the perception that leaves with the people who need these products.

So if we're suffering, if we agree that we're suffering from a lack of knowledge now, then let's learn from the mistakes that we've made in the past.

CHAIRMAN CAPLAN: I don't want to cut off the discussion, but, Ed, the last--

DR. GOMPERTS: As I see it, there really are two issues here, and one is the six-month cut-off from the point of view of new variant. And the second issue is the impact on the blood supply. And the bottom line is that there's insufficient information on both of those.

And it's been mentioned frequently today that we will have a review of the information that's available focusing primarily on the new variant issue. But I would like to be quite sure that there will be a continuing evaluation from the point of view of impact of blood supply. And if indeed there is a substantial impact and that there are individuals that are being harmed from the point of view of availability of blood and blood component, then, in actual effect, this issue of whether there is--and there probably won't be much more information on the new variant risk issue--but if there is a risk to individuals who need blood and blood components, then this whole thing should be re-evaluated, and perhaps the 12-month target be introduced or scrapped, whatever. So I think both need to be looked at.

CHAIRMAN CAPLAN: I guess what the Chair thinks is that we may decide to put some other motions on the table about this, but I suppose we should move a vote on the question about whether we concur--I guess to phrase it right--we concur with the FDA directive. We'll wordsmith that slightly.

So let me call that vote. All in favor of that proposition, please raise your hand. Concur. We concur. We go along with it, we agree with it.

[Show of hands.]

CHAIRMAN CAPLAN: I have five votes in favor; is that correct?

We don't concur.

[Show of hands.]

CHAIRMAN CAPLAN: We abstain?

[Show of hands.]

DR. NIGHTINGALE: The count that I have, with the Chairman not voting, is five votes in favor of the motion, three votes opposed to the motion and five abstentions. Are there any corrections to that? I think not. The motion carries.

DR. PILIAVIN: No, it doesn't carry, not with that many abstentions.

CHAIRMAN CAPLAN: Isn't a nonplurality? Yeah. The motion dies or something.

DR. NIGHTINGALE: For the time being, we'll let the motion speak for itself at the moment.

CHAIRMAN CAPLAN: Now we can spend a few more minutes, if people would like, to entertain other motions.

MR. ALLEN: Excuse me, Art?

CHAIRMAN CAPLAN: Yes?

MR. ALLEN: There's something I need to know. For people that we talk to and they ask us, they bring up these questions about things that happened in the past, who is accountable? You know, there's no motivation for any changes if no one is going to be accountable for these issues.

DR. SNYDER: Theoretically, it's the government.

MR. ALLEN: That's what concerns me. Now, I need to know who is accountable.

DR. NIGHTINGALE: In legal circles, I think there's substantial evidence that the people who work for the government are held accountable for the actions of the government during the time that they were responsible.

CHAIRMAN CAPLAN: The argument here is that in the legal arena there have been a number of instances wherein public officials have been charged for malfeasance, malpractice, crimes in the dealings with the blood supply. That's what Steve is talking about; the French cases, Irish, Canadian in some years. So there is liability that way.

However, let me go back to see if anyone wants to offer any other motions. And just in the spirit of encouraging, we could say it might be important for us to revisit this, it might be important for us to ask for criteria development, it might be important to make sure that we get put in the loop for the review process for all possible things.

DR. HOOTS: I'd like to put together or at least for us to draft a composite motion that addresses particularly the issues of Colonel Fitzpatrick and Dr. Gomperts, and then also probably include the fact that we be at least kept in the loop from this issue on a regular basis, particularly because it is so difficult, obviously, once things are enacted for them to be reversed. So we want to be sure that when people ask, "Well, it's been there, nothing has happened, what are people doing about it?" that we can answer that question as representatives for all of the people for whom we speak by serving on this committee. And I think, if nothing else, we need it for that reason, but also for a broader reason.

Because I think even the people who made this decision or voted finally for this decision not today, but previously when it was enacted, it offers them something to know that there are always people scrutinizing and charged with scrutinizing it on a regular basis. And I think the more heads we put together on issues in which there's insufficient information, at least more perspectives are brought to the table.

And I think for a number of us, the whole issue of how and why is so hard to capture, at least for me it was, in one motion about yes, no or maybe, that I would like to see it broken down more specifically. And particularly as Colonel Fitzpatrick said, I think just saying it's going to be looked at is not sufficient. I think Dr. Gomperts' point about the fact when there is a definite negative on the blood supply to the point, as other speakers said today, where people's lives are being impacted, and no one's life has shown to be impacted by the theoretical risk of variant CJD, then we have to act, and I think we have to say that very strongly.

CHAIRMAN CAPLAN: I can make a motion, right?

One motion I'd like to put forth is that specific criteria for review of the current be developed and presented to us at the next meeting.

DR. GOMPERTS: Second.

CHAIRMAN CAPLAN: Discuss? That's obviously open to friendly amendments.

DR. GOMPERTS: Could you say that again?

CHAIRMAN CAPLAN: That criteria be developed for review of the policy and that they be submitted to us by the next meeting.

DR. GUERRA: I guess, Art, my question would be: What are the elements of those criteria that you would like to see developed?

CHAIRMAN CAPLAN: What I have in mind here is specific criteria that talk about impact on donor unavailability, that we're monitoring that, to get to Keith's point, encouragement of public-private collaboration to show impact on supply in terms of blood type availability and deaths and adverse event, and criteria that indicate when we will sunset the policy so that--admittedly, there's always going to be ambiguity about how to interpret scientific data, but more information than just the science will tell us.

DR. HOOTS: Can we include as well the science? Because--

CHAIRMAN CAPLAN: Oh, sure.

DR. HOOTS: Not only that Steve does what he's promised, which is disseminate to us and anyone else in the public, vicariously, that wants what the deliberations were, but actually some new--or maybe it's not new. I just don't know, but the things that I raised this morning about if we get into a bind of having to say we would like to reverse direction, but we are prepared to go all the way back to nothing. What scientific balancing act can be done? The impact of blood type, the impact of genotype on codon 129, the impact of age, all those things that can be actually--again, may add way too much complexity to an algorithm for a blood bank to have to go through, but in terms of a decision process is not anywhere near too complex to be considered by people who are making this decision.

DR. NIGHTINGALE: With due respect to the Chairman, I would suggest that from my own perspective the motion does not capture the complexity of the issue or the decisions that need to be made.

DR. CHAMBERLAND: I guess I'll second that. As being probably someone working for an agency that would be involved in trying to respond to this motion, it's not that we don't--I don't think any of the agencies of the Public Health Service want to be non-responsive, but I don't think we even known enough information about this new emerging agent to be able to identify criteria, quote, that would allow us to sunset the issue or change it in some way. And I think what I'm hearing more is that the committee, perhaps at a subsequent meeting, would like an update, like a mini-review on the last six months of information about new variant CJD, the science, the epidemiology of it, and then if, in fact, our monitoring system is in place, what preliminary information would we have about what we're finding in terms of monitoring supply.

I would feel much more comfortable if we could--the agencies of the Public Health Service could supply the committee with information about what we know, but I don't think anybody right now can give you criteria about whether we would be in a position--what the criteria are here and now to in any way change, take back, rescind that guidance.

So I'd be more in favor of giving informational updates that can be discussed.

DR. AuBUCHON: The consternation just expressed by the last two speakers regarding the proposed motion I think reflects the likely longevity of the guideline.

DR. NIGHTINGALE: As one of the two speakers, I would not agree with that.

DR. CHAMBERLAND: And I think just in the lifetime of this advisory committee, we have seen the guidance on CJD, classic CJD, change. And, again, it was at the instigation of this committee, asked the Public Health Service agencies to revisit the CJD guidance, so it was out there about withdrawal and quarantine policies. So just in the two or three years--I mean, this revised guidance puts into writing a practice that was implemented last September for all intents and purposes. But recall that for classic CJD in the last year we have changed what had previously been an FDA guidance, I believe would be the correct term, about quarantine and withdrawals for classic CJD.

I know it's not very popular, but the guidance on hepatitis C lookback has also changed, and we'll address that in a subsequent session. So these guidances--and I don't want to speak for my colleagues at FDA, but these guidances do change as time and information--but I think we're in a totally different position with respect to new variant because classic CJD is something that has essentially been endemic in the population for a long, long time. So we've had the ability to retrospectively as well as prospectively more systematically evaluate the information, the data at hand.

This new variant is a whole new thing, and so we're all on a learning curve, and there is going to be some time to accumulate data, whether it be positive data, such as there seems to be some epidemiologic association with blood transfusion, and it will always be an association that we'll epidemiologically be able to speak to, or the accumulation of negative data, and it's going to be a place like the UK that we're going to have to just continue to watch.

CHAIRMAN CAPLAN: One thing that occurs to me talking about criteria is that we could ask, in the spirit of what I was trying to put forward, not so much that a sunset law be written, but that the dimensions of what's going to be collected will be there and then reported to. What I meant by that was the impact on supply, shortages of blood types, laboratory experiments with animals, death rates in other countries, if we saw--perhaps more than just saying the science will dictate, but if we got a spelling out of the dimensions that are going to be examined, that might help us understand. That includes, by the way, this issue, which I know bothers a lot of people on the committee, about how do we get to six months in terms of when it gets you for protection as opposed to one year or three months or one day.

We have a country, by the way, operating with no days. That's England, since their whole blood policy is they're transfusing each other and they have a waiting period of nothing. If they didn't do that, they'd have no blood. So that's a criteria that is very clear. They're going to keep using whole blood there, and they have no waiting period.

Now, we, unfortunately, have no disease, but we've got the six-month period--I don't mean "unfortunately." Unfortunately, we have a waiting period in there, but we don't have the disease. They have the disease but no waiting period.

The irony isn't lost on some of us that, therefore, trying to understanding how you get to six months and thinking about the dimensions of that might be important.

So if I could explain my own motion, I guess I'd say what I'd be looking for is that we get the opportunity to review, that we hear from the agency and its co-agencies in trying to implement the policy what the dimensions are that they're going to be looking to. Is it death rates in Europe? Is it death rates in mice? Is it death rates in the number of people who didn't get a particular blood type because there was a drop in the supply? What is it? That's what I want.

DR. SNYDER: Art, basically the idea of an update at every meeting covers that.

CHAIRMAN CAPLAN: Yes.

DR. SNYDER: To try to spell out something that is, as Mary is saying, so new--

CHAIRMAN CAPLAN: It's tough.

DR. SNYDER: Yes, exactly. So, you know, a guarantee of an update, what more can you really do?

DR. CHAMBERLAND: Yes, my fear is that we don't want to box this in. I mean, we're open to any and all information. We obviously want it to be well grounded scientifically, but my fear would be is if the committee spells out, well, we want to hear about X, Y, and Z data, well, there may be other data out there that doesn't quite fit that box. So it's kind of--that's what we're doing in PHS, is laboratory data in animals, epidemiologic data in people, diagnostic assays that are being evaluated out there.

CHAIRMAN CAPLAN: We'll come around this way.

DR. GILCHER: Art, what I would like--exactly what Mary has said--is the update at each meeting, but something else, and the other part that I would like is the update on the scientific information, but how it specifically relates to the deferral selection criteria by someone who is really able to do that so that we can then discuss that.

DR. GUERRA: Yes, Art, my concern is that it's fine to have updates at every meeting, but we do need to have an endpoint because otherwise we're having updates five years from now. And I think that, you know, we're dealing with a disease that probably has so many variable presentations in terms of long incubation periods or maybe it might be possible during this time, not unlike what has been done with trying to better document the incidence of a condition like polio around the world, that you'd develop some sentinel measures, something like whether it's ascending flaccid paralysis as a measure for whether or not polio might still be present. Is there something--and, Mary, maybe you know--some sentinel health-related condition that perhaps could serve to provide some indication that, yes, CJD is emerging in a population?

DR. CHAMBERLAND: Are you talking about new variant?

DR. GUERRA: Yes.

DR. CHAMBERLAND: Well, it may be possible in a country like the UK where it's an ongoing problem. But in the United States, where we have no evidence of BSE and certainly no evidence of new variant, I think we at CDC--Larry Schoenberger has previously articulated this, that we're going to want to have confirmative diagnosis. I mean, we're going to have to go for quite stringent criteria. You know, my comments earlier this morning, we're out there looking. It's not as if we're closed off to exploring, investigating more carefully potential suspect, probable cases, whatever you want to call it. But I don't think we're at a point in this country that we could use surrogate kinds of markers for a disease when we don't even know--we don't even think we have the disease right now. There's no evidence that we have it.

