THE PRESIDENTIAL COMMISSION on the HUMAN IMMUNODEFICIENCY VIRUS EPIDEMIC HEARI NG ON Safety of the Blood Supply AIDS in the Workplace Health Care Worker Safety May 9, 10, 11, 1988 August 24, 1988 TO OUR READERS: The Presidential Commission on the HIV Epidemic held over 45 days of hearings and site visits in preparation for our final report to the President submitted on June 27, 1988. On behalf of the Commission, we hope you will find the contents of this document as helpful in your endeavors as we found it valuable in ours. We wish to thank the hundreds of witnesses and special friends of the Commission who helped us successfully complete these hearings. Many people generously devoted their volunteer time in these efforts, particularly in setting up our site visits, and we want to fully acknowledge their work. The staff of the Presidential Commission worked around the clock, seven days a week to prepare and coordinate the hearings and finally to edit the transcripts, all the while keeping up with our demanding schedule as well as their other work. In that regard, for the Hearings on AIDS in the Workplace, Health Care Worker Safety, and Safety of the Blood Supply, we would like to acknowledge the special work of Jackie Knox, Eileen Nicosia, Robert Mathias, and Peter Michael, in putting together these hearings, and Margo Payne, in editing the transcript so it is readable. For the really devoted reader, further background information on these hearings is available in the Commission files, as well as the briefing books given to all Commissioners before each hearing. These can be obtained from the National Archives and Records Administration, Washington, D.C. 20408. One last note--We were only able to print these hearings due to the gracious and tremendous courtesies extended by Secretary Bowen's Executive Office, especially Dolores Klopfer and her staff, Reginald Andrews, Sandra Eubanks and Phyllis Noble. Sincerely, Buy x. Msp aD: Y | oy L. Gaul Gloria B. Smith Executive Director Administrative Officer PRESIDENTIAL COMMISSION ON THE HUMAN IMMUNODEFICIENCY VIRUS EPIDEMIC COMMISSIONERS ADMIRAL JAMES D. WATKINS, CHAIRMAN UNITED STATES NAVY (RETIRED) COLLEEN CONWAY-WELCH, Ph.D. JOHN J. CREEDON THERESA L. CRENSHAW, M.D. RICHARD M. DEVOS KRISTINE M. GEBBIE, R.N., M.N. BURTON JAMES LEE, III, M.D. FRANK LILLY, Ph.D. HIS EMINENCE JOHN CARDINAL O'CONNOR BENY J. PRIMM, M.D. REPRESENTATIVE PENNY PULLEN CORY SerVAAS, M.D. WILLIAM WALSH, M.D. PRESIDENTIAL COMMISSION ON THE HUMAN IMMUNODEFICIENCY VIRUS EPIDEMIC SAFETY OF THE BLOOD SUPPLY The Hearing was held at the Executive Conference Center 850 West Michigan Street Indianapolis, Indiana Monday, May 9, 1988 COMMISSION MEMBERS PRESENT: ADMIRAL JAMES D. WATKINS (RET.), CHAIRMAN COLLEEN CONWAY-WELCH, Ph.D. JOHN J. CREEDON THERESA L. CRENSHAW, M.D. RICHARD M. DEVOS KRISTINE M. GEBBIE, R.N., M.N. BURTON JAMES LEE, III, M.D. FRANK LILLY, Ph.D. BENY J. PRIMM, M.D. PENNY PULLEN CORY SerVAAS, M.D. POLLY L. GAULT, Executive Director COMMISSION MEMBERS NOT PRESENT JOHN CARDINAL 0’ CONNOR WILLIAM B. WALSH, M.D. I-N-D-E-X PAGE WELCOME Admiral Watkins, Chairman 2 Cory SerVaas, Hearing Chair 2 INDIVIDUAL TESTIMONY Reverend Donald Wade, Indianapolis, Indiana 2 PANEL _ ONE OVERVIEW OF THE BLOOD SUPPLY ; Dr. Edgar Engleman, Standford University Hospital 5 Blood Bank Dr. Ross Eckert, Professor, Claremont McKenna College 8 Claremont, California, and also Member, FDA Blood Products Advisory Committee Dr. Thomas Asher, Chairman of the Board 12 HemaCare Sherman Oaks, California Leslie Dutton 17 PANEL TWO INTRAOPERATIVE AUTOLOGOUS TRANSFUSION Dr. Charles Huggins, Director 58 Transfusion Services Massachusetts General Hospital Boston, Massachusetts Dr. Robert Valeri, Director 62 Naval Blood Research Lab Boston, Massachusetts Mrs. Dorothy Polikoff 64 Dr. Gerald F. Giordano, Director 67 Southern Arizona Regional Red Cross Program Tucson, Arizona PANEL THREE SAFER BLOOD TRANSFUSIONS Dr. William Ledger, OB/GYN, New York Hospital, 94 Cornell Medical Center, Ithaca, New York Dr. Richard A. Montagna, President 96 Cellular Products, Inc. Buffalo, New York ~ I-N-D~-E-X (continued) PAGE PANEL THREE (continued) Dr. Derick Bonewitz, Abbott Laboratory 103 Chicago, Illinois Dr. Paul Parkman, Director, 107 Center for Biologic Evaluation and Research, Food an Drug Administration Bethesda, Maryland Dr. Jay Epstein, Division of Blood and Blood 111 Products, Food and Drug Administration PANEL FOUR CONCERNS OF HEMOPHILIACS Mr. Charles Carman, Chairman 136 National Hemophilia Foundation Cleveland, Ohio Dr. Bruce Evatt, Director 140 Division of Host Factors Centers for Disease Control Dr. Fred Rickles, Chief 143 Hematology and Oncology University of Connecticut Alan Brownstein, Executive Director 145 National Hemophilia Foundation New York, New York P-R-0-C-E-E-D-I-N-G-S 9:00 a.m. MS. GAULT: Good morning, ladies and gentlemen, distinguished witnesses, members of the President’s Commission, my name is Polly Gault. I am the designated federal official here today, and in that capacity it is my privilege to declare this meeting open. Mr. Chairman? CHAIRMAN WATKINS: Good morning. The Presidential Commission is delighted to be here in Indianapolis on the HIV Epidemic hearings that we’ll hold for the next three days, 9, 10 and 11 May, and we’re going to be reviewing three important issues. The first day we’ll focus on the safety of the nation’s blood supply, including the adequacy of blood tests, the ongoing concerns of hemophiliacs, and safer blood transfusion methods. The second day, we’ll deal with the workplace and how private companies, including small business and the Fortune 500, plus public sector employers, set their AIDS policies. And, the third day, we’ll center on health care workers, including testimony from researchers who conducted recent studies on the medical risk to workers who care for persons with AIDS. For these hearings, we have selected Dr. Cory SerVaas, who has been a leader in the nation’s effort to cleanse the blood supply, and also, Doctor Theresa Crenshaw who has been a leader in promoting self donation of blood in surgery, and then finally, Mr. Rich DeVos, our senior member from business, who is an expert in the field of AIDS policies in the workplace and how business can better deal with the epidemic. So, to get on with the hearings this morning, I’11 turn over the first on the blood supply to Doctor Cory SerVaas, home ported here in Indianapolis. DR. SERVAAS: Good morning. Welcome to Indianapolis. You all know it never rains in Indianapolis in the summertine. We’re going to keep it that way. Reverend Wade gives us all hope, and he will tell us about the positive ways in which he has been able to counsel others who have a difficult time coping with AIDS. Reverend Wade got AIDS from a blood transfusion, and he will explain how he feels we should handle the blood supply to make it safer, and testing, and things such as that. Reverend Wade. REVEREND WADE: Thank you, Madame Chairperson, and Members of the Commission. It is indeed an honor to have the opportunity to speak before this body this morning. I certainly cannot speak as an expert witness, because I am not an expert in any particular phase of this disease, except I’ve been battling AIDS for the past year, and I would like to share some of my thoughts with you. By way of history, as Dr. SerVass mentioned, I contracted the AIDS virus through open heart surgeries in 1984. There were two within a period of a month. I received multiple units of blood, and in one or more of those units there was a contaminated unit with the AIDS virus. It was interesting that I asked my surgeon shortly before the surgery if there was any chance of my picking up the AIDS virus, because I’d been reading something about it, and he assured me that it was a million in one shot. I’ve since thought that I would go back and tell him that I was that million in one shot. Though I sincerely wish that the blood supply in 1984 had been safer than it was, and that the blood I received in the transfusions had not been contaminated, I’m still grateful for its availability, for even though it was contaminated, had I not received it, I would nct be here today. However, in retrospect, and thinking of the period of three years from the time that I contracted the virus until finally I was tested for the AIDS antibodies, I wish that there had been some kind of a call back with the hospital. It wasn’t really until I began to read in the press releases from CDC that if you’d had a blood transfusion from ’77 to ‘’84 it would be well to be tested. That was the first time that it had ever occurred to me that I might actually be carrying the AIDS virus. And then, in January of 1987, I began to develop some of the telltale symptoms of AIDS and was tested and tested positive in both the initial test and the Western Blot. It would have been helpful, I think, had I known sooner and could have been working on my general health and so forth in trying to prevent the onset of a full-blown case of AIDS. One of the things that I’ve noted as a I’ve read press releases concerning AIDS, it always refers to it as fatal, which isn’t very comforting to a person who is suffering from AIDS. Another thing that it does is that it refers to the person with AIDS as "victims." But, if you look it up in the dictionary, you discover that a victim is defined as "hopeless and helpless," and somehow I do not feel hopeless, and I certainly don’t feel helpless as I deal with this particular disease. I might mention also that the support from the > Indianapolis community has been tremendous for me and for my family. I have appreciated, first of all, the support of my family, the support of the church that I served when I contracted 3 AIDS and informed them of this fact through a video tape one Sunday morning. I have appreciated the support of the media in Indianapolis and the community at large. I have not felt any kind of discrimination or a put down because I’m suffering from the disease, and that I appreciate very, very much. Early in my illness, I discovered that there were basically two ways that I could approach the disease. I could either spin wheels, and burn rubber, and dissipate all my energy in that manner and become a dried up, bitter, old man, or I could say to myself, "I’ve got the disease, there’s nothing I can do about that, but now that I’ve got it, what do I do about it?" We chose the latter of the two options, feeling that this was more useful, and determined that, perhaps, there was something that we could do, my wife and I, that could be useful and helpful to others in combating and working with the AIDS situation. So, during the past year, as time and energy have permitted, we’ve been actively involved across the state, speaking to churches, youth groups, civic groups and so forth, concerning AIDS education and the problems that it advances. I’ve also been involved in the Damion Center, which is . the local AIDS clearing house here in the City of Indianapolis. I’m a member of the support group. I received a great deal of support from each member of that group, and hope that in turn I/m able to give some kind of support to then. Statistics indicate, I think, at the present time that the blood supply is about 98 percent safe, but I would hope that we would continue to work on ways in which we could make it even safer, both in the matter of testing and in the blood supply itself. If you happen to be caught in that 2 percent number, it isn’t really very comforting to know that the blood supply is 98 percent .safe. So, I would hope that we would continue and redouble our efforts, both in the private sector and in the governmental sector, in dealing with the blood supply across the nation. In closing, I would like to share this thought by the philosopher, Horace Callum, who remarked on his 73rd birthday, "There are those people who shape their lives by the fear of death, and persons who shape their lives by the joys and the satisfaction of life; the former live dying, the latter die living." And, I pray that I might die living, using the time and the energy that I have in helping AIDS education, in helping people to understand AIDS and its problems, the things that happen to a person with AIDS, and, perhaps, making this last part of my life as useful to others as I possibly can, that truly I might die living. Thank you. DR. SERVAAS: Thank you, Reverend Wade. .4 DR. SERVAAS: Our next -- CHAIRMAN WATKINS: Reverend Wade, let me say that one of the few joys that we have in this Commission is to listen at the front end of a set of hearings from people with AIDS, young people, older people like yourself, others afflicted. We do that purposely, to make sure that not only the Commissioners and our staff, but everyone here understands how sensitive’ we are to the human being at the end of the set of bureaucratic obstacles in the way of progress on this set of issues. And, your outlook towards life, your sense of hope, of course, is one that we admire a great deal. We consider you one of the heroes of this epidemic, and the option you picked to do everything you could to tell the story and to help others is extremely important to us and to everyone here this morning. So, we thank you very much for coming, and we’re going to move on to the next panel, because we need to get on to the detailed questioning, But, we thank you for the inspiration this morning. REVEREND WADE: Thank you. OVERVIEW OF THE BLOOD SUPPLY DR. SERVAAS: The Overview of the Blood Supply will deal with ways in which blood for transfusion and blood products can be collected and made safer at less cost. Obstacles to safe blood include the window of time during which the antibodies have not yet developed in a recently infected individual. We're going to hear this morning from Dr. Engleman, Dr. Eckert, and Dr. Asher, and Ms. Dutton, and if you’1l take your places at the panel. Dr. Engleman won national recognition for having directed one of the first blood banks to use surrogate testing to defer blood that could cause AIDS and other transfusion-related diseases. He courageously led the way and put Stanford University’s reputation on the line when he refused to discontinue the program in the face of attacks from other blood banks. His foresight and resolute stance caused other blood banks to follow his suit when patients began coming to Stanford University Hospital for their surgery to be assured of safer blood. Dr. Engleman. Dr. Engleman: Thank you, Dr. SerVass. It is a pleasure to be here. I think that the main reason I was invited relates to my role as Medical Director of the Stanford Blood 5 Center, but I would also like to mention that I am a full-time member of the Stanford Medical School faculty, where I direct a fairly substantial research laboratory, and the major focus of this research over the past five years has been the pathogenesis of AIDS. The Stanford University Blood Center is quite unusual in that, number one, it is part of a major university, number two, it has two goals, one of which is to collect, process and provide blood to one of the largest users of blood and blood products in the country, namely, the Stanford Medical Center. But, a second goal is to perform fundamental research in the fields of immunology and hematology in order to try to make improvements in the safety of the blood supply. And, there actually is a long tradition at Stanford in developing new blood tests. Convinced that AIDS represented a serious threat to the safety of the blood supply, in 1983 we decided to screen our blood donors with a test designed to reduce the spread of AIDS to recipients of transfusions. We used an indirect or surrogate test which measured the presence of certain types of white blood cells called T cells. This T cell test is no longer used as a primary AIDS screen, although, it is still used, as some of you may have heard already, as a prognostic indicator in patients infected with the AIDS virus. We began to use this test on July 1, 1983, and shortly thereafter we realized that the test seemed to be working, because several of the donors who tested abnormally when contacted turned out to be members of groups known to be at high risk for developing AIDS. These were individuals who should not have been donating blood at the time, based on voluntary deferral guidelines. In March 1984, we heard from a physician in southern California, some 500 miles from our location, that one of our July 1983 donors had come down with AIDS, and the physician was concerned about the recipients of this man’s blood. Fortunately, his blood had been discarded because of the test we had performed. Unfortunately, the same individual had donated to a number of other blood banks, and at least a dozen or so people had received his blood. Finally, in 1985, after the AIDS antibody test became available, we used that new test to confirm that, in fact, our T- cell test had eliminated the majority of AIDS contaminated blood that came into our blood bank. In summary, the T-cell test worked very well. Throughout 1983 and 1984, we experienced something less than a positive response from the remainder of the blood banks 6 and from the blood banking organizations, and what I have attempted to do in my written report to the Commission, is to analyze why there seemed to be resistance by blood bankers to performing tests like ours back in 1983 and, and ‘84, and through the beginning of ’85. And, I want to just highlight a couple of those points if I might. -The first is that the test we were using was not a specific for the AIDS virus, since the AIDS virus had not been discovered at that point. It was a surrogate test which identified an abnormality that was present in a high proportion of AIDS patients and high-risk persons; but only a small proportion of the general population. We knew that a number of individuals who tested positively in our test were not necessarily AIDS carriers. The goal of our test was to screen out as much of the contaminated blood as possible, and we were allowing for the loss of some perfectly normal blood. We think that the blood banking community resisted the adoption of this and other simpler tests, in part because they had not, prior to this point, ever adopted a surrogate sort of test like our’s, and there was, for reasons that I can’t fully understand, a natural resistance to anything less than a perfect test. In addition, we had previously experienced a general resistance, when one of my colleagues at Stanford, two of my colleagues, Doctors Carl Grumet and Ann Yeager developed a test for antibody to cytomegalovirus (CMV). ‘They applied this test to donated blood, and demonstrated that by using CMV-antibody negative blood they could avoid the severe consequences of cytomegalovirus infection in transfused newborn infants. This work was widely publicized and published in peer review journals. The test was very simple and cost about $1.00 or $2.00, and yet, it was another five years before the blood banking industry guidelines even acknowledged the potential importance of applying this test. Hence, the refusal of blood banks to adopt indirect, imperfect AIDS tests in 1983, ‘84, and ’85, is not really a surprise. In our view, however, the tragic consequence of the failure of blood banks to follow Stanford’s lead has been that hundreds and probably thousands of people have been unnecessarily infected by HIV and will die as a result. At this point, what we believe to be most important is to consider what might be done to ensure the safety of the blood supply in the future and we have come up with a number of specific recommendations for the Commission’s consideration. First, we feel that there has not been any kind of formal inquiry into the response of the blood banking community to AIDS in 1983-85, either by the blood banking organizations themselves or by an outside entity. And, we would recommend that 7 : ais . . a task force of qualified objective individuals be formed to carry out such an evaluation. The reason for that is because, as far aS we can tell at the present time, the blood banking community still doesn’t understand or recognize that more could have been done during those early years than, in fact, was done. That worries us, because we’re concerned that in another ten years when this is, perhaps, forgotten, or at least the public concern abates, that yet another virus or another threat to the blood supply will arise, and a similar, inadequate response might occur. _ We do not think that such a task force should be formed in order to cast blame. We think that the purpose of such an inquiry would be to try to figure out why the blood banks reacted so slowly, and to make recommendations, so that the same kinds of problems do not recur in the future. In addition, we believe our physicians and nurses are, in general, poorly trained in transfusion medicine, and there should be much more emphasis on this area in medical and nursing schools. We also believe that there should be an effort to target research on transfusion medicine problems and steps should be taken to make sure that the innovations that are developed are heard and applied quickly by the blood banking community. I think I’1l stop here and refer you for details to the report that was provided. Thank you. DR. SERVAAS: Thank you, Dr. Engleman. DR. SERVAAS: Dr. Eckert, Doctor Ross Eckert, is a Professor of Claremont McKenna College in Claremont, California, and he’s also a member of the FDA Blood Products Advisory Committee, and he will discuss innovative alternative methods of collecting safe blocd. DR. ECKERT: Thank you, Dr. SerVass. Good morning, ladies and gentlemen. Dr. SerVass referred to my membership on the FDA Blood Products Advisory Committee, however, I want to emphasize today that my remarks are given in my private capacity only, as a non- medical specialist on this subject, and that no official support or endorsement by FDA is intended or should be inferred. We know how serious this problem is. 4 million Americans each year are transfused. The process and the policies by which we collect blood have an enormous effect on our society. 8 And, people -- physicians and potential transfusion recipients -- have been skeptical about the claims made for the safety of blood practically since the inception of AIDS. They are still skeptical, to a degree, today. I believe that skepticism was valid then, and that it is still valid. Blood bankers say today that blood is now as safe as it can be, but I don’t think it is, and I’1l try to explain why it isn’t, what the obstacles to safer blood are, and then explain what my recommendations to make it safer are. Dr. SerVass has already explained the window problen, and I’m sure everyone on the Commission understands that. I would emphasize that a recent article published in the New England Journal of Medicine provided a "worst case" estimate that, "as many as 400 recipients of screened blood may become infected annually," 460 people. These are estimates. They are based on various calculations, and there are different estimates by different estimators, but this is by no means a wild, unreal scenario. And, we know that the rates of HIV antibody are greater in large cities, where most of the surgeries occur and where so much blood is drawn. We know that the virus is mutating rapidly. We are encountering now HIV-2, and before long there will be other HIVs, I’m afraid. Tests are being derived for these things, but one must emphasize how slowly, really, medical science advances. It took several years to find the disease, to describe the disease, several years more to find the HIV virus, several years more to develop a test for it, and so we go. The hepatitis problem has never thoroughly been solved. Scientists have been trying for 20 years to locate the variety of hepatitis viruses that are loose in our society. They located one, and thought it would solve the problem. It solved only 10 percent of the problem. So, we see, really, and it’s a fundamental point that I want to emphasize to you today, and even to the physicians among you, as to how slowly medical science really advances, and how much of a bet we are placing as to the future of our society if we rely only upon the advance of medical science. I would emphasize to you to include in your report as well the importance of hepatitis, not only because some of the same risk groups are at risk for both diseases, but because this is such a serious and potentially lethal disease. Even with current testing methods, perhaps, I estimate 500 people a day are being infected with non-A, non-B hepatitis in this country. Even after taking into account that 40 percent 9 of these who survive their primary illnesses for which they were transfused -- their automobile accident, their chemotherapy or whatever -- and about half of those who are estimated to have normal liver biopsies as a result of their transfusion, still about 4,000 recipients per year will develop cirrhosis with five to ten years of their transfusion. 4,000 people per year is a staggering statistic, and if we put it in perspective, it is tantamount to losing the passengers on a fully loaded DC~-10 every month. What’s my proposal? Well, it’s very simple. My proposal is to deal with the source problem of the spread of all these viruses. The source of the problem of the spread of these viruses, insofar as the blood supply is concerned, is our huge donor pool. 9 million or so people per year, who donate an average of one and a half times per year, is too many people, too many people donating too infrequently. What we need are fewer people who donate more often, and I call these donor registries, which would be panels of low-risk regular donors who are known to be in good health, who have not been transfused since 1977, who agree to a detailed confidential medical history including questions about venereal diseases and multiple sex partners that are not asked at present, who agree to more extensive testing than is now routine, such as, perhaps, in some communities for the T-cell reversals that Dr. Engleman has developed, and especially in cities with high HIV rates. These donors would give as often as their good health allowed and be replaced with new donors from the same groups only when absolutely necessary. We know that registries are effective. They worked at the Mayo Clinic, where they have been tried. I also fully endorse Dr. Engleman’s proposal for surrogate testing. We need more surrogate tests. We need more tests that err on the safe side, in excluding donors who might be at risk rather than saying, well, they are probably not. Again, this is because we have so few specific tests. We need more surrogates. And, the one I emphasize that we not discard, which it has been proposed from time to time to discard, is the syphilis surrogate test. Normal blood banking refrigeration kills the syphilis spirochete, but if you had to choose between a transfusion for yourself between two bags of blood, one that had dead syphilis spirochetes in it and the other that didn’t, you would probably sensibly choose the one that didn’t have them, because someone who is sufficiently promiscuous to have been exposed to syphilis probably is exposed to other things that can’t be detected by medical tests and that are not killed by normal blood banking refrigeration. So, I would disagree with the proposal that this test should be abandoned. It is a very important test. It is not redundant; it is not wasteful. 10 What are the obstacles to safer blood? Minimum standards for screening donors and testing blood are established by the FDA, that the FDA relies largely on blood banks for advice on which standards to set, and the incentives of the blood banks to improve safety are weak. Why is this the case? Well, very briefly, in most communities blood banks are sheltered from competition, they are non-competitive or monopolistic organizations. As a result, patients who want to shop for better blood find it extremely difficult to relocate, and then, of course, in emergencies and many serious illnesses this is simply out of the question. Blood bankers obtain blood not by payment but by begging for it. This is difficult, and more testing and screening means more rejections and more replacement solicitations. Blood banks are staffed with sufficient personnel to handle the expected volume of their donations, but a marked decline in donations or in the amount of blood fit for transfusion could cause layoffs and, perhaps, shortages, and we know that some hospitals have already established competitive sources of blood. Another important factor that affects blood bankers’ incentives for blood safety is that they are exempt in almost every state from strict liability in tort for transfusion disease. I would favor such exemptions only for blood banks that have established donor registries of the sort that I have outlined, because that would indicate that they taking every possible step already within their grasp, easily within their grasp, to reduce transfusion disease to the absolute minimun. Now, blood bankers today claim that registries may work at the Mayo Clinic in rural Minnesota, but they would be too expensive in big cities. This is something of a "Catch 22." We’ll never know until we try, and in many cases, I’m sure the lives saved will exceed the extra costs, if, indeed, there are extra costs. I’m not convinced that there are extra costs on net, but, surely, we must recognize that the lives saved would have to be laid against that. And, if registries can reduce transfusion disease in rural Minnesota, where the Mayo Clinic is located, they will probably reduce transfusion disease anywhere. So, I’m concerned not only with the present level of viruses that we have to contend with in our society, but I’m concerned for future viruses that may come along, and that we have in place in advance of those diseases arriving, mechanisms that will not only reduce the transmission of diseases that we already know of, but diseases that haven’t even arisen yet. So, I urge you in your final report to give FDA three recommendations to reduce the spread of HIV and other transfusion 11 diseases known, as well as those that we don’t know about. To begin to assess additional surrogate tests to prevent further deterioration in our blood supply, that’s my first recommendation. Second, FDA should retain all surrogate tests that are now required or used to screen blood until specific tests are developed. And third, most important I believe, FDA should require all licensed blood and plasma centers to adopt donor registries. Thank you. DR. SERVAAS: Thank you, Dr. Eckert. DR. SERVAAS: Dr. Asher will discuss specialized blood services that prepare large quantities of platelets from single donor to assure a safer product than that obtained in the conventional way of pooling platelets of eight to ten donors for a single therapeutic dose. He discusses selective pedigree donors. Dr. Asher. DR. ASHER: Thank you very much. I do appreciate the opportunity to be here and discuss, I think, a very simple problem, and, that is, the problem we’ve all known, that blood is hazardous. As a matter of fact, blood is the most dangerous drug in the world. The real problem is, of course, it’s going to remain that way. There is no reason to think that blood will not always be totally hazardous as new microorganisms come into our culture, and as medical science slowly develops specific diagnostics tests. The basic problem, or the problem behind solving this, unfortunately, is not dictated by science and research. It seems to be dictated by social, political and economic factors. You’ve heard the previous speakers make reference to the fact that there is an establishment. There definitely is. There is a blood industry, which is basically a monopoly, and, as such, it has all the flaws that go with a monopoly. It fosters complacency, it fosters arrogance, defensive action, a desire not to move. And, that is the state of the blood industry today. ~ While all of us who are involved in providing some sort of blood products and services have to go through our basic problems of actually practically delivering the "good," we all have a responsibility, at the same time, of delivering the best possible "good." Yet, the monopolists, which are basically about 250 blood centers in the country that provide your run-of-the- mill ordinary blood products for transfusion, each one operates within a geographical monopoly, where they do not have to worry about how much they charge for their product, they have a total captive customer list. The hospitals have no choice. They have to go to their regional supplier, and they will pay what they want to pay. They have no concern about the cost of providing this, since it is all a pass through. 