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Blood Safety Transcripts

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

13th Meeting

HOW SHOULD THE GOVERNMENT RESPOND TO
THE CURRENT PUBLIC DEBATE OVER LEUKOREDUCTION?

Volume I

8:07 a.m.

Thursday, January 25, 2001

Hyatt Regency Capitol Hill Hotel

400 New Jersey Avenue, N.W.

Washington, D.C. 20001

PARTICIPANTS

Arthur Caplan, Ph.D.

Larry Allen
Michael P. Busch, M.D., Ph.D.
Rajen K. Dalal
Richard J. Davey, M.D.
Jay Epstein, M.D.
G. Michael Fitzpatrick
Ronald Gilcher, M.D.
Edward D. Gomperts, M.D.
Paul F. Haas, Ph.D.
William Hoots, M.D.
Karen Shoos Lipton, J.D.
Lola Lopes, Ph.D
Gargi Pahuja
John Penner, M.D.
Jane A. Piliavin, Ph.D.
David Satcher, M.D., Ph.D.
John Walsh

Paul R. McCurdy, M.D.
Stephen D. Nightingale, M.D.
Mary E. Chamberland, M.D.
David Snyder, Rph, D.D.S.
CAPT Lawrence C. McMurtry

CONTENTS

AGENDA ITEM

Welcome Roll Call

Comments by the Surgeon General
David Satcher, M.D., Ph.D.
Department of Health and Human Services

Conflict of Interest Policy at Advisory
Committee Meetings
Stephen D. Nightingale, M.D.
Executive Secretary, Advisory Committee on
Blood Safety and Availability

FDA Perspective
Jay S. Epstein, M.D., Director
Office of Blood Research and Review, FDA

THE CASES FOR AND AGAINST UNIVERSAL
LEUKOREDUCTION

MODERATORS:

Morris Blajchman, M.D.
McMaster University

Eleftherios Vamvakas, M.D.
New York University

DISCUSSANTS:

Harvey Klein, M.D.
National Institutes of Health

Edward Snyder, M.D.
New York University

James AuBuchon, M.D.
Dartmouth University

Walter Dzik, M.D.
Harvard University

S. Gerald Sandler, M.D
Georgetown University

Paul Ness, M.D.
Johns Hopkins University

PUBLIC COMMENT:

Jacquelyn Frederick
American Red Cross

Stephen Binyon
Baxter Corporation

Sam Wertham, Ph.D
Pall Corporation

Lawrence Petz, M.D.
American Hospital Association

Neil Blumberg, M.D.
University of Rochester

Jeffrey McCullough, M.D.
University of Minnesota

David Cavenaugh
Committee of Ten Thousand

Patrick Collins
National Hemophilia Foundation

Celso Bianco, M.D.
America's Blood Centers

Jim O'Connor
HemaSure, Inc.

Jeffrey Miripol
Terumo Corporation

Ronald Sacher, M.D.
University HealthSystem Consortium

Dennis Goldfinger, M.D.
Cedars Sinai Medical Center

Mary Foss
Breanndan Moore, M.D.
Mayo Clinic

Merlin Sayers
University of Texas Medical School
Carter Blood Care

Rich Vogel
Hemophilia Federation of America

Jason Bablak
Immune Deficiency Foundation

PROCEEDINGS

DR. NIGHTINGALE: It is 8:07 a.m. Good morning. My name is Stephen Nightingale. I am the executive secretary of the Advisory Committee on Blood Safety and Availability. Welcome to the Thirteenth Meeting of the Committee.

The agenda for this meeting, following Dr. Satcher's remarks, is to discuss how the government should respond to the current public debate over universal leukoreduction. There will be invited presentations on this issue this morning. This afternoon is devoted to public comment on this issue.

Tomorrow morning, Dr. Jong Lee of FDA will discuss his agency's current approach to this issue, including the Guidance to Industry on Leukoreduction that was posted on the FDA website Tuesday afternoon. Following Dr. Lee's presentation, the committee will discuss the issue and determine what, if any, recommendations it wishes to make.

After this, Dr. Paul McCurdy will summarize past efforts by the public and private sectors to monitor the United States' blood supply, and we will solicit comments from the committee and the public on this matter. We will continue to solicit comments after the meeting until about April 1, and we plan to hold further discussion and ask, pending approval by the incoming administration, the committee to determine what, if any, recommendations it wishes to make on this issue at the next meeting of the committee. That meeting will be on Thursday, April 26, and Friday, April 27th, 2001, at the same location.

Following this discussion, the floor will be open for old business and then for new business. Matters not related to the agenda items may be raised under old or new business, but not before.

I would now like to document the presence of the committee members for the record.

Mr. Allen? Mr. Allen is in transit.

Dr. Busch?

DR. BUSCH: Present.

DR. NIGHTINGALE: Dr. Busch is present.

Dr. Caplan is in transit. His train arrives at 8:05.

Dr. Chamberland?

Dr. Chamberland is present. Could you speak into the microphone for posterity and for legal recording, if you would, please.

DR. CHAMBERLAND: Present.

DR. NIGHTINGALE: Mr. Dalal?

MR. DALAL: Present.

DR. NIGHTINGALE: Welcome.

Dr. Davey?

DR. DAVEY: Present.

DR. NIGHTINGALE: Dr. Epstein?

DR. EPSTEIN: Present.

DR. NIGHTINGALE: Colonel Fitzpatrick?

COL. FITZPATRICK: Present.

DR. NIGHTINGALE: Dr. Gilcher?

DR. GILCHER: Present.

DR. NIGHTINGALE: Dr. Gomperts?

DR. GOMPERTS: Present.

DR. NIGHTINGALE: Dr. Goosby is unable to attend this morning. Dr. Guerra is also unable to attend. I usually don't give specific excuses. There will be two exceptions today. Dr. Guerra did wish to communicate to the committee and the public his regret that he couldn't be here. He has to testify before the San Antonio City Council today and tomorrow, and he tried to change, but could not.

Dr. Haas?

DR. HAAS: Present.

DR. NIGHTINGALE: Dr. Hoots?

DR. HOOTS: Present.

DR. NIGHTINGALE: Dr. Kuhn is unable to attend as well, but Dr. Kuhn cannot attend because he is pleased to announce, as he has asked me to do, that on Monday, January 22nd, that Jan and John Kuhn gave birth, actually his wife--

[Laughter.]

DR. NIGHTINGALE: --to Kristin Marie Kuhn, 4 pounds 8 ounces, 17 1/4 inches, and Joseph Kuhn, 4 pounds 6 ounces, 17 1/4 inches. Both are doing well.

The acting chair will entertain a motion of congratulations and best wishes of the parties. Do I see a motion?

DR. DAVEY: So moved.

DR. NIGHTINGALE: Dr. Davey motions.

DR. EPSTEIN: Second.

DR. NIGHTINGALE: Dr. Epstein seconds. I believe it's unanimous. I will communicate that on your behalf. We are very happy for them.

Ms. Lipton?

MS. LIPTON: Present.

DR. NIGHTINGALE: Dr. Lopes?

DR. LOPES: Present.

DR. NIGHTINGALE: Welcome.

Dr. McCurdy?

DR. McCURDY: Present.

DR. NIGHTINGALE: Dr. Piliavin?

DR. PILIAVIN: Present.

DR. NIGHTINGALE: I'm sorry. Ms. Pahuja?

MS. PAHUJA: Present.

DR. NIGHTINGALE: And Dr. Penner?

DR. PENNER: Present.

DR. NIGHTINGALE: Dr. Snyder?

DR. SNYDER: Present.

DR. NIGHTINGALE: Mr. Walsh?

MR. WALSH: Present.

DR. NIGHTINGALE: And Dr. Winklestein is unable. He has clinical duties today.

I will defer the reading and discussion of the conflict of interest statement until after the Surgeon General's remarks.

Dr. Satcher?

DR. SATCHER: Thank you very much. I want to join in welcoming all of you to this meeting. I was just thinking, I believe it was one year ago today that we met here, and it was in the midst of one of Washington's worst storms, so bad until the government was closed. But I was really impressed with the fact that so many of you persevered and, despite the weather, the Advisory Committee met here one year ago. It's just another example of the commitment and dedication of members of this group, and we appreciate that.

Now, these are interesting times in Washington, as you well know. And the good news is that this may be the last time you come in and have to remove a prescription from your seat before you sit down, a prescription from the Surgeon General. But, seriously, former Secretary Donna Shalala certainly expresses her deepest appreciation for the outstanding work of this Advisory Committee, and I join her.

I don't know if you know what my situation is, so I will try to tell you. I speak to you this morning really as acting secretary. Governor Thompson was unanimously confirmed as secretary yesterday, but has asked me to serve as acting until February 1st. So I'm in the role of acting secretary.

As assistant secretary for Health, along with the other political appointees, my resignation was effective January 20th at noon. On the other hand, to make this a little bit more complicated, as Surgeon General, I have a term appointment which goes through February of 2002. So you're not completely rid of me yet, but as you can see, things are changing.

We have two new members of the Advisory Committee, Dr. Lola Lopes, and Dr. Lopes is from the University of Iowa, and Dr. Rajen Dalal of the Chiron Corporation, and you have met them. I'd like to welcome both of you and thank you for your willingness to serve.

I would also like to welcome, once again, Mr. Larry Allen, Dr. Gomperts and Dr. John Penner, who have agreed to serve an additional term on the Advisory Committee.

In addition, I would like to thank Dr. Jim AuBuchon and Dr. Marian Secundy. I know Marian is not here. But they recently completed their terms on the Advisory Committee. I'm delighted that Dr. AuBuchon has returned to be a discussant on this morning's program. So welcome back, Jim, and we look forward to a continuing collaboration with you.

I'd also like to thank Dr. Paul Ness, Dr. Harvey Klein and Ms. Karen Lipton for the Presidential Award that was given to me by the American Association of Blood Banks at their annual meeting in November of last year. I'm sorry I was not able to be there to receive the award in person. I'd also to congratulate my colleague, Dr. Jay Epstein, who also received a Presidential Award from you at that meeting and certainly is a person who has been an exceptional public servant and continues to be.

A few minutes ago, really, I had my picture taken with Rory, the red cell, the mascot of the American Blood Center's program called "My Blood/Your Blood" campaign. The purpose of this campaign is to educate the next generation of blood donors about the need for blood donation and the personal satisfaction that comes from blood donation. I congratulate America's Blood Centers for this effort, and I'm happy to join with the National Heart, Lung and Blood Institute in endorsing it.

At the same time, I want to applaud the American Red Cross for its program aimed at high school and college students. And the program is called, "It's What's Inside That Counts." Both of these initiatives are really critical to our efforts to assure the continuing availability of blood in the future. Please let me know if there is anything else we can do to help either of you to make these programs successful. They are very important programs.

I'm also happy to see Dr. John Immanuel--does everybody know Dr. Immanuel? Where's John? Please stand. Welcome. He's from the World Health Organization. The World Health Organization has made blood safety throughout the world one of its highest priorities, and we're very pleased with that as we try to continually take a global approach to public health, and this is one of the most important aspects of that global approach.

But last spring Dr. Immanuel outlined his vision for the global collaboration for blood safety to this Advisory Committee. And I understand that the first meeting of his group was last November. Several people who are here today attended, and I understand it was a very successful meeting. Dr. Immanuel, we want to wish you and your colleagues in Geneva, and throughout the world, continuing success in this effort. We understand how critical this is and how critical our role in it is.

Before I get to today's agenda let me just say that I look forward to continuing to work with you as Surgeon General. And I want to just point out that, as many of you know, as Surgeon General I've had some areas of priority. Of course, one of them has been Healthy People 2010, the nation's health plan for the next ten years, where the two goals are improving the quality of life of Americans, especially older Americans, and, secondly, eliminating disparities in health among different racial and ethnic groups in this country.

In addition, we have released Surgeon General's Reports in several areas, and some of them are totally new. Of course, we continue to target tobacco use. But in July of 1999, we released the Surgeon General's Call to Action for Suicide Prevention, and a lot of work has gone on throughout the country in that regard. And in a couple of months we're going to, in fact, release the national strategy for suicide prevention.

In December of 1999, we released the first ever Surgeon General's Report on Mental Health, pointing out not only the magnitude of that problem in this country, but also the fact that we have the ability to intervene, to treat, to return people to productive lives and positive relationships. And the American people have responded quite enthusiastically to that, and that's going to be going forward.

We also released the first ever Surgeon General's Report on Oral Health in the year 2000, and likewise the response has been great to that.

Last week we released the Surgeon General's Report on Youth Violence Prevention, a major concern of people in this country. And I believe that report, which was put together by a very talented team of scientists and community leaders, will help to make a difference.

So those will continue, and I look forward to working with you on those. But I also want you to know that I will work very closely with you in pointing out to the American people the importance of organ and tissue donations, in general, and certainly the importance of maintaining a safe blood supply in this country. Likewise, the Hepatitis C Education program will be a priority of mine and supporting the look-back. So, in that regard, I look forward to working with you.

Today and tomorrow the Advisory Committee will consider the question of how the government should respond to the current public debate over universal leukoreduction. This morning Dr. Klein, Dr. Snyder, Dr. Dzik, Dr. AuBuchon, Dr. Sandler and Dr. Ness will recapitulate that debate for us here. And I'm grateful to them for their willingness to do so and to Dr. Blajchman and Dr. Vamvakas for moderating this discussion. You know by now that when I say we are listening, it's true, we're listening. Even when we're not here we're listening.

This afternoon will be devoted to public comment. We will listen carefully to everything that each of you has to say. At the same time, I hope that all of you participate in today's discussion. We'll remember how important it is for us, as we look at these issues, to look at them from a broad perspective, considering the scientific, the economic and the political implications of these recommendations. And I assure you that we will treat each of these with equal respect.

On tomorrow's program, I'm pleased that Dr. Lee will be able to discuss the guidance to industry that FDA released earlier this week on leukoreduction. And I appreciate the efforts that Dr. Epstein and his colleagues have made in developing this document and releasing it in such a timely fashion.

Finally, I want to thank, once again, all members of the committee, past and present, for all of the efforts over the past four years to really work to assure the safety and availability of the United States blood supply. As you can imagine, I have worked in government with a lot of Advisory Committees. This has been an unusually productive Advisory Committee, dealing with the very critical aspects of the health of the American people. And I just want you to know that we have appreciated your efforts and look forward to your future work.

Thank you.

I'd be happy to respond to any questions or comments.

DR. NIGHTINGALE: Dr. Satcher, thank you very, very much, on behalf of the committee. Dr. Satcher does not have to listen to the conflict of interest statement, but the rest of you do.

[Laughter.]

DR. NIGHTINGALE: Given the agenda of this meeting and its economic implications, the statement of conflict of interest regulations that govern this meeting is of more than routine interest, and I urge you to listen to it carefully. The following announcement is made as part of the public record of this meeting to preclude even the appearance of a conflict of interest by any participant.

It has been determined that all interests reported by the Advisory Committee members present no potential conflict of interest in relation to the discussion of universal leukoreduction. In particular, as specified in Title 18 of the United States Code 208(b)(2), a special government employee, which all Advisory Committee members are, may participate in the manner of general applicability; for example, advising the government about its policies regarding 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 member of a class.

The example given in 5 CFR 2640.203, which implements Title 18 of the United States Code at 208(b)(2) 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 the Advisory Committee's recommendations. The chemist's employer will be affected by the new standards only as a part of the class of all pharmaceutical companies or other research entities that are attempting to develop an AIDS vaccine.

However, if the discussions involve a specific product or a specific firm in which the member has a financial interest, that member should exclude her- or himself from the committee discussion, and that self-exclusion should be noted in the public record. In respect of 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.

The purpose of this meeting is to conduct a full and a fair discussion of the complex and contentious issue of universal leukoreduction as possible. For the invited discussion this morning, we have invited six highly respected transfusion medicine professionals whose views collectively represent the broad range of public opinion on this issue. And we have invited an additional two equally respected transfusion medicine professionals to moderate the discussion so as to ensure as full and fair a discussion as possible.

We have invited each of these individuals to present their own views and not as representatives of a group or of a corporate point of view. These individuals are invited guests and not special government employees. So we will ask them, as we ask any member of the public who speaks at this meeting, to disclose any current or previous financial arrangements with any specific product or firm upon which they plan to comment.

In the further interests of fairness, we have allotted four hours of this meeting for public comment. If an unintended consequence of this allotment is that we have time on our hands at the end of the day, we will adjourn for the day rather than begin discussion of the issues that are scheduled for tomorrow morning.

When I was planning this meeting, I was uncertain when or even if the FDA Guidance on Leukoreduction would be published. Since it was only published on Tuesday evening, which was too late for me to communicate it to all of the committee members, I would encourage the members and the interested public as well to use this time to review the document prior to the presentation by Dr. Lee tomorrow morning.

Is there any question that any committee member or any member of the public wishes to raise about the conflict of interest policies at this meeting?

[No response.]

DR. NIGHTINGALE: I see none. Thank you very much.

Dr. Caplan's train did leave 30th Street Station in Philadelphia at 6:30. He will be here momentarily. I will ask dr. Penner to act as the acting chair, as necessary. But I think in the interest of time and full and fair disclosure we can move on to the next agenda item, which Dr. Epstein wished to make a few comments.

Jay?

DR. EPSTEIN: Thank you very much, Steve, for the opportunity to provide a few remarks which I hope will help clarify the current situation with respect to FDA regulation regarding leukoreduction so that there are no misconceptions as we enter the discussion.

As many of you know, FDA has worked with the blood community and with the public to try to develop an approach toward leukoreduction as a product standard for a number of years. In March 1995, FDA convened a workshop on leukoreduction, following which the Agency issued, in 1996, a guidance document for industry covering product specifications, process controls and validation requirements.

Subsequent to that, in September of 1997, we discussed the effectiveness of leukoreduction for reducing the risk of blood transmission of cytomegalovirus relative to the use of cytomegalovirus antibody negative units. In 1998, the United Kingdom made a decision to adopt a policy of universal leukoreduction and a number of countries followed suit. Although, in many of these cases the potential, the theoretical potential, to reduce the also theoretical risk of variant CJD was the motivation for many countries to adopt a policy of universal leukoreduction, at FDA we thought it was appropriate for our country to consider whether leukocyte reduction should become universal based on its scientific merit.

We, therefore, brought before our own Blood Products Advisory Committee in September 1998 the question of leukoreduction. And the question that we specifically asked is whether the benefit-to-risk ratio associated with leukoreduction was sufficiently great to justify requiring the universal leukoreduction of all nonleukocyte cellular transfusion blood components, irrespective of the theoretical considerations for transfusion- transmitted CJD. I should also mention that because matters of cost are not part of FDA's mandate in considering product safety and effectiveness, this question was asked without consideration of cost.

So based on the issue of scientific merit and independent of any potential benefit for CJD, the committee voted essentially unanimously--13 in favor, none opposed, 3 abstentions--in favor of FDA developing a policy on universal leukoreduction.

Now, we are, of course, aware of the controversy that has surrounded both the scientific debate and the concern over cost and cost reimbursement raised by universal leukoreduction. However, we have issued an updated guidance which, as has been noted published earlier this week, it was placed on the World Wide Web on January 23rd. And this guidance establishes FDA's current expectations for standards applicable to leukocyte-reduced blood components, particularly in the area of product standards and quality controls.

We have also moved forward to facilitate the licensing scheme. Now, we have done this consistent with the advice of the Blood Products Advisory Committee in an effort to encourage the wider use of leukocyte-reduced products because of the known benefits and in consideration of additional potential benefits that I'm certain will be discussed at this meeting.

However, I wish to make very clear that the guidance document does not create a mandate or an obligation for universal use of leukoreduction. So the compliance with the guidance at this point is voluntary. The guidance, in and of itself, does not obligate either the industry or the FDA. However, it is a statement of the Agency's expectations regarding the necessary product processing conditions, standards to be met and quality controls.

So, again, being aware of the controversy surrounding the question of universal leukoreduction, what FDA seeks out of this discussion is a sense whether it is timely now to go forward with rule making that would require universal leukoreduction in the United States or whether some other approach should be pursued in consideration of the global economic and policy issues.

It is also our hope that the committee will be able to comment, in particular, about the more general problem of cost reimbursement as it affects opportunities for blood safety advancements, both now in relation to leukoreduction and in the future for other potential advancements.

So, again, Steve, thank you for the opportunity to provide this clarification because I think it would have been most awkward to go forward with a misconception where the Agency actually standards currently on policy.

DR. NIGHTINGALE: Jay, thank you very much. Does anybody have any questions for Dr. Epstein before we proceed?

[No response.]

DR. NIGHTINGALE: I am, in fact, delighted to see that there are not because I think, for the first time in the 13 meetings of this committee, we are, in fact, ahead of schedule. Several of the discussants this morning have already asked me if they really had to stick to 15 minutes, and I told them that I had asked them to condense their talks to 15 in the hopes that they could do so in 30.

[Laughter.]

DR. NIGHTINGALE: Again, for the morning, we want to have as full a discussion as we possibly can. On behalf of Dr. Satcher, the Department and all of us, thank you very much for being here.

And if I could declare Dr. Penner to be the acting chairman of the meeting, John, would you like to introduce the panelists.

DR. PENNER: Thank you, Steve. I think the panelists have already been introduced initially with Dr. Satcher, and I think we could probably proceed directly with Dr. Blajchman and Dr. Vamvakas to proceed with their program and call on the presenters as they wish.

DR. BLAJCHMAN: Good morning. I'm Dr. Mo Blajchman from McMaster University in Hamilton, Ontario, Canada. I'm very pleased to be here to moderate or to co-moderate this session with Dr. Steven Vamvakas, a very close colleague. We've worked together on this issue for many years.

As a start, first of all, as you've heard, there are six panelists this morning, and I'm not going to make any introductory remarks because our first speaker, Dr. Harvey Klein, is going to introduce the topic. And we're going to have the six speakers in the order that was listed in the original announcements: Dr. Klein, Dr. Snyder, Dr. AuBuchon, Drs. Dzik, Sandler and Ness, in that order.

As you've heard, each is intended to have about 15 minutes, and after each presentation we hope to have about a 10-minute discussion. We would like to keep the discussion to the issue on the table. There will be plenty of time in the afternoon for public comment, so we would hope that the questioners for each of the speakers deal with the topic that that person talked about rather than to give their opinion about the topic.

So I'd ask you all to keep to those guidelines. And Dr. Vamvakas and I will try to keep the controversial and the personal opinions out of it. We want to make sure that the facts and all of the relevant issues are put on the table for the committee to debate and make a decision on.

So without further ado, I would like to call on Dr. Harvey Klein. Just one other thing that I might mention. After the six speakers have given their talks, Dr. Vamvakas and I will each probably have about a five-minute summary. Dr. Vamvakas will speak primarily summarizing the con point of view, and I will try to summarize the pro point of view, and that's after the six speakers and the questioners have given their comments.

So with that agenda on the table, I would like to call on Harvey Klein. Dr. Harvey Klein is the director of Transfusion Medicine at the NIH here in Washington.

Harvey?

DR. KLEIN: Thank you very much. It's a pleasure to be here. I would like to point out that when I was originally invited, I was asked to give an overview and not limited to 15 minutes. And so I may take care of your committee's being ahead of schedule in short order.

In the overview, I'm sure that my own biases and prejudices on this issue will appear, and I'd simply like to point out that they are not the position of either the National Institutes of Health or of the American Association of Blood Banks, but they are my own.

The basic tenet of component therapy is to give the component that's required and only the component that's required. However, over the years, we're certain that there are other components in the blood that we do transfuse, and among those components are passenger lymphocytes that are present in virtually all blood components. So in this slide it simply demonstrates--whether you can read it or not--that in whole blood, packed cells, platelets by apheresis, platelet concentrates, there are a substantial number of white cells that are transmitted during the transfusion.

We haven't been terribly concerned about these in the past for several reasons. By and large, they haven't done a great deal of harm, and we really didn't have the technology to remove them and to quality control the removal of these cells. Over the last decade, both of those have changed. We now know that the passenger lymphocytes do have a variety of adverse effects, including febrile reactions, alloimmunization, a variety of cell-associated infections--viral, and bacterial and others--acute lung injury, graph versus host disease, rejection of solid organ transplants and perhaps immunomodulation. I'll discuss the major ones in some detail.

The first that I wanted to mention was febrile transfusion reactions. Many physicians say that, well, this is more of an annoyance to the patient, but that's because they're not the patient. These may be relatively mild, only a degree of elevation or they may be quite severe. We can't really predict which patients will develop febrile reactions from blood transfusions and only about 20 percent of those who do will have a second reaction to the next transfusion. These reactions are less common with red cells than they are with platelets and some have said less common with apheresis platelets, but that remains a debatable point. In addition to being an adverse reaction to the patient, these reactions frequently interrupt blood transfusion, result in an evaluation that takes time and funds and sometimes results in the blood being discarded.

Now, we've known since the 1960s that 80 percent of these reactions can be prevented by leukoreduction and by leukoreduction that used the technology of the 1960s and '70s. We now know that with the current technology, removing counts of less than five times ten to the sixth cells per component, we can prevent many, more than 90 percent, but not all of these reactions. We also know that we can prevent them by removing plasma from the cellular components, perhaps because there are components in the plasma released by the white cells that caused these reactions, but that is impractical. And we also know that we can't prevent all of these reactions by leukoreduction because the reactions are multifactorial. So much for febrile transfusion reactions.

The next issue becomes alloimmunization. And again we've known that when blood is transfused, patients may develop antibodies to any of the components--red cells, platelets, even plasma proteins and white cells. One of the problems is that when antibodies are developed to some of the white cell antigens, the HLA antigens among others, that the patient may subsequently become difficult to transfuse with platelets, occasionally even impossible to transfuse.

It's been known for many years that if you remove most of the white cells from the cellular components of blood, you can dramatically decrease the rate of alloimmunization to the white cell antigens, specifically the HLA antigens, on the surface of the cell. And if you concentrate on this final column, where leuko-reduced cells are compared with controls, you can see that in a variety of studies there's been a dramatic decrease in production of HLA antibodies by patients transfused with leuko-reduced blood--the largest such study supported by the National Institutes of Health, the so-called Trapp trial, which looked at more than 260 patients randomized, showed, again, a dramatic decrease, highly statistical significant in the production of HLA antibodies when leuko-reduced components were used.

As you might expect, there was no decrease in other antibodies, since alloimmunization to platelets, which were not removed from the component, does occur. And in addition to producing antibodies, these patients do become difficult to transfuse, are refractory to platelets. And once again, in the Trapp trial, there was a statistically significant difference, lower refractoriness to platelets in those who received leuko-reduced blood components. And these are just some of the data showing that the control group had a very high rate of alloimmunization compared to all of the treatment arms with leukoreduction and ultraviolet radiation in the treatment arms, and not only alloimmunization, but also refractoriness to platelets as well. Again, highly statistically significant difference in the leuko-reduced arms.

So, if I could summarize alloimmunization, leukoreduction reduces HLA alloimmunization of multiply transfused patients. I believe the data are fairly certain about that. Platelet refractoriness is also reduced, although to a lesser degree. And, of course, there is little or no effect on platelet-specific antibody formation.

Now, it hasn't been demonstrated that patient survival has been improved by this. But once again the numbers are relatively small. One would not expect to see that really in trials so small, and the patient population was a single population, acute myelocytic leukemia, and there are populations that might produce more of a risk.

I would also point out that one of the problems with all of these studies, and particularly the Trapp trial, is that when patients were admitted into the trial, they frequently had already been transfused. If a patient presents with an illness to a community hospital, prior to the diagnosis being made, frequently that patient will be transfused. If the transfusing physician gives components with leukocytes, that patient may be permanently alloimmunized before one recognizes that this might be a case where leukoreduction would be effective.

The next issue I'd like to mention is the transmission of cell-associated viruses, and I'll use cytomegalovirus as an example. This was first identified in the '60s. It is a white cell-associated agent. We know what the cells are. The exposure to this agent is frequent in the general population, and 40 to 80 percent of adults tested will actually have been exposed by antibody prevalence studies.

Ordinarily, when we want to give blood that's negative for cytomegalovirus, we use blood that's tested and found to be seronegative. We also know that the infection rate in susceptible patients who get a contaminated unit is about 30 percent. We also know that blood that tests seronegative may transmit infection. It's not 100-percent safe. What happens if you get a cytomegalovirus infection? Well, most of them are simply asymptomatic. You don't even notice it, the patient doesn't. It's a seroconversion. But there is a primary infection that looks much like mononucleosis. And a small percentage of the remaining post-transfusion hepatitis is probably due to this agent.

Certain populations can get severe disease, disseminated infections, pulmonary infections, gastrointestinal infections and infections of the eyes that result in blindness, and these are usually premature infants, patients who have inherited or acquired immunodeficiency syndromes, patients who have undergone solid organ transplants and are immunosuppressed and those who have received bone marrow transplants.

There's also a concern about reactivation of disease; that is, those subjects, the 40 to 80 percent who have already been exposed to cytomegalovirus, but seem to be normal. If they are transfused, perhaps their cytomegalovirus infection will be reactivated and cause a problem.

Now, I think what we know is that by compulsive removal of leukocytes from cellular components of blood, one can prevent exposure to cytomegalovirus, although recent studies have cast some doubt on this. Again, as we look at the variety of studies, the numbers of patients and the leukoreduction compared to controls, I think you'll find that while controls transfused almost always have high percentages of CMV seroconversion, those who receive leuko-reduced components, very, very, low.

The largest such study in bone marrow transplant patients carried out in Seattle using bedside filtration, and I'll come back to this in a little bit, while showing both seroconversion among the control group and the group that received leuko-reduced blood, showed that they were essentially equivalent. There's no statistical difference between the gold standard of testing and leuko-reduced components.

Once again, when a patient presents at a hospital, you may not know whether or not that's a patient who would have substantial harm from cytomegalovirus or whether that patient has already been exposed when the units of blood are first transfused. And if those units of blood have leukocytes and are from someone who has a CMV infection, that can be transfused.

Now, this isn't the only cell-associated virus. There are other herpes viruses; here is cytomegalovirus; HHV-5; there's also Epstein-Barr virus, which can be transmitted by transfusion. Studies haven't been done to show that leukoreduction prevents this. We assume that it at least reduces the exposure. There's also HHV-8, which has been associated with Kaposi sarcoma. This virus can be transmitted by blood. Whether it actually causes this disease is unknown and whether leukoreduction would reduce such a problem has not been studied. There are other cell-associated virus, and of course any emerging virus that's cell-associated would be reduced, if not prevented, by leukoreduction.

So, in summary, I think what I know is I believe leukoreduction dramatically reduces, but doesn't prevent, febrile reactions related to leukocytes. It reduces transmission of cytomegalovirus and other cell-associated virus. It dramatically reduces HLA alloimmunization and reduces platelet refractoriness.

Now, we've known for many, many years that patients who receive blood transfusion have changes in their immune status, changes that we can measure in the laboratory: decreased circulating lymphocytes, changes in subsets, changes in the kinds of lymphocytes and a variety of other factors that we can measure in the laboratory. What we don't know is whether any of these have any clinical significance.

But going back to the '60s, a very interesting observation was made, and that's that patients who were transfused developed what's known as delayed hypersensitivity. And this is a surgical study looking at patients who were negative for exposure to tuberculosis by a skin test, who were transfused with blood from donors who had a positive skin test and had been exposed to tuberculosis. And surprisingly, one week, four months and even eight months after transfusion, the previously negative patients who had received positive donations became themselves positive. Something in the transfusion had transmitted passive immunity, lasting as long as eight months or longer.

And with some elegant studies by Dr. Michael Busch several decades later, we've seen that lymphocytes, which are in cellular blood components, when the blood is transfused, they persist in the circulation, they may decrease and then reappear in the circulation, and in this particular study that Dr. Busch and his associates published, for a week or more.

Subsequently, Dr. Busch looked at trauma patients who had no other disease but trauma, were transfused and had markers which could be followed by molecular biology, techniques, demonstrating that some of these patients had donor lymphocytes circulating for a year, a year and a half and longer. Now, those lymphocytes may not have done any harm, but they are present and circulating.

We also know that blood transfusion seems to be associated with a variety of immune changes. Patients who have been transfused with allogeneic blood and receive organ allografts, hearts, kidneys and perhaps livers, the allograft appears to survive for a longer period of time. There has been some literature on recurrence of malignancy, susceptibility to infection that suggests that somehow the immune system, if not suppressed by transfusion, is at least changed.

There is evidence in the laboratory of viral reactivation, CMV, HIV, after transfusion, but clinical studies have not confirmed this. And then there's a syndrome known as graft versus host disease, which I'll at least touch upon.

In the '80s, retrospective studies looked back at patients who had had cancer resected, primarily colon cancer, but a variety of other cancers as well. And the observation was made that in some of these groups, patients who had received blood transfusions had a shorter cancer-free survival and shorter overall survival than those who had not, suggesting to some an immunosuppressive effect of blood, suggesting to others that this was simply an artifact, that those who required transfusion had more extensive disease.

But on the basis of some 70 observations or more, controlled clinical trials have been carried out. Unfortunately, it's very difficult both to carry out such trials, and now that three have been carried out, to interpret the results. Those trials are on this slide--they may be difficult to read--a study by Oliver Busch, a study by Heiss in a single institution and a Dutch study. And I think if one looks at these studies carefully, two of which were negative; that is, no difference between either transfused patients or patients transfused with blood that was leuko reduced and those who are not, there was no change in either survival or tumor-free survival. One study found a significant difference.

During the course of these studies, which I find difficult to interpret at this point in time, the observation was also made that patients who were transfused or patients who were transfused with blood containing large numbers of leukocytes may have more frequent postoperative infections. I have a variety of studies on this slide from Denmark, studies from the Netherlands, and studies from the United States, which we can discuss in some detail, but I'll just show you a little bit of the data.

These are data from the Danish study looking at infection rates after transfusion and leuko-reduced blood, allogeneic blood and no transfusion at all, showing that blood that had its white cells removed was equivalent in a low postoperative infection rate and statistically significantly lower than those who received blood that had more leukocytes in it.

If one looked at the kinds of infections or reoperation in these patients, once again, leuko-reduced blood was essentially equivalent to no transfusion and statistically lower than patients who received allogeneic blood.

And finally in one somewhat controversial study looking at postoperative mortality in a group of patients who received either allogeneic blood that wasn't leuko reduced or fresh or stored leuko-reduced blood in cardiac surgery patients, mortality was decreased in those patients who had the leukocytes removed from their blood--an interesting observation.

My conclusions, from looking at those data, was that leukoreduction may reduce the immunomodulatory effects of blood transfusion, it may reduce postoperative infections and most of the data lean in that direction, but it's certainly not clear-cut, and it may reduce the mortality in some subsets of surgical patients who receive four or more units of blood, but this particular observation needs to be confirmed.

Now, how much leukoreduction is enough? The answer to that scientifically really isn't known. We have some data from animal studies suggesting what the levels ought to be, and now we have some studies in man that suggest that the levels we're using are probably low enough. This slide was prepared prior to the new guidance 24 hours ago by the FDA. The U.S. standard had been fewer than five times ten to the sixth leukocytes in all components tested. And with a component recovery, red cells or platelets of greater than 85 percent of what one started with, the new guidance is closer to what one sees with the Council of Europe, looking at less than one times ten to the sixth cells and putting together a different standard for quality control.

There has been the issue of whether leukocytes should be removed prior to the storage of the blood or whether it's sufficient to send a filter and a blood component up to the bedside, so-called bedside leukoreduction versus laboratory or pre-storage leukoreduction. Leukoreduction in the laboratory, especially pre-storage, is done under much more controlled conditions. The laboratory performs its quality assurance and quality control studies, which are not done when units are leuko reduced at the bedside. There are changes that occur in the blood components when they're moved from the laboratory to the bedside, which might alter the kind of leukoreduction that occurs with bedside filtration. During the course of storage of blood, cytokines and other components may appear from cells in the blood. And if those cells are removed prior to storage, cytokines don't accumulate.

And finally, bedside manipulation of blood components may result in adverse reactions in at least one kind of reaction; a severe hypotensive reaction due to a generation of bradykinin components has been reported in bedside leukoreduction, but not in leukoreduction performed in the laboratory.

A final word about adverse reactions, and that is passenger leukocytes during certain conditions, especially in highly immunosuppressed individuals, but also in individuals who are tissue close or tissue identical, the immunocompetent lymphocytes may engraft and may cause a disease known as transfusion-associated graft versus host disease. In this disease, the mortality approaches 90 percent.

Now, we don't believe that leukoreduction using the current technology is sufficient to eliminate transfusion-associated graft versus host disease. And those patients who are at risk, blood components need to be irradiated. However, it may well be that some component of graft versus host disease is, in fact, reduced by reducing leukocytes below the levels that we currently are using. We simply don't know that.

There are a number of current issues that remain. Is there a scientific justification of using universal leukoreduction rather than leukoreduction just for those patients that we know require leukoreduction? Well, that's what we're here really to talk about today.

Bedside filtration versus blood center pre-storage filtration, I think that issue is settled, and I don't think that there's any reason to believe that bedside filtration should continue, except when pre-storage can't be performed. Licensing criteria, implementational logistics, and then of course there is the economic burden of unfunded mandates. And certainly there are failures of filters. We know that about half of individuals that have sickle trait don't filter well or when they filter, don't leuko reduce well. And that's an issue that we at least have to address.

So let me conclude with what I see as the advantages of universal leukoreduction, reduction of febrile reaction, reduction of alloimmunization, and white cell-associated infections, as well as eliminating some of the micro aggregates, which aren't eliminated by the standard filter that we use at the bedside.

Prevention of inadvertent exposure, that is of patients who you don't know will require leuko-reduced blood when they first present, but whose barn door may be left open if you give blood that isn't leuko reduced; interdiction of emerging cell-associated agents, viruses and others by leukoreduction; and, finally, there are certain operational efficiencies that are involved in having only one kind of blood component on your shelf, leuko-reduced blood, compared to two different stores.

There are disadvantages of universal leukoreduction. You do lose some of the cellular components, some of the red cells and some of the platelets, 10 percent, approximately, when you leuko reduce; there are these adverse reactions of the bedside filters; there is filter failure that was talked about; and, finally, there is an economic burden. Some have said this is the cost. Perhaps it's an issue of reimbursement.

Thank you for your attention.

[Applause.]

DR. BLAJCHMAN: Thank you very much, Harvey. I will entertain questions specifically to the content of this presentation. I think the format is to start with the members of the committee and then open it to the public.

Questions from the committee to Dr. Klein?

DR. DAVEY: Harvey, could you maybe touch a little more on the problem with sickle-trait blood. Maybe other speakers will, but could you let us know a little more about that.

DR. KLEIN: Well, this is an emerging issue, and it's been recognized that during the course of filtration a small number of units either don't filter at all or don't filter very well. As it turns out, up to half of those units come from blood donors who carry the sickle gene, sickle trait. About 10 percent of African Americans carry this gene. So that it becomes difficult, in terms of the blood that is either discarded because it hasn't filtered at all or a question of those units that filter, and you may not know that they're not leuko reduced. Some have advocated testing for sickle trait, and this is a strategy that's been used at some blood centers.

Why this occurs isn't clear, and a great deal of effort is going into looking at that. It appears to occur with virtually all of the filters. In many sickle-trait donors, it occurs every time they donate, but it does not occur with every sickle-trait donor, about half. We really don't know why.

DR. BLAJCHMAN: Other questions?

Mike Busch?

DR. BUSCH: Yes, Harvey, you alluded to the issue of CMV and the controversy over the Bowden study. I'm just wondering what your personal assessment and the NIH policy is with respect to substituting leuko-reduced blood for CMV antibody-screened blood, and also just to comment that the FDA guidance, I see, has indicated that if you're going to use blood that's CMV safe, you actually need to validate the individual product as leuko reduced, meaning the standard, which would be much more expensive than antibody screening of that unit. So I'm wondering what your feeling is about that issue.

DR. KLEIN: Yes. The Bowden study, of course, did use bedside filtration, and we believe that there may well have been filter failures. And when I say filter failures, it's not always the fault of the filter. In the past, we have used bedside filtration, and occasionally I would find the filter on top of the refrigerator at the bedside, so that it probably didn't do much good for the unit of blood that had already been transfused.

So we believe that if appropriate quality control is done in pre-storage leukoreduction in the laboratory, that blood that is leuko reduced is equivalent to tested blood, and we use them as equivalent in our laboratory.

We do process control of our testing. We don't test individual units of blood going to patients for CMV purposes. We don't count each individual unit. And I presume that I'll be commenting as an individual, although probably not as an institution, on that particular part of the guidance.

DR. BLAJCHMAN: If I could take the prerogative as chairman to make a comment that might be of interest to the members of the committee relevant to the last question, as most of you probably know, Canada has been universally leuko reducing all its products, cellular blood products, since July of 1999. So we have almost an 18-plus-month experience.

This issue of CMV testing of leuko-reduced blood products for patients particularly at risk was discussed at a consensus conference held in Canada exactly a year ago last January. And the proceedings of that have recently been published, and the actual statement will be published in Transfusion in the next couple of months. I'm not sure exactly of the publication date.

The decision of the consensus conference, which was not unanimous--of the ten panel members, seven voted in favor of continuing to do serologic screening, even when leuko-reduced blood is provided, particularly for patients that are immunosuppressed like bone marrow transplant patients. So because of the filter, the failure of preventing, completely preventing transmission both by leukoreduction and by serologic screening, the consensus conference recommended, not unanimously, that even in the face of leukoreduction, that CMV screening should be continued to be done for selected groups of patients.

Jay?

DR. EPSTEIN: I just wanted to comment on two points. First, I should have made clear that the guidance document that FDA published this week is a draft. And at this stage it is not intended directly for implementation, but only for comment. So we certainly welcome comments on the document.

The second is that the position taken by the FDA with regard to pre-storage leukocyte reduction versus bedside leuko reduction, is that pre-storage leukocyte reduction should be generally preferred. So we recognize that there may be some handful of instances where, for whatever reason it's impractical, but we are in agreement with the opinion of Dr. Klein that data have demonstrated superiority of pre-storage leukocyte reduction.

DR. BLAJCHMAN: Dr. Hoots?

DR. HOOTS: With regards to HLA alloimmunization, are there any studies, are there any modelings that have been done in terms of, obviously with senescence of humans you get mild immuno incompetence over time, towards the ninth/tenth decade let's say, is there any suggestion that complications related to alloimmunization will go up related to aging?