CHAIRMAN CAPLAN: Let me try another tactic here and see if we can get ourselves out of the box. I'll pull my motion off and try a different strategy here.

DR. PILIAVIN: You have to have the concurrence of your second.

CHAIRMAN CAPLAN: Oh, my second? Who seconded me? Ed did.

Maybe we could ask for this, then: a regular update on how the guidelines for deferral of donors relates to new variant CJD, and that we get that at each meeting. It seems to me what we're asking for is a connection between what the deferral policy is and what people are trying to struggle with.

I think we're also saying that we want to be kept in this loop because the science itself, as we know from other issues--this is not part of the motion. This is dragged into explanation. But there are others the science won't tell us. We're going to have to be thinking about the cost trade-off, cost/benefit trade-off. So it seems to me what we want is that regular update that connects the deferral policy to what is known and what the agency--what the government has collected on new variant.

DR. NIGHTINGALE: I think that a motion would be superfluous. You will be kept up to date with the best information that we have.

COL. FITZPATRICK: Since I brought up the criteria, knowing that we do have a vast lack of knowledge and that it would be highly impractical to expect you to come to the next meeting and say we have six criteria and if these are met we'll reverse the deferral, maybe the better question would be, as I know CDC and FDA, I'm sure, are working on it, is developing the questions that need to be asked to develop criteria. What do we need to know? We need to know the incubation time. We need to know if it's been transmitted. We need to know the results of the animal models. And we know we won't develop that data in the U.S., but we have to have the UK data in order to do that. And so starting to build the box rather than having the box, which you'll get with the updates.

CHAIRMAN CAPLAN: Well, maybe we don't need a motion, then, if we've got a commitment to get the regular update. That may be--is that something that we feel comfortable enough with instead of trying to urge it forward?

DR. HOOTS: Maybe we should say, then, that we would like an avenue for our questions or queries to be at least addressed. It may be that there is no answer. But is anyone doing X, Y, or Z? And if not, then why not? Is it because the data just is not available because it takes too many resources to get that?

That's my concern. If we leave a blanket "let's just let it go and give us what we got," then there's no incentive for everyone around this table and everyone on the outside and everyone at Blood Safety to say, well, if we only--if we really knew this, we could narrow the confidence interval from 500 to 500,000, down to 1,000 to 10,000. So suddenly we've made a quantum leap--not a very important one, but it starts getting there. That's my concern. I know that the scientists are, you know, looking at this, but I think we need to be asking these questions. You know, are we making--we're not--Jane is absolutely right. We're never going to get--we're never going to prove the negative. But if everybody who turns up in--if nobody gets new variant CJD in the next 24 months, then that doesn't prove that it's all gone. It just proves that there must be some--at least a bimodal distribution. But if it continues to go at some slope, then that tells us something.

These are the kinds of things scientifically that I think we need to be--you know, as part of our discussion along with what's the impact of taking these people out of the donor pool. Otherwise, you can't balance the--you can't try to balance the risk versus benefit.

DR. GOMPERTS: From my point of view, the guidelines have been generated in a situation where there's very little data. I would like to be reassured that these guidelines will be revisited on a regular basis, looking at the accumulation of information that will take place, A, on the impact on blood supply, B, what's going on in the United Kingdom and the rest of Europe and elsewhere.

There is data that is going to come through, and I would like to know that these guidelines are being revisited.

DR. AuBUCHON: By my estimate, about 150,000 Americans are about to be scared out of their wits that they have mad cow disease, for which we have no test, no believable information for them, and really no good counseling. And I think the least that we can do--I'm speaking as the government; I'm part of the government--what should be done for these individuals is that they know that on a regular basis this committee, as I guess their best representative, will hear from the regulatory bodies that are overseeing this that they are indeed looking at it and they're sharing with us the best information that is available.

CHAIRMAN CAPLAN: Do you want to try that as a motion?

DR. AuBUCHON: That was a second to your motion.

[Laughter.]

DR. NIGHTINGALE: I think we're there, Art.

CHAIRMAN CAPLAN: Well, if we have some wordsmithing, why don't we put up or down on a vote on this, and then we can probably move on. We will go in the spirit of that this committee wants to be kept advised at each meeting about the policy and its impact--we'll wordsmith this thing--and be able to assure the American public that the policy of deferral as it stands continues to be reasonable in light of the evidence. We'll try to struggle that out and let you read it, but is that something we want to make sure we say? A second?

DR. HOOTS: Second.

DR. SNYDER: I've got a question. Why can't you just--if you're going to send a letter to Dr. Shalala, just put it in--

CHAIRMAN CAPLAN: We will.

DR. SNYDER: --that's what you'd like to have happen. That seems better than a motion. It suits the purposes, and it does give the reassurance that you're looking for, Jim.

CHAIRMAN CAPLAN: I think you've got--I mean, I need a sense of the group that they want it in there. That's what I'm looking--

DR. PILIAVIN: Yes.

CHAIRMAN CAPLAN: Okay. All in favor of my incoherent motion?

[A show of hands.]

CHAIRMAN CAPLAN: Opposed?

[No response.]

CHAIRMAN CAPLAN: Abstained?

[No response.]

CHAIRMAN CAPLAN: All right. We'll submit that.

DR. HAAS: Art, just in the spirit of the comment that was just made, I think we also want to be saying to the public--again, the "we" that Jim is talking about--we want to be saying that we don't know what this thing is doing out there, and what we're doing is taking the most cautious action we can to try and stay on top of it. If that message is not getting out, then the fear that several people have mentioned around the table is a very real fear.

CHAIRMAN CAPLAN: Okay. In some cruel spirit, I'm going to move us right into the availability of blood products discussion. I think this committee has struggled with the problem of shortage of blood products for some time. We have tried to make a variety of suggestions about what to do to help remedy that.

As you will recall, there were problems that were arising due to CJD. There were problems that were arising due to manufacturing capacity going off line. There were problems coming up about reimbursement, and there were many other problems that had put limits on the availability of important blood products, such as IVIG.

I think it was also the case that there was a shortage of information and data, which we tried to encourage be made more available so that we could figure out a little bit more about what was going on. But maybe I can turn to Steve and ask what we can say at this point about the situation with respect to availability.

DR. NIGHTINGALE: I think two issues have been brought to the attention of the committee by its membership, and they've requested it be put on the agenda. Mr. Walsh's letter was included in your packet. Those two questions that we were requested to consider were, first of all, flat or in some cases declining production of plasma derivatives in the face of increasing demand, and the second issue was uncertainties regarding the reimbursement climate.

In discussions with those who wished to have these issues addressed, the consensus was that we would address each of these issues separately and that we would begin with a discussion of the production issue first. And I believe that there is general agreement that we would begin with industry. We have a comment from academia, and we have comments from both the Immune Deficiency Foundation and the Alpha 1 Foundation for today.

So if I could begin by inviting the representative of the IPPIA, Mr. Dennis Jackman.

MR. JACKMAN: Good afternoon, everyone. We're going to put an overhead up here, and I appreciate the opportunity to address the committee on supply of plasma therapeutics.

We are acutely aware--I want to start out by saying that the industry is acutely aware of the importance of these therapies and aware that there is a tight supply situation in some of these therapies as well. But we're taking a number of steps to assure that we can meet the needs for those therapies.

First of all, to help out with that--those are our member companies, of course, Alpha Therapeutic Corporation, Baxter Hyland Immuno, Bayer Corporation, and Centeon.

First of all, to help us to understand the situation, which is one of the recommendations of this committee, we instituted monthly data gathering which is disseminated to appropriate authorities and to a number of the consumer groups here in the room that gives a very good picture on what U.S. distribution is of all the plasma-based or derived or the recombinant analogue therapeutics. That gives us a very good picture, a reliable picture since it is monthly, of what the trends are and gives a balance between distribution and actual inventory.

Secondly, the companies have committed to emergency supply programs. All IPPIA member companies are engaged in emergency supply programs, and, in fact, they then joined in partnership with the IDF, the Immune Deficiency Foundation, on an emergency supply program in December of 1998. So there's an effort to make sure that those that are in most need and where there's a shortage situation are able to obtain product.

That was also something that was recommended by this committee, that there be attention given to an emergency supply situation. So we have taken action on that.

There was a discussion of--the other thing that we're doing that is very proactive is we're investing in plant upgrades and process improvements, and we're talking about hundreds of millions of dollars over time being invested in upgrades that will result in greater production, greater reliability of production, greater yields on plasma, and have an impact on supply as well.

One company, for instance, has an application in. They're doing a clinical trial--we hope to have the results next year if everything proceeds positively--that could increase the yields off a liter of plasma 5 to 40 percent. That would be a major impact on the supply situation.

Another company had made a commitment to increase their plant capacity in one of their plants and did that, and that was approved by FDA in partnership with FDA, and that increased the yields from that plant significantly as well. So there are a number of things that are very real that are happening that are having an impact on supply.

We're also talking about increasing manufacturing capacity. A number of companies have major investments in new manufacturing capacity. For instance, one of our member companies is building a brand-new, an entirely brand-new facility for the production of IVIG, which could increase their production of IVIG by 40 to 50 percent, if everything goes as planned, by the year 2003 or early 2004. So that's another example of investment, and that's a major commitment of resources.

There's an ongoing investment in CGMPs, current good manufacturing practices. That means manpower, training, and also equipment, and it's also other things that we're doing, which is partnering--trying to partner with the FDA to get a better understanding and guidance on what the GMPs are. To that end, we've sponsored or had together a workshop on GMPs, the first one of those in the spring. We're hoping to have others on that so that we can increase our understanding and increase compliance with GMPs, and then in the long term, that's going to have a major impact on supply as well.

Saying that, we know there are some bumps in the road there. We're working hard on it, and we hope we'll have a positive impact over time with supply.

Another area is R&D. There are major commitments in R&D, and those are, again, in the tens of millions of dollars per year, and it's a significant amount. What we're talking about there are new forms of therapies, which are important--we don't want to stay status quo--and at the same time new processes that could have a greater impact on yield and availability of supply.

One of the commitments that was also made, the next point, is licensing and importation of additional IVIG products. There actually has been action on that, and there will be a report today from the companies engaged in that. And that's actually Baxter--the president of Baxter Hyland Immuno, Larry Guiheen, will be talking here and giving some reports on their efforts there.

The other is to work on optimizing the regulatory environment. What we mean by optimization is trying to achieve that balance between absolute product safety, which we all support, and at the same time maintaining acute awareness of supply as a safety issue, trying to achieve that balance. And so to that end, working with the agency where we can to try to bring new information to light on where you get good returns on investment in safety and regulation, and where maybe you don't get such good returns. So a dialogue we think is important. Early involvement we think is important. And we think we have some of that.

Another example, though, of that whole thing is what happened recently at the BPAC meeting where there was a recommendation on post-donation information, inadvertent contamination, and an algorithm was recommended there that would have, we believe, a very substantial impact on supply, the potential, a huge impact on supply. Industry is developing and ready to implement actions to address the concerns of post-donation information and are working with the agency and planning to meet with the agency to talk about exactly how we plan to approach this. And we think we can reach the goal without a large negative impact on supply if we can follow industry's plan.

The other is on addressing reimbursement concerns. Obviously, we have major concerns there. We'll talk about that a little bit later. It's on the agenda. But, clearly, the level of reimbursement has a tremendous impact on the ability of manufacturers to invest and to produce therapies, and it has a direct impact on availability as well.

Saying that, that investment, we also--going back to the regulatory environment, we would like to try to do whatever we can to see that therapeutic biologics are given as much attention on product and process reviews as some other things, such as protease inhibitors, looking at that under fast track, and some of the provisions that exist under FDAMA and other provisions like that, because we do think there's a supply situation here that needs to be addressed, and that's one way of addressing it.

So we'd like to work together on those things. We believe that if we do all of these initiatives--and we are implementing them; I want to say these a very real--we will work our way out of the supply shortages over time. We know there are going to be some bumps in the road. There have been. But we think we have very concrete actions here that will allow us to meet patient demands and needs.

That's my presentation. Thank you very much.

CHAIRMAN CAPLAN: A quick one or two questions? Yes, John?

MR. WALSH: Dennis, are any of your member companies here that are experiencing GMP difficulties and inability to produce product going to present at all? Are you prepared to answer any questions with respect to closings and availability issues?