12 They only have one dilemma, the basic regional blood bank, and, that is, can I get enough donors? They have to appeal to the public, and I think on a philosophic basis they have tied their hands so that they do not get enough donors to come into the centers to be selected or screened as to the best possible donor. This is because they have taken a philosophic, almost a social attitude, that there is only one conceivable way to attract donors, and that’s with the concept of altruism. No concern isy given whatsoever towards the basic tenet of human nature, and, that is, that there should be some self-interest in everything we do. I believe we all recognize the fact that all of our own individual attitudes are a combination of wanting to do something good for our fellow man, and, at the same time, having some self-interest for ourselves, whether it just be the good feeling of doing something good, or whether it be even reimbursement for the time and effort that we put into doing something good. It’s a dual recognition. This basic problem, though, that the blood centers have, of tying their hands, of being wedded to almost a theology, and you really have to deal with blood center a number of years as I have, and I’ve got to admit I’ve been in a javelin throwing contest with what is called the "volunteer sector" for a number of years, except that I’ve been on the catching end. Things have turned around in the last few years, and I find that my sector, the commercial sector, which is a very distinct portion, having adopted stronger screening procedures in the spring of 1982 voluntarily, we find ourselves in the very positive end of it now, and it’s very rewarding, and I hate to say, personally I find it very satisfactory that the other fellows now catch a few javelins, and I think they deserve them. The correction, though, of their attitude, which is one of protectionism, doing nothing whatsoever to embarrass or discourage their volunteer donors, as defined by them, is unfortunately supported by the very agency, the Food and Drug Administration, which regulates them. As you know, a monopoly leads to complacency. It also leads to protectionism, and it leads to a lot of "old boy club-ism." And, unfortunately, in the case of the regulatory body that regulates the volunteer blood industry, there is a lot of musical chairs back and forth between positions of authority, and a lot of "old boyism." The worst example being, the Blood and Blood Products Committee to the FDA, is totally comprised of the volunteer sector, who have a great deal of influence and, basically, utilize their philosophy, which is fairly consistent with the overall philosophy within the Food and Drug Administration. A great deal of criticism has been pointed at the FDA for this elitism of their Advisory Committee, and as a result they have actually put onto their committee one member, they 13 felt, that represented the commercial industry. He’s a non- voting member, and, actually, he does not represent the commercial industry, he represents the vendor to these very blood banks, representing a large company that sells their products and are totally dependent upon the volunteer industry for their sales. And, he is sort of a token member of this committee. This is a little bit frightening. I’ve summarized the differences between the two sectors of the blood industry, and I won’t go into great detail on this, but there is what is called the "blood sector" and there is what is called the "plasma sector." They both have a great deal in common. The blood sector, essentially, makes fresh blood products out of about 15 million donations a year in the United States. The plasma sector makes plasma out of fresh blood from donors, so, in a sense, they are identical in that they take, hopefully, normal, healthy human beings as donors and provide products for injection. They take about 10 million donations a year, as opposed to 15. The fresh blood sector sells their products. They use a euphemism. They indicate that they charge for their services, they do not sell the blood. I just don’t see the rationale behind that. It’s like the baker doesn’t sell his bread to you when you go to the bakery, he sells you the fact of his inconvenience, he got up at 2:00 a.m. and started kneading the dough and baked it, but he’s not selling that loaf of bread to you in the morning, he’s selling his services. But, their industry, the volunteer blood industry, is $1 and a quarter billion a year in the United States. The plasma sector and the products, these are manufactured products eventually, gamma globulin, albumin, that’s a $1 billion a year industry in the United States. What are the differences? Philosophically, the volunteer sector believes in altruism as their means of getting donors. They believe in monopoly. They fight constantly that they have this God-given: right to the exclusivity. I truly can’t emphasize it enough, it is almost a theology, and if you talk enough, and you have been in this industry enough, and I believe the gentlemen on my right, although I shouldn’t speak for them, probably recognize this, it’s the attitude as though on the day of creation of the universe, with all the clouds of hot sulphurous fumes about us, the hand of God reached through this cloud with a bottle of blood and said to the volunteer blood bankers, "Here, take this, spread this among all men exclusively." It’s truly amazing how philosophically involved this monopoly has gotten through 40 years of monopoly. In contrast, the plasma sector truly is a competitive, profit-oriented, and I should mention, tax-paying organization. They pay taxes on their $1 billion a year. The volunteer sector, 14 on their $1 and a quarter billion a year, pay no taxes. In some cases, they actually compete nose to nose in what, in my opinion, can only be described as unfair competition. Anyway, it’s a fantastic natural situation, where the purveyors of fresh blood, which is really what we’re talking about here, don’t operate under the natural laws of economics, supply and demand. They only have one concern in life: can they get donors, and to these ends they are frightened to death to directly question donors as to their lifestyle, particularly, and this is true today, the plasma industry voluntarily directly questions their donors, the volunteer industry has fought it, they’ve fought it in writing, they are supported by the FDA in that, who has created a double standard of guidelines, one for the fresh blood industry and one for the plasma. The fresh blood industry, they say they are concerned about adequacy of product. I might add that what they are saying is, can we get enough donors, we will defer enough donors, or too many donors, by asking direct questions? Simple arithmetic will show that if you defer, even a huge number of donors, the cost savings is so dramatic that you can afford to spend almost $2,000.00 in recruiting efforts to get an otherwise normal donor to replace that individual, and I have done the arithmetic, other people have done the arithmetic, and it is staggering. The availability of funds on a cost- effectiveness to avoid a relatively few number of AIDS infections that could be converted, that money could be converted, to increase recruiting efforts. Now, I do have some recommendations, obviously. There is no sense in my talking unless there are recommendations, and I think they are very straightforward and, frankly, I don’t think they cost anything. I think all they cost is a realization of human nature and pushing our regulatory bodies, who, in spite of the fact that I’ve criticized them, I think are imminently scientifically qualified, and a large number of them, I believe, are very fair and open-minded. But, there is a pervading philosophy within the entrenched bureaucracy, this, too, has become a monopoly within certain aspects of FDA, where a social philosophy has overridden what I think is a practical delivery of a very needed product or a series of products. I think the regulatory agency has to be encouraged to promote stricter donor screening standards. Strangely enough, in 1975 they did it, and by their own admission they enforced some very poor screening tests that had between 15 and 40 percent efficacy in weeding out hepatitis B carriers, and they said at that time, "In spite of this very poor test, we think the best test available has to be used." They changed their mind since 15 1975, and I think it is due to the influence of the volunteer sector and the "old boys club." - I think, too, the government should encourage more imaginative donor recruiting techniques. We do need more donors. We do have to screen them more specifically, and out of those we select these selected donors. I refer to my donors, who, I’m in a very sophisticated form of blood product provision called "Hemaphoresis." We call our donors a Registry of Selected Donors. We can do that, because we motivate them, not only with the basic public good that they do, and the fact that their products are much safer, and they get a great deal of pleasure out of that, but we’re not afraid to pay them. They spend three hours in our facility to do this, and they deserve some reimbursement for their time. But, that’s their choice. We offer it to them, they can take it and give it to a charity, they can keep it themselves, and they have this dual motivation. I think the government has to encourage a broader approach to recruiting. This present message is "altruism only." It’s sort of a guilt trip concept of recruiting, which is very restricted. I have prepared a list of 17 motivations for people to give or sell, it doesn’t matter, their blood or blood products. I presented them to the FDA Blood and Blood Products Advisory Committee a year and a half ago, and, I think, created a bit of a stir because there was even a mixed concept within that same group about the reality that they are all subconsciously using some of them. I think probably the most important recommendation I could make, and the easiest one to augment, is to rescind the National.Blood Policy. This is a policy which has stigmatized the broadening of messages, recruitment messages, to the public, and, of course, the worst part of it is, and this is my own personal, I guess, crusade, I felt that it promoted one side of a | political philosophy, and I looked into it.'And, using the Freedom of Information Act, was able to find that it is totally illegal. It had zero legislative authority. It had zero executive authority. I have this in writing from the White House itself, that there was no authority whatsoever for it to be published. The President, back in 1972, had asked for a study of the safety and the adequacy of the blood supply. For want of a better word, a couple of social engineers within the bureaucracy of our government, and there are people like that, they are well- meaning, but they have allowed their own social philosophy, promoted a policy, put it into the Federal Register, without any authority whatsoever, and it became the National Blood Policy, 16 which was a very narrow concept. That is easily enough rescinded. I believe that competition between blood centers should be encouraged, and there is one very easy way, tell the government, in the government-run hospitals, and in those that are government funded, have competitive bidding for blood. They have competitive bidding for every other drug, every other service within these VA hospitals and government-funded hospitals. It’s very simple to make part ‘of their operation, have competitive bidding. And finally, I think the Federal Trade Commission, or the Justice Department, should be asked to look very closely at the unfair, anti-competitive practices that are being done, not only by individual blood centers, and I can’t hold them too responsible, but, really, by their trade association who truly have, in my opinion, some unfair competitive practices, and I happen to be the victim of one of them, and am being victimized right now by it. These are practical things which I don’t think cost a lot and, obviously, should be expanded upon, and I cannot tell you how grateful I am to have this opportunity to present then. Thank you. DR. SERVAAS: Thank you, Dr. Asher. DR. SERVAAS: Our next panelist is Ms. Leslie Dutton | from California. She’s literally a walking encyclopedia of knowledge about blood, and she has been asked to serve on the American Blood Commission Advisory Council. Ms. Dutton. MS. DUTTON: Thank you, Dr. SerVass. I’m going to agree, but I’m going to be a lot stronger about what these gentlemen said. One of them said more could have been done by the blood banking industry to protect the public. Another one said that medical science moves very slowly, and Dr. Asher talked about the "old boy" network. Well, let me tell you what the blood industry has done to the American public, what we have been deceived about the safety of blood, and they could have done a lot more, something very Simple. As President of the American Association of Women, our organization, in 1985, realized that 93 percent of all the AIDS cases nationwide were males. Now, this wasn’t something that 17 only we knew. In California, it’s 98 percent, and yet, when we asked FDA Commissioner, Frank Young, and we asked the blood collecting organizations, trade organizations, what the donor base was by gender, we learned that less than one third of the nation’s blood donors were females. And, in talking with the Irwin Memorial Blood Bank, only 27 percent of their donors were females at a time when 98 percent of all AIDS cases in California were males, and they still are to this day. This is unforgivable. We didn’t need a test. We didn’t need millions of dollars for a research project to tell us, very simply, by increasing the female donor base we would have had a much safer supply. When we realized this, our organization set out to implement an all-female blood donor recruitment program for any regional blood banking operation that. would be willing to label their units by gender donor source, male or female, for emergency transfusions, in order to prevent the spread of AIDS through transfusions. I can’t tell you what a frustrating experience that was. Armed with statistics from the CDC, and from the health departments in each state, we were rejected one after another, and some: of these gentlemen here can tell you about the frustrating experience that we had. We were willing to do this. We asked the Red Cross to, please, put out a patriotic call to the women of America to give blood immediately, we needed it. This was two years ago. Not one word! With the multi- millions of dollars that the Red Cross is making from selling donated blood, you would think that they could have put out a little bit to make an appeal to women to come forward. You remember back in World War II, women came forward and gave blood for our boys overseas, and it’s very unfortunate that over these past years women have been led to believe, simply because they haven’t been sought out, that this giving blood isn’t necessarily something that they should do. They should be doing it. They should be doing it right now. / But, more importantly, physicians and patients should have the freedom to choose the safest possible blood available, and that means, by disclosing the gender donor source of blood we should have the right to know the risk involved. If it is male blood, and it’s in a high-risk area, we should have the right to request female blood. I’ve had personal experiences of trying to obtain female blood for a friend who was on his death bed, the physician prescribed female blood, the hospital tried to accommodate it, and the Red Cross refused to identify from the computer code number on the bag whether or not the donor was female. My friend died, but the fight goes on, and that’s why I say it is so great to be here today to be able to bring you the message about what could be done very simply, without multi-. millions of dollars. 18 I would just like to say that we offered the Kaiser Hospital in Oakland to put together an all-women’s blood donor recruitment program if they would label their units. They adamantly refused, they were rude, they treated us like we were ridiculous. And, I would just like to say that Kaiser now has put out a notice to 50,000 members of their health plan who received blood transfusions from 1977 to 1985, because the blood they received may be tainted with AIDS and they have to test them all. This is during that period of time that we had offered to help improve their donor base with female blood. And, at Cedar Sinai Hospital in Los Angeles, they are recalling 700 babies, premature babies who were born, and transfused, many of them without their parents knowledge, who may have received tainted blood. This is just a tip of the iceberg of what’s been going on. Yes, they could have done a lot more, and they should be doing a lot more. When you heard Dr. Eckert talk about the window, he was referring to the window of the AIDS antibody test now being used. There are an unknown number of people that do not develop antibodies, that can be identified by the only blood screening test that we now have. And, some studies have shown that the antibodies may not develop in as many as three years. So, even if they test negative, we are still not certain, and in just this last February there was an article published in the New England Journal of Medicine, a study that showed where six males had donated their blood, they tested negative for the antibodies, the blood was transfused, others became infected because they eventually became infected. So, the test that we are now using is not perfect by any means. And, the Red Cross, which controls 55 percent of the nation’s blood collecting operations, by monopoly, made a statement, Doctor Alfred Katz, before a Senate Appropriations hearing in Washington in September of 1985, right after the Red Cross had launched a major public relations campaign to convince the public that the blood supply was safe, Doctor Katz testified that, "The AIDS antibody test has theoretical and practical defects, and that we must have a better, more sensitive test that can identify the virus itself." Now, this is at the same time as his organization is telling the public the blood supply is safe. The way the blood industry has handled the AIDS epidemic is appalling, and when you think about the some 20,000 hemophiliacs in this country that have been sentenced to death because the scientists and physicians or the leaders of that community that were charged with helping that community have sat silently, and they-knew that it was 93 percent male. They - 19 certainly could have immediately started recruiting female pools of donors for blood. And now, we have people that don’t have much future. ‘ I agree with Dr. Asher, that monopoly is part of the reason why the "good old boys" system in the blood industry is the way it is today. But, there is another reason. The blood shield laws, most of the states in this country have laws that say that the providing of blood for medical transfusion therapy is a service rather than providing a product. And, therefore, they are not liable, because it is not a product, it’s a service. In the absence of having financial responsibility for negligence, the blood banking industry has demonstrated a public "be damned" attitude. This is what’s caused the "good old boy" network. This is why they didn’t do anything about the female versus male ratio of donors, and I think it’s time that we compared the blood banking industry to similar industries, such as Coca Cola or the oil refining industry, where natural resource is treated, and processed and converted into a product before public consumption. And, let’s hold them accountable for that product that they are delivering, and delivering in a monopoly- type atmosphere where we do not have the freedom to choose. We cannot walk across the street and pick another product. We are captive, the public is captive. My suggestions would be that we’ve got to change the blood shield laws and hold these people accountable. And secondly, we’ve got to make a patriotic call to the women of America to come forward and give blood, and we should disclose the gender donor source on the blood units, just like to we do now, we disclose whether or not the donor was paid or voluntary. That decision was made on the basis that paid donors were supposedly higher risk for hepatitis. Well, with the statistics as they are today, and continue to be today, female blood is far safer and the public and the physicians and the medical community should have the right to know the gender donor source. I thank you very much. DR. SERVAAS: Thank you, Ms. Dutton. DR. SERVAAS: We/’ll start the questioning from the Commissioners with Doctor Primn. DR. PRIMM: Good morning. I had a couple of questions, one particularly for Dr. Engleman. You talked in your written testimony about HTLV-I, and you did not mention HIV- 2 as something that bothers you for possible testing. I’d like to have some idea of what you feel about that, and are there any 20 tests on the market that will certainly distinguish that organism in blood? Number two, Ms. Dutton, or you, too, Doctor Engleman, or, Dr. Eckert, you talked about testing for the antibody, core and envelope antibodies, and that it is a possibility that we can’t pick those up. We know the Finnish study or the Scandinavian study showed between 18 and 24 months sometimes when people are exposed, and they are tested constantly during that period of time, and show up negative, when, indeed, they should have been positive, and that there was a window there where, unquestionably, they didn’t form antibodies. What about doing the antigen test and the antibody test on individuals from the outset, or on our blood from the outset? MS. DUTTON: Well, there is Abbott Laboratories. DR. PRIMM: Yes. MS. DUTTON: It’s evidently waiting for approval of their virus test for the antigen, and by all means, the minute it’s available, we should be testing donors before they give the donation. This would save a lot of money, of processing and testing for all these other things and handling it, if we test the donor before, and we should do that as soon as possible. And then I might add, I hope that we act swiftly, and we need leadership as this antigen test becomes available, because let’s not forget what happened with the antibody test. We have laws across the country in different states that restrict the use of the antibody test. In California, it’s an anonymous testing situation. So, I certainly hope that we’re not going to get into this political boondoggle with the antigen test, and that, perhaps, your Commission can come up with some recommendations about how we can avoid that, and make sure that we don’t get the restricted use on an antigen test. DR. PRIMM: One of the reasons, Ms. Dutton, that I have heard that women are less apt to be persons who would donate blood is, because on a monthly basis, through menses, they lose so much blood, and the incidence of anemia among women. Now this certainly may not be factual, this certainly might be mythical, but that’s a reason why they are reluctant to give blood, or, the old wive’s tale says that they shouldn’t give blood because of the great deal more of anemia and loss of blood naturally, and, therefore, they should, you know, conserve ali the blood that they could. Another question for you, Ms. Dutton, is, I wonder are there any girls in the "good old boy" network that you talked about, or are there any black boys, or Hispanic Boys in that 21 "good old boy" network of this monopoly in blood and plasma services? MS. DUTTON: Well, I think probably Dr. Asher would be more qualified. I can tell you that I haven’t seen too many in my exposure, but, of course, I’m not in the industry. With regard to your first question about women as qualified donors, we did correspond with all the major blood collecting organizations and asked them the question about whether or not the woman’s situation would be a hindrance. All of the responses that we got back said that they would be delighted to accept female blood donations, and they recommended, since women are prone to anemia, that they always recommend iron supplements if they are a regular blood donor. But, there is nothing to prohibit them from giving blood, unless there is a medical condition. DR. PRIMM: One other questions, Ms. Dutton, before I leave you, and, that is, you talked about the labeling of blood. As you know, there is a disproportionate representation among those persons who have been thus far diagnosed to have AIDS and reported to the Centers for Disease Control of blacks and Hispanics. And, I’m wondering, you talked about the marking, sexual markings on donated blood. Do they have racial markings on donated blood? MS. DUTTON: Not that I know of, but -- DR. PRIMM: Because, maybe some wouldn’t want to get some black blood, or someone might not want to get some white blood. MS. DUTTON: Well, I guess it was a couple of weeks ago that the Food and Drug Administration did put out an advisory regarding ethnic or racial origin for people that immigrated just recently from countries where the new strain-of the HIV virus. And so, in that sense, race does play a factor, where those people have come here from other countries, and this new strain is here, and we don’t have a screening test for it. . DR. PRIMM: Okay. That’s very important. And, Dr. Engleman, I guess I can turn to you with that question. Dr. Engleman: Sure. Let me go back to your earlier questions. With respect to HTLV-I, first of all, I did comment in my report about the fact that the industry does favor, has gone on record as favoring HTLV-I screening. HTLV-I, of course, is a virus that causes a neurologic disorder as well as a form of leukemia. 22 DR. PRIMM: Dr. Engleman, I had asked the question about HIV-2. Dr. Engleman: Yes, I know. DR. PRIMM: So, you are leading up to it? Dr. Engleman: I am leading up to it, right. DR. PRIMM: Thank you. Dr. Engleman: I think that the fact that the blood banking leadership has supported the concept of HTLV-I testing earlier and more aggressively than they did HIV-1 testing reflects a desire to convince the public that the blood banks are more determined to deal with HTLV-I than they were perceived to be with AIDS and I think that’s fine. I only wish that blood banks would start testing for HTLV-I instead of just talking about it. With respect to HIV-2, which is a second strain of the AIDS virus that was initially identified in West Africa, and the need for HIV-2 testing there, I think the need will arise. However, as of today’s date there is not evidence that HIV-2 has penetrated the blood supply. In contrast, HTLV-I positive donors have already been identified in several locations around the country. I think there is little question that HIV-2 infections will increase in this country and that HIV-2 screening of donated blood will be necessary. Fortunately, with respect to HIV-2, I believe that there are screening tests that have been developed. They are not yet licensed by the FDA but I am confident that they will be, and that we will incorporate such tests. As far as HIV-1 antigen testing is concerned, I would, however, differ with the implications of the last few statements. There are HIV antigen tests available, ELISA tests. They are not formally approved, but we do lots of tests that are not formally approved. But to my knowledge they have not been shown to substantially improve the safety of the blood supply because they do not pick up a high percentage of the HIV-antibody negative individuals. On the other hand, there are other tests for the virus which are under development that involve nucleic acid detection that look very promising. And again, I tend to be somewhat more optimistic with respect to the ability of our science and technology to catch up, and I would guess that within a year or two, at most, we will have access to these very, very sensitive and specific tests. 23 But, the current versions of the HIV antigen tests are simply not that good, at least not in my judgment. DR. PRIMM: Do you anticipate, Dr. Engleman, any separation of blood on the basis of race? Do you anticipate, for example, because the Japanese have a higher incidence, supposedly, of HTLV-I, some Caribbean blacks have a higher incidence of HTLV-I, and some southern blacks in southern cities have a higher incidence of HTLV-I in their blood, do you anticipate a separation of blood on that basis? That’s what I was trying to get at with Ms. Dutton. Dr. Engleman: Yes. Well, I think you are touching on an extraordinarily important point, and, that is, how much reliance do we place on our ability to test blood as opposed to using other measures to try to screen out donors? Personally, I prefer to rely on medical history, physical exams, and blood testing. I would be concerned about the implications of separating blood on the basis of race or gender. I think the notion, for example, of identifying blood by gender becomes a very difficult one, because I can tell you as the director of a blood bank that recruits volunteer donors recruiting donors is not easy. In our own blood bank, the majority of the donors are males. Recruiting females is difficult. First of all, there are minimum weight requirements, and there is no question that a higher proportion of our female donors are too anemic to donate. That doesn’t mean there aren’t lots of eligible women donors, but I think to transition from what is now a 60/40 male versus female donation group to an all- female group would be extraordinarily difficult. The second point is that while an all female blood supply might have been useful back in 1982, or ’83, or ’84, it no longer would be as useful, in my judgment, simply because relatively few HIV positive individuals donate blood now, and we have HIV testing in place. It’s not perfect, but it’s pretty good. And, there is no evidence that I know of that suggests that other communicable diseases, such as non-A and non-B ‘hepatitis, are any less frequent in women than in men. So, I think that while it’s an interesting suggestion, and might have been considered back in the early ’80s when some of the other ideas should have been heard as well and were not heard, I’m not sure that it offers any advantages today. DR. PRIMM: Thank you very much, Dr. Engleman. 