DR. KLEIN: I know of no such data, but that's complicated by the fact that there are clearly alloimmunization rates, depending upon the disease. And, again, if you go back to old data in the '60s, you find that patients with acute myelocytic leukemia may have a 30- or 40-percent alloimmunization rate with multiple, multiple transfusions. It may be 70 to 80 percent, if you're an aplastic. Though none of the studies that I showed you were with aplastic anemia. But everyone who takes care of patients who has aplastic anemia know that this is an enormous problem when you have one patient who's alloimmunized and refractory related to alloimmunization. One of our patients this week had a cerebral hemorrhage.

DR. BLAJCHMAN: Dr. Penner?

DR. PENNER: Harvey, platelet survival data I know is out there, but I'm not recalling it with the leukoreduction. Can you comment on that?

DR. KLEIN: There really doesn't appear to be any damage to the cells with leukoreduction, either to platelets or to red cells.

DR. PENNER: And then what about the numbers--

DR. KLEIN: Excuse me. If I could just say there are some data that suggest that by pre-storage removal of the leukocytes the blood components are, in fact, superior because of substances released by the leukocytes into stored blood over time.

DR. PENNER: And then maybe you would comment on the numbers game. We used to do some crude separation by sero aggregation many years ago and felt that we weren't really separating out a lot of cells, but we felt it had an impact. And the data on numbers, how solid is that right now?

DR. KLEIN: I took out my slide showing different preparations. By spinning and buffy coat removal, you can remove about a log; with washing, a log to a log and a half; with freeze thawing, perhaps two logs; with current filters that we're using, three logs/four logs. You can really get the numbers. Where the problem becomes counting the cells in quality control, and the filters are so efficient in doing that, really, that using the one times ten to the sixth number is not going to really be an issue in terms of the technology, in my opinion.

DR. BLAJCHMAN: My co-moderator, Dr. Vamvakas, has a question.

DR. VAMVAKAS: I'd like to go back to HLA alloimmunization. You showed eight studies I think enrolling patients with hematologic malignancies receiving multiple transfusions of both red cells and platelets. And we know that in these patients leukoreduction does, in fact, reduce HLA alloimmunization. But is there any reason to believe that should we leuko reduce the blood that goes to surgical patients, trauma patients, the 90 percent of patients that we transfuse, there would be again a reduction in the prevalence of alloimmunization?

DR. KLEIN: Let me answer that by saying there's obviously reason to believe this from animal studies and from multiparous women who obviously are otherwise normal and become exposed to their child's antigens and become alloimmunized. Are there good data on other populations? No, there aren't good data.

DR. BLAJCHMAN: There's a question over here. Sorry. I don't know your name.

COL. FITZPATRICK: It's Mike Fitzpatrick.

Harvey, back on the log reduction levels, is there any data, are there any studies to indicate what level of reduction we need to achieve what we're looking for?

DR. KLEIN: No, I think that's a terrific question. And the answer probably is we selected these levels primarily based on animal studies and some early studies where we saw that a log reduction or leukocytes in the range of ten to the seventh probably wasn't enough. There doesn't seem to be much of a lower limit, although some animal studies say if you take out every last leukocyte, there are some adverse immunologic effects in animals. But we're not going to get that far.

So it looks as if there's a broad range, but we can't answer either the question of how much is really the magic number, the red line, or how frequently you can give how much, over what intervals, that will reduce alloimmunization, prevent CMV infection, et cetera, et cetera, et cetera. Those studies haven't been done.

DR. BLAJCHMAN: I think we'll go for a couple of minutes to entertain questions from the audience. There will be another opportunity later on to ask questions, so there will be that opportunity.

When you ask a question, there's a microphone. Please identify yourself and where you're from. Any questions from the audience?

[No response.]

DR. BLAJCHMAN: If not, I think we'll move on. Thank you very much, Harvey.

Our second speaker this morning is Dr. Ed Snyder from Yale University. Dr. Snyder is past president of the ABB, and he'll enlighten you with his point of view.

DR. SNYDER: Thank you very much, Dr. Blajchman. I'd like to express my appreciation to Dr. Nightingale and Dr. Caplan for the privilege of addressing this group about our experience at Yale. I actually have a much simpler task than some of the other speakers in that I don't have to explain why one should switch to leukoreduction. All I need to do is explain what we did at Yale, which is what I intend to do.

The question is, is the switch to universal leukoreduction ivory tower or is it just better medical care? A little bit about Yale so you can understand what we're about, to compare with other institutions. We were founded a long time ago. We have a 900-bed tertiary care facility that includes the Yale Children's Hospital and obviously is associated with the Yale School of Medicine.

I think it's particularly important, considering what I've been doing for the 22/23 years of my academic career, to state up front clearly my conflicts of interest. I am a paid consultant and have been on advisory boards to a whole slew of companies, most of which make the filters or leuko reduce the products that are used in the United States today. The asterisks refer to companies that I am not currently advising this particular year, but I am clearly for Baxter & Pall, Cerus and Terumo. And, in addition, I have current research grants for these four companies listed.

I do not own any stocks, options or equity in any of the companies. And if the companies that I do consult for sell ten million filters or one filter, it doesn't have any effect financially. This is important in view of I think some comments that were raised during some ABB workshops about conflicts of interest. So I wanted to state this clearly up front.

This is, by the way, what our lab does at Yale. We provide a forum for corporations to obtain data that can be used in support of FDA licensure, among other aspects.

A little bit about the patients we transfuse at Yale. There's about 7,400 patients transfused a year. You can see it going from 1993 to the year 2000. We use approximately 50,000 units of blood products a year, a little higher during the heyday of our liver transplanters and then down less as they have wound down. So we're using about 45,000 products during the year. Our red cell usage is about 23,000 units a year. And you can see this going, again, from 1988 to the year 2000.

And then the question is how do we leuko reduce and what are we currently doing? Well, prior to 1998, 20 to 30 percent of the blood we transfused our patients were leuko reduced using bedside filtration. In April of '98, we switched to pre-storage leukoreduction technology. Our cell supplier is the Connecticut Red Cross, and that's where we get all of our blood from, which would imply by sole supplier. In January 1999, we made a commitment to 100-percent pre-storage leukoreduction, and I'll go into that a little more now.

So what was done? We made a commitment to 100-percent pre-storage. And I have been doing work for corporations that make filter products since 1978 when I started at Yale. So this was not motivated by financial gain or anything other than just, as you will see, an interest in improving what we believe is the public health of the patients at our institution.

The commitment we made in January, in May 1999 is when it was implemented. So the blood bank made its decision in January of '99 to go to 100 percent. The Transfusion Committee was consulted, and in March of '99 ratified this concept. It was brought forth to the hospital medical board, which ratified it in April of '99.

Where were we going to leuko reduce? All inpatient and outpatient areas, and obviously at such a hospital we have a full clinic with oncology patients and so forth.

How were we going to fund this? Well, first, was by cost shifting, that is, we would, instead of paying for CMV testing, we would apply those dollars to the cost of the filters; we would have changes in transfusion policies, which I will discuss, including better monitoring of utilization, indications of using these products for all the patients; internal blood bank budget reallocation. We did that. We took areas that we thought were less useful and applied it to the areas which we believed would provide an improvement in medical care.

Major impact was a decrease in wastage by increasing efficiency, decreasing our outdating. And the distinction again, wastage are products that are prepared for transfusion, entered and not used or sent to the operating room and expire unused or returned to us later in the evening, as opposed to outdating, which are units that sort of expire on the shelf without having been released from the blood bank. This relates to inventory control and so forth. So there were efficiencies there to look at.

Decreased utilization. Again, we had a fairly low utilization. We audit approximately 36 blood components a month--I'm sorry--probably 36 audits a year. We audit every blood product that goes out in the institution, all transfusion reactions, we audit red cell--we pick a day and audit every red cell platelet and plasma and cryo unit that was used that day to see if it was indicated. So those 3 times 12 months is 36, plus the additional ones that are done by the Quality Assurance Department at the institution.

And I stress this, that no new monies were allocated. We did not get a largess from the institution. We were made to internally make this commitment. And why did we do it? We believed there was a sincere improvement in blood safety and quality, and improvement in patient care, and improvement in the public health in the City of New Haven. We knew we were not going to cure cancer. We knew we were not going to save the world. We were trying to see if the cost of this implementation would have a positive impact on the health care of our patients in using our own cost-effective analysis, which I will show you.

This slide shows, it's a little hard to see in red are the units that were regular units; blue is the pre-storage leuko reduction. This slide starts I think October '98. And prior to April is when we switched to pre-storage. So all of these units are pre-storage. And as you can see, it took us--we implemented it sometime around April or May, which I think is here, and it took us almost a full year or more to get to 100-percent leukoreduction, and we were using bedside filters during this time in between. So we're now at 100 percent. These are for red cells.

So how did we do this? Well, we had an immediate cost savings by stopping CMV testing. It would be a bit of a concern, reading the draft document, where every unit would now have to be tested for this purpose. But, regardless, we stopped CMV testing and used those dollars, since the CMV testing approximated filter costs in our area.

We decreased outdating and wastage, but it was slight because we had a pretty good effort with red cells. So it was only about .5 percent outdating and wasted, but we did due diligence in trying to decrease that. Increased monitoring of red cell usage, we were monitoring and making sure the transfusions were appropriate, again, by stepping up using our fellows and our residents, which we have the luxury to do. We stopped using bedside filters and could shift some of those dollars, but there still was a cost, and the cost was $280,000 for the conversion.

This is a slide showing our CMV seronegative use. These are CMV sero-tested negative units. And the conversion was again sometime around here, and it took a while, but now we're--we still have some. Because of the blood shortages, it's sometimes difficult to obtain blood that's pre-storage leuko reduced. So this is what we have done up to this point.

Well, as part of my due diligence, I pursued to see what other hospitals in the United States were doing as well. And I came across this photograph in the newspapers which showed Superman receiving a blood transfusion. One of my colleagues, upon seeing this, said, "Well, there's your answer. Superman doesn't get leuko-reduced blood. There's no filter in the line."

I was chagrined. So I actually called the Metropolis blood center, spoke to the director, my good friend, Jarriel [ph], and I asked him about this, and he said not to worry, pre-storage leukoreduction.

[Laughter.]

DR. SNYDER: So that clearly explains why there is no filter. But ever mindful of the FDA guidance, 606.122, paragraph B, to use a filter in the administration equipment, if you look closely, there are 270 micron filters right over there.

Lest you think, however, that I am biased by my friendship, let me point this out, that this photograph also shows Lois Lane donating double the usual amount of blood and her saying that she'd gladly give it all. She doesn't want to go on living. So I bring to the FDA's attention that the Metropolis blood bank may have some conflicts as far as the validity of the donor screening and also their SOP for blood donations.

DR. SNYDER: Our platelet pool history goes back to prehistoric times, if you will. We used to use a twelve-unit pool, we then used ten, nine, eight, six, five, in response to primarily budget reductions, improvement in the quality of the product provided by the Red Cross.

Currently, a unit of random donor platelets, which is what we use almost exclusively, is about eight times ten to the tenth. So that has allowed us to go to a four-unit pool, which is what we have now, and still have a product that we believe is acceptable.

In the future years, we're going to probably switch to a virtual platelet transfusion where I just show a picture of platelets to people and bill them for my time.

[Laughter.]

DR. SNYDER: Clearly we can't go below four, and I have made sure the institution is aware of this, but this drop from five to four--now, obviously if people need additional platelets, we give them two pools, but what effectively happens is instead of the post-transfusion count going up to 80,000, let's say it may go up to 60,000, which is sufficient for most of the clinical needs.

Obviously, we have more blood products available and the proof of the pudding would be in the number of units of platelets we transfuse, and it has dropped. We use about 5,000 pools a year; it has dropped about 5,000 units; and there was a major savings.

Our ability to monitor this, we were not sure this was going to work well, but we are currently using, as I say, a four-unit pool, and our patient population seems to be doing just fine, being closely monitored.

The way we transfuse platelets at Yale, we start off with pooled random donors with pre-storage leuko-reduced platelets that are provided by the Red Cross.

If that doesn't work, we then go to compatible--cross-match compatible random single donor platelets, which are provided again by the Red Cross, which are process leuko reduced.

Then if that fails, we will then go to HLA-matched single-donor platelets. We have evidence of HLA antibodies, after appropriate allo-screening.

If that fails, we then often go back to random single donors and what I call a political apheresis where we do it to assure the clinicians that we're trying our best and we'll try one more time before we go back to random donors, because there is still this magical thinking among some clinicians that randoms are better than pooled.

If that fails, we then go back to pools. Further problems will lead us to a pooled drip where we use three units every four hours through an electromechanical infusion pump which basically gives 18 units a day and allows the clinicians to have some platelets running in under the concept of when all else fails, do something. That seems to work generally. And then sometimes we'll switch to IV immunoglobulin if things get truly disastrous or we get to the magical areas, aardvark tongue, eye of newt, staph proteinate columns and God knows what else.

We actually had very few of these kinds of problems since we have started using leuko-reduced products. We have much fewer of these difficult patients like the type that were mentioned by Harvey.

We did have one young woman when I first came to Yale who had aplastic anemia and had antibodies and had severe menometrorrhagia and also intraocular bleeding, and Dr. Bovey, who was the director at the time, hoarded about 60 units of platelet to try to overwhelm her anti-platelet and HLA antibodies, and we gave her literally 60 units of obviously volume-reduced platelets in a day and failed to get her platelet count up above 8,000.

So when you have such patients, they are almost impossible to treat. Certainly today, it would be very, very difficult to hoard that number of--many units of platelets, but I think the point is well taken: It's better to prevent than it is to treat.

So our random donor platelet usage here, this is about 20,000, 25,000. Again, what you see here is the drop in the pool size. These are the number of units that we're using.

Our single donor platelets--this increase in the year 2000 is related to the fact that we've been doing a study for a company looking at pathogen inactivation, which uses a single-donor product. So that increase is not typical, but is related to the study.

So how do we at those platelets? Well, the transfusion committee ratified 100 percent again in the April-May time frame I mentioned. Prior to June '99, we have 30 percent leuko-reduced CNV negative at the bedside. We changed to 30 percent pre-storage leukoreduction in June and had a commitment to 100 percent from the supplier.

This--in green, you see here the number of platelets that were bedside leuko reduced, and then it was switched over in blue to pre-storage leukoreduction--I think this says about June, I think, if I can see--and as you can see, it took us a while to get to 100 percent. So we are now transfusing 100 percent leuko-reduced red cells in platelets.

Again, the immediate cost savings--we stopped CNV testing, which was okay with our oncologists. We checked with them. There was some reluctance for patients for allo bone marrow transplants. We did speak to several transplanters at institutions where they are using pre-storage leuko reduced under full CGMP and they didn't have a problem with it, and knock on pressboard, I guess, or wood, we haven't had any problems.

Our patients are monitored constantly for seroconversion with not just antibody testing, but urine and swabs and so forth, looking for antigenemia.

So we have a full surveillance of patients, and it's not that we're missing them or ignoring them. A transplant patient who would get CMV obviously is not kept secret. They get extremely ill, as you are well aware.

And again, the CMV testing was cross-shifted to cover the filter, stopped using bedsides, decreased the pool, which also fit into the reductions for the general hospital budget, and we improved--the fact that the Red Cross was able to supply us with a four-unit product that was acceptable for our needs clinically fit into this as well.

The major benefit we had was a decrease in outdating and wastage. Yale is often asked to be sort of Blood Center South. We're asked to supply blood products, platelets and so forth to a variety of institutions. We've stopped doing that generally. The Red Cross' responsibility is to provide blood products for other hospitals. And we cut down, based on the fact that we eliminated multiple parallel inventories. We didn't have CMV negative leuko reduced, CMV negative non-leuko reduced, leuko reduced not CMV tested, not CMV tested non-leuko reduced. It was extremely confusing and we had a lot of products that obviously would outdate.

By eliminating that, we were able to decrease from 13 percent to 3.2 generally our outdating, which was the major financial saving, plus the loss of about 5,000 units of platelets by decreasing the pool size.

So that only CMV safe products were in inventory, we lowered our trigger to 10,000, and the cost of conversion was zero. And we were able to do this. There are people who will come up here and say, well, that's great that Yale can do this. We can, we have already done this. And as I say, this is what we did at our institution. We found a way to cover the cost and 280,000 is admittedly not insignificant.

So let's look at what results there are. Let's look at some data. All of these will have a blue line which goes like this, which is the percent of leukoreduction seen on the right-sided ordinate. So our percent of leukoreduction here--I think it's about April or May as we worked our way up to 100 percent.

This is the percent of reactions. For red cells, it's the number of reactions per month over the total number of units and we were using about 1,600 units of red cells a month. So each one of these bumps--I think that says one--what does that say? I can't see that number, but it's--.05. It's .06 is roughly one reaction. So as you can see, these are allergic reactions, because the idea was if we had a decrease in febrile, that's great; maybe you're just not looking at the patients anymore; you threw your thermometers away, you don't really care.

So we looked at our incidence of allergic reactions and that didn't seem to change very much with the implementation of leukoreduction.

So now we looked at febrile reactions, and in each of these reactions, the red cells, .06 percent is one patient, so somewhere up around here would be about ten patients a month. And as you can see, as we implemented leukoreduction, it doesn't look like there was much of a change. But if you at a best-fit curve, what you see is a drop. And when I studied this, you realized that we never really had gone below this level if you carried this out to previous years until you started leuko-reducing, and now there's a period of time when we have three months where there was basically one reaction, febrile reaction to red cells for several months in a row which we just had never seen, and we're spending much more time down in this area.

So there's a trend down in febrile reactions to these patients, which we view it as a positive result.

So now we look at allergic reactions to platelets. Again, this is the degree of leukoreduction here, 100 percent, and you can see the allergic reactions--the reactions here, it's about .5 percent for one reaction as opposed to .06 because we use about 250 pools a month. So each--a bump of one represents an allergic reaction here. That's .05 I believe is what that should be.

So these were the allergic reactions. What happened to the platelets? This is what happened to the platelets. This is one patient that had--one patient had three reactions and here's one patient that had two reactions. We have essentially eliminated febrile reactions to platelets. The levels here have dropped. There was one in this month, one in this month, in this month, none in January, February, April, May, June, July, August, September, October, November. We had no febrile reactions; yet we did have reactions through allergic indications.

Did we cure cancer? No. Have we made the world safe against evil and danger? No. But we have, believe, for this result, shown that in our experience, the incidence of febrile reactions have changed.

This asterisk is that this was one individual who had eight out of eight reactions on the allo screen and was very strongly alloimmunized. If I eliminated all the reactions, you wouldn't believe me anyway, so it's good that the patient actually had a bump there.

But I think this is impressive in that it seems to work. This is the mix of all patients. I haven't broken it down into those people that are multiply transfused and those people that have come in for the first time, but we will certainly be able to do that.

So what about cost? Well, I wrote down what a febrile reaction work-up is at Yale, direct cost and incremental. The blood bank work-up, I could say it was $40, but incrementally, it's probably about $12 for reagents and so forth. Microbiology, a culture is a $7 incrementally; urinalysis, about $3; and pharmacy with meperidine and acetaminophen is about $1. We didn't even include doctor or nurses' time because I didn't think that certain people in the audience would let me get away with that. Well, they're there anyway, so what do you mean they--you know. If you put one percent of a doctor or ten minutes of a guy who's making $100,000, that sort of inflates your statistics and they're playing games.

So I think $23 in incremental cost is not unreasonable for what a work-up costs. Some may say, well, that's still way to high. Plus if you have to give a new red cell unit or a new pool of platelets, you can add $100 or $300. So it can get up--it can become expensive.

If you have ten reactions a month to each of these, maybe 20 a year--that's 240 reactions--the monies can get up there. I'm not saying that we are covering our costs; I said we were out to improve medical care, improve the quality.

I don't like to use the word purity--I know the FDA has used the term purity--because it's somewhat pejorative, implying that non-leuko reduced is impure, and I don't think that has the right connotation. I think it's just a better quality product.

So what percentage is this of our budget? The total Yale New Haven Hospital budget is $498 million. This 306,000--and I'll show you how I got to a little higher than 280,000--actually, I inflated it by 10 percent to let people--so no one could come up and say, well, you're not counting inflation and things do increase.

This slice over here is actually $4 million. We couldn't get a line of 306,000 that you could see, so I asked the person who made the slide to make the smallest wedge of pie that anyone could see and that's what it cost the hospital.

Our budget is 3.8 percent, 306,000 out of an $8 million blood bank budget, including salaries. And you could say, well, that's just great, we can't afford 3.8 percent. Well, our administration redid the hall of the administrative corridor--the lights, the walls, the floors, the ceiling. This was more than 306,000, and I don't deny them the right to have well-lit, good foot walking distance when they come into the institution. The point is, if you want to find the money for something like this, you can find it. We did it our way. I'm not saying everyone needs to do it. But I'm not impressed by the idea that we don't have the money to do this. I was very impressed by some of the correspondence out there, but I feel strongly that this was a good way to spend $306,000.

So if you feel that a patient doesn't need leuko-reduced blood products, for most people, surgical patients, that's correct. What happens when they come back 20, 30 years later and then have their cancer and then have already been alloimmunized? What do you do then?

Maybe we should stop giving tetanus shots because who's likely to run into a rusty nail? And if they do, they'll run into it many years from now and I won't be around, or enforcement of seatbelt use.

Preventive medicine, preventive care, is a tradition in the United States and in the world, and I think this falls into that category. So that was our guiding philosophy.

As far as the care of a young patient, of such little concern--when we discussed this at the UHC meeting, which will be discussed by the representative, it was brought up that children, you know, should not have tooth-shaking chills before they get a leukoreduction--earn the right to get a leuko-reduced filter. I don't think that's necessary. Yes, that's obviously quite, you know, tugging the heartstrings, but that's the reality. We did find that we can decrease the incidence of febrile reactions by switching to 100 percent.

I believe in the big three as the major reason immunomodulatory effects need additional data, and that was not our motivation, to decrease length of stay or to stop post-operative wound infections, et cetera. We felt that these were valid and we believe that certainly number one was certainly sufficient.

These are my own personal thoughts. The primary driving force for this in the U.S. is the FDA, who are being driven by Congress and who are being driven by the weight of voter/public opinion. That I believe is reasonable.

Red Cross and other centers are slowly converting. How quickly and if they will convert is not my concern nor my area. There will be representatives speaking. And I think that the cost should, however, come down as the products improve.

So in conclusion, we converted from 30 percent to 100 percent at a cost of 280. Platelets were a wash because of the decrease in the pool size and the decrease in outdating. And I incremented 10 percent here, which amounts to about 50 cents a unit that we use. We use about 50,000 products a year, about $26,000. So it went up about 50 cents through the cost of inflation, so I made it 306,000. The rationale again was to improve safety and quality, improve patient care, and we believe to improve the public health in the City of New Haven.

Thank you for your attention.

[Applause.]

DR. BLAJCHMAN: Thank you, Ed.

I would like to open for questions from the committee. Yes, please.

DR. GILCHER: Ed, Ron Gilcher.

We converted our system on July 1st of 2000. In order to attempt cost justification, one of the things that I did with all of our hospitals--71 in our system--was to look at the use of microaggregate filters. In fact, some hospitals used 100 percent of their transfusions with a microaggregate filter, and we advised stopping the use of microaggregate filters.

Interestingly, in some of those hospitals, the transfusion service itself didn't know about the use of the microaggregate filters because that cost was in the nursing service. But looking at this together, we put together a package overall in our system that suggested that about 40 percent of the cost of leukoreduction could be shifted in terms of costs by just eliminating the use of microaggregate filters in our system.

When you showed on your slide reducing or stopping the use of bedside filtration, did that also include the use of the microaggregate filter?

DR. SNYDER: No, it didn't. In order to control filter use, we hand them out in the blood bank. Microaggregate filters are available on the floor in some of the specialty units, but the number that are used are very, very small. So that did not include a shift away from microaggregate filtration. It would have been nice if we could have had that cost saving as well, although it probably would have been very small at Yale. It was pretty much stopping the use of bedside filtration.

DR. HOOTS: One question that intrigues me, and I don't want to be presumptive and preempt the people who may be on the con side, but the whole question of whether you universally leukodeplete versus on-demand essentially is obviously a question of medical discretion, and the reason I want to ask you this question is because you have the graphs that suggest there was a period of time from '98 until 2000 when you were not universally leukodepleting; so therefore there was clearly a discretionary period based on physician choice.

Now, clearly a significant percentage likely for those 30 percent that you started out with in '98 were oncology or aplastic patients. Of the ones that were not, one of the things that has bothered me about this whole question is, which physician or which type of dialogue was occurring for those patients to get leukodepleted blood? Was it the treating physician? Was it the blood bank physician? Were they in dialogue? Because there is a concern that a lot of the information that's being imparted today is very, very well scientifically designed and it obviously is controversial, and it's somewhat arcane for people who don't know this literature very, very well.

So I'm just intrigued by who made those decisions and on what basis, if you have any information to that.

DR. SNYDER: Yes. The blood bank were the ones who made that decision primarily. Anyone who was admitted to an oncology floor received leuko-reduced and irradiated products to whatever ability we had it. The problem is, as was pointed out by Dr. Klein about inadvertent missing of patients because when you have a large institution, patients get boarded on other floors, and you don't know that they're an oncology patient if the intern or the resident writing the orders isn't up to speed, and so you can inadvertently provide a non-CMV negative product for someone who actually needed it.

That was a major concern for us, and, you know, I say major concern--how often did it happen, Dr. Snyder? It happened infrequently, but by the same token, the United States electorate believes that one in two million as an incidence of HIV is unconscionable. We are dealing with extremely small numbers as being very important to the public health. So if we had one in 7,000 patients a year who got CMV positive blood who should have gotten CMV-negative, who didn't get irradiated, and we give the CMV-negative or CMV-safe now equivalent to pre-storage leuko reduced and irradiated, to all patients who have a malignancy, who are immunosuppressed, who are on immunosuppressive agents, if we were not universally leuko-reducing, those groups of patients would clearly be the ones to get it.

So we made the decisions. Occasionally somebody would call in and let us know, but we have a fairly good tracking system for that.

DR. BLAJCHMAN: Go ahead, please.

MS. LIPTON: Dr. Snyder, I just have two quick questions, one of which is I've heard the concern that in order to accommodate the cost, increase cost, that people are looking into transfusion services, about changing transfusion practices, and you did talk about the pool size.

Could you just sort of briefly summarize what you did to follow up those patients. If you're really only taking them up to 60,000, is there a concern.

The second thing that I noticed, and I don't know if anyone is going to talk about, but the whole issue of errors and accidents and trying to maintain dual inventories. Did you have any experience as you switched from two to one? Were you able to track any efficiencies or fewer errors in that arena?

DR. SNYDER: Regarding the, did we have the appropriate effect on the increments, we looked occasionally to see what the post-transfusion increments were. We relied pretty much on the house staff's notification of us if there was a problem, if they didn't get an increment. Our house staff, as most house staffs are at any medical center, or attending staffs, very aware of what the post-transfusion increment should be, if it's stopped their patient's bleeding or not. And we just weren't getting phone calls. Those that we were on an anecdotal basis were getting concerns from was the operating room where they felt that a four-unit pool was too small and we would negotiate with them. We have the luxury of having several blood bank directors at Yale who do this full time, and therefore, if someone had a problem, they called us and we dealt with it, would give them extra pools if needed.

But as far as the medical and surgical floors, we didn't do a formal study of the increments, but we weren't--as I say, the proof was that the number of products that we gave during the year had dropped and hadn't gone back up because people were now asking for multiple pools.

So our presumption was--and we haven't heard any people complaining about additional bleeding. People can handle a much lower platelet count. I think everyone is getting more comfortable with that.

The second question was were there errors during the switchover. Errors are something that we like to avoid at all times. I cannot--I can remember there may have been one or two situations where someone who should have gotten an irradiated blood product didn't because we didn't know that they were an oncology patient. That's still a concern. And we discussed whether we should irradiate all blood in advance and we decided not to do that.

So we are still keeping close tabs on who the people are, but many patients are referred from outside areas, we don't know what their history is, so we try to minimize that.

But having one inventory that is fully leuko reduced makes much less stressful as economies of scale for savings, and we believe is better for patient care.

DR. BLAJCHMAN: For the information of the assembled, Dr. Ness is going to be discussing this issue of double inventories and errors, and possibly some other members.

We'll start over here. Mike?

DR. BUSCH: Ed, one comment, one question.

There was a paper on transfusion a couple of years ago that looked at the issue of split apheresis, and when they split the apheresis and gave basically half dose, which a lot of people are doing, there was a resulting increased patient exposure to multiple donors, so they ended up demonstrating that the lower dose did translate into increased exposure.

I think, you know, it's a strategy--if the products are truly, you know, better in terms of content or functionally and you're offsetting that, that's fine, but I do think this needs to be studied further in terms of reducing costs by reducing the content of the products.

The other question is logistically, I'm not real up to date. When you shifted from transfusing filtered pools at the bedside, you had a single filter that was applied to the pool, whereas, if I understand it correctly, you're now using pre-storage leuko-reduced platelet components where there are--is it true that there are individual filters for each of the individual donor platelet components, or can you pool and store a filtered pool and what are the cost implications? Are you using four filters now where you were using one before? What is all that about these days?

DR. SNYDER: Well, yes, we are using four--well, we're not--our supplier is using four filters. That was all factored into the equation as to the cost. And the $280,000 is not what it cost us to provide blood, filtered blood to the patient; it's the increment that it costs to provide 100 percent leukoreduction, and that includes the additional cost of filters subtracted from the savings that we got by decreasing our outdate by 10 percent. So 5,000 times whatever we were paying for platelets was a fair amount of money, as well as some of the other savings that we were able to do by cost shifting.

So that was all worked out. We obviously cannot pool and then leuko reduce and store for anything more than four hours because that's illegal, but we--so we are using four units of products that are leuko reduced, and it would be very nice if, in the future, if pathogen inactivation comes along, if pooling could be done with pathogen inactivated products that can then be stored as pools, we could only perhaps use one filter at the time. It would be done in the blood center.

Now, if you want to talk about costs, pathogen inactivation will make for a lovely meeting sometime in the future.

DR. BLAJCHMAN: Mary.

DR. CHAMBERLAND: Yes. Your description of implementation of universal leukoreduction at Yale is truly very impressive.

I think that most people here obviously would recognize that the kind of hospital that Yale New Haven is is a minority of hospitals in the United States, the large tertiary medical care center, and I'm not sure if it's a fair question to you, and maybe the panel will discuss this, but I wanted to ask your views on how feasible, how practical implementation of such a program might cut across other hospitals. Most hospitals in the United States are much smaller, bed-size and complexity, et cetera. So your views or perhaps others about how this practically could be done, what particularly facilitated its implementation at Yale.

DR. SNYDER: I think this is a superb question for the panel. In general, never wanting to not answer a question, I will just answer it briefly.

Our feeling is that the smaller institutions are probably less likely to have people that are following transfusions as closely as we can; therefore, universal leukoreduction would be more beneficial for those patients. If you have a 500-bed hospital or a 300-bed, you'll have proportionally less blood products used, there will be a lower cost. What percentage it would be of your budget obviously would change.

But I believe that if you feel that it's a public health issue, which is what we do, then I believe there are ways to increase efficiencies to find the dollars to do this so that patients who don't need it necessarily today will still be able to come in and get the benefit of it ten or 15 years from now.

I think the FDA is getting more concerned about activities at unregistered facilities. It's now going to be a requirement that they report errors and so forth. So I think we need to find ways to help smaller hospitals achieve this goal if people feel it's a reasonable goal.

I am sure there are people in the audience suffering from the pain of undelivered speech, as Jack Hoke says, that can't wait to get up and say why it's not necessarily; but we felt that it is important and even at small hospitals, it can be done.

DR. BLAJCHMAN: Richard.

DR. DAVEY: Yes. We've heard from Harvey that a red cell unit loses about 10 percent of the cells in the filtration process. So there's the possibility that heavily transfused patients' red cells may actually need more transfusions with ULR blood than standard blood with increased cost and increased exposures. I believe Mark Brecker has some data that shows there's no difference. But I wonder if you have looked at this at all at your institution.

DR. SNYDER: Well, what we've looked at is the--we haven't looked at it directly. Indirectly as a surrogate, if you look at the total number of red cells transfused, that has gone down. The number of patients has stayed about the same. The demographics and the medical graphics of the patients have stayed roughly the same. So we don't believe that we are transfusing extra blood to make up for the void volumes lost in the filters.

Again, the same thing that happens with platelets happens with hematocrits. If your crit was going to go up from 19 to 22.4, and it goes up to 22.1, it's not something that would be picked up by anyone. It's below the level of detectability of the culture counter or whatever machine you use.

DR. BLAJCHMAN: Ron?

DR. GILCHER: Just about the time that many of us were putting in universal leukoreduction or putting in leukoreduction period, blood centers were switching from the 450 ml collection to the 500 ml collection, and I want to point out that there clearly was an offset.

We didn't see in our own system a reduction in red cell usage because we went to a 500 ml collection, nor have we seen an increase in usage by, so to speak, losing some red cells, which does occur. It's really been offset, I think, by the shift from the 450 ml to the 500 ml collection.

DR. SNYDER: That's a good point.

DR. BLAJCHMAN: Question over here.

CAPTAIN SNYDER: Yes, I have a quick question. Am I correct in my presumption that for smaller hospitals, universal pre-storage leukoreduction would be superior to the bedside leukoreduction? Number one, I'm assuming that the cost of the filters is the same. Number two, the savings in nursing hours and the lessening of mistakes, but probably also the concept, and that's what I would like you to comment on, of pre-storage versus post-storage leukoreduction.

DR. SNYDER: Well, the question is an extremely good one and one that I'm sure other people here could answer better than I as far as the savings and so forth and the concerns of small hospitals.

There's no doubt in my mind that if a product comes down pre-storage leuko reduced and all you need to do is infuse it through a 170-micron filter, that it eliminates the types of problems that Harvey alluded to where you find filters on top of the bedside.

For a product that has no moving parts, blood filters--bedside blood filters stop working at an alarming rate. Pre-storage leukoreduction prevents that because you don't get some of the platelets, you don't get a lot of the aggregates that may form during storage by removing the white cells and so forth up front.

So I think it certainly improves safety because if all you have is a pre-storage leuko-reduced product under CGMP, that you have something that's safer generally for everyone, and most--especially small hospitals, the nursing staff may not have the time to devote to transfusion practices. The physicians are often doing autopsies or surgicals and there may be one person running the blood bank. So that's when it's needed even more.

DR. BLAJCHMAN: Dr. Penner.

DR. PENNER: Just a quick question. Probably Dr. Klein could answer this a little bit easier. Is there any significant granular site function persisting in the platelet product?

DR. KLEIN: After about 24 hours, there's virtually nothing. There really aren't enough cells even relatively early in the storage to affect anything in terms of benefit, but there are sufficient numbers of granular sites to effect alloimmunization or to transmit the agents that are contained in granular sites.

DR. PENNER: So any anti-infective properties really are not significant in this?

DR. KLEIN: In terms of removing bacteria, there's quite a controversy about this now. If you leave your component for a few hours and then leuko reduce, you decrease the risk of transmission of bacteria, and there's a literature that says that's so. There are some other studies that really don't confirm this.

So I think the feeling is that you may get some benefit in reduction of bacterial infection, but I don't think that the data are quite as strong as we like to see them.

DR. BLAJCHMAN: I think we'll open questions for the audience. Dr. Petz, would you go to the microphone?

DR. PETZ: I'm Dr. Petz from Los Angeles.

Ed, about your process, I would submit that $280,000 or $306,000, whatever it is, is still a significant amount of money, especially for a little rinky-dink hospital like Yale.

Ed and I are good friends, so I hope he doesn't mind comments like that.

In a more serious vein, though, some of your estimates of costs shifting are made on the basis of things you could have done and should have done anyhow and really have nothing to do with leukocyte reduction. It also applies in spades to the comment made by Dr. Gilcher. Eliminating microaggregate filters and saying, well, that pays for leukocyte reduction--you should have been eliminating them anyhow.

So I would say that your estimates of costs are really--and how you minimize the costs are really using some things that are irrelevant to the discussion.

DR. SNYDER: I think your comments are very well taken. I sort of look at the--almost like immunological spring cleaning, if you will. We looked at what we were doing, we realized that there were inefficiencies, and we took the opportunity to correct those inefficiencies and thought it would benefit the conversion to leukoreduction.

Had we been as efficient as we ought to have been, as you correctly point out, we would not have had those savings and it would have cost us more. That's why I incremented that 10 percent, thinking that would be an example.

Your points are well taken, and if institutions are already at a level higher than we were when we started, this is not a benefit that you can gain, that is correct.

DR. BLAJCHMAN: Dr. Klein.

DR. KLEIN: Dr. Snyder, I don't mean to impugn your credentials as an economist, and I hope you won't examine mine, but if I understand it correctly and if the committee understands it correctly, the blood that was leuko reduced that Yale used comes from the Red Cross. They do the pre-storage leukoreduction. So, in fact, the $280,000 I presume are charges to Yale and not actual costs, and some of the other things that you mentioned were costs and some were charges, or do I not understand that correctly?

DR. SNYDER: No. The $280,000 were charges to us, to our cost center, charges from the cost of obtaining the blood from our supplier.

DR. KLEIN: Right. I think sometimes there's a difference between costs and charges.

DR. SNYDER: That's correct. We did not increase our charges to patients for those bloods, however; basically it's a pass-through. And we were able to internally reallocate to keep that at the same level.

DR. BLAJCHMAN: I think what we're going to do is take a physiological break at this moment in time, and we'll reconvene in 20 minutes, or 15. So we're starting back at 10:20.

[Recess.]

DR. BLAJCHMAN: Can the committee members please sit down. Committee members, please take your seats.

[Pause.]

DR. BLAJCHMAN: Committee members will not get their expenses if they are not seated in the next two minutes. I think we'll proceed. Please take your seats. Thank you.

Do we have a quorum of committee members?

Before we proceed to the next speaker, a bit of housekeeping. It Is likely that this session will not end until approximately one, so lunch will be between one and two, and the afternoon session will begin at two p.m. because we're running slow and I'm allowing, have allowed perhaps a little bit more discussion, but that's okay.

Before the next speaker stands up to speak, I would like--there was a question by a member of the committee about what happens--the experience of small hospitals. This was a question to Dr. Snyder. And somebody came to me during the coffee break and she indicated that she has some experience in a small hospital.

Is Ms. Chance here? Where is she? Yes. Can you respond to that question about the impact of universal leukoreduction in a small hospital, please?

MS. CHANCE: Yes.

I'm from a 156-bed county hospital just north of Indianapolis, Indiana, and my study that I have done, well, since the 1980s--we did bedside filtration and then went to pre-storage--but mimics exactly what Dr. Snyder has just presented.

Don't underestimate your medium- to small-size hospitals because they can implement this process in a very timely manner. Our costs were not only up-front exactly to the share of unit to cost ratio as Dr. Snyder, but it also reflected--in our in-patient stays, we actually documented one to three days' stay off of the original time on similar cases.

So our savings began to be internally in the in-house stays and some of the other treatment plans that doctors had. So we did make up that cost in a little different way.

DR. BLAJCHMAN: Thank you very much.

I would like to turn over the microphone to my distinguished colleague, Dr. Vamvakas, who will introduce the next three speakers.

Stephen.

DR. VAMVAKAS: Thank you, Mo.

Well, if we all get the impression that there is some will on the part of the government to spend some money on transfusion safety from the very fact that this meeting is being held, Dr. Sonny Dzik from Massachusetts General Hospital will review alternative ways to allocate this money to ensure the safety and the welfare of transfused patients.

Sonny.

DR. DZIK: Thank you, Steve. Thank you, Mr. Chairman, for giving me the opportunity also to present to this committee.

The audio is a little fuzzy in this room, and so I'm going to maybe step back from the microphone and try and speak louder. If you have any trouble hearing me, let me know.

My name is Sonny Dzik and I'm the co-director of the Blood Transfusion Service at Massachusetts General Hospital. I have been involved in research and the application of leukocyte reduction technology for about 20 years now, and I appreciate very much the opportunity to speak before you today.

In the interest of disclosures, I should tell you that I'm on the Scientific Advisory Board of the Hemasure Corporation, which is a company involved in the production of leukocyte reduction filters.

More importantly for the purposes today, I want you to you know that I work every day in a hospital where I not only run a transfusion service, but I also care for patients who are getting transfusions, and I wish to make three points for you today. I would like to leave the lights relatively bright because we don't need to fall asleep.

First of all, I would like to draw a distinction for you between patient safety--excuse me--draw a distinction for you between blood safety and patient transfusion safety.

Secondly, I want to focus on the topic of immunomodulation because that's particularly relevant to universal leukoreduction.

Third, I would like to alert you to current studies that are in progress that are designed to provide valuable information on the issue that is before this committee.

Let me begin with this simple line drawing that describes a series of interconnected processes that represent blood transfusion therapy for patients.

We begin on the left over here with the recruitment and selection of an adequate number of safe blood donors through donor testing to the production of a finished product that is labelled and boxed up and delivered on trucks every day to hospitals throughout the country.

The goal of this part, of course, is the production of a safe product, but it is obvious that there is much more to the story.

In order for a patient to receive safe transfusion care, six additional processes occur in the hospital. These include the collecting of a pre-transfusion sample from the intended recipient for typing and cross-matching; making a proper medical decision to give the patient blood based on an appropriate indication; selecting the correct product or modifying that product appropriately; issuing the correct unit to the right nursing station; administering the correct unit to the right patient; and finally monitoring the patient for signs of adverse reactions.

Thus, the overall delivery of safe transfusion therapy to a patient depends not only on the quality of the product, but also on the quality of the processes that follow product preparation.

Here, I wish to emphasize the difference between blood safety, and I mean by this product safety, blood safety, and contrast that with patient transfusion safety, meaning the safety and performance of the entire process.

I want you to keep this big picture in mind as you go through your deliberations concerning our topic. I work every day in this area, and I want you to know my most important message first. If this committee wishes to exert its authority to really improve transfusion care for Americans in hospitals, you must consider the needs of the entire process, you must show leadership by directing resources towards the weakest link in the health care chain that connects the donor to the recipient.