MR. JACKMAN: Well, in terms of closings or availability issues that are company-specific, I don't have specific company information on that. And there is a company that has problems with a closure right now, as we all know, and they are not in the room. And so I don't have any specific information. But I think that's between the company and the regulatory agency as to how they work that out.

CHAIRMAN CAPLAN: Fernando?

DR. GUERRA: Thank you for your very informative presentation. How does industry track demand beyond just the number of doses that are ordered or, you know, for the number of different products in terms of the morbidity, the diseases, the conditions that are emerging that perhaps are requiring the use of some of these products? Because some of those conditions probably today are non-existent or they're being managed in other ways. Does industry see a continued growth and increase in demand based on some of the disease processes that obviously have existed in the past but perhaps the changing character of diseases is such that maybe the demand is not quite what it was before?

MR. JACKMAN: I think that industry is always interested in finding new solutions and new cures for new problems, and that's partially what R&D-intensive companies do. So where there is demand that is produced by unsolved and unmet medical needs, industry will invest in that and do the R&D that's necessary where they see that having that demand and that need. So, yes, as part of R&D, of course, companies are engaged in trying to find either new delivery systems, new indications for products, and new forms of technology to address diseases that currently are unmet medical needs. And I think it's a very important part of our industry.

CHAIRMAN CAPLAN: Okay. Thank you.

MR. JACKMAN: Thank you.

MR. ALLEN: One quick one.

MR. JACKMAN: Oh, yes?

MR. ALLEN: Do you have any projections over the next four or five years on what the needs are going to be and how your organizations are going to be able to meet those needs?

MR. JACKMAN: That is something that--actually, we had a discussion on that at BPAC. First of all, the industry as a group does not collect or project demand out for four or five years. We don't project demand. As a result, there are some issues surrounding that on the legality side. But there are people that may try to do that and try to project demand, and they're third-party independent research companies, like the Marketing Research Bureau. They do some of those projections.

Also, individual companies will try to estimate what they think might be happening, of course, as they're trying to think about whether to build that plant or not. But I wouldn't say that it's necessarily four or five years out. I guess at a certain point it becomes rather unreliable.

MR. ALLEN: They do it on, like, a year-to-year basis? Is that what they're doing?

MR. JACKMAN: Every company does their own--if they're projecting what their needs are, they would be doing that in their own methodology. That's basically a competitive type of behavior where companies are trying to assess what they're going to do in that environment. So, really, the association does not engage in that.

MR. ALLEN: Okay. Do you think it would be advantageous to do something like that? Would it help?

MR. JACKMAN: To try to project demand?

MR. ALLEN: Would it help the people that need these products if there was a better way of identifying what the demands are going to be?

MR. JACKMAN: If there were reliable third-party information that existed out there that tried to say, you know, this is what demand is, there might be some use to that.

The difficulty is the reliability of such data, and looking generally at demand models that exist for a lot of products out there, demand is affected by so many things. It's affected by reimbursement. It's affected by changes in prescribing habits. It's affected by so many things that you could have a wide variation on what the demand is.

On the other hand, you could, you know, eventually--theoretically, you could maybe project something and with a wide range of bounds, if you will, of what the demand is. What that would do in terms of projection beyond what is already done individually by companies, I can't speculate. I can just say that I know that companies individually are looking at those kinds of things, obviously, as part of meeting unmet medical needs. When you define an unmet medical need, you have to say, well, there's a need there, and then that's partially projecting demand. So that's the kind of thing that's happening at a micro level to some extent.

CHAIRMAN CAPLAN: Okay. Thanks.

MR. JACKMAN: Thank you.

CHAIRMAN CAPLAN: We've got Larry Guiheen next from Baxter.

MR. GUIHEEN: Thank you very much. The purpose of my speaking here today is to give this committee an update on the progress that Baxter has made on the initiatives that we outlined in both April of last year and in August of last year around the supply of IGIV and recombinant Factor VIII.

I am pleased to report concerning IGIV that Baxter had three initiatives that have all been completed and will yield about 60 percent growth in the supply of IGIV of Baxter's products. This is over our 1998 levels. These three things were based on increasing plasmid fractionation, process improvements, as well as the ability to import.

The first initiative was around fractionation capacity. The FDA licensed our Rochester, Michigan, facility late last year, which allowed us to have additional capacity to produce IGIV.

Second was the FDA licensure of a new purification technology that increases the yield of the current amount of plasma that we put through our processes. This allows us to increase the supply of our GammaGuard SD, and this was approved in June of this year by the FDA.

The third initiative was focused on our ability to import more product into the United States from our European facility. This month the FDA licensed IV Gamma EN, which will begin to be shipped in the month of September in the United States.

By accomplishing these three initiatives, the total IGIV supply will increase by about 30 percent in 1999 and again another 30 percent in the year 2000.

Baxter also remains committed to even further increases in the U.S. supply of this vital therapeutic. We are engaged in several projects intended to increase Baxter's IGIV supply over the next several years.

Lastly, I wanted to just comment about the recombinant Factor VIII situation. In August of last year, we testified that if our Thousand Oaks plant was approved, we would be able to increase supply of this product by 40 percent in the United States. The Thousand Oaks was approved late last year, and since that time we've been able to increase the supply by over 40 percent in the U.S. market. Right now it's our belief that the supply is meeting the current demands.

Thank you.

CHAIRMAN CAPLAN: Questions? John?

MR. WALSH: One quick question. Thank you for a good presentation. The IGIV community is lucky to have you working on their behalf. This regards A1PI availability. Is Baxter in a position to increase, in the event it's necessary, the supply of 4.1 paste to maximize the effectiveness of the single product, single manufacturer for A1PI right now?

MR. GUIHEEN: We are looking at that right now with one of the companies that actually produces that product.

MR. WALSH: Thank you.

CHAIRMAN CAPLAN: Keith?

DR. HOOTS: Your 30 percent increases in your own production capacity, if longstanding withdrawal or non-production by one of the suppliers were to be maintained, would you be able to make up that difference because of CGMP issues, the present--the company that's presently not producing?

MR. GUIHEEN: Our estimates--and, again, I don't have the exact numbers around the other company's production, but probably not be able to meet that.

CHAIRMAN CAPLAN: Okay. Thank you.

MR. GUIHEEN: Thank you.

DR. NIGHTINGALE: Are there any other representatives from industry who wish to speak at this time? If not, I believe that the patient communities wish to speak, and on the list that I got on behalf of the community, Dr. Jerry Winkelstein is the first speakers, to be followed by Mr. Thomas Moran, both of the Immune Deficiency Foundation, and Dr. Mark Brantly and Ms. Buelow will be speaking on behalf of the Alpha 1 Foundation.

Dr. Winkelstein?

DR. WINKELSTEIN: Thank you very much. I'll introduce myself and say that I'm the Chairman of the Medical Advisory Committee for the Immune Deficiency Foundation. That's about 20 percent of my time. Eighty percent of my time I see patients and do research in the field of primary immune deficiency diseases at the Department of Pediatrics at Johns Hopkins.

I'm here actually wearing both hats, and I have the most pleasant activity of the afternoon, which is to change pace and talk about the diseases rather than the problems, although I'll end up with some of the problems, obviously.

This group has been educated over the last number of years, and I'll reiterate some of the points that I made about a year and a half ago and remind you that the disorders that I'll be talking about are collectively called the primary immune deficiency diseases. Now, these are disorders of the immune system in which the primary defect is intrinsic to the cells and tissues of the immune system, and they're in contrast to secondary immune deficiency diseases in which the immune deficiency is not intrinsic to the cells and tissues but it caused by an exogenous agent, such as the AIDS virus, occasionally measles, radiation, chemotherapy, certain drugs such as prednisone. These disorders result from some form of other genetic or unknown intrinsic defect of the cells and tissues of the immune system.

Next slide, please?

There are a lot of different disorders lumped under this category. There are over 70 different disorders affecting virtually every functional compartment of the immune system. Depending on whether you're a lumper or a splitter, that number can approach 100 different disorders. For instance, one form of a primary immune deficiency disease, severe combined immune deficiency disease, was originally felt to have two different etiologies. With molecular genetic techniques, it has now been shown to be due to at least 12 different distinct molecular pathogenic mechanisms.

There are three popular misconceptions about these disorders. One is that they're very uncommon and so rare that one need not really pay attention to them. The reality is that the most common occurs approximately one in 500 to one in 1,000 individuals, and collectively, the 70 of them are more common than leukemia or lymphoma of childhood.

The second misconception is that these disorders are largely limited to infancy and childhood. These are not disorders of adults. That is largely due to the fact that these disorders were originally described in the most severe form within a pediatric population. But, clearly, the majority of patients are now well into adult life and span anywhere from 20 to 70 or 80 years of age.

The third popular misconception is that the symptoms are always severe, always life-threatening, and that these patients are very difficult to take care of and really have a very poor prognosis. That, fortunately, has also changed. The symptoms may vary significantly from very mild to very severe, but there's virtually none of them, none of the disorders, for which a true therapy cannot be delivered, and that is in part responsible for the fact that large numbers of the patients now are adults.

Next slide, please?

Now, these are some of the primary immune deficiency diseases. The first one on the list is a disorder in which the patient produces no gamma globulin of any sort. It is the first one I talk about because it was the first one described in 1952. Common variable immune deficiency is a disorder of all age groups. It's an unknown etiology disorder in which the patient has reduced levels of immunoglobulin for reasons that are unclear. One form of that is a sub-class deficiency where only a portion of the IgG is missing. There are other disorders as well: X-linked hyper IgM syndrome, which is missing certain immunoglobulin classes but not others; severe combined immune deficiency, the so-called "boy in the bubble" disease, the Wiskott Aldrich syndrome; a disorder also called ataxia telangiectasia. And the reason I grouped these disorders and selected them out of the list of 70 is that these are the most common disorders which require treatment with intravenous gamma globulin.

Next slide?

This is Colonel Bruton, who just died last year in a nursing home in Ohio, who was a medical officer at Walter Reed Army Institute in the early 1950s and late 1940s. He wrote a single case report of the first patient with a primary immune deficiency disease. For a period of time, this single case report was the most widely referenced piece of literature in the pediatric--the most widely referenced paper in the pediatric literature by non-pediatric journals. It was really a landmark discovery.

In the next slide, I've extracted some of his original description. This was a child who I'll use as an example of how far we've come. This child came to Dr. Bruton with recurrent pneumococcal bacteremia and sepsis, or bloodstream infections with a very common organism, the pneumococcus. The child repeated infection a number of times with the same serotype or exact same type of pneumococcus, indicating that he was not developing any immunity of his own.

Dr. Bruton had the advantage of the Walter Reed Army Institute laboratory across the street, took his serum across, and had it electrophoresed in a research lab, and it showed that he had no gamma globulin. That's the bottom.

What I've left out, unfortunately, is that he then started the patient on gamma globulin, and up to about two years ago, this young child had turned out to be an investment banker, had done well and lived somewhere in Northern Virginia. I don't know, since Dr. Bruton died, what happened to that original patient, but gamma globulin was life-saving.

Next slide?

This is the protein that most of you will be concerned about during my presentation. This is a schematic representation of gamma globulin, and what I'll point out to you is that on the left there is a variable region of the molecule which, much like a lock and key, fits over certain antigens that are foreign to the individual. It varies from gamma globulin to gamma globulin molecule, so there will be a set of these for tetanus, for polio, for any number of cold viruses, for tissue antigens from other individuals. Virtually all foreign material can be represented, and much like a lock and key.

There are two other kinds of immunoglobulins: immunoglobulin A and immunoglobulin M. I'm only showing you immunoglobulin G because that represents the largest fraction of what's purified for intravenous gamma globulin.

Next slide?

This is a very protective molecule. It works by opsonization, which I'll show you in the next slide. It neutralizes certain viruses such as polio. It will neutralize toxins such as diphtheria and tetanus toxin, and it activates the complement system. It has very, very broad and different protective effects. Many people feel that one of its most important is opsonization, and I'll describe that on the next slide, if I could.

You needn't turn the lights down. This is just the pneumococcus incubated in antibody or gamma globulin, and the fluorescent circle around this germ represents, if you will, the antibody attaching to it.

On the next slide, when white cells in your body then see the gamma globulin on the surface of these microbes, they ingest them. And as you can see in the very center of the slide, the small black dots within the cell have been opsonized by gamma globulin, ingested, and will be readily killed. That happens to be the pneumococcus on this slide, a very common pathogen causing pneumonia, sinusitis, and ear infections.