24 Dr. Asher, the question I asked you, were there any girls in the "good old boy" network, or any black boys in the "good old boy" network, or minority boys in the "good old boy" network. DR. ASHER: I think you can guess the answer to that. There are very, very few females. There are really very few, if any, minorities. It is a true stereotyped "old boys club." You mentioned the racial labeling issue. As you might be aware, 40 years ago that was -- DR. PRIMM: Absolutely. DR. ASHER: -- quite common, and it has disappeared. I have seen no attempts whatsoever to do that. However, an interesting example was in Salt Lake City, when all of this started, as you know, Salt Lake City is basically a city of Mormons. The hospitals there are all Mormon owned and Mormon run, and they asked the local Red Cross Blood Bank in Salt Lake City to start labeling the blood whether they were from Mormons or non-Mormons. The Red Cross refused to. So, the four or five major hospitals said, okay, we’1ll set up our own blood centers, and for the first time in 40 years, it’s gone full cycle now, blood banking is back into the hospital. They were very, very successful in providing 100 percent of their needs, and for the first time in its history, the volunteer blood banking industry actually had a regional blood bank close. It went bust, pure and simply that, because all their customers said, you’re not doing what we want. I’m not talking about whether what they wanted was right or wrong, it was their option, and it had a very significant impact. DR. PRIMM: There is a great deal of significance about what you talk about in Utah. As you know, if you are black in the Mormon Church, you cannot go to heaven. DR. ASHER: Yes. DR. PRIMM: Eldridge Cleaver, of course, is a Mormon, and I guess for blood donation he would be eligible to donate, but I’m sure his blood would be separated. And, they have a very famous star basketball player at the Brigham Young University who is black, who is also a Mormon. So, that’s very interesting. DR. ASHER: Yes. DR. SERVAAS: Doctor Lee? 25 DR. LEE: Many of us realize the wisdom of what you are saying, Ms. Dutton. I’ve had two platelet transfusions in my life, and both of them have been from a nun, and this is my nun, and I keep her in good health at all times. I don’t know whether she’s black. I don’t care what color she is, but she’s my nun. I know what she doesn’t do. Dr. Engleman: How do you know that you received products from this individual, because until very recently it wasn’t possible to influence -- DR. LEE: I know, because the head of our blood bank took the blood from this nun -- Dr. Engleman: Okay. A Y DR. LEE: -- for me, personally. CHAIRMAN WATKINS: In the "old boys club." DR. LEE: I bet this was part of the "old boy" network, except the blood banker was a woman, and the nun, of course, Was a woman. Let me ask a penetrating question here. I do not understand how the blood sector got these certain privileges. And, why are these differences there? I don’t understand. DR. ASHER: You mean the philosophic differences or the operational differences? DR. LEE: I’m mainly interested in operationally, how dia the blood sector develop this privileged character and the plasma industry go off into the commercial arm? How did this happen? DR. ASHER: I’d say by public relations, a philosophic PR concerted effort by the volunteer sector to foster its own personal philosophy, which, of course, resulted in a monopoly. The plasma sector was really originally the commercial blood sector, and it had no place to go. It was legislated out of existence, or PR’d out of existence, as providing fresh blood products. Of course, it was not a healthy sector itself, and I’m talking about maybe 25 years ago, where it needed serious reforn, and what happened is, they threw the baby out with the bath water and created a monster. DR. LEE: Does the panel agree, I guess you two gentlemen are- from the other side of coin, I mean, does this 26 panel agree that everything should be approached in the same way here? DR. ASHER: Well, I’m the only person who is in the commercial blood industry -- DR. LEE: Yes. DR. ASHER: -~- So, I don’t know if we agree or disagree. DR. LEE: Well, I want to find out. DR. ECKERT: I’m not sure I understand the question you’ve raised. DR. LEE: Why should the plasma sector be paying taxes and be set up on this competitive basis, and why should you not be paying taxes and be set up on this relatively monopolistic -- in this monopolistic way? DR. ECKERT: Well, I may not be the correct person to’ answer that? I don’t represent anyone but myself here. ’ DR. LEE: Well, the blood sector. DR. ECKERT: Dr. Engleman maybe be a better perdon to answer that. Dr. Engleman: Well, let me just mention, if you don’t mind, that I hadn’t met any of these people prior to our arrival last night. Even though I think each of us has in common that we have something to criticize about the blood banking practices, I have focused my criticism the blood testing issue, but I think it is fair to say that a philosophy arose, led by the Red Cross and others, of community responsibility, the notion that communities should be responsible for providing blood in an anonymous fashion for their own community needs. Now, that philosophy has gained dominance, and has been dominant for a number of years. And, what you’ve heard today is that there are some flaws in the system, and each panelist has emphasized one or more of the system’s shortcomings. I think the donors today, the donors at blood banks are primarily volunteer donors, Since they are not paid. The blood banks are, in the main, non-profit, run by well-meaning people, sometimes not so very efficient, but generally well-meaning. But, in any event, each of us has a very different point of view about this, so tll pass the mike. 27 DR. ASHER: Just quickly, before Ross, because he’s the best qualified person to talk about it, this is an economic thing. The paid donors are also volunteer. I mean, they are not hit over the head, knocked unconscious and dragged into a place. It’s a straightforward business deal. The paid donor comes in and he says, "I’m going to remain in good health, I’m going to become a repeat donor, I’ve committed myself to this program, make myself available." The commercial center says, "Well, I’m going to treat you well. I’m going to make sure that we are clean, safe and so forth on you, and we/re going to pay you, and it’s a hand-shake business deal with a full divulgence of perfect informed consent." It’s just like every other normal transaction in life. Where, in the volunteer center, the informed consents are deficient. The donor does not have a full idea of what he’s getting into. He’s recruited on a guilt-trip concept. It’s really not a fair, neat agreement between people. DR. ECKERT: If I could respond to your question, Doctor Lee. The whole thing came about during the late 1960s and the 1970s, and it came about because hepatitis was traced to a certain kind of repeat donor who was paid very little and was usually ill. It was believed at the time that these derelicts, and low-income, and very poor people, in many cases, who sold their blood to commercial organizations, were lying in order to get a few dollars. And, the conclusion incorrectly drawn from that belief, in my opinion incorrectly drawn, was that in order to prevent people from lying and, perhaps, selling contaminated blood to yet a few dollars, that we had to go to a completely unpaid system. The truth of the matter was that most of the hepatitis at work in our society then was still non-A, non-B hepatitis, and most of it was sub-clinical. And, many of these people didn’t even realize that they had been ill. So, it’s very difficult to lie about something that you don’t understand to begin with, and yet, many of them were ill, and they were extremely low-income people, and they needed the money and they were selling their blood. Well, what was the defect of that system? It wasn’t that blood was bought, simply bought. What was the defect was that they were paid so little. Think what your circumstances would have been last night, if you were limited to a hotel room that would have cost - ~ if you could have paid, by law, no more than $5.00 for a hotel 28 room or $1.00 for a meal. When we use cash, cash works in a very direct way in our economic system. You target the quality of material you get by the amount that you are willing to pay. So, if you are only willing to pay $5.00, you are going to wind up with circumstances that most of us would not find very comfortable. If you pay more, you wind up with very. different circumstances. So, the problem of that era was that we were not -- within the context of a paid blood system -- we were. not paying enough, and because we were paying so little, we were targeting an unhealthy group of people, people who had been sick and who should not have been blood donors. \ So, in some cases, collecting blood through a very large donor pool was better than using cash to target sick people. And, the volunteer philosophy gained great adherence on that basis. However, if I could only take another moment to add, it was never demonstrated that the volunteer philosophy was better than a donor registry approach, or even a donor registry approach combined with cash. And, the Mayo Clinic, in the 1970s, operated a very successful donor registry system with cash donors. And so, the point is, a selected healthy group of donors is always going to be safer than a large pool, although, a large pool may be better than using cash to target the wrong people, and that’s the medical underpinning of the debate that came about by which the volunteer philosophy \became so ingrained. It is not the case, in my opinion, that a volunteer philosophy is superior to getting a smaller number of healthy people, who maintain their health. The donor registry proposal that I proposed to you would be broadly superior to collecting blood from so many people in a society in which viruses move about very easily. DR. LEE: Now, you had, I thought, you know, really, I’m sure you all agree probably, but you phrased it the best, you said selected donors is the way to go. DR. ECKERT: Yes. DR. LEE: Now, Dr. Asher agrees with you. I didn’t hear Dr. Engleman. DR. ECKERT: May I quickly -- DR. LEE: And, I know Ms. Dutton agrees. 29 . -DR. ECKERT: -- add something to the remark I made just a moment ago? DR. LEE: Yes. DR. ECKERT: My donor registry proposal bears none of the characteristics of the way blood was solicited in the 1960s and 1970s. I am not -~ if it becomes necessary to pay some donors in a donor registry system, I want the panel to understand, unambiguously, I am not advocating, in any way, shape or form, a return to that system. That was not a satisfactory systen. — | But, that does not mean that one could not establish a donor registry system effectively and safely today, whether or not one pays for blood. Now, I’m not sure that one would need to pay donors in all communities,. or even in many communities, if we improve the way in which we encourage people to donate, and impress upon them the importance of this, and impress upon them registry | techniques. In fact, I can imagine many public spirited persons feeling that the donor registry approach was a more satisfying way of giving blood than through the large pool regular donation approach that we have now. But, I’m not an expert in this, and these are questions that you should put to blood bankers, and to people who've thought about this in connection with their own experiences. But, I am convinced we haven’t tried hard enough. I’m sorry, I shouldn’t have gone on so long. You wanted to ask anpther question. Dr. Engleman: I didn’t comment about the donor registry approach earlier. I’m not fundamentally opposed to trying new things. I think that’s one of the problems in the industry, if you will, is that there has been so much resistance to trying out new things, new tests, new concepts. On the other hand, I think you have to be aware that there are physical limits as to how many times an individual can donate a pint of blood. It’s about five times a year, assuming that that individual doesn’t become anemic. Furthermore, the supply of blood donors has been limited, only 3 to 5 percent of healthy individuals are blood donors. I don’t want to poll the members of the Commission, but I would suspect that only a small percentage have ever donated blood. There are lots of people that don’t want to donate blood. It’s possible that by changing our recruitment techniques we can improve that, but, nonetheless, blood donors are a limited 30 resource. And so, while I would say we should explore these alternatives, I’m not yet prepared to endorse wholesale radical Ghanges in a blood banking system which has, in the main, served the public well. On the other hand, I would agree that changes are needed, and so to that extent, I would concur with the notion that we should examine the problems and consider alternative approaches to their solution. DR. LEE: And, does the panel believe, you ducked the original question, that all aspects of the blood donor system ought to be treated the same, tax-wise? DR. ECKERT: Well, I don’t -- I’m not going to comment, express a preference one way or the other. our society establishes -- allows for non-profit organizations and allows for profit organizations. My criterion is, which one is doing the better job of making blood safer? And, I want to say that I think Dr. Asher’s organization has done a splendid job, and that his techniques deserve to be emulated, regardless of the profit status or non-profit status of the organizations. They deserve So be emulated by hospital blood banks and by the large system collectors. He has shown that this is a feasible approach, and I think he’s to be commended for having done so. On the other hand, I want to add that I favor, as my remarks indicated, I favor competition, and if the non-profits compete with the profits, I think that’s just dandy, and if the profits compete with the non-profits, I think that’s fine, too. Because, through a competitive process, each of these organizations has a stronger incentive, to use an economic term, to adopt brand name tactics ~~ to try to produce a perception in che mind of the public that they have higher quality services and that they have something to lose. It must be understood that they have something to lose if they do not provide a quality that is associated with their brand name. That is a tremendously powerful force in our economic system, and it is all to the good. It benefits consumers enormously. So, I favor any system that tends to enhance quality and to make producers accountable for the quality of blood that they produce, and I certainly share Ms. Dutton’s argument about the blood shield laws. I don’t think that there’s much that the Federal government can do about blood shield laws, because these are state laws, although, if you share our skepticism about it, you could include something in your report about it. DR. ASHER: I think I’m closest to the, as again I say, the "catchee" of the javelin. I truly believe that there is room for both, because I believe in maximum experimentation. So, there is not wrong with the not-for-profits competing against me, 31 but as long as they compete within the constraints of the Federal Trade Commission, the Sherman Anti-Trust Laws, which is | not the case. A perfect example is, I’m providing a very sophisticated product, which is demonstrably safer in my particular area in Los Angeles. A couple of local hospitals now have said they are going to stop buying my products and take, truly, a product that’s not as well produced, pure and simply, because their trade association has part of an accreditation system for their blood bank the comment that they will be cited for not being in compliance with the trade association’s recommendations if they rely upon any paid donors. So, here a superior product is not being allowed there. Now, that’s unfair competition, as far as I’m concerned, and that might very well lead to some very significant legal action. DR. LEE: Are you talking of the FDA? DR. ASHER: No. I’m talking about the American Association of Blood Banks, their accreditation system, which is like a Good Housekeeping Seal of Approval. No, FDA has, although in the past they tried very hard through subtle pressure to put a stigmata upon anything to do with paying for blood or profit making, that’s changing a bit, but they’ve been very circumspect in this in recent years. No, I’m just talking about competition has been good. Actually, there were none of these sophisticated products available in Los Angeles until we started making them available, and, as a result, a year and a half ago, the Red Cross started to make them. It was competition that dragged them into starting to produce a better product. And, I’11 compete against anybody as long as I’ve got a fair shot, but when they bring these unnatural restraints into it, it is difficult. So, the answer to your question is, no, I think there’s nothing wrong with allowing both profit and non-profit to compete. Just, let’s stay within what we think is fair competition. MS. DUTTON: I would just reiterate my concern about accountability, and I think it is worthwhile looking into the fact of, what kind of role the non-profit structure in the blood collecting industry has played in the lack of accountability. Any profit-making industry has to account and, frankly, I’m under the impression that the non-profit sector of the blood industry, part of their problem is that they haven’t been accountable. 32 DR. LEE: Thank you. DR. SERVAAS: We’ll start the questioning at the other end. Doctor Lilly? DR. LILLY: Dr. Engleman, I wonder if you could just elaborate modestly on the idea of what is now tested for and what is not tested for, and, particularly, with emphasis on what is not tested for that, perhaps, could be tested for at the present. Dr. Engleman: Well, what I attempted to emphasize earlier was that, for a number of years, particularly, '83, ‘84 and the early part of ‘85, there were indirect tests for the AIDS virus that were available which, in my judgment, should have been used. They worked. They didn’t work 100 percent of the time, but there is no question based on the data available today, and the inferential data that was available then, that they should have been used to reduce the incidence of AIDS transmission. Subsequent to all of the events that took place, namely, the public pressure on the blood banks, the realization that the reassurance that was being provided by the leadership of both the government and the blood banks, was grossly out of place. The blood banks have now incorporated the same kinds of surrogate tests (that they rejected three years earlier) as screens for non-A, non-B hepatitis. One such test is called the Test for Antibody to Hepatitis B Core. The Hepatitis B core has no direct relationship to non-A, non-B hepatitis. We are using that test as a surrogate marker. We are also using a liver enzyme test, called ALT. Elevated blood levels of this enzyme suggest liver inflammation, and we’re using that as a second surrogate marker, again, for non-A, non-B hepatitis. We use a syphilis test, which has been in for many years, aS a screen. It was referred to earlier. We, of course, type the blood for the A, B, and Rh factors. We perform another hepatitis B test, which is a test for the antigen of hepatitis B virus, a very sensitive, very Specific test. Nonetheless, we still have a few cases of hepatitis B that result from transfusion, because none of these tests are perfect. Let’s see, have I missed any? I don’t think I have. Well, of course, HIV-1, which is a principal screen. This is, of course, for antibody to HIV-1. Those are the tests that are currently in place in all, or nearly all, blood banks in this country. 33 In my judgment, HTLV-I antibody screening should be in effect as soon as possible. I think we’ve already seen excessive delay with respect blood bank screening for HTLV-I. There are commercial tests that have been developed. They are not yet licensed by the FDA, in the main, because there are not yet reliable confirmatory tests, and I can understand that there would be some reluctance to encourage everyone to be using a test for which we don’t have a confirmatory test. Nonetheless, I think that there should be considerable pressure brought to bear to bring these HTLV-I screens out for blood donor screening purposes, because HTLV-I is quite pervasive around the country, with blood donors having been identified as HTLV-I positive in experimental surveys. So, I think HTLV-I screening should not be delayed any longer. And, there will be other viruses that come down the pike, HIV-2 for sure, and there will be others. DR. LILLY: The test that you mentioned for CMVs that was developed at Stanford -- Dr. Engleman: Yes. DR. LILLY: -- has that been developed commercially? Dr. Engleman: Yes. There are a number of commercially available CMV tests. DR. LILLY: Is that used regularly? Dr. Engleman: Pardon me? DR. LILLY: Is that used regularly by blood banks? . Dr. Engleman: Yes, but not regularly enough. I think the failure to test for CMV is one of the most under-publicized and under-stated disasters in the blood banking industry’s history. Cytomegalovirus, or CMV, has been shown unequivocally to cause substantial disease, morbidity and mortality in individuals whose immune systems are impaired or immature, such as the premature newborn. An inexpensive test has been available since 1980, and I think it’s an embarrassment and a disgrace that, in fact, the test still isn’t mandated for use around the country. However, the majority of blood banks now use it to identify CMV seronegative blood for transfusion into premature infants. 34 I should add parenthetically that had CMV testing been used when it should have been used, for these kinds of . transfusion recipients, in my judgment many of the cases of AIDS that were caused by transfusion to infants of contaminated blood would have been completely avoided, because, like the T-cell test and the test for Hepatitis B core antibody, CMV-antibody was also a good surrogate marker for HIV. DR. LILLY: One more question, a philosophical one.The testing that you do, do you test blood or blood donors? Dr. Engleman: We test blood. Today, most of the tests are performed after the blood is donated. At the moment, it is the most cost-effective way of doing it, so we’re testing blood. DR. ASHER: Doctor Lilly, may I add to that? Actually, both the donor is tested and the blood is tested. The blood is tested for the safety of the recipient. The donor is tested for the donor’s safety, a very important aspect of it. So, there are two responsibilities of a blood bank, and a lot of people forget that former one, and I’m sorry to say I feel that certain parts of the volunteer sector are not being totally honest, nor totally protective of their donors. DR. LILLY: Let’s see, I have a final question. Ms. Dutton, I just wanted to check up on one thing that you said in answer to a question, and see if I understand it. I didn’t get down the exact quote, but something to the effect that either the antigen test or antibody test for HIV, as a political “boondoggle." I was struck by your use of that word, and I wish you would elaborate on it. MS. DUTTON: Yes. In California, as also in other states, laws were passed to conceal the identity of people who tested positive for the antibody test. And, as it stands now, the only way that people can be tested is with their consent, or if they go into a blood bank. And, it has created horrendous problems. DR. LILLY: So, they can be tested either voluntarily or involuntarily. MS. DUTTON: Well -- DR. LILLY: So, I’m not quite sure what is being excluded here. 35 MS. DUTTON: -- their blood is screened when they donate, their blood is screened when they donate, but they can be tested voluntarily, but it’s also anonymously. DR. LILLY: Uh-huh. MS. DUTTON: So now, we’re approaching licensing a test for the virus, and this panel has an opportunity -- DR. LILLY: I’m sorry, I’m confused. MS. DUTTON: All right. There’s a difference between antibody and virus, did you know that? DR. LILLY: Yes, uh-huh, I’m quite aware of that. MS. DUTTON: All right. The laws that are governing the use of the antibody test, not -- \ \ DR. LILLY: Oh, okay, you should be more precise. You didn’t say the antigen test, you just simply said the virus test. MS. DUTTON: Antibody test, I’m sorry. Does that clear that up? DR. LILLY: The antigen test, okay, that’s the one that is being tested for -- MS. DUTTON: That’s right. DR. LILLY: -- licensing. MS. DUTTON: It hasn’t been licensed yet. DR. LILLY: Okay. MS. DUTTON: And, what -- DR. LILLY: Now, let’s go on -- MS. DUTTON: -- I was expressing, a concern, hoping that it wouldn’t become a political football, like the antibody test became, where now we are having to reevaluate the law and making horrendous efforts to try to -- DR. LILLY: Let me interrupt you. What is the difference between the test that would be done at an anonymous testing center and the test that is done on the blood of that same individual at a blood bank. MS. DUTTON: There is no difference in the test. 36 DR. LILLY: Uh-huh. Then, I’m not quite sure what the objection is to the existence of the one. MS. DUTTON: Well, we’re talking about two tests. We have laws on the books now that regulate the use of the antibody test. - DR. LILLY: Right, okay. MS. DUTTON: You can either have it screened through - the blood bank when you donate, or you can go into:a testing center -- DR. LILLY: Right. MS. DUTTON: -- and have it tested anonymously. Okay? DR. LILLY: Uh-huh. MS. DUTTON: Now, on the horizon, the FDA is about to license a test for the virus, or the antigen. DR. LILLY: Uh-huh. That will presumably be available for use in blood banks. MS. DUTTON: Presumably. DR. ASHER: It’s available right now. DR. LILLY: Right, okay, but I’m just trying to see what the objection is to anonymous testing. : MS. DUTTON: Oh. Well, because it’s created horrendous problems. DR. LILLY: I’m afraid I don’t see it, but, perhaps, you could explain it to us. MS. DUTTON: Oh, you don’t? Okay. Well, number one, physicians, surgeons, health care workers, are being asked to come into blood contact. There has been a great deal of testimony and public debate about the fact of whether or not they should have the right to know that the patient that they are treating is positive for ‘the antibody. And yet, the law precludes that -- DR. LILLY: That has nothing to do with -- MS. DUTTON: -- from happening. 37 cm + DR. LILLY: I’m afraid I still don’t understand why there should not be anonymous testing centers. I mean, you are now talking about the -- . . MS. DUTTON: No, no, I’m sorry. We certainly are not communicating. The objection is not to the anonymous testing centers. It’s to the confidentiality law that precludes health care workers, surgeons, law enforcement personnel, victims, all of these people. DR. LILLY: Okay. Well, that’s something we’ve already dealt with in this Commission a good bit. DR. SERVAAS: That’s right. We’re actually talking about the blood, and we are anxious to get questions to Dr. Engleman, and Dr. Eckert and Dr. Asher about the technical things. We are not discussing the testing at this point. DR. LILLY: Okay. I was just -- DR. SERVAAS: At this point, we’re talking about blood supply, and so, we’ll go to -- DR. LILLY: Go ahead. DR. SERVAAS: -- Commissioner Gebbie. MS. GEBBIE: Several of you raised points about the existing oversight process for the whole blood industry. You raised it in various ways, that it is too close to the industry, that it is a closed network, that it doesn’t include the right people, that it’s not capable of criticizing what happened in the past to give us right information. I’m not sure everybody understands, and I keep getting lost in the current oversight of any one blood bank or any one plasma center, I believe it’s a federal license, is that correct, for everybody? DR. ASHER: Only if the products are entered into interstate commerce, which is not true of everyone, in which case they are just regulated by their individual states. MS. GEBBIE: By their state. But, it’s the same entity within the federal system that regulates both the blood banks and the plasma centers? DR. ASHER: Absolutely, and they also hold the identical establishment license. The only difference would he 38 the product license, and there are a good dozen different types of blood and plasma products, each one have their separate minimum requirements. MS. GEBBIE: And, there is an advisory committee of some sort that works with the FDA in overseeing that process, you mentioned that Dr. Engleman. Dr. Engleman: Yes, there is. MS. GEBBIE: What is the current composition of that committee, not by name, but by categories of kinds of people? Dr. Eckert is on that committee. DR. ECKERT: Yes. I should correct Dr. Asher’s remark a little earlier. He said that the committee was composed strictly of people from the fresh blood sector. DR. ASHER: The voting members. DR. ECKERT: The voting members, to the degree that it has membership from the blood banking organizations, that is true. I believe I’m recalling correctly that there are two such members on the committee out of 11 voting members now. Most of the other members are medical school faculty, and scientists, hematologists and people of that sort. I am the sole economist and the sole non-physician, non-natural scientist person on the committee, and was appointed just last year, and I should take this moment to say that you should probably put your question to the FDA people as they appear this afternoon, or consider putting your question to them. But, I credit the FDA for appointing someone outside the blood banking and medical specialties to the committee, and I’m pleased to be there. So, I would want to acknowledge that there is at least, to my extent, some diversity on the committee. DR. ASHER: This is current. This didn’t happen before. This is a result of the public pressure, the advent of consumerism in blood banking. MS. GEBBIE: Well, those questions were background for what, to me, is the more critical question to those of you who are critical of the system. I still hear that in at least the tone of your voices, and, that is, how should that committee be constituted? What would its ideal composition be if it were to be capable of providing the kind of oversight that you seem to be talking about that’s been missing so far? Or, should some different body be constituted completely outside of the FDA for some reason, and, if so, would you clarify? 