I'm about to tell you that the weakest link in the process is over here towards the right side of the figure, and that universal leukoreduction is not the correct choice to make the most significant impact on patient safety.

In the United Kingdom, there's a program of hemo-vigilance, which is a nationwide system for reporting adverse outcomes related to transfusion. This pie chart shows the results in the UK during the period from 1996 to '99. This is essentially the national report card on the status of transfusion safety in the UK.

As you can see by the size of the orange wedge, the single largest problem in patient transfusion safety has to do with the mis-transfusion of the wrong blood to an unintended recipient.

Other problems are identified, including pulmonary reactions in graft versus host disease and a small residual risk of transfusion-transmitted infections, mostly due to bacteria.

Of particular note, patient problems related to donor leukocytes--that is to say problems which would be addressed by universal leukoreduction--are virtually non-existent, and are certainly not the number one priority.

Although the U.S. does not have such an organized system of reporting adverse transfusion events, there are complementary data to demonstrate that in the United States, patients receiving transfusions are put at significant risk for a variety of non-infectious complications.

This slide shows you estimates of the current--today--risks of transfusion in the United States. The scale across the top, left to right, is a logarithmic scale. The vertical lines are ten-fold differences in risk. Thus, for example, the risk of HIV transmission is ten to the sixth, or one in a million.

As you can see, if you need a transfusion today in America, you are a thousand times more likely to receive the wrong blood in error than you are to be exposed to HIV. You are also a thousand times more likely to suffer cardiopulmonary complications than you are to get hepatitis. You are also much more likely to suffer from poor decisionmaking that causes you to be inadequately transfused--so-called under-transfusion. It's important to recognize that universal leukoreduction addresses none of these problems.

The current situation in the United States is quite understandable. As a nation, we have focused considerable wealth and energy on making a better product. That effort, fueled by government and the FDA, has brought about a remarkable improvement in the quality of the fluid.

But I ask you what good is a virally safe or even leukocyte-reduced product if given in error to the wrong recipient? What good if it evokes cardiac complication and if it is used inappropriately in the first place?

Hospital health care is full of error as described in the Institute of Medicine report which I hope each of you has read. I brought you a copy of this IOM report. It's in a book, it's available on the web for 20 bucks. If you haven't read it, you really ought to read it. It's a spectacular thing to read.

The IOM report calls for action by the U.S. government to reduce errors in hospitals by at least 50 percent in the next five years. While the IOM's report discusses medication errors as an example and points to the issue of first doing no harm, I am sure you appreciate that the problems currently in hospitals which result in the misdelivery of medications are fundamentally the same as those that result in the misdelivery of blood products.

So to summarize my first message to you, people like me who work in the hospital want the Committee on Blood Safety and Availability to recommend improvements in transfusion care, but we know that what is needed to improve safe transfusion will not come from universal leukoreduction. We also know that additional costs which are weighted towards the fluid will inevitably steal further resources from the process of transfusion.

The slide shows you 20 years of regulatory influences on transfusion. We can all agree that there has been a tremendous investment in the safety of the fluid, and this has paid off handsomely. However, there has not been governmental leadership in the process part of transfusion and the economics of health care in this country have resulted in a dangerous decline in the resources devoted to the delivery of safe transfusion therapy. The IOM report tells us that it is time that you put this situation into better balance.

Secondly, I would like to draw a distinction, which Dr. Klein, I think, has already outlined saying, between selective leukocyte reduction and universal leukocyte reduction.

This slide lists the three generally accepted indications for leukoreduction as applied to selected patients. Using these medical guidelines, leukoreduction of approximately 20 percent of the national red blood cell supply is needed.

It's a good figure to keep in mind, so let me repeat it: To provide the blood that is needed for medically proven benefits of leukoreduction requires that about 20 percent of red blood cells undergo leukoreduction.

Now, the selective application of modern biotechnology is not a bad thing. Indeed, selective use of technology is a fundamental basis of good medical care. Examples include the judicious use of antibiotics rather than their indiscriminate use.

We know that excessive use of antibiotics simply leads to drug-resistant bacteria. In radiology, best medical practice results in the selective application of CT and MRI scans for patients who have specific medical indications rather than their use as routine screening procedures, and in laboratory medicine, we require the focused application of laboratory diagnostic tests rather than the indiscriminate use of batteries of tests applied to all people.

Selective use of blood components is also the current standard of care. This slide shows a list of the blood products that are currently selectively applied in my hospital.

Take a look at this. This is quite a long list. In reviewing it, I want to emphasize to you that we do not use each of these blood technologies for all transfusion recipients even though each technology is of proven benefit for some patients.

Now, the proposed reason to apply leukoreduction to all patients rests on the premise that it will prevent immunomodulation of transfusion recipients. Immunomodulation is a broad and an imprecise term, but it is generally regarded as some form of immunosuppression. Researchers have had a difficult time trying to demonstrate that leukoreduction would have any impact on immunomodulation because the exact mechanism of immunomodulation, if indeed it exists, is currently uncertain.

Clinical studies of immunomodulation have focused on two major issues: post-operative infection and the recurrence of tumor. Shown on this side is a compilation of the randomized controlled trials designed to determine whether the use of leukocyte reduction would decrease post-operative infection.

The slide makes the following points. Clinical trials have addressed two subsets of surgical patients: colorectal surgery patients and cardiac surgery patients. No studies have addressed all surgical patients, let alone universal transfusion recipients.

The column on the far right shows the 95 percent confidence intervals of relative risk of infection. Three trials, with the underscored results, have shown benefits. Two of these were done by the same investigator in Denmark. Three trials have failed to show benefit, and one is somewhat on the fence.

Importantly, all of these trials, except for the very last one at the bottom of the slide, were conducted in Europe using blood products whose leukocyte content differs from those prepared in the United States. They were also done using other health care technology and antibiotics and the delivery of health care as applies in those countries and not in the United States.

Only the bottom trial by Tarter was, in fact, conducted in the U.S. Let's look more at Tarter's study.

Paul Tarter randomized 59 patients to receive leukocyte-reduced blood or non-leuko reduced blood. It's important for the committee to see that this was a small study and not of a size needed to establish national health care policy.

A breakdown of the patients is shown on this slide. Small studies often result in unbalanced groups by chance alone. You'll note that in Paul's study, the non-leukocyte reduced arm, shown here--this is the non-leukocyte reduced arm shown on the left--was weighted by chance to two bad risk factors; namely, a high percentage of patients with diabetes, and a higher percentage of patients undergoing rectal surgery, which carries a greater risk of bacterial infection.

The results of Tarter's studies are shown here. This is length of stay, post-operative length of stay, hospital charges and infections. There was no statistical benefit to leukocyte reduction for the prevention of post-operative infection or shortening of hospital length of stay.

This next slide shows a compilation of the randomized control trials examining whether or not leukoreduction would decrease the chance of post-operative recurrence of colorectal tumors.

Each of these studies was conducted in Europe using a blood preparation with a different baseline leukocyte content than that found in the United States. None of the three studies demonstrated any advantage to leukocyte reduction.

I believe that while well-meaning people may interpret these studies differently, I also believe that nearly all should agree with the statement that currently there is not conclusive evidence that universal leukocyte reduction would actually result in any demonstrable benefit with regard to the purported immunomodulatory effect of transfusion.

Third, I want to make the committee aware of current ongoing studies that may prove quite valuable in the process of decisionmaking regarding this topic. I want to point out, however, that any mandates for universal leukoreduction will prevent the ability to do prospective randomized controlled trials in the United States and forever close the door on the ability to get outcomes-based evidence on the actual value of this technology.

As someone who works in academic medicine and believes that advancement in health care occurs only through the scientific process, I must tell you that the premature required deployment of any unproven technology may turn out to be a reckless national strategy for health care.

This slide, the current well designed studies that are underway to assess the health care value of leukocyte reduction, these studies are in various stages of maturity.

In contrast to the previous studies, each of these, with the exception of the Dutch trial, and the Dutch trial is here, each of these uses standard red blood cells as prepared in the United States. In addition, these trials have a much larger end number and a greater statistical power and statistical confidence than the study by Tarter et al.

Our own study at Massachusetts General Hospital truly addresses the question of shifting from selective leukoreduction to universal leukoreduction because as you can see in the slide, we did not restrict ourselves to any particular patient subgroup.

This slide will give you a flavor for the design of the MGH study. All patients not already assigned to receive leuko-reduced blood for standard medical indications were automatically randomized upon admission to the hospital to receive either pre-storage leuko-reduced blood or non-leuko reduced blood. Approximately 3,000 patients were randomized in the six-month interval between February and August.

Shown here on the left are the primary and secondary outcomes of our study. As you can see, we will compare the two groups for mortality, length of stay following transfusion, and total hospital costs. Our study will also examine secondary outcomes, such as antibiotic use after tan, length of stay in the ICU and post-op, transfusion reactions and readmission rates.

In addition, we will do multivariate analysis to explore whether leucocyte reduction provides a benefit to selected subgroups of patients based on their specific diagnosis, the dose of blood given, their age, gender or severity of illness.

Our study data is currently being analyzed by an independent group of statisticians and the results will not be available for a couple of months, so I cannot show you the results because I simply do not have them. The only preliminary information I do have is shown on this slide, which is a comparison of total hospital length of stay with the leuko-reduced group on the left and the non-leuko reduced on the right.

This is not the outcome that we will ultimately report in our study because we wish to focus on length of stay following transfusion, and this is total hospital length of stay, and the slide shows you that the total length of stay between the two groups shows no benefit to leukoreduction.

In summary, I would like to remind you not to lose sight of the big picture in the overall process of safe transfusion care for patients, and if you like to think by analogies, as I often do, I would draw your analogy to airplane travel.

I would urge you to be very cautious about allocating more money to invest in the aircraft, to make it a better and better aircraft, forgetting about the needs to train the pilot, the air traffic control team to keep the runways open and that sort of thing. It's not just about making a better product.

I have three summary points.

First, the committee should understand that government resources are urgently needed to address problems of safe transfusion that are not improved by leukoreduction technology.

I ask you please not to be naive on matters of reimbursement. You should recognize that were you to vote in favor of universal leukoreduction, no matter how well intentioned your wording regarding reimbursement, financial resources spent on the product will come at a cost to the process. In this regard, you should be very cautious yourselves to first do no harm.

Second, I want to remind you that there is nothing wrong with the selective application of biotechnology. Indeed, selective use of technology based on clinical studies is the hallmark of top-quality evidence-based medicine. Furthermore, experience has shown that the excessive application of technology, such as drugs, x-rays and screening lab tests, squanders resources and imposes risk without benefit.

Universal leukoreduction rests on the currently unfounded premise that routine transfusion recipients are today experiencing some form of immunosuppression which would be prevented by leukoreduction. However, published studies from Europe provide conflicting results on this topic, and the single study using products and health care delivered in the United States is too small upon which to base national policy.

Third, there are numerous well designed clinical trials that are currently in progress which will provide significant new information on the issue of universal leukoreduction.

For these reasons, I suggest to you the following:

First, I urge the committee to recommend against universal leukoreduction at this time; and second, I urge the committee to actively pursue solutions to the actual transfusion safety problems faced during inpatient therapy in the United States.

There, in fact, are good data on transfusion errors, on cardiopulmonary side effects, and on under-transfusion and over-transfusion. Don't be blind to them.

There are also solutions to these problems, both people solutions and technology solutions; however, these solutions will not be implemented and transfusion practice will not get safer without government support.

Finally, I urge you to understand the responsibility that you bear to turn from a narrow and restricted focus on blood as a product towards a commitment to improving the quality of transfusion care for patients.

Thank you very much for your attention.

[Applause.]

DR. VAMVAKAS: Thank you, Sonny, for the hospital perspective.

We will now have questions from the committee members.

Dr. Davey.

DR. DAVEY: Sonny, thanks again for your usually clear presentation. It's always nice to hear what you have to say.

A couple of questions. First, you did comment on the ongoing studies. It was a very clear point. Can you give us some idea of roughly how long, from your estimate, it will take for all of these studies to be completed; and secondly, maybe a little more broadly, I think Ed Snyder made the point that there are some preventative issues in leukoreduction. Especially in transfusing young people, you don't know what's going to happen to them later in life, and it might be better to prevent than to cure. I think maybe the analogy with the MRI breaks down right there because that's not a preventative strategy.

Could you comment on those two issues, please?

DR. DZIK: Sure. With respect to the first, the timing of the studies, it's scheduled, it's planned that at the ISBT meeting in Paris in July, three of these large studies will be presented publicly: the Boston study; the Dutch trial that Leo Vanderwatering is doing--that's a two-center study in Amsterdam and Lydum focused on cardiac patients in particular; and also the United Kingdom pre-/post-intervention study which is done in nine hospitals focused on cardiac and orthopedic. So the next three to pop out will be available in July.

The three then that follow that will be a study in Portland, Oregon that Lynn Boshkopf is organizing. That study is just beginning now and I don't think we'll see results of that for certainly more than a year from now.

Darrel Triulze is just getting approval from his IRB right now to do a randomized trial in Pittsburgh, so I don't think you'll see that until 2002. And the Canadian trial, which is a very, very large pre-post study--Dr. Blajchman knows all about it--should be out in around 2002 as well.

Regarding the prevention versus treatment issue, I think that is an important thing to consider. There are a lot of what-ifs, I think, with respect to leukoreduction. You know, what if there is a new virus that comes into the system, and what if, you know, you're transfused at age 14 because of a trauma event, and then at age 40, you need a kidney transplant.

I think my response to all those--the global response to that, I tried to describe in my talk. I think it's more imperative that we deal with the what is problem, the problem that we actually have that we know exists, rather than dealing with a speculation problem, because I know we have a problem with poor collection of the correct sample, and of misidentification of patients, and giving the wrong blood to the wrong people.

So from my perspective, rather than dealing with some what ifs, I'm more interested in dealing with the current, what is.

DR. VAMVAKAS: Dr. Epstein.

DR. EPSTEIN: Sonny, I also appreciated your well considered remarks.

Could you just comment. You alluded to the fact that the European products differ from the U.S. products. They are mainly buffy-coat depleted, which means that they are too some degree leukocyte depleted.

Could you comment on what the degree of leukocyte reduction is in the European product, and could you comment on how relevant you think that experience is with animal data that have at least suggested or in some people's minds demonstrated that there is a progressive correlation of benefits with degree of leukocyte reduction.

DR. DZIK: Well, yes, I mean, I think the animal data is, of course--in medicine, that's the way it works. We do our work in animals. Animal data I think is essential, it allows us to generate hypotheses about what happens in health care, but it's important, then, to do clinical studies, of course, to understand whether the effects observed in animals really bear out in health care practice.

So I think you're right, if you look just at animal data, you come away with a conclusion of benefits that might be perhaps stronger than if you look at clinical trials. But I feel that it's very essential that we not prematurely make conclusions about technology in the absence of results in human beings.

I think Mike Busch's preclinical work on viral reactivation in HIV-infected cells is a perfect example of that, which was correctly followed through in the VAT study, which failed to show, to demonstrate the pre-clinical hypothesis when tested in human beings. So I think the animal stuff is important, but it's only one piece of the solution.

Regarding the dose of leukocytes, just for everyone to be aware, the leukocyte-reduced blood in Europe is presumably--in these studies was running around ten to the sixth per unit because that's been the standard in Europe. The control arms have been typically buffy coat removed, but then not further leukocyte reduced, and buffy coat removal is generally thought to be about one log. It's actually really more like 70 to 80 percent, just a tad less than one log leukoreduction. So in that sense, it's a kind of mildly leuko-reduced product compared with an appropriately leuko-reduced product.

More telling for me, though, are the unrecognized differences in health care practice between Europeans, European health care and American health care. I was very much struck by a study published in the New England Journal of Medicine that looked at post-operative infections in colorectal cancer patients.

Now, this would be a topic which would otherwise seem to be a topic all about leukoreduction, but the study had nothing to do with leukoreduction. What they did is randomize patients having colorectal surgery to receive slightly extra oxygen ventilation during their surgery, a higher--they turned up the oxygen meter so that they got a higher concentration of inspired FIO2, inspired oxygen, compared with people getting standard oxygen.

The patients who were given higher degrees of oxygen had a significant, substantial, easily demonstrable decrease in the incidence of post-operative infections following colo-rectal cancer surgery. That's a slight but obviously in this case very important difference in medical therapy, and medical therapy differs around the world, so I think we just have to be cautious--because we're being asked to set policy about the U.S., we have to be cautious about making that policy in the absence of studies conducted in the U.S. because our treatment plans differ a little, different from other countries.

Yes, sir.

COL. FITZPATRICK: Mike Fitzpatrick. I want to thank you for pointing out the current studies that are going on, and I wanted to ask a question.

I had the opportunity to train with Dr. Huggins many years ago when--

DR. DZIK: One of the club.

COL. FITZPATRICK: --when the facility was 100 percent thawed deglycerolized red cells. I wondered if you had or would be able to at some point in the future put in perspective from a historical content what happened to febrile and allergic reactions in your facility when you shifted from frozen blood to normal packed red cells in concert with your current study.

DR. DZIK: That's a very interesting--what Dr. Fitzpatrick is referring to is he worked with Dr. Huggins. Dr. Huggins worked at the NGH where I work now, and called Mr. Freeze by those who loved him. There was a time when our hospital released almost only frozen deglycerolized blood done by the Huggins method, I might point out, and it would be very interesting to pore through some of those old records and see what happened when we essentially abandoned all of that frozen blood and went to more traditional type therapies.

Sam Spears is still at NGH and probably has those records, and when I get home, that's a very clever idea. I obviously don't have any information with me.

CHAIRMAN CAPLAN: I think the committee is aware that both product and process has to be attended to. Next time we meet, we'll be looking at issues such as compensation, no-fault insurance, trying to find ways to elicit increases in monitoring and quality assurance, which I think are not unique to blood but get in the way sometimes of detecting the blood errors.

I was wondering if you could comment. I haven't heard anything yet. In addition to differences in practice between Europe and here, do differences in the racial and ethnic makeup of the two societies make any difference relevant to our thinking about immunological effects and what we might try to protect against in the fluid?

DR. DZIK: Well, that's an interesting question. I'm not aware in this area of immunomodulation, okay, the immunosuppressive effect, I'm not aware of any data that suggests that this effect is enhanced in any way if the transfusions occur from an out-bred polymorphic, polygenetic diverse society such as ours. A bit more the opposite. In fact, one of the threads of this tantalizing kind of inquiry has to do with the persistence of the cells in the patient after transfusion. Actually, Dr. Klein referred to this where Mike Busch has shown in certain cases, you can see the donor cells persisting. That's more likely to occur in a homogeneous in-bred population as occurs, for example, in Japan where you have an island people who have very similar HLA types, and so the leukocytes don't appear as foreign to the recipient and they can kind of last a little longer.

In a diverse society like ours, it's much less likely that those cells would have any kind of immunosuppressive impact because they're seen as non-self rather easily by the recipient.

So I think the--I don't think there is any data, but if one were to speculate, I think you'd speculate that there's less of an effect in a diverse society.

DR. GOMPERTS: I have a question. In your institution, are you currently practicing selective leuko-filtration?

DR. DZIK: Yes.

DR. GOMPERTS: And I assume you're also tracking errors and accidents in your institution.

DR. DZIK: Inadequately.

DR. GOMPERTS: Okay. Are there errors and accidents associated with patients getting blood that is--they should be getting leuko-filtrated blood, but they're not?

DR. DZIK: I'm sure there are. It was asked earlier whether there was a dialogue about this topic, and I think it is an important topic to this issue.

The way our system works is that people order blood through a computer, the doctors on the floor order blood on a computer, and when you enter the computer screens where you get a chance to select products, your options for picking leuko reduced or CMV negative are right there before you. So one question was, do the doctors--are they made aware that they have this option? In my hospital, they're very well aware of it. You've got to get through that computer screen in order to get to the next one.

When they do order blood, and we have people of varying levels of sophistication ordering blood, but when they order blood and they call for this modification, it triggers a--the request is automatically applied, so they get what they ask for, but the request triggers a review by the blood bank people to see whether the request matches hospital-approved guidelines, approved by the transfusion committee for the selective application of the technology.

Now, that's true whether it's washed cells or frozen blood or leuko-reduced blood or irradiated blood and all those things.

So are there breakdowns in that system? I'm sure there are. What I am more concerned about is the recent data I found in my hospital, which I believe is--I'm proud of where I work, but one in 300 samples drawn to type the patient, has his name on it, 1 in 300 has somebody else's fluid in the tube. So we're making a phlebotomy error 1 in 300 times.

DR. GOMPERTS: I understand what you're saying. The question that I'm asking is, by carrying out selective leuko-filtration and patients are getting unfiltrated blood that should be getting selective, are you tracking the negative outcomes and consequences to those individuals.

DR. DZIK: No, we're not tracking them in any--well, in any active way other than--all of these tracking systems are very passive, and if people tell you about a problem, you know about them, yes.

DR. GOMPERTS: Thank you.

MR. DALAL: I found your chart on the process to be a good reminder of where the safety infractions are. You made a comment, then, that the financial reimbursement of universal leukoreduction might come at the cost of the overall transfusion process.

Could you comment on that a little bit in terms of why we should think of this as a zero-sum; that is, why it should be only one or the other if we consider this problem--these problems need to be addressed in, say, the next two to three years?

DR. DZIK: Sure. I think you're hitting on a very, very important issue. There are three elements here. One is what's happened, what's the past shown me. If the past is any indicator, it will come at a cost to the process because we've had to pay. I've had to pay higher prices to buy a better product from my supplier, and I don't begrudge that. I welcome the better product, mind you, but I've had to pay for that with a fixed reimbursement health care system. And I've had to do cost shifting, which you heard about earlier, and the only other bucket I can take that out of is the process part of the bucket.

So one thing is just what's already happened. I'm very sensitive to the degradation of the system that has already occurred. That's one point.

But you might say, "Well, what if we just changed all of that and caused it to be, with additional money put into the pipeline?" I think that's where you were going with your question. There are two things I want to state about that, more money flowing down the pipeline.

The first is don't be naive about whether I get the money or not. I don't mean me, of course, but don't be naive about the fact whether or not that money actually gets to the transfusion service in the hospital so that it is relieved from its effort of continuous chipping away at safety issues to pay for costs. If you put money into the way our system is currently designed, it's going to get disbursed in the hospital. I'm sure the hospital will greedily suck up whatever money comes down. But my budget, my cost center, I'm Cost Center 7761, will stay the same, and I have to still meet my budget, and I'll be asked to meet that by chipping away at the corner. So that's my part about not being naive. Be very careful in your understanding about how reimbursement works in the United States.

And then my final point, "Well, what about some more money in the system?" If you've got some more money, I've been trying to say I would much prefer, from my perspective, that you spend it on something else, if you really want to make the patient have a safer outcome.

DR. PENNER: Your screen is interesting. I would guess, though, that about 80 to 90 percent of blood is ordered by a physician who writes an order "two units of blood," and therefore has no concept of what else is available and how it should be ordered unless he's dealing as, say, a high level of utilization and a Hematology/Oncology Service or something of this sort.

I'd be interested in your format. Is there anything in the screen that the individual has to defend the use of a nonleuko-reduced blood or if he orders it, it just goes through the screen, it's only if he orders it leuko reduced that it has to be at least passing through this filter.

DR. DZIK: If a person orders the--if I heard your question right--if the doctor orders the blood as just ordinary blood, then he'll get ordinary blood.

DR. PENNER: But that may be wrong.

DR. DZIK: And it will not trigger--right, it may be wrong--it will not trigger review in my system.

DR. PENNER: So this is the educational aspect that we're missing, which is I think, unfortunately, going through, in most of the hospitals they just don't know about it, and that's at the doctor level, not at the institutional level.

DR. DZIK: And while I'm concerned about that, I'm much more concerned about some of the other things I highlighted.

DR. PENNER: I think you've got a chance to fix institutional things. It's very hard to fix the doctor thing.

DR. DZIK: Well, yeah. Every time you turn your back on the process towards the product, just be cautious. Please don't say that's not my area because I've got no other Surgeon General to appeal to, I've got no other government to appeal to to fix the process.

DR. BLAJCHMAN: Sonny, I'd like to ask you a question, if I may. Incidently, it was a very nice presentation, and I agree with most of what you've said, but I don't think that the choices between the two issues, universal leukoreduction versus safety. And I think in Canada we have been universal leuko reduced. We've also introduced the concept in many areas where we've put into place safety officers to deal with some of the issues you've raised, and the two issues are not mutually exclusive.

The next point that I'd like to put to you, you pointed out, and correctly so, and I provided you with some of the information for the slides, about all of the upcoming studies. There are six studies. Four of them are randomized, two are observational. The largest of those is a Canadian study and observational study which will have about 15,000 patients before and after.

Now, we have, and you haven't addressed this, there are tons, hundreds of observational studies out there. You haven't mentioned them in your discussion. There have been at least seven randomized trials that you alluded to, and you pointed out correctly that those studies were mostly small studies. The four RCTs that you pointed out are small studies. You're going to get the results from those six studies, two of which, as I've mentioned, are observational. You're going to have to consider that data, that new data, together with the existing data.

I don't think there's going to be any one study or even those six studies together that are going to definitively give you the answer. Science is an ongoing process, and I may have more to say about that later. But how are you going to analyze that data, even when you have it, and how are you going to make a decision? Because two or three years down the road you're going to have six additional studies in place, but you have to visit that data in the context of the existing database, and that has to be analyzed.

And as you know, Sonny, Steven Vamvakas and I have suggested that a metanalysis of individual patient data be done on the poll data. We put a proposal to do that into three agencies in Canada and the United States, and those three grants were rejected, primarily because the data was seen as not relevant. It was mostly from Europe. But I think you need to consider how you're going to analyze the new data in the context of the existing data.

DR. DZIK: Well, I won't repeat the question.

[Laughter.]

DR. DZIK: To respond to your first part about the fact that it's not one or the other, Canada has done both, Canada has both put in filtration and has tried to address safety. I would just, I want everybody to understand that the Canadian reimbursement system is not the same as ours. If you don't understand that, you're--

So Canada is Canada. We're speaking American English today, not Canadian English. So I think the Canadian experience and the experience in the United Kingdom, for me, are interesting for one reason that's occurred in both countries. Following the implementation of universal leukoreduction in each of these countries, they've looked at their hemo vigilance data, that data I've shown you in those pie charts, and they said, "You know, we still have a problem."

And so now they're spending money on what they should have done in the first place, which is Canada and the United States are developing transfusion safety officers to try and throw some additional people at the problem of the process that's there. The United Kingdom is investing the equivalent of what would be in the U.S. $30 million in the first year alone, specifically to look at problems of wrist-banding difficulties that they're having, drawing wrong patient samples, mistransfusion of patients.

So the U.K. has awakened to the fact that they had to take, and they did take, probably for them, the correct political decision regarding mad cow disease, but that that didn't address transfusion safety. And so now they're getting around to doing that this year. So I think that experience is interesting, but its reimbursement structure doesn't apply to the reimbursement structure in the United States.

Now, regarding the additional trials, you are right. They will need to be considered in the context of the previous trials. But what I've tried to tell you is that for the United States, we've got an N of 59, and if we wait a little bit, we'll have an N that's in the thousands. And I would submit that that's going to be better data upon which to make a scientific-based decision.

Dr. Snyder? My longstanding friend, Dr. Snyder.

DR. SNYDER: You showed this table, the time line, which was very appropriate, and commented on how the weakness was on the right side and not on the left side.

DR. DZIK: Right.

DR. SNYDER: But is it not, clearly, it's a multifactorial concern, transfusion safety. One implementation of any event is not going to change everything. So you have to sort of look at nibbling away. Would it not, for example, make for a safer airplane if you had come up with a jelly gasoline that worked well or a material for the seats in a plane that didn't burst into flame and aid smoke poisoning and so forth and supported the air frame of that plane? It wouldn't solve the whole problem, but it might make for some degree of safety because there isn't one intervention that's going to solve all of the problems.

Similarly, your own admission was that you had the risk of giving the wrong unit to the wrong patient. If you had a universal leuko-reduced system, that would at least minimize some concerns in that regard, and not everything. So it's a question of there is not one egg that's going to solve this problem in the basket. Is there not some benefit to starting with this? You may say that it's just too much money for the benefits you're going to be getting. We would probably part company on that point, but I think you have to start somewhere.

DR. DZIK: Yes. Mind you, don't misconstrue me. I'm not a Luddite, and I'm not against technology. I'm trying to speak to the issue of what are the priorities? Where do you spend your money? I couldn't agree with you more, Ed, that we need to attack the problem at a whole variety of levels, not just at one level. If I could have one thing, I'd have what's on the back end of most of your cars. If you go through toll booths, there's a little transponder on your car that will automatically know that your car just went through the toll booth and can deduct the toll right out of your bank account. If you think about that, that's an amazing technological event we all take for granted.

FedEx delivers 14 million packages a day, not a year, but a day, using advanced bar code technology, and they can tell you where your package is. I would like to see transponders on the wrists of people and on the bags, too, so that if you bring the wrong bag in the room, the thing starts rattling and beeping and says, "Don't give that blood." Because, you know, if it's leuko reduced, but it's the wrong ABO type, it's not going to do the patient any good at all.

DR. VAMVAKAS: Thank you, Sonny. We are going to hold the rest of the questions for the afternoon.

Next, Dr. Jim AuBuchon from Dartmouth will talk to us about the cost of universal leukoreduction. Jim is an expert on the cost-effectiveness of transfusion practices, but today he has chosen to talk about cost, rather than cost-effectiveness, for reasons that will become apparent pretty soon.

DR. AuBUCHON: I appreciate the opportunity to join you once again to discuss an issue that you know is of great importance to me. And also in the spirit of truthful disclosure, I should note that I, too, sit on the Scientific Advisory Board of HemaSure Corporation, I have accepted speaking honoraria in the past from Pall Corporation, and I have performed research studies for most of the companies that have apheresis instruments that collect leukocyte-reduced products. None of those individuals may necessarily be happy with what I'm about to say.

[Laughter.]

DR. AuBUCHON: Although you may expect me to speak against universal leukoreduction, that is not my intention. I will emphasize that leukoreduction is beneficial and cost saving for some patients. However, we do not have data to conclude that these benefits and savings will occur when applied broadly to all patients. I will echo the remarks of Dr. Dzik that selective application of a technology is the most common and wisest approach.

I will discuss cost of universal leukoreduction, but I will attempt to do this in a way that will allow you to see how else these resources could be better spent to save patient lives. It is not a question of whether or not to spend money or improve transfusion safety, it's a question of how.

Others have spoken about the benefits that leukoreduction may offer. While I will not be detailing these further, I will need to briefly mention some potential benefits that should not be tallied as a cost savings attributable to universal application of this technology.

The reduction in febrile reactions that may occur because of leukoreduction will be minimal for two reasons: First, most patients who are sensitized to substances carried on white cells are already receiving leuko-reduced components through selective application of this technology.

Secondly, there are alternative means by which fever occurs after transfusion. For example, patients can also make antibodies to foreign proteins carried in the plasma that they receive along with red cell or platelet transfusions. The vast majority of multiply-transfused patients develop these antibodies. These antibodies are entirely independent of transfused white cells, and removing the white cells will have no effect on the likelihood of reaction through mechanisms such as this.

If patients are not exposed to leukocytes in transfusions in the first place, they can reduce the chance of becoming alloimmunized and reduce the likelihood of becoming refractory to randomly-selected platelet transfusions. However, as with febrile reactions, the multiply-transfused patients already have the selective indication for receiving leuko-reduced components.

Leukoreduction is most successful in avoiding HLA immunization in patients who have not been exposed to white cells before. Most of these prior exposures come to women during pregnancy. Only a few are attributable to transfusion of components that were not leuko reduced prior to the recognition of the hematologic disease that will require multiple transfusions. This has prompted some, as you've heard, to call for universal leukoreduction to ensure that these patients will receive the benefits of filtration.

A study at our hospital noted that fewer than 10 percent of patients with leukemia transferred from outside hospitals in Northern Hampshire had ever been transfused before. Therefore, implementing universal leukoreduction to prevent these exposures would affect very few patients. Furthermore, a failure to provide a leuko-reduced unit when there is a special indication for it is a symptom of the kind of systems failure that represents the real threat to patient safety. I will return to this later.

Most of the medical and economic benefit projected for universal leukoreduction is related to avoiding the effects on the recipient's immune system that exposure to a donor's white cells may bring. Whether the immune system changes have clinically-important effects remains uncertain, as you've heard. I've spent the largest portion of my academic career in the 1990s in the field of decision analysis, cost-effectiveness analysis in particular. And I have been asked on more than one occasion to construct a cost-effectiveness analysis for universal leukoreduction. So far I have not undertaken such an analysis because I feel that I cannot accurately define the benefits, if any, that will be achieved. With the new data being collected right now, I may be able to do this analysis soon, but at the moment the benefits are just too elusive to quantitate.

What about other reasons to apply leukoreduction universally? The decision to implement universal leukoreduction in several European countries was, according to colleagues there, in response to public concerns about mad cow disease. We have the information now to know that prions are present free in plasma, and the Transmissible Spongiform Encephalopathy Advisory Committee of the FDA has failed to endorse leukoreduction for safety against variant Creutzfeldt-Jakob disease. Therefore, I will not consider the possible effects of this disease in my analysis.

So what will universal leukoreduction cost, and where are these costs coming from? The incremental processing fees charged by blood suppliers in this country for leuko-reduced units vary by a factor of two. This difference may reflect how many of the ancillary or hidden costs that I will describe the supplier is including in the calculation. This range may also reflect the need of some suppliers to bolster their revenue through this additional service. I do not have access to the internal documents of blood suppliers to resolve this dilemma entirely, but I will be able to give you a good estimate of the cost of universal leukoreduction from several resources.

There are many ways to remove leukocytes from blood components. Filters can be used as part of the collection set or sterily docked onto the unit before storage or used at the bedside. Components collected by apheresis can be collected in a manner that excludes most leukocytes. Any of these approaches require special equipment and some personnel time.

There are also hidden costs of leukoreduction related to the many aspects of good manufacturing practices that apply, as well as logistic issues. In particular, the quality control requirements proposed by the FDA are substantial in number and are even more substantial when it is realized that the counting of leukocytes in leuko-reduced units currently, in general, must be conducted by a time-consuming, special manual method.

What to do with a batch of units that fails quality control checks where leukoreduction has not been clarified. If all units are required to be leuko reduced in the country, one cannot simply issue the nonconforming units as regular units. Either significantly more quality control counting will be necessary or the units will not be transfused, either of which represents a large cost to the system and possibly a negative effect on patient care.

Unfortunately, units of red cells from donors with sickle-cell trait do not filter well, as you've heard. This means that there will be fewer units from African-American donors, with their special red cell phenotypes, available for support of sickle cell disease patients. It also suggests that additional quality control checks may be needed. Thus, there are many costs to universal leukoreduction beyond just the cost of the filter.

An independent study to define the economic impact of universal leukoreduction was commissioned by the Canadian government several years ago. This study looked at the costs and projected benefits of applying leukoreduction to all patients in Canada or to just those likely to be transfused multiple times, and it looked at the cost according to whether the leukoreduction was performed at the blood center prior to storage, at the hospital after storage or at the patient's bedside immediately before transfusion.

For a variety of reasons, as you've heard, most American hospitals prefer any leukoreduction to be performed at the blood center prior to storage, and I will concentrate on the economics of this approach. I have taken the estimate of the Canadian government, converted it to U.S. currency and scaled it up to U.S. annual volumes. This estimate suggests that using leukoreduction for all multiply-transfused patients would cost relatively little because of the amount of components used by this group and because of the benefits that these multiply-transfused patients receive from selective application of leukoreduction.

However, leuko-reducing red cells and platelets for all patients would cost about $660 million above the basic cost of securing blood components. This is the cost of leukoreduction. What hospitals, and therefore the health care system, would pay for it would undoubtedly be higher.

We must also account for multiply-transfused patients already receiving leuko-reduced components for specific indications. This group has been estimated to require about 20 percent of all transfusions in the U.S. One would then calculate an increase in cost to extend leukoreduction to all U.S. patients to be about $534 million. It should also be noted that this independent governmental analysis included that the health benefits purported to accompany universal leukoreduction would have a small impact on health care costs overall and certainly come nowhere close to covering the costs of leukoreduction. Thus, from this approach, we would estimate that universal leukoreduction would add about a half a billion dollars annually to health care costs in this country.

How does this estimate compare with the direct costs we know of? The least-accurate way I have to project leukoreduction costs is from direct costs, since these do not include all of the hidden or indirect costs. As I've mentioned, nor do they include production labor costs. However, based on transfusion volumes in this country and the costs as I know them, the annual direct costs for providing all red cell and platelet transfusions as leuko reduced would be between $360- and $680 million, as compared to nonleuko-reduced units.

It is unlikely, in my opinion, that we will stop with red cells and platelets if we go to universal leukoreduction. Despite the absence of even clinical suspicion that the fewer number of white cells and plasma are troublesome, at least one filter manufacturer and one blood supplier have already suggested that leukoreduction should be applied to plasma as well. This would add approximately another $75 million to the annual cost of leukoreduction or, in other words, this calculation approach concludes that universal leukoreduction will cost about a half a billion dollars annually. Now, this may sound like small potatoes in Washington, but it represents an amount equal to about one-quarter of the entire blood acquisition budget of the transfusion service that is, as Sonny has noted, operating on a budget.

These calculations are comparable in their outcomes to the experience of the British. The United Kingdom's national health service estimated that conversion from selective to universal leukoreduction would cost 35 million pounds. Converting to U.S. currency and scaling to U.S. volumes, their experience would predict a cost of $672 million annually or, in other words, about a half a billion dollars. Thus, although some details are lacking from each of these analyses, their common result lends credence to the estimate.

One of my esteemed colleagues has estimated that the increased cost of leukoreduction could be managed within a fixed blood bank budget by saving on other items. As Dr. Snyder noted, clinicians could be encouraged to use more conservative transfusion triggers, thereby transfusing purer units, instead of using apheresis platelets, pulls the platelets from whole blood units which are lower in cost, might be used more frequently. The number of units used in such pools might also be reduced.

Finally, since HTLV-1 and HTLV-2 are transmitted via leukocytes, testing for them might be dropped, saving one or two dollars per unit in testing costs. However, all except the last of these could be accomplished without shifting to universal leukoreduction. And many hospitals already have accomplished all that they feel they safely can in these areas without reducing transfusion effectiveness and safety.

Furthermore, it is unlikely, I believe, that the FDA would condone dropping a sensitive test for a pathogen in favor of a less-effective approach to prevent virus transmission. Thus, the potential for most hospitals to make up the cost of universal leukoreduction in other ways is very limited.

The cost of universal leukoreduction is substantial, but it is really immaterial. If universal leukoreduction is shown to be beneficial, it will undoubtedly be implemented. We will soon have the answers regarding universal leukoreduction potential for improvement. For me, the important question is whether we should commit resources now when we already know we have larger problems to deal with.

The financial plight of hospitals is often mentioned. The limited resources available to them and, more specifically, allocated to transfusion services is well understood by those working in the field. Requiring that additional resources be directed toward leukoreduction may have unintended effects of causing more problems than the requirement might be expected to alleviate.

In a 1997 survey of the College of American Pathologists, 8 percent of responding transfusion service laboratories noted that they had recently made operational changes due to budgetary constraints that had reduce the safety of transfusion, and 6 percent noted that they had observed an increase in the number of significant errors because of changes associated with financial constraints.

Similarly, a prominent academic institution reported last fall an 80-percent increase in transfusion service incidents over the last seven years and a quadrupling in the number of patient sampling errors. We do know how patients can be harmed by transfusion, and we do know how to make transfusion safer. If we allocate resources to other areas, however, these major threats will go unheeded.

For my hospital, a small academic hospital, converting from selective universal leukoreduction would add 20 percent to our blood acquisition costs on top of a 10-percent general increase we recently received from our blood supplier. Is this how we should be allocating our resources?

As mentioned by Dr. Dzik, the biggest risk faced by a red cell recipient is receiving the wrong unit of blood. One way to reduce this risk is to implement a comprehensive quality improvement system that encompasses all aspects of sample acquisition, pre-transfusion testing and patient transfusion. This committee has previously heard about and been excited by this approach to error reduction. However, lack of resources to implement such a system is the most frequently-stated reason for not using them. And over three dozen hospitals drop out of the AABB annually, most often citing inability to meet its quality assurance requirements.

A transfusion safety officer's salary to help address issues of quality improvement would amount to only a dollar or two per unit and allow us to track problems with transfusion and fix them. From purely an economic perspective, investment in preventing mistransfusion at three to four dollars per unit for a barrier or for an electronic system shown on the slide would cost one-tenth the cost of leukoreduction. An automated system designed for reliably typing patient samples in a medium-sized laboratory would cost my hospital one-quarter of just one year's cost of conversion to universal leukoreduction would be.

Universal leukoreduction would cost far more than these interventions. Would it improve patient care? Well, we don't know yet. Do we already know ways to save more lives at less cost? Absolutely, yes. Approximately two dozen fatalities, two dozen fatalities occur every year in this country from patients receiving the wrong unit of blood, and more undoubtedly are not reported. Taking steps to prevent this problem would have a direct, positive and predictable benefit for transfusion recipients.

Bacterial contamination of blood products, platelet units in particular, remains a major threat to transfusion recipients. High-tech solutions to detecting bacteria and blood components are under development. However, even today we could culture platelet units to determine whether or not they are sterile. This costs under $20 per transfusion or less than 10 percent of the annual costs of universal leukoreduction.

Based on data from the intensive French study and on data from the CDC, the risk of death from bacterial contamination is approximately seven per million platelet transfusions. That means that 15 to 20 patients die every year in this country from bacterially-contaminated platelet units, deaths that could be averted by spending far less money that universal leukoreduction requires and instead culturing platelet units.

So what's the bottom line? It's clear that universal leukoreduction will cost the United States a lot of money, approximately half a billion dollars annually. There are other innovations that can prevent documented dangers that are far less expensive. What would I suggest? I believe that all connected with transfusion medicine should focus their attention and their energies on the problems that posed the greatest risk for transfusion recipients.

Regardless of media attention, we professionals in the field should transfer our primary attention away from viruses or, now, universal leukoreduction to mistransfusion and bacterial contamination and quality improvement to ensure the safest possible transfusion for all patients. The FDA should bolster this redirection with regulatory action to spur us on. This committee should encourage the FDA along this path and lead the new administration towards the wisest application of health resources.