Next slide?

Well, what's the evidence that for this population of patients these 12 or 15 diseases or 10 or 12 diseases that are treated with gamma globulin, what's the evidence that it does any good? The evidence, as you can imagine, has never been a study showing in a controlled fashion, double-blinded and placebo-controlled, that this works because it was so logical when the patients were first discovered that gamma globulin would be of benefit. No one chose, fortunately, to have a double-blind, placebo-controlled trial.

However, if you look back over a period of time at the kinds of therapies that have been instituted, the conclusion is going to be that the IV gamma globulin at high doses significantly decreases the number of hospital days, for instance, on this slide. Now, this happens to be one disease, X-linked gamma globulinemia. This is a study out of Great Britain, and you can see for a historical period of time when there was no gamma globulin that children generally had 14 days of hospitalization per year, with intramuscular gamma globulin, which you cannot deliver adequate volumes, usually. There were 16 with IV gamma globulin when it was first initiated at low-dose therapy. It dropped somewhat, but not significantly. And then when IV gamma globulin became available in the kinds of supplies we've come to depend on, the number of hospital days per year dropped dramatically.

The next slide looks at this kind of information from this same study, a different way, which is how high, if you will, the trough level of gamma globulin is in the child or the adult before their next dose. And if you just look at, for instance, the number of episodes of pneumonia per year, you can see that when it's too low, the first one, less than 150 milligrams per deciliter, the average child or adult will have roughly one pneumonia for every two children. When you bring the level up to the normal level in a normal individual, it drops very significantly. The same is true for all infections and days in hospitals. It's just another way of looking at this.

So the summary statement really is that this study and many others have show that this material is genuinely life-saving.

Next slide?

I picked this out as a slide to show you because there's a dimension to this that transcends, if you will, some of the issues that have been brought up, which is that this material makes this kind of disease very livable for children as well as adults. Most of the patients receive intravenous gamma globulin at home. It's very difficult to have them come in to see us because they do extremely well. There's little, if any, school absenteeism. Many parents say that the children especially don't seem to miss any school. There are no special diets or restrictions such as children or adults with diabetes might have. They lead a full life with competitive sports in many instances. So they lead a relatively normal life other than the two to three hours every month that they're hooked up to intravenous gamma globulin.

The adult has other problems. Next slide? They also often get intravenous gamma globulin at home if they wish. Some of them learn to self-infuse. There's full employment, normal activities. Their two major problems are health insurance and the genetic implications for some of these disorders.

Next slide? Almost done.

As you know, there has been a shortage of this material over the last two years, and the Immune Deficiency Foundation, a patient advocate organization, has been helping in many ways to alleviate that shortage, and they have surveyed physicians at different points in time, and the foundation has asked me to tell you the results or show you the results of the survey that was performed in this month.

Next slide?

The purpose of the survey was to determine the degree of difficulty and nature of the problems physicians perceived that they had in obtaining IVIG for patients with primary immune deficiency. It was a one-page questionnaire, just finished last week.

Next slide?

These are the results. The survey stratified the physicians as those that had greater or those that had equal to or less than 25 patients. There were 195 surveyed. Out of those that had the largest number of patients, 140 were returned; 110 of those had filled the form out. Less than 25 patients, there were 1,300 physicians on the list; 265 were selected by the foundation to be surveyed; 102 responded.

Next slide?

And these are the results of those responses. What I've got in the third column, August '99, are the physicians, the 110 physicians who had greater than 25 patients on IV gamma globulin under their care, and they are best compared to the preceding April '98 and August '98, which also surveyed just physicians who greater than 25 patients. And you can see that the data shows that there is a trend, slowly but surely coming down, of those that are having trouble. Those that are not having trouble, conversely, are going up.

Now, in August of '99, they also surveyed--the foundation surveyed some physicians who had fewer than 25 patients. There's no comparative data for this because this wasn't stratified before, but the data is represented on the right side.

The next slide shows the kinds of problems we're all having, and really, the numbers are pretty much distributed. But the kinds of problems are postponement of scheduled infusions, switch to a different brand, which often means the patient--usually should mean the patient has to come in under medical supervision because they're not completely equivalent in terms of reactions, or switch to a less preferred IVIG brand, perhaps the patient is sensitive to IgA, has anti-IgA antibodies and really must have a brand that is very low in contaminating IgA. Interval between infusions has been increased very significantly in terms of the number of physicians that have had to do that. The dosage is reduced and over a quarter of the patients who are substituted alternative therapies fortunately is down to about 6 percent.

Next slide? And the last slide, I believe.

Has the shortage of IGIV had a negative effect on the health of any of your patients? And the answer is that about a third of the physicians--and this is coming down slowly but surely, but a third of the physicians still feel because of the maneuvers that they've had to institute that the health of their patients has suffered.

That's the last slide. Clearly, some progress has been made, in part because of the foundation and industry's ability to cooperate. The guaranteed supply program has helped tremendously. But I should tell you that it seems to have plateaued. In the last month, I've had to have three patients come to me from home health care agencies that I normally take care of, but they're infused at home, one from Ohio, one from northern Pennsylvania, and one West Virginia, traveling to Baltimore to have products switched because the supply of the preferred product for that patient has not been available. So that in many of our experiences, although the general trend has been quite positive, fortunately, the problem still exists for a large number of physicians and their patients.

Thank you.

CHAIRMAN CAPLAN: Questions?

MR. WALSH: Do you currently have organized health surveillance in place for immunodeficient patients?

DR. WINKELSTEIN: The Foundation has a contract from the NIH to register, construct registries of many of the disorders that I showed you. But this is a physician registry, not a patient registry. But the Foundation has plans over the next year to develop an ongoing surveillance mechanism to look at risk-benefit ratios of this product, long-term consequences. Since the patients on IGIV, with primary immune deficiency diseases have been on for sometimes nearly 20 years. They represent an important, if you will, canary, in terms of what might be transmissible and what kinds of problems might develop over many years.

And if I can speak for the Foundation, they've been able to partner with the American Red Cross to spend this next year in developing just the kind of thing perhaps that you're asking about. From the patient's point of view, that's not an insignificant concern, which is what does happen. If you put a one-year-old on IV gamma globulin with X-linked agammaglobulinemia, now you can almost be sure they'll receive it for 59, 69, 79 years. It does look as if the long-term consequences of that specific immune deficiency has really been improved so remarkably that now long-term safety becomes a concern.

MR. WALSH: Thank you.

DR. WINKELSTEIN: Thank you.

CHAIRMAN CAPLAN: Okay. Thank you.

Thomas Moran?

MR. MORAN: I'm Tom Moran. I'm president of the Immune Deficiency Foundation.

The IDF is coming forward today on behalf of our community to discuss the chronic shortage of IGIV in the U.S. marketplace. As you've just heard from Dr. Winkelstein, many primary immunodeficient patients, approximately 25,000, in the U.S. are dependent on regular infusions of IGIV to maintain their health. Without IGIV these individuals are vulnerable to life-threatening disease and chronic disability.

The IGIV shortage, which for our community, began in December of 1997 and persists today, has caused increase illness and is a source of extreme anxiety for patients and families, depending on this therapy. In fact, if the number of people who we estimate who have gotten ill as a result of the shortage had become ill as a result of, for example, product purity or product-safety related issues, you could well imagine the hue and cry really from all quarters.

I'm a little bit concerned that I think we're becoming collectively accustomed to this shortage, in part out of human nature, we just adjust to things over time as a society, and also I think because some of the solutions that we could discuss seem to imply a trade-off between product safety and product availability. And those are very difficult kinds of discussions to have and ones that people typically like to steer around.

Jerry Winkelstein's presentation describes the situation confronting physicians and patients at a time when the IGIV market supply had been slightly improved over 1998. The first half of 1999, approximately 7,850,000 grams of IGIV had been released into the U.S. marketplace. If we had the same rate of release in the second half of '99, that would total about 15,700,000 grams of IGIV. That compares with 15,200,000 grams last year. So that's a half-million gram improvement--again, assuming that the rate of release for the second half of this year would be as strong as the rate of release for the first half of the year. However, that also compares with a 17-million gram release in 1997. So we're still at a 15.7-million gram level, which is still 1.3 million grams below the 1997 level.

In fact, I was very interested in Larry Guiheen's remarks earlier, from Baxter, with respect to their ability to bring some additional product into the marketplace, but I think it was the question that was asked that related to the situation of Alpha Therapeutic, where they were closed as of last week for an indefinite period of time, is an indicator for the second half of year that is substantially more negative.

We also had withdrawals Friday and this week from ZLB, who fractionate for the Swiss Red Cross, bring products into the U.S. under the labels Panglobulin and Zaniglobulin. And those products are being withdrawn.

The problem isn't so much the withdrawals from the marketplace, but a concern from the patient groups that perhaps if, in fact, rectifying the problem that created the withdrawal means that production has to slow down or is reduced as a result of remedying whatever problem occurred, you know, we're going to face a challenge from there as well.

If we add up the, the IDF, if we add up the pluses and minuses, looking into the second half of '99, looking into a crystal ball, we would have to guess that the total release of IGIV for the second half of '99 will, in fact, be below the first six months of this year. And so we're sliding slowly back into the kind of problem I think that we experienced in 1998.

I think I would like to just make an aside comment, and address it to IPPIA, the data that Dennis Jackman referenced has been very helpful and is basically the source of the information I just gave you a moment ago. I think it's time, however, and I'll come back to this at the end of my presentation, to suggest that industry and FDA might want to consider the next step in data collection, and that is to begin to try to make some projections going out one or two quarters. There's a lot of uncertainty in making those projections, and there may even be some misgivings related to creating self-fulfilling prophesies. But I do think that it would be a good idea for industry collaboratively, and perhaps with FDA, to begin the effort to try to predict supply going out one quarter, two quarters. That will enable those of us who are involved in trying to deal with the shortage to take some steps that might prepare us for what may occur.

Based on the information--well, based on an expectation of 15.7 million grams or less for this year, I'd like to remind you that, even at that level, reiterating some of Jerry's data, 46 percent of clinical immunologists treating over 25 patients are still postponing infusions, 35 percent are increasing the intervals between infusions, 28 percent are reducing the dosages and 6 percent, as Jerry pointed out, are employing alternative therapies. We assert that such strategies imply the likelihood of adverse health effects among our patients.

Based on our sense of vulnerability over the foreseeable future, our community respectfully offers the following recommendations to the committee. And I'd like to say these are not so much recommendations to the committee per se, but represent recommendations to all of the institutions and organizations sitting around the table as well. We have representatives here from FDA, from industry, from the National Institutes of Health and so forth. So we're kind of speaking to the audience here as well.

The government, we think, should immediately launch a study to assess the public health consequences of the current level of IGIV supply across many indications, including primary immunodeficiency diseases. I mean, frankly, we're standing here speculating. We think people are getting sick. It would seem to be appropriate. IDF did a survey last year that indicated that people were getting sick. I think it's an extremely important public health question to be able to objectively identify the health consequences at certain levels of IGIV output.

As Jerry pointed out, there is no health surveillance program in place today to monitor the health status of primary immunodeficiency patients, and so we would need to have some sort of initiative outside of what we at IDF normally do. And I would also encourage that we not only look at primary immunodeficiency diseases, but the other disease states for whom IGIV is a medically beneficial therapy.

Our second recommendation is that industry should continue its commitment to support IGIV emergency supply programs like the IDIF Safety Net Program and continue to work with patient organizations like the IDF to promote IGIV rationing protocols in both hospital and home care settings. We would also invite the Public Health Service, HHS, FDA and so forth to join us in that effort because, if we are going to be in a chronic shortage situation for a protracted period of time, it is extremely helpful for home care pharmacies, medical center pharmacies and others to consider priority protocols for the use of that material within these institutions and settings.

The current system of IGIV distribution is primary market driven, and although not static, it was developed over a long period of adequate supply. A patient's ability to obtain life-sustaining treatment depends exclusively on the setting where they obtain their treatment and is not related to medical necessity. Patients are currently migrating from setting to setting or from Ohio to Maryland to obtain therapy. Conversely, in most cases, a patient's IGIV is not portable if they are forced by circumstances to change providers. Voluntary efforts like Safety Net and medical prioritization protocols are essential until the market adjusts to the new reality of chronic undersupply. Industry and government must take the next step in tracking supply by making reliable projections related to product availability at least six months into the future.