39 DR. ASHER: Well, no. Advisory committees work. I mean, they are a very valuable part of the FDA. It’s just that the composition, the choice of composition has been so narrow. People have been chosen because they believe a uniform thing. MS. GEBBIE: So, if you were starting from scratch, give me your ideal composition of this committee. What kinds of people, how many of them? DR. ASHER: Well, the number is a workable number. Right now, they consider 11, I believe, a workable number, and I certainly wouldn’t want to change that. But, I think there should be at least two or three people represented on that committee from the plasma sector. Remember, they are sticking 10 million needles a year into people’s arms, and their products are actually going to more recipients than the volunteer industry. Obviously, you need the people from the volunteer industry on it. They have the experience in that particular place. I think you need people like Dr. Eckert on it, who has shown a lifetime interest in blood, and has written books on it, and has looked into it, and looks at it from the outside with a very analytical viewpoint. You do need, perhaps, an additional consumer representative on the committee, representing, perhaps, something like the National Hemophilia Foundation. But, it’s really not so much what the person represents, it’s the person himself. Is it a person who has demonstrated open-mindedness within his part of any sector of the industry? Is it a person who is innovative, a person who is willing to examine, instead of a closed mind. And, unfortunately, the Brahmans, the high priests of the volunteer sector, are the ones that are chosen to be on this committee, and that’s not the open-minded person. MS. GEBBIE: Dr. Engleman, do you agree with that composition, or would you do it differently? Dr. Engleman: Well, I haven’t made a study of the FDA Advisory Panel, except that I know -- my colleague, Carl Grumet is on that committee -- and I think he’s quite open-minded. He was one of the people that developed the CMV test. I think that, in fact, as an indirect consequence of the AIDS epidemic, there have been major changes in blood banking, not necessarily welcome changes to the establishment. 40 The AIDS epidemic has resulted in some beneficial consequences for blood banking practices. There is a much more aggressive approach to blood testing. The FDA seems to be more aggressive than they have been in the past, and I think a lot of these changes are for the good, and should be recognized as such. That doesn’t mean that the blood banking organizations themselves have undergone fundamental change. The AABB, for example, publishes guidelines for blood banks and transfusion services, and those guidelines probably have the force of law, simply because they establish the standard of care. And, those guidelines are too conservative, in my judgment, and need looking at. MS. GEBBIE: Conservative meaning not having changed much, aS opposed to conservative meaning heavily protective of the blood supply? Dr. Engleman: The former, not the latter. MS. GEBBIE: Okay. Dr. Engleman: I think they could be much more aggressively protective of the blood supply. " MS. GEBBIE: I want to push you a little bit more. You asked very specifically for a critique of what happened in the early ‘80s, in order that we might learn from it. Is this newly revitalized, somewhat changed Advisory Committee to the FDA what you were thinking of, or are you thinking of a different body, and, if so, what kind of a body? Dr. Engleman: Well, that request was the result of considerable soul searching. One of the most disturbing aspects of what happened in ’83, '84 and ’85, is the fact that here we are in 1988 and none of the blood bank leadership has even acknowledged that more could have been done during those years. Now, that, to me, is extraordinarily troublesome, because it suggests that the blood bankers really don’t think more could have been done during those years, and, if so, that suggests that they don’t understand the problems in their own industry. And so, it seemed to me that a reasonable, responsible thing to do would be to undergo an objective evaluation. Don’t believe me. Don’t believe this panel of critics. You know, there is no reason why there shouldn’t be an evaluation by qualified people, physicians, academicians, scientists, economists, the public, to evaluate what happened in 1983 and 1984 and why, so that we can look at the way decisions were made and what are the problems. But, without a full analysis, it is 41 doubtful that the blood banking system will respond and make the changes necessary to protect the safety of the blood supply in the future. MS. GEBBIE: Is the currently revitalized or reconstituted FDA Committee capable of doing that, were we to ask them to, or do you have in mind some different body, and, if so, what? Dr. Engleman: I don’t have in mind a particular body. However, I did suggest in my report that such an evaluation or investigation could be carried out under the auspices of the National Academy of Sciences, or the National Institute of Medicine, or, conceivably, under the government. I have no a priori reason to say the government shouldn’t be involved in such an investigation. But, I don’t think that the people who are investigating should be the people who are being investigated. [ think the probe should be carried out by an objective, highly qualified panel that has representation from all sectors. DR. SERVAAS: Dr. Eckert? DR. ECKERT: Could I just respond briefly to her question? The committee has 11 members, and I believe that includes these two non-voting members Dr. Asher referred to, an industry representative who sits on the committee who is non- voting, and there is a consumer representative who is on the committee, non-voting also. And, those are of long standing. Those memberships have carried with the committee for a number of years, and the committee was just increased in size by two voting members last fall. As to the issue that you’ve raised and that you asked Dr. Engleman about, whether this is the appropriate committee to engage in the proposal that he has recommended, I’m not sure it is, because it is my understanding, and, again, I hope you ask the FDA people when they come here today about this, but it is my understanding that this committee can only advise on matters that the FDA raises to it. It doesn’t have any independent autonomy. It convenes when the FDA has issues that it wants to raise, and to obtain advice on. By law, it has certain duties under FDA statutes to give advice on certain narrow questions pertaining to license new products and new drugs, but that’s a very separate kind of activity than what you propose. So, although I’m very new to the committee, and have not seen, except in one meeting, how it operates, I doubt very much whether it’s the right organization to do this. 42 Dr. Engleman: I would just mention very quickly that they are very busy in doing what they are doing, and they have a great deal of responsibilities. I think the kind of thing I had in mind is something that would require an extensive time, perhaps, taking several months, before coming up with recommendations and assessment. I don’t think that that body -- I don’t think the people who are volunteering to serve on the FDA Advisory Panel have agreed to that kind of intense service. DR. SERVAAS: Mr. DeVos? MR. DeVOS: I get the feeling some time that we are talking about business, because reluctance to change is difficult for everybody, and I’m sure you don’t mean to be bashing FDA. Relative to this whole matter, you know, we’ve been talking about the fact that what we really need in some parts of this industry is new blood, if you’ll forgive me, or do we need some blood letting of certain other people who are in the industry. But, forgetting politics, and profit or non-profit, I’m a layman, you are talking to all doctors up and down this line. This Commission has got to come back with, hopefully, some recommendations on proposed changes to improve the blood supply. Now, we’re not likely to get into the political, or black blood, which is red or blue blood, which is also red. I have to ask you the question, is there no simple way to test the blood as you receive it to make sure that it is safe, and I include the possibility of holding blood for a period of time, to where you could see if the antibodies develop. I see heads going no. The next question just leads to the fact then, then you are all going backwards a step to try and see if you can’t do some other screening. Dr. Engleman: Sure. I think it goes without saying that there is one form of blood that is almost completely safe, and that is your own blood. And, perhaps, this Commission has already heard about the value of autologous blood, I guess you are going to hear this afternoon. I think all of us here on this panel would concur, the problem is there a number of instances where you cannot get your own blood, particularly in emergencies, and some people cannot pre-donate. But if you have a choice, autologous blood is the safest blood. 43 Beyond that, homologous blood is potentially dangerous, and, as you’ve already heard, we don’t have a specific test for non-A, non-B hepatitis. There will always be viruses and other infectious agents that will be in the blood supply. So, we do not and can never have a perfect system. Nonetheless, we have a responsibility to make it as safe as possible. MR. DeVOS: I’m not speaking of all the other viruses. We are involved with HIV here, and I’m just trying to see, but you are just saying, you are really confirming, there is no way to test the blood for sure. Is that only because of the little time lag in there? Dr. Engleman: No, not entirely. It turns out that even with the best of tests, there are always going to be degrees of sensitivity, and even though we have a very good hepatitis B test in place today, there are still individuals who donate blood who happen to be infected, they don’t know it, and the test misses then. ’ We are approaching that point with our HIV testing. It’s now an antibody test. As I said earlier, within a year or two we’ll have additional tests that will improve the safety, but we’ll never get to the point, I don’t think, where there is absolutely zero risk of getting HIV infection through a blood transfusion. MR. DevVOS: Well, I understand, you know, nothing is perfect, and no test can be perfect. But, in the main, we’ve come a long way, but we’re not all the way, I gather. Dr. Engleman: I think that’s a good assessment. DR. SERVAAS: Doctor Crenshaw? DR. CRENSHAW: One of the things that I’d like to know the current state of, if you can share it, and, perhaps, your opinions of it, is the donor notification. A case just recently came to my attention of a woman who was notified five years after she received a transfusion that she received contaminated blood. Unfortunately, she died a year before that, four years after the transfusion, and a diagnosis of her disease was not made. I hear different things, and I understand the rationale for why originally there was a delay in informing donors, for fear that it would flood the blood bank industry with people who wanted to be tested and to get free tests in areas where they weren’t available. But, now that that time has past, has there been any rethinking, and how quickly are people being notified, or how quickly do you think they should be notified? 44 Dr. Engleman: Are you referring to recipient notification or donor notification? DR. CRENSHAW: Donor, well, really both. Dr. Engleman: Because -- DR. CRENSHAW: I gave you an example of a recipient. Donor as well, yes. Dr. Engleman: Well, I think the main problem here is one of recipient notification, where people have been transfused any time over the last decade, and do not know whether or not they were exposed to HIV. In the San Francisco area, there has been recently, in the last year, an effort mounted by some of the hospitals to send letters and communicate with people who have received blood, so that they might use their own judgment with respect to getting tested for HIV. I personally believe that that is a good thing, and I think that in our area, at least, this should be done, and I’ve made that recommendation to our medical center. But, all blood banks are currently struggling with what we call "look back" programs, where we are attempting to notify everyone who might have received a unit from an individual who subsequently came down with AIDS, or who subsequently tested positive for HIV. And, I can’t overstate the changes that have taken place in the blood banking community, and the degree of burden shift that has gone to the blood banks. We’ve been very critical of the blood banks, and I think rightly so, but right now the blood banks are inundated with new programs and new responsibilities, including the responsibility for notifying recipients. I think that all recipients of blood transfusions in the last decade deserve the right to be notified, to be aware, and to have the right to get tested. That’s my personal view. DR. CRENSHAW: What about donors? Dr. Engleman: Well, donors are all tested now, and -- DR. CRENSHAW: No, notification. Dr. Engleman: As far as I know, donors who are tested aS HIV positive are so notified. We do have a law in the State of California that says we have to wait 60 days. DR. CRENSHAW: That’s what I’m asking about. 45 Dr. Engleman: Oh, okay. That’s a state-by-state variation. Currently, the law in California states that once a positive HIV antibody test is obtained on a blood donor we must wait 60 days in order to discourage individuals from donating blood simply to obtain an HIV test. Since there are now numerous AIDS testing centers throughout California where HIV tests can be obtained anonymously, I think that that law has outlived its usefulness. I guess that’s all I want to say on that point. DR. CRENSHAW: Thank you. The other thing that I wanted to ask is, we had an article in a San Diego paper that indicated that there was importing of blood from San Francisco to be used in San Diego, and it made a big splash in the newspapers. And, that raised the issue of intranational migration of blood, and most people live under the impression that if they get blood somewhere, they get blood from that community, and if it’s a low- risk community that they are okay. I understand that in the not so distant past, America used to import blood from Africa and other countries. So, I’d appreciate knowing the status of both the international and intranational importation and exportation of blood. DR. ASHER: A number of years ago, there started to be imported red cells into the United States from Switzerland and Germany. There were about 300,000 units, it was referred to as Euro-Blood, very much like petro dollars, and that’s just what it was. The Swiss and German Red Cross needed more plasma than they needed red cells, so they drew their donors in excess of the red cells, they took off the plasma for their own internal needs, and sold this to the New York Blood Center, who, in turn, used some themselves, sold it to their own local hospitals, and shipped around and sold around the United States to other centers that were in short supply. This came into a lot of criticism, not because it didn’t make sense, it made great clinical sense, and economic sense, and everybody gained from it, but what happened was that it was divulged either to the donor, nor the recipient, so it was a case of just not full information. And, it was also not told that each where along the long a mark-up went onto it, and here these marvelous organizations that were not paying taxes, and put themselves up as very altruistic people, were making money, and deservedly so. It’s just that they didn’t admit it. This has ceased in the last couple of years. Because of this sort of criticism, the German and Swiss donors got a little bit annoyed. They said, why should I be giving my red cells to these rich Americans over here, and it really has slowed down. Right now in the United States, blood moves all over the country as shortages occur, and, again, this is called a clearing house, like a bank clearing house, and it makes a lot of sense. Once 46 again, though, people, you would think, should know about it. the thought of blood, though, going from San Francisco to any other city, I’m sure that rumor is unfounded. It just seems to ne, the blood supplies there are so unsafe, it is a hot spot, and ~ just would -- I cannot imagine the blood bank in San Diego accepting blood from San Francisco. It seems so impractical. DR. CRENSHAW: Here’s the reference and how I came to knew asout it, “San Francisco Blood: small amount imported here Latoere AIDS tests available." DR. ASHER: Well, there has always been an interchange, yes. DR. CRENSHAW: Thank you. DR. ASHER: It’s international commodities, the plasma er placma products are really an international commodity. It’s sold, bartered and exchanged, not unlike hog bellies, or frozen orange tulice. DIR. CRENSHAW: Thank you very much. DR. SERVAAS: Dr. Engleman, I am impressed with your Cy, magna cum laude from Harvard, and all of these publications that yeu’ve done, and Columbia University, MD, and your position at Stantord, I’m impressed with the fact you would come here and tell us the things you are telling us. But, particularly, I am impressed with this paper that you wrote in 1983, and our Admiral and all of us are very concerned that we study things where your peers have reviewed tem. And, in this case, in ’83, that was a blockbuster report ts your peers, was it? Dr. Engleman: Well -- DR. SERVAAS: And, it wasn’t published, and I’d like you to tell us, if you can, why would such an important document noc have been published in the peer review. Dr. Engleman: Well, let’s go back historically. That was in 1983 when we started our screening program, the AIDS Surrogate Testing Program at Stanford Blood Bank. We submitted an abstract for presentation to the Axerican Association of Blood Banks’ meeting, the national mceting that was to take place in November of 1983. Our group, I think, has a reasonably sound reputation from a science perspective, and it was a bit of a surprise to us that our abstract was rejected for inclusion on the program. 47 And, as I indicated in our written report to the Commission, not only was our abstract rejected, but when it came to the final program, the subject of AIDS was not on the formal program at all. And, this was one of several attempts to present and bring te the blood banking community our ideas about screening blood donors for AIDS. It was rejected. The subject of AIDS had, essentially, no place on that November, 1983, meeting, and I think that it’s not so much a reflection of any kind of conscious conspiracy on the part of the blood bankers. I think it simply reflects the fact that the blood banking community had not faced up to the unequivocal fact that AIDS was upon us. And, I think that whenever they heard some good news, like the risk of developing AIDS from a transfusion was less than one in a million (a figure which turned out to be a gross underestimate), they immediately seized it. They did not appreciate the magnitude of the problem, and, apparently, did not think that the problem was of such a nature that it needed to be discussed at their national meeting in November of 1983. It simply reflects the extraordinary reality that the community of blood bankers blew it badly in those years, and I think this is no more than just a reflection of that. DR. ASHER: I am not as charitable as Dr. Engleman. I think there is a conscious exclusion of his very significant data, and there have been other examples of conscious exclusion of data which didn’t match the theology of the people, particularly, Doctor Taswell’s studies of many years that he kept submitting that they would not publish concerning the make-up of his donor pools at the Mayo Clinic. And, it’s the only conclusion one can reach, is that there was an attempt, really, to not include in this particular time data they didn’t like. DR. SERVAAS: You think Dr. Engleman will go down in history as a hero of this particular time, because right now he’s doing tests that not all blood banks are doing? DR. ASHER: Well, he’s certainly a leader, and I think he demonstrates the best aspects of what many other people in the volunteer industry do too, and, that is, more concern with the goals of the industry than in their own personal ease of life. And, I think that there are -- there is a hard core of people who really believe in that. DR. SERVAAS: Were you finished? Dr. Eckert? DR. ECKERT: I would want to commend him also publicly for what he has done. His blood bank was bold, and prudent, and was prepared to err on the safe side, rather than on the side of risk, in the patients that were under his care indirectly, as 48 director of that blood bank, and I think Stanford should be commended, not criticized. They should be applauded and emulated for the splendid, splendid job that they have done. And, certainly, it is tragic that in science, as in elsewhere, we tend at times to try to settle scientific questions by a show of hands. And, from Galileo on, we know that this is not an effective way to deal with scientific questions. It just doesn’t work. It can solve temporary political problems in an industry, or in a committee, or in an organization. We’ve all encountered in our own lives episodes of this outside of medicine, or wherever we work, but it really never settles anything over the long run. DR. SERVAAS: So, I think what you are really saying is, maybe, can we say that the Commission should take Dr. Engleman’s suggestions for the future very seriously. DR. ECKERT: I certainly would. DR. SERVAAS: And, my question for Dr. Asher is, no, I think this is for Dr. Eckert, you, I believe, said that it was a $1.25 billion business, and do you know, or Dr. Asher would he know, what is the margin of profit on that? DR. ECKERT: No. I haven’t made any estimates of that kind. You may be referring to the Money Magazinepiece where I made some comments about dollars. DR. SERVAAS: What kind of margin of profit is there on that billion and a quarter? WITNESS: Well, the billion and a quarter sales of fresh blood profits, nobody knows what the margin of profit is, because this is a case of accountability and the volunteer sector is not accountable. Some of them publish, and are required to publish, financial statements. But, all I can say is, the professionals that I have given to, and some of which have published on it, refer to these financial statements as "creative accounting." In the commercial $1 billion a year plasma industry, why, historically it is probably the least profitable of the entire drug industry. And, if they operate on a 4 or 5 percent profit margin on sales, I would be surprised. DR. SERVAAS: But, you have to pay insurance, and do these shield laws, these state blood shield laws that protect the non-profits, do you have the same protection? DR. ASHER: Oh, yes, yes. 49 DR. SERVAAS: You do. DR. ASHER: The same blood shield protection, and that’s an issue that really needs careful study, and I am not so sure they should be removed, perhaps, changed. Right now, they are not shielding as much as people think. They just shield relative to product warranty. There is no shield there for negligence, no shield for malpractice. DR. SERVAAS: Yes, Dr. Eckert? DR. ECKERT: But, it has to be recognized, I think, that a negligence case is much more difficult -- DR. ASHER: Yes. DR. ECKERT: -- to organize and to demonstrate. It is much more difficult to demonstrate negligence than strict product liability in tort. So, the laws then, or the common law, either the statutes or the common law decisions, in whichever state is following either statute law or common law, that do shield the blood collectors, whether the for-profit or the not-for-profit, are very important, are very important. And, I said in my remarks, we don’t shield manufacturers of drugs, or aircraft, or of power lawn mowers from badly designed products or unsafe materials. I don’t think we should shield blood collectors, when they are in a position to take steps that can reduce risks enormously through more effective testing of the sort that Dr. Engleman has done and that I have proposed and agreed with. DR. SERVAAS: Dr. Engleman, you do a lot of tests that other blood banks are not doing, as I understand it, and my question is, on HTLV-I, for example, while it hasn/t yet been licensed by the FDA. Are you able, when you want to, to get that test and use it in research? Dr. Engleman: Well, in fact, our blood bank has been - - is doing HTLV-I screening right now. We haven’t announced it publicly, but we’ve been screening all of our blood donors for HTLV-I antibody for a number of months because we think it’s needed. We wish all blood banks were testing for HTLV-I, right now. But, I want to reemphasize that we are in a rather unusual circumstance, in that our blood bank is both a blood bank and a research center, with these two distinct and complementary 50 activities. And, most blood banks around the country are not research oriented, they are not equipped to be so, and so, it is not unnatural or terribly surprising that we and a few of the academic blood banks like us would be the ones to be more aggressive and come up with new approaches. So, while I appreciate the flattering comments, I think what we need is more of this kind of research orientation, innovation orientation around the country, so that it isn’t so isolated. I would just like to make one or two other comments, if I might. DR. SERVAAS: Please. Dr. Engleman: One concerns this whole question of tort laws and legal accountability of blood banks. I’m troubled by this. As one who gets calls from attorneys on a daily basis about transfusion associated AIDS, I have not convinced myself, nor have the lawyers convinced me, that lawsuits are the answer to this problem. We are such a litigious society, so much of it seems to be wasted time, energy and emotion and money, and I’m not convinced that approaching this thing from a legal perspective is going to have any long-lasting benefits, other than, perhaps, create more regulatory problems for us to contend with. I do think there should be more openness and more introspection, which has been missing for a long time from the community of blood banks. Anyway, I’11 stop there. DR. SERVAAS: You made a remark about the syphilis testing in 1975. Who made that remark, and could you explain that? DR. ECKERT: I’m sorry, which remark? DR. SERVAAS: About syphilis? DR. ECKERT: Which remark about syphilis? DR. SERVAAS: I thought you said that we didn’t -- that we then stopped testing. DR. ECKERT: No, we’ve never stopped. DR. SERVAAS: Was it hepatitis, or what was it? DR. ECKERT: No, we never stopped -- to my knowledge, we‘ve never stopped testing for syphilis, but the American Association of blood banks at one time proposed deleting the 51 syphilis test from its procedures manual, and, presumably, I would imagine, from the FDA’s requirements. The FDA has not taken that recommendation, and I think it would be a very unfortunate step if it did. DR. SERVAAS: Okay. DR. ECKERT: For the reasons I’ve already explained. Do you want me to repeat them? DR. SERVAAS: No. I think Dr. Engleman had something. Dr. Engleman: I wouldn’t disagree with that at all. The only other point I would make is that, since the four of us here are critics of one sort of another, I think it would be useful at some point for the Commission to hear from the major players. Maybe you already have, or you intend to, but I am sure that none of us has voiced their perspective and their point of view, and I think it should be heard. DR. SERVAAS: Yes. We’ve heard from Doctor Jerry Sander, and a lot of the establishment, at this point, we’ve already heard from. Dr. Asher or Dr. Eckert, could you tell us, we hear rumors that the Red Cross is worth, has assets of $500 million, or now, probably a billion, do you have any estimates on the validity of those statements, either you or Dr. Eckert? DR. ASHER: I think we both do. DR. ECKERT: Well, all I know is what’s in their annual reports. DR. SERVAAS: Which is? DR. ECKERT: And, these are public documents. They are filed by the auditing firm that assists the Red Cross in preparing those, and I don’t know anything that isn’t contained in those. And, I can’t recall what the numbers are. DR. ASHER: They are roughly $500 million. DR. ECKERT: So, I would only refer you to those. DR. SERVAAS: Dr. Asher? DR. ASHER: Well, they have a very large liquid asset position. As a matter of fact, and this has been published and has not been refuted, although, the Red Cross responded to the publication, and I’m afraid the response was reminiscent of a 52 Viennese waltz. The basic fact was that if the Red Cross were considered among the profit-making organizations today, it would rank something like 430 in Forbes 500, based upon gross sales. Forbes also, though, writes their 500 on profit, or what the Red Cross refers to, excess over revenues, they rank them on profit as a percentage of sales, at which point the American Red Cross Blood Program would rank 79th among the Forbes 500. I think those numbers speak for themselves, and the fact that they’ve not been refuted is significant. DR. SERVAAS: Thank you. Doctor, or, Penny Pullen, do you have questions? MS. PULLEN: I don’t have any questions. I know Doctor Primm has another question. DR. SERVAAS: Doctor Primm? DR. PRIMM: Yes, thank you. I’d like to ask Dr. Engleman and Ms. Dutton, if you had to design an optimal battery of tests that'could make our blood supply safe, because we have so many different organisms and viruses that can be transmitted that haven’t even been mentioned here this morning that I know both of ‘you all are concerned with, the herpes virus, for example, can, indeed, be transmitted, the herpes papilloma virus can, indeed, be transmitted to blood, blood products. My concern is what would you suggest to this Commission as an optimal battery of tests that would make it safe for me to get a blood transfusion here in Indianapolis, Indiana today if something happened to me? MS. DUTTON: Well, I’m going to defer to the scientific people on this panel. My prime concern was improving the donor base with the safer donors, and I wouldn’t pretend to be an expert on tests. So, I think someone else could answer that. DR. PRIMM: You know, Dr. Engleman, you had said in your written testimony that, really, AIDS allowed us to begin to look at other things, or, sort of was the catalyst, okay? Dr. Engleman: Yes. DR. PRIMM: And, I’m always talking about AIDS as a window of opportunity for people in the health profession, and if you can use that window to -- Dr. Engleman: Well, I agree that AIDS, as I said, has had some beneficial consequences, and this is the one major good consequence, wnich is that it alerts us to the other problems 53 associated with transfusion. As I said earlier, even if we dida thousand tests, we couldn’t guarantee the absolute safety of the blood supply. And, at some point you will hear that we have to draw the line, because each test costs money. And, the question arises, where do you draw the line? DR. PRIMM: But, you are talking about a life now, you see. Dr. Engleman: Oh, listen -- DR. PRIMM: But, each test costs money, but nothing is as valuable as a life. Dr. Engleman: I couldn’t agree with you more. Nonetheless, at some point, you have to draw a line. Now, it is my belief that the line needs to be drawn in a much more aggressive location than has been drawn in the past. Believe it or not, many blood bankers still contend that a test (such as the hepatitis B core antibody test) which was only going to detect 40 or 50 percent of AIDS shouldn’t have been used. That remains the company line, and, obviously, I’m not a believer in that point of view. On the other hand, as to where to draw the line, there has to be some limit, and I don’t think I can stand before you here today and give you a list of ten tests that would solve the problem. I think this needs ongoing vigilance and a very major input from the scientific, academic community, and people that are sophisticated about infectious disease problems, because that’s what we’re really focusing on, is infectious problems. And, that is one of the reasons why I’ve urged this Commission to agree with the recommendation that we have a blue ribbon panel, if you will, that actually investigates this whole issue of what went wrong, and why, and what’s needed to be done now. I don’t think one can come up with a simple pat answer at this point in time. I think there are changes that are needed, but only after a thorough examination of the blood banking system and its problems. MS. DUTTON: In response to that, I just wanted to say that this is why I feel so strongly about accountability. As problems develop, and as the people in our scientific community determine how much they want to spend in screening blood, and what procedures they want to use, they may or may not be right. But, when they have to be accountable, they are going to be a lot more careful. 