We should continue to use leukoreduction where appropriate, where it can help a specific patient for a specific reason, and ensure that all patients who can derive benefit from it are provided this intervention. We should not apply resources indiscriminately.

None of us should get caught up in media hype, pseudo-scientific speculation or wishful thinking that universal leukoreduction is the greatest thing since sliced bread. We will soon have important additional information about what it may do for us, and we should and must take appropriate action that is commensurate with proven benefits. However, leukocytes in blood do not represent the next AIDS epidemic. They are not unknown and they are not untracked. We have developed a successful hemotherapy in their presence over the last 50 years. We should not miss the proven opportunities to improve the transfusion process further by directing our attention toward documented risks while chasing after potential ones.

Now, there is much more to this economic analysis obviously than financial cost. Universal leukoreduction has a potential human cost in distraction, distraction from the greatest dangers that recipients face through the transfusion process, and this cost should not be ignored.

Thank you.

[Applause.]

DR. VAMVAKAS: Thank you, Jim.

Karen?

MS. LIPTON: Yes, Jim, I just--all of the figures that you calculated were based on an increased cost because it's assumed that we're 20 percent. Now, my understanding is that really in the U.S. we're closer to 40 percent; am I right about that?

DR. AuBUCHON: The latest data that I have seen, and they do not come from a blood supplier recently, so they may be somewhat out of date, come from Tim Goodenow, Washington University, from about a year ago, at which point his data indicates about 20 percent in the United States as a whole. It may well be higher than that because of the push recently by many blood suppliers to shift toward universal leukoreduction. Nevertheless, that represents an expense that may not have benefit attached to it.

MS. LIPTON: And I was just looking at the incremental costs from where we are here today because I think it's unlikely that people who are using it now will stop using it, no matter what happens in this committee or the FDA.

DR. AuBUCHON: Well, I would imagine that Dr. Snyder will probably not stop using leukoreduction universally no matter what this committee might suggest. But there are many hospitals that have essentially been forced by their blood supplier to convert to leukoreduction, being told that that's the way it's coming out the back door. If you want blood from us, that's the way it's coming. And for those hospitals, they may well revert to selective application of the technology if they have the opportunity.

DR. VAMVAKAS: Yes?

DR. HOOTS: Jim, I'm a little confused about this 20 percent. I mean, I know where a significant subset of it comes from oncologic and aplastic patients. In terms of the HLA alloimmunization relative risk and relative benefit, some of the studies that have been alluded to today do cite a slight improvement or a slight decrease in alloimmunization which, I don't know, I couldn't infer from because I didn't have the raw data in front of me, whether that actually translated to an improved clinical outcome related to either prior transfusion or pregnancy.

Now, obviously, pregnancy represents a significant subset of the total recipient population, a substantial percentage obviously of half the population. Is that enough of an issue, the HLA alloimmunization related to women who have formerly been pregnant, in terms of their relative risk for subsequent alloimmunization relative to men or to nonpregnant females, and does that, in any way, contribute to the targeted N that you would choose who are ideal candidates for leukoreduction?

DR. AuBUCHON: I certainly would not want to speak against motherhood or the benefits of motherhood, even if it does have some side effects, including the potential for HLA alloimmunization. There are relatively few studies that have attempted to address this in the transfusion literature. But the ones that are there are similar to the one slide that I showed that indicate that those individuals who have been pregnant prior to being exposed to any blood component are more likely, at the beginning of their therapy, before their first exposure to transfusion, to be alloimmunized. Obviously, this would not apply to the male half of the population.

Therefore, the potential benefit is uncertain for the group that has already been previously exposed, although for most women, they would have been exposed to pregnancies from a relatively small number of men, and therefore would not have been broadly exposed to a large number of different HLA antigens.

HLA antibodies are interesting, however, in that they are unlike red cell antibodies. If a patient is immunized to a red cell antigen, for example, if you are Rh negative and receive an Rh positive unit and make the Rh antibody, you will remain immunized for life and all future transfusions will need to be negative for that antigen in order to have the red cells survive.

That's not true with HLA antigens and antibodies. In fact, HLA antibodies can disappear during continued administration, continued exposure to the HLA antigens. The cause for this is not clear, but just because someone has been exposed to nonleukocyte-reduced blood after a bicycle accident at age 14, does not confine that individual to HLA alloimmunized in perpetuity. HLA alloimmunization does not occur after the majority of single-unit transfusions as far as we are aware. It's usually seen after multiple transfusions and does not necessarily last the lifetime of the patient.

DR. DAVEY: Jim, just following up on Keith's question a little bit. We're do know that 20 percent of patients may require leukocyte-reduced products, but I'm not convinced that 20 percent or 100 percent of the physicians or surgeons in this country know exactly who to order that blood for. I mean, we have a group of experts here that obviously are clear on this, but many physicians and surgeons aren't, so that some blood might be misordered, patients who require it may not get it, a problem that would be solved, perhaps, by universal leukoreduction and those costs identified, of course, with patients who are inadvertently injured by this.

Can you comment on that, please?

DR. AuBUCHON: A good point. Let me address platelets and red cells separately. Platelets are transfused primarily to hematology and oncology patients. At our institution, over 90 percent of all of our platelet units are transfused to hem/onc patients. Our hematology and oncology staff and, I believe, in general, hematologists and oncologists are very familiar with the benefits of leukocyte reduction for their patients. And although certainly some errors in ordering could occur, I think most hem/oncs would order leukoreduction appropriately, and particularly for a platelet transfusion.

For red cell transfusion, the majority there are not performed, not given to hematology or oncology patients. And in a system where you are depending upon the clinician to order the correct component or the component with all of the right attributes, you do run the risk of an error being made. The approach that we have taken at our institution is a little bit different than that from Mass General. Rather than placing the burden on the ordering physician, even with some prompts and some assistance to instruct them, we have taken the burden on ourself in the clinical laboratory, and that is that we simply provide leuko-reduced blood for all patients on the Hem/Onc Ward. And for patients in surgery, we require them to answer a question as to whether or not the patient has or is suspected to have a malignancy.

But for all other patients, we look up their diagnosis in our computerized medical records system in order to determine for ourselves whether or not they would benefit, and we have a standard list of selective applications of leukoreduction that our Transfusion Committee feel could be supported by the published literature. So we have taken that burden on ourselves.

We have taken the additional step, since we have a computer system in place, to treat the requirement for leukocyte reduction as we would treat a red cell antibody, and that is that the unit must have that attribute of being leukocyte reduced before it can be released, signed out on the computer system to the patient who needs selective leukoreduction.

These techniques are being applied in university hospitals, that's true, but the techniques are ones that are becoming extremely common across the country and computer systems are no longer confined to just the larger institutions. Also, those patients who have complicated hematology and oncology cases who are more likely to be multiply transfused are more often cared for in those institutions.

So I believe that there are simple mechanisms that will cost some resources, but are relatively easily applied that would address that concern.

CHAIRMAN CAPLAN: Jim, I heard you say that you didn't want to do the cost-benefit because the benefits were not clear yet. Then you struggled very successfully to talk about the cost issues, and then sort of gave us some things to think about about benefit.

I'm curious, though, knowing you somewhat, as you review the European literature and capitated systems, where choices have to be made, too, or Canada about process safety versus product safety, what does their experience show in terms of cost-benefit and the actual impact on the cost of providing blood services there? We've heard people say, "Well, look, we went to universal leukoreduction, and we've appointed the blood safety officers too." And as far as I know, every one of those countries is a capitated system of reimbursement.

DR. AuBUCHON: They are capitated, that's true, but the reimbursement is tied to the same governmental agency that sets down the requirements for delivery of health care, where that connection does not occur in this country.

There are two studies that I can think of that directly address your question having to do with cost after implementation of universal leukoreduction. One is a Danish study, which indicated quite large cost savings associated with universal leukoreduction. However, there are some methodologic interpretation problems with that study, and I don't intend to go into all of those right now, but it's not widely accepted in this country as being applicable.

The other is Dr. Vamvakas's study, and I will let him comment on that, but it was clear from his study, as he pointed out, that the issue of being transfused at all is a poor prognostic factor and that as you address the presence of more and more co-morbidities in the patient population, you explain away more and more of the apparent transfusion effect. And so if you only account for ten co-morbidities, you have a larger transfusion effect than if you account for 20. And maybe if you went as far as to go to looking at 30 co-morbidities, which becomes a horrendous study, there may be no transfusion effect apparent at all.

MR. DALAL: Jim, there's been suggested that the cost of leukoreduction could go down over time. Now, if this were an industrial product or a consumer product like a hand-held calculator or the cost of delivering a letter overnight we could see how economies of scale, et cetera, would bring the cost down.

Do you see that there are such economies of scale in the manufacturing or learning curve effects in the use of the product in blood banks that would result in reduction of the cost over some period of time?

DR. AuBUCHON: Certainly, to go from a zero volume to some finite nonzero volume, there is a hump of inefficiency that must be overcome. I think we are probably well beyond that already in American transfusion medicine with somewhere between 20 and 40 percent of units currently being leuko reduced. Blood centers know how to do it. What would be needed now would be additional staff or additional equipment. I would not expect to see huge economies of scale occur at this point at the level of the blood center.

I'm really not in a situation where I can speak to the economies that might be achieved at the manufacturing level. I can only state that as a customer, as we have seen the use of filters increase dramatically over the last several years going from somewhere less than 10 percent of components being leuko reduced to somewhere 20 percent or above at the moment. We haven't seen those cost savings yet. Probably competition in the marketplace is going to be much more important than any efficiencies of scale at the manufacturing end.

DR. VAMVAKAS: Dr. Busch?

DR. BUSCH: Jim, just you mentioned the issue of filtering plasma. And I think it's something that could drop through the cracks through the rest of today, so I thought it would be worth focusing on for a minute. I'm aware that in Europe some of the derivative manufacturers have pushed in their perception or marketing of safety to use pheresis machines that result in a lower leukocyte content. But to my knowledge, there is no evidence that the leukocytes, the very low level of leukocytes in fresh frozen plasma have any adverse consequence for recipients. And I'm concerned about that being brought along for the ride here and it being a marketing issue.

I'm curious, one, whether any of the speakers on the panel have any evidence or have a feeling as to whether there's any justification for filtering plasma. And, two, I was trying to browse through the FDA document, but I didn't see, they talk about all transfusable components being leuko reduced, but I just wanted to be clear, and perhaps Jay could comment on whether FDA has addressed the issue of plasma.

DR. AuBUCHON: Do any of my colleagues have any data to address leukoreduction in plasma?

DR. BLAJCHMAN: I think the answer is that there are no data except the sort of quantity of leukocytes that is present in plasma. And I don't remember the numbers offhand, but it's quite significant. So I think one can anticipate that some of the alloimmunization and possibly some of the other effects.

The other point that I would make with regard to that is that in Canada, where we do have universal leukoreduction, we don't have to specifically filter the plasma, the residual plasma, the FFPR byproduct. Leuko-reduced plasma is a byproduct of the processing that's currently in place; that is, of the universal leukoreduction process.

DR. EPSTEIN: We addressed this issue on Page 7 of the draft guidance. We do not cite any known data, either on adverse effects of nonleuko-reduced plasma or on any purported benefits of leuko-reduced plasma. The only position that we take in the document is that if a product is to be labeled as leukocyte reduced, then it should meet the same standard for residual leukocytes that is being promulgated for other components. But we are not, in the document, taking a position to encourage it for plasma or discourage it for plasma.

DR. VAMVAKAS: Any other answers to the question?

Dr. Gomperts?

DR. GOMPERTS: If you're asking the question in regards to plasma, the question should be asked, what about cryoprecipitate?

DR. AuBUCHON: I do know that the leukocyte content of plasma units, according to published studies and our own experience when we've looked at this, can extend upwards to the neighborhood of ten to the seventh white cells per unit, not that every unit has that number. But a whole blood-derived unit of plasma has approximately ten to the seventh.

Cryoprecipitate, I am not familiar with any data on how many white cells end up in cryo.

DR. VAMVAKAS: Sonny?

DR. DZIK: I just want to make a comment about the plasma just to remind the committee that content and FFP, in some studies you may read, is a measurement drawn before the plasma is frozen and that the act of freezing plasma is very, very deleterious to living cells. There's no cryo protectant. So what you get, we don't give the patients frozen plasma, we give them thawed plasma, and in the process of thawing, any decision about this really needs to be regarded on, first of all, if you're doing counts, you want to look carefully to make sure this is counts done after you've already thawed the product.

And then, secondly, you should have a suspicion that the biologic effect of previously--of cells that have undergone a freezing step that may not be the same with regard to alloimmunization and all of that stuff compared to a fresh living cell. These cells are generally dead.

DR. VAMVAKAS: I was just about to say we will hold the questions for the afternoon, but just one more.

DR. KLEIN: I just wanted to comment on this issue because it said plasma, and there are different kinds of plasma, as everyone knows. There's plasma that's relatively fresh, there's plasma that comes off stored units as in refrigerated, and then of course there's fresh frozen plasma. Most of the plasma used in the United States is, in fact, fresh frozen plasma. And while you can still count white cells in fresh frozen plasma in sometimes substantial numbers, anecdotal information suggests that this isn't harmful. There are no good studies.

But just addressing the three issues that we've addressed for leukoreduction, there's almost no evidence, in fact, there is no evidence, that CMV is transmitted by fresh frozen plasma. Alloimmunization, the studies are poor, but there's no evidence that alloimmunization is a function of fresh frozen plasma. And febrile reactions, as I'm sure you know, are almost unheard of, although they do occur occasionally with fresh frozen plasma.

There is one study from Dr. Paul Holland's laboratory in Sacramento suggesting that the white cells or lymphocytes that persist in fresh frozen plasma have in vitro function, but I know of no data that suggests that there's an adverse effect to the recipient of those components.

DR. VAMVAKAS: Thank you.

Dr. Sandler, from Georgetown, will now give us a further perspective from the hospital and the patient.

DR. SANDLER: My name is Jerry Sandler. I'm a professor of medicine and pathology, and I direct the blood transfusion service at Georgetown University Medical Center here in Washington, D.C.

I've practiced hospital-based hematology for 32 years, which involves a lot of blood transfusions, except for 12 years when I was the associate vice president and the chief medical officer at the national headquarters of the American Red Cross. And during those 12 years, I worked very closely with colleagues at the FDA on blood safety because I was Red Cross's designee for the FDA license to operate.

During those years, I think we were advocates, very aggressive advocates, for blood safety. On my watch, we introduced anti-HIV testing, ALT testing, antibody Hepatitis B core testing, antibody to HTLV-1 testing, and we laid the template for HCV testing, which continued while I was still at Red Cross.

I drag you through that history because somehow on today's agenda I seem to be put in the corner of someone who's against something, and I'm really not against. I'm for doing things right. And as Dr. Mo Blajchman said, science is an ongoing process, and the number one reason that we do not want to regulate this is you will stop science dead in its tracks because you can't do studies.

The viewpoint that I want to present to you is that the data are inadequate for a federal regulation to require, and I have italicized universal leukoreduction. And I think everyone has made the point. The issue isn't whether leukocyte reduction is good or bad. It's good. It's fine. The issue is whether you want to override doctors and stop science at this point in time, and you don't. Universal leukocyte reduction would halt randomized studies and prevent further studies of a potentially important effect. We will no longer be able to go to our patients and say, "We want to find out something. We'd like you to get either leukocyte reduced or not because we have to study this further." Science is an ongoing process, and we can't do that any more because it would stop dead if we went forward. I want to tell you three stories.

Story one: And Dr. McCurdy, like me, remembers this. It was 1966 when the observation was made that leukocytes in the red cells that were given to dialysis patients caused acute rejections of their kidney transplants. And based on that science, nationwide, the American Red Cross provided leukocyte-reduced blood. It was frozen, thawed, deglyced, nationwide. Fortunately, the FDA held back and did not make a regulation because a few years later science just went upside down, and it was shown just the opposite that giving transfusions actually helped people get kidney transplants, and it became the practice to do that. And now we use Cyclosporin.

If you stop with the regulation before science is finished, you do an awful lot of harm.

The second story is the VATS story. My hospital, Georgetown University Hospital, was invited to participate in a very important randomized, multi-center, blinded, controlled study of leukocyte-reduced red cells. The hypothesis at the time was this: If you give leukocytes with transfusions, it will cause perturbations in the immune system of HIV-infected people and CMV-infected people such that the infections won't be controlled as well, they will progress, and there will be an adverse outcome.

Well, given all of the observations that we've all heard and the confusing and blurry science that we've heard, we were very reluctant to do that, to withhold from our patients the benefits of leukocyte reduction, but we went along with the study. We went along with the randomized blinded study so that patients with HIV and CMV infection either received leukocyte reduced or nonleukocyte reduced. And I worried like hell about that because, gee, I thought I'm depriving people of the best of science.

Well, the results are in, and Dr. Busch is a major investigator, and you have to keep me honest, Michael, if I don't get the results right. The results showed that HIV infection and CMV infection did not progress to the point in either group that you could see a difference. The ultimate measurement was death. And if I understand the study right, using leukocyte reduced and nonleukocyte reduced could not be shown to make a difference in the final outcome. Also, to our great surprise in this population of patients with HIV, there was absolutely no evidence that using leukocyte-reduced blood prevented febrile transfusion reactions.

The point I want to make with the second story is that science is ongoing, as Dr. Blajchman said, as recently as now because this study isn't even published yet, but it has gone through peer review and a variety of other things. There's a lot of information out there that you don't want to stop. You just don't want to stop that information. And the kinds of assumptions that went into that study that turned everything upside down must go on until the science is clear.

Third story: The phone rings this morning, 5:00 in the morning. "Dr. Sandler, one of the patients has had a very severe febrile transfusion reaction. He's having rigors now." Last night I met with the family, who are very informed about leukocyte reduction, and made sure that that patient received leukocyte-reduced blood, pre-storage by all of the material that has been marketed and made available to the family. The patient had the worst febrile hemolytic transfusion reaction that I've seen in the last six months in my hospital. Filter failure. You're not going to blow this problem away by regulating a filter. The science isn't ready for this, and the filter isn't of a quality that you want to regulate it, so we've got to do it. Leave this decision to doctors, at least for the while.

Why are we having an urgent meeting today? There is no acute public health danger requiring drastic action today. This is not AIDS, where something new has happened. It's not CJD, it's not mad cow disease. Those are the kinds of situations where something new happens, and when something new happens you've got to have an urgent meeting in Washington and get the Feds in, and you've got to regulate and you've got to do things that individuals can't do.

You know what? We have been transfusing blood like this for 60 years. For 60 years this kind of blood with leukocytes in it has been given to people in the United States of America. If it is so bad that the Feds have got to come in today and regulate it, I don't know where we've been because we've been looking at this problem for 30 years. I don't know how you read through this stuff this past weekend because you got the same stuff I did. I couldn't figure heads or tails of this 30 years of work. This is not something that's baked enough for a regulation. This is only half-baked.

Today's meeting is urgent because policies and business plans have caused the public outcry by hospitals, and that includes mine as one of them, nationwide that are being forced to accept, to pay for and to transfuse leukocyte-reduced red cells that are not ordered by the patients' physicians. I got a letter from my community blood supplier many months ago, "We're going to start sending you leukocyte-reduced red cells, and we're going to charge you $40."

And I wrote back and said, "Thanks, but no thanks. I'll continue to order what my physicians want," and by the way, the training of them is done by me. We have meetings with each department, we go over this, and leukocyte reduction is one of the top issues. I do present both sides of the issues very, very carefully. People order through a computer. They have their choices. The choices are there.

Well, what happened? We start getting this blood. And I came before this very committee, and I said to you, You know what last month happened? I got a bill for $20,000 for blood that I didn't order and about 200 physicians' orders were changed by the process of my local blood center meeting a production goal. Some administrator had a production goal that he had to achieve so much leukoreduction. So we got the stuff, we had no choice, we had to pay for it, and we changed doctors' orders. Let me tell you, if a nurse on the ward read one of the pro articles and changed the order, and then afterwards said to me, "Look, Dr. Sandler. I read this stuff. There's immunomodulation and there's all these terrible things that I've read about so I changed the doctor's order, and I made sure the patient got the leukocyte-reduced blood," we would have fired the nurse. I wish I had a way to fire the person that made us change those orders.

But the worst effect, the worst effect is one that you also know about because I was before this committee to show you a bar code reading--this is my Palm Pilot, but it looks just like it--a bar code reader. We were the first hospital in the United States of America at Georgetown to start bar code reading that went through the whole system because a major problem in the United States is errors, and we didn't have one, but we didn't want to have one. Well, that was April. I was ready to move this into oncology for $37,000, but I had a $20,000 bill to pay for blood I didn't order that someone thought better for my patients than the own physicians. Safety became hijacked at my hospital. We couldn't buy this, and we haven't been able to buy it since because someone knows better for the patients than our doctors.

What are the arguments that are made for not waiting until we get really convincing science or a medical consensus? The first argument I hear is: Well, no study could be conducted to prove the benefits of leukocyte reduction. I have two comments on that; one, if it's not that obvious after 30 years, we really have to think carefully today before we force this on American medicine.

The second is you heard from Dr. Dzik that you can do studies, but you won't be able to do them, as you pointed out, if you close the door today.

The second argument I hear is: Waiting for convincing evidence, and I put it in italics, like the AIDS epidemic, will be too late. That's the bogeyman argument. This is not something new. This is not like the AIDS epidemic. There is no reason to rush into this because something new has happened.

Third argument: Europe and Canada have taken the lead in blood safety. Boy, would they like you to validate their decision. They can't wait for you to validate their decision. There is no medicine in the world better than American medicine because we've made the right choices. You mustn't rush into this for other reasons. We have guests from Canada. We have guests from Europe today. I won't comment on that further.

A purer product is a better product. Let's talk about what goes on in the X-ray business because that was brought up as a model. There are some X-ray machines, MRIs and CTs, that can make clearer pictures. They can give you clearer pictures, clearer definitions, they can even find smaller, little lesions, but because they have not been shown to be able to detect cancer earlier and give a better outcome, they aren't being fostered on hospitals in the American public.

Until outcome data show that they work better, the concept that I make something purer or I can make something clearer or I can make something technically better is not the way to go in medicine. The way to go in medicine is to show that the outcome is better.

The last argument I hear is: The blood suppliers can't manage two inventories. That's baloney. Let me tell you how that's being done now and how it should be done. We've heard that in patient populations 20/30 percent are a good selective audience. That's about the way it sort of breaks down. It turns out in Washington it's not that way because 100 percent of the CEOs of every hospital in Washington wrote to the blood supplier and said, "Hey, we don't want it." But let's say that about 30 percent of hospitals in a community make a decision and their physicians want it or maybe it breaks down in some way that 30 percent of doctors, however you want to go.

The decision in this community has been those that want it will be subsidized by hospitals like mine that don't want it. That's the concept of universal. So the hospitals, 30 percent in this community that want it, they don't have to pay for the real cost of the change that they want. They get it by having my hospital go into something that we don't want and a lot of patients getting something that costs more that don't need it. And then that lowers the price so it can be $30 or $40 surcharge for those that want it.

That's not the way to do it. If someone wants something special and new, they want nuts or chocolate things on their ice cream instead of plain vanilla, they pay a surcharge for what they want. So they want it, let's say it's 30 percent. The inventory gets filtered to a point of give them a 20-percent margin, 50 percent, and they can get everything that they want, and they can pay for the cost of the change in the community that they want. You don't have to go to universal to give the people what they want.

I have no objection to receiving leukocyte-reduced red cells. They're fine. I've got no objection to that. They're not bad. It's the federal regulation that everything has to stop and be universal that's bad. So if they filter 50 percent in my community, they send 30 percent to the hospital that wants it, and they have to pay for the other 20 percent margin so they can be sure to get it, it's perfectly possible.

That's all I have to say today. Thank you very much for your time.

[Applause.]

DR. VAMVAKAS: Thank you very much, Dr. Sandler.

Questions from the committee?

[No response.]

DR. VAMVAKAS: From the floor?

[No response.]

DR. VAMVAKAS: Well, the presentation was so convincing that nobody can possibly ask for clarification.

DR. BLAJCHMAN: We'll move on to the next speaker before the final summaries.

Dr. Paul Ness from the Johns Hopkins University, who is head of Transfusion Medicine at that institution, will share with us his thoughts about the issue on the table.

Paul?

DR. NESS: Thank you, Mo, and thank you, committee, for allowing me to give you my thoughts on the issue of selective versus universal leukoreduction. I guess I don't thank you, though, for making me number six because you've heard a lot of detailed presentations, many of the things that I'm going to say have sort of been alluded to, but perhaps I will put a little bit different perspective on this.

First, in terms of conflicts, I could show you a laundry list of all of the companies I've worked for, and I don't remember them all. I'll just say that none of them are going to influence my thinking on this issue. I speak as an individual. I'm also the immediate past president of the AABB, and what I'm going to say is not AABB policy, it's my own thought.

I previously worked as the CEO of the Chesapeake and Potomac Region of the American Red Cross. I still work there part time as a senior medical director, but, again, the opinions that I'm going to state are mine. Although the experience of working in the Baltimore-Washington community and seeing how transfusion medicine is actually practiced in some smaller hospitals than mine, I think has, in many ways, influenced some of the things I'm going to say.

Most of my experience comes from my over 20 years of experience working at Johns Hopkins, which some people might say is in the Washington-Baltimore community. It's 30 miles up the road. And we do things a little bit differently than some of the hospitals in Washington.

I would first of all say, in reference to the numbers that Ed Snyder from Yale gave you, our volumes are about double what Yale is. So Yale is very big and busy. Perhaps we're even bigger and busier.

All of our red cells we are now attempting to be leuko reduced. We used to do it selectively and had about 30 percent of our red cells selectively ordered or used, often by consensus with patients' doctors based on protocols, et cetera, but we are moving to 100-percent leukoreduction. In terms of platelets, we use 100-percent single-donor platelets which are leuko reduced. The reason we do that, actually, is because of the problem that Dr. AuBuchon mentioned about bacterial contamination, which is an issue I hope this committee will come back to.

We have data that are on present transfusion that shows that the risk of a septic event from a platelet transfusion, if you do randoms, a pool of six, is on the order of 1 in 2,000 events, which we can reduce to 1 in 15,000 events by going to single-donor platelets. I would also tell you that, of those events, about 20 percent of them are immediately fatal within 24 hours. So I think that's something you ought to think about.

One of the other things, though, we do I think that may add some perspective to some of the remarks that Sonny Dzik made, and this is not something I did, it was what I inherited, is that our blood budget actually is a central hospital function. We have our own budget in the Department of Pathology for running and administering the blood bank, and we obviously have a lot to say about what goes in and doesn't go into the blood budget. But I think that, in some ways, may prevent some of the sort of trade-off mentality that I think is affecting Sonny Dzik and other hospitals, where if we try to improve the fluid, we might have to compromise by making the choices internally about what we do with staffing and testing issues. And I think that actually reflects the fact that, even though we may have some influence on blood utilization, in reality, we can't really control it.

So, anyway, the current debate, which you've heard about for a long time now, I think actually is a very interesting microcosm of a lot of the stuff this committee has been dealing with. It clearly deals with the issue of blood safety. Clearly, I think a very important issue is that of reimbursement, which the committee has spent a lot of time thinking about in the past and I think really is the sort of "sleeping giant" here, in terms of getting this thing implemented.

But the other thing that I think which hasn't been tied in, except loosely, is that this committee, through influence by the IOM report and such, has been very much concerned about error and accident reduction. And I believe that there are some important things to be said for moving to universal leukoreduction to reduce errors and accidents.

So what I'm going to talk about is selective versus universal leukodepletion. And what I would tell you is that my remarks and most of my thoughts on transfusion medicine are really based on what I have gleaned in the last many years from patient and physician concerns who, in professional or social events, always ask me, "How safe are transfusions with respect to AIDS and other infectious complications?" And even though this committee knows the litany of data that says they are very, very safe, most people, when I tell them that, immediately move to the second question, which is, "Are there any alternatives or modifications that I can use to avoid blood transfusions or reduce the risk of transfusion complications?" because most patients and their physicians want a zero-risk blood supply.

These are the things that we've looked at as transfusion alternatives, starting with things like autologous options, pre-deposit, hemodilution and rhomper [ph] salvage, the use of pharmacologic therapies, drugs like EPO or DDAVP instead of blood components, the thirst, hopefully, someday for a blood substitute, the use of apheresis to reduce donor exposure, pathogen inactivation. And on this list, I would include leukocyte reduction because I think it is a way, in many cases, of reducing volunteer blood donor risks.

And I think what we're coming to, and I've written about in Transfusion in 1999, is what I would call a new generation of blood components, which feature a lot of apheresis collections not only for platelets, but perhaps red cells in plasma, the issue of leukodeletion, which is captivating us today, the hope of pathogen inactivation in blood substitutes.

The real issue is obviously how do we choose and how do we implement these new actions? And I think you can tell, from my previous remarks, that I think we have had a fair amount of patient input and physicians' opinions, and I think most of them would say they want leukoreduction. We, obviously, are going to be influenced by regulatory issues, but right now there is no regulation that says that we have to do this, but that's certainly something that we may anticipate.

What we haven't talked about a lot, and I think is a very persuasive argument, is the quality assurance issues. I think the FDA is giving us a series of guidelines that allow us, with better filters and filters which continue to evolve, to be able to provide reliably the fluid which is leuko depleted. The question I would then ask, do we have the system, such as Sonny Dzik described, to reliably say that that leuko-depleted blood or whatever blood we want to get to the patient is really there. And he described what he thought is the weak link.

I think what I'll describe to you is I think that there are many other weak links. And I guess if I look in the mirror tomorrow morning, I'm willing to say, as I'm shaving, maybe I'm a weak link.

Anyway, we have to consider the economic issues, which I think are very important in this and really are, I think, inhibiting the introduction and the reimbursement issues, which you've heard a lot about. But when we have a product, which we know works for certain indications, and when we have certain specific indications and others that are more controversial, we end up with a discussion of the selective versus universal use.

Now, one of the areas that, and I think Sonny or Jim, somebody showed previously a lot of the examples of how we use selective transfusion protocols in transfusion medicine routinely, and so that's sort of our standard of care. I think, though, there is some danger in doing that for some of the things we do.

In the issue of irradiated blood, which most of us apply selectively, we all know that it's indicated to eliminate the risk of transfusion-associated graft versus host disease, which is almost always a fatal complication of blood transfusion. And most hospitals have a list of patients whom they think, selectively, we should provide irradiated blood for, including those with congenital immunodeficiency, bone marrow and solid organ transplants, neonates or patients receiving blood from family members.

In the issue of leukodepletion, you've heard already that most of us believe that the first three issues or signs on this list are generally good, clear-cut indications that, in fact, they do reduce transfusion reactions in the vast majority of recipients, they will reduce the risk of alloimmunization, at least in the platelets and oncology patients. They do reduce the risk of infections from cell-associated viruses due to CMV. And some people believe that it will reduce the risks of immunomodulation. I, myself, am not sure. I don't know.

But I guess I'm framing my opinion by saying I believe we really need to apply leuko-reduced blood to those first three indications. If you believe universal leukoreduction will give you number four, that's a throw-in. But what I would guess I would say to you is I don't believe, the way our current health care system works in blood centers, hospitals, et cetera, that we can reliably provide the patients who selectively need leuko-depleted blood with a blood they need under our current way that we operate.

I would illustrate to you some of the problems with selective transfusion protocols because I believe many patients who meet criteria for selective protocols, such as leukoreduction or irradiation are not recognized. For example, in the issue of transfusion-associated graft versus host disease, I can tell you an anecdote which is in the literature about a child who came into a local hospital, was one and a half years old, presented with pneumocystis pneumonia, previously had not been seen. The assumption was made by the treating physicians that this was a child who had HIV infection. And no one thought that because it was HIV infection he needed irradiated blood. Blood was administered, the work-up pursued. At the time, it became clear that this kid was not HIV-positive, and actually this was a child with his first infection presenting at age one and a half with congenital immunodeficiency. It was too late to do anything about it. This child subsequently developed transfusion-associated graft versus host disease and died.

I can give you another example that had a lot of media attention, at least, of a patient I believe in New England who received a drug called Fluderabine. Fluderabine is a drug used for cancer chemotherapy. It's well recognized by many oncologists that patients who are getting cancer chemotherapy may be at risk for transfusion-associated graft versus host disease. This particular patient, however, was getting blood because he had, I believe, rheumatoid arthritis or an autoimmune type of disease. And it was not recognized, because the physician wasn't aware of the risk of transfusion-associated graft versus host disease, the patient got nonirradiated blood and got transfusion-associated graft versus host disease.

So I think there's lots of literature. And if you read through the literature on transfusion-associated graft versus host disease there are many of the patients that you could see whom you would have said they should have gotten irradiated blood, but they didn't because the clinicians or the system providing the blood to them did not recognize that they ought to be on that selective list.

We've mentioned previously the Trapp study, getting more perhaps to the area of leukodepletion. In the Trapp study, this was a large study of 500 patients with acute leukemia taken care of in seven academic centers around the country. And protocols were written so these patients, when they were admitted, would get placed on leuko-depleted red cells and various types of platelet products.

I participated in one of the centers, actually, at Johns Hopkins, and we set up protocols such that when these patients came into the hospital, we would get up, whether it was in the middle of the night or not, randomize the patient so we would make sure that they didn't get off-study transfusions. And I was surprised, actually, when I looked at the data from the Trapp study published in the New England Journal, to see that if you looked at all of the patients entered, 73 percent of the patients entered into the Trapp study had off-study transfusions in the two weeks before they were entered into the study. And I said, "That doesn't make sense. Most of us, in all of the sites, were committed to getting them randomized."

And then I realized most patients with acute leukemia are not coming directly to Johns Hopkins for their therapy. They go to the community, they go to their doctor's office, they may go to an emergency room. Somebody sees they have a low platelet county, they're anemic, they get transfused. And the doctor who is making that transfusion order probably doesn't recognize the need for leuko-depleted blood components, so that it really, to me, argues, in terms of the public health concern, saying that if we really want to reliably get these products to patients who need them, we need to do it universally and not just in my hospital. It has to be communitywide.

Now, what are the problems with some of these of selective transfusion protocols? I've already given you examples of physicians who do not recognize the requirement. And before we beat up too much on physicians, again, becoming mea culpa, admitting that I'm the weak link, I get an hour and a half to lecture to second-year medical students, and I have all of the committees with clinicians, whatever. But we have house staff, we have other doctors, they're getting bombarded all of the time with information about new drugs, new tests, new transfusion options, new regulations, new reporting things. I think it is naive of us to think that they are always going to remember that they need to use leuko-depleted or irradiated blood for all of these indications.

It's asking too much. We try to intervene and set up ways to avoid it, but I think we can't always blame or depend on the ordering physician to really make that decision. I just don't think we can keep them up to date well enough, and our outreach system isn't adequate.

I think also we know that patients are transfused at different sites. Within my hospital we have an outpatient center at the hospital. We have an outpatient center 20 miles up the road. We send blood out in coolers to patients, and we also have patients treated sometimes at Hopkins, who go to other patients or other hospitals for their care. So that unless we're doing the same thing in every place, patients are going to get different kinds of blood.

Patient location in the hospital. I've heard people say, "Well, we always give our oncology center patients irradiated blood or leuko-depleted blood, but the reality is, many patients get admitted to the hospital, they're boarding in another unit--there's no bed in the oncology center, or they may come into the hospital with a diagnosis which is now--they've broken their hip--where nobody knew that 10 years ago they had a bone marrow transplant or something of that sort. So I believe that location in hospital is a good surrogate and it helps, but it certainly is not a fail safe.

Computer--databases we've talked about are not complete. Even in my own hospital they're not complete, and if we have to rely on medical records from other places, we're not going to catch all the patients.

And finally, we set up systems in many hospitals where the blood bank staff hopefully will intercede and catch patients who might need these irradiated or leuko-depleted units. And what happens though, if you look in most hospitals, is there is a major technical shortage of medical technologists that is affecting us. Fewer of the people are now transfusion specialists. Many of them are more generalists, and we're now moving, in many parts of the country, to centralized transfusion services, such that patients have their blood administered by a centralized community facility where the technologists and the medical staff are not necessarily right at the patient's bedside, making these kinds of things more difficult.

So in conclusion, I don't think we should only call a transfusion error, an ABL error, a patient sampling error. I think they are not limited to the events that occur within the blood bank, and I think a very important part of getting blood to the correct patient is also minimizing the risk that they're going to get an inappropriate component. I believe the failure to provide an indicated blood component is a transfusion error, and that complicated systems, such as selective protocols, make errors more likely, and hopefully that simplification of the transfusion options at the blood-bank level, at the physician-ordering level, will be required because staffing issues that will not--of staffing issues that will not be quickly resolved.

And I guess, finally, I believe that universal leukoreduction is a means of reducing transfusion errors, and the only reliable way in our current health care delivery system to guarantee that patients with the three proven indications will be transfused with a requirement--required blood components, and if in fact, there is an immunomodulation benefit, that's good too. Thank you very much.

[Applause.]

DR. BLAJCHMAN: Any questions from the panel or from the committee to Dr. Ness? Ed.

DR. SNYDER: Dr. AuBuchon talked about implementation of a computer system that might be beneficial, and it was alluded to also by Jerry Sandler. I know at our institution, if we were to put in a computer system that would track, like FedEx might, transfusions, it would cost a lot of money for capital, a lot of money for training. It would be a one- to two-year phase-in, not to mention the problems that occur during transitions. Since you have a somewhat more complex institution than we apparently do, how would you see computerization as a solution to this problem financially, compared to what Jim mentioned as a half a billion dollars and some of the benefits that others--that I think it would be a very long run for probably a short slide in our experience anyway.

DR. NESS: Well, I would think that's true. And I think it's also--we've been very slow to be able to get full-service computerization issues, even at what the US News & World Report considers the number one hospital. It's very--you know, computer implementation is difficult. It's expensive. The training issues, for people using computers, are very hard. I certainly am not against it, and would like to see better order-entry systems, which would take physicians down the track that some people have talked about, and I think those are wonderful. I just don't think they're complete.

DR. BLAJCHMAN: Dr. Penner.

DR. PENNER: Just to underscore one of the comments that Paul Ness made with respect to the physicians, the students and the house officers. Transfusion medicine is about the lowest point on the pecking order of what to retain for the exams, and the memory of it drops out very, very quickly. So I think relying on a physician to keep these all sorted out all the time is not very realistic.

Another comment too, and that is with respect to the reporting of transfusion reactions, and particularly with the European examples. I'm just remembering many years ago when porcine factor VIII, the antihemophilic factor for hemophilic patients that was made from a pig blood, was initiated as a product that would be available. And we kept hearing how great it was and there were very few reactions and so on. And then we heard that a few of our colleagues went over to some of the British hospitals to watch what happened when the patients were getting the porcine factor VIII, at that time was rather crude. And the patients were--looked like they were in seizure. Their temperatures were 103, 104, and there was a good deal of misery, obviously, was there. And the colleague who was visiting, asked the physician who was in charge of the patient, he said, "This patient looks like he's having a reaction." And then the physician turned and said, "Oh, they all react like that. That's nothing. We don't even bother with that."

And so I'm wondering if some of the data that we're seeing may be a little bit more restrained with respect to the reactions, and although the British have a stiff upper lip on many of these things, maybe some of their data is reflecting that.

Barring that comment, I think maybe the last thing is just to the panel, and that is, for those of you who are advocates of selective leukoreduction, do you advocate having the leukoreduction units in your emergency room, or do you depend upon that to be ordered as need be?

DR. SANDLER: This is Jerry Sandler from Georgetown. We don't have blood in the emergency room. We have a vacuum tube system to all of the areas, so that when an order is made, let's say in the emergency room, the OR or other places, the blood is put into a vacuum tube--it's put into a container, and it's vacuumed down into the ER.

But I think the essence of your question is, if you don't know who the patient is, how do you know who's going to get leukocyte reduction? And the answer is, I don't think that it's an issue of everyone having to get leukocyte reduction every single time.

DR. PENNER: Jim, what do you do in your emergency room when things are going down and you need about ten units of blood while everything is pouring out? Does it automatically come in as leukoreduction or you just throw in whatever you got?

DR. AuBUCHON: The logistics of our system appear to be very similar to Georgetown's. When a patient needs ten units of blood in a half an hour, what they need primarily are red cells and fluid, and the presence or absence of leukocytes is probably immaterial. What the surgeon is trying to do is stop the bleeding to get them to survive. Although I certainly would hope that every patient who could benefit from leukocyte reduction would receive the appropriate component.

The committee should also take into account the numbers involved here. There are somewhere between 3-1/2, 4 million different patients transfused in this country on an annual basis. There are--help me, panelists--maybe 100,000 new acute leukemic patients every year in this country? Somewhere in that vicinity, some of whom--say the half that are women, in all likelihood, particularly for the adults anyway, have been previously pregnant and exposed to some HLA antigens. The chance that a child with leukemia will be treated in a community hospital I think is pretty much zero. And the chance that an individual who receives one or two transfusions that are not leukocyte reduced before being transferred to a tertiary care center with a higher probability that they will get the correct unit and become alloimmunized because of that is very small.

So in answer directly to your question, we, in the emergency room, would only transfuse leukocyte-reduced blood when the selective indication indicated.

DR. NESS: Jim, I don't believe 73 percent of the Trapp study where they got off-study transfusions presumably in the community is very small. I think that's pretty large. Now, you may have a better outreach system up in New Hampshire and Vermont to get patients into Dartmouth than we have in Baltimore-Washington or in the six other Trapp centers, but I think you're--I don't think that's a small risk. I think it's a big risk.

DR. AuBUCHON: Well, 73 percent received transfusions and they were off-study transfusions in that they were before they were enrolled in the Trapp study, but that doesn't mean that they were non-leukocyte-reduced components.

DR. NESS: But the vast majority were not leuko-reduced.

DR. BLAJCHMAN: Keith Hoots.

DR. HOOTS: Jim, I'm not sure that that doesn't happen. I mean, as a pediatric oncologist, it's not that unusual for a kid who has a platelet count of 2,000, a hemoglobin of 5.3 and a white count of 1,000 to be seen in an emergency room, and immediately get transfused before anybody asks anything of them. And then they call us and say, "We want to transfer the patient."