The fourth suggestion is that the FDA should give an even higher priority and report regularly on their efforts to expedite their review and approval of new IGIV preparations, expedite lot release for currently manufactured product and respond quickly and with a sense of urgency to industry responses to FDA enforcement actions. Industry and FDA must minimize the length of plant closures and manufacturing slowdowns.

Again, we alluded to a company who was closed for enforcement action last week. I don't have the definitive data. But in the past, I've seen that this company's market share is somewhere in the neighborhood of 20 percent. If this company stays out of production for three months, six months or longer, our suggestion is that, you know, the company and FDA work as closely as they possibly can, and we assume that they will, to minimize the length of that shutdown, if necessary.

Finally, our last recommendation or suggestion is that consideration must be given to permitting the distribution of IGIV currently under clinical trial for which adequate safety data already exists if the market requires it. Consideration should be given to other sources of manufactured product which, for various reasons, are not being released today in the U.S. market.

I mentioned one of the withdrawals earlier. Depending on the nature of the withdrawal, if there is product stacking up on the shelf, and then there's an issue that doesn't relate to patient safety, product purity, efficacy of the product; for example, a hypothetical example would be a labeling type of problem or something of that nature, if it's not a health risk, then, while under normal circumstances we may delay lot release to remedy whatever situation, you know, under certain situations, we might want to consider steps to get that product out the door faster.

Mr. Chairman, members of the committee, we request your support in implementing these recommendations and suggestion. They cut across several agency jurisdictions and extend to the private sector.

Thank you very much, and I'd be happy to answer questions.

CHAIRMAN CAPLAN: Let's do one. Jane?

DR. PILIAVIN: This is essentially a sociological question. Would you say that the people who are being put at the most risk are disproportionately poor and minority?

MR. MORAN: We know--I'll tell you the one thing that we know, and I think it was a part of our survey, and that is that there has been an increased reduction in the amount of free or in the product available to indigent individuals as a result of that shortage. That's data that I have. So I would say I think it's probably a reasonable assumption that that, in fact, is the case. That's the way things always go. But we also have the data as well to support the fact that there is less free product for indigent cases.

CHAIRMAN CAPLAN: Okay. Thanks, Tom.

MR. MORAN: Thank you.

CHAIRMAN CAPLAN: I'm going to ask Nancy Buelow and Dr. Brantly to come forward and speak for the Alpha 1 community. I will really ask you both to come up and go one after another fast.

MS. BUELOW: Good afternoon. My name is Nancy Buelow, and I am a member of the Alpha 1 Association board of directors. We are the membership organization that represents all alpha 1 patients. I am here today as a patient and to represent all of the alpha 1 patients.

As you are aware, the critical shortage of Prolastin has greatly affected our community. We have been without our full prescription doses of this life-sustaining drug for almost two years. We have new patients being diagnosed daily who are not able to get treatment. We now have Vietnam veterans who are able to get no product at all because they get their treatment through the VAs.

Without our Prolastin therapy, we are vulnerable to lung infections and pollution. Any lung infection causes us to lose lung function. I have 36 percent lung function. I'm really fine with that, but I don't want to lose any more.

The April 28th short-term recommendations of this committee stated that industry should explore with the Food and Drug Administration strategies for reallocation partially processed plasma material from one manufacturer to another in order to optimize production of alpha 1-antitrypsin and other plasma derivatives. We have been waiting for solutions. Can you tell me if there's been any progress or if you've come to any conclusion on this?

It was also stated that industry should explore with the FDA labeling and disclosure strategies which would increase product availability without compromising public safety and trust. We would like to be included in this exploration. We need to be able to go back to the others, like myself, with reassurance that more comparable products will be approved and available soon. We have heard that other manufacturers on clinical trials have had problems. One of them, as you heard today, that was engaged has been shut down. Another manufacturer suspended their infusion protocol to pursue aerosol therapy. We would like to ask the Secretary to encourage re-evaluation of this decision and to reopen their IV product research.

While we do not want to jeopardize safety, we would like your help in getting products still in development to the patients as soon as feasible. We ask that the review process be accelerated and that clinical trial requirements be reasonable without compromising our safety.

The last recommendation of this committee was industry and government to explore the impact of a temporary decrease in exportation of plasma derivatives while they are in short supply in the United States. Because of our worldwide communication network via the Internet, we are in communication, and there have been no indications to us that shipments have decreased recently to Spain and Germany. Has industry and FDA come to any agreement on how to facilitate a temporary decrease in exportation of these life-sustaining products?

For me and many others like me, some of those who don't share my good health, this is a life-and-death disease. We have lost an unusually high number in our community this year and will continue to do so in increasing numbers as the supply of Prolastin remains constant and the demand increases as more patients are being diagnosed.

Currently, only a small fraction of our population has been diagnosed. The medical experts believe that 1 in 37 people carry the alpha 1 gene. Think of the impact if all of those with alpha 1-antitrypsin deficiency were diagnosed and identified. How would we treat those patients? How would we counsel and educate them? What could we tell them?

The Association is hard at work trying to increase public awareness of this disease. We feel it is our responsibility to find and diagnose these patients before extensive damage is done to their lungs and livers. But once diagnosed, there will be no treatment available for them. It used to be that we couldn't help alphas until we found them. Now we have trouble helping them when we do find them. We implore you to help find solutions to these problems.

Another subject I would like to briefly address is that of the proposed changes in Medicare reimbursement. HCFA-1005-P, APC 906, the prospective payment system for hospital outpatient services. Forty-four percent of our community have either been forced to retire due to medical issues related to alpha or have reached an age to qualify for Medicare. The regulations, as currently written, promise to limit access to infusions of this scarce product.

As pointed out in our comments at the April meeting of this committee, the reimbursement would bundle drug and nursing into one pass-through payment of less than $75. This is for a treatment that averages over $1,200 a week. This regulation pulls the rug out from under 44 percent of people with alpha 1 who find themselves with Medicare their only form of coverage. This payment system is unreasonable and unfair. What we have asked for is a separate payment system for Prolastin, using the existing HCPCS code so that lifesaving treatment will be available for us under a similar system to clotting factor for the hemophiliacs and chemotherapy for cancer patients.

Please give our requests your most serious considerations. We, the alpha community, cannot solve these problems alone.

Thank you.

CHAIRMAN CAPLAN: Nancy, one question. Do you feel like your patient group has enough input into the FDA decision-making process about expediting new drugs? I mean, how do you have input there?

MS. BUELOW: We can always have more. We would like more. We would like more.

CHAIRMAN CAPLAN: I took the question.

Dr. Brantly?

DR. BRANTLY: I basically come here as the chairman of the Medical and Scientific Advisory Board to the Alpha 1 Foundation. And obviously, many of the things we want to recommend I think are the same for the National Association and the Foundation.

One of the Foundation's recommendations to HHS and all of the agencies is to support development of new therapies for A1PI. We are also keen to make sure that there is an adequate supply of the raw material that is the 4.1 paste to made available to the manufacturers that are capable of production of the alpha 1-antitrypsin.

We strongly recommend and encourage the continued development of licensing of additional sources of A1PI, and specifically for some of the companies that have dropped their IV projects to then pick them up again.

We also, realizing that there needs to be a great deal of work in developing new therapies, we encourage the NIH to expeditiously fund research directed at identifying surrogate markers for lung disease so that they can be used in clinical trials, so we can demonstrate efficacy for some of these drugs.

And then finally, in consideration of the current vulnerability due to a single manufacturer and a single product, we encourage the FDA to support the development of multiple formulations and delivery mechanisms of aerosolized alpha 1-antitrypsin. The community definitely doesn't want to be in the same situation with aerosolized alpha 1-antitrypsin that we currently are in with the IV alpha 1-antitrypsin. So multiple formulations would be one solution to that problem.

Thank you very much.

DR. HOOTS: When we last heard a report on supply, there was a question about recombinant alpha 1 or Prolastin. And as I recall, the NIH holds the patent rights to that. Has anything moved forward on that?

DR. BRANTLY: Well, there actually is a study ongoing currently. It's a pilot study using transgenic alpha 1-antitrypsin from PPL. And that's one of the first studies that's going on right now.

CHAIRMAN CAPLAN: Okay. Thank you.

Well, let me open the floor for some comment and discussion. Oh, we've got another--okay.

DR. HOLLAND: I thought I had included in my letter to Steve that this is another topic I wanted to say a few words on.

DR. NIGHTINGALE: Dr. Holland, if you are going to talk about the reimbursement, we are talking about supply first.

DR. HOLLAND: I'm talking about supply.

One of the hematologists in one of the communities we serve heard that I was coming to this meeting and asked me to bring you a letter. I will give it to you, and you can enter it in the record.

But basically he gives me three brief case reports of three patients with a need for IVIG, who were doing well on a stable supply, but with a shortened supply, had multiple health problems because they either had to be discontinued or shortened. One had hypogammaglobulinemia, one had acquired hypogammaglobulinemia and one had an acquired clotting disorder.

And I think the main message he wanted to get across was that all of these changes in the supply, including the impact of the new proposed guidelines, really have an adverse effect on patients. And I believe it was brought up earlier, we can talk about supply and how much is used and how much is not used, but we really need to have in place some way of monitoring the impact on patients because he has some examples, and I could give you additional examples, of increased morbidity, if not mortality, and certainly increased costs in health care to patients who are suffering from the lack of IVIG and other plasma derivatives. And it just brings to mind that these changes which are being proposed were going to be even more restrictive on that, they're even less necessary.

And I would conclude basically with just reading one sentence from his letter. And he says, and I quote, "I am reminded daily in my practice of the lifesaving qualities of blood products. And I'm hopeful that we'll be able to continue to utilize them with thorough and appropriate, but not excessive or hysterical, safeguards."

Thank you.

CHAIRMAN CAPLAN: The reason I'm moving this along here is I think we've got at least one speaker on our lookback who can't be here tomorrow, and I want to make sure I leave some time today to hear from him. And I also want to get us out of here at a relatively reasonable hour. So we may get into it and then come back to it.

But let's open the floor for discussion. I have one comment, in response to testimony. This committee did comment on the export issue. And as far as I can tell, the communication back from government was we are not going to change that policy. So even though we made a recommendation there, what you found in Spain or Germany or what seems to be going on with respect to supply of IVIG, I think on that one we didn't get our advice accepted. I don't think they have been willing to get into the international trade, and exchange and contract issues, which isn't to say they shouldn't, but it's probably going to take direct pressure on Congress to make something happen there. Because I think right now there's not a willingness to get into the export issue. That is my response to what we recommended. We didn't get a priority to keep product here.

I had a question, which anybody can answer for me, related to that. I believe it to be true that the British are importing plasma now, and where are they getting it? I mean, this is in the exacerbation of blood product problems going elsewhere type thing. There may be reason to worry, related back to our new variant CJD problem, that there's increased interest in bringing in blood products from here or other places that might skew that shipment issue overseas. That's what I'm concerned about.

Other happy comments or other new discussion points? We did have some suggestions given to us by people offering testimony, which we can certainly come back to tomorrow if you're too tired to get to them today, but I made notes on some of those. Other comments or discussion?

One other thing the Chair was a little interested in was the discussion of projecting data, which Tom brought up and others have mentioned. My impression is, if I'm not mistaken, from where we are with IVIG is that we're sort of two steps forward and two steps back because we've got people expanding capacity in parts of the industry and then loss of capacity in other parts of the industry.

I'm not convinced that we're not going to be sitting here a year from now with the same discussion on our hands about the current sources of supply, and it does seem to me that attention to some of the issues about expedited review and rationing protocols are important. We've said that in the past. I don't know that we have to pass more motions about it, other than to sort of repeat our concern about it for the record. But I don't know what other committee members feel, but I haven't heard anything yet that made me feel that the supply problem is going to be solved, even with increases in the Baxter capacity, for example.

MR. WALSH: I think you're right, Mr. Chairman. But I also think we need to be forever mindful that some of the issues related to protocol, the design of protocols for INDs, is really critical. And I think we need to stress to the FDA that we need to get creative and collaborate as closely as possible with industry, as they are starting to do, to make protocols reasonable enough to move forward drug development.

In A1PI, we had an IND product that was ready to go for PLA approval. It's stopped dead in its track because of GMP problems. So the alpha community, as per testimony of Nancy Buelow and Dr. Brantly, is stuck with one product and one manufacturer still.