54 DR. ASHER: Absolutely. The mechanism exists to do what you want. We do have an excellent FDA. The people are technically very competent. The Advisory Committee are technically very competent. They just have put philosophic restraints on themselves. The same thing happened in 1975-76, relative to hepatitis B, and it was corrected or had attempted to correct it by the General Accounting Office, that truly competent body in the federal government, by the way, obviously, a wing of the Legislative Branch, not part of the Executive Branch, who prepared an extensive report on the subject of hepatitis B and what can be done to reduce it. They came up with a series of recommendations that in retrospect look marvelous. They are true heroes, but it was refuted by the powers that be at the time in the FDA, in the Blood Bank Division, and I might add, the Chief of that Division at that time is now the number two man in the American National Red Cross, and has that same basic philosophy. And, they countermanded, they overrode the recommendations of the General Accounting Office. I would like to see the General Accounting Office get back into the act today, and this time not be sort of overridden, but have somebody listen to what their answer is. DR. SERVAAS: Doctor Primm mentioned papilloma virus, and I have a question for Dr. Engleman to clarify that. Does the human papilloma virus that’s believed to cause cervical cancer, is that transmitted in a blood transfusion? Dr. Engleman: I must confess, I’m not an expert on that particular subject. Virtually, all herpes viruses, which that is not, are transmissible through blood transfusion. This includes the entire family of herpes viruses, including Epstein Barr virus, and so forth, the virus which causes chicken pox, they are all herpes viruses. DR. SERVAAS: Yes, right. Dr. Engleman: Those are transmissible through blood transfusion. I’m not certain about the papilloma virus. DR. SERVAAS: The papilloma virus is an important virus for cervical cancer now. Dr. Engleman: To be sure. 55 DR. SERVAAS: The hema-papilloma virus, but I didn’t know that it was transmitted in the blood. And, Doctor Primm, do you know? DR. PRIMM: I’m not sure. I should. You all just strike that from the record. DR. SERVAAS: Not a herpes virus. It’s not a herpes virus, Doctor Primn. Dr. Engleman: I don’t believe it is, but I’m not certain. DR. SERVAAS: Thank you for clarifying. Mr. Chairman? CHAIRMAN WATKINS: Well, I’d just like to say, if it makes you feel any better, we’ve made 187 recommendations in only three areas. Every other area we look at is, frankly, wormy. The nation is not ready for this virus, has not been ready for it. It’s not ready for the next one, and the panel this morning, I think, has thrown into the melting pot the things we have to do, another tough set of issues. If you look back on what we have not done in our malaise and lethargy, if you will, in slower moving times, the retro virus will be one day looked back on as probably the major catalyst for change in the nation across the board in a range of areas other than health care. If we don’t respond to it, I don’t see the longevity of this nation as a leader in the Western World, because I think it’s that fundamental. We’ve looked at health care delivery, we've looked at drug abuse, we’ve looked at drug development, and every place we look this system cannot handle it. The institutional process is almost bankrupt, just dealing with infant AIDS alone in New York, we were there last week, they don’t know how they are going to handle it in the public hospitals. The system doesn’t even respect the public hospital role, and yet, that’s where the patients are being dumped, if you will. I don’t like to use that term, because I’m not demeaning the patient, I’m talking about the system. And so, we’re just in another area here of the same kind of malaise, and the system works along in slower moving times, and somehow we survive from year to year, Now, we’re startled by the spectral fatality that this brings to bear. So, I would just like to say that when we double those recommendations as we go in a month from now, I hope that we can put what you’ve said today into some sort of a balance, because there isn’t’ any one finger that can be pointed at anyone. We all 56 “ave to share the burden of this epidemic, and one of the ‘aading obstacles to getting around that, I am afraid is still in “ho eyes of the beholder discrimination. We cannot do all the 2>’ngs the doctors say we ought to do, whether it’s testing for Gais, or testing for that. The kinds of things we need to do, at vhe right time, both in the interest of the individual and the muplic health, seem to be forded by a number of these things “hat get into the psycho-social aspect of this epidemic. So, you’ve given us -- this is the first time we've really focused on, you might say, the other side of the blood bank debate. I/’11 have to say, in all the witnesses, and they a£e@ approaching now over 500, who have come before this Coraission that it has not been raised as a major issue. It goesn’t mean that we aren’t concerned about the blood supply, but w~ceple in your own profession, medical profession, have not come out and said, this is a major issue here and an obstacle. They admit it has been in the past, but the blood supply is generally cleaned up to the extent it needs to be to match other things. This is -- I’m just telling you that’s what comes from others, so this is a different point of view this morning from “he panel, and very important for us to hear, to put these yarlous things into balance for our final report. I think it’s been an excellent panel, and I commend Jr. SerVass for bringing us to Indiana, first, and, second, to ensure that we heard your side of the story this morning, so that we can try to put it in the proper perspective as we go into our “nal report. DR. SERVAAS: I just wanted one final word to Dr. Asher, and thank him especially for coming, and this afternoon you won’t be here to hear this, but we understand that the for- srofics were the ones who started the testing in the heat factor treatment for the hemophiliacs, and that the non-profits had to follow suit after the for-profits did this, and so, I think we who are interested in free enterprise certainly would commend you fer having done this. We’ll be talking about that this afternoon. Thank you all for coming from California. Dr. Engleman: Thank you. Intraoperative Autologous Transfusion CHAIRMAN WATKINS: We’d like to proceed now with our second panel on Intraoperative Autologous Transfusion. I’d like io turn the panel over to Doctor Theresa Crenshaw, who will be the panel Chair for the remainder of the day. Dr. Charles Huggins, Director of Transfusion Services, vVassachusetts General Hospital, Doctor Robert Valeri, Director, 57 Naval Blood Research Lab, Boston, Massachusetts, Ms. Dorothy Polikoff, and Doctor Gerald Giordano, Director, Southern Arizona Regional Red Cross Program in Tucson. DR. CRENSHAW: The next panel that we are going to hear from is the panel on Intraoperative Autologous Transfusion. Most people are familiar with autologous transfusion as it refers to donating your own blood in advance, but they are not so familiar with the procedure we’re going to discuss on this panel, which is the possibility of getting your own blood back during surgery that you lose during surgery. This technique eliminates the risk of HIV infection, other infections, new infections we don’t know about, and other possible complications of homologous blood transfusions. In addition to the witnesses testifying before us today, written testimony has been submitted for the record by Doctor Lester Savage, who recommends the application of this technique for all surgeries to which it applies, and Ms. Caricobe, who is the daughter of a man dying of AIDS, transfusion-related AIDS, that could have been avoided had this procedure been used. I want to welcome you and thank you, and I’m very much looking forward to your comments. Dr. Huggins? DR. HUGGINS: Thank you. It’s a great pleasure to be here. Blood transfusions can be lifesaving, but their complications can be fatal. Reactions have been known to occur for many years, and infectious disease has represented a continuing problem. Donor screening and application of pre- transfusion laboratory testing can reduce the incidence of infectious complications, but they cannot eliminate them. The risk of blood transfusions has been widely varied from one in 5,000 for HIV, to one in 500,000. Actually, this is really irrelevant, because everybody would agree that the risk is not zero, and that it is critical to assume that every transfusion that one gives may possibly cause what could be a fatal infection. At Massachusetts General Hospital, blood usage increased every year until 1982, at which time we started to declare a war on transfusion. Blood transfusion had become very largely a routine, and we have attempted to de-routinize the transfusion of blood by eliminating transfusion by transfusion protocols, by modifying surgical techniques to accomplish the same objective but losing less blood, by instituting informed consent requirements, which gets the concerns of the patient out on the table with the doctor so that they can talk with the doctor about alternatives to transfusion. And, each day we review a sheet showing the patients that were transfused the previous day, and we go through the 58 previous day’s operating room schedule. This has proved to be a very effective technique to look at blood use by different operations. And ,if four surgeons are doing the same operation, and three never use blood and one always uses two units, we have a discussion, and that generally has been quite effective in getting thoughtful blood usage. We have a very active pre- deposit autologous program, and now just under 10 percent of the blood at Massachusetts General Hospital has been donated in advance by the patient. P We have an active program, mainily with orthopedics, to ado hemodilution and hypotensive anesthesia, in which we take off two units of blood after induction of anesthesia, replacing the volume with a lactated ringer solution, inducing hypotension to lower the patient’s blood pressure and reduce the amount of bleeding. If you do that and reduce the blood cell content by 15 percent, you lose the same amount of blood as you might had you not done hemodilution, you cut blood loss 15 percent. At the end of the operative procedure, the patient gets the two units of blood that were taken off. They get the fresh platelets and clotting factors. \ Intraoperative autologous, autotransfusion is something that has intrigued surgeons for many years. In general, the experience has been that surgeons or anesthesiologists expend a tremendous amount of work doing this, and then they would ask themselves whether they were thanked for it or whether they got paid for it. And, generally, the answer was no, and they tended to lose interest. It was only about 15 years ago when the commercial sector recognized the potential for devices that could be used to aspirate blood from the operative field, anti-coagulate it, store it in a reservoir, and then return it, filtered, either washed or unwashed. It is ideally suited for vascular, cardiac and big orthopedic operations, contraindicated in patients with bacterial infection or where there may be open bowel or open trachea, for fear of disseminating bacteria widely into the recipient. Similarly, contraindicated in patients with malignancy, for fear of aspirating malignant cells out of the operative field, and reinfusing them and possibly causing metastatic disease, spread hemotogenously by the returned blood. All of these options put together, including post- operative salvage, have permitted an absolute blood reduction of almost 25 percent between fiscal ’82 and fiscal ’87. It is probably substantially higher, because the numbers that are in the little paper that I prepared include autologous as a pre- deposit, as well as conventional blood. 59 Similarly, we have been able to effect substantial reductions in usage of fresh frozen plasma, and I’m in the curious position of being director of one of the largest hospital blood transfusion services in the United States, that is going around telling people, for goodness sakes, don’t use our product. Let us see if we can figure out some way so that you don’t have to use this blood. I have a few slides showing intraoperative autotransfusion in the operating room, and it might be appropriate, to see these now. This is a picture in one of the major vascular operating rooms at Massachusetts General Hospital. Lost under the drapes is the patient, with the patient’s head up in about the middle of the screen where the two anesthesiology ladies are, and the feet down at the right-hand side. Off to the lower left is one of the two machines that we have for large volume intraoperative autotransfusion. This is called the Baylor Rapid Autotransfuser. We have two of these devices, and we have a Haemonetics Cell Saver Four. Coming off of the operative field under the elbow of the surgeon, whose back faces us on the left, is a suction line, where blood is being aspirated from the field. That blood is anticoagulated by a slow-drip heparin solution, and it goes into the large reservoir that has approximately 1000 ml of anticoagulated blood. Periodically, blood is pumped out of the bottom of the reservoir via a pump, that is at the IV nurse’s left hand, into a washing bowl where the cells are concentrated and washed, and down at the very bottom of the machine is the supernatant from the washing solution. Next Slide, please. That’s the picture of the blood in the cardiotomy reservoir, something over 1,000 ml of blood and anticoagulant. Next, please. Here the blood is mixed manually as a low-tech operation, and then will be pumped via the pump into the bowl. Next, please. These are the tubes of blood on the left, saline in the middle and the one on the right is blood that has been washed for reinfusion. The pump in the top of the washing bowl. Next, please. These machines can either be operated in an automatic or a semi-automatic mode, giving whatever degree of control one would like. In thoraco abdominal aneurysms, where the blood fills the scuppers as we run this equipment in a full automatic mode. Next, please. This is the effluent from the wash solution going into its waste bag. 60 Next, please. And, there is the blood actually being reinfused from up above into the patient. It’s put through a blood warmer to warm it. The most we have recovered is over 55 units. We did 39 units with a patient the other day. These were in ruptured aneurysms. It is a very desirable technique, and it does conserve the use of human blood. ! I believe that’s the last slide. Oh, the one last Slide. As you can see, the machine fits off in the corner. It’s not in the surgeon’s way. As long as the suction is adequate and the return is rapid, we’ve had excellent response from our surgical colleagues and anesthesia colleagues. “We do 20 to 25 cases a month, and, undoubtedly, that will be getting higher. So, this is one of several modal ities to try to minimize the transfusion of human blood and get it out of a routine which it had fallen into over the courge of many years. CHAIRMAN WATKINS: Dr. Huggins, what’s the efficiency of the whole process? For 1,000 out, what goes back to the patient of the original blood that was -- DR. HUGGINS: Admiral Watkins, we get probably about 85 percent efficiency. This depends a little bit, if blood is flowing extremely rapidly, and we’re having to pump at the highest speeds to return a unit in two and a half or three minutes, there we are going to lose some blood. If blood flow is somewhat slower, where we can reduce the rate of the filling speed, and the washing, recovery is higher. CHAIRMAN WATKINS: So then, the augmentation of -- you still have an augmented blood supply, other than the -- DR. HUGGINS: Some of the -- many aortic aneurysm patients that in other years would traditionally take four, or five or six units of bank blood, we can do with no blood. And, these people tend to be older. The fact they have the aneurysm, means that they also are likely to have heart problems, and brain problems. These patients in general, are not good candidates for the pre-deposit autologous program, because of the likelihood of getting a coronary, or a stroke, or actually dying in the donor chair. DR. CRENSHAW: Are you finished with your remarks? DR. HUGGINS: Yes, ma’am. DR. CRENSHAW: All right. Dr. Valeri, please? 61 fe. Wy rae Me - 7 fi DR. VALERI: Dr. Crenshaw, Members of the Commission, thank’ you for the opportunity to appear before you today to discuss intraoperative autologous transfusions. a Autologous blood is fast becoming the transfusion product of choice, because of the serious risks associated with homologous transfusions, ‘of which AIDS is by far the most frightening. There are several ways to provide autologous blood products for patients undergoing surgical procedures. Autologous blood products can be collected weeks, months, or even years before an anticipated surgical procedure and stored in either the liquid state at 4°c or in the frozen state. Red cells can be stored in the liquid state for six weeks, and red cells can be frozen and stored in the frozen state at -80°C for at least ten years. Autologous blood products also can be collected intraoperatively and post-operatively. My presentation today will focus primarily on intraoperatively collected blood products for autotransfusion. Autologous blood can be obtained in the operating room just prior to open heart surgery procedures using the extracorporeal bypass circuit and reinfused following surgery. The extracorporeal bypass circuit, which consists of mechanical pumps to circulate the blood and an artificial lung to oxygenate the blood, produces damage to the red cells which carry oxygen to tissues, as well as damage to the platelets and the plasma clotting proteins which are involved in clotting. This damage may be avoided by collecting the blood product from the patient immediately prior to the extracorporeal bypass. The blood can be reinfused following surgery to restore the red cell volume and prevent bleeding which may occur post-operatively, without the need for homologous blood. One method is to collect one to two units of whole blood into an anticoagulant solution before surgery and store it at room temperature during the surgical procedure. Alternatively, a half to 1 liter volume of platelet-rich plasma can be collected from the patient before being exposed to the extracorporeal bypass circuit, stored at room temperature during the surgical procedure, and reinfused at the completion of cardiopulmonary bypass. Crystalloid solutions and colloid solutions are used to maintain the patient’s blood volume following removal of the whole blood or the platelet-rich plasma. Autologous shed blood collected during surgical procedures must be anticoagulated to prevent clotting. The shed blood can be aspirated into a reservoir or container using negative pressure. When patients are anticoagulated with heparin 62 during extracorporeal bypass surgery and during vascular surgical procedures, their shed blood properly collected can he reinfused through blood filters with or without washing. When the patient is not anticoagulated, the shed blood should be washed to remove the activated platelets and plasma proteins so that only the red cells will be recovered and reinfused. One of the most important aspects of intraoperatively collected autologous blood is its freshness. It is well known that bieod products deteriorate during liquid storage. Autologous whole blood and platelet-rich plasma obtained immediately before surgery exhibit excellent quality. hutelegous shed red cells, whether washed or not, are similar in quality to red cells stored in the liquid state at 4° for less than one week. The FDA standards limit the storage of red cells in the liquid state at 4° for 42 days; platelets in the liquid state at reom temperature for five days; and plasma in the frozen state at -20° for one year. Blood banks customarily dispense the oldest blood products first in order to prevent outdating. Ligquid- preserved red cells and platelets, and plasma stored for the maximum storage period exhibit only marginal quality at the time of transfusion. The quality of autologous blood products collected during intraoperative surgery is far superior to that of homologous liquid-preserved blood products. More importantly, autologous blood products do not transmit infectious disease or cause immunologic complications such as these associated with homologous blood. Surgeons and anesthesiologists, by maximizing the use ef intraoperative autologous transfusion, can ensure that patients will be receiving the safest and the highest quality blood products available. RECOMMENDATIONS : 1. Educate the medical profession, specifically the anesthesiologists and surgeons, as well as the public, that intraoperative autologous blood products for surgical procedures Such as cardiopulmonary bypass, vascular Surgery, and orthopedic surgery, are now available to reduce or even eliminate the need for homologous blood products. 2. FDA and the blood banking community endorsement of the intraoperative transfusion of autologous blood products. 3. Development of a standard for reimbursement of the costs related to the collection and reinfusion of intraoperative autologous blood products. 63 . 4. Development of programs to train personnel in the collection, processing, and reinfusion of intraoperative autologous blood products. 5. Research support for the development of simple methods to collect, anticoagulate, and filter washed and unwashed shed blood. 6. Develop standards for the quality of shed blood collected and reinfused during surgery. Thank you for your attention. DR. CRENSHAW: Thank you very much. Dorothy Polikoff. MS. POLIKOFF: Thank you. My name is Dorothy Polikoff. My husband, William Polikoff, was a World War II veteran. He survived the Bataan death march and was a POW for three and a half years, but he did not survive AIDS. He died December 9, 1987. His death was unnecessary, and I will explain to you how his death from AIDS and my infection with the AIDS virus could have been avoided. I am 63 years old and was infected with the AIDS virus from my husband who died several months ago from the complications of transfusion related AIDS. He was transfused in 1984 during cardiac bypass surgery while under the care of the veterans Administration Hospital in San Diego. His surgery was performed under their auspices at the University Hospital in San Diego where he received three units of blood. University Hospital had available at that time, the equipment to perform intraoperative transfusion, \but it was not used for my husband. If this technique had been applied, he would not have needed to be receive someone else’s blood and neither of us would have become infected. Unfortunately, none of our doctors ever mentioned that there were alternatives to homologous transfusion. The possibility of AIDS infection was never discussed. My husband never fully recovered from that surgery and at that time neither of us understood why. He was hospitalized on various occasions since. In June of 1986, I became seriously ill] and was diagnosed as having hepatitis B. Bill was tested two days later and was told he was a carrier. I spent the rest of that year fighting for my survival, still unaware that both of us were infected with the AIDS virus. A few months after my release from the hospital, after reading articles of AIDS being transmitted by blood transfusions, both Bill and I asked our doctors if we could be tested for AIDS. They told us there was no need to worry or that it was not necessary, but neither of us were completely reassured. One day, we passed by a health fair that was distributing condoms and information about AIDS at the VA 64 Hospital. They advised us to go to the County Health Department to be tested for the AIDS antibodies which we did on March 12, 1987. In the meantime, Bill had developed a tender lump under his arm and went to the VA emergency room where he was treated with antibiotics. Since the lump did not disappear, he was scheduled for a biopsy on April 2nd, which coincidentally was the Same day we were scheduled to return to the Health Department to learn about our AIDS antibody test results. On that day Bill was admitted for his biopsy, we learned from the Health Department that we both tested positive to the virus. We brought the slips to our doctor and told him the results. We were both upset. I was almost hysterical. I couldn’t believe what I was hearing, and Bill was furious. Not only had the doctors at the VA Hospital refused to test us for the AIDS infection when we requested it, but then made the diagnosis even more upsetting by implying that I had been unfaithful rather than acknowledging that the transfusion was responsible for both of us having hepatitis B and AIDS. THe doctors later apologized for these remarks. Bill got sicker and sicker. His disease progressed rapidly and during the last months of his life, there was extensive central nervous system involvement resulting in AIDS dementia -- a very difficult death. I have symptoms now and the disease frightens me, but what frightens me even more is how I will manage when I get sick and need medical treatment. I will not receive care for AIDS from the Veterans Administration unless I pay for it even though I have this disease as a result of the treatment my husband received through the VA. He became infected through transfusion, but my infection could have been prevented if any of the many doctors we saw had cautioned us not to have sex. As we became aware of the possibility of AIDS through the media, we stopped having sex, but by then it was too late. As it was, we had sex infrequently, perhaps five times after his transfusion. It would not have been a great deal to give it up had we only known. Although nothing can be done to bring my husband back to life or to restore my health, I hope our experience don’t go to waste and can be used to prevent situations like this from ever having to happen again. That is why I am here telling you our story. There are things to learn from our experience. The whole unnecessary tragedy could have been avoided if intraoperative transfusion had been used instead of homologous blood. I feel that we should have been tested as early as possible after the transfusion was given and advised not to have sex until the results were known. This would not have saved Bill’s life but could have saved mine. Instead, no one would deal with the issue, and we had to make diagnosis by ourselves. 65 Because the Veterans Administration will not take financial responsibility for my medical care, my resources will eventually be exhausted as this diseases runs its course. Without help, I will die indigent and without proper medical care under circumstances that seem to me worse even than the disease itself. My fear of this robs my peace of mind and drains my strength. I try to be strong and face this disease with courage and determination, but I am haunted by remembering how my husband died and live in dread of the same fate for myself. I hope you will take steps to prevent this from happening to anyone else. The Honorable Senator Pete Wilson has opened a Congressional Investigation into my situation and with his help and support, I am hoping that the Veterans Administration will decide to provide me with the medical care during my illness. I have several urgently needed specific recommendations: 1. Please educate doctors and the public about intraoperative transfusion so that no one receives someone else’s blood unnecessarily. 2. Make it a crime for those who knowingly sell their contaminated blood to blood banks. 3. Require that physicians or counselors advise their patients not to have sex if there is a chance that they have become infected with the AIDS virus. 4. Provide training for health care professionals to deal with AIDS patients in a sincere and compassionate manner. 5. Advise physicians to make testing easily available to anyone who requests it, without putting obstacles in the way or forcing them to justify their concern. 6. Provide a place to live in dignity and with friendship for those who cannot live alone -- seniors, like myself. 7. Provide health care in both the Veterans ADministration and private hospitals for those who are infected. 