DR. AuBUCHON: Were that to occur, that does not consign this child to a fate worse than death. Even if a single transfusion--or a single episode of transfusions were given without leukocyte reduction, that does not imply that this child is not going to be able to be treated successfully in their leukemia.

DR. BLAJCHMAN: Question over here.

COL. FITZPATRICK: I just want to make a comment on a couple of things. I want to thank Dr. Ness for his interpretation of what's going on, and ask a question. But I've been the director of six major military medical center blood banks, and I've had adolescents removed from transplant protocols because they received non-protocol-related transfusions and did not receive CMV-negative or leuko-reduced product, and I think that's very significant to those patients.

I also have seen the panel bounce around the impact of a CMV transfusion to a patient that is supposed to receive CMV-negative blood, but I haven't heard what we usually hear in the way of an elaborate model of your cost when a patient comes down with CMV who should not have it, a patient gets graft versus host that should not have. We always get elaborate illustrations of the cost of preventing one case of HIV, but I think while I agree that gathering statistics that would be reliable to give us a cost of that, that that's a factor that needs to be considered in a decision to universally leuko-reduce or not, that there is a patient impact when you receive a--what in some cases is a fatal disease from a transfusion.

And the other is that I think all of us in our NICUs give only O blood, and there's a significant reason for that, because of the chance and risk of giving the wrong type to the wrong baby, and I fully support those panelists who have said we need to work on both sides of the safety factor, we need to get the right product to the right patients.

DR. NESS: Thank you for those comments. I think that you're right, that we don't recognize as a system the real cost of treating these transfusion complications, and even, for instance, some of the data that you've seen today which tried to give some of those costs, I think underestimates it significantly. Ed Snyder presented what it costs to treat a febrile reaction at Yale, but I would tell you that a lot of patients who get a febrile reaction are immediately put on antibiotics. If it's a serious reaction in a community hospital, they're probably immediately transferred to the ICU. So these are costly kinds of events that can occur.

I can also tell you that we're quantitating, you know, sort of health care costs, but any bump in the road of a patient who has any kind of transfusion reaction, for the patient and their family, is a horrendous emotional cost to those patients. They don't know that the febrile reaction that they're having is benign. They assume the worst, and this is something that we really as a society ought to try to prevent.

DR. BLAJCHMAN: Sonny, I think you had a comment.

DR. DZIK: I did. I wanted to make a comment, and ask Paul a question. The comment was just that others in the audience may be sharing the same thing, just to urge you not to perhaps sink into anecdotes, the child you remember with this or that. I mean, it's just they perhaps pull the issue into clear focus, but they don't get to a kind of a dispassionate solution.

DR. NESS: Well, I don't think these were anecdotes. These were--

DR. DZIK: Let me finish my point.

DR. NESS: I'm sorry. Go ahead.

DR. DZIK: So that when one consider, you know, two systems of blood delivery and whether one results in more reactions that add more costs and antibiotics, all the things you alluded to, I would just suggest you just wait for the data, you know. I mean, you know, rather than make an implication based on the absence of the data.

And could I ask my question of Paul before we--

DR. NESS: Sure.

DR. DZIK: My question was that it seems like you spend a lot of time pointing to the problems of identifying correctly who ought to get it, that you're concerned about the--essentially the process, the system, the kind of--of that system in which we're told what we should provide, and essentially would like to try and address that with a product solution, right? You make the product all like that, then you won't have to deal with breakdowns in identification. And I guess I'm not sure that that's the right way to go, and I have--the analogy might be, certainly people come in the emergency rooms with headaches who don't get put into a CT scanner, so you can find episodes of the misuse, someone who's having a brain hemorrhage. The only way around that would be to just CT scan everybody with a headache in the country, which doesn't seem like the direction we want to go in.

So what I'm wondering is, don't you at least acknowledge a potential alternative to--if there's a problem with the process of receiving information, to basically address that? And might that not have other spinoff benefits to the patient?

DR. NESS: Well, a couple of things, Sonny. First of all, the cases I reported are all published, so that they're not anecdotes. And with irradiated blood, you know this is, fortunately, a relatively rare event, so all you have is case reports and big series don't help. But I agree with you that emotional anecdotes are not necessarily the persuasive argument, they just are examples of things that we ought to think about.

I believe, as you believe, that our process for delivering transfusion care needs to be improved. I think the information part of it would perhaps help in improving it, but I think that, you know, I think we over estimate in some ways some of the parts of that information system even with computers, even with better education. I just think that in many ways, some of the issues that we are talking about are pretty arcane to most doctors and most people, and to assume that by any means that we're going to 100 percent get these things avoided, I think that's wrong. You noticed also that I'm not leaping to say that this is a wonderful thing to reduce the risk of immunomodulation. I don't know that I even believe that, so I focus my remarks on this, I say if we really believe those first three things, and most of us, I think we are not delivering that reliably now in our current health care system.

DR. BLAJCHMAN: Two last questions. Dr. Hoots.

DR. HOOTS: I was actually going to ask his question after Jim's talk and kind of ran out of time, but it's apropos what Dr. Dzik just commented on about waiting for the data. And maybe I'll address it to Jim, but I think anyone on the panel who wants to chime in, it would be helpful.

And this has to do with--if your study, say the MGH study, were a clinical trial, instead of a natural history study randomization, then you would have a power endpoint calculation of what you would consider a statistical difference that you would consider an advantage or equivalency between a placebo or between the two arms of the study. Clearly, you have some things in mind about what would change your mind from your studies about your point of view on universal leukoreduction. And having been involved with studies that ranged from mortality endpoint, which as Jim has already alluded to, is fraught with all kinds of difficulties because there are so many steps along the way that impact mortality versus length of stay in ICU versus that. What would it roughly take, from your type of study, on items 1, 2, 3 up there, which are acceptable indications for ULR, to influence your point of view, or what would it take on item 4, which might be a reduction either in infection or cancer recurrence, to really change your mind on this? I think I'm having trouble figuring--it's good to say wait for the data, but if we haven't thought about what the data would say that would change our minds, I'm not sure that it's going to solve our problem.

DR. DZIK: Well, with respect to our own study, I think that we felt including mortality was an important endpoint. It's an unarguable endpoint, at least, and since it is a randomized trial to the two arms, we expect there to be balanced into each arm the other kinds of things which could impact on mortality. So if the stuff saves lives, then let's do it. I think we're all--everyone agrees that's kind of the--we're in the common pursuit of trying to preserve lives.

I don't think, for my personal opinion, that it has to achieve the mortality hurdle in order to be persuasive technology. I think the other real advantage of our study is that we're going to--our primary endpoints--we're only allowed three primary endpoints. One is death. And the other two are oriented towards money, length of stay is a wonderful encapsulated figure for essentially resources given to the patient; and we're going to look at total hospital costs. And I think the value of looking at those two things, is that at least, if there is a benefit to be seen, we can see the downstream benefit.

You know, I've personally--one of my main interests in this study, we know what the upstream cost is. We know what we have to pay, the price we must pay to our blood supplier to give us the product. We speculate about the downstream health care benefit, the downstream financial return that we might achieve. The lady from the smaller hospital, Ms. Clark, I think, referred to a shortening of length of stay that helped to defray the costs. But that was a pre/post study and involved a very small number of patients.

So I think to answer your question specifically, I'm hoping our study will help give people like you a better understanding of the balance of cost and benefit, especially at the economic basis, because it might pay for itself.

DR. BLAJCHMAN: The very last question. Then we'll summarize. Dr. Gurnzheimer.

FLOOR QUESTION: Terry Gurnzheimer, Seattle, Puget Sound Blood Center.

We were also one of the trial sites for Trapp, and Paul, as I remember it, although a great majority of those patients did indeed get transfusions at outlying hospitals that were not leuko-reduced, we could not show that those patients actually did any worse in terms of alloimmunization, as long as they later came in and got leuko-reduced blood. So there is nothing to suggest that if you get several units, in fact, of non-leuko-reduced blood initially, and then later on, as late as two weeks I believe, get leuko-reduced blood, you do any worse in terms of alloimmunization.

DR. NESS: I understand that point, and it's--I thank you for bringing it up. I think I was mainly trying to point it out as a process-delivery question, which basically says that even when you try to do it, our current system doesn't allow us to do it reliably.

DR. BLAJCHMAN: Can we save that for afterwards? We want to take the next 10 minutes or remaining time in this hour for Dr. Vamvakas and I will--to summarize. And by way of summary, I basically have--will speak, summarizing, and indicating my thoughts relating to the pro side of universal leukoreduction.

I was very pleased that Dr. Sandler chose to use my definition of science, and with respect to everybody in the room, I'd like to show that this is the process of science. This doesn't project very well. But it's a continuum. We start off in ignorance. We then do--make some observations, do some trials, observational trials, RCTs, and then we hopefully then get knowledge. The point is, of this slide, is I put a scale of zero to 10, zero being ignorance, and 10 being knowledge. We never, ever achieve knowledge. We are always in the process of going between zero and 10. So for each of the indications relating to leukoreduction, the topic under discussion, and for every issue in science and medicine, we're somewhere along that continuum. So, for example, for prevention of transfusion reactions, we may be, just arbitrarily off the top of my head, maybe 7 or 8. For TRIM, transfusion immunomodulation, we may be 5 or 6. But nonetheless, there is some uncertainty in every decision.

And one of the things that I want to take up is what Dr. Sandler said. We take decisions based on the evidence available. That does not, has not stopped science dead yet. It won't happen if the committee recommends universal leukoreduction at all. And in the Canadian context, universal leukoreduction was implemented. We still put together a study, a pre/post study, a large study, to ask the question relating to the efficacy of universal leukoreduction.

Can I have my slides, please?

Apropos of this point that science is a continuum is this quotation from Sir Anthony Bradford Hill. I'm not sure that many of you know who Bradford Hill is or was. This man was--is the father of randomized control trials. He was the first person in the 1950s who conducted randomized control trials to ask the question relating to the efficacy of streptomycin for the use--for the treatment of patients with tuberculosis. There are three randomized control trials. His team headed them. And they're very faulty studies when you look in retrospect at them. But the data showed fairly clearly that streptomycin was effective. Late in his career, Sir Anthony Bradford Hill, at a lecture to the Royal Society of Medicine, London, made this statement. "All scientific work is incomplete, whether it be observational or experimental. All scientific work is liable to be upset of modified by advancing knowledge." He said, however, "This does not confer upon us a freedom to ignore the knowledge we already have or to postpone the action that it appears to demand at a given time. There comes a point in time when we potentially have to make decisions on the basis of the available data." It doesn't have to be today, it doesn't have to be tomorrow, but sometime a decision has to be made.

And in the context of leukoreduction, it seems to me, on the basis of a cause and effect relationship and the data that's available, that I think it is--in my opinion, with regard to transfusion immunomodulation, which I think there is a lot of data out there, and that data is both experimental, observational, and also based on animal data, that there is an immuno-modulated effect associated with the infusion of transfusions, and in my opinion, that benefit the patients who receive blood products, should benefit from that, those observations, and on that basis, leukoreduction, which should be universal.

I'd like to pick up a point that Dr. Sandler related to. He made a statement with which I agree, that in the United States you have the best medicine in the world. I don't disagree with that. However, I would point out, with respect from a Canadian context, the availability of that best medical care to the population is severely impaired.

Now, we all agree that these three--probably most of us agree that these three clinical benefits of leukoreduction, their avoidance of platelet refractedness, reduction of transfusion reactions, avoidance of most CMV transfusion. And then there's this issue of immunomodulation and mortality associated blood transfusion, and there are a host of laboratory-based things that there's no clinical evidence.

I have analyzed this data, and then Jim AuBuchon said that he hasn't done a cost effective analysis, and I agree it's very difficult to do because the endpoints are difficult to obtain. But there's another analysis that has been suggested by the group, the epidemiology group at McMaster, and this involves the concept of the number needed to treat or NNT. And this represents the number of patients that we need to treat with a particular intervention in order to prevent one additional bad outcome. So the NNT is the reciprocal of the absolute risk reduction, so the number of patients that reduce, that are actually reduced by a particular intervention. And data based on published randomized control trials suggest that non-hemolytic febrile transfusions, with pre-storage leukoreduction, you can reduce 25 percent of the number of transfusions. You can't eliminate, but you can reduce that. The number needed to treat therefore is 4, 1 over 25. With post-storage leukoreduction, the absolute risk reduction is 11.7 for an NNT of 8.6. Prevention of platelet refractoriness, based on the Trapp study, 10 percent absolute risk reduction, from 16 percent to 6 percent, if I remember the numbers correctly, an NNT of 10, and for CMV infection, an NNT of 13.2.

Also for some of the likely beneficial effects to prevent bacterial infection based on the Van de Watering study, the absolute risk reduction is 5.6 for an NNT of 17, which means we--and need to treat 17 or 18 people to prevent one infection based on that data. Mortality also based on the Van de Watering, is absolute risk reduction of 4 percent for an NNT of 23.

Contrast this through the NNT to some of the other transfusion-associated interventions that we've instituted, for example NAT testing, the absolute risk reduction is somewhere around 1 in a million for 5 units per patient, let's say. The NNT is something of the order of 200,000. For HCV, not testing, the NNT is 60,000.

So, clearly, on the basis of this type of analysis, the number needed to treat by the specific intervention of leukoreduction is very, very significant, and very much better than the NNT for these other interventions.

Now, I have grappled with this issue of universal leukoreduction for a long time, and I've come to the conclusion based on an editorial, or when I was asked to write an editorial by Jeff McCullough for Transfusion, two years ago, approximately, and I sort of went and decided that we should institute universal. I would recommend, or I voted for universal leukoreduction, not because the data was solid, but for these reasons. I felt--and I still feel this way--that it isn't likely that a definitive--and an operational word here is "definitive"--RCT will be forthcoming in the foreseeable future. Most of the available RCTs from Europe have considered a question--and this has been dealt with--that may have little relevance to the clinical transfusion practice in North America. There are other evidence about TRIM, for example, relating to renal allograft survival and patients with recurrent spontaneous abortion. There is a lot of evidence from experimental studies, and there's lots of evidence from observational studies, and in particular, three large observational studies that have been published recently.

Now, evidence-based health care. I come from an institution, McMaster University, that started the whole concept of evidence-based medicine, and nowhere in the writings from the pundits at McMaster--and I don't consider myself a pundit--does evidence-based medicine equal RCTs. The two are not synonymous. Evidence-based medicine describes a process of explicit conscientious and judicious use of the best available evidence from research to guide health care decision making. It should be explicit and replicable, and it should be used as part of decision making. It should be judicious, rather than blind adherence to research evidence. And it should be centered on the use of the best available evidence that exists at a given point, and it's not fixated on RCTs or med analysis, as some may think. Evidence-based health care is based on guiding decision-making process, not making the decisions. You have to take the totality of evidence into account to make the decision. And I hope that that's what we've done today.

Concerning the issue of allowing physicians to make decisions for their patients, I'm sympathetic to that thing, but I don't know that any physician can predict down the road what's going to happen.

And by way of closing, I want to make one other point. And I do this with the utmost respect. I'm a visitor in this country. I visit this country quite often, and as a Canadian, as a non-American, I want to make the following observation. It seems to me that this debate on universal leukoreduction has nothing or very little to do with the science. I think the issue of universal leukoreduction has basically become the battleground, the battleground for reimbursement. There are expensive interventions that are coming down the pike, blood substitutes, pathogen inactivation. That's going to be--leukocyte reduction is going to be chicken feed compared to the cost of those things. The committee, the governments, the powers that be in this country, need to solve the issue of how you pay for those interventions.

And this is what's happening today in my opinion. We are--this battle, this bun fight that's going on, if you like, has to do not so much with the science--yes, the science is not definitive--but the major issue is the issue of how does one pay or how are the blood transfusion services, how are the hospitals going to be reimbursed for doing this? This is the issue. This is the real issue. The rest of it is quoting the emperor really has no clothes, and I'd like to play the part of a person who says that.

[Applause.]

DR. VAMVAKAS: Well, I have to make the con case without any visual aids, so that I hope everybody can hear me.

I have to say that nobody disputes the fact that there are three proven indications for leukoreduction. However, these three indications have been demonstrated in patients with hematolytic malignancies, a highly selected population, perhaps 10 percent of the total transfused population who receive multiple transfusions of red cells and platelets. There are absolutely no empirical data to allow an extrapolation of these benefits from the population of patients with hematolytic malignancies to the large majority of transfused patients who undergo colorectal surgery or something like that.

If some patients who need leuko-reduced components do not receive them, this is a serious medical error, and the way to fix it is to change the process, not to change the product. Perhaps the most constructive recommendation that can come out of this committee tomorrow might be to triple or quadruple the amount of time medical students and residents spend on transfusion medicine in this country.

The argument for universal leukoreduction does not relate to the three proven indications. It relates, as Dr. Dzik pointed out, to transfusion-associated immunomodulation, the very sensational endpoint of mortality, cancer recurrence and postoperative infection.

So what do we have about these three endpoints? With regard to mortality, we have an observational analysis from the Netherlands, showing statistically significant survival benefit thanks to leukoreduction. At the same time, we have an observational analysis from the vital activation transfusion study, the only NIH-funded study in this area, which shows a statistically significant survival detriment from leukoreduction. So the existing studies have generated intriguing, albeit, conflicting hypotheses about an association of how--transfusion with mortality, and these hypotheses need to be investigated further in future studies.

When it comes to cancer recurrence, the results of the three available randomized trials are negative.

When it comes to postoperative infection, the results of the seven published randomized trials are contradictory. They are contradictory because two studies from Denmark have generated positive results, and if these studies are excluded, the remaining five studies show negative results.

Also, we are here debating whether to implement pre-storage leukoreduction. The seven available randomized studies would point against that. The two studies from Denmark that showed a dramatic benefit from leukoreduction both used post-storage leukoreduction, whereas the trial of Hubeatal [ph], that found no adverse transfusion effect, used pre-storage leukoreduction. And in the study of Van de Watering, et al., there was no difference in outcome between the pre- and post-storage leukoreduction arms.

So we are not talking about the science not being definitive. We are talking about the science being completely conflicting or negative. So the question, whether we need to implement universal leukoreduction in the US, is not a question of cost effectiveness or cost. It pertains to the lack of efficacy of the procedure to confer the purported benefits. It does not have to do with money. And based on current knowledge, American patients are not being deprived of any treatment that might conceivably or potentially benefit them. If tomorrow the scientific results change, we can be here again to argue for implementing universal leukoreduction.

And finally, taking one more point, I would like to respond to the poignant point made by Dr. Blajchman about the American health care delivery system. If medical care is not available to a segment of the population, one has to wonder whether universal leukoreduction is the appropriate thing to do to advance medical care for Americans. Thank you. [Applause.]

CHAIRMAN CAPLAN: Well, I want to thank the panel for a very stimulating and an insightful and provocative debate. I think at this point we will simply go to lunch. We will reconvene at 2:00. Dr. Penner will be in the chair, and we will listen to public comment and question at that time, and take that right to 5 o'clock today.

[Whereupon, at 1:07 p.m., there was a luncheon recess.]

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

[2:17 p.m.]

DR. NIGHTINGALE: Would the committee members please take their seats? Will the committee members please take their seats? Celso, sit down, and take a couple down with you. If you want to talk second, sit down. Can you all please take your seats? And if you're in the audience, if you could please stop talking, we would like to start the afternoon meeting.

This is Dr. Nightingale. I need to make an announcement about the order, and if you miss the order, you will be confused. In about two minutes we are going to start the order as it is stated on--hey, quiet. Could you take your seat, please? We need to get started. Thank you.

We are running a little bit over. There is an order in the agenda on the second page. The way you should read it, is you should take each line and move from left to right. That's an approximation of current American politics. Ms. Frederick and Dr. Bianco will be the first two speakers.

I understand that there are some members of the audience who need to make an airplane. I also understand there are many members of the audience who would just as soon speak soon and go home thereafter. I would like to differentiate between the two.

After Dr. Bianco speaks, those who are willing to state for the public record that they either have a plane to catch or a bill to pay, should approach the microphone and identify themselves and make their comments. I would like, as much as possible, to maintain the order that I've established on the second page of the agenda. And I thank you for your confirmation to it.

Dr. Penner.

DR. PENNER: Jacquelyn Frederick is coming up, representation from the American Red Cross. Jackie, good to see you.

MS. FREDERICK: Mr. Chairman, and members of the Advisory Committee, I'm pleased to speak with you today about universal pre-storage leukocyte reduction, the next step towards improvement in safety and purity.

My name is Jackie Frederick. I'm the executive vice president for biomedical services for the American Red Cross.

The safety of the blood supply is the Red Cross's number one priority. We are dedicated to discovering and implementing better ways to improve the safety of the blood supply through research and technological advances.

Today we call upon the FDA to mandate the implementation of universal leukocyte reduction. The American Red Cross believes that the removal of contaminating leukocytes from all cellular blood products should be universally implemented as a means to further increase the safety of the blood supply and improve patient outcomes. The American Red Cross is implementing universal leukocyte reduction because we believe it is best for the patients who need blood transfusions. Currently 77 percent of the red blood cells we distribute are leuko-reduced. Leukocytes are known to cause adverse reactions, as we heard this morning, and there is no debate that removing contaminating leukocytes provides a purer, and hence, safer product.

Physicians cannot always ascertain prior to transfusion whether their patient will have an adverse reaction from products containing leukocytes, and leukocytes have no benefits to patients receiving these products. The opposition to universal leukocyte reduction is based upon the promise that this safety advancement should be available at the discretion of physicians. The Red Cross believes that all patients should be able to avoid unforeseen adverse reactions to transfusion, and they should not be limited in their ability to have access to safer and purer blood products. By requiring universal leukocyte reduction, FDA is insuring that all patients will have access to these products.

We also believe that cost should not be the determining factor as to whether or not to implement or adopt a safety improvement. On average, a unit of leukocyte-reduced red blood cells will cost about $30 more to produce than a non-leukocyte-reduced product. This is a small price to pay for a significantly improved product. We understand that hospitals and physicians and blood centers are under pressure to control costs, and that this is challenging in light of our ever-increasing medical costs and technology. However, final decisions as to which safety improvements should be adopted by the blood-banking community have not historically been based on cost. Cost considerations cannot and will not be a factor for the American Red Cross in the decision process to provide the safest blood and blood products available.

I would also add, as kind of the person where the buck stops here for half the nation's blood supply, that daily I am faced with safety improvements that include process and product, and I will tell you, I have to make both process and product improvements. It's not an either/or decision.

Universal pre-storage leukoreduction builds upon other recent initiatives in improved blood, such as P24 antigen testing, nucleic acid testing, and continual review of our donor deferral criteria. These steps are consistent with the public policy framework that was adopted from the lessons learned through the AIDS tragedies, whereby incremental steps to improve blood safety are implemented as soon as they are available.

And let me quote. "Where uncertainties or countervailing public health concerns preclude completely eliminating potential risks, the FDA should encourage, and where necessary, require the blood industry to implement partial solutions that have little risk of causing harm."

Those words are not mine. They come from the landmark 1995 Institute of Medicine Study on HIV and the Blood Supply, the study that elevated public policy decisions relating to blood safety and availability to the Surgeon General and created this committee. The IMO study and numerous steps taken during the 1980s, as a result of the AIDS tragedy, helped form the public policy decision-making framework, which exists today, to insure continued improvement in blood safety and availability. It established the policy that incremental steps to improve blood safety be adopted as soon as they become available.

The American Red Cross believes it is important to continue to embrace that framework and to adopt incremental improvements where there is little risk of causing harm.

Congress has provided clear direction that the safety of the blood supply is a national public health priority. Since the start of AIDS epidemic, members of Congress, as representatives of the American public, have voiced concern about the safety of our nation's blood supply. Last month Senator Orrin Hatch of Utah stated that patient access to a safe and adequate blood supply is a national health priority. He noted that the blood-banking and transfusion medicine communities are constantly working to assure that safety improvements for blood are implemented as soon as they are available. Congressman Phil Crane of Illinois, in November, noted that two recent initiatives have been introduced to increase the safety of the blood supply, NAT and leukoreduction. He stated that we must act now to insure that patients are receiving the safest possible blood products.

The mandate for a leukocyte-reduced blood supply began well over two years ago, when FDA determined that it was more expedient to move toward universal leukocyte reduction than to examine each specific indication for its use. At the September 1998 Blood Products Advisory Committee, BPAC voted unanimously that the benefit to risk associated with leukocyte reduction were sufficiently great to justify requiring universal leukocyte reduction. At the June 2000 BPAC meeting, an FDA representative stated that FDA remains convinced at a scientific level, independent of cost, that ULR is an improvement in safety and purity.

In conclusion, the decision of the Red Cross to support universal leukoreduction is based on our ethical, professional, legal and regulatory responsibility to provide the safest product we can supply to the American public. We believe that universal leukocyte reduction is no different than any other incremental improvement in the advancement of blood safety, and must be adopted without further delay. We urge the FDA to make a clear and unequivocal statement mandating universal leukocyte reduction.

Each of us here today has an important public health responsibility to advance blood safety. We respectfully urge the committee to support patient access to universal leuko-reduced products. Thank you again for this opportunity.

DR. PENNER: Thank you, Jackie. Ms. Frederick's comments are available on the handout. And if you would stay up for a moment, if there are any questions or comments from the committee first?

[No response.]

DR. PENNER: Then comments from the audience, or questions?

[No response.]

DR. PENNER: I think the Red Cross's approach is pretty well recognized at the moment. So, thank you very much, Jackie.

MS. FREDERICK: Thank you.

DR. PENNER: Our next speaker is Celso Bianco from the American Blood Centers. Celso?

DR. BIANCO: Hi. Thank you for the opportunity to speak here. I'm Celso Bianco. I'm the executive vice president of America's Blood Centers.

ABC, America's Blood Centers, our 75 community members provide half of the nation's volunteer blood supply. We appreciate the opportunity to address the issue of universal leukoreduction, and we have three major comments in the issue.

First, ABC's concerns reflect the diversity of opinion nationwide on the justification for ULR. Some ABC members have implemented the universal leukoreduction. Each of these blood centers work with the hospitals and physicians in their communities to develop a policy and strategy to best serve their patients. Those are about 40 percent of our members that successfully carried out this program.

Many other ABC member leuko-reduce only a portion of the blood components that they provide to the hospitals, a decision reflecting once again the judgments of the hospitals and physicians in their communities.

Thus, ABC believes that the local medical community must make decisions about ULR. Such decisions must take into account the immense financial burden to a hospital, given that Medicare and Medicaid currently do not reimburse hospitals for leukoreduction. Without adequate funding for this increased blood cost, hospitals may be forced to cut funding in other parts or areas of patient care.

Therefore, we ask the committee members to approach the issue of ULR within the context of community choice, as it avoids thorny issues of disagreements about the gray areas of science and unfunded mandates.

Second, ABC asks this committee to continue to press the Secretary of Health and Human Services to assure blood safety measures are adequately reimbursed. While the committee has significantly contributed to the awareness about this issue, it is not yet resolved. Reimbursement by Medicare and Medicaid for blood safety measures lags behind reality for nearly five years.

Third, while ABC agrees with FDA on many of their positions taken on its recent draft guidance on leukoreduction, we have several concerns about its recommendations, most of which are minor and will be taken up directly with the agency. However, there is one issue raised in the guidance that is of great concern indeed to ABC and its members. FDA recommends that blood centers consider screening all donors for sickle cell trait because donations from people with this trait cannot be adequately filtered with current FDA-approved filters. While the suggestion appears simple, it is flawed by not recognizing the social consequences and the complexity of such undertaking.

Among the troubling issues raised by the proposal are the following. Screening donors for sickle cell trait is essentially genetic screening. That's because you are looking for a genetic abnormality in the donor's blood. Genetic screening, that is a departure from the disease testing blood centers perform routinely, requires substantial counseling and informed consent because the results can significantly affect the life of those individuals who have sickle cell trait. The vast majority of individuals with sickle cell trait are in good health. The problem is with the filtering device, not with the donor. What should donors do with such a test result? How might such results affect their lives? Are there racial discrimination concerns with such screening?

Second, does the suggestion for screening imply that we should defer those donors? Most are African-Americans and also hispanics, and they do not carry some common red-cell types. Therefore, their blood types may be desperately needed by many recipients. How do we explain the deferral? How do we compensate for the loss of these valued and often rare blood donors? Is it fair to defer somebody because of flaws in the filters?

Rapid tests that are available for screening for sickle trait have never been validated in the donor genetic setting. Furthermore, medical guidelines for identification of sickle cell carriers recommend hemoglobinopathy and electrophoresis, not a solubility test that is what would be used for blood centers. We sincerely hope that this committee, with its broad view of ethics, science and business, will dedicate a few minutes of discussion tomorrow to address this issue.

Finally, a reminder of ABC's position. ABC considers the decision about implementation of universal leukoreduction to be a local medical decision. Thank you.

[Applause.]

DR. NIGHTINGALE: Dr. Bianco, this is Stephen Nightingale. May I have a clarification for the record, please? In the American Red Cross statement, on the second line of page 2 the statement is--says that "On average a unit of leuko-reduced red blood cells costs $30 more to produce than a non-leuko-reduced product." It is my recollection that other figures have been presented to the committee on this subject. Would America's Blood Centers, you as its representative or you as an individual, or any other member of the panel, wish to comment as to whether or not they concur with that statement or if they would rather provide another number?

DR. BIANCO: I believe I can respond to that question. This is a ballpark figure. It varies tremendously around the country. It depends on the method that is used for leukoreduction, that is, if it is on-line collection of blood versus sterile docking devices, the procedures that are used in the hospital, the frequency with which units are quality controlled, the methods used for quality control, but I would say that $40 to $30 is what we hear is the ballpark of the figure of cost for the blood center.

DR. PENNER: Questions from the committee? Yes.

DR. GILCHER: Ron Gilcher, Oklahoma, on the committee. Making some comments to what you said, Celso, and then I'll address the cost issue as well.

With respect to sickle trait testing, or better said, testing for the sickle hemoglobinopathies, solubility testing is one way of screening. At our blood center we will put this in for 100 percent of our donor base regardless of race, obviously. Currently, we test all non-caucasians, but as of April 1st, this will become a single test done one time, captured in the computer.

Now, what happens to those donors that are positive? They will be asked to do non-red-cell donations in our system. We will not exclude them as donors, and I think that's very important.

And I clearly want to point out that this crosses all races, that is, sickle cell trait. When I was at the University of Pittsburgh, we found seven caucasian individuals with sickle cell trait during our frozen red cell program testing.

So the point that I want to make is that I think it is important to do the sickle cell screening. It shouldn't have a racial issue because, in fact, it occurs in all races, and there is an alternative for these individuals to do non-red-cell donations, namely, platelets and/or plasma.

Addressing the cost issue, we clearly know what it costs us to do this now, and I reported to this committee at a prior meeting that our cost ran approximately $20 per unit. Now, I want it understood that the cost in Oklahoma may not reflect necessarily what the cost in other parts of the country are. Now, I would like to update that by saying that the addition of the sickle screening or sickle hemoglobin screening for all of our donors will add, and we're now probably closer to about 22 to $25 as we work this out. So I think that the $30 number that was in the Red Cross statement is in fact pretty accurate, in terms of being plus or minus $5. Thank you.

DR. PENNER: Ron, do you have to have them sign, when they come in as donors, for the screening test for the sickle cell?

DR. GILCHER: No, it's not--they do an informed consent that is tests that will be performed on every single donation. So it's part of the testing. And remember, every donor does sign informed consent.

DR. PENNER: And so this is not open to the public, obviously, and so there is some means of preserving the information and--

DR. GILCHER: Yes.

DR. PENNER: --keeping it intact, just as we do with our others.

That's an important question. Would you respond to it?

DR. BIANCO: Well, it's not a response, it's a comment. I have great respect for Ron. He has been very effective in what he has--and he's one of the blood centers, ABC members, that are very successfully and prevented universal leukoreduction.

The comment is, it's not a question that everybody has the sickle cell trait, Ron, but certainly the sickle cell trait is identified as a very high prevalence trait among African-Americans and among hispanics. And so the impact that this will have in these donor populations that we make a tremendous effort to recruit, particularly in order to maintain enough blood types, rare blood types to serve our minority recipient population, this will be impacted. That is, a donation, an alternative donation of platelets or plasma is not going to resolve the red-blood-cell type. So I'm concerned about it.

The second thing that I wanted to say, when we do it like that, I feel very uncomfortable with what we do today ethically, that is, that we do the testing, and essentially nobody that does the testing, as we prepare units to be transfused in our neonatal wards and other areas where we sickle-cell-screen the units, we don't tell the donors. And I think that we changed, this country has changed, our thinking has changed, and we came to a point where I think that we have the obligation to share that information with the donor and provide appropriate counseling and appropriate measures.

DR. GILCHER: And I'm going to respond to that, because I think that's extremely important what you just said, Celso, that the donor must be notified. We are in fact putting that in place, and that's--it's extremely important that the donors understand that if they are positive, we will not use their red cells. They also need to know that they in fact have this, and we do keep that confidential, so we--

DR. BIANCO: Are you planning to provide electrophoresis to give them an accurate reflection of their hemoglobin status?

DR. GILCHER: Currently only solubility testing, because it will pick up the C's and the S by the electrophoretic pattern.

DR. PENNER: Dr. Epstein?

DR. EPSTEIN: Celso, we've heard it said that about 50 percent of the blood units that failed to filter effectively, in other words, leukocytes not removed--it's a filter failure--are associated with sickle trait. Conversely, I've seen data that suggests that somewhere between 40 to 80 percent of persons with sickle trait will not filter correctly, and that depends what you accept as the acceptable residual white count.

So my question back to you is: even if you're not doing universal leukoreduction, you're still doing it for indications, so you still have this problem in the unselected donors. So if you argue against sickle trait screening, what is the alternative proposed remedy for a problem which is well recognized, namely, filter failure attributable to sickle trait?

DR. BIANCO: The best solution, obviously, Jay, is not available. It's for the manufacturers that are sitting here in the audience to be aware that this is a very serious problem, and work on filters that will not clog, and try to understand the relationship. It may be just the oxygen tension inside that filter or something like that, that is causing a problem.

Obviously, the second-best solution is the screening. I do not want to oppose the screening. I think that what I tried to say or what we tried to say as ABC is that there is a lot of thought that has to go together with it because it has other consequences besides the impact on leukoreduction, and I don't want us to miss those very important issues.

DR. PENNER: Dr. Sandler, would you have a comment on this? You've been handling a lot of these cases, the sickle cell problems and being able to deplete the cells.

DR. SANDLER: In my current situation at Georgetown, we get all of our blood supplied to us by the community blood center, so I'm not involved in doing screening.

DR. PENNER: Okay, thanks. Yeah, Larry?

MR. ALLEN: I was just going to ask Dr. Gilcher in regards to a referral for the donors that do test positive, some type of referral service. Do they explain to them about the trait and the issues around the trait?

DR. GILCHER: We have available at our blood center what we call a Transfusion Safety Patient Services Department, that in fact handles doing consultation for any test, any positive test, or--in this case we will also do that for individuals who want more information. The letter which we designed allows them to call us and ask us about more information.

DR. PENNER: Dr. Hoots?

DR. HOOTS: I was just going to ask--I wasn't quite sure--were you having difficulty mainly with the follow up of the screening and not the actual screening itself?

DR. BIANCO: That's correct. The intent here was not to reject the FDA proposal just because it's screening. The intent here was to raise the awareness of everybody in this community, that a decision about 100 percent screening of our donors has very serious social implications, and also will affect the distribution of rare bloods that we have access to.

DR. HOOTS: And I would not disagree with that. I would just add that a number of states, some for as long as two-and-a-half decades, as you know, have been doing hemoglobinopathy screening for all races, including some of the larger ones like New York and Texas. And it's actually had a tremendous public health benefit, so I don't--in terms of--the screening itself is only going to impact people in those states who are over the age of 20, because they're already screened anyway. So that's the reason I asked that question.

DR. PENNER: Dr. McCurdy?

DR. BIANCO: Those are our donors by the way.

DR. McCURDY: Sir, there are--there is considerable knowledge about the biochemical and physical chemical characteristics of sickle hemoglobin under a number of different circumstances, and most if garnered in the '60s and perhaps into the '70s. And I think that it would be an excellent idea if filter manufacturers and/or others that are interested in this problem, would consult with some of these people that know the basic science of sickle hemoglobin. I suspect, from my background in sickle cell disease and some of the things that I did in those days, that there may very well be a technical fix for this that would take care of the problem. But I think it needs some expertise in sickle hemoglobin itself.

DR. PENNER: And Karen Lipton?

MS. LIPTON: So sorry. I'm just curious. When you use the term "informed consent", are you trying to distinguish that from the type of consent we get now for screening people for infectious disease, and if so, how do you distinguish getting an HIV test, which can have a profound social effect on the person who's getting the test result, from finding out a genetic testing results?

DR. BIANCO: I think that it is big--are the big issues of informed consent. Everybody that comes to us to donate blood expects to be tested for AIDS and hepatitis. It's in their comprehension. That's in all the literature that goes to them. There is a whole educational process, in essence, that it done during the recruitment. They have no idea about genetic screening. And if we start it today as we go to universal leukoreduction with 100 percent screening, I think that we have to go to that educational process, so when they can sign their names in the bottom of that page, they understand what they're signing.

MS. LIPTON: But it's not--the process through which you do that at the blood center would not be any different than what you do now for infectious disease screening.

DR. BIANCO: No, no. The process--but you have to add to the package of education, you have to add to the package of counseling. You have--like in New York State, you cannot make a diagnosis of hemoglobinopathy based on a solubility test. There is a state requirement that you go to electrophoresis. You have several consensus conferences from NIH and all that, that all recommend that you go. So I think that we'll be assuming a responsibility to either make arrangements for these people to have electrophoresis or do it ourselves. So I think that it's a bigger process that has to be thought through.

MS. LIPTON: But not one the would eliminate the idea, just that these are things that have to be take into consideration?

DR. BIANCO: Right.

DR. PENNER: Dr. Sandler again. Jerry?

DR. SANDLER: Yes, Dr. Penner, I'm sorry. I didn't quite think as quick as you did when you asked me the question. Your question, as I interpret it, refers back to the time, when for about 15 years I directed the National Reference Laboratory, including the Rare Donor Registry of the American Red Cross.

DR. PENNER: Absolutely.

DR. SANDLER: Yes. And in that capacity, we supplied blood to maybe 10,000 to 20,000 African-Americans with sickle cell disease, whose chronic transfusions caused alloimmunization, and they needed what Dr. Bianco has explained as "rare blood."

Now, the rare blood is a blood type that came with the sickle cell disease genes to persons of African origin. So as we look for rare blood for sickle cell patients, we're looking for blood types that will be found almost exclusively in persons of African ancestry on both sides, who are very likely to have sickle trait. I don't believe that there is a statistic that will tell you what fraction of the 10 to 20,000 units a year supplied by the Rare Donor Registry have sickle trait in it, but there has got to be a very high percentage. And the rarer the unit, so to speak, the more likely it's going to have sickle trait as part of that.

So that implementation of this should not go forward in any way until the implications of that to the African-American community are clearly defined. We should know, before you do anything, what is the percentage of blood supplied to the sickle cell population of America through the Rare Donor Registry that has the sickle trait that will no longer be available when the filter takes them out.

DR. PENNER: Now comments from the audience. Yes, sir? Could you identify yourself, please?

FLOOR QUESTION: Dr. Petz, Los Angeles.

Just one quick comment about cost estimates that I've heard. It's been stated that the cost to produce a unit of leukocyte-reduced red cells is $30. But the charges to hospitals are as high as $45 per unit. So we must realize that the hospitals are going to carry a higher brunt of the expense than was indicated by the $30 that was mentioned, and I don't think we should ignore that thought.

DR. PENNER: Thank you. Any other comments from the audience? Ms. Frederick?

MS. FREDERICK: I just want to clarify that $30--that was a $30 average cost across all 36, and it is true that the price will vary depending on the geographic market, as do the costs vary, depending on the geographic market.

DR. NIGHTINGALE: This is Steve Nightingale. I am a nephrologist by training. Why should the price vary by geographic market?

MS. FREDERICK: Because at least in the American Red Cross our prices are more or less determined locally, not nationally. So, for instance, when we provide blood in Omaha, Nebraska, it is less expensive to actually collect blood and run a blood center in Omaha than it is in downtown Los Angeles.

DR. NIGHTINGALE: I understand that, but is it less expensive to leuko-reduce?

MS. FREDERICK: Yes, because of the labor costs and the facility costs, et cetera.

DR. PENNER: All of the overhead. Yes, Jerry?

CAPT. SNYDER: I was just going to remind Steve of RBRVS.

DR. NIGHTINGALE: Steve is aware of RVR--whatever it is--Steve's aware of whatever it is.

[Laughter.]

DR. PENNER: Yes, Karen?

MS. LIPTON: I just wanted to make one comment about the Rare Donor Registry, because, Jerry, as you know--and it's now both--it's an AABB and Red Cross initiative for the entire country. But in their protocols now, when they release, if it is a rare unit, they often do not--they will use units even if they can't either leuko-reduce it or do certain types of testing. So I think your point is valid, but not with respect to the Rare Donor Registry. I think we need to focus on the group of patients who would be transfused from the traditional population, because I think the Registry handles that issue already.

DR. SANDLER: Karen, let me just repeat it in case what I said wasn't clear. You would have to take out from the filter process all the blood going into the Rare Donor Registry.

MS. LIPTON: I understand, yes. Just as in other cases that there are units and there are donors that have certain markers that they would transfuse anyhow because it's a rare unit, and it's more important for the patient to get the rare unit. They have--I mean, there are a lot of instances. Is there someone here--Jackie, do you know much about the Registry?

MS. FREDERICK: No.

DR. SANDLER: Let me explain how this works. You take 300, 500 units of blood that's collected in an open population from all people, doesn't matter what their race is. All of those units of blood are then tested to see if they have any of the rare markers. Now, in order to be doing that, you have to collect all of that blood without putting it through the filter system. Otherwise, you know, you're not going to end up--you're not going to be able to do it. You're going to have to take blood out of the system to do that.

I think you're going to have to find out what fraction of blood that is actually being supplied through the Rare Donor Registry to African-Americans with sickle cell disease has the trait in it, and then you're going to be able to go forward. I don't have a clue, but it's going to be very high.

DR. PENNER: One last comment on this. Go ahead, Paul.