The 4.1 paste is an issue. Bayer has indicated off-line that they are looking for additional 4.1 paste, the raw material necessary. But that's not impacted by any export issues. There's plenty of companies that are no longer burning the 4.1 paste or aka the sludge, if you will, and they are saving the 4.1 paste that should be available. Again, I think we need to encourage the HHS to make certain that we do everything possible to make that product, the raw materials, available for optimization of manufacturing.

So with respect to the aerosol development, for A1PI, there's a lot on the table right now. PPL Therapeutics, as Dr. Brantly testified to, is a potential for transgenic product. There are at least two other companies developing--interested in designing IND trials. We need the Office of Orphan Drugs, we need to ask the Office of Orphan Drugs to be flexible in their interpretation of the Orphan Drug statute regs to make certain that we don't get stuck with one licensed product downstream that may or may not be more or less efficacious, dry or wet, for example, aerosol or plasma, than the other. So we ask some flexibility with respect to interpretation of that statute.

DR. AuBUCHON: Personally, I feel somewhat I guess impotent is the right word in this discussion because most of the issues that we face in this shortage issue are beyond the scope of what the FDA at least has traditionally dealt with or that the Federal Government seems to be able to deal with.

I, personally, would like to see that the committee, not necessarily make any new recommendations, but just to let the Department know that we remain concerned about the ongoing shortage, the problem has not gone away and that additional attention needs to be focused on this, to the extent that the Federal Government can solve the problem or help solve the problem.

DR. HOOTS: I was pleased to hear that Baxter had gotten licensure for European-produced IVIG, and I presume there are other possibilities for new INDs or PLAs from Europe particularly. And it seems to me that maybe we want, at some point, to just find out what's in the pipeline or at least hear what's in the pipeline and what the possibilities are and what the potential impact of that would be for both IVIG and for Prolastin if there are potentials.

And then if there's cGMP issues, then obviously that's more difficult for us to deal with because that's purely regulatory. But we can at least say that we're concerned, and we want things to speed through the process as quickly as possible.

If there are design issues that could protect safety, but at the same time streamlining clinical trials, broadening clinical trials or whatever, or utilizing data from the EU, partial data at least that might cut the design and implementation time down, I think we ought to at least consider addressing those issues, by the FDA addressing them with us, to see if there's anything that could be done that's not already being done that wouldn't compromise safety, but would speed up new products.

Because if I understood, if I'm processing what I heard a year-and-a-half ago and now, there's still not the supply problem in Europe for IVIG specifically, and it sounds like even for Prolastin, that there is in the United States. So clearly there is a market drive in this direction which, if there weren't impediments to impede it, should allow more product to flow this way, as long as there were safety issues kept in mind.

DR. GUERRA: Along with I think staying informed about certainly some of the new products and the production capacity, the licensure, IND process, I think it's tremendously important for us to, from time to time, receive information about the surveillance and the changing pattern of some of these diseases, the age distribution of diseases, the life expectancy, those other important triggers for decision-making in terms of availability of some of these products.

And I think we heard it stated several times that I think people are certainly living longer. We're dealing with a population that certainly is requiring continued support of these products at a time when they also have a lot of other comorbidity that I think would be important for us to try to keep informed about.

CHAIRMAN CAPLAN: Jane?

DR. PILIAVIN: I remember from that last discussion that we had, what someone said a year-and-a-half ago, but there was some talk of off-label use. And I'm wondering to what extent that has been monitored and if anyone has been trying to decrease that off-label use so that there will be more of the supply for the people for whom it's actually been designed.

CHAIRMAN CAPLAN: Well, I know there was a campaign about use--I saw, just happened to read in the JournaloftheAmericanMedicalAssociation directives coming out about off-label use. So I know there was a push on the physician side to try and educate about appropriate use and the scarce supply. I don't know if it's ongoing. That was probably nine months back that I saw that. Does anybody know beyond that? There was definitely a push to do something--yeah, Tom?

MR. MORAN: It's not ongoing, but I think we'll get it going again. I think that it didn't distinguish only between off-label and on-label. It made actually a different distinction, medically necessary versus not medical necessary.

But regardless, the answer is there was a push about nine months ago, it kind of subsided a little bit, and we'll be working with industry and hopefully FDA around getting that push going again.

CHAIRMAN CAPLAN: It sounds to me, from this discussion, that we do want to indicate our concern about getting the best available data for morbidity and mortality on these diseases so we can keep tabs on that, the surveillance issue. It seems to me we would like to hear something from the FDA about the issue of expediting development and design issues with respect to speeding up in the face of ongoing and likely to be chronic shortages in existing supply into the future.

So I don't know if we need a motion on these, but if that's the sentiment of the group, I'll try to get that into our communication to the Secretary and then see if we can see if there's anything more to be done. I would like to think that we're not getting obstacles on this one, in terms of regulations, but it's probably appropriate for the group to indicate concern that the shortage problem from existing sources is still going to be there, and that has to weigh in the regulatory behavior in evaluating new possible sources I guess is what we're pitching toward or veering toward. Is that accurate?

DR. GOODMAN: Yeah. I'd just say that from my brief time at CBER and working with the people working on the IVIG particularly, that we'd be delighted to make a presentation about those issues at the next meeting. We would have been happy to do it at this meeting. And you shouldn't regard that as something you really have to go to great lengths to impress. We can commit right now to doing that.

But also I know that the exact points you brought up, whether it's clinical trials, lot release, when critical safety issues aren't involved, these things are on everybody's mind, and people are acting on them at this time.

MR. ALLEN: Is it possible to get the FDA involved in working out some type of projections based on demand, since industry, for whatever reason, seems to have some issues doing it within their own groups? It seems like, without some type of projections, we're dealing with a mystery here. We don't know what's going to be needed down the road.

CHAIRMAN CAPLAN: Let me take a whack at that, and then anybody else who wants to get in, including people in the room, can answer that.

I guess my feeling is, probably not FDA for that one, but I think the projection, as I infer it, is bad--short, short, short until new sources are found. So that it looks like for the next year we are struggling with on-line/off-line and the same old supply issues. That's why I was asking Tom a little bit about what difference would it make if we knew that we were--I can tell you we'll be short in six months, and I can project we'll probably be short in a year, given just what I've heard here.

So I don't mind doing it--it's not that I'm against it--but it sounds to me like we're still in a manufacturing bind, and we're still exporting, due to whatever public policy reasons and market forces. Product is moving both for alpha stuff and for IVIG stuff.

So that's the world. Now what? We can bring pressure to try and change the policy, although I don't think it's going to happen simply from the administration on the foreign policy issue. That's what I was saying. I don't think they've--they're not willing to go there unless Congress or somebody else gets feisty about it, and then we're stuck with getting new things out there, new trial designs and then trying to figure out if there are appropriate protocols in place for dealing with what we've got.

So I'm not against it. I just, when I listen to what the situation is, it doesn't sound--I could do the projections. It's sort of more of the same for a while.

Does anybody else want to jump in there?

MR. MORAN: First of all, you're correct. I mean, that's sort of the way I see it. But, you know, the other thing is that there may well be significant health differences between say a 5million gram release over the next six months and a 7 million gram release. So it's really a matter of maybe not doing finite projections, but how bad is it going to--is it going to be real bad?

And actually if you put the manufacturers in the room, I know there's some legal and this and that, and they all said, "Okay. This is what we've got on the dock, and this is what we've got coming in, blah, blah," you know, you could probably come up with a reasonable projection on that kind of macro basis, and that might well be helpful.

That's my comment.

MR. WALSH: Without--and at the risk of overemphasizing, I would just like, for the record, to state that, at best, if Alpha Therapeutics goes online in a reasonable time frame, goes back online in a reasonable time frame, we're looking at another year before there's another product for A1PI. The middle situation, if Centeon gets back online with their IV protocol, it's 18 to 24 months away, optimally. And then an aerosol development with a full-blown clinical double-blind trial, we're looking at three to four years.

So the reality for the alpha 1 community is there's as many people on therapy as there is that can't get therapy. And all we need to do is make certain that we keep the momentum up and seriously look at clinical trial design issues and getting product available during trials to as many patients as possible. And that's all we ask. We know we can't do the impossible.

MR. ALLEN: But wouldn't it be helpful to know what your community needs?

MR. WALSH: We need at least 60 milligrams per kilogram per week times 4,000 people, but we're not going to get that. And we probably need 90 milligrams per kilogram per week. If we have an aerosol product, we might be able to take care of between five and seven or eight or ten people with the same product as one person with IV, theoretically. We don't know that yet. But the bottom line is we need product, and it's not as if Bayer can all of a sudden double their manufacturing capacity without a new fractionation facility.

So I think, with due respect, Larry, projections are nice, but the projections are right in front of us now, and I think we don't need to complicate it any more than that, unless the FDA feels that it's necessary for consideration of clinical trial design. And if that's the case, then we need to focus on that and get that data.

CHAIRMAN CAPLAN: Jessie?

DR. GOODMAN: I was just going to say that with IVIG I think the projection kind of approach is very difficult. And one of the things that I'm trying to begin to sort out that I understand there is some data about is how the product is actually being used. And if we're in a situation where because of the current manufacturing capacity, the current let's say prescription rate--I'm not saying need--the current consumption, desired consumption of the product can't be met, then, while practice of medicine is specifically not an FDA purview, we have to ask, if you have a limited resource, is it being used appropriately.

And I think that asking those hard questions, which would require partnerships that go well beyond government, sounds very appropriate in the next couple of years for being sure this resource is used optimally. I'm not saying that it isn't, but I think we need a more careful look at that, and then how education and voluntary partnerships, such as were described before, could perhaps, you know, if we have a limited amount of product, improve the health outcomes maximally from that product.

And so to some degree, if this committee is interested in that, that might--and I'm not saying I know exactly the right way to do it--but that might be an important thing to explore a little more systematically. I hear all kinds of wild, having been out in the practice of infectious disease quite recently, I've certainly seen IVIG use for lifesaving indications, and I've seen it used in circumstances where the evidence for its efficacy is more questionable, although it may be fervently defended by those who use it.

And perhaps the issue of supply means that this particular issue can't be ignored at this time.

DR. CHAMBERLAND: I just wanted to say that CDC is also very interested in examining how IVIG has been used. We have done some work with the Immune Deficiency Foundation, and we are, on a fairly modest scale, trying to examine usage patterns and how those change over time. So we're attempting to, again, with limited resources, to look at usage patterns.

But I think Tom made the comment that there was a flurry of activity, an FDA letter, a "Dear Doctor" letter that went out, an MMWR that went out a few months later that reiterated the usages.

So I think it's time to, probably since the supply issue doesn't seem like it's going to be optimal for some time, to reiterate those messages and then continue to monitor how the product is being used, if we can get that.

DR. GOODMAN: We would welcome suggestions or other partners for how to do that better; you know, should pharmacists and health care systems be involved in this, for instance.

CHAIRMAN CAPLAN: Maybe one of the things we could ask for, Jessie, is, in addition to some comments maybe at the next meeting about design issues and expedited product development, what's doable, what isn't doable, what's going on, it might be interesting to hear both what is happening at this point with respect to understanding reasonable use in the face of shortage, and that might lead to a conference or some other mechanism for disseminating that information. So I think the group would be interested in hearing about that, if you want to try to pull something together with Mary or take different parts of that.

It does seem to me that we've probably reached the end of the line, and I think Steve got the Hepatitis C Lookback Session moved over to tomorrow morning to start us off?

DR. NIGHTINGALE: I would apologize to those whom this inconvenienced. It was a deliberate decision to let the discussion of the first agenda item proceed. I felt that was an extremely valuable discussion.

We do have the reimbursement concerns, as they relate to availability of plasma derivatives to discuss this afternoon. And I believe that we should conclude today's meeting at that point. I believe that the discussion of the Hepatitis C Lookback is a very important one and should be discussed at a time not only when everybody is available, but, quite frankly, awake. This has been a long day.

So I think we should move to the end of Agenda Item No. 2, and there are several speakers who would like to address that. I believe we had previously agreed that the industry would proceed first. Dr. Weinstein would make his presentation thereafter, and the patients would discuss that as they wished.

Mr. Jackman, do you wish to return to the podium?