8. Hospice facilities must also be made available. I would like to thank you for the opportunity to be here today and tell my story. I’d he remiss if I did not mention Doctor Theresa Crenshaw, and highly commend her in her earnest endeavor and determination towards the prevention of spreading this devastating disease. I hope it helps you to set policy and make recommendations that will prevent others from going through this devastating experience. Thank you. 66 DR. CRENSHAW: Thank you so much, Dorothy. DR. CRENSHAW: Dr. Giordano? DR. GIORDANO: I don’t know what I can say after that. I think she just gave the most important argument to implement the program of intraoperative autotransfusion and autologous blood that I’ve ever heard, and I would really invite her to come to Tucson and speak to my nurses sometimes who come out of the OR after spending 24 hours and are exhausted, to really get an idea of how important their work is. Well, let me go on. Autologous blood is clearly the best option, and besides the risk of the HIV epidemic. © There is no risk of transfusion reaction. © There is no risk of isosensitization. © There is preservation of the autologous supply. I’m going to limit some of my remarks, because Dr. Huggins and Doctor Valeri have covered a lot of the things that I think are important also. However, despite all of the above, infectious disease prevention remains the cornerstone and the overriding reason presently for the increasing use of autologous blood. In addition to the incontrovertible fact that it is the best transfusion option and that the reduction of human suffering and loss associated with the infectious diseases is Significant, I honestly believe the reduced cost of dealing with the consequences of disease transmission is significant. Although the risks of transmitting HIV infection with blood, and of contracting NonA NonB is really quite small and decreasing, the cost is overwhelming to the society. I don’t want to avoid an issue that I think is very important, that is, pre-deposit autologous blood, which you will have a later session, and isovolemic hemodilution, which Dr. Huggins touched on, represent excellent and relatively inexpensive ways to achieve the increased use of autologous blood in the general population. And, these programs should be the backbone of an active autologous transfusion service. Doctor Valeri is the world’s expert on frozen autologous blood storage, and this is presently available, but the major issue facing the nation here is its utility as it relates to its cost and its availability. For the group of people who cannot participate in pre- deposit programs, for people who have religious convictions against the use of a pre-deposit program, and for those individuals who will need more blood than be collected for 67 ¥ | themselves, the use of Intraoperative Autotransfusion (IAT) represents an excellent option. I won’t go through the mechanics, because Dr. Huggins has nicely shown it. Okay. Most investigators agree that the procedure truly decreases homologous blood transfusion. The procedures where there is a significant probability of utilizing this much blood are well defined at the moment. _ They are in the arena of cardiovascular, orthopedic, vascular and trauma surgery and occasionally in neurosurgery and obstetrics. The question of whether the use of IAT will be employed in low blood loss procedures is something which has to be addressed within the next several years. I come to you today, I guess, in three capacities. One, I’m the Director of the Volunteer Blood Services of Southern Arizona, the Director of the Red Cross. I come to you, too, as a practicing physician, who spends most of his practicing medicine and, quite frankly, taking care of AIDS patients, the last one of which last night before I took the plane here, and I come from a family who has received homologous blood so I have a great deal of interest. , I’m also new to the blood bank industry, if you will, having only taken the position as Director of our Blood Bank in 1985. At that time, it became very evident to me that a real” need for autologous blood was in the community. I had a different problem, though, and I think many blood banks face a different problem than has been noted here. I have an area of greater than 20,000 square miles which I have to supply with a pre-deposit program and an Intraoperative Autotransfusion program, and I think we’ve succeeded in doing that, and I would like to tell you how we‘ve done it; Doctor Crenshaw has asked me. I have given a manual which we have circulated to every physician in our area on our to access to program. Presently, the national average for pre-deposit prograns is 1.5 percent. In Southern Arizona, we are running 7 percent pre-deposit autologous blood, and, that is, 7 percent of the blood in our region is distributed to our hospitals as pre-deposit. We have mobile units that go around to our outlying communities once a week and collect autologous blood. They are brought into Tucson, they are processed, and they are shipped to anyplace in the nation where the patient will need that blood. Secondly, I have an active Intraoperative Autotransfusion program. We have seven nurses, nine machines. Our machines run 24 hours a day, seven days a week. Last month, we performed 189 procedures in Tucson. 68 You should be aware that this is a very demanding procedure for personnel. 50 percent of our procedures are performed after hours, that is, hours when most of us are tucked in bed, home and asleep. They are emergency procedures, they occur in the form of cardiovascular, vascular surgery and trauma. 54 percent of our procedures have less than 24-hour notice, and 24 percent of our procedures are STAT, which means that the center must respond on an immediate basis to a request for the procedure. Despite all of these demands, it truly can be done. It can be done very cost effectively. In our experience now, a little over 1,700 or 1,800 cases, we have only failed to respond six times, so we carry a fairly good track record, and we’ve been able to provide this service for our community. We’ve started to collect the autologous plasma and platelet that Doctor Valeri suggested or mentioned several minutes ago, because we felt that our use of plasma and platelets in our community was too high. As a result of our program, I’d like to give you some of our results, and I’ve given them to Doctor Crenshaw. The use of red cells in cardiac surgery in our region has gone from eight into two units. Plasma has gone from seven to two units, and platelets have gone from eight to two units. That’s been a significant reduction in blood usage. I say that the program has "paid for itself," in simply blood processing fees to the blood center, and when I consider the prevention of human suffering and cost of infectious diseases, I think it’s been even higher. Thank you. DR. CRENSHAW: Thank you very much, Doctor Giordano. I thank all of you. I’d like to begin the questioning to my left with -- we’ll go back to Doctor Lilly, please, be my guest, Doctor Gebbie. MS. GEBBIE: A couple of different questions. First, just to clarify the potential impact of some of the approaches you’ve been using. It sounds like you are moving, Doctor Giordano, toward the 10 percent figure that Dr. Huggins presented as in place in his institution. Is that a maximum, or what is the potential of that pre~donated approach, were it fully and aggressively implemented everywhere? DR. HUGGINS: I think it probably could'go to 20 or 25 percent. We have a little brochure that we leave in doctors’ waiting rooms telling patients about the pre-deposit autologous program, that doctors, in general, in the past tended not to want 69 to frighten the patient, and tended not to raise this issue. But, with the little brochure in the waiting room, if the patient says, "Doctor, can I bank my own blood?" Marvelous idea. So, I think that will be going up. We're expanding, the youngest we've taken blood from is 13. Maybe we can go down even lower than that. DR. GIORANDO: I would agree, and I would also echo what Dr. Huggins says. Our youngest patient has been in that age group, perhaps, even younger. Our oldest patient has been 93. And, one thing we found is that the elderly patient makes an excellent pre-deposit donation patient, and they have a very low incident of reactions. So, we find them an excellent donor. MS. GEBBIE: Then also, what is the potential impact on the intraoperative procedure? Again, if that were fully and aggressively. implemented, what percentage reduction in homologous transfusions would that have? DR. GIORANDO: I could say that in our region we’ve had an 80 percent reduction of blood and blood components in cardiac surgery. In vascular surgery, I believe the Rochester, Minnesota group has reported about a 50 to 60 percent reduction. In orthopedic surgery, it’s a little more difficult to judge, because the collection rates from the orthopedic procedures aren’t quite as high as they are from the vascular and the cardiovascular surgery. DR. HUGGINS: I think it’s going to increase. Trauma is primarily at night. We, unfortunately, are not organized to do that. At Massachusetts General Hospital, at this moment, I’m ashamed to say, we are set up for intraoperative salvage between 7:00 to 3:30. Our OR gets started late on Thursday because of rounds, and they like to put big orthopedic cases on Thursday. I go to the operating room and do it myself Thursday afternoon. The doctors say, "Why are you here?" I say, "I don’t get paid overtime, but it’s important that this be done," and we are going to be working on improving our staffing. MS. GEBBIE: One of our responsibilities is to propose legal changes that would make a difference. As I’ve been listening very closely to what you’ve said, a large part of what you are talking about doesn’t sound to me like policy issue, but more one of changing medical practice, 70 which I’m not sure any policy recommendation in the world ever cnanged. It seems to be an educational process kind of thing. But, I would appreciate some comment on that. The one policy thing I clearly heard several of you state is the reimbursement issue, that there is time and effort involved here that is not clearly reimbursable under present schemes, and we might be able to comment on that. Did I miss some other public policy issues that this Commission should put in its report that would really make a difference in moving this process farther along? DR. HUGGINS: My administrators haven’t come to me and sald, “Gee, we’re losing our shirt because you are not getting reimbursed for what you do." MS. GEBBIE: So, that really isn’t a big issue. DR. HUGGINS: Well, Massachusetts is a very peculiar State. We, until recently, have had a very complicated formula that gives the hospital the maximum amount of revenue that can be earned. You are guaranteed your revenue. Success or failure is related to management of cost, and that if we can save three or more units of blood, that, in fact, is saving on the cost side, which is where it is effective. I think the things that the Commission could recommend very strongly would be increased investigation on the use of biood substitutes. These are very close, I believe a human hemoglobin preparation is under IND investigation of a new drug, I understand that there are bovine preparations, these could go a very long way to reducing homologous blood usage. MS. GEBBIE: Are there barriers to that research, or is it. just that there aren’t enough researchers who have gotten excited about it? DR. HUGGINS; I think it’s probably a certain amount of money, but I don’t think -- these are big dollars, in terms of an overall effort. And, once something gets licensed, then that money -- that doesn’t need to be spent. Other areas where I think research can help us are with efforts to stimulate red cell production by means of erythropoietin. This is now prepared by recombinant techniques. The lack of erythropoietin is what gives people the anemia of kidney failure. Kidney patients can now be relieved of transfusion requirement by erythropoietin. There are studies on AIDS patients with AZT, post- operative regeneration, if that went more rapidly, then the doctors might not panic and give blood. 71 MS. GEBBIE: I know I sound a little repetitive. I want to be really clear whether these very good and very interesting projects are not going forward because there is no money there, because the funding agencies are biased in some way against these projects, or just that there aren’t enough doctors who have gotten the point here and are out aggressively pursuing this. DR. HUGGINS: I think it’s the latter. A lot of this equipment you can buy, you have to worry about who pays for the capital. We have staffirg problems. The other problem with intraoperative salvage is the unpredictability of how much blood a particular patient is going to lose. You can line up 100 patients with abdominal aortic aneurysms. Blood loss will vary from none to ten units. But, being able to predict, which person is going to be the ten, and which is going to be the one or two is impossible. So, I think the strategy there is to try to set up for the small, but yet, be able to shift gears if it looks as though this is going to be one of the bigs, to reduce your up-front costs to a level at which it is one or two units, you are not killing yourself, but yet, be able to handle it. And, these are areas where many people are investigating. DR. CRENSHAW: Dr. Huggins, apropos Doctor Gebbie’s question, you have a suggestion in your written recommendations that informed consent prior to surgery would help educate doctors. Would you elaborate on that a little bit, because that’s something we could encourage. DR. HUGGINS: Informed consent was introduced at Massachusetts General Hospital in January of 1987. Our counsel advised that this really doesn’t do you much good, in the event of a lawsuit, and we recognize that. However, this has turned out to be a very good opportunity to get the issue of transfusion out on the table between the doctor and the patient, so that the patient can express his or her fears, or concerns, and say, "Gee, Doc, isn’t there anything we can do?" We have a little brochure that goes to all patients before admission. It tells them that our blood is all from volunteer donors, collected by us and the Red Cross. It tells them about autologous, it tells them about what they can do if they live a long distance to have autologous collected. We do designated donors, we tell them about that program, and actively involve the patient in this. This has been, in fact, a very productive thing. I really think everybody should have that opportunity to discuss, and informed consent is an excellent mechanism for that. 72 MS. GEBBIE: Did you have any other comments on the policy issue, Doctor Giordano? DR. GIORANDO: No, except that I have a feeling that cost may be more of a factor than we are accounting for right now. And, perhaps, not as much in the intraoperative autotransfusion arena with reimbursement, but in the pre-deposit autologous blood programs, where the fact that, indeed, it does cost an increased amount of money to collect the blood. But, that’s an issue that you are going to deal with another day, and I would leave it for that panel. As far as intraoperative autotransfusion is concerned, I think that most insurance carriers, indeed, do cover that as a procedure. MS. GEBBIE: Thank you. I might have another question to ask later. DR. CRENSHAW: Mr. DeVos? MR. DeVOS: Maybe I missed it. Can you tell me what one of those machines costs? DR. GIORANDO: They range from a low of about $20,000.00, to a high of about $38,000.00 to $40,000.00. MR. DeVOS: Can you also -- DR. GIORANDO: I think it is more important for you to ask me how much does it cost to run one. MR. DeVOS: Well, that’s intended cost. DR. GIORANDO: Exactly. MR. DeVOS: That was my next question, but go ahead. DR. GIORANDO: A procedure could cost about $300.00 to $350.00 if it is done reasonably, efficiently and effectively, and I think that if a blood center, and this is from my perspective, passes on a cost of $350.00 to a hospital per procedure, then the hospital will be getting a reasonable product at a reasonable price. MR. DeVOS: How many machines have been sold? DR. GIORANDO: I don’t know how many machines have been sold around the nation. We have nine, eight or nine, in our region. 73 MR. DevOS: Okay. What would an average hospital require, how many machines? DR. GIORANDO: That’s a good question, and if I may carry that a little further, I think that’s a perfect case for a blood center supplying this, if, indeed, we can. The reason is that some of our hospitals would need as many as four to five machines, and I think the utility or the advantage of the blood center doing this is that we can mobilize four to five machines for one hospital at one time, with four to five operators, and then we can move them out to another hospital that would need more machines. So, one hospital is not left spending a huge amount of money for this capital equipment to keep this amount of disposable software available, and to keep the personnel trained. I think if you look at the most difficult part of maintaining these programs, it’s the personnel. The personnel have to be, (A) very, very dedicated to this program to spend that kind of hours; and, (B) they have to be very skilled in the operation of these machines. Again, when you have a cadre of nurses who are accustomed to apheresis products, for example, Tom Asher this morning was discussing the single-donor platelet program that he has. Well, our nurses do the single-donor platelets for Southern Arizona, and the same apheresis nurses will do intraoperative autotransfusion, so we use those nurses with this knowledge of this apheresis technology. So, we have skilled operators at all times available. We keep at least two of the people en call at any one time, and we have a backup to bring in four if, indeed, needed, day or night. MR. DevOS: I salute the progress. It just strikes me the emotional problem of a doctor having to say to a patient that the blood supply may not be all right is a terrible one for him to have to acknowledge and get into. You know, he can give them 98, and then you can talk to Ms. Polikoff, and I salute you, Ms. Polikoff for your frankness and your courage in coming here. MS. POLIKOFF: Thank you. MR. DevoS: I had bypass surgery in ’83, you know, but for the grace of God I’d be where you are, and so, I thank you for coming here. But, the dollar thing I’m not sure is as big a hindrance as the emotional problem of having to acknowledge maybe there is some question here. 74 DR. GIORANDO: I have no problems. I think that it is absolutely worth it, obviously, or I wouldn’t be doing it. MR. DeVOS: Well, thank you. Theresa? DR. CRENSHAW: Penny Pullen? MS. PULLEN: First, I would like to express appreciation to you, Ms. Polikoff, because I know this was very painful for you, and that you are living with a lot of pain. MS. POLIKOFF: I have a little hearing problem, I can’t hear low speaking voices. MS. PULLEN: I’m just saying thank you to you. I think that your coming here and giving us your testimony in the manner that you have today has helped the Commission focus what our thinking needs to be. Perhaps, Dr. Huggins can answer this. How widely available is the intraoperative system? You have it at your hospital. Is it widely available throughout the United States in most surgeries? DR. HUGGINS: I don’t know. Obviously, the companies that make the equipment have sales figures. They don’t share those with me. I think there are about eight major teaching hospitals in Boston, I would say that probably most of them have at least one machine. For the community hospitals in the area of Eastern Massachusetts and Southern New Hampshire, Red Cross has a big machine, van, trained operator, and they can schedule a session a week from Thursday at 9:00 o’clock in the morning. And, that has provided a very valuable service. I think this is something that the small. units, particularly, where you may not have to wash for trauma patients, may be appropriate in some of the community hospitals, particularly, in rural areas that get the high-speed automobile accidents. So, I think, as with many other things, there probably are a number of ways to skin the cat, and that we’re still trying to explore what the most effective ways are. I would say that probably it is the exception rather than the rule for the 6,000 or so hospitals in the United States to have equipment for intraoperative salvage. MS. PULLEN: Even on a contracting out type of basis, like the Red Cross making it available? 75 DR. HUGGINS: Well, this is very new, and the Red Cross has only done this within a few months in the Northeast Region. And, the person in the Red Cross in our area that’s been involved in doing it was very active in this at Mayo Clinic before coming to the Northeast Region. MS. PULLEN: So, it’s not just a matter of reluctance, it’s a matter of the equipment is not available everywhere. DR. HUGGINS: That’s correct. Again, it is most cost effective if it is by the blood transfusion service, rather than surgery or anesthesia, but many blood bank doctors tend to be a little uncomfortable in an operating room environment, particularly, if the surgeon starts to scream at them. It doesn’t put them totally at their ease. It’s clear that this is a major function of blood banking. The days when the blood bank director just looked at compatibility testing and signed reports, I think, are over, that the blood bank directors and hospitals in the United States must take a much more aggressive involvement in decisions of transfusion therapy than they have in the past. MS. PULLEN: Is any of you aware of any circumstance or location where certificate of need legislation, applicability to equipment may have caused a limitation on this? DR. HUGGINS: I think that in Massachusetts a certificate of need is required for something that costs over $600,000.00, or much higher than any of these intraoperative machines. So, I don’t believe that under any circumstance that could have been a limiting factor. MS. PULLEN: Doctor Giordano, you wanted to jump in on that? DR. GIORANDO: I perceive this a little bit differently. I don’t perceive the machine availability as the major limiting factor. I feel competent personnel availability is the major limiting factor. And, indeed, you can walk the corridors of enumerable hospitals in the United States right now where cell salvage devices have cobwebs, and the reason they have cobwebs is because they don’t have the trained dedicated operators. And, again, not to say that making machines available isn’t important, but the experience of most people who are active in this program is, that unless you have the trained dedicated operators, the machines don’t work quite as well. MS. PULLEN: Do you know whether there is any effort going on to include this type of training, in medical education, and in nursing education, in continuing education? 76 DR. GIORANDO: I know that my center has been visited by four to six other centers, not only Red Cross centers, but AABB, American Association of Blood Banks, and CCBC centers, and we are training them, we have trained some of them. We are training United Blood Service, which is the blood supplier of Northern Arizona, their personnel, in how to operate these machines. I know the Red Cross has this as a major focus for this year, to supply dedicated operators. As Dr. Huggins has remarked, Popovsky is doing this very actively in the Northeast Region. We came into this in November of ’85. I think we were the first group that started it for the Red Cross. But, the blood suppliers of the nation clearly recognize the importance of this, and in cooperation with the blood bank directors, I think that you are going to see this technology just explode within the next several years. Again, providing the dedicated competent operators. MS. PULLEN: I have repeatedly been told that there are administrative barriers, difficulties and challenges involved in the policy of collecting pre-deposit autologous donations. And then, actually getting them to the operating theatre at the appropriate time, at the appropriate theatre, and my own mother had some experience with this, I’m afraid. I wonder whether you could comment on that. You seem to have solved these. Are they easily solvable? DR. GIORANDO: Well, I don’t know if I’ve solved then. We’re trying to solve them. Yes, there are more difficulties doing it, but it is doable. It is very clearly doable. Dr. Huggins does it within his hospital. We do it for the Southern Arizona Region, and as far as I can tell, we’ve been very successful in doing it. We tag the blood specifically, and we send it to the hospital, and we track it all the way through our system, and we’ve all developed mechanisms by which this can be done. It’s more difficult to collect a pre-deposit unit than a routine homologous unit, but, again, it can be done, and it can be done effectively. MS. PULLEN: And, you think it’s worth trying? DR. GIORANDO: I think it’s worth trying. I think it’s the most important thing we do. 77 DR. HUGGINS: Absolutely. MS. PULLEN: I wish you’d tell the Illinois blood bankers that. Thank you. DR. HUGGINS: Well, I think it is too, and often times the more you hear about how difficult it is, and how it is to track, and do what not, people are saying, I don’t want to do it, but I’m not quite certain how to justify it. It’s like brain surgery. Once you know how to do it, and figure out the systems, it’s easy. MS. PULLEN: Thank you. DR. CRENSHAW: Dr. Primm? DR. PRIMM: Yes. Dr. Huggins, I had one sort of technical question. I wondered about the incidence of increased post-operative bleeding after the procedure. Is there an increase in post-operative bleeding secondary to the anticoagulants, seepage, et cetera? DR. HUGGINS: I would say, generally, no. In most cases, we use 30,000 units of heparin and a liter of saline, but then that gets washed out before the patient gets those blood cells. We have not been involved extensively with intraoperative yet in our liver transplant cases. I know the Mayo Clinic uses trisodium citrate, which tells me that maybe in the liver transplant patient, if they get a little bit of heparin back in that, that they may have had some bleeding. We have used trisodium citrate, and that works perfectly adequately. DR. PRIMM: What about cell-fragility? Doctor Valeri, you were going to -- DR. VALERI: I wanted to comment about the heparin, because that’s an important issue. DR. PRIMM: Absolutely. DR. VALERI: If a high does of heparin is used and the washing efficiency is ineffective, significant levels of heparin will be infused into the patient and bleeding will occur. With regard to red cell hemolysis, red cells can be clotted, and they can be released from the clot with minimal hemolysis and have survival values of 90 percent. Intraoperatively collected shed blood will not be used effectively until surgeons and anesthesiologists are convinced of 78 the excellent quality of these red cells. All patients subjected LO surgery requiring blood transfusion should be made aware of tne risxs associated with homologous blood. The patient should be informed of the use of intraoperative autologous blood. Patients are asking -~ "Do i have an option’? They do have an option to receive their own blood which is safer and of a higher quality than homologous blood products which are routinely eiministered. I think you are going to see a much greater interest in the use of intraoperatively collected autologous b.00d! products. Quality standards for preserved blood were estab? ished in the late 1950s and early 1960s, a time when risks écsoeciaved with blood transfusion were not a major concern. The current quality standards for preserved blood products are only rininal standards. DR. PRIMM: My concern was if we don’t talk about exactly those minute kinds of problems, cell-fragility, if we con’t talk about the microaggregate-amorphous debris, and, you know, that’s a term that’s descriptive, that you’d have to have ouite a lit of medical science to know what these : ievoagozegate-anorphous debris really are. What are they? We : Going to have to kind of spell that out, I think, and talk esouc some of these problems along with all the good things that cen happen here. I think that’s really important to making this WORT DR. WALERI: Well, it’s very important that you realize if your blood clots, you are going to end up with clottable material, and the issue is the best way to get rid of Enese ni croaggregate~amorphous debris. I believe that the development of filters is a very important area of research. Filters should be developed to effectively remove not oily the microaggregates but also heparin, citrate, and fat from tre shacd blood. The Commission should cite as one of the most Lupostant research and development areas the development of filters which would significantly improve the use of intraoperative autotransfusions. There is concern that the iafusion of blood which is hemolyzed will trigger intravascular coagulation and renal injury. However, shed blood properly collected as nonwashed blood and washed red cells is a high quality blood product. CHAIRMAN WATKINS: Doctor Valeri, do you have that rocommendation contained in your official statement to the Commission? DR. VALERI: Yes. CHATRMAN WATKINS: We need, in specific detailed terms, rae kecommendation you just made, for us to take a look at it with our own medical review people. It’s a very specific 79 recommendation, and it seems to have a great deal of merit. I’m not a doctor, so I can’t tell, but we have enough on the Commission. You’ve given us something that has some meat to it, and I’d like to make sure we have the complete recommendation. DR. VALERI: Sure. I’d be very happy to provide it. CHAIRMAN WATKINS: Thank you. DR. PRIMM: And then, I’1l1 finish my question. I’d just like to salute you, Ms. Polikoff, for your testimony here this morning, and I enjoyed talking to you earlier over breakfast. So -- MS. POLIKOFF: And, a little kiss. DR. PRIMM: Well, it was wonderful. Thank you. MS. POLIKOFF: Thank you. DR. CRENSHAW: Dr. Lee? DR. LEE: I certainly am impressed with the technical advances in this field. Two questions. Do the rest of the blood bankers support this? Do you have everybody on your team, or is there a dissident group, are you in the minority? DR. HUGGINS: I think everybody basically now feels that any form of autologous blood is preferable to bank blood. I think degrees of enthusiasm may vary somewhat, but I think everybody --that’s generally recognized. It doesn’t take great intellect to know that your own is better than somebody else’s, in terms of reactions and infection. DR. VALERI: Again, what you are faced with is the reluctance of people to change. What I have learned is it is very difficult to change established procedures. But this is what must be done. CHAIRMAN WATKINS: The medical doctors from the American Medical Association have said publicly that change at their institutions, their school process moves at a glacier pace. Do you agree with that? DR. VALERI: I agree with it completely. CHAIRMAN WATKINS: Now, having heard their confessions in that regard, what’s being taught in the medical schools today about this particular procedure? How well is it addressed? Are we on the front-end of technology there? Do we look at this as 80 an option? Is this being addressed thoroughly? This was a great presentation we had today, and you all are competent witnesses coming before us. Who is picking up the banner and charging with this throughout the medical system, and I’m talking now, the fundamental education process again. DR. HUGGINS: This is a major problem in blood banking. The formal training at the Harvard Medical School in the second year consists of a one-hour lecture and a three-and-a- half hour laboratory session in the afternoon. Otherwise, people have contact with residents. That’s one of my major functions, is to meet with the residents, meet with students, talk with them in the hall, be present in the operating room, where they can come up and ask me questions. There are several nice little brochures that have been made. There is a practical problem in medical school curricula, that every department considers that their little bit is slightly more important than everybody else’s. CHAIRMAN WATKINS: In the section that we have dealt with in the past on medical education, we have found similar problems, to which the American Medical Association leadership thoroughly agreed. AMA held a very important national convention on education in March for health care providers across the board, not just medical doctors, but others as well. Here’s just another case when the system seems to be so sluggish that it doesn’t pick up on these things until much later downstream, as opposed to putting it at the front edge. Not necessarily everybody is going to use it, these are the kinds of things that can be encouraged today from data we have. And, what recommendation can we make in that regard about this? It seems to me that’s just