DR. HAAS: Jerry, what proportion of the Rare Donor Registry supplied units are frozen? Because if they're frozen, they probably would have been tested for sickle trait before freezing to insure that they were deglissed [ph] with the proper procedure.

DR. SANDLER: The answer is I totally don't know because I've been out of that for ten years, but I can say that in the past, none with trait were frozen because you couldn't get them out, and in the present time I get about--at Georgetown--out of, let's say, 25, 30 units I get, I get half of them liquid, and the other half come pedigreed frozen so they're not sickle-less.

DR. McCURDY: The need to do a--use a special procedure for deglissing sickle cell trait blood was something that we paid attention to when I was a blood center director, which began in the middle '70s. So that's been well know.

DR. BIANCO: Paul, it's well known, but it's only a fraction of the units with sickle cell trait that will really give you promising degliss. The vast majority of them, for some reason, don't. I've run a pretty large program in New York, and we were not screening for sickle cell as we put them in the freezer.

DR. PENNER: There's an area that's going to require some attention, and we'll have to cover it again.

Comment again from the audience?

DR. GOLDFINGER: Thank you. Dennis Goldfinger, Los Angeles.

The last I heard, something under 10 percent of the African-American population carries sickle cell trait, and since there's no linkage between the sickle hemoglobin and the red cell antigenic composition, we would not expect to lose more than about 9 percent of these donors. And since half of those at least seem to filter all right, we're talking about probably less than 5 percent of the African-American donors who carry these--the proper antigenic composition for transfusion to patients for sickle cell disease.

So while it's an unfortunate loss, it's not a catastrophic loss.

DR. PENNER: Unfortunately, that group is in very high demand and short supply.

Any other comments from the audience?

Then if you don't mind, we'll go on. Thank you very much, Dr. Bianco.

Jeffrey McCullough? Dr. McCullough from the University of Minnesota. Go ahead, Jeff.

DR. McCULLOUGH: Thank you very much. I do swear that I have an airplane conflict schedule.

DR. PENNER: And anyone else who breaks out of order will have to swear. They're snowed in up there. You won't be able to get there.

[Laughter.]

DR. McCULLOUGH: It only doesn't snow in July.

I am from the University of Minnesota. I hold a variety of children's association chairs, and I'm the director of the Molecular and Cellular Therapy Center there. I'm also appreciative of the chance to speak. I'm the editor of Transfusion, and we go out of our way to publish all high-quality research representing all points of view on this subject. And so I don't get a chance to express my own opinion in that forum.

In the interest of full disclosure, I am an unpaid adviser to the American Red Cross, and I have research grants from them. But I have not discussed what I'm going to say with anyone, and I'm here representing myself and no organization.

There is agreement on several indications for the use of leukocyte-depleted blood components. We've heard this morning that three of them are the reduction in the frequency and severity of febrile transfusion actions, prevention of alloimmunization and platelet refractoriness, and the prevention of transmission of cytomegaly virus. These applications apply to a meaningful but modest proportion of our patients, and Dr. Ness has made a powerful argument for the use of universal leuko-depletion based only on those three indications.

There are, as the committee has heard, three other possible indications for leuko-depleted blood components, but there's far less agreement about those. These are, first of all, a possible-- prevention of a possible excess of certain malignancies following surgery, prevention of possible excess of post-operative infections, and, thirdly, prevention of the theoretical possibility of transmission of prion disease or new-variant CJD.

As you know, there is a difference of opinion about whether these last three complications do occur and, if so, the extent of the problem. There does seem to be good, reasonably good data that if these complications do occur, leuko-depletion would prevent them.

But we are in the unfortunate and uncomfortable position of trying to determine a course of action based on incomplete data, as Dr. Blajchman has so nicely shown.

More than 25 years ago, it was made clear that transfusion can alter the immune response when Opeltz and Terisaki (ph) published their landmark study of the effects of blood transfusion on kidney transplantation. Despite the intervening 25 years, we still don't understand the basic science of this mechanism, although I do believe that in the next few years this will be better understood.

So, thus, while we don't understand the exact scientific mechanism, it seems clear to me that transfusion does exert an immunomodulatory effect.

A great statesman once said--actually, I wish I knew which one it was, I'd love to quote him. But a great statesman once said that the mark of a person is what they do in the absence of complete information. And that's the setting that we're in. The data is not ideal, as has been described very nicely to this committee, but despite this, I'm here to urge the committee to recommend universal leuko-depletion.  There are very few additional risks associated with implementing this therapy, and I'm convinced it's better transfusion therapy for our patients. And this is the first and foremost issue.

Having made this decision, there are then many other issues that the committee would need to address, such as how to cover the costs, the discussion we just heard about sickle cell trait, and others. But to me, the first and foremost decision is: Is this better transfusion therapy? And I wanted to go on record with the committee as urging the adopting of universal leuko-depletion.

I thank you for the opportunity to speak, and I congratulate the organizers of the meeting for a wonderful opportunity that we all have to hear this discussion.

DR. PENNER: I think that was a great general argument. Thank you, Dr. McCullough.

Jeff has had a long history with the Red Cross and blood banking and certainly has a lot of background to discuss the issue.

Now, any comments about Dr. McCullough's statements or questions from the committee?

[No response.]

DR. PENNER: From the audience, anything to be added?

[No response.]

DR. PENNER: You seem to have struck a very clean, pure note and not controversial subjects. Thank you.

DR. NIGHTINGALE: Is there any other member of the public who, A, wishes to comment and, B, has a transportation or other conflict that precludes us from continuing on the schedule that's on the agenda? I see none. Thank you very much.

DR. PENNER: Then we'll proceed, and Stephen Binyon from Baxter Corporation. Mr. Binyon?

MR. BINYON: Good afternoon. My name is Steve Binyon. I'm here today representing Baxter Health Care Corporation. Through its Fenwald (ph) Division, Baxter provides products for the collection, processing, and transfusion of blood and its components. We have participated in the blood-banking field for over 50 years, working with clinicians, industry organizations, and regulatory agencies worldwide to enhance the safety and quality of blood transfusions. Our commitment to this effort is ongoing, and we appreciate the opportunity to address the committee on the topic of universal leukoreduction.

As you've heard from this morning's speakers, there is scientific evidence demonstrating the association between leukocytes and blood and a variety of transfusion reactions. We believe there is agreement in the medical community that leukocyte reduction of cellular transfusion products reduces the risk of non-hemolytic febrile transfusion reactions, transfusion-transmitted CMV infection, and HLA alloimmunization.

Baxter supports the implementation of universal leukoreduction of cellular transfusion products in the United States. We respectfully request that the committee and the Food and Drug Administration consider the following points as the possible implementation of universal leukoreduction is deliberated:

Throughout the history of blood banking in the United States, the regulatory authorities and industry organizations have worked to establish standards that apply to blood-banking processes and transfusion products nationwide. This focus on consistency and accountability has resulted in the blood supply being safer today than it has at any other time in history. It also provides assurance to those individuals who require blood transfusion that they will be provided with transfusion products that meet consistent safety and quality standards, regardless of the patient's geographic location.

As you consider universal leukoreduction and the means by which to implement it, we ask you to focus on a process that will provide leuko-reduced blood products that are consistent in cellular composition and which are processed in a reproducible and controlled manner. Appropriate quality control measures and GMP procedures that meet current standards for blood component processing will be critical.

We strongly believe that pre-storage leukoreduction technologies, either through filtration or processed leukoreduction, offer the best means to implement universal leukoreduction in a consistent, controlled, and measurable manner. However, the definition of pre-storage leukoreduction, which we understand to mean that which occurs within three days of blood collection, should be consistently applied across all transfusion technologies.

The potential economic impact of universal leukoreduction must obviously be considered. Clearly, there are costs associated with the development and implementation of new medical technologies. We believe that the costs associated with the potential complications of transfusing non-leukoreduced cellular products are likely to outweigh the incremental costs associated with universal leukoreduction.

A precedent for universal leukoreduction exists in several countries, including Canada. These countries face similar debates, and we have an opportunity to learn from the international community in our efforts to ensure an efficient and effective transition to universal leukoreduction.

Finally, we believe that sufficient capacity exists in the industry to meet the demands of blood centers as they make the transition to universal leukoreduction, regardless of the time frame for implementation.

In summary, we support implementation of universal leukoreduction using either pre-storage filtration or processed leukoreduction as an important step to further enhance the safety of the blood supply.

Thank you again for this opportunity to address the committee.

DR. PENNER: Thank you, Mr. Binyon.

Comments from our committee?

DR. NIGHTINGALE: Mr. Binyon, this is Steve Nightingale. I have a question that you may not wish to comment upon, and the question is this: If leukoreduction were made universal, would you care to hazard a guess as to whether the cost would go up, go down, or stay the same? I can imagine scenarios under which each of the three might occur. What would you?

MR. BINYON: Well, I guess the beauty of being the VP of regulatory affairs is that I'm seldom asked to provide an opinion on a question like that. And, quite frankly, I would agree with your assessment. Certainly--

[Laughter.]

DR. PENNER: All of the above.

MR. BINYON: Without any purposeful effort at levity there.

I think that, you know, clearly, Baxter, as well as the other manufacturers, operate as businesses, but we work closely with our customers and the transfusion medicine community. And I think overall our effort is simply to provide the best-quality products that our customers want to use.

DR. PENNER: I would think the other manufacturers would say the same. Thank you.

MR. BINYON: Well, you can ask them.

DR. PENNER: Any comments from the audience or questions?

[No response.]

DR. PENNER: Thank you very much, Mr. Binyon.

MR. BINYON: Thanks.

DR. PENNER: Our next speaker is Mr. O'Connor from HemaSure.

This looks like it's going to be formal.

MR. O'CONNOR: No, it's not so formal. I'd like to start off by thanking the committee for allowing HemaSure to speak today. For the record, I'll start off by saying that HemaSure is in favor of universal leukoreduction. And I will have some comments on cost, to address that question, although they will be somewhat vague.

I'd like to speak to the issues of universal leukoreduction in the context of adoption of innovation. The benefits of any new technology take time to understand and to adopt. Early adopters lead the way with a vision of the benefits of leukoreduction. Leukoreduction is in the rapid growth phase of this adoption curve. Today the value and efficacy are being challenged. At some point in time, adoption of leukoreduction will be at its maximum, and a level of standardization will be reached. Eventually, new technology through innovations may displace leukoreduction as we know it today.

Technology innovations, like leukoreduction, cost money. Manufacturers invest heavily during the growth of adoption to lower unit costs. Competition bring these lower costs to the users.

Motivation for these investments include the value of better health care for the patients and for the health care system; also the anticipation of the rapid adoption by the users causes manufacturers to invest. With the adoption, manufacturers have the ability to invest in innovations to meet the challenges of new problems, so as we get our payback from our investments, that money can be used to go on to solve new problems.

To see the benefits and adopt leukoreduction, users must perceive and measure value. In the value equation, there are costs and benefits to the patients and to the health care system, and most of them have been pointed out quite clearly today.

Many of the real costs, outside of equipment and filters, in our case, and the labor, have not been itemized. As pointed out earlier today, the problems of selective leukoreduction have real costs. I believe Dr. Ness pointed that out very clearly. By looking at these real costs, there can be some savings, and that savings can be passed on to adopt universal leukoreduction.

There are two ways to pay for leukoreduction: one is incremental investment, and here we're looking for government and third-party payers to be involved; the second is a shift of the investment. The shift of the investment, as we've seen today, takes creativity and work, and I have to applaud the work at Yale and the other small hospitals who have seen their way to be able to do this.

As a manufacturer, we have options to invest further in transfusion medicine innovations. We can invest in cost reduction, but this requires a large number of units to be produced. And this cost lowering can be passed onto leukoreduction, to the users of leukoreduction.

Manufacturers, though, have to obtain a very clear picture of what these target volumes will be. Investment in new technology to solve other transfusion safety issues, such as the transfusion safety issues pointed out by Drs. Dzik and AuBuchon, requires identification and specification of the problem. The same value equation will apply to the costs and benefits of these new technologies, and somewhere a higher cost will have to be taken on as the adoption takes place.

So meetings like this, I think, allow us to come together to understand each other's needs. As a manufacturer, HemaSure is looking forward to working with the transfusion medicine community and investing further into improved health care.

Thank you for your time.

DR. PENNER: Thank you.

Are there any comments or questions from the committee? Paul?

DR. HAAS: Just so I'm straight, is HemaSure on the upward slope of the cost or on the downward slope of the cost?

MR. O'CONNOR: Right now we're holding steady. We're holding steady as we've been going on the downward slope.

DR. HAAS: And was your comment when you talked about--well, let me ask the question a little differently. If universal leukoreduction were to become a fact, were you implying that that would lead to a lower price to the users?

MR. O'CONNOR: My own opinion is it could, just as computers and PCs cost less today than they did 15 years ago. And I believe with these innovations and competition that there will seek a lowest minimum cost, at some point, as do most markets.

DR. PENNER: Any comments from other members of the committee? From the audience?

[No response.]

DR. PENNER: Dr. AuBuchon, any comments? Jim? No?

Thank you very much, Mr. O'Connor.

We have Pall Corporation, so Mr. Wertham will speak, and then Mr. Abrams and then Ms. Chance.

MR. WERTHAM: Thank you very much. Good afternoon. I'm Sam Wertham, President of the medical group of companies within Pall Corporation. We are the dominant developer and supplier of filtration technology at the hospitals and the blood centers. Pall is a 54-year-old company with 32 years in the medical filtration field. We sell directly and to other suppliers that support the U.S. blood-processing needs. We are global and provide products and systems in all countries that leuko-reduce their blood.

With due respect to the other filter manufacturers here today, Pall is the leader. We have more experience, more products, and more services to offer our customers than anyone else in the world.

We are not here today to speak on the merits and the clinical benefits of leukoreduction. Many of these benefits have been established and documented in the circular of information for the use of human blood and blood components. The Food and Drug Administration has stated in several forums and in its draft guidance this week its support for universal leukoreduction as an improvement in both blood safety and purity.

As we have already heard this morning, additional data about leukoreduction can still be sought and could prove useful in furthering our knowledge. It will not remove or reverse what we already know. Therefore, we cannot justify postponing action that could benefit the public health without incurring any appreciable risk.

We at Pall are pleased that the question posed to this committee is whether or not there is a need for a mandate for the implementation of ULR. We are pleased because of several concerns about the practice of selective leukocyte reduction.

As Dr. Ness so eloquently said this morning, there are significant problems with selective transfusion protocols. Many patients who meet criteria for the protocol and should have leuko-reduced blood are not recognized by the physician, and that it would be very difficult and perhaps indefensible to put at risk a subgroup of patients on the myriad of doubt regarding its cost savings. If even 20 percent of the patients are excluded from ULR, the cost of special conditions and handling of the non-filtered portion of blood is more expensive than filtering 100 percent. And I'm sure there are many blood-processing experts here today who can attest to that.

How can we justify subjecting any patient to a potential transfusion adversity when there is technology available to reduce the frequency of such a risk? How can we consider mortgaging someone's future health since we cannot reliably predict what a patient's future blood transfusion needs will be and thereby compromise their health and the cost of their health care tomorrow by our actions today?

I can't imagine that the American public would believe it is either just or equitable that the FDA characterize this as a safer and purer blood product not be made available to all people who need a blood transfusion. I understand they are distressed that doctors and hospitals make the choice of who receives filtered blood and without informed consent on the part of the patient.

I know you will be hearing more about how the public feels from patient organizations this afternoon and also from a poll of the general public that will be presented later today.

If ULR is not mandated, we fear that our country may move forward with a two-tiered blood system based on cost. And as a nation, we should not view blood as a commodity where the economics of supply and demand are applied. This should not be the driver in deciding on the routine use of new and better technologies and at the expense of patient safety, especially in an environment when there is so little direct patient advocacy for blood safety.

I would like to use the remainder of my time today to review how Pall Corporation can help make universal leukoreduction a reality in the U.S. The three areas that I will focus on are: one, the quality and standards Pall can bring to the implementation of ULR in the U.S.; two, our manufacturing capacity to meet the needs of ULR here; and, three, our experience in the planning and implementation of ULR around the world and how we can apply that here in the USA.

Pall has been in the forefront working with the scientific community to establish quality standards for counting residual leukocytes. We published a reference guide for the U.S. blood-banking community and provided training to both hospitals and blood centers around the country. Pall has led the filtration industry in the development of products and technology that consistently attain the lowest level of leukocytes to assure consistent and reliable leukocyte reduction processing.

Our products exceed the current U.S. standard of less than 5 million residual cells, and also exceed the standard set by the Council of European Standards of 1 million residual cells, and that also apply to the new FDA proposal of less than 1 million cells.

Our products consistently average 200,000 residual cells, providing a greater margin of safety than any other device. This is the technology that Pall currently provides around the world and across the U.S., and we will continue to provide the U.S. with the highest-quality technology in the ongoing move towards ULR.

In anticipation of leukocyte reduction in the U.S., both blood processors and the FDA had previously raised the question of product availability. At the April 2000 meeting of this committee, we were able to report that Pall had ramped up its filter production and added an additional state-of-the-art manufacturing in Italy so that Europe could be served locally. As a result, we accomplished our goal for increased manufacturing capacity to support a rapid expansion for routine, high-volume blood filtration in the U.S. This was based on the expectation of virtual ULR in the U.S. by the end of the year 2000, as expressed by the FDA at the December 10, 1999, implementational review meeting.

Although we do not know for certain how much of the U.S. blood supply is currently being leukocyte reduced, since we've heard some different numbers from various sources today, we arguably estimate it to be approaching 60 percent, and we have good numbers on this. We do know that we can state here today that Pall is ready and able to meet the needs of filtration technology for ULR in the U.S. Our capacity is more than enough to meet the total U.S. requirements with a healthy margin of safety.

I'd like to take a few minutes to tell you about some of our experiences around the world and the planning and implementation of ULR and its applicability to the U.S.

Pall has worked with the 10 nations that have implemented universal leukoreduction and also with the 14 countries that are moving towards routine filtration. We have worked closely with many of these nations, including the U.K., France, Austria, Canada, to help ensure efficient and timely implementation.

For example, in Canada, Pall has been an integral part of the implementation team in planning and serving as a quality control testing base starting with the training period through implementation and operation. In addition to providing our technology and filter systems, we provide statistical process mapping for the 14 blood centers of the Canadian blood services and the blood center of HemaQuebec. We continue that role today.

Based on our efforts around the world, albeit on a smaller scale than the U.S., and in some cases where there's a more limited united blood practice, we know that the implementation of ULR will not be achieved overnight. It has averaged anywhere from 6 to 18 months in the countries we have worked with. Based on our experience, we can work together with the blood community to ensure that ULR is achieved with the highest standards and in the shortest time frame possible. However, this cannot be done in a reasonable time frame if the blood-banking community has not yet developed its implementation plan.

We know that the American Red Cross, as you have already heard, has made a commitment to ULR and has made significant strides in its implementation. We are pleased to be working with them.

We request that this committee ask the blood-banking community here today what plans and processes they have already put into place to follow the recommendation that the FDA's BPAC committee made over one and a half years ago. Pall as a manufacturer is doing its part, but we can only continue to be effective in meeting the goal if all sides of the equation have also done their part.

I want to conclude my testimony here today by reiterating a point made by Dr. Lee at the FDA at a BPAC meeting. He said: Insufficient reimbursement, not cost, is the primary obstacle to ULR. Pall also believes that this is the case. We do appreciate that cost is an issue, and at this juncture hospitals bear the bulk of the burden.

We at Pall want to work together with the community not only to ensure consistently reliable products that meet the highest standard of quality for ULR, timely, efficiently, and cost-efficiently, we also want to work together to help bring about positive change and direction for reimbursement to help improve the safety of the blood supply for all Americans. We are for mandated ULR.

Thank you. I appreciate the opportunity to speak to you, and I'd be happy to answer any questions.

DR. PENNER: I think we'll hold the questions, maybe with one exception. What, approximately, is the cost of one of your filters used for host donation, roughly? I know you can't be specific.

MR. WERTHAM: Yes, $15.

DR. PENNER: Okay. That gives us an idea.

After Ms. Chance and Dr. Abrams' talks, maybe we could have comments from the audience at that point. Mr. Abrams?

DR. NIGHTINGALE: Is Mr. Abrams here? The microphone is yours, sir.

MR. ABRAMS: We have some slides.

Thank you very much for having me here. My name is Stats Abrams. I'm the senior vice president with Roper Starch Worldwide. We are a global survey research firm, and so far today we have heard from the medical profession, and we've heard from the manufacturers. And what we're going to provide is a little information from the general public.

As I was mentioning, we're going to hear from the general public from a survey that was run, and it was sponsored by the Pall Corporation. The methodology here with this survey was telephone interviews with a national sample of over a thousand adults. The sampling frame was what they call an RDD system, which includes all telephone households in the United States, whether listed or unlisted. And from that frame, we polled, using probability selection procedures, the sample for this study.

As a result, the percentages that we're coming up with are going to be within a sampling error of plus or minus three percentage points.

As you can see, the study was conducted in December, and all--I recall it having been mentioned before, it was about different areas of the country. This sample represents all four census regions of the United States, represents correctly all age groupings, income groupings, household composition, race, sex, all the basic demographics.

The purpose of the study was to ascertain public attitudes on the use of filtered blood in transfusion, the importance of knowing whether or not a hospital practices selective or universal leukoreduction, and the patient's right to be informed whether or not they are receiving filtered blood.

A little bit of the characteristics of the group. We see that just under 40 percent have either themselves or a family member, a close relationship, has had a blood transfusion. When we asked them about the awareness of filtered blood, we can see that just less than half of the adult population of the United States has heard of that. And we didn't go into a lot of other detail how knowledgeable. We just know that we got almost half the people saying they'd heard it.

When asked the question whether or not they would want choice of getting filtered blood if they or a family member needed a transfusion, 87 percent of Americans want the choice of getting filtered blood.

When asked whether or not a doctor or hospital should tell them whether they should be receiving filtered or unfiltered blood, 91 percent believed that the doctor or the hospital should inform them whether or not they will receive filtered or unfiltered blood.

When asked about the right to know, we have over--we have 87 percent are upset that some doctors and hospitals decide which patients receive filtered blood without informing the patient. As you can see, women are a little more upset about this than men.

We asked whether or not they believe patient rights are violated if the hospital or doctor does not ask if they want filtered or unfiltered blood, and we're sitting here saying over 75 percent believe their rights as patients are violated if they are not offered the choice of filtered blood.

We also asked them whether or not they would like to know prior to receiving a blood transfusion which hospitals provide filtered blood to all patients, and we're getting nine out of ten want to know prior to receiving a blood transfusion which hospitals practice ULR.

We then asked them whether or not, given the same thing of the doctor--no variation of doctor treatment and technology with the awareness of whether a hospital does or does not offer filtered blood, is it a factor in the decision of which hospital to go to, and, again, the great majority, 87 percent say this knowledge would be a factor in the decision of which hospital to go to when a blood transfusion is needed.

We also asked them how fair or unfair they believe it is that some people in the U.S. get filtered blood while others do not. Three-fourths think it is unfair that some people in the U.S. get filtered blood while others do not. And we have not fair at all at 51 percent and not very fair at 23.

All these feelings are equally as strong for people who have had experience with blood transfusion as well as those who have not. I found that a little surprising. Adults under age 35, the group with the least experience with transfusion, have the highest desire to want the right to choose filtered blood and be informed about which hospitals provide filtered blood to all patients.

So, in conclusion, Americans do have strong feelings. They want the right to know whether they receive filtered or unfiltered blood, whether or not a hospital practices ULR. They want to have a choice. And they say ULR would be a factor when deciding upon a hospital to go to if a transfusion is needed, and they believe it is unfair that some people who require blood transfusion are given filtered blood while others are not.

That is basically it.

DR. PENNER: Thank you, Mr. Abrams.

DR. NIGHTINGALE: Mr. Abrams, I'm sitting next to the chairman. This is Steve Nightingale. I wanted to ask a question. I suspect some others will also. I may have missed it, but in the question did you ask any of your respondents how much they would be willing to pay for the filtration?

MR. ABRAMS: No.

DR. NIGHTINGALE: I thought so.

Why don't we hold until after--

DR. PILIAVIN: Steve, don't make me hold on--

DR. NIGHTINGALE: All right.

DR. PILIAVIN: --the thing that I really know something about.

DR. NIGHTINGALE: Jane, I won't hold you back. Go for it.

DR. PILIAVIN: One brief technical question first. How many call-backs did you use?

MR. ABRAMS: How many call-backs?

DR. PILIAVIN: Yes.

MR. ABRAMS: Four attempts on all households.

DR. PILIAVIN: Okay. Well, that's good. Did you ask them any questions about anything other than this issue about filtered blood?

MR. ABRAMS: No.

DR. PILIAVIN: So you have no idea how many of them would be upset if they weren't asked something else?

MR. ABRAMS: That's correct.

DR. PILIAVIN: Okay. Have you ever thought at all about the demand characteristics of your situation?

MR. ABRAMS: Excuse me?

DR. PILIAVIN: The demand characteristics of the situation.

MR. ABRAMS: What do you mean--

DR. PILIAVIN: You don't know what that means?

MR. ABRAMS: Well, I want to know what you mean by it.

DR. PILIAVIN: Well, you tell me what you think I mean by it.

[Laughter.]

MR. ABRAMS: I don't understand what you're asking.

DR. PILIAVIN: Okay. There's a very well known flaw in research design that's referred to as experiment or demand. Essentially what experiment or demand means is that you can ask questions in such a way that the expectation of the correct answer is embedded in the question. All of these questions have that characteristic. People are self-presenting in this study as knowledgeable consumers even though they haven't a clue what he's talking about.

MR. ABRAMS: I would disagree because I think the questions were not leading questions. They were saying do you or do you not, or do you do this or not. I feel that those questions were asked objectively. I think there's no question in terms of knowledge about what white blood cells and everything else like that is beyond them in many instances, but I do know one thing. If they sit there and they think something's in that blood that could cause them some problem, they're going to be upset. And, frankly, I'm a little surprised the percentages weren't 100 percent. And I think that the fact--

DR. PILIAVIN: So am I.

MR. ABRAMS: --that they are in the high 80s and the 90s is the fact they are concerned. And I don't think that this term--and I've been in this business for over 40 years, and also have worked with Westat for 12 years, which is well known in terms of its work for health and human resources. But I think there is no question in my mind that the fact that these people have the concern that there is something in the blood that could cause them a problem are upset about it and would like to know.

DR. PILIAVIN: Of course, they want everybody to think, including the interviewer, that they are knowledgeable consumers, and, of course, anyone wants their health care to be as perfect as possible. You'd get the same question--you'd get the same answer no matter what you were asking them about with regard to their health care.

MR. ABRAMS: I'd take issue with you on that because I've had many studies where we have asked questions about various diseases and everything, and quite frankly, I haven't seen scores this high.

DR. PENNER: Well, at this point why don't we go on to Ms. Chance and then--no? Oh, they're lined up. You seem to have struck a note. All right. Why don't we have a comment, and, Ms. Chance, just hold for a second and we'll have the question from the audience.

FLOOR QUESTION: Harvey Alter, NIH. First, I want to make a financial disclosure statement. It cost me $4.75 to get here today by subway. I wonder if somebody could reimburse me for that.

[Laughter.]

FLOOR QUESTION: Secondly, every one of the presidential polls this past session were plus or minus 3 percent, and you see where that got us.

Thirdly, 50 percent of your people didn't even know what filtered blood was. Did you exclude them from the questioning?

MR. ABRAMS: No, because what we're talking about is the fact that they were aware that there was a process called "filtering blood," and the fact--whether they knew actually what it did or what, but the fact that it reduced contaminants being transmitted to them was important. And also I'd like to say something, too. Most political polls are under a very tight deadline date. They're like done over one night. And bringing up the question which came up here, call-backs are unheard of. And, also, when you get something so close in any survey, a point or two difference, then the pollster is sitting there and making a very subjective interpretation of what those results are. But you need fantastically huge--at the 50 percent level, to pick up a one- or two-point difference, you need a sample of 5,000 or something of that magnitude, and they're doing 500, 750, maybe 1,000.

FLOOR QUESTION: But if half your sampling doesn't even know the process they're voting on, it seems irrelevant what they say.

MR. ABRAMS: Oh, I disagree with you strongly. They are aware that there is a process that reduces contaminants coming--you know, after the screening and testing. But their reaction is they get upset if there's something still in that blood which could cause them a problem. We're not talking from a doctor's point of view or a manufacturer's point of view and what is fact or not fact. It is what the perceptions are of the people, and that's what drives attitudes and behavior.

DR. PENNER: Yes, the next question--oh, you were answering--

FLOOR QUESTION: I'm answering the question as to what the public, in another opinion poll, not this one, responded in terms of what it was willing to pay for a unit of leuko-reduced blood. You can find this reference at the Coalition for Transfusion Medicine. They have a website. The full survey is there. My recollection is that the public was asked, Would you pay as much as $70 for a unit of filtered blood? And their response was, virtually universal, yes.

DR. NIGHTINGALE: Is the characteristic of the polled sample at that website?

FLOOR QUESTION: I'm sorry?

DR. NIGHTINGALE: Are the characteristics of the polled sample at that website also?

FLOOR QUESTION: Yes, they are.

DR. PENNER: So if you were asked whether you would like to drink pure water or not so pure water, it would be worth at least $70.

Yes?

FLOOR QUESTION: [inaudible], Seattle. I would just submit to you, sir, that if I were told would I take contaminated anything, my answer would be no.

DR. PENNER: Ms. Chance, please, and we'll cover some more comments later. Would you introduce yourself, Ms. Chance, please?

MS. CHANCE: Yes. I'm Nancy Chance, and I'm not subsidized by anybody to be here today. I came on my own accord.

I'm Nancy Chance from Riverview Hospital, bloodless surgery and medicine coordinator, as well as the blood bank coordinator, in Noblesville, Indiana. I appreciate the opportunity to speak before the committee today about my experiences with routine leuko-depletion at Riverview.

Riverview is a 156-bed hospital, full service, not-for-profit, located in Hamilton County, Indiana's fastest-growing and most affluent area. Riverview brings the science of medicine to our community's doorstep each day. New technology and innovation efforts affords us the opportunity to serve our community in even a better way.

We have been providing leukocyte-reduced blood products to our oncology patients since 1980s early on at bedside. We have witnessed dramatic and positive results. Several years ago, when these filters were marked for budget cuts, 31 of our nurses rallied to the support of the blood bank and to the blood bank coordinator, which was a medical director, to go to administration to rally their plea and their case.

Direct observation had actually beat our study. The nurses actually saw the difference at bedside. Direct observation had shown even before the results of the study were released that patients do better when they receive leukocyte-reduced blood products.

Our mission is to provide the highest-quality treatment to those who entrust us with their care. We have had to ask ourselves how could we justify giving treatment to some patients and not giving it to others. The answer is quite simple. We can't, nor at Riverview do we.

In 1988, we made our pre-storage leukoreduction 100 percent as a routine for all patients. But like all the hospital colleagues, we had to figure out how we would pay for our value product. Our value analysis team, which is called VAT at our institution, processes--encompassed all the hospital services. Every department is represented on this team, and we--they show us how we can cut costs by--first of all, we negotiated with our blood center for new pricing on our blood and blood products. The other 42 hospitals within our central Indiana area rallied, too, and also we were able to negotiate a cheaper price. There are processes where numbers do speak, and so the other hospitals did agree.

By minimizing our in-house inventory of filters, we actually had 16 different filters when we started, and now we only have two selective processes for the nurses to choose from at bedside.

We also saved $120 on that filter process and eliminated the logistic nightmare.

We also moved nurses wherever we needed them, and by that I mean we didn't have to have a cost in ongoing educational process for each filter. We were able to do it on an orientation or a yearly basis where they're reassessed, and when they are able to move around throughout all the different hospital settings, ICU and surgery, and et cetera.

We also discontinued CMV testing, which we're very confident about.

Our patients are doing better with filtered blood and take less time to treat. We estimate that we saved $3 million between 1988 and 1998 treating the post-op--not treating the post-op infections. More than $80,000 on length of stay was also realized.

We're doing fever antibody workups, alloimmunization, and using--and seeing a marked reduction in transfusion reactions requiring workups and additional meds. Savings are estimated at over $30,000 from '95 to '98 on this.

The savings over three years were a quarter million dollars, and our CFO has really sat up and take notice of this. In fact, he encouraged me to come today.

But how do we measure dying, the dollar amounts that we put on that? If you ask a patient or a family, they'll tell you it's priceless.

On a personal note, I'm not speaking to you as a blood banker. I'm speaking to you from a family experience. My personal story is made up of--made me a strong advocate of leukoreduction. Several years ago, my brother-in-law's twin brother was diagnosed with myelogenous leukemia. He was being treated at the largest hospital in central Indiana with the most opportunities. He was denied leukocyte-reduced products until two weeks before bone marrow transplant. Over a seven-month period, I listened and sat and watched daily as he begged for pre-medication for platelets and blood products. He died seven months later, not of the leukemia but of host versus grafts.

Just after that, we had two myelogenous leukemias present, a 57-year-old and a 33-year-old mother that had just delivered. In that instance, we in our health care facility fought to ensure that the benefits of these filters were used early on and continued throughout the process. If every patient was given leukocyte-reduced from the onset, regardless of the treatment, I believe they have a much better position.

It's ten years later, and both of those people are still with us and doing their jobs and going about their daily activities. They are only two of several hundreds that we've seen a positive result on.

A lot of argument against leukoreduction centers on cost. I am a major proponent of finding and eliminating the cost of poor quality. In our hospital environment, the key measures of this is the consequences of the costs of treating complications. The cost of poor quality continues today to be a significant cost to patients, payers, providers, and the nation. Experience shows us that money we spend on leukocyte reduction will save us somewhere else. I know it's hard to understand, but sometimes we have to dig a little deeper.

If our institution at 156 beds can accomplish this goal, I think any institution of any size can.

I urge you to continue the fight for universal leuko-depletion. People's lives depend on it. And I thank you for the opportunity to speak to you today.

DR. PENNER: Thank you, Ms. Chance.

Are there questions or comments from the committee on any of the speakers, the last three speakers? Or from the audience, any additional comments? Yes?

DR. VAMVAKAS: I have a question for Mr. Wertham. You said that the Pall Filter Company is ready to provide filters for all of the U.S., and we all know that in the past year or so there have been filter recalls, and at least to my knowledge, last fall for some time the only available filter used to be your filter, the Pall filter, because others had been usually voluntarily recalled.

Should we come upon a situation where you provide the filters for the entire country and your filter is recalled, would there be a contingency plan so that there is blood the next day, not the next week or two weeks later, to transfuse patients who are bleeding?

MR. WERTHAM: I understand the question. The period last fall that you referred to, there was only one product code of several offered by that manufacturer that was recalled, meaning that their other capacity continued as an option to buy if they wanted.

Concerning our product, I can relate to you that we make the product in many manufacturing locations, a replicate product that is identical. And so the likelihood of any catastrophic event putting down all the manufacturing would be highly unlikely, we believe impossible.

We also manufacture overseas, and those plants are FDA approved, so we can export from overseas, import to the United States if necessary.

I know all the manufacturers have published on their capacity buildup anticipating ULR, not only in the United States, Western Europe, but globally, and I believe that supply line is quite secure at this time.

DR. PENNER: One last question back there.

FLOOR QUESTION: Thank you very much. My name is Bill Teague, and I'm with the Gulf Coast Regional Blood Center in Houston. I'm not an expert on surveys, and I can't relate to the young lady's comment about the validity of this survey. But I do believe, regardless of what you think about this survey, that it highlights the public's absolute fear of the blood supply. And I believe as we talk about these items, we urge the committee to be very sensitive to the public fears and the trust that this country needs in its blood supply to have an adequate donor support.

There is a direct correlation between fear of getting blood and fear of donating blood, and we've all had shortages, and I'm concerned that the committee should be very sensitive to the public's perception of what you do if there's any hint that you're not protecting the American public. Not only will the recipients suffer, but I believe we'll suffer from the donor supply as well. So I just urge you to consider that, please.

DR. PENNER: Yes, I think we all agree with you and there's no problem. Our worry is maybe about that 11 or 12 percent in that survey.

Now, if we could go on to Mr. Miripol for Terumo Corporation?

MR. MIRIPOL: Thanks very much for giving me the opportunity to speak to the committee. Dr. Nightingale, thanks for inviting us. And once we work out the technology--hopefully it won't blow up. As we are getting ready here...

[Pause.]

MR. MIRIPOL: We're not getting ready here.

DR. PENNER: Next time we'll bring a blackboard. It always works.

MR. MIRIPOL: Or a flip chart, right. It looks good on my screen, I can tell you that. I realize that folks have got flights to catch, so--reboot it? Okay. One quick reboot here and we'll see what happens.

[Pause.]

DR. PENNER: If you want to work with that, we could go on to our next speaker and then have you--

MR. MIRIPOL: I think we're ready here, maybe. Well, while we're getting rebooted, again, I am Jeff Miripol and, again, thanks for the invitation to speak. Hopefully I'll be able to go through my presentation. But in a nutshell, Terumo Medical Corporation is one of the manufacturers that supplies blood collection containers and products to U.S. blood centers and hospitals. And I'm going to speak about a specific area regarding leukoreduction. I guess basically you're watching this thing boot up. So while we're going on with this little demonstration of Windows 2000, we are in favor of leukoreduction. I guess I look at it this way: What kind of blood product do I want to get? But at the same time, we don't want to mandate--or we feel we aren't the folks in the driver's seat to actually mandate what kind of process, what kind of a product the hospitals should use or the doctors should use.

But we do provide a specific product that is used as part of leukoreduction, and that is the sterile tubing welder. And the sterile tubing welder allows the blood centers and the hospitals to--

[Laughter.]

DR. NIGHTINGALE: We won't look.

[Laughter.]

DR. PENNER: Who is supporting you? Bill Gates?

[Laughter.]

MR. MIRIPOL: I ought to do some kind of comedy act. I feel better. Thank you.

I always have a fear of these things happening, and it finally happened. I'm going to go through a whole litany of settings.

One of the things that we want to make you folks aware of here at the committee and the doctors and hospital staff and blood center staff comfortable with is that this issue of supply and capacity, which Sam Wertham spoke about and the other manufacturers spoke about as well, is, I think, an important issue, but we want you to understand that, regardless of the technologies you employ or you want to employ, we are able to supply the devices and the wafers that are required in some cases to do leukoreduction.

And why is this thing not opening? There we go. This is supposed to be a 66-gig hard drive.

[Pause.]

MR. MIRIPOL: All right. That's me.

[Laughter.]

MR. MIRIPOL: Okay. So what I really want to talk about is that we are offering a product--and it's been available for some time; the FDA has incorporated this product into its guidelines--which allows flexible technology, allows the blood center to do leukoreduction under various conditions, and allows leukoreduction with any dockable filter. And I guess that's my point there. In other words, you have a lot of choices available. It also allows leukoreduction at various points in time, and also, if required, allows the transfusion service to also do leukoreduction.

The point also is that this system is process-controllable, fits into the blood center service or transfusion service work flow, and we believe the discussion here kind of alluded to or touched on economics. We believe this system is extremely economical. And also, as an aside, I would also point out that there is, I think, a real issue in terms of reimbursement and cost within the health care system in the United States regarding blood products in general. And I think this is something that needs to be addressed because, speaking from a manufacturer's standpoint, frankly, the margins in this business are terrible.

Anyway, this process also allows you to have a standardized process but with flexibility. We also as a manufacturer have developed specific validation and support technologies. Much as Pall has done, we have developed something called the weld test kit which allows the user to test the welds in terms of their integrity. We also have training of the blood center staff, and we supply the devices and repair the devices and supply service contracts on the devices.

So basically we try to support the blood centers, support the hospital, from kind of a soup-to-nuts standpoint.

The other point about this technology, it is cost-effective and flexible, as I am pointing out. And it allows you to work in either high-volume or in lower-volume or ad hoc type environments. So whether you believe that leukoreduction needs to be done 100 percent or if needs to be done on specific units, this is very flexible. You can do the leukoreduction on the night shift. You can do leukoreduction after you do testing. So that also is a way of reducing costs.

One of the key things I wanted to really bring up, though, and kind of spend a little bit of time on is supply. I think, again, Sam spoke to this, and the other manufacturers I think have talked about it. We supply now two types of sterile tubing welders for the blood-banking environment. We have two different sources, two different manufacturing sites for the wafers. In the U.S., we have a local wafer supply, which is adequate, right now as of today, this minute, able to supply a running rate of 6.72 million wafers per year. This is the actual disposable that's used in making the sterile dock.

We have a wafer supply from our factory in Japan which is able to supply at this moment a running rate of about 4.2 million wafers per year. By July 1st of this year, we will be able to supply from the U.S. in excess of 840,000 wafers a month, and from our factory in Japan another 500,000 wafers per each month to the U.S. blood supply.

So I just want to make the point, make you folks aware, that from a supply standpoint we have multiple manufacturing sites, and we don't believe that supply is a limiting factor here whatsoever.

That's it.

DR. PENNER: Thank you. That was brief when you got down to it.

MR. MIRIPOL: Thanks. Sorry for the technology.

DR. PENNER: Any questions for Mr. Miripol? If not, thank you.

Then we'll go on to Mr. Sacher, Ron Sacher. Dr. Sacher?

DR. SACHER: You can call me "Mister." That's fine.

DR. PENNER: I was going to put a T in there and accuse you of being related.

DR. SACHER: Well, people mistake me. Do you want me to boot it up as well? I better boot it up as well. Excuse me. This new technology.

I can at least introduce myself. My name is Dr. Ronald Sacher, and I'm presently director of the Hawksworth Blood Center at the University of Cincinnati and a professor of internal medicine and pathology there. I was formerly chairman of the Department of Lab Medicine at Georgetown University Medical Center, where Gerry Sandler, of course, worked. And we had a terrific relationship. I miss you, Jerry.

My task today is I actually represent the University HealthSystem Consortium, and I'm here to present the opinions and the deliberations of the UHC's expert panel evaluating the concept of universal leukoreduction. I also have on the slides, when we eventually get to them, an analysis that UHC did on the patterns of practice of use of leukocyte reduction amongst the member hospitals of the University HealthCare System.