MR. JACKMAN: Thank you. What I'm here to talk about is reimbursement, and specifically the outpatient prospective payment system that's proposed by HCFA. We talked a lot about supply, and when we have supply that meets all of patient needs, the fundamental thing is having the ability of providers to stock that--in this case hospitals--and have it available for people in an outpatient setting. So you could have all of the supply in the world, but if the reimbursement system is distorted to the point where hospitals will not be able to afford to stock the materials, then we're going to have some problems.

Thank you. First of all, we are talking about the prospective payment system that was proposed for hospital outpatient services in a HCFA-proposed rule September 1998. Right away I just want to talk about what the impact of that proposal is. One, reduced or eliminated patient access to therapy, period. If hospitals can't stock therapies, patients have no access. That's one thing.

Secondly, the reimbursement environment greatly impacts the investments in plants, new capacity, R&D and new therapies. So if we're talking about supply and future supply, then reimbursement and how it's modeled will have a tremendous impact on all of those items there.

Ultimately, we are talking about reduced availability if this is to go through.

Quickly, to explain what it is. It takes a lot of different procedures, this proposal by HCFA, and includes services or products and combines them into an ambulatory payment classification. So it takes a lot of various activities and combines them into one. For instance on infusion therapy, it proposes $99 for all infusion therapy, except chemotherapy in APC 906 and $38 in 907 for injectables. The problem is that for plasma-derived therapeutics, these payment rates dramatically undercompensate hospital costs for these therapies.

Now, just to give you some real examples, quick examples. On hemophilia, if a person with hemophilia were to come into an emergency room with a life-threatening bleed, a typical regimen might be 3,500 units of clotting factor for a 70-kilogram patient, and using rates that actually HCFA pays for inpatient reimbursement for hemophilia clotting factor, that's about $3,500. That certainly is not $99.

Then we look at IVIG. We're talking about generally thousands of dollars per treatment. Examples would be marrow transplantation, 35 grams, one to two days pre-transplantation, maybe weekly after that for 90 days post-transplantation. You look at the cost per gram, and you can see that's thousands of dollars per treatment. The same thing with acute ITP. For alpha 1-antitrypsin, it was referred to earlier, 4,200 milligrams, on average, for a 70-kilogram person, we're talking about approximately a thousand dollars per treatment. Somebody said $1,200 per treatment. It's certainly not $99.

These are special-need populations, and they are special-need therapies. I want to point out that these aren't like some of the other therapies. Hospital outpatient is an especially necessary venue for some of the patients that are treated with these therapies. Part of that is because, for instance, for alpha 1-antitrypsin, a number of physicians really don't care to administer in their office because they are not comfortable with that. They are concerned about some of the side-effect potentials, and it just can't be done there. So if you take it away from the hospital outpatient setting, you could be denying care.

HCFA has viewed the cost of drugs, in general, and biologics as incidental to treatment in their proposal. These therapies are not incidental to treatment. Incidental to treatment means like, you know, think of somebody having an outpatient surgical procedure, and they get saline solution as part of that. Well, that is incidental. But these are the therapy. So that the majority of the cost of the treatment is actually the therapy itself.

The other thing is that these are distinct high-value, higher cost therapies that don't fit into an APC bundle; in other words, if you look at the costs I just cited for those various treatments and therapies, they really don't combine very well with other infused therapies, such as antibiotics or, in some cases, saline solution. So there is such a difference that they have to be separated out.

And then ironically, in a way, HCFA's been working on a report to Congress on special needs populations on Medicaid. Clearly, the populations that are treated with these therapies we consider special needs. So on the one hand, people are trying to address special needs populations on Medicaid, on the other hand, we have a proposal under this outpatient prospective payment system, which basically denies special-needs populations care.

What are the solutions that we believe? We believe that separate therapeutics for--separate therapeutics from the hospital services. We just pointed out that the therapeutics are the major part of the service being provided in these cases. Provide therapeutic-specific cost pass-throughs, and that's not a great new radical idea. Actually, there's a tremendous precedent for that.

First of all, there's a congressionally mandated inpatient pass-through for clotting factor. There's published rates that come out. It's based on a calculation that goes out there. And Congress and others recognize there was a need to make sure that there was separate reimbursement for clotting factor, for instance, because they were finding that hospitals were not stocking it under the DRGs that exist, which are very similar to the hospital outpatient proposal that we are facing right now.

So why would you have a separation on an inpatient basis and then have a $99 infusion rate on an outpatient basis? That's a distortion. And that same applies to the other therapies we talked about, given their level of cost.

The physician setting, for instance, the reimbursement rate is 95 percent of average wholesale price, not $99. Current outpatient is on a reasonable cost basis. So that seems to be a much better approach.

We just want to, a final point is the Secretary has authority under the Balanced Budget Act and under the Social Security Act to basically not include any therapies she sees fit in this outpatient prospective payment system, to exempt then, essentially. And so we would suggest that the Secretary should exercise that authority and these needs so as to not deny access and availability.

We're glad to have the opportunity to bring this before the committee because this is the Advisory Committee on Blood Safety and Availability, and we think this has a tremendous impact on availability.

Thank you very much.

DR. NIGHTINGALE: Are there any other industry speakers who wish to--Ms. Ducca?

MS. DUCCA: On behalf of the American Red Cross, I'd like to thank you for this opportunity and thank you for bearing with us at this time of the day. It's been a long day, so we do appreciate your time.

We would like to present our perspectives on the prospective payment system for hospital outpatient services specifically pertaining to infusion therapy, APC 906. I will run through the background quickly because Dennis has already covered much of this.

In 1997, Congress instructed HCFA to develop a prospective payment system for outpatient services to contain Medicare costs. The prospective payment system is just a one lump-sum payment that covers all of the expenses involved in an individual service. To implement this directive, they proposed the regulation back last September. They took thousands of procedures and grouped them into 346 APCs, which stands for Ambulatory Payment Classifications.

The APCs are supposed to be groupings that are comparable clinically and with respect to use of resources so that there is some similarity in each of these groupings. It also bundled the products and the procedures into one lump-sum payment.

So, for our purposes, what that means is that the products that we're looking at and the service, the actual action of infusion, is all paid for in one system. And our concern is that the payment rates that HCFA came up with do significantly underestimate the true costs, and I'm going to show you some data as well on that.

The impacts, again, Dennis has discussed this. I will just mention a couple of these. The real potential exists that this will jeopardize patient access to the most clinically appropriate products and services. And there have been a lot of meetings on this topic, a lot of discussions among health care providers over the past few months. A lot of experts have put a lot of time into this. And since I've been at Red Cross almost five years, I haven't seen any issue that has drawn out this many meetings and concerns.

And among those that are familiar with HCFA, and hospitals and health care delivery, there's a real clear consensus that there could be actually shutting down of certain services because the financial impacts are just so severe.

We're also concerned about the potential impact on research. This would include both the basic and developmental, the types that Red Cross is involved in, for example, at our Holland lab. But we also feel that if a clinical trial is best conducted in an outpatient setting, this will certainly jeopardize the ability to do that simply because payments will restrict any kind of activity in outpatient settings.

And of course once this occurs, since Medicare is especially designed for elderly populations, we have a real significant population at risk here of not receiving their treatment. It doesn't mean other populations aren't involved, and they will be, but we're talking about elderly being hit first.

This is a listing of the therapies that are involved in outpatient settings that involve blood or related products. Red Cross is involved in all of these therapies. We are only talking about the first one today. Tomorrow I'll talk about some of the others. But we want to cover infusion therapy today, 906.

Some of the products that Red Cross distributes are listed here. We are involved In Factor VIII, in IGIV, and in albumin. Those are a listing of patients they cover.

And I am going to show you some data, cross-comparisons of our charge data to HCFA's APC rates. We developed this data based upon a treatment for a 70-kilogram patient, about 154 pounds. This was just to give us a baseline. And as Dennis said earlier, the APC payment rate is $99 for infusion therapy. And I want to make it clear that that $99 is a cap. HCFA will only pay about 80 percent of that. There is a copayment. So we're talking about even less than that amount.

Red Cross selected our average product charges for July--not yet, not yet--for July through December of 1998 just for this cross-comparison. There was no special reason for selecting that time period other than it was December of '98 that we really understood the impact of this regulation, and it was at that point that we started working on a letter filing comments to HCFA, and we just for simplicity selected the most previous six months' worth of data in order to make the comparison.

Another point I want to make here is that we believe that in evaluating the cost of providing a service, there are three elements that should be covered: the product, the actual procedure, and any associated overhead such as supplies, insurance, maintenance. All those factors should be included in evaluating cost.

Next slide?

Okay. I have two examples here of the data analysis that we did. The first is for IGIV Panglobulin. Again, this was a prophylactic treatment, if a patient were just to be in a hospital outpatient setting and need a preventive treatment. We looked at the number of units, the charges that we charge per unit, and the average product charge to treat this 70-kilogram patient was over $1,300. And when you compare that to the payment rate of 906, which is $99, you have a minimum loss for that hospital on one patient on one session of over $1,200. And, again, that's before we ever get to the cost of the procedure and the overhead.

Next example. We did the same thing for albumin. The ARC product charge--again, this is our 70-kilogram patient. Given the number of units and the charge per unit, it would cost you just for the product $741. Again, 906 is going to reimburse a maximum of $99, so that the hospital's minimum loss just for that one time, one patient, is $642.

So, as you can see, we have some real problems here. I'll make a comment on why we think that there are these discrepancies. These are projections of why we think there are discrepancies. We never were able to get the entire underlying database to go back in and re-analyze. But one of the problems is the differences in billing practices across hospitals. HCFA used the charge information from the hospitals. A patient comes in, HCFA bills--I'm sorry. The hospital will bill HCFA for the Medicare patient, and the bill may have one charge and it may have multiple charges, depending on the treatment given to that patient. But not all hospitals charge in that fashion. Some will charge the specific code. Some will charge varying codes or--I'm sorry, a general code so that there's a different way of billing HCFA, and that may have contributed to some of the problems.

During the analysis, HCFA also decided to exclude those bills that has multiple procedures, so that only the single-procedure bills went through the system. They also excluded the more expensive procedures by doing this process that they call trimming so that they took any bill that came in with charges that were three standard deviations above the geometric mean were systematically eliminated from the analysis.

So what you've got, what your problem is is that you've got a systematic elimination of the sicker patients and the patients with more problems and more procedures, and you're biasing your data downward to the less expensive patients.

Now, I wish I could give you, you know, a numerical analysis, but, again, we were unable to do that due to inability to get all of the data.

We are equally concerned--it's already been mentioned by Dennis Jackman and some others. This problem, the outpatient setting, it needs to be fixed. We would like to see the derivatives paid for based on the costs, essentially what some refer to as a carve-out. These are highly variable clinical conditions, so they don't meet the criteria of clinical similarity that's required in the Balanced Budget Act. They are also highly variable in terms of the doses and the sources of the product, so that in terms of use of both clinical and use of resources, it's not the same. And we are most concerned about ensuring an appropriate setting be available to the patients who need these products.

In studying and researching this, it's pretty clear that some of these patients must received this in an outpatient setting just because of the monitoring that's involved or other conditions. And just transferring that to a physician's office isn't going to work for them.

That concludes what I have to say, and if there are any questions, I'll be happy to answer them.

DR. NIGHTINGALE: May I open up the floor for any questions? Dr. Hoots?

DR. HOOTS: I think I can give you one source of error, which is based on experience with the DRG, on the pass-through for clotting factors. Part of the problem is the ICD9 code; 286 is a lump code for all congenital coagulation abnormalities. They sampled multiple hospitals around the United States, most of which may see one or two of the very mildest form of the disease. So there's an instant leveling, and they probably do what you also implied, which is when they have extreme outliers, like hospitals that take care of large numbers of these patients, whether it's primary immune deficiency at Johns Hopkins with Dr. Winkelstein, or hemophilia at large hemophilia centers, they were systematically not included, at least--or they were considered outliers and, therefore, their relative impact on the cost was diminished.

So that if you have an average hospital that sees one von Willebrand's patient every two months and they're treating with an intranasal AVP, for instance, and you project that over 40,000 hospitals, you come up with $99 because you've excluded all the real costs. It works if you're dealing with diseases like rhinorrhea and you're treating with a decongestant because you've got 400,000 or 4 million cases and it does equalize. It doesn't work for rare, expensive, chronic diseases. And we almost lost--for the inpatient DRGs, we almost lost hemophilia programs in the United States when they implemented the program. And it took two years of lobbying Congress to get that pass-through created.