important as everything else. If you can’t get the doctors on board that this is a good procedure, how does this 13 person Commission convince anybody? DR. HUGGINS: Actually, the NIH has had a very far- sighted attitude establishing Transfusion Medicine Academic Awards, and for the last several years they have, I believe, awarded four per year. These awards are for young medical doctors that want to make a lifetime commitment in the field of transfusion medicine. They provide salary support, not at a gigantic level, but at an 81 adequate level, so that these people can get involved with their organization in their medical school, trying to establish transfusion medicine as a viable program. I think this is something that certainly should be very highly commended. CHAIRMAN WATKINS: Dr. Huggins, could you give us a recommendation of what we might include in our report along these lines, and, perhaps, we can enhance it. Sometimes when we hear they are establishing these things, it’s a half man-year away. I don’t know what the order of magnitude is, and resources are in short supply, but there is a continuum across this line, from schools, to the federal level, to state, to local levels, to others that should be included as part of the education process? If you feel so strongly as you do, it seems to me that here is one way to inject ourselves into it by taking advantage of what kernels of excellence in thinking there are alcng these lines, and try to enhance those and bring them to fruition more. So, there may be some things that we could do in this report, and I’ve been impressed by the testimony this morning on this issue, but we need some help on to saying it right and putting the right leverage and the right pressure without overplaying it, and see if we can’t help you out over the coming years in the -- DR. HUGGINS: I would think the Transfusion Medicine Program of the NIH is an excellent program, that it could probably stand to be increased 50 or 100 percent, from four, to six, to eight awards annually and, that these ought to be, basically, five year programs so that people can get involved in it, and coordinate teaching of medical students, residents, and to act as a community resource for information on the transfusion field. There are all manners of ways you can do this. I eat lunch at the doctors’ lunch table every day, and I’m in there buttonholing, and what not. CHAIRMAN WATKINS: Do they say, "Here comes Dr. Huggins again?" DR. HUGGINS: They do. CHAIRMAN WATKINS: "He’s going to talk to us about transfusions at lunch." DR. HUGGINS: Yes, and I tell them what a good job they’re doing, and, "Use less blood." DR. LEE: Could I ask one more question? The first panel got my mind going on this possible national program, say, of selected donors, and pumping it up in a way which could be 82 made very palatable for the general public. Would this panel go for selected donors, rather than the voluntary? DR. HUGGINS: How can you pick somebody that is extraordinarily unlikely to be able to transmit HIV infection? I submit, you can’t tell the content of books from their cover. DR. LEE: You can’t tell a book from it’s cover. Well, there are several little -- DR. HUGGINS: All right. We could, pick all female blood donors. I think there could be merit in that progran, particularly, if they were all, say, over the age of 40 and hadn’t used drugs. That’s fine. That’s going to improve your level of risk, but it’s not going to totally eliminate it, because some of them may have had their hip operated on and got some blood transfusions. Obviously, prior transfusion is a concern. I think what Dr. Asher was talking about is a small, stable, generally paid donors that give over, and over and over again. And, the only -- and there might be merit in that. On the other hand, if you get one infected person in the stable, and that person has donated repetitively, the spread of infection could be enormous. So, I would be interested in seeing what the plan might be. I certainly would not categorically support or reject at this moment. I would be highly circumspect. . DR. VALERI: When I went to medical school, I was told that if I needed a blood transfusion to only receive it from an individual who had given blood previously and whose blood had been followed very carefully, in the recipients. Basically, this is what you are trying to develop. But, with all of the diseases now, it is going to be extremely difficult, depending upon the incubation periods, to be able to come up with a group that will not transmit disease. So, I’d be a little reluctant to agree with that policy. DR. LEE: Do you have your doubts too? \ DR. GIORANDO: I have a great deal of reservation. I guess, being the person that has to supply the 1 million people of Southern Arizona, my major concern is that selected registry, to me, is a very appealing option. However, my problem is that, it would appear to work best on a very small scale, but to try to translate that to a national blood system would be very 83 difficult. I heard a great number of suggestions, all of which were excellent. Bring the donor in, test the blood, and then bring them back. I think that’s an excellent idea, if I could only get my donors to do that. I have to, and they are right, it’s difficult to get donors. It is a constant daily struggle. The volunteer donor, however, I don’t know if the committee ever dealt with the CUE issue. Did Dr. Sandler ever discuss the Confidential Unit Exclusion, and the call-back issues here, and what we try to do to make certain that that volunteer donor, indeed, does have more of an opportunity to give of themselves, and to warn us that, indeed, their blood might not be safe. Although, some of the question we ask may not be terribly explicit, we think at least that they are reasonable. However, with every blood donation comes what we call a confidential Unit Exclusion, and, that is, the individual is asked to go off to a private area, and is taken to a private area, where they check on a card whether they want their blood transfused or not transfused. And, what we try to do by this, is give those individuals who had peer pressure to come to the blood center and donate, even though they are in a high-risk group, an opportunity to self-exclude themselves. We do get self- exclusions in that way. Before they leave the blood center, a little tag is torn off and they are given a little tag with their whole blood number and asked if, indeed, within the next several days they change their mind, please call us back. We will not ask you why you don’t want your blood used, we’ll discard it, and, indeed, they do call back. So, the system, indeed, does work. We have a whole bunch of checks in that system to try to give our volunteer donors, even though we don’t ask them these explicit questions, chances to come back and self-defer themselves at a later time. Interestingly, if you were to come into the blood center and not check, because you forgot to check whether you wanted your blood transfused or not, we would discard your blood. We would not use it. We would not take the risk. So, the steps we take to prevent any problems are extraordinary. Again, no step we take is going to make this blood supply absolutely safe, except giving your own blood, and I think that’s the topic of today’s conversation. Let’s get your own blood back to you. DR. CRENSHAW: Thank you. Dr. SerVass? 84 COMMISSIONER SerVAAS: Thank you. Mrs. Polikoff, I can’t thank you enough for coming here. Your courage is so commendable. Because you were here, I hope that our Commission will want to recommend that all persons who have had blood transfusions since 1977 be tested. I hope we can get some kind of state legislation going, some federal legislation going, as a result of our Commission, that we can be activists enough to get this moving so that we will have routine hospital check-ups and call-back-ins so that your husband he would have been routinely tested as will everyone who has any kind of blood transfusion in the future. I hope that we can get with you and find out what some of the other tests are that we should be giving to the people who have received homologous blood transfusions. Because you were here, we are motivated to help get this done for you because you’re not well enough to do it all alone. We thank you for traveling this far with your failing health. You’re to be blessed for this. The question that I really wonder is, how many Mrs. Polikoffs are there? I think that one of our earlier witnesses had told us that there are 2,000 blood transfusion patients now - - and I’m not sure this is the right number -- but, I see Deborah Taylor in the audience and she knows how many figures in Indiana we add on to the number of patients we have to get the number of infected persons we have. Isn’t it two zeros, if you have in Indiana how many patients, Debbie, in Indiana? MS. TAYLOR: Well, if you’re talking about the CDCs -- COMMISSIONER SerVAAS: Yes. Don’t you add two zeros? MS. TAYLOR: -- people that are infected, then we have 50 to 100 that have AIDS. COMMISSIONER SerVAAS: All right. So, if it were 100, just for easy figuring, and if this 2,000 figure is right, wouldn’t that mean that there are 200,000 people out there, or 100,000 to 200,000? MS. POLIKOFF: I don’t think anyone will ever know until later on. COMMISSIONER SerVAAS: We don’t know. MS. POLIKOFF: That’s the unfortunate part of it. Because people have transmitted it to others unknowingly. COMMISSIONER SerVAAS: Are we off-base? 85 MS. POLIKOFF: Then, there are others that have transmitted it further on. You won’t know for years, actually. COMMISSIONER SerVAAS: How many died and how many got blood transfusions? How many deaths were there? If you were just estimating, Dr. Huggins, Doctor Valeri, Doctor Giordano, how many would you estimate that we’ve had to date? Do we know at all? DR. GIORANDO: I think we do. COMMISSIONER SerVAAS: Do we? DR. GIORANDO: Well, we did a look-back on our entire system. I’m sure Doctor Sandler spoke to you about that. In November of ‘86, I took every HIV-positive donor and I looked at the recipient of their blood for as far back as they had ever donated in Southern Arizona, and so did the entire system. Please don’t hold me to this, because my memory is failing as I develop my Alzheimer’s disease, but my memory is that there are 12,500 people who received HIV-infected units, that we know of. COMMISSIONER SerVAAS: That’s what I thought, the number 12,000. DR. GIORANDO: And then, about 50 to 60 percent of people who were transfused will die within a year of their transfusion, not from HIV infection, but from the underlying disease which indeed caused the transfusion. I think the figures are -- again, we’re down to a population of about 6,000 at risk, of which there are presently about 2,000 to 2,500. CHAIRMAN WATKINS: Are these nationwide figures you’re giving us, Doctor? DR. GIORANDO: Again, Admiral, let me just tell you that I will send to you the official figures. This is my recollection, and I think that’s correct. It represents about two percent of the HIV cases right now, and I think the incidence is decreasing. COMMISSIONER SerVAAS: What would you think of having patients sign, when you give your informed consent -- of having some kind of legislation, federal or state legislation, that says you must make that patient aware of the fact that they have the option of autologous intraoperative transfusion or pre-donating their blood or directed donation, if they want it? Can’t we do that and make it expedited? DR. HUGGINS: The thrust of the legal side is, "Doctor, what was the indication for that blood? Couldn’t you possibly have done pre-deposit or intra-operative or ...?" And 86 then, you have a delightful 37 year old mother of two sitting there and, boy, the jury’s going to find for her. That will change behaviors quite smartly, I would think. DR. VALERI: That would probably be the most effective way to educate people, with the informed consent. COMMISSIONER SerVAAS: Yes. Could we make a law? DR. VALERI: Yes. I would think that would be the most effective way to get people to understand that there. are alternatives, not only the patients, but also the doctors. COMMISSIONER SerVAAS: Then, could you recommend to our Commission that we recommend that such legislation be considered? Is this appropriate for you to do? DR. VALERI: Absolutely. DR. HUGGINS: Absolutely. There are people that may not be competent, mentally, but, there are well-defined legal mechanisms to move ahead. We certainly have found the informed consent to be extremely helpful. COMMISSIONER SerVAAS: So, that would be two things we could recommend legislation on: informed consent, and testing all blood recipients for all of these virus’, AIDS included. Would that be something the panel could agree on? DR. GIORANDO: If I may put my own personal bias in, if they wish. DR. HUGGINS: It would have to be if they wish. It’s voluntary. COMMISSIONER SerVAAS: Oh, sure. Routine. So, they would do it, be tested, if they’ve had blood transfusions, unless they have a reason not to want to, just like Jehovah’s Witness or whatever reason you want not to. You don’t give it. DR. HUGGINS: When CDC came out with this recommendation, my phone rang off the hook for days. Rather than trying to talk desperate people out of it and say, "Well, we’re a low risk area and you didn’t get much," my policy was, "If you’re concerned, let’s get tested. Here’s how we’ll do it and put your mind at ease." COMMISSIONER SerVAAS: Could we ask Ms. Polikoff how easy it was for her to go and get tested? She couldn’t do it at the hospital. Was this a simple thing for you to go find the other place? 87 MS. POLIKOFF: Well, at the Health Fair was the only time that we found out that we could be tested down at the health county building, that they did not do the testing there. That’s how we knew to be tested at that time. I mean, actually -- COMMISSIONER SerVAAS: Was that convenient for you and near your home? MS. POLIKOFF: I beg your pardon? COMMISSIONER SerVAAS: Was this convenient for you and near your home, for you and your husband’ to gb there to find this or to go to this place? It wasn’t your hospital were you went to be tested for AIDS. MS. POLIKOFF: Well, I’m not aware if they did it or not, but this is how it happened that we found out where we could be tested, when we asked at the hospital, at the clinics, to be tested. They told us it wasn’t necessary. I didn’t know where to go to be tested otherwise, or my husband, to be sure, until later on at this time at the health fair. We did. We went down the next day to be tested. COMMISSIONER SerVAAS: At a health fair? MS. POLIKOFF: At the VA. The Veterans Administration had a health fair, which was very encouraging, because we learned many things there. At that booth where he was handed -- he laughed at that time -- after 40 years, you were being handed a condom. He said, what would he do with it, unfortunately. But, they told us, after he mentioned he had the sores and we had the hepatitis B, they suggested we go there for the testing and that’s how we found out, unfortunately. COMMISSIONER SerVAAS: Thank you. DR. CRENSHAW: Doctor Gebbie, you have a follow-up question? MS. GEBBIE: I just wanted clarification. Were you finished? Go ahead and finish. MS. POLIKOFF: I have a hearing problem and I can’t hear if someone speaks softly. MS. GEBBIE: Okay. My follow-up on this was actually to the physicians about that later point on the informed consent process. I just wanted to make sure we hear clearly what you were recommending. My general experience working with medical groups is that they don’t like having the detailed specifics of 88 informed consent in a statute. And yet, I think I heard the three ef you nod and say, yes, you would be supportive of a statute requiring specific information in an informed consent abeut this particular blood transfusion procedure. DR. HUGGINS: I think the things that people should be warned about are three: one, reactions; two, hepatitis; three, "IVY. To go into all the other little things that you can get is pointless. Those are the big three. That’s easy to warn and discuss alternatives. MS. GEBBIE: I’m not querying the informed consent, of wnich I am extremely supportive, and the standard of medical ovaetice which ought to support much clearer informed consent in all settings. I’m pushing a little bit on the political process of figuring out what to write in a law that tells every doctor what to put in informed consent and how clearly you support that orecess, and I heard a "yes" and a “yes" and a "yes." DR. GIORANDO: I’m not sure. I’m not sure that one can write a law that covers every contingency. If I may suggest, xy would suggest that the Commission recommend that informed consent be given for each and every blood transfusion. Exactly what’s contained in that informed consent, will have to be left to people to work that out at a later time. Am I answering your question? MS. GEBBIE: Well, you’re starting to talk about what I see are the problems of trying to recommend a law about this informed consent process. I want to be real clear before we jump after that kind of recommendation. DR. GIORANDO: I see what your concerns are, and I think your concerns are perfectly valid. I’m not certain that a Jaw should spell out everything that should be said, but perhaps a recommendation that, indeed, informed consent for the use of homologous blood is indeed a desirable thing where a law should be given. And then, let the individual groups create this. Because, the interest, primarily, of the Commission is HIV. Whe interest, primarily, of some of the blood bankers is noe as much HIV, but is in non-A, non-B hepatitis, which is a more Significant problem for us. Transfusion reactions and iso- sensitization are more significant problems for us than, indeed, EV. So, I would let us write that, if you would. MS. GEBBIE: And you don’t think the changing standard of medical practice in recent years calling out these problems has been sufficient to make physicians more explicit in this consent process around transfusions? 89 DR. GIORANDO: I don’t think that it always disseminates down. I don’t think physicians are very different from anyone else. That is, people like to ignore issues that are very thorny and that make them uncomfortable, and I think that that’s a real problem. I have a feeling that they might really welcome this, if indeed given the opportunity to do this ina realistic and compassionate way. DR. CRENSHAW: Dr. Huggins, did you have a comment to add? DR. HUGGINS: Obviously, informed consent can go in many ways. We basically have two types of form. One is used around a surgical procedure, which includes blood before, during, and after, say, a pneumonectomy. We then have another form that is used for medical patients that may have uremia, leukemia, and those we like to have redone at least every year. That will cover a series of transfusions. Trying to get an informed consent for each individual unit of platelets or that sort of thing would be completely unworkable. But, that type of procedure consent, and then the course of therapy consent has worked out really quite practically. DR. VALERI: Just aS a‘comment as a Commission you can make a recommendation that the medical profession actually go out and get informed consents for blood transfusions, and with that, you can, educate the patient of the risks associated with homologous blood. MS. GEBBIE: I heard that recommendation from all of you very clearly, and I think that one’s a very straight forward one. It was taking the next step of putting it into a statute. I wanted to find out how far you were prepared to go in that direction. DR. CRENSHAW: Dr. SerVass, you had a follow-up? COMMISSIONER SerVAAS: Yes. I wouldn’t back down on putting it in. I think that we’ve been wholly inadequate. Dr. Huggins, how many people die years after their surgery from hepatitis every year, from transfusion hepatitis, would you guess? This is our policy. We have informed consent. We should tell them about hepatitis. We should tell the public about the possibility of this marvelous new equipment, I think, and have that be part of informed consent and legislate on it. Because, we haven’t done it right in the past. It hasn’t filtered down fast enough, and I think we shouldn’t be having this conversation in front of Ms. Polikoff. She wouldn’t 90 be sitting here today if we had had such legislation. We’ve had autologous intraoperative transfusion for a good while now, not just recently. We’ve had directed donations, and autologous donations, pre-donating, all available. I’ve seen studies on this where five percent of the people who could be getting it do. And this has gone on for several years. Now, I don’t think it’s premature to change our statute and write it into the statute, because I think it will help doctors. Am I wrong to fight for this for Ms. Polikoff’s sake and the other hundreds like her who are out there? DR. HUGGINS: I can assure you I will join the fight. That’s what we’re doing. We have declared war on blood transfusion -- COMMISSIONER SerVAAS: Why do we have to hold back ona state legislation or federal recommendation out of this Commission? Why would we have to say, "No, we’re going to just wait and just put it into the general informed consent"? We already have a general informed consent. DR. HUGGINS: I agree. I support this strongly. DR. CRENSHAW: Thank you, Cory. Admiral, you have another question? CHAIRMAN WATKINS: I just want to clarify one point, because we’ve used some térms here that I want to make sure we’re straight for the record. We’ve talked about "voluntary." We’ve talked about "routine." The word "routine" has been used. We talk about "mandatory." I/’d like to get the consensus. I assume the panel is talking about that they do not favor mandatory testing of patients, but only the blood of blood donors, and then to offer individual testing to those, both in their best interests and the interest of public health. Is that correct? Is that what we’re talking about? back now and just hear the difference between mandatory, voluntary, routine, andisome other things on this particular issue. We‘ve talked the a lot of things and I’m trying to go DR. HUGGINS: \n general, in American blood banking, all blood is tested after the blood has been collected. The eleventh commandment of blood banking is, thou shalt not rely on previous records. Each donation is a discrete event. We warn every blood donor that we will do anti-HIV testing, that counseling will be available and that if they don’t want to be anti-HIV tested they should not donate blood. 91 So, that is the extent of our mandatory -- CHAIRMAN WATKINS: I understand. I just had heard a lot of things and we were talking about a number of things and I was confused as to whether we were getting those mixed up. DR. PRIMM: There is no difference in testing the blood of a donor than in testing the donor. You’re really testing the donor when you test the blood of a donor. CHAIRMAN WATKINS: I’m just trying to separate the issue of mandatory. Mandatory is on the blood, and the voluntary is on the second testing of the individual if they so desire, or to get those results and provide the necessary counseling. DR. HUGGINS: Nobody has to donate blood. Donors are volunteers, so that that’s a voluntary agreement to be tested. The person knows he or she is going to be tested. DR. CRENSHAW: Thank you very much. I have a question I'd like to wrap-up with. As I was looking into this process, I originally began to find out what kind of research we needed to do to make this procedure possible and more widely available. I discovered, to my surprise, that we’ve had the technology for the last ten years, and my efforts went in a totally different direction. Because, as we’re trying so hard to prevent AIDS and to do the best for the public welfare and individuals, this seemed to me like an under-utilized resource that was being overlooked while we were going off in directions that also needed to be explored, but at the expense of perhaps what we could capitalize upon here. Granted that we don’t even have enough of these devices in standing operating rooms, I want to take us a little into the future and see what the possibilities are to make up for lost time, specifically relating to trauma, emergency room, and mobile trauma units. I understand there’s a 20 pound portable available, and the major people who will not have this device useful to them are those who lose their blood on the highways. Can you comment a bit about what could happen if the resources were available or the interest on ambulances and mobile trauma units and emergency rooms, anybody who’d like? DR. HUGGINS: Limitless. The military, obviously, has made very effective use of helicopters and I think these could either be available in the helicopter or the helicopter could be available to get the injured patient as quickly as possible to a medical facility. In some way, that might be better than to spend time out in the field with the chopper blowing dust all over the place, to get them back into the hospital. 92 Bob, you’re the expert on that. DR. CRENSHAW: What about ambulances and emergency rooms? DR. VALERI: Well, right now, the Department of Defense, is deploying cell washers in all of the deplorable hospitals. What you’re interested in is a much more portable unit. Obviously, there are companies that will be developing this kind of technology, and I would envision that with the current interest, it will be in the not too distant future. DR. CRENSHAW: Yes. I understand that one such unit was dropped into the Honduras battle field, and I’m wondering about its applications for civilian use. Also, one of the things I learned is that obviously with this you don’t need type and cross-matching. So, if it were more generally available in emergency rooms, some people would get their blood when they needed it as opposed to the delay. Is that a correct assessment? DR. GIORANDO: Oh, I think so. I think there’s a concept that we like to employ, called the "collect first concept," that is, if it’s a ways from the operating room to the emergency room. But, I’m not sure if you have to have a machine in the emergency room if the operating room is relatively close. What we do is, we have all of the collection supplies in the operating room. When a trauma patient arrives, the emergency room nurses automatically set up exactly what you saw Dr. Huggins set up in the OR. That is, we have all our reservoirs there. Our response time is about 15 minutes in any emergency. We could have a unit anywhere in any hospital within 15 minutes. So, they’re collecting, and our people are on the way. And by the time the blood’s collected, we’re there to salvage it. So, it really is a very viable concept. The technology will be here soon to do this on a portable basis. I’m absolutely certain. And when it is, I think we should be ready to put it out into the field to help people. DR. CRENSHAW: Thank you so much. DR. HUGGINS: The actual ability to provide compatible blood is not really a rate-limiting step, Doctor Crenshaw. We have a very active emergency room, and our blood bank can get blood to a patient in 30 seconds. 93 DR. CRENSHAW: Pretty good. All right. I just want to thank you all. I want to thank you, Dr. Huggins, for sharing with us your expertise, and a model program that if a hospital has this device available it is not too costly to apply. You go to the operating room and make sure that no one who doesn’t need homologous blood gets it. And I think that that’s a real pioneering effort on your part, and I want to commend you. And for you, Doctor Valeri, to be studying the blood and looking at what we can do to give the best blood regardless of what options are available. And to you, Doctor Giordano, for being an incredible pioneer within the Red Cross. Both you and Dr. Huggins are competing with yourselves in terms of selling units of homologous blood and putting yourselves out of business in one way, and developing a whole new career mid-stride. I think this takes a tremendous amount of courage and dedication and forward thinking. And to you, Dorothy, for being here and for sharing with all of us from your heart. I know how deeply committed you are to protecting other people from having to go through what you have been through. I think you’ve made a big step in that direction. Thank you so much. We will reconvene at 1:30. (Whereupon, the hearing was adjourned to reconvene later this same day.) A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 1:45 p.m. DR. SERVAAS: We’ll start this panel so that we can have plenty of time to ask questions. We're going to talk about safer blood supply and tests for the blood supply. We hope we'll be able to zero-in again on what we can do to help the FDA in every way we can if there is indeed a bottleneck there because of lack of funding, we’re going to see what the Commission could recommend to make it possible for us to get rid of the bottleneck. We’ll start with Doctor Ledger. DR. LEDGER: Thank you. I/’11 get rid of my cough drop here. I’m the Head of Obstetrics and Gynecology at the New York Hospital, Cornell Medical Center, New York City, not in Ithaca. 