For those of you who don't know, UHC represents approximately 80 academic medical institutions. This represents approximately 70 to 75 percent of all academic institutions in the United States, and the surveys that we did--or at least that were done by UHC, in fact, two members of the audience who participated and did most of the work are here. That's Joe Cummings and Tom Ratgow (ph)--represent, I think, some very interesting data which I hope to present to you when we eventually get this up here. And I think I'm going to be a little quicker than our previous speaker. Hopefully.

As I said, these opinions--excuse me--the trouble is when your finger is too quick. These opinions represent the opinions of the expert panel, and I'm going to present those as soon as I can get this organized here. Okay.

A survey was conducted in the latter part of 2000 to ask several questions of the members, and 64 respondents acknowledged--these were blood bank directors, representing a response rate of about 82 percent. Six questions were asked. Obviously they're listed on this slide.

Do you believe in universal leukocyte reduction? What are the indications for leukocyte reduction? How is LR performed, pre- or post-storage? What percentage are of leukocyte reduction at your hospital? So we do have some data. And what percentage of platelets are leukocyte-reduced at your hospital as well as what percentage are apheresis versus pooled?

The first question, these are the results, and as you can see, in terms of do you believe that published reports document substantial health benefits, 69 percent responded no, 31 percent responded yes.

In asking questions specifically the indications for leukocyte reduction, of course, the three main indications were the commonest, that is, the reduction of platelet alloimmunization, reduction of CMV, and reduction of febrile non-hemolytic transfusion reactions. There was also a significant response in terms of reducing alloimmunization in transplant patients.

The rest of the indications are listed beyond this, and certainly they include some of those that we spoke about a little earlier that have been covered.

Question 3 was: How do you supply leukocyte-reduced components? And, in fact, as you can see here, the majority did supply it as pre-storage, post-storage representing 35 percent.

Question 4: Approximately what percentage of red cell units are leukocyte-reduced at your hospital? You can notice here that a significant number of respondents, at least half, responded less than--well, certainly less than 25 percent.

Question 5: What percentage of platelets are leukocyte-reduced at your hospital? Half of the respondents acknowledged that the majority of platelets were leukocyte-reduced, in fact, representing 70 to 100 percent in at least 50 percent of the respondents.

And Question 6: Approximately what percentage of platelets are apheresis versus pooled from whole blood donations? And here you can see that a good number do supply--well, essentially leukocyte-reduced components that are apheresis-derived.

So the summary of this analysis, which served as the basis of convening an expert panel, was that academic hospitals in the United States tended to be against ULR by a ratio of about two to one; 43 percent already use leukocyte-reduced component red cells and 72 percent platelets; and, of course, the indications that were predominantly the significant indications you've already heard. Also, a fourth one, to decrease alloimmunization in transplant patients as well. And LR components supplied pre-storage in the vast majority of cases.

This served as the basis for convening the expert panel, and, in fact, a meeting was held in October last year where presentations were made by many of the participants in the audience, and the process of consensus conference strategy was evolved. The participants--am I doing something wrong here? Maybe I'm highly charged.

Anyway, participants included, of the panel, seven physicians representing the disciplines of transfusion medicine, pathology, internal medicine, and hematology, and the evidence was evaluated based on an analysis of all articles published in English from 1990 through August of 2000. This represented a voluminous amount of work, and 173 documents were assessed, including, as you can see, not only original reports meta analyses, and reviews.

The evidence-based grading system was used. It used predominantly the U.S. Preventive Services Task Force criteria, and also the ACC American Heart Association grading system. And it followed the symposium presentations.

The format was a consensus conference development, and, again, evidence tables with an analysis of bibliography. Specific questions were raised to the panelists, and I'm going to cover those, and the recommendations, which I'll also summarize, were broken down into clinical, administrative, and policy.

The critical evaluation of scientific and clinical evidence focused on leukocyte-reduced blood and the concept of universal leukocyte reduction.

The grading system is listed on this slide and indicated several categories of evidence. The Type I, of course, is from well-designed, randomized, controlled trials; Type I-II, well-designed controlled trials without randomization; II-II, well-designed cohort or case controlled analytic studies, preferably from one or more centers or research groups; Type II-III evidence, published evidence from multiple time series, with or without the intervention; Type III, evidence from respected authorities based on clinical experience and expert committees; and Type IV, essentially insufficient evidence.

In addition, the clinical recommendation grading system involved the classes that are listed on this slide: Class I, unanimous or near-unanimous in favor of the recommendation; Class II-A, the majority in favor of the recommendation, but with conditions that have conflicting evidence or a divergence of opinion, yet still favoring recommendation; Class II-B, where the majority of the panel was in favor of the recommendation, but the usefulness was less well established; and, of course, Class III, where it was unanimous or near-unanimous against the recommendation.

Now, asking the specific questions and then coming up with our specific indications, these are the following recommendations. And as I indicated, I'm here as the representative of the panel to present the findings and deliberations.

The first recommendation: to decrease the incidence of subsequent refractoriness to platelet transfusion caused by HLA alloimmunization in patients requiring long-term platelet support. These were very strong, Class I and Type I evidence, with unanimous recommendation, and these were based on what you've heard earlier, results of eight randomized trials that examined the use of leukocyte-reduced components to reduce HLA alloimmunization and refractoriness.

With regard to the second question, to provide blood components with reduced risk for CMV transmission. The evidence was Class I, Type I, again, very strong. The panel voted in favor with a six-to-one vote. Most of this Type I data demonstrated that leukocyte reduction nearly totally eliminates the risk of CMV transmission. And, again, the results were obtained primarily in patients receiving chemotherapy, which, as has already been alluded to, may not be equivalent in all patients.

Three, to prevent subsequent febrile non-hemolytic transfusion reactions. Again, these are the well-established indications we heard earlier. The evidence, Class I, Type II-III, the vote was six to one, and this recommendation applied to both red cells and platelets. It will not prevent febrile non-hemolytic transfusion reactions in all patients, and that there is no published data from randomized trials that by design examine the potential impact of LR components on the incidence of febrile non-hemolytic transfusion reactions, although you've heard some data from different institutions this morning.

Finally, to decrease the incidence of alloimmunization in non-hepatic solid organ transplantation, evidence Class I, Type II-III, again unanimous, again applying to platelets and red cells; again, no data from randomized studies, but significant clinical data that clearly demonstrates a lower incidence of HLA alloimmunization in those who receive leukocyte-reduced products.

Getting now to insufficient evidence to justify LR, first of all, one, to prevent reactivation of endogenous viral infections such as HIV or CMV. We've heard about the VATs data. This was Class III, Type I, very strong evidence against it.

To prevent general immunomodulatory effects, Class III, Type I. There are five Type I studies that were evaluated, and the comment was made that there's suggestive increased risk for post-operative infections in patients who receive standard blood components. But you've heard conflicting data, of course, and that was the issue. Many confounding variables make the comparative analysis impossible.

Again, this is all focused on evidence-based analysis strategies.

There's no scientific justification to reduce hospital lengths of stay in transfusion recipients, Class III, Type I, only one Type I study in cardiac surgery which showed no difference. Some of this, of course, has already been alluded to, and what I am summarizing now is the UHC's strategy for assessing and analyzing this.

There are well-designed clinical studies that incorporate lengths of stay as a primary endpoint. Certainly they would be justified and would be of substantial value.

The other unjustified practices and their evidence is listed on this slide, and I think some of these have already been discussed, and, of course, there's no justification for using it on that basis.

With regard to the second component, that is, administrative recommendations, the following were the recommendations: that the use of pre-storage methods for leukocyte reduction is recommended for preparation of the red cells and non-apheresis platelet components in community blood centers or hospital-based blood banks, and this is obviously whether you do select them or you don't select them.

Class I, Type II, I, for platelets and Class II-A, Type III for red cells. The implementation of universal leukocyte reduction to maintain a single inventory we felt on the basis of the data is not justified, certainly from a scientific or policy perspective. And this, again, is Class II-B, Type IV.

With regard to the final comment on policy recommendations, this was not unanimous. The benefit-to-risk ratio associated with leukocyte reduction is not sufficiently high to justify requiring universal leukocyte reduction of all cellular blood components. The committee voted five to two.

The benefit-to-cost ratio, however, is similarly unjustified. This was a seven-to-zero vote. The implementation of universal leukocyte reduction for the purposes of assuring harmony of blood policy between the U.S. and other countries is not justified from a scientific or policy perspective, and that there is no justification, at least on the basis of available science and our objective assessment, for mandating universal leukocyte reduction on this basis.

Thank you very much for your attention.

[Applause.]

DR. PENNER: Any comments for Dr. Sacher from the committee?

[No response.]

DR. PENNER: From the audience?

[No response.]

DR. PENNER: Thank you for your very nice presentation and the fact that the instrument got off the ground and we got pictures.

Our next speaker is Dr. Lawrence Petz? Larry is from the University of Rochester. Excuse me. I mean from the American Hospital Association. I slipped down. We just gave you a new position. You can advertise your book now.

DR. PETZ: Thank you. I'll do that.

Good afternoon. My name is Dr. Lawrence Petz, I'm emeritus professor of pathology and laboratory medicine and former director of transfusion medicine at the University of California in Los Angeles.

I'm here today on behalf of the American Hospital Association's nearly 5,000 hospital health system network and other health care provider members. I'm also representing myself as a physician, a taxpayer, a payer of health care premiums, and a potential recipient of blood products.

The most important consideration regarding universal leukocyte reduction should be the scientific data.

I have chosen to review this briefly and I have chosen to quote from the summary chapter of the book by Vamvakas and Blajchman entitled Immunomodulatory Effects of Blood Transfusion.

In the summary chapter, they reviewed the significance of possible immunomodulatory effects of transfusions, and this quote I have taken from this chapter:

"The issue of whether any deleterious immunomodulatory effects of allogeneic transfusion can be prevented or abrogated by leukocyte reduction remains unresolved."

In regard to cancer recurrence: "Whether the transfusion of standard allogeneic red blood cells increases the risk of cancer recurrence has not yet been addressed by randomized controlled trials."

In regard to post-operative infection, the chapter states, quote, "In conclusion, the cost effectiveness of the use of leukocyte-reduced allogeneic blood components for the prevention of post-operative infection has not been established."

In regard to other potential side effects, such as reduction of virus activation, reduction of bacterial substance, prevention of transmission of other viruses, and the prevention of possible new variant CJD disease, the chapter states, quote, "None of these other potential benefits from leukocyte reductions is presently established in accordance with the tenets of evidence-based medicine."

Now, I don't purport that this is a balanced and complete review of all the data about leukocyte reduction and its significance, but the question that this raises is how is the committee going to decide what is right and what is not right?

This issue of universal leukocyte reduction is a very specialized area of transfusion medicine, which is a very specialized area of clinical pathology, which is a very specialized area of pathology, which is a specialized area of medicine. And for people to digest all of this in one session I think is exceedingly complex.

How to make the decision? I would like to submit that one important consideration is that the committee ought to be aware of and to consider the very strong scientific consensus against universal leukocyte reduction. That hasn't these brought out at this meeting yet except with the previous speaker's comments.

Indeed, 31 physicians from 25 medical centers felt so strongly about the issue that they submitted their views for publication in the Journal of Transfusion, which is the journal of the American Association of Blood Banks.

It is significant that none of these physicians would have any personal economic consequences resulting from implementation or lack of implementation of universal leukocyte reduction.

The letter was published in the June issue of Transfusion and states in part that, "For selected indications, leukocyte reduction has been well documented by clinical trials." But it goes on to point out that, "The signatories of the letter have reviewed available data and it is our view that published reports fail to document a substantial health benefit that would serve to justify leukocyte reduction of components transfused to all patients."

The letter goes on to state: "We would strongly oppose measures that would compel us to supply only leukocyte-reduced blood products for all of our patients."

Now, the transfusion medicine specialists who signed the letter are Dr. Robert Thurer from Harvard; Naomi Luban from Children's Hospital of Washington; James AuBuchon with Hitchcock Medical Center; and Leo McCarthy from Indiana University Medical School; Sonny Dzik and Christopher Stowell from Massachusetts General Hospital; Brendan Moore from the Mayo Clinic; Eleftherios Vamvakas from New York University Medical Center; and Will Armstrong from the University of South Carolina School of Medicine; and Michael Kantel from Southern California Permanente Medical Group; Elaine Jeter from Providence Hospital, Columbia, South Carolina; Joanne Becker from Roswell Park Cancer Institute; Martha Higgins from St. John Hospital, Detroit, Michigan; Susan Galel from Stanford University; and Steven Kleinman from the University of British Columbia; Carol Marshall from the University of California, Davis; Richard Newman and Jose Ocariz from the University of California, Irvine; Douglas Blackwell and Lawrence Petz from UCLA; Pearl Toy from the University of California, San Francisco; Earl Oberman from the University of Michigan Medical Center; Don Siegel from the University of Pennsylvania Medical Center; and Thomas Price, Joe Slichter and Terry Gernsheimer from the University of Washington Medical Center; and Paul Mintz from the University of Virginia Medical Center; Lawrence Goodnough from Washington University School of Medicine; Edward Lipford from Carolina's Health Care System, Charlotte, North Carolina; and Marcus Simpson from the George Washington University in Washington, D.C.; and somehow I neglected to include the name of Herbert Silver from Harvard Hospital, Hartford, Connecticut.

I would like to emphasize that physicians who practice medicine, including those that I have just named, have the responsibility in their daily practices of balancing patient needs with reasonable resource expenditures.

They have experience in doing this throughout their medical careers and have become skilled in fulfilling this responsibility and discussing their recommendations with patients in adequate detail.

Now, as an aside, I would like to point out that manufacturers of filters who we recently heard from do not practice medicine. It is also true that the American Red Cross and other blood centers do not practice medicine.

These organizations do not have the responsibility to balance patient needs with resource expenditures. Theirs is a different perspective and an incomplete one, and the committee members must determine how to weight such comments in their evaluations. After all, a filter manufacturer could design questions that would in a survey give the answers they want, plus or minus three percent.

I point out next that the Office of the President of the University of California in June of last year developed a letter protesting the forced implementation of universal leukocyte reduction. The letter was sent to six California members of the House of Representatives who are on a House Commerce Committee whose jurisdiction includes oversight of the FDA, and these are the representatives to whom the letter was sent.

The signatories of this letter include William H. Gunther, Vice President of Clinical Services Development, the president of the University of California, and the transfusion medicine specialist and hospital directors or executive officers of all five University of California Medical Centers, which includes San Francisco, Davis, Los Angeles, Irvine and San Diego.

Next I would like to just reiterate very briefly the comments that were made by our previous speaker about the University of Health Systems Consortium Consensus Conference that was held in October of last year. The composition of the panel is listed here. The chairman was Dr. Harold Oberman of Michigan University.

The policy--two of the policy recommendations that I think are most important among the ones that were described are, first, the expert panel concluded by a vote of five to two that even ignoring costs, the benefit associated with leukoreduction is not sufficient to justify requiring universal leukocyte reduction. That's in contrast to a vote of the Blood Products Advisory Committee a couple of years ago.

In the second vote in which the committee considered costs, which is what the Blood Safety and Availability Committee is charged to do, the vote was unanimous that the available evidence does not justify requiring universal leukocyte reduction.

Next on a related note, as also was mentioned by the previous speaker, over 80 percent of transfusion medicine directors responded to a University of Health Systems Consortium formal survey regarding their opinion of universal leukocyte reduction. Of the 64 responding transfusion medicine directors, 44, or 69 percent, felt that there was not documented substantial health benefit justifying universal leukocyte reduction.

That's a bit about the science. A couple of ancillary issues before I conclude.

One question that's frequently asked is if you were the patient, when do you want leukocyte-reduced products? Patients are asking for it, they've said they must have it.

This is a very critical question and it points out the conflict that frequently exists between the societal viewpoint and a personal viewpoint about medical procedures. What is beneficial for society as a whole may not be optimal for every individual.

Now, this is a very complex issue that involves economics and ethical and medical decisionmaking, and it cannot be properly resolved by simplistically recommending that everything be done for everybody regardless of how trivial the benefit and regardless of how large the cost.

The Blood Safety and Availability Committee has a responsibility to balance the issue of high cost with inconclusive benefits. There are times when it is appropriate to not recommend expenditures of large sums of money, and universal leukocyte reduction is an outstanding example.

We can have the slides off, please.

The science, as we've heard even from Dr. Blajchman, is inconclusive, and as we've heard from Dr. AuBuchon, the cost would be half a billion dollars a year. That's this year, next year, every year from now on. In the next decade, we will be spending $5 billion. We should be sure we're going to get something for that money.

One other ancillary comment. Some individuals espouse that if universal leukocyte reduction were fully reimbursed, it would then be reasonable to implement it. I can't disagree more because the source of funding of universal leukocyte reduction does not affect the scientific data regarding its justification.

Whether funds to pay for universal leukocyte reduction come from hospital budgets, blood transfusion service budgets, insurance companies, HMOs, or from my taxpayer dollars, the lack of justification for this expenditure from the nation's health care resources has not changed. These resources could be better spent on other health care measures that could certainly save lives.

In conclusion, then, the American Hospital Association believes that ensuring the safety of the nation's blood supply is essential in providing high-quality health care within its hospitals and health systems.

It's clear that leukocyte-reduced blood is indicated in a targeted basis in conjunction with the orders of patients' physicians, and should a scientific consensus emerge, as was mentioned a number of times, should a scientific consensus emerge on the benefits of universal leukocyte reduction, the American Hospital Association, all of us, would strongly favor its implementation. But for now, I feel that it would be inappropriate for the members of the Blood Safety and Availability Committee to overrule the published recommendations of numerous transfusion medicine specialists throughout the United States, to overrule the stated opinions of almost 70 percent of transfusion medicine specialists surveyed by the University of Health Systems Consortium, to overrule the University of Health Systems Consortium Consensus Conference Panel on Universal Leukocyte Reduction, and to overrule an emphatic statement by the Office of the President of the University of California. To do so would force physicians to practice medicine against their best judgment.

That concludes my testimony, and I ask that a written summary of my testimony, which can be supplied, is put into the record, along with the letter that was published in Transfusion, the letter from the Office of the President of the University of California to the House Commerce Committee, and the result of the University of Health Systems Consortium survey.

Thank you.

CHAIRMAN CAPLAN: Thank you, Dr. Petz.

[Applause.]

CHAIRMAN CAPLAN: Do we have comments from the committee or questions?

Yes.

COL. FITZPATRICK: Dr. Petz, did you or the Health Consortium consider the subjects brought up by Dr. Ness on the reduction of error rate and the potential of transfusing the wrong component to the wrong patient in any of those questions that were asked or in the articles that were reviewed?

DR. PETZ: I don't know that those were parts of the articles reviewed. That kind of question comes into the thinking of all of the specialists in transfusion medicine who consider these questions. We're on the daily firing line of all those issues, and we understand transfusion errors, we understand getting the wrong blood to the wrong person. Whether something was given as leukocyte reduced or we want to get the AVO type right, those are part of the thinking process. I don't know that it was done any more specifically than that, and maybe Dr. Sacher would want to comment on that.

COL. FITZPATRICK: I would just suggest that--I would agree that we consider that on a daily basis in our decisions, but if we're going to base everything on science and statistics as you have suggested, leaving that out of the equation is almost as biasing as the questions from the survey that Paul used.

DR. PETZ: Well, that's debatable.

CHAIRMAN CAPLAN: Okay. Dr. Hoots.

DR. HOOTS: Yes. I don't know if I should address this to you or to Dr. Sacher, but I guess I'm perplexed. On that next to the last or penultimate conclusion that you put up from the University Hospital Consortium, now, the FDA Advisory Committee voted 13 to zero that the benefit-to-risk ratio, right--I'm talking irrespective of resource allocation--the benefit-to-risk ratio favored universal leukocyte reduction, and yet here, five people voted that that was not the case, two voted to agree with the FDA Advisory Panel.

I have yet to hear enough data on risks to the procedure to show that a ratio of benefits which you've already acknowledged, which at least reached 20 percent minimally of the population, are counterbalanced with a comparable 20 percent or greater risk to implementing it to people who may or may not need it other than cost.

If you take resource allocation out of the equation, I don't understand that. Based on all the data that you've cited, which we reviewed, I don't understand that conclusion.

DR. PETZ: The conclusion is based on the fact that targeted leukocyte reduction is indicated, but not universal. Now,--

DR. HOOTS: Wait a minute. Hold it.

DR. PETZ: --let me just mention also --

DR. HOOTS: Wait a minute. If you are going to draw a benefit-to-risk ratio, you have to take all the benefits and all the risks.

DR. PETZ: Okay.

DR. HOOTS: And I don't understand how you can remove all the benefits and then left with either--minuscule risks and therefore the ratio is in excess a risk over benefit. I don't understand that.

DR. PETZ: You would not have voted with the majority. But on the next question, which is the question that this panel needs to answer--

DR. HOOTS: But do you understand why I ask this question?

DR. PETZ: Yes, I understand the question.

DR. HOOTS: Because it's important. If we're going to take consensus panel input as a rationale for a judgment, we have to be darn sure that that processing is gone through in the same way, or else that we agree with how the processing took place.

The second part, I won't--I mean, we can--we have been debating the second one, and I don't have issue with that. I mean, I understand that one. But the first one, I have some real issues with.

DR. PETZ: Okay. One point, going back to the Blood Products Advisory Committee meeting that is always quoted as 13 to zero, Dr. Lee from the FDA, in the transcript of the meeting in December of '99 that was held supposedly about implementation of universal leukocyte reduction, and the transcript is on the web, pointed out that that vote was very unenthusiastic in favor of universal leukocyte reduction. He stated that --

[Laughter.]

DR. PETZ: If you'll let me finish--that if you graded their vote on a basis of one plus to three plus in favor of universal leukocyte reduction, it was a weak one-plus vote. And so it's not too farfetched to take another group of persons who are voting on the same issue and come up with a different answer even though you wouldn't agree with it.

DR. HOOTS: No, I agree with that, I'm just talking specifically about rationale.

CHAIRMAN CAPLAN: Dr. Vamvakas.

DR. VAMVAKAS: I was at the meeting of the UHC and I would like to answer your question.

There are some risks to leukoreduction. There have been complications like severe hypotensive reactions to leuko-reduced platelets. I think that more importantly, people were afraid of a potential impact on the supply.

I asked this question earlier and the gentleman assured us that there can be no risk to the supply. Because I was in New York City a few months ago when one filter was recalled, I do not share his enthusiasm or optimism that there cannot be any risk to the supply, and I think that this is one of the charges of this committee and that this issue should not be bypassed so abruptly.

CHAIRMAN CAPLAN: Dr. Sacher, you have a comment.

DR. SACHER: Yes. Actually, well, of course, you know, both Dr. Petz and Dr. Vamvakas have commented about that, but that was the most contentious issue, that particular thing, and as you can see, whereas a lot of the others were unanimous, this was not.

Guess which side I was on? I actually came with no preconceived ideas. I really sort of tried to stay assessing this on its merits. And I think when we came up with this question, the key point was the U before the LR, universal leukocyte reduction and benefit to risk.

It was debated very hotly with the points that you raised, and I think they are legitimate, but I think overall, when we evaluated all of this in an objective way as scientifically as we could, the vote is as it was.

CHAIRMAN CAPLAN: Yes, Karen.

MS. LIPTON: So the specific--I'm still struggling with the same question. So the specific risk that you were balancing was one of supply?

DR. SACHER: Well, there were several risks, and Dr. Vamvakas, of course, was one of the presenters there and there were a number of other presenters, and in fact there were both sides of the equation as, in fact, you've seen here.

It was an assessment of that question of benefit to risk for all of those factors of universal leukocyte reduction.

MS. LIPTON: And the risks of universal leukocyte reduction as articulated there were red-eye syndrome and availability?

DR. SACHER: Well, that was one, and, of course, the other issue was, what is truly the benefit of universal leukocyte reduction? That was the issue that, in fact, was debated and generated most of the dialogue overall, benefit of the universal.

MS. LIPTON: And what way did you vote?

DR. SACHER: I'm sorry?

MS. LIPTON: And what way did you vote?

DR. SACHER: How did I vote. Well, I like even numbers.

CHAIRMAN CAPLAN: Dr. Petz, just a quick question. Were there any treating doctors in that group? They were all--

DR. PETZ: Yes, there were.

CHAIRMAN CAPLAN: --pathologists?

DR. SACHER: Well, I'm a hematologist oncologist. I happen to be a pathologist and a practicing clinician. In fact, Dr. Penner may remind you, you actually--I gave a talk on ITP at your institution a while ago. It must be my hair loss that's--

CHAIRMAN CAPLAN: Absolutely. And mine likewise.

Were others, though, besides you?

DR. SACHER: Well, on the panel?

CHAIRMAN CAPLAN: Yes. It looked like the panel were predominantly blood bank directors--

DR. SACHER: Yes, there were. Certainly--

CHAIRMAN CAPLAN: And no other hematologists.

DR. SACHER: Heavily represented from the point of view of transfusion medicine. I think Dr.--yes, actually Dr.--there's one more, one missing here, and I'm blocking his name. Yes, there were actually two clinicians who actually actively practiced. The rest were pathologist transfusion medicine physicians.

CHAIRMAN CAPLAN: Okay. Thank you.

And Dr. Blajchman.

DR. BLAJCHMAN: Dr. Petz--Larry--you suggested that if universal leukocyte reduction were to be instituted in the U.S., that this would take the decisionmaking away from the doctor, and therefore certain health care needs would not be provided to the patient.

I would like to put to you a very, very clear question. What health care needs would not be provided to recipients of universal leuko-reduced blood?

DR. PETZ: Well, some of them were even pointed out by Dr. Sacher. Those would be applied not just to one hospital. One could implement a safety measure of identifying the tracking of units, and you can't do that and spend that amount of money for that and spend an equal amount of money for something else, and--

DR. BLAJCHMAN: With respect, you're not answering the question.

DR. PETZ: What--

DR. BLAJCHMAN: What health care needs would not be provided to the specific recipient of leuko-reduced blood products?

DR. PETZ: I guess I don't follow the question. If we spend the money for leukocyte reduction, we can't spend it for other safety measures is the principle we've been talking about.

DR. BLAJCHMAN: You are implying a specific recipient would be impaired.

DR. PETZ: Now you're talking about--getting back to individuals. The question of the individual versus societal view is the key issue in the front of this committee, and one benefit-- trying to work this out on an individual basis is in conflict with the societal viewpoint, and that is the key issue you need to consider in this resource allocation versus safety.

CHAIRMAN CAPLAN: Okay. Yes?

DR. PILIAVIN: I think an answer to that would be that if there was a higher risk to any individual patient of having a bad outcome from mismatched blood than there is having a bad outcome from having blood with leukocytes in it, then for any given patient, doing this trade-off between the leukoreduction and safety measures would argue for the safety measures and not for the leukoreduction, not just for society, but for every given patient.

CHAIRMAN CAPLAN: Thank you.

Yes?

QUESTION FROM THE FLOOR: Yes. I just wanted to get back to--it seems that the comment I made earlier about something that Dr. Ness said was perhaps not understood when he again spoke about patients getting the wrong blood in terms of needing leuko-reduced blood and not getting it.

From the studies that we've done where we know patients did not receive leukocyte-reduced blood who were supposed to, we did not see any difference in outcome in the study. And so I know some of the concern was what happens to the patient who presents at a community hospital, does not get leukocyte-reduced blood because the clinicians are unaware of it and doesn't get it for another two weeks, three weeks, four weeks; and what we saw was there was no difference between those patients and the patients who were initial put on leukocyte-reduced blood in terms of rate of alloimmunization.

So we really did not see that patients getting the wrong blood, i.e. getting non-leuko reduced blood who should have gotten leuko-reduced blood, one unit versus another, made any difference.

CHAIRMAN CAPLAN: Perhaps maybe just one question, Dr. Petz. If the patient develops a febrile event following the administration of one of the blood products, what is required at that point from the standpoint of the hospital and the attending physician?

DR. PETZ: Well,--

CHAIRMAN CAPLAN: What procedures do you go through?

DR. PETZ: Excuse me?

CHAIRMAN CAPLAN: What procedures do you go through? What is the approach or the management that's recommended?

DR. PETZ: That procedure is not uniform for all hospitals. It depends in part on individual hospital policy. What we require is that there be an immediate check to make sure that there isn't a hemolytic transfusion reaction by getting a blood sample to the blood bank and checking, simply looking at the plasma, see if it's red, and we try to get a urine specimen to see if it's red, and we also repeat a Kuhne's test [ph], which is a very inexpensive test. If those tests are negative, we don't go beyond that.

CHAIRMAN CAPLAN: Would you get blood cultures?

DR. PETZ: Not necessarily. If there is a fever greater than 2 degrees Centigrade caused by the transfusion, then we would get cultures, but that's a minority of products and that's based on bacterial infection, which is why we do that.

CHAIRMAN CAPLAN: But those are ones with the high fatality rates.

DR. PETZ: High what?

CHAIRMAN CAPLAN: Those are the ones with the fatality rates, correct?

DR. PETZ: Yes. We look for those. Right.

CHAIRMAN CAPLAN: Yes. So that you would want to get blood cultures, but then you would wait for the blood cultures to come back before you would treat on the basis of an infection, or would you start treating with an antibiotic right away if the--let's say the patient had a temperature of 104 after blood product.

DR. PETZ: Often these fevers resolve very quickly and antibiotics are not necessary. If the treating physician were to feel that antibiotics were necessary, that could be done. It usually is not.

CHAIRMAN CAPLAN: Well, for example, if you had an hyrcinia intercatalica [ph] following the administration of a red cell and the patient dies very quickly if you don't get the antibiotics in. So how do you discern or separate those, which are rare, quite right, but they do represent a serious problem because they're fatal?

DR. PETZ: Well, I mentioned what we do do is get cultures if the fever goes above 102 degrees. We haven't really even seen any of those problems in the decade or more that I was there. So conceivably, we would miss one, but at a cost of five billion dollars in a decade, we don't think that we can afford that.

CHAIRMAN CAPLAN: Well, I remember the one in Detroit about--what was it?--five years ago that--

DR. PETZ: It happens, but--

CHAIRMAN CAPLAN: --the policeman who had his surgery and then--

DR. PETZ: It happens, and those are the kind of issues that the Blood Safety and Availability Committee need to balance--resource allocation with possible benefit. The benefit is very small. You can cite individual cases, but that's not the way to do it.

CHAIRMAN CAPLAN: Would you be less likely to be concerned about temperature--or let's say more likely to be concerned about temperature if you had used leuko-depleted blood and you got this temperature of 102, 103? Would you consider more likely that infection would be a problem?

DR. PETZ: I don't think there's enough data--any data on that to resolve that question, and I think we would probably use our standard protocol.

CHAIRMAN CAPLAN: Okay. Thank you.

Yes, Jerry.

DR. SANDLER: Mr. Chairman, if I could show two very quick slides, I think I can help address the question what specific adverse effect might be involved to the individual patient.

CHAIRMAN CAPLAN: Okay, if you didn't bring a dozen slides, Jerry.

DR. SANDLER: No, two quick slides. I was very quick this morning.

May I see the first of the two slides I put there?

The first--we're addressing safety, although I don't believe the subject is truly safety, but we're going to call this safety. The nation's number one blood safety issue is blood shortage, and the most dangerous unit of blood is the one that's not there when someone needs it.

From where I sit, operating a hospital blood transfusion service, I've had shortages within the last six months almost every other week.

You've been hijacked today. The ship has hit an iceberg and you're rearranging deck chairs. There are real serious problems out there that effect safety that this minor safety issue has taken all of your time, all of your attention, everyone's attention, while the ship hit the iceberg. On the next slide, I'll show you the iceberg.

What you're looking at is the number of blood units that were collected, if you could focus that, on the top, and on the bottom is the number of transfusions that were given from the late 1980s until the present time, data from the National Blood Data Resource Center as recently as a couple of weeks ago.

Now, back in the late '80s, there were about two million units of blood in reserve. If I called the Blood Center then and said, I'm out of blood, what do you have? They usually said, hey, we've got some blood for you, we'll send it over.

We're down to less than a million units in this margin. There is a severe blood shortage. Safety issue today is shortage. Anything that you do that's going to further put the supply in jeopardy is not a theoretical thing that you need these P values and a whole room of people that are confused as hell today as to what the truth is; this is life and death issues, anything you do to reduce safety. You're going to have filter failures; you had them as recently as September; you're going to reduce blood from sickle cell disease. There is something that goes into the equation that you're looking for--you do something that's going to reduce supply, you will objectively reduce safety.

CHAIRMAN CAPLAN: Yes. I don't think we've been disregarding this since that was the topic of the last couple of meetings, collections, and we're concerned about collections, which seemingly is not improved. So it's the California situation, that deja vu, and we'll have the rotating brownouts.

DR. SANDLER: Right, but this is the thing that's missing in the equation that wasn't brought up, and I want this to be in the equation as you see it.

CHAIRMAN CAPLAN: That is always in the equation. If we remove people who have gone to the British Isles for six months, if we remove people of certain ancestry, whatever we do, we cut down that pool, so people have to work much harder at the blood centers in order to bring those donors in, and we would hope that they would work out something a little bit more aggressively on a local regional basis, which it used to be, to bring those donors in. But I don't think that has been forgotten, but I appreciate your point. We still have to protect the donor population that's coming in.

Any others? Yes. Go ahead.

DR. GILCHER: Jerry, in response, our system is universally leuko-reduced. We have had no shortage of blood for sickle cell patients. We're using new technology such as double red cell collection.

I think the remarks that were made before that you'll only lose ten percent or less of the people who would be an endogenic, that's been absolutely no problem, and we have had no reduction in blood supply at all by going to universal leukocyte reduction. I would ask you to come on to Oklahoma.

CHAIRMAN CAPLAN: Dr. Goldfinger from Cedars Sinai Medical Center.

DR. GOLDFINGER: Thank you for the opportunity to comment briefly on the subject of universal leukocyte reduction.

This is a subject that I've studied, implemented and discussed for over 30 years. Some of you will remember a washed cell is a happy cell. It used to be dangerous to advocate for leukocyte reduction, although this is clearly a more receptive audience.

Sadly, the progress has been slow in bringing transfusion therapy out of the Dark Ages and in gaining widespread agreement that the time has come to say goodbye to the passenger leukocytes that contaminate most blood components.

If we consider blood as a drug, a view which the FDA surely assumes, then leukocyte reduction can be viewed simply as one step in purification. In its mission of assuring purity, potency and safety of all drugs, the FDA recognizes that with increased purity, uniform potency is more easily achieved. Furthermore, greater safety is likely as patients are administered the active ingredient with fewer possibly dangerous contaminants.

Many drugs begin life as impure organic substances of plant or animal origin. While our first efforts to administer penicillin may have been in the form of impure mold, further manufacture allowed for the delivery of the active ingredient in a uniform potency and with an improved safety profile, to say nothing of the aesthetic value of swallowing a pill rather than the raw material.

The utility and safety profile of insulin was surely improved when the active ingredient could be separated effectively from its contaminating neighbors within the pancreas.

When I began in medicine, 100 years ago it seems, patients with congestive heart failure were often treated with digitalis leaf. Many physicians resisted using the newer, more purified, and more expensive preparation of digoxin. After all, the impure natural product seemed to work well enough. Nobody would make that argument today.

Blood is a raw material containing hundreds of substances. Purification of this material is essential in the quest to assure uniform potency and improve safety.

The patient who requires red cell transfusion cannot possibly benefit from the simultaneous infusion of contaminants. We accept that volume reduction achieved in the preparation of packed cells is a good thing for many patients. Inactivation of pathogens in many blood components is becoming possible, and while some resistance will be seen because of their increased cost, these safer components will surely become the standard of care for all of our patients in the near future.

Similarly, excellent technology now exists for the removal of leukocytes from all blood components. While no one disagrees that these cells can be the source of many untoward reactions, some argue that the financial cost for achieving universal leukoreduction will be excessive and that additional prospective clinical trials are required to scientifically justify this effort.

These are the same arguments that were put forth over 20 years ago when I and a few others suggested that it was time to give all of our patients the benefits of leukocyte-reduced blood components.

Whenever one recommends a change in established practice, it is generally accepted that he or she should have to prove the point. But in this case, we have two drugs, one safer, the other less safe. Since we now have the technology to make this safer blood component available to all patients, it is logical and reasonable to demand that the burden of proof should lie with those wanting to continue to transfuse unmodified blood components.

Finally, it seems that transfusion medicine physicians should be patient advocates first and foremost. I believe that we are far too cavalier and perhaps a bit arrogant when we suggest that we should determine which of our patients should receive the highest quality components. Knowingly exposing our patients to the risk of serious transfusion complications surely cannot be the right thing to do.

If I could conclude with three sentences from a chapter that I wrote and was published in 1981:

"In this time of cost-containment, any increase in the price of medical care must be viewed with great concern. Nevertheless, it is imperative that we continue to search for safer, more effective blood products to meet the increasingly complex needs of seriously ill patients. Any manipulation of a unit of blood is likely to result in increased costs; however, when the result is a component with superior clinical value which can reduce significantly the risks of therapy, then such increased costs may well be tolerable."

That was 1981.

In the current issue of Transfusion, you will see a letter by me and seven other individuals that addresses the point that Dr. Petz raised, but presents a different viewpoint, also by I think some good transfusion medicine specialists.

So thank you very much for this opportunity.

[Applause.]

CHAIRMAN CAPLAN: Thank you very much.

Any questions for Dr. Goldfinger from the committee?

[No response.]

DR. PENNER: From the audience?

DR. GOLDFINGER: If I could just make one final comment, and that is that I believe that anyone who thinks that the issue here is not cost is really fooling him or herself.

DR. PENNER: Thank you, Dr. Goldfinger.

Our next speaker is Dr. Blumberg from the University of Rochester.

Neil?

DR. BLUMBERG: Thank you. My name is Neil Blumberg, and I am the director of Transfusion Medicine and professor of Laboratory Medicine at the University of Rochester. I'm here strictly on behalf of myself and my longtime colleague, Dr. Joanna Heal [ph], who, as some of you may know, has also collaborated on a mortgage, and two children and a few other things.

[Laughter.]

DR. BLUMBERG: I have a very large private university payment starting this year.

The disclaimers are we don't represent the Red Cross, my wife's employer or the University of Rochester. We have received lecture honoraria in the past from Pall Baxter, who manufactures filters. Back in 1991, we had a $20,000 research grant from Pall to study leukoreduction and acute leukemia. Those are the disclaimers.

I think everybody can probably see this. You've heard a lot about the benefits of leukoreduction. I'm going to talk about transfusion immunomodulation, and I'm going to give you a rather different view than most of the speakers have given you. And I will say this is based on 20 years of research in the field, both in the laboratory and in the clinic, including randomized trials. And what I'm going to say will sound melodramatic, and in fact I will be quite happy to be the first to admit or we'd be the first to admit that it's controversial, and contentious and a minority point of view. But I would also remind the committee that all major scientific changes and interpretation, and this constitutes one I think, are resisted initially. When someone wise said you should wash your hands, we know it's now the most important way of preventing infection, a lot of people didn't think that was a very good idea, and the data wasn't enough at the time.

When the Surgeon General's report said in the mid-sixties that smoking is bad for you, something that we all pretty much agree to in these days, with rare exception, many physicians disagreed with that conclusion, both on the basis of the data at hand and long-accepted practice.

Well, I think the same thing is happening, to some extent, with transfusion immunomodulation, and I'll give you our view, which I think you should all realize is, once again, a minority view, but I think informed by longstanding research and clinical practice in this area. I certainly agree that there are other problems that are pressing in transfusion medicine, but I think this particular one has the potential, as I will show you, to be more important as a public health issue, in terms of number of lives at stake, than all of the other complications we have discussed taken together.

I don't have time to go into the immunology, but there actually is a fair immunologic literature now on what is going on in blood transfusion immunomodulation. It's fairly complex. It's very different than we've conceptualized blood transfusion immunology for the first 100 years or the first 70 years. But more modern concepts of these came along with more modern concepts in immunology. And it basically boils down to transfusions don't only stimulate antibodies; for example, when you get a tetanus vaccine, you get antibody formation, there's a whole other part of the immune system, the cellular immune system, that is heavily affected by transfusion. I don't have time to go into that, but there's a fair amount of animal model epidemiologic and now randomized control data.

Many of these changes, either clinically or laboratory measurements, can be reduced or abrogated, as I will show you from randomized control trials, by leuko-reduced or autologous transfusions. The reason I mention autologous transfusions, even though it's not part of the agenda today, is that studies using autologous transfusions illuminate whether the concept of immunomodulation is the correct concept. Some have suggested that this may not exist at all. I think that that is really not an adequate interpretation of the literature at this point.

If we just look at the randomized trials of leuko-reduce blood, and you've seen some of these before, and I'll call your attention to the last column, which is the change, the reduction, if you will, in postoperative infections in the six studies that have been done. And I've included some studies that didn't really look specifically at postoperative infection in detail, such as the Gott study. I've included it for completeness and fairness.

And one looks at the kind of range that we're seeing. In fact, if we're going to eliminate any studies, and I don't advocate eliminating studies, I would eliminate the Hubiers study, which wasn't really designed to look at postoperative infection, and was done in multiple centers and in too small numbers that you could, in fact, look for a center effect, and the Gott study. In fact, and those are the three smallest effects, one in which there was actually a decrease in postoperative infection.

And I would maintain that both the animal model and the epidemiologic data, the epidemiologic data, for example, that shows us that smoking is associated with lung cancer and heart disease is very similar, if not in quantity, but thrust, to showing that transfusion is the single best predictor in many studies of postoperative infection. This is nonleukocyte-depleted transfusion.

The other thing that's interesting, although we can't seem to agree on what is statistically significant and what the author said, is I would say that there are six studies here. There were four studies, randomized studies of autologous transfusion. So there are ten studies in the literature. Forgetting what Dr. Dzik says or what I say, what do the authors say in their conclusions whether these studies showed evidence of benefit to patients of leukoreduction or autologous transfusion? Eight of those ten authors claimed benefit in peer-reviewed publications.

And what I would ask the committee to consider when you consider these contradictory testimonies, not to believe me, not to believe Dr. Dzik or Dr. Vamvakas or Dr. Blajchman or any of us, but ask yourself what did the authors say? What is the likelihood that eight out of ten peer-reviewed, randomized controlled trials would come to the wrong conclusion? And I would submit that it's extremely unlikely. It's not a slam dunk, but it's extremely unlikely. These are unpopular ideas, but I think they are fundamentally correct and that the scientific literature suggests that transfusion immunomodulation is a clinically significant phenomena, and I'm about to show you what the quantitative nature of that will be.