Now it's more acute, and that's the reason I'm commenting directly because I think hospitals no longer have the type of reimbursement they had when the inpatient DRGs were implemented. And hospitals, particularly tertiary academic hospitals that take care of these very complicated, expensive diseases like primary immune deficiency, coagulation disorders, Alpha 1, have been squeezed ever so more tightly both by HCFA and by managed care. So what will happen, predictably, if this were to be implemented is that those hospitals immediately seeing the kind of cost deficits per individual that you saw would say: We can no longer afford this program, we are going to cancel the program, we're going to ask whoever is taking care of these patients to leave or not to take care of them because we're not going to allow them to be admitted; and if they show up in our emergency room, we're going to make sure that they get spread out over emergency rooms everywhere else so that we can share this loss.

Immediately, the people with expertise to manage these diseases will be either discouraged from managing these diseases altogether, or else the patients will be shunted to places where there are no people with the expertise to manage these diseases. And so the impact is instantaneous. It is profound. And that's the reason you've seen, I think, so much of a response from the selected targeted communities.

If we think we have problems with shortages, which we clearly do, if we superimpose onto that access problems that may be actually an order of magnitude greater, we will literally be having--well, it's just unthinkable. And I know--it's interesting. I read the entire September 8th Federal Register, which was tedious, to say the least. And there was one small allusion in one sentence to this potential problem, but the response to it was--well, we know we'll get responses. But there was no--you know, it was--and then subsequently scanning and reading not quite to the same detail the 1999 modifications where they went to a lot of trouble to correct typographical errors and to upgrade the coding system, there was nothing else said about the whole phenomenon.

So I don't know if that means that they finally consider this as a serious issue of access and, therefore, are prepared to do what you've recommended, which is to carve out. But I think it's incumbent on everyone who has passion about what we've talked about in the preceding hour about supply to have at least that amount of passion about access, because if there's supply and no access, it doesn't do us any good, anyway.

DR. NIGHTINGALE: I am not sure what could be added to Dr. Hoots' comments, but I open the floor to those who would wish to do so. Are there any other comments from the committee?

[No response].

DR. NIGHTINGALE: At this point let me make a programmatic announcement. It's clearly after 5 o'clock. We have come a long way. We have a long way to go. We do have one more speaker, Dr. Weinstein, who does not live in Washington and I suspect would not be able to present to us tomorrow. However, I believe that it is really in the best interest of the government that we preserve the quality of the discussions, the comments up to and including the last ones. I'd recommend rather than try to jam an agenda through, we do have the authority to delay, although not accelerate, agenda items that are posted in the Federal Register.

May I ask for an informal poll of the committee? Would you be willing to suspend the discussion after Dr. Weinstein's presentation and begin the discussion again at 9 o'clock tomorrow morning? Or would you like to pursue? By way of showing my own hand, I believe that we will have sufficient time tomorrow to discuss all the remaining subjects on the agenda adequately. But I solicit your input. Would anyone like to comment? Mr. Walsh?

MR. WALSH: I'd certainly concur with your recommendation, with the understanding that we're going to be able to make some specific recommendations or resolutions tomorrow.

DR. NIGHTINGALE: Yes, and in particular, I have substantial concerns about resolutions that are passed by any advisory committee, not only the one that I'm Executive Secretary of, after 5 o'clock. I think a study could be done of the quality of those recommendations, and I would predict its outcome.

With that, Dr. Weinstein, are you still with us? Thank you, sir.

DR. WEINSTEIN: Thank you, Dr. Nightingale. You are right. I would not be available tomorrow. I'm here today on vacation with my family and promised them that I would just be gone from 1 to 3 o'clock and then I would join them at the Holocaust Museum. I think I'll be in for a holocaust of a different kind when I get back to my hotel.

At the very least, I know I won't have to say certain things about the background of the Balanced Budget Act and HCFA's proposed rule. Already much of the background has been presented. Let me point out, please, that I have distributed a primer for those who aren't familiar with it.

This was originally prepared in December 1998 for presentation to the New England Region Red Cross, and, therefore, some of the numbers--all those numbers which say $229.19, which was the reimbursement for APC 369, have since skyrocketed to $325.49. In addition, 906 at that time was $73.98, and now we are fortunate to be offered $99.29.

I would like to say, first of all, that I do not believe that a carve-out of any kind is a solution to the problem that we're discussing. There are too many things involved here. We're not just talking about plasma products. We're not just talking about Alpha 1 protease inhibitor. We're talking about retuxin, remicade, albumin. We're talking about zulfran and kitril. All of those biological therapies, either plasma-based, they're recombinant analogues, or any modern biological therapy that has made life at least livable, if not tolerable, for patients with cancer and blood disorders, all of these will be reimbursed at the same rate of $99.29. Think about it.

How many individual carve-outs can be created to accommodate this? What I'm hoping this committee will advise the Secretary or the Surgeon General to advise the Secretary is that the whole thing makes no sense. It's wrong. HCFA knows this. They've been informed in detail by the American Society of Hematology, by the American Society for Apheresis, by the AABB and others, and they have the numbers. The analyses have been done.

They were originally called upon to prevent all, quote-unquote, unnecessary increases in health care expenditures. How is HCFA supposed to do that? How are they supposed to define "unnecessary increases"? They chose, therefore, to prevent all increases. And that's the conundrum that they began with.

So they have therapeutic plasma exchange, which the American Society for Apheresis has determined through its own research costs a hospital--costs a hospital, I'm not talking about charges now--anywhere from $1,450 to $1,640 to perform on a good day when albumin is plentiful. And for this they want to pay $329. It can't be done. It simply can't be done.

You've already seen the numbers for APC 906 infusion therapy. They will pay a hospital to start an IV in the outpatient setting, start an IV and hang D5, waiting for the real drug to arrive. For that they'll pay $99. When you hang the winrow or the retuxin or the IVIG, you still don't get any more money for it. This just can't be done.

What went wrong? HCFA used faulty models, as has been described by Ms. Ducca from the Red Cross. They made serious errors, mostly, I believe, on bad advice from their consultants from 3M. And they excluded the majority of treatments which represent the majority of patients who receive these expensive therapies.

I don't know anyone with a serious disease who gets one plasma exchange, period. It just doesn't happen. And I also know that in my own hospital, where we do almost 800 plasma exchanges a year, we bill for the plasma exchange, but the pharmacy bills for the albumin. So they didn't capture the product with the service, as has been described already. They made naive and unjustifiable assumptions, and yet they stuck with their model. And they focused on nursing costs, little fixed costs, and ignored the variable costs of providing the expensive products that go along with the services.

It has been estimated that of the $89 million spent in the previous year on blood services, HCFA left $17 million in in their new model and distributed the other $72 million throughout the health care system. So that when a patient comes to St. Elizabeth's Medical Center in Boston for IVIG infusion, the health stop down the street will get some of that money that should have paid for the IgG. And they feel that's justifiable because at least the money is still in the health care system. It's supposed to be revenue neutral the first year. This is crazy. It's absolutely crazy.

So where are we, then, in August of 1999? And why am I as a practicing hematologist here for the first time in my life, panicked that if I don't speak to anyone who will listen to me, this may all actually happen?

Well, for one things, I don't want to see patient groups fighting with each other over who gets the carve-out. I don't think that will work. I think it's silly for us to send products overseas when we have patients about to bare their teeth to determine which therapy is approved and which is not.

We know for IgG there are three major groups who have reviewed appropriateness of therapy. There's the University Hospitals Consortium, there's the NIH Consensus Conference, and there's FDA. They all have different lists. Which one are we going to choose? If we have product, let's keep it here, and let the President or the Congress explain to the public why policy demands we send scarce products overseas.

In the meanwhile, we have a convergence of interest. It's remarkable how under this threat industry, hospitals, physicians, and patients all want the same thing. We want to be able to get therapy, and we want it paid for with our tax dollars. That's not a difficult thing to get our hands around.

But HCFA's proposed rule provides no accommodation for this and, even worse, no accommodation for new technologies. Anything new, anything discovered a year after the proposed rule goes into effect will have to be pigeonholed into an existing APC. That means that it either is paid $329 or $99, unless it can be given sub-cu, in which case it's $38.

All outpatient blood services, biological services, therapeutic apheresis services, all parenteral biologicals will no longer be available, period. I know my hospital and all teaching hospitals in Boston, which despite increased business are losing money by the millions every--this year and next year, and on forward, they can't afford to take a loss anymore. So all these products will not be available.

My elderly patients with bone marrow failure will not be able to get leukocyte-depleted red cells and platelets in my clinic, nor will they get Procrit. They will not get Neupagen. They will get nothing because my hospital will not provide it.

Ron, tell me what I'm supposed to do. What are you going to do in Oklahoma? You know that there's no answer to this question. Jim, there's no answer to it if this goes forward.

So patients, elderly patients, will be given a choice. Hospitals will exercise their legal rights and make them sign a waiver saying we can't give you outpatient therapy, but we can admit you to the hospital for this. However, there's no guarantee that Medicare will approve this inpatient treatment. Therefore, you may be responsible for the bill. This is what hospitals are allowed to do.

They will do this. Patients will be admitted to the hospital for their blood transfusion, for their IgG infusion, for whatever it is. And, retrospectively, Medicare will disallow the admission, and the patient will receive the bill. And upon looking at that bill for $4,000 for inpatient treatment, the patient will have a simple choice: Do I pay my rent or do I pay my bill? Courtesy of the Health Care Financing Administration.

The irony is that tomorrow this committee will meet to discuss whether industry should recoup the costs of federally mandated blood safety measures by increasing the cost of their products. Why are you bothering to discuss this when Medicare has no intention of paying for these products, no matter what industry is going to charge for them? I find that ironic and frustrating, and I hope you do as well.

As scientifically advanced as we are, we have a premier medical system, health care capability, and we're developing a Third World distribution and reimbursement system.

I don't think, as I said before, that multiple carve-outs are the answer because I think it will be very complex. But I think that HCFA should be made to follow the law. I think the APCs are supposed to be grouped by clinical similarity and similar use of resources, and there's no way that transfusion of packed red cells and therapeutic apheresis or stem cell collection for transplant should be grouped together. They don't meet the criteria for similarity.

I think that HCFA has to be made to acknowledge that this rule, this proposed rule, is crazy. It won't work and it's damaging, and people will get hurt. And there can either be a cost pass-through, as has been proposed today that may work, or there can be a paired APC system, as they're trying to put together now for the service and the product with respect to chemotherapy. But I suspect that's unworkable as well because there are too many products involved. Or they can create a national fee schedule along the lines of the clinical laboratory fee schedule, which at least is something that can be reviewed every year and kept up to date.

I don't know what the answer should be. I'll leave that to others whose job it is to come up with a solution. But I beg this committee to advise those whom you advise not to allow HCFA to persist with this proposed rule. Everybody, including HCFA, knows that it won't work, that it will be damaging, and people will get hurt. And I hope someone will have your ear, and thank you for listening to me.

[Applause.]

DR. NIGHTINGALE: Dr. Weinstein, if all our speakers were as eloquent as you, we could proceed to midnight.

[Laughter.]

DR. NIGHTINGALE: Thank you for your comments.

Does the panel have any questions for Dr. Weinstein? Ms. O'Connor?

MS. O'CONNOR: I have one question. I don't know if you can answer it. Is there any way to estimate the total number of people who are involved in these? I mean, are we talking 100,000? Are we talking 10 million? To put something concrete--I think it's easier to get people to go along with something if you say there are between 10 and 15 million people who are affected by this versus 5,000.

DR. WEINSTEIN: Right. The bottom line is I can't give you the answer you seek, but I can tell you that last year there were approximately 180,000 apheresis procedures performed in the United States. There were about 12 million transfusion events. I know about a third of apheresis is performed in the outpatient setting, maybe 40 percent. If you add in all those who depend on IgG for autoimmune disease, for immune deficiency disease, et cetera, I think you'll be getting up to seven or eight figures, population.

DR. NIGHTINGALE: Are there any other questions?

[No response.]

DR. NIGHTINGALE: In that case, I would like to thank once again Dr. Weinstein and all our other speakers for their participation. It's been a most valuable day for the committee. And with the asset of the committee, I will use my powers under 41 CFR 101-6.101-19(e) and declare the meeting adjourned until tomorrow morning at 9 o'clock when we will continue with the same agenda item.

[Whereupon, at 5:31 p.m., the committee was adjourned, to reconvene at 9:00 a.m., Friday, August 27, 1999.]