Well, in the van der Watering study, there was a 4-percent drop in mortality in a randomized trial, and this was due to decreases in multi-organ failure, primarily. Without going into detail, multi-organ failure is primarily thought to be due to inapparent or initial infection. So the fact that, in fact, the infection rate was only different than a P value of .06, which is not exactly statistically insignificant, as suggested by Dr. Dzik, pales beside the fact that, in fact, we're talking about 4 out of 100 patients in this randomized trial died in the nonleuko-reduced arm in excess of those who died in the leuko-reduced arm.

We recently did an implementation trial, and this is a controlled, case controlled, pre- and post-study, and we also found a nonstatistically significant, but measurable, decrease in mortality in open heart surgery, which is the subject of these studies.

Now, postoperative infection sounds like a fairly benign thing, unless you're a surgeon. Now, we're from laboratory medicine, hematology, oncology and transfusion medicine. I don't think we have any surgeons here, and I haven't even played a surgeon on daytime soap operas. But surgeons tell me that postoperative infection is the single most common and feared complication. Infection is the problem. And why is it a problem? It's because it has a very high mortality rate. It's obviously very low in minor wound infections, it's very high in pneumonia, but this is not a problem that is potentially small or nonlife-threatening.

Let's see if we can get at the nature of what the estimates are from the data. Well, in the randomized control trials, it's not unreasonable to suggest that if you believe that transfusion immunomodulation is real, and I am pretty much 99.99-percent certain, to use the filter manufacturer's figures, that this is the case, the literature suggests that there's a 10-percent difference in infections. That's 200,000 fewer infections per year in the United States, approximately, using this sort of estimate.

If the fatality rate is on the range of 8 to 15 percent, which is also from large cohort studies in the literature, we're talking about 16- to 30,000 potential fewer deaths. Now, I grant you there are wide competence limits about these estimates. Could they be half this? Could they be a quarter of this? Of course. Could they be twice as large? Yes. I think both of those are unlikely. But the worst-case estimate from implementing leukoreduction, at least in surgical patients, is that maybe we'll save a few hundred or a few thousand lives, not tens of thousands of lives.

If we look just at cardiac surgery, there are about three-quarters of a million cases done a year. If you use the two numbers from either our implementation trial of 2 percent or the van der Watering randomized control study, we're talking about 2- to 4-percent fewer deaths just in cardiac surgery alone. The potential, the potential exists for tens of thousands of reductions in deaths.

What about cost? We've all talked about cost. Well, I'm going to tell you that I think this is one of those rare technical advances that, in fact, may not only pay for itself, but save money. It's the proverbial "free lunch," if you will, although obviously a complex one, from all of the testimony you've heard.

In our cardiac surgery implementation trial, from 1997 to 1998, comparing two surgeons' patients undergoing the same two operations in the same hospital, we found that when we switched patients who got transfused from leuko-reduced blood to nonleuko-reduced blood, our costs decreased, and these are actual costs, not charges, $1,700 per patient. The nontransfused patients operated on for the same surgical procedures and the same surgeons during the same time period, 1997 to 1998, actually had an increase in costs, which presumably has to do with inflation.

So somewhere between $1,700 and $5,700, because there's a delta here--I mean, costs might have increased had we not introduced leukoreduction--if we use the lower number here, we're talking about three-quarters of a million cases nationwide times our savings, and this is just a rough estimate. I'm not going to stake my financial future or my academic career on this being the exact number. But I'm saying potentially, if these are extrapolatable to the national scale, and this is an American institution, a fairly typical one, I think, doing open-heart surgery, the savings might be enough to pay for universal leukoreduction two to three times over.

If we look at the savings from a different standpoint, there actually are four studies. They've been described as being flawed. I would maintain that all studies are flawed. It's easy to poke holes in things. But when you've got ten randomized trials in peer-reviewed journals and eight of them say this is a good thing, you have to seriously consider whether something real is going on here, regardless of the criticism of the individual studies.

These are cost results from a randomized trial of leukoreduction, Jensen in Denmark; our own studies using autologous transfusion--a remarkably consistent pattern in four separate studies, two of them only in abstract form, which is that each allogeneic unit that is not leuko reduced or autologous may be associated with about $1,000 to $2,000 in additional costs. That becomes real money, even by Washington standards, when you multiply by 6 million units transfused to surgical patients a year.

So I'm not saying we're likely to save 1 percent of the national health budget, but the potential is there, from randomized control data, hard hospital cost data that we've acquired. It's not a lot of data, but it's there.

So, in summary, based on six randomized trials of leukoreduction and the four in autologous transfusion that provide intellectual support, most of which show benefit of some sort, we suggest that the committee recommend leukoreduction of all transfusions to patients undergoing surgery with allogeneic blood as evidence-based medicine. That will probably mean that we're leuko reducing 67 or 80 percent of the blood in the country, if you agree with that.

And so it then becomes logistically, perhaps, reasonable to leuko reduce the entire blood supply. And the potential benefits I'm suggesting might exist are thousands or tens of thousands of unnecessary deaths prevented and perhaps billions of dollars of health expenditures prevented.

Thank you very much for your patience.

[Applause.]

DR. PENNER: Thank you, Dr. Blumberg.

Questions from the committee?

DR. DAVEY: This is just a comment. I appreciate your analysis. How do you equate your conclusions with what the IHC found after a very careful analysis of the data on these very issues and came to either a six to one or a seven to zero vote that there just isn't justification? They didn't look, perhaps, at the author's conclusions, which may be a bit biased, they looked at the data.

DR. BLUMBERG: I think it was 5 to 2, wasn't it? All I can say is they didn't invite me to talk, a common problem.

[Laughter.]

DR. BLUMBERG: When you're with spouse, unpopular ideas, one way they have of dealing with the fact that you've provided some of the data and that you have opinions that don't fit in with the majority, is they just don't invite you to talk. So you don't even get a chance to try to convince people. That's one thing. I don't think that's unfair. I think, you know, if you don't get invited to participate in the AABB Committee on Leukoreduction, despite having published most of the extant American data, then you don't participate in the AABB's document.

Whereas, people who clearly feel the other way, that transfusion immunomodulation is not a serious problem, probably not going to turn out to be important, are being invited to participate. I think science is not a popularity contest. You can be in the minority, you can have all of the data on your side. You can eventually be proven to be correct. There's no doubt in my mind we're going to be proven to be correct in the large picture here. But those who are saying that transfusion immunomodulation is not a problem are just simply wrong. They're not stupid, they're not misinformed, they're not poorly motivated, but they're wrong. And that's all I can say.

I don't know why it is that this is so contentious. One of the possibilities is that it is a very controversial idea. It forces us to change our whole idea of how transfusion is used. One of the things that's happening outside the purview of this committee is there is a strong bloodless medicine and surgery movement because a lot of folks are feeling that transfusion has never been thoroughly evaluated for its risk-to-benefit ratio in many settings.

Dr. Blajchman has been part of a very large randomized trial that suggests that getting more transfusion, rather than less, when you're critically ill, may be bad for you. Why is that? Well, it could be because of the immunomodulatory effects. It could be that transfusion of stored blood may not be as good as we as physicians suppose. I'm going off on a little tangent here, but I think we're in a time of great ferment intellectually in this field, a challenge to many of the underlying assumptions that we were all trained about.

DR. PENNER: Dr. Blumberg, you're supporting the Galileo effect?

DR. BLUMBERG: Well, I don't want to compare us to Galileo. There are a lot of other pioneers in this field. And I think the impression we got is if you talk to transfusion medicine physicians and hematologists/oncologists, and hematologists/oncologists, for those of us who have treated those patients at various times in our career, use blood all the time, as you know. It's really part of who we are as physicians. You will find that 90--80/90 percent of them are basically negative about the transfusion immunomodulation story.

If you go to transplant surgeons, on the other hand, where there is a defined literature suggesting that transfusion really does alter outcome, you will find that 80 to 90 percent of them, and I'm just making these numbers up, I grant you, 80 to 90 percent of them will say, "Gee, of course, transfusion has clinically significant immunomodulatory effects." So some of this is the effect of who we are, and how we've been trained and what our inclination is to view.

And it doesn't give me any great pleasure, as a transfusion medicine doctor, to say, "Heck. Transfusion isn't all it's cracked up to be, and it's a lot more dangerous," but I think that's what the facts are, at the moment.

DR. PENNER: Any questions from the audience?

Yes?

FLOOR QUESTION: I've, actually, I've been impressed with Neil's comments and Neil's research, and I think this is a controversial area. I would like to say that, as far as the UHC is concerned, I felt that it was as objective as it possibly could be. We used criteria, and the choice of the audience, the choice of the participants, clearly, I didn't choose them, but it was put out to--it was publicized, individuals were invited to apply, there was a committee, as well as input from transfusion medicine directors. So, Neil, I apologize that you weren't on that list. I don't know what, you know, certainly you may well have even applied for it. But it was done in an objective way, and I think I'd just like to put that on the record.

DR. PENNER: You're speaking in Washington, D.C., you understand.

DR. BLUMBERG: I don't want to, in any way, impugn the motives or the practice of the people who made those decisions. But I think there is a tendency, when people are outspoken, when they have unpopular ideas, that you have a tendency to be excluded from those sort of things because it makes life easier on everybody else to not have people like us around.

DR. PENNER: Dr. Blajchman?

DR. BLAJCHMAN: Yes, I'd like to make a comment about the existence or nonexistence of transfusion immunomodulation. I think if you speak to most transfusion medicine scientists, physicians, other people involved, I think the vast majority would agree that there is such an entity as transfusion immunomodulation. It's clear, since Sopels [ph] and Terasaki [ph] published their data with regard to the effect on renal allo transplants.

What is under discussion is the issue is what is the clinical relevance of that? And I think the clinical trials, particularly randomized control trials, as you've heard many times today, you look at the totality of those, they are conflicting. If you look at the animal data, it is not very conflicting. It shows very clearly that there's an immunomodulatory effect.

One of the reasons that I feel that there is not an acceptance that leukoreduction may be important to avoid the immunomodulatory effect is that we haven't got a clear-cut indication as to the mechanism of this entity that is clearly, in my view, evident, is clearly there. You don't know anything about the mechanism. There's lots of clues. I have a slide with about 15 mechanisms that have been postulated, but we don't know what the mechanism is. When we don't know the mechanism, we tend to avoid or tend to shift our thinking in terms of, if we don't understand the mechanism, then it must not exist. And I think that's where the leap is taking place. If aspirin were to come on the market now, when we don't know what the mechanism with some of its side effects, it would not be--it would have a hard time going through the regulatory process.

So the point I'm making, I want to make the point, and agree with Neil, and Neil has been a proponent, and very early on in the story said immunomodulation does exist and is clinically relevant. A number of us, including myself, have tried very hard over the years to try to provide data that that's true. But it is true, it does exist. I think most people would agree that it exists. What is the magnitude of the effect clinically? That's what's unknown. What is the mechanism effect? That is unknown.

DR. PENNER: Yes, Dr. Snyder?

DR. SNYDER: Ed Snyder from Yale.

I was at the UHC meeting, and I presented, and I was enthusiastic about leukoreduction. Mark Brecker presented, he was enthusiastic. Carolyn Whitson from Mount Sinai in New York made a couple of comments in favor of it. I don't want the committee to get the feeling everybody was walking around saying, "Leukoreduction, oh, my god, oh, my god." Seven people voted. The committee, the people who presented the first day were allowed to sit on the sideline and watch, some of us in agony, actually, as the seven individuals who were the judges actually voted.

And there were certain comments going back and forth that were off the record that implied that some of the comments made formally on the record might not necessarily reflect some of the views that were off the record, but that's neither here nor there. The point is that's the way human beings are. They have a public posture and perhaps a private posture.

There was a good deal of enthusiasm from people who do treat clinical patients on a daily basis in favor of leukoreduction, and that should come across.

One last comment, I was also at the BPAC meeting in September 1998, and I thought the hands went up with great gusto in favor, 13 to 3, with no abstentions. And I saw them go up, and they went straight up.

DR. PENNER: We've got Dr. Moore to speak now from the Mayo Clinic, and I think he will carry on some of the other entities.

Thank you, Dr. Blumberg.

I'm sorry. It's not Dr. Moore, it's Ms. Foss.

MS. FOSS: I am Mary Foss. I am in an administrative position at the Mayo Clinic Division of Transfusion Medicine. I am here with Dr. Breanndan Moore, and we would like to share a few of the cost data and some of the potential benefits that we've been considering, as we've been contemplating whether or not we should go to a 100-percent leuko-reduced blood supply in our institution. So I'll start with just a few volume statistics to put in perspective the size of our practice, as it relates to some of the cost data that I will share in a few minutes.

At Mayo Clinic, Rochester, we transfuse about 44,000 red cells each year; 54,000 platelet unit equivalents; about 15,000 fresh frozen plasma; and about 7- to 8,000 cryoprecipitate.

Our blood supply comes from units of blood that we collect at Mayo and a supplemental supply of blood that we receive from the American Red Cross in St. Paul. We, at Mayo, collect about 56 percent of our red cells that we use and about 71 percent of the unit equivalents. A little more than half of those unit equivalents come from apheresis donations, and the remainder come from random donor platelets that are made from our whole blood donations.

So because we rely so heavily on those random donor platelets in our situation, we feel that if and when we go to a 100-percent leuko-reduced blood supply, we'll need to continue to make random donor platelets. Consequently, we're going to need to switch to the more expensive collection sets.

So when we looked at the cost that that would mean for us, in terms of the units that we collect at Mayo, starting at the rate that we were at when we started these contemplations based on patient demand for leuko-reduced products, which was 17 percent of the red cells and 70 of the platelets, and we looked at our supply costs, given the situation and the kinds of sets we used at that time, and compared it to the supply costs only I'm talking about now when and if we go to 100 percent, and we see a difference of about $24.50. And this, I want to state once more, is just for simply the increase in supplies. We have not been able to come up with a way to adequately assess and measure the potential benefits.

So when we look at the extra charges that we're going to have when we go to 100-percent leuko-reduced blood supply, that is, for the blood we receive from Red Cross, we'll pay about an extra $28 for each red cell and about $15 for each platelet unit equivalent. And for the units that we collect at Mayo, we'll pay an additional $24.50 per each unit that we collect. And we estimate that the total annual incremental cost to convert to a 100-percent leuko-reduced blood inventory at our institution will be $1.2 million.

So when we got to that conclusion of $1.2 million, we stepped back and said we want to make sure we have adequately assessed the benefits that could justify the costs. We know that we wouldn't make the decision based on cost alone, but we wanted to make sure that the decision we were making was scientifically, medically appropriate and basically that we were making the right decision for the right reasons.

So, with that, I would like to turn it over to Dr. Moore to share with you some of his thoughts and ideas about this leukoreduction conundrum that we find ourselves in.

DR. MOORE: Thank you. I'm Dr. Breanndan Moore, Mayo Clinic, Rochester, and I want to thank the committee for the opportunity to address them.

The first point I would make is that this committee and everybody in the room deserves a gold medal for stamina, if nothing else.

[Laughter.]

DR. MOORE: The second point is that I find myself in agreement with Dr. Blajchman, Dr. Blumberg and Dr. Goldfinger in saying this is about money. I honestly believe that if the cost per unit of collection and processing a unit to make it leuko-reduced was $5 and not $30, we probably wouldn't be here. But let me look at just one aspect of the question of cost.

Surgical procedures annually in the United States make up about $18 million. Postop infections occur in three main areas: the surgical site, catheter related and then pulmonary. And there are, indeed, others.

Just look at surgical site infections alone. About 2.7 percent of these operations are associated with a surgical-site infection, making up 486,000 cases in the U.S. per year. We know that approximately 50 percent of the transfused blood goes to surgical patients, and this is from a study by Dr. Vamvakas when he was with us some years ago. Others have agreed.

Multiple studies have demonstrated various risk factors for the surgical-site infection. And the factors that have popped out from these studies have been increasing age of the patient, spinal surgery, high-admission hematocrit, which is interesting, and in many of them, allogeneic transfusions. We cannot avoid the issue. It's there. It's one of the factors.

Now, these are the data from Dr. Vamvakas's study showing that approximately half, in various age groups, men and women, half of the blood really goes to surgical patients. So we're impacting, if we have universal leukoreduction, we're certainly impacting a lot of surgical patients. And it's been implied that this doesn't matter. My contention is it might really matter. It isn't just hem/onc patients. But the relative contribution of these allogeneic transfusions to the risk of SSI is unknown for most surgical operations. There's a hint that it's there. There's some data that are better than others. We can't really get away from it.

This is one particular study from Heiss in Lancet, a study of postop infections, localized or systemic, in 120 patients having colorectal cancer surgery. And the odds ratio, by multi-variate analysis for transfusion being associated with the infections, was 2.84. Again, you can't ignore this.

I'd like to draw the group's attention to a study by Kirkland, etal., from Duke University, where they did a matched cohort study of surgical-site infection alone, not catheter, not pulmonary. And they looked at mortality, which was clearly higher in those with the infections; those requiring ICU admission, clearly higher; median hospitalization, clearly higher; and median direct costs, clearly higher. This should be surprising to nobody.

Looking at survivors who required readmission, it was again much higher in those with surgical-site infections. And the excess hospitalization that they did was about 12 days. This isn't peanuts. The incremental hospital costs were $5,000, and the total direct costs attributable to just SSI in just 255 patients was $1.9 million in one institution for 255 patients.

If you have 255 patients with an incremental cost of $1.9 million, and you then look at the national figure of 486,000 patients who probably have surgical-site infection per year, this translates into 3,764.1 million dollars of hospital-based cost for this entire cohort across the country. Even in Washington figures, that's not peanuts.

Now, we don't know the proportion of inpatient surgery across the board that is, in fact, associated with transfusions. If every inpatient surgery was associated with a transfusion, you could calculate what the savings might be by preventing it. We don't know that. A goodly portion, we believe, goes to these patients.

So, in summary, and then I have some questions, we believe that allogeneic transfusion exposure appears to be one of many significant factors in postop infection. The results of multiple studies clearly implicate the contained white cells in the blood as the culprit. The potential savings to society are enormous if postop infection rates could be significantly reduced. And most experts agree that there is a real need for very large prospect of randomized clinical trials to assess the role of allo white cells, red cells, plasma, free hemoglobin or even iron content, all of which have been reported to be associated with infection in this postop infection.

My plea would be do not make the decision before we get some more data. Because if the real issue is money and it can be shown that the darn thing is cost effective, there is no argument.

Now, this leaves us with certain questions and a couple of comments, quoting from Dr. Dzik, who may or may not be in the audience still. He said, although several benefits leukoreduction used for selected patients have been documented by scientifically-designed clinical trials, medical benefits and their associated health care savings have not been conclusively demonstrated for universal leukoreduction. Basically, we need more data.

If we look at the British experience, Lorna Williamson and Mike Murphy have both made this kind of comment: That the 40 to 50 million pounds per year in Britain, as the cost of universal leukoreduction, would be entirely offset by a mere 1.2-percent reduction in postop infection rates. They're making the same point. If you could demonstrate that postop infection rates could be significantly reduced by as little as 1.2 percent, in Britain, that would pay for all of leukoreduction.

So the questions I have are, and this committee has all sorts of ethical, moral, and other considerations: If a therapeutic modality is indicated and beneficial for patients with certain conditions, should one routinely prescribe that course for all patients, whether or not they have that condition? An example would be would you advocate the routine use of the most expensive antibiotics for strep throat, where simpler and less-expensive penicillins are perfectly adequate?

In the presence of finite health care funds and the increasing pressure to demonstrate cost effectiveness of that spending, are we not politically, morally and ethically obliged to do everything we reasonably can to validly measure cost effectiveness before we make mandates, particularly when they're expensive?

Should we permit the suppliers of a product with a potential for an enormous financial windfall to unduly sway government to mandate a medical practice change which will be paid for not by them, but by patients? What has happened to protection from conflict of interest?

And, finally, don't we need to make the right decisions for the right reasons?

Thank you.

[Applause.]

DR. PENNER: Thank you.

I think we have time for some questions. Yes, Keith?

DR. HOOTS: Do you happen know, and this is getting back to the question I asked earlier, are the trials that are ongoing are they set up to determine a 1.2-percent difference? Do they have the power to tell that kind of difference?

DR. MOORE: Only those who are involved directly in those trials would know exactly the power of those--

DR. HOOTS: Because that's usually, to get that kind of difference, takes a huge, huge N.

DR. MOORE: Right. And that's why I suggested multi-center trials might be necessary. I can't answer for those that are ongoing.

DR. PENNER: Dr. Nightingale?

DR. NIGHTINGALE: Breanndan, could you go back to question number four and advise us in more detail how we might avoid the conundrum that you raised.

DR. MOORE: You mean the question of conflict of interest?

DR. NIGHTINGALE: How are we being unduly swayed and what advice would you give us?

DR. MOORE: I raised a question, I didn't make a statement.

[Laughter.]

DR. MOORE: It is up to you, as a group, to decide whether you are being unduly swayed. I found it difficult, and perhaps it was a little bit disingenuous of the manufacturers of filters to try and lecture us about the good to society of using their product, which they will sell at huge cost. So I'm not saying that--this is a free country. Everyone has a right to say what they want. They have a right to make their point. But I don't think that this committee should be, and I don't think it is, naive about this question. That's all I'm saying.

DR. PENNER: Other questions from the committee?

[No response.]

DR. PENNER: From the audience?

[No response.]

DR. PENNER: Thank you, Dr. Moore. We appreciate your additions.

Merlin Sayers?

DR. SAYERS: Thanks. My name is Merlin Sayers, and my affiliations are the University of Texas Medical School and Carter Blood Care, which is a community independent blood program serving the Dallas-Fort Worth metroplex.

I'll have to say, at the outset, that my comments are a little oblique to the issue of universal leukoreduction, but they do certainly bear on safety and availability. If any of you suspect that you are not going to have learned anything new by the time I'm finished, let me assure that your suspicions are well founded.

[Laughter.]

DR. SAYERS: By way of a preface and to emphasize all of our antiquity in this blood banking business, let me go to the national blood policy in 1973. It was published in the Federal Register, and the long-term aims of that policy, which grew out of debates for concern for transfusion-associated hepatitis, the ultimate aims included improvement in the quality of the supply of blood and blood products. And here it is nearly 30 years later and discussions about transfusion safety and the adequacy of the blood supply continue.

These issues have been addressed at a number of different levels, including Congress, the Food and Drug Administration, the Office of Technology Assessment, the blood banking organizations. And safety and availability, and this is my excuse for talking about what I'm going to refer to, safety and availability is a central theme for this committee.

Now, while there is no doubt that the risks for transfusion-transmitted infection are remote by comparison with the risks of the diseases that justify transfusion in the first place, and while some enhancements in transfusion safety may be so small that large enough studies to show their efficacy are just not feasible, there continues to be a drive toward what Dr. Chalmers Zerk [ph] has referred to some years ago as the zero-risk blood supply.

Now, the enhancements in transfusion safety recently have been attributed essentially to two factors: Firstly, and increasingly, comprehensive donor history; and, secondly, the implementation of a number of new tests that look for serological evidence of potential infection.

Now, with more earnest scrutiny, donor deferral rates have increased. And at least as far as the serological tests are concerned, these deferrals are more frequently a reflection of nonspecificity in the tests than they are a reflection of true infection in the donors. And these increased deferral rates have, along with other changes in the process, especially the length of time that it now takes, have contributed to what has already been referred to as a chronic inadequacy in the national blood supply. And blood programs are facing increasing difficulties in maintaining hospitals' inventories for an increasing number of patients that are becoming transfusion dependent.

Now, while the availability of blood is usually measured in terms of the number of healthy potential donors in a community and their receptiveness to recruitment, I'd like to spend just a couple of minutes emphasizing that blood safety and availability is not simply a matter of recruit, test, prepare components and distribute. There are other contributors, less obvious influences, that compound the challenges to safety and availability. Take, for example, the fact that the blood banking marketplace, at least as far as donor testing and secondary processing like universal leukoreduction is concerned, is not bristling with a host of different manufacturers all jostling for a market share.

Lack of competition in, for example, the blood donor serological testing market, has the potential to impair safety and availability for reasons quite unrelated to the efficiencies the blood programs may introduce in donor recruitment. Without competition amongst test kit manufacturers, it's unlikely that improvements in sensitivity and specificity could emerge at the pace that should be expected from a more dynamic market. As it is, most of the conventional serological testing of blood donors in this country is handled by kits from only two manufacturers. One of these manufacturers recently entered into a consent decree. And while the consent decree did not apply to kits for the serological testing of donors, this incident was a reminder to blood bankers that with few vendors in the marketplace, the elimination of one vendor for whatever reason, could result in monopoly control for the survivor.

Now, concern for the number of vendors in the marketplace is not limited to the manufacturers of test kits. This meeting is debating the appropriateness of universal leukoreduction, and again, there are not many filter manufacturers. To all intents and purposes, there are only two. And to compound this potential for a monopoly in the marketplace, in September of last year, one of the filter manufacturers recalled certain lots of their filters out of concern for leaks that could potentially cause bacterial contamination.

Now, this firm-initiated recall of leukoreduction filters was another reminder of the different variables that affect the blood supply and availability equation. The recall prompted the FDA to point out that while contamination was a possibility, the risk to public health from blood shortages would far outweigh the benefit of a general withdrawal of blood products filtered with the recalled lots.

Now, attendees at this meeting also heard about the importance of quality control, and quality monitoring and quality assurance are addressed in the draft guidance for industry that Dr. Epstein spoke about earlier. And Dr. Klein remarked that the efficiency of leukofiltration is probably at the point where the major difficulty is in counting residual white cells. Now, in this regard and remembering that the safety of the leuko-reduced product is confirmed by white cell counting, there are only a limited number of counting techniques available for blood programs which are suitable to the industrial scope or perspective or scale that we have to invoke at the larger centers.

So it was disappointing then when the distributor of an automated micro-volume fluorimeter that many centers were using for white-cell counting, decided against continued support of this instrument in the marketplace. This decision was a reminder to blood centers that the pursuit of safety and availability and reliance on instrumentation to achieve these goals, can be influenced not only by the compliance and recall incidents that I referred to earlier, but also to marketing decisions which are made independently of user input.

Now, a final concern that speaks to market issues potentially threatening safety and availability is the patenting of various genomes. Genomic amplification testing for infectious disease in blood donors--and this concept, remember, was a concept promoted by Dr. Kessler in 1994, when he was head of the Food & Drug Administrate--this concept is now being played out by the nationwide testing of volunteer blood donors for HIV and HCV, by yet unlicensed nucleic acid amplification testing. This is being conducted under an investigational new drug protocol which is approved by the Food & Drug Administration.

Now, against this background, the commercialization of biological knowledge will certainly influence what blood banks have available for testing donors and what they have to charge to recover costs for the tests. There is ample case law confirming that genes are patentable, this is not to be disputed. Patents are an old legal device designed to encourage innovation by granting inventors short-term monopoly rights. The issue though has become how tenaciously those rights are guarded, and the extent to which the inflexible application of these rights discourages both entry into the market by other suppliers and research by other investigators.

Q. Todd Dickinson, who is the head of the US Patent and Trademark Office, has suggested that biotech companies should make available patents to other companies and to academic researchers on what he refers to as "reasonable terms."

Now, no one would want to deny innovators and entrepreneurs a return on their intellectual research and development investments, but the availability and safety could be jeopardized if licensing constraints are so inhibitory that competition amongst suppliers for blood banking business is stunted.

Thank you for this opportunity to address you about my concerns for some of the issues which are, as I started out by saying, slightly more oblique to universal leukoreduction.

DR. PENNER: Thank you, Dr. Sayers. Any questions?

[Applause.]

DR. PENNER: We have four more speakers, three of whom are representing hemophilia populations and it would be nice if you could kind of consolidate some of the comments so that one wasn't repetitive if possible. And the would by David Cavenaugh, the Committee of Ten Thousand, followed by Rich Vogel and Patrick Collins, and perhaps we could just take all questions after the three have spoken.

MR. CAVENAUGH: Thank you, Dr. Penner.

As we go into the tenth hour of today's work, we do appreciate your including the patient organizations in this. We'd rather be on the back of the bus than not on the bus, and I want you to know that we will be brief, because we're all used to getting six minutes for a doctor visit. And we're glad to be here.

The Committee of Ten Thousand supports interested strongest terms the requirement of pre-storage ULR for blood and blood products. While strict trials data remain pending on the efficacy of leukocyte-depletion and reduction in removal of the viral or prion agent for CJD, reduction of immunomodulation and other postoperative morbidities have proven its value. Comparison of sites of administration have shown pre-storage to be the best value in terms of consistency, cost and efficacy.

The lack of data is endemic to prudent, early protective measures. We didn't have referee journal data on HIV in 1983, so lots of us watched our children die before high school. Precautionary is an important principle in medicine, particularly if you're the patient.

The ramping up IMD use of ULR by most blood agencies over the last 18 months, with by some estimates, 4 to 8 million units per year by now being leuko-reduced, has led to no red flags of loss of protection from known clinical agents, no pattern of error or contamination once in widespread implementation, and no shortages due to the escalation of production costs. Cost is always going to be an issue, but if thwarted by it, we would essentially be saying that safety is not worth the cost and instead we should make a risky product widely available, rather than do the work necessary to make every unit in distribution, quote, "as safe as it can be" in the words of FDA, Red Cross and others.

Of course, balking at cost would mean that those put at risk, all consumers of blood and blood products, from the one-time transfusion recipient--like you could be where, God forbid, you were in a car accident this weekend--to the hemophiliac infusing weekly for the prophylaxis protection, that it may enable him the semblance of normality in his life, would be formally disenfranchised by such a position, and place him at danger. This scenario is too close to the truth for many consumers.

Last week, in urging broader geographic donor bands to keep the risk of CJD low in the US blood supply, we were reminded once again of the many factors other than medical safety that have been used in resisting incremental improvements to the purity of the US blood supply.

Of course, cost is a code word for HCFA reimbursement rates. The blood community has had mixed success in bringing HCFA into these discussions of precautionary measures at an early enough point such that reimbursement adjustments can be in the works at the time the policy is set. Hopefully, this parallel work can increase in the future.

The accumulation of evidence and momentum favoring ULR should not be assumed to have been halted by the TSE Advisory Committee's unwillingness last summer to specifically indicate that there was evidence to support ULR in blocking CJD transmission. Other data on ULR efficacy exists in abundance and has been supported by BPAC, and the lack of data confirming that CJD cannot be blood-borne remains a dangerous reality. It is recommended in so many countries now implementing it, despite the cost in order to protect their blood, should be taken not as panic, but as evidence of repeated thoughtful review and benefit analysis. CJD may be in the blood. Transmission capabilities between the novel agent, the prion, are said to activate it, that are known but essentially massive within the individual organism. These two facts alone, plus the exploding debates about food-borne transmission, including now cautions on diet supplements containing brain, should be enough to warrant full speed ahead with prudent cost projections and involvement of insurers at the earliest opportunity. Thank you.

[Applause.]

DR. PENNER: Rich Vogel, please. We're going to have all of the questions after the three are finished.

DR. NIGHTINGALE: The Hemophilia Federation of America has given me a written summary of their presentation, which is somewhere on this desk. It will be passed out as soon as I find it, and I apologize.

DR. PENNER: Mr. Vogel?

MR. VOGEL: Thank you. Rich Vogel, President of the Hemophilia Federation of America. I'd like to thank the committee for giving us a chance to speak once again.

Two years ago we addressed the topic of leukocyte reduction for blood products. Both the FDA's Blood Products Advisory Committee and this esteemed panel considered the pros and cons, and came to the conclusion that it was definitely in the best interest of the patients in this country who receive blood and blood products, to institute the leukoreduction process. It was recognized that it is an expensive procedure, but when done pre-storage in the blood-bank setting, the benefits are greater than the cost.

We have been following implementation in various parts of the country and agree that the process is about 60 percent complete. A large portion of the hospitals that have not converted are small, rural hospitals.

Jan Hamilton, executive director of the Hemophilia Federation of America, spoke with the head pathologist at a large community hospital this week, where they have been 100 percent leuko-reduced for three years. The biggest difference they have noticed is the pre-leukocyte reduction. They experienced up to six or eight post-transfusion febrile reactions per month. In the last three years there have been virtually none. The physicians on staff understand and appreciate the service. The pathologist let Jan know that if he is having surgery and needs blood, he will see to it that it is leuko-reduced. He also compared the process to when most of the blood transfused in hospitals was whole blood. As the physicians learned that it was better for the patients to only give them the portion of blood they needed, and that it made the blood supply go further, changes were made. As we make progress in medicine, we don't go backward.

Pediatricians today wouldn't dream of not immunizing their patients with the appropriate vaccines. In hemophilia today there is very little whole blood or fresh frozen plasma used, and very little cryoprecipitate except in most unusual circumstances.

Jan is facing knee replacement surgery, and will make sure that the blood she receives has been through pre-storage leukoreduction.

A local blood bank, part of the United Blood Services System, that covers most of southern Louisiana and Mississippi, is currently offering a choice of leuko-reduced blood and non-leukocyte-reduced blood. However, this cannot continue because it is much too costly. If you are comparing leukoreduction between bedside, pre-storage at the hospital, and pre-storage at the blood bank, pre-storage at the blood-bank level is much more cost effective because it removes more possible problems at the start while the blood is fresh. If you wait until it's done at the hospital, then you don't have the product available until after the quarantine period has passed. If it done bedside, there is a lot of room for white cells to look through, plus it takes a lot of RN time that is expensive and in short supply. In addition, pre-storage done at the hospital requires a lot of more expertise, expensive equipment, and raises the cost immensely.

Over the last few years you have heard us make please to err on the side of safety. We have asked that we not revisit the early '80s and the HIV holocaust, nor more recently, the hepatitis-C onslaught. In addition, we have asked that we not treat the threat of CJD or variant CJD the way we approach HIV and hepatitis-C. It is true that we haven't proven that CJD is transmissible through blood, but we haven't proven that it isn't either.

We ask for the deferral of British donors, as other nations have done. Now others are also deferring western European donors as well. Is that necessary? We don't know, but there surely has been problems with CJD in western Europe, and we have seen it evolve in our country with the Vermont sheep, and evenly recently with a patient in Wisconsin. Still we don't know if the transmission is through the bloodstream, but we don't know that it isn't.

While it is true that all these things reduce the available supply of blood, it is also true that we need to make a concentrated effort to increase the numbers of blood donors. Would you prefer to have a unit of blood laced with CJD, hepatitis-C, HIV or CMG, rather than have to scrounge for enough blood that is clean? I think you know what our response is.

Our community has been the canary in the coal mine long enough, and we would like to see the United States continue to act in a proactive manner, and educate the patients and physicians on the importance of leuko-reduced blood. Once more, communication and education is the name of the game.

I would like to add a few other thoughts. Now, I'm not a doctor or a researcher, a manufacturer or a blood banker. I'm a consumer who has been using blood and blood products consistently for 45 years. In that 45 years I have contracted HIV, hepatitis-A, B and C, and have had numerous febrile reactions. And as a severe hemophiliac, I was deeply disturbed this morning by Dr. Sandler's presentation. What really upset me was the statement that he made when saying science would stop dead in its tracks if a federal mandate for leuko-reduced blood was in effect.

To paraphrase a quote from Don Francis [ph] during a meeting in the early 1980s about the transmission of HIV. "How many dead people do we need in the name of science, 10, 15, 100, 1,000? Give us a number."

I applaud the European and Canadian medical profession for implementing universal leukoreduction.

I'd also like to pose a question to this committee, in fact, everyone in this room. If your loved one needed a blood transfusion, wouldn't you want the safest blood, no matter what the cost? And if your answer is yes, which I'm sure it is, shouldn't this be offered to the general public? Thank you.

[Applause.]

DR. PENNER: Thanks, Mr. Vogel. And Patrick Collins? Pat?

MR. COLLINS: Yes. Good afternoon, or should I say good evening? I think we've all learned a very valuable lesson here today, and that is, if you want to speak publicly, set your flight arrangements for 3:00 p.m.

[Laughter.]

MR. COLLINS: But with that being said, the NHF endorses universal leukoreduction as another incremental improvement in the advancement of blood safety. Leukoreduction, along with nucleic acid testing, more stringent donor screening, donor deferral and so forth, are incremental and necessary steps toward the theoretical goal of complete safety of the blood supply.

Now, while complete theoretical safety may never be possible, we must never stop trying to achieve the goal. As history points out, when we become lax in this effort, there are severe negative consequences.

Is leukoreduction the answer to all potential problems in the area of blood? Of course not. Leukoreduction does not address some major issues the were raised today, most notably, human error. However, leukoreduction is yet another scientifically incremental step towards blood safety. To use the airline analogy raised earlier, it is vitally important to train pilots, air traffic controllers and so forth, for this will save an uncountable amount of lives. But it is also important to improve scientific and safety advancements, such as escape slides, less flammable fuels and so forth. The same principle holds true for leukoreduction in terms of the blood supply. It is not one or the other.

The mandate for leuko-reduced blood has already begun. As stated throughout the day, the FDA Blood Products Advisory Committee has voted unanimously that the benefit to risk associated with leukocyte reduction was sufficiently great to justify requiring universal leukocyte reduction. NHF encourages this committee to follow suit. Thanks.

[Applause.]

DR. PENNER: Thanks, Patrick. Any questions or comments for our last three speakers from the hemophilia organizations, from our committee, or from the audience? Thank you all--oh, yes, go ahead.

DR. GOLDFINGER: Dennis Goldfinger, Los Angeles. Just one quick comment.

I think these last speakers present a view that's different from what was said earlier. Dr. Petz mentioned that asking a patient what he or she would like doesn't tell us the societal view. Unfortunately, asking a group of transfusion medicine experts what they would like also does not present a societal view. There's unfortunately been a pattern of rejection of those new technologies that tend to cost more money, whether it's leukocyte reduction or viral inactivation of blood components, or single-donor platelets, or autologous transfusion.

So I would just beg the committee to be sure that the input is broad and even, when attempting to make these kinds of decisions.

DR. PENNER: Thank you. We will review all biases.

Now, our last speaker for this morning is Jason Bablak from the Immune Deficiency Foundation.

MR. BABLAK: Good afternoon. My name is Jason Bablak, and I'm vice president of the Immune Deficiency Foundation. I'm going to basically just summarize what was already a brief statement.

Basically, while universal leukocyte reduction will not directly affect the treatment or health outcomes of individuals with primary immune deficiency, IDF supports the implementation of ULR for the US blood supply for the following two reasons.

First, we agree with the 1995 Institute of Medicine report that called for instituting incremental blood safety steps as they become available. Leukocytes are known to cause transfusion reactions, and removing them will result in a more pure and safer product.

Secondly, the Food & Drug Administration's Blood Products Advisory Committee unanimously voted to recommend that the FDA require ULR based on the benefits associated with this procedure. BPAC is the advisory committee charged with providing scientific and medical advice to the agency on blood-related issues, and we believe a unanimous recommendation from this committee is a powerful endorsement of this technology.

IDF believes that the safety of the nation's blood supply is of paramount importance, and we encourage this committee to recommend the taking of incremental steps such as this to continue to improve the margin of safety in both blood and plasma products. Thank you.

[Applause.]

DR. PENNER: Thank you, Mr. Bablak. Any questions or comments from our committee or from the audience? Yes, sir. Dr. Moore.

DR. MOORE: Just a quick question. Is it true that the Immuno Deficiency Foundation was founded or funded by the Pall Medication Corporation?

MR. BABLAK: I'm sorry. Would you ask that again?

MR. MOORE: Is it true that the foundation which you represent was funded or founded with the help of money from the Pall Medical Corporation? Pall, P-a-l-l.

MR. BABLAK: Not to my knowledge.

DR. PENNER: Any other questions or comments?

[No response.]

DR. PENNER: At this point, I'd just like to take about two minutes and try and attempt to summarize a few of the comments that we've been hearing throughout the day, with perhaps some consensus statement. I think it would follow this way, and we'll see what the committee feels.

At this point, from what we've heard, there has been no evidence to indicate that leukocyte-reduced blood is dangerous to the recipient, with the caveat already mentioned, that filter may fail, and that might be a risk factor. That's number one.

Number two, there is no argument that leukocyte reduction is not beneficial for some patients. And I think we've all agreed that some patients would benefit.

Number three, there is questionable benefit for patients with other conditions, which may include reduction in morbidity with respect to infection, reactions to the cellular elements, and perhaps immune modulation. And that's the "may."

And then four, and that's recognizing also that this has not been established, but may be a possibility.

And then lastly, there are benefits that are for--let's see--there are benefits for society as opposed to the individual, that by prioritizing the improvement of blood safety collections, mismatched blood, et cetera, may be a reasonable approach for this problem.

So the latter elements, from what I'm seeing from our discussion come down to whether it is beneficial for society versus beneficial for the individual to receive the blood products.

Now, are there comments maybe on those statements? On the first statement, you agree there's no harm done to the patients at least within reason?

DR. NIGHTINGALE: Dr. Penner, I am going to play the designated federal official here for a minute, and I'm also going to play the bad guy. I am the bad guy that has kept you here until 6 o'clock today. You are the good guys who have contributed to this day, and I, on behalf of the United States Government, which I do represent officially here, I thank you all for your participation.

The purpose of this day was to hold a full and fair hearing of this very complex issue, and if we were successful, it was because of your efforts. We are certainly exhausted at this point. I do sense a consensus here.

And the agenda does not permit for any voting today, because I am concerned that a vote taken after so much information is exchanged would be in retrospect subject to very legitimate question. Discussion may proceed as long as people wish to discuss, but any semblance of voting, I think, needs to wait.

DR. PENNER: No, there's no vote planned on this, but I think perhaps before we leave, if there are any comments or questions before we finish. Yes?

CAPT SNYDER: Yes, I concur with Steve. I haven't had a chance to look over the FDA's new recommendation, number one. Number two, it is late. I think that we all have a lot of information that we need to look at tonight, and with all due respect, I think we're going off into a territory that I would rather see when I'm fresh in the morning.

DR. PENNER: Yes. No attempt to go off. We're going to be relieved of our duties. In fact, since we did not take a break this afternoon, I think we'll allow it right now.

We will see you tomorrow morning and summarize it then.

[Whereupon, at 6:00 p.m., the committee was recessed for the day.]