94 I want to focus on approaches that we’ve used to try to limit the use of blood products on the obstetric/gynecology service. Because, our goal is really to avoid the use of blood products in this particular group of patients. There are some situations that occur that the blood loss is unexpected, and it’s massive. There’s really no way to predict that. We see situations in obstetrics where there’s a premature separation of the placenta, a ruptured tubotopic pregnancy, and those in which women have had an automobile accident while they’re pregnant and have massive blood loss, totally unexpected. There’s no way to prepare for that except co take care of the situation. In New York City, our consumers, the obstetric/gynecologic population, are very concerned about the safety of the blood supply. There has been a consumer push to trey te limit or avoid the use of blood products in this population. We’ve looked at two alternatives mostly. One has been the use of autologous donation by the patients themselves, and I want to share with you very quickly our experience with that and to say a few words about directed donors. First of all, autologous donations can be done both in obstetrics and gynecology. We have a program now in which we’ve had almost 100 pregnant patients who, with careful monitoring, have been able to give blood prior to delivery and have had that blood available to them at the time of delivery. This program seems safe, it can be done. It’s not particularly effective as far as the frequency of use. Of the first 50 patients that gave blood this way, there was only one who required a unit of blood to be given to her at the time of delivery or post-partum because of excessive blood loss. There were many more units donor than were actually used. In gynecology, it’s been a much better situation because much of our gynecologic surgery is surgery in which the biood loss is not massive, but it is enough to require transfusion. In these situations, patients have the capability of giving blood before the procedure, of using medical techniques te try to avoid bleeding if they’re having heavy menstrual periods because they have uterine leiomyomas, so that they have a chance to build up their blood count. In this situation, it works out very well, for most of these women do receive their own biood products, which is obviously the safest. We also have situations in gynecology in which patients have a pelvic malignancy, in which they may require a radical cperative procedure in which the blood loss may be greater than anything that they’re going to store pre-operatively. It is a 95 ' ! situation in which they just don’t have the capability of donating enough units of their own blood before the surgery. In these situations we’ve made use of directed donors by family members, and in many cases in gynecology, we’ve used the husband. Now, there’s been a lot of resistance to this, and I have to confess that my bias as an obstetrician is that much of this resistance is resistance of the same nature that I heard years ago when obstetricians first began to talk about allowing husbands in the delivery room. Husbands really didn’t belong there. They were going to be in the way of the nurses and in the way of the doctors. Basically, it was that we didn’t want anyone in the delivery room who wasn’t part of the medical team. The fact of the matter is, it’s a dead issue now. I think all obstetricians would say that the husband’s presence is a benefit, and I think the same approach has to be applied here with directed blood donations. What these patients are saying is, "I can’t guarantee the safety of whoever I pick any more than the blood bank can, but it’s my decision. I’m picking the person to give blood for me, and if I have to receive the blood then I’ve had something to say about my own medical care." As a physician we have to support this. Autologous donors, particularly the autologous donations where the blood is not used, directed donations in which the patient does not receive the blood, generate hospital expenses. These blood units are not used for other patients in our hospital. The issues of cost, I think, will have to be handled by the Commission as far as making recommendations. But, I think, within the framework of obstetrics and gynecology this approach virtually eliminates the need for homologous blood transfusion. Thank you. DR. SERVAAS: Thank you. DR. SERVAAS: Doctor Montagna? DR. MONTAGNA: I guess I have the opportunity to change our focus slightly from that of this morning and part of this afternoon. The Commission has been listening to testimony regarding the HIV, and I would like to now address another retrovirus, namely the Human T-cell Lymphotropic Virus Type I, or HTLV-I. I would suspect that overall, our national goals and national policies regarding the HTLV-I should essentially be predicated on the fact that we have learned a lot about the transmission of human retroviruses with respect to HIV. It would seem to me that our overall goal should be to allow or not allow ™, 96 the suffering and particularly the tragic experiences described by Mrs. Polikoff this morning to be in vain. I would like to take advantage of the slide projector and run through a very brief presentation of HTLV-I. May I have the first slide, please? With respect to HTLV-I, we’re confronted with something slightly different than what we were confronted with HIV, in the sense that with HIV we were confronted with a disease for which the etiological agent was not known. With respect to HTLV-I, on the other hand, when it was first discovered we were confronted with a virus and no one was particularly sure what diseases it may or may not have been involved with. It was the first human retrovirus discovered, approximately in 1980, and it’s clear now that it is involved in the etiology of at least two different types of diseases, namely Adult T-cell Leukemia, or ATL, and a neurological disorder known as tropical spastic paraparesis, or TSP. There are also some indications in the literature that other neurological disorders like multiple sclerosis may be, in fact, due to a virus related to HTLV-I, although that has given rise to some controversial findings. Just in this past week’sNew England Journal, Doctors Bhagavati and Bernard Poiesz were able to show that a compressive myelopathy may in fact be due to HTLV- I. I’d like to very briefly summarize some of the differences and similarities between HIV and HTLV-I. Next slide, please. It’s not surprising that since both of these viruses belong to the same family of viruses, they have many common structural and functional features. From a size standpoint, both of them are particles of approximately 100 nanometers. Their densities are similar and, again, not surprisingly, their genetic organization is very similar. Both of them are RNA viruses, and the organization of the particular genes is very similar. I draw you attention to the next issue, which is the fact that there is an obligatory step in the infection cycle of any retrovirus, namely that the RNA is transcribed into a DNA form which must obligatorily be integrated directly into the host genome. I think it’s this fact that, from a public health standpoint, we have to keep in mind. Because, what it really means is that the individual who is infected with a retrovirus for all practical purposes is infected for life. And until 97 methods are developed to eliminate such integrated sequences within an infected host, that individual must be considered a biological hazard, not only to himself but any future sex partners and even potentially to some family members, as we'll discuss with HTLV-I. Obviously, the requirement for reverse transcriptase is real because of the fact that both of these viruses are RNA viruses and require a step to transform that information from an RNA form to a DNA form. Next slide, please. Both of these viruses attack the same cell, the helper T-cell. They have some different effects, and we’ll discuss those in a moment. Next slide, please. The modes of transmission are clearly very similar, intravenous drug abuse, particularly in the case of HTLV-I, is a predominant mode of transmission. But, sexual transmission and blood transfusions that have been documented primarily in Japan, and recently a study that was done at the Sloan-Kettering, indicated that some patients there may have acquired an HTLV-I infection as a result of transfusions. And maternal transmission of both of these retroviruses has been documented. Next slide, please. Despite the similarities, there are some differences. It’s the differences that we should key on. Although both of the viruses effect the same target cells, namely the T helper cell, with respect to HIV the effect is cytopathic. That virus kills those cells and brings about the disease state that we know as AIDS. With respect to HTLV-I, the effect is not cytopathic, but instead the cells are transformed from a normal phenotype to a malignant phenotype and gives rise to at least the one disease that we know of as Adult T-cell Leukemia. How or why the effect to bring about the clinical syndrome of TSP is related to infection or even if it is involved with the infection of T helper cells is currently not known. The third issue, namely the length of the incubation period, is another issue that I think we need to key on in terms of national policies. Because, with respect to HIV it’s clear that the time from infection to the manifestation of disease symptoms is relatively short. With HTLV-I, it appears that we may be talking about a length of incubation that runs in the order of several decades. From a public health standpoint, if in fact an HTLV-I infection or an epidemic were to become evident within the United 98 States, it might be several decades before we would even know about it if all we were looking at were disease manifestations. Fourthly, sero-positivity among family members is not an uncommon phenomenon with respect to HTLV-I, where we don’t see it so often with HIV. Now, initially that was of great concern to everyone involved in the field, because it gave rise to some concerns that we might be dealing with an agent that could be casually transmitted. However, now it is very clear that that is not the case. Instead, it is presumably due to infections from a mother to her children. I/’11 have a little bit more to Say about that later. Also, there is another major difference between these two viruses in the sense that cell-free transmission is possible with HIV, where it is not as readily occurring phenomenon with respect to HTLV-I. That may have some implications in blood products that do not contain blood cells, particularly plasma products. Of course, one would have to be assured that cell-free transmission does not occur with HTLV-I, and would also have to be assured that cell-free components were indeed cell-free. Now, I would like to briefly describe a test that was developed by our firm to detect the antibodies to HTLV-I. Next slide, please. Like the first generation HIV test, this is a test that was developed to detect antibodies to HTLV-I. It initially was evaluated by the American Red Cross as part of their study that was reported recently in Science. It is.a test that is developed to detect antibodies to the viral components, and it is a relatively simple and straightforward assay to run. One of the first questions that we raised, and it was at the direction of the Food and Drug Administration that they requested and we agreed with their request that one of the major stumbling blocks was how would one determine the actual sensitivity of these tests. It was suggested by the FDA, and as I said we have agreed with that suggestion, that we should define the sensitivity of these tests based on their ability to detect antibodies in people that we know are indeed infected. The way we can tell that they are indeed infected is to look to see if they have genetic sequences integrated into their genomes. May I have the next slide, please. Therefore, we have looked at 65 people who are U.S. patients. Every one of the people represented on this slide has been shown to contain HTLV-I genetic sequences via a method known as "Polymerase Chain Reaction," which is a method to amplify and detect specific gene sequences. 99 You’ll note that of the 65 people evaluated, 64 of them had reactivities when evaluated with our test. This says two things. One, that these patient populations are indeed infected with the virus and the test was able to pick up those antibodies that were produced by the infection. However, it also says, as you can see, that there was one Adult T-cell Leukemia patient that was not picked up. That patient was the subject of a manuscript that will be in press, by Doctor Bernard Poiesz, and that particular ATL patient is indeed a biological sero-negative. That individual does not possess antibodies to HTLV-I, as judged by more sensitive techniques, including Western Blot and Radioimmunoprecipitation. What it says is that no test is perfect, and we would not want to stand here and say that this test, or any other test, is perfect. We can not be expected to pick up antibodies in an individual where they do not exist. However, by the same token, it would be unlikely for an ATL patient to appear at a blood bank and attempt to donate blood. So, I think the risk from that standpoint is rather minimal. Now, at the same time we wanted to evaluate the prevalence of HTLV~-I antibodies in the random blood donor population. As you know, Doctor Gerald Sandler has conducted an extensive study throughout the United States and has shown that the prevalence of that antibody within the U.S. population is approximately 0.025 percent. May I have the next slide, please? Among volunteer donors, we found a prevalence rate of 0.09 percent. Actually, it’s 0.085. I rounded everything off to two decimal points. In the paid plasma donor population it’s slightly higher, .14 percent, but overall about one per thousand. I would caution, however, that the Red Cross data may be more realistic in terms of the overall prevalence of the antibodies to this virus because of the way their study was conducted and because of the fact that they looked at a broader spectrum of geographical sites. Although, if you look at some of their sites, some of them did have antibody prevalences as high as 0.1 to 0.15 percent. May I have the next slide, please? We then wanted to take a look at some potential populations to determine whether populations that have already been defined as high-risk for HIV infection are also at high-risk for HTLV-I. As a result of the data that you see before you, primarily the intravenous drug abuser population is the one that expressed the highest number of antibody-positive individuals. 100 I should point out that when we’re defining somebody as antibody-positive, they were people that were scored as positive by the test and confirmed by Western Blotting techniques. We also looked at 64 AIDS or ARC patients to determine whether that population or anyone in that population was either doubly infected with HIV and HTLV-I, or whether the test would have any false positive reactions as a result of the related antibodies to HIV. All of the AIDS and ARC patients described there were HIV-positive, but none of them as you can see were positive for HTLV-I. May I have the next Slide, please? We had the opportunity to evaluate a family of an Adult T-cell Leukemia patient. I draw your attention to individual number seven. For those of you who may not be familiar, circles are females and squares are males. The ATL patient number seven is antibody-positive for HTLV-I and also contains integrated genomic sequences to HTLV-I as determined by the Polymerase Chain Reaction Gene Amplification Technique (PCR). When looking at that individual’s siblings, we found that four of her sisters, numbers four, nine, ten, and eleven, were negative for antibodies and also negative for gene sequences by PCR. Two of her sisters, namely numbers five and Six, are positive for antibodies and positive for gene sequences. Her brother, number three, is negative for both gene sequences and antibody presence. We then had the opportunity to look at a generation before that, and at least look at her father, who is individual humber two. That person is sero-negative with respect to antibodies and is also negative with respect to gene sequences. Unfortunately, we have not yet had the opportunity to evaluate the mother, who is alive but we have just not had an opportunity to evaluate any specimens. Individual number seven is married to an individual who, at this point in time, has no symptoms of any disease, however that person does harbor antibodies to HTLV-I as determined by the test, and also harbors integrated gene sequences. So, that person is also infected. They have three children, a daughter and two sons, all of whom are sero~negative by the test and also are negative for gene sequences. What I think this points out to us is that we have to deal with two issues with respect to HTLV-I positivity. One, the person who may be infected may become a secondary reservoir for additional infections within their own family. It’s our suspicion, although we haven’t been able to prove it yet, that persons number five, six, and seven are infected via vertical transmission from the mother. We would 101 .suspect that when we’re able to evaluate the mother we will find someone who is positive for HTLV-I, and we suspect that person number seven infected her husband via sexual transmissions. Fortunately all of the children are sero-negative and gene sequence-negative. - I think one obvious question this has to lead us to is, where does this bring us to in terms of the cost of protecting the U.S. blood supply? I know that the blood bank community has grave concerns, as Il think we all would share, that as we identify more and more retroviruses we’re going to be confronted with more and more costs. One of the approaches that our firm is taking is the development of a test that would allow us to simultaneously detect the presence of antibodies to both of these viruses. May I have the next slide, please? Consequently, we have developed a test that we call the "HIV/HTLV-I Combination Test." Although this slide says "a proposed algorithm," it really should say "two proposed algorithms." The least expensive algorithm may not be the best one. What we would consider to be the best one is that an individual would be screened using the combination test, and if the result was negative, that blood should be released for transfusion. However, we agree and I’m sure our colleagues here from the Food and Drug Administration would agree that that algorithm can only work if the combination test is at least as sensitive as any of the existing HIV tests and HTLV-I tests. Otherwise, that first step, which acts exactly as a sieve, would cause us to miss people that we should not miss. On the other hand, if a sample showed up as positive, the most beneficial method to continue the algorithm would be to take that unit of blood and evaluate it in duplicate on two separate tests, an HIV test and an HTLV-I test. Thereby, the costs of confirmatory tests that would be required would be reduced since we would know which ones to perforn, plus you would have more information to give the blood donor. On the other hand, if you’re looking for a less expensive way of doing this, the positive result could then just be followed merely by a duplicate test on the co ination test itself. The only difficulty with this approach is that this test was not designed to tell specifically whether the antibody responses were HIV or HTLV-I. It’s only meant to show that it is and/or HIV and HTLV-I. May I have the next slide, please? This indicates what we suspect would be the cost savings of this type of a test. Now, it’s our policy not to make 102 any claims regarding the sensitivity and specificity of any test while it’s still in clinical trials, and I’m sure our FDA colleagues would agree with that. I would like to point out, however, that the cost savings will be a function of the specificity of the test, assuming that the sensitivity met the stringent criteria that the FDA would set as well as we would set ourselves. If there were no false positives and if you made the assumption that there were no antibody-positives in the population, and if you walk through these assumptions it would be a 10,000 test to run and you had no false positives, you would in essence save 10,000 tests. Because, instead of running 10,000 HIVs and 10,000 HTLV-Is, you would only have to run 10,000 instead of 20,000. If, on the other hand, if you had a one percent false positive rate with a specificity therefore of 99 percent, you would have 100 individuals that would have to be rescreened. And »£ you rescreened them in duplicate, you’d be running a total of 10,200, or saving 9,800 tests. You can move through the assumptions and you can see that no matter what level of specificity the test ends up with there would be some significant savings to the blood bank community. I would like to conclude by stating that I think all of our policies should be aimed at making the blood supply as safe as possible, and certainly keep in consideration the cost that it requires to do that. In the final analysis, we as industry as well as the Food and Drug Administration should continue operating in conjunction with each other in the collegial fashion as we have had the opportunity to operate in and solve all of these dilemmas as they come up. Thank you. DR. SERVAAS: Thank you, Doctor Montagna. DR. SERVAAS: Doctor Bonewitz? DR. BONEWITZ: Thank you, Madame Chairman. Since the introduction of the first blood screening tests in March of 1985, the diagnostics industry has accelerated its efforts in both basic research and in the development of new Hiv tests. These efforts have yielded some unexpected and some important results which are of significant implication for controlling the epidemic and for the medical care of persons who are infected with HIV. When I speak about HIV diagnostics here in my comments, I mean the tests which a physician would use to make a diagnosis or a prognosis or a decision about the care of his patients, as distinguished from a screening test that is used to test large populations of individuals who are healthy, such as 103 blood donors. Now, despite this progress (which I will comment on briefly and submit for the record a longer testimony), we are frustrated that the AIDS research and medical communities are not fully able to benefit from these advances. Notwithstanding the government’s high priority in fighting the HIV epidemic and the FDA’s fast track status for screening tests and drugs, manufacturers have experienced a significant difficulty in the process of delivering HIV diagnostic tests to the medical community. We therefore wish to relate to the Commission some of our observations on the disappointing rate at which new and better HIV diagnostic tests are moving through the regulatory process. The primary focus of this hearing is on the safety of the blood supply, but I would also like to go beyond that in my comments and paint a broader picture for you with respect to HIV testing. I can do that, I believe, by highlighting four categories of tests. First, tests for basic and clinical research. Second, diagnostic tests. That is, tests for use in the diagnosis and management of patients with HIV infection. Three, improved versions of the current blood screening test. And four, an area where I may not have time in my prepared comments but one I would like to call to your attention nonetheless: tests which have been specifically designed for use in underdeveloped countries of the world. Essential diagnostic tests for any disease often start out as research tests. As an example, in 1985, Abbott developed a pair of tests using genetically engineered proteins to measure two specific types of antibody. Use of these research tests soon led to a serologic description of the course of HIV infection, a discovery of potential significance for patient care. The second category, diagnostic tests, is those shown to be useful for patient diagnosis and management. Again, as an example, in 1986 Abbott developed for research use a test for HIV antigen. The antigen test often gives the earliest indication of HIV infection. This finding was recently shown to be of immediate practical importance in controlling the spread of the disease. Soon after infection, some individuals become ill with non- specific symptoms typical of mononucleosis or the flu. If HIV infection is suspected by a physician and an HIV antibody test is 104 ordered, the physician may not correctly diagnose the patient’s condition since antibody will usually not be present at this early stage of the infection. In other words, an infected individual may go undiagnosed and not learn that he is infected and infectious to others. Abbott submitted this test to the FDA in May of 1987. There is currently no approved test available today which could substitute for the antigen test in this particular situation. I might also comment that one can imagine the use of this test in that context, that is as an aid in the diagnosis of HIV infection in persons recently infected, could also have an indirect favorable impact on the safety of the blood supply since these individuals are potential blood donors. Other published research on the antigen assay suggests that it can indicate when an individual is more likely to develop symptoms of AIDS or the AIDS-related complex, and can show that a patient is favorably responding to therapy. The third category of tests is improvements to the existing blood screening tests. In early 1987, a second generation screening test was introduced throughout much of the world. Instead of using whole virus, this test is manufactured using purified viral proteins obtained by genetic engineering. This test is more sensitive, able to detect lower levels of antibody which are characteristically present in recent infection. And because the test is made with purified proteins, it is more specific. That is, it has fewer false positive results. At this point, I would like to relate to you some of our observations on the current scientific and regulatory environments which effect the introduction of new HIV diagnostic tests. First, the FDA is facing an unprecedented number of applications for licensure of HIV diagnostics. Since the advent of the HIV epidemic and the initial licensure of five companies to market antibody screening tests, many more diagnostics manufacturers have applied to market similar kits, and some companies have filed license amendments for process and product improvements. And as manufacturers began to develop tests for diagnostic as opposed to screening purposes, even more license applications can be anticipated. Second, access to the FDA AIDS review staff is limited. Manufacturers are finding it increasingly difficult to meet and consult with FDA staff. We are told by FDA that this is due to the staff’s heavy work load and other AIDS-related activities. 105 Third, HIV diagnostic tests are not the highest priority for FDA. Tests for blood screening remain the primary concern. Tests for screening blood are required by law to be regulated as biologics. Normally, tests for diagnostic use are regulated as medical devices. However, current FDA policy is to regulate all HIV diagnostics as biologics. FDA feels that the expertise in evaluating HIV diagnostics is available only in the Office of Biologics. Now, this means that all applications for HIV diagnostic tests must be reviewed by the same small group whose charter is protection of the blood supply. Under these circumstances, diagnostic tests can never be a top priority. In fact, FDA’s blood screening priority is now testing for the HTLV-I virus, an important public health need in its own right. FDA has indicated that screening tests for HTLV-I will be given fast track status for approval. These tests are being reviewed by the AIDS review group, which further increases the demands on their time. As a benchmark for you in terms of the timing of submissions, Abbott Laboratories filed its FDA submission for HTLV-I antibody screening test in December of 1987. And finally, point four, current FDA regulatory policy for HIV diagnostics has no provisions for the sale or distribution of tests for research use. As a company heavily involved in AIDS research, we have a strong commitment to support the AIDS research community. However, as a company regulated by the FDA, we’re reluctant to distribute experimental test kits to researchers outside of the FDA review process. We’re frustrated that no process currently exists to allow us to distribute HIV tests for research use only. These restrictions are unique to biologics and are particularly severe for HIV research, because FDA treats all HIV tests as biologics. Regulations governing medical devices do permit the sale of diagnostic tests for research use only. Now, in conclusion, I think there have been significant contributions to the basic understanding of AIDS and HIV infection, contributions made by the diagnostics industry. New tests have been developed and shown to be of diagnostic value in the care of infected patients, and a second generation of blood screening tests is already available to some parts of the world. I might comment here that much needed tests for the underdeveloped countries of the world, some of which are severely affected by the epidemic, will soon be ready. But, the diagnostics industry is concerned and frustrated that the health benefits offered by these products are not being fully realized. 106 So, we urge the Commission to take a leadership role in clearing the delays in bringing these much needed health care products through the appropriate review process to physicians and researchers around the world. Thank you, Madame Chairman. DR. SERVAAS: Thank you. I think I should explain here that our Chairman, Admiral Watkins, pinpointed the FDA as being a place where help was needed. In fact, he described it as having almost third world conditions when he went out to see how many things needed to be done and how few people and how under-funded they are. They aren’t being funded in a crescendo the way some of the organizations like NIH and others who are providing work for them are. I think that it was quite remarkable that he was able to do that early on, and in our interim report we recommended that for drugs we get right to it and even on some of the screening tests. Now, we’re talking about diagnostic tests and screening tests for the blood supply, and it’s with this spirit of cooperation that we have the dialogue between the manufacturers who have the tests and how they view it and how Doctor Parkman and Doctor Epstein would view it. We went there, and I might add that we went to the FDA and in our interim report recommended a kind of award, Presidential award for deserved recognition and honor to some of their employees so that we could build morale and attract more good reviewers in the FDA. DR. SERVAAS: Doctor Parkman was good enough to come to Indiana as he is a very busy person, and to come out this afternoon and to bring Jay Epstein, who knows all about these tests. Doctor Parkman is going to tell us how he thinks we can help them get underway more. DR. PARKMAN: Thank you very much. We are pleased to be asked to come and testify again before the Presidential Commission. Doctor Young was very sorry that he was unable to be here today. He is in Geneva, doing government business with the World Health Organization. I brought along with me today Doctor Jay Epstein, who is from our staff in the Division of Blood and Blood Products and who is on the front lines in dealing with the tests that we use for screening, and other types of tests that deal with the HIV epidemic and with HTLV-I, and other laboratory tests. The safety of the blood supply is one of the primary responsibilities of FDA in combating this terrible epidemic. We do this in a variety of ways. We license facilities that have to 107 do with blood and blood products. We license the products themselves. And we develop regulations that deal with these products. I thought I might share with you for just a moment the protections for keeping the blood supply safe, as safe as is possible in the HIV epidemic. And also, as a second point, I’11 give you my perspective on the demands which are made upon the Agency by the epidemic of AIDS and an idea about how problems in both of these areas can be solved. Once HIV was known to be transmitted by blood and blood components, it was obvious that there needed to be a mechanism to enhance the safety of the blood supply. In March of 1983, we published recommendations for self-deferral of blood and blood products donors who were at increased risk for AIDS. At that time, you must remember, the virus had not been discovered and there was only epidemiologic data to help guide us. Over the years since then, we have updated these recommendations numerous times. I think the count, if I am correct, is about six times. In October of '86, for example, we began the Confidential Donor Unit Exclusion Recommendation, which was described very well in one of our earlier panels and which I’1l not dwell on further, except to emphasize that it is a very important protection that allows a blood donor to privately and confidentially exclude a unit from transfusion if the donor believes that’s appropriate. Once the AIDS virus was recovered, the development of tests which could detect antibody, of course, was extraordinarily important. In March of 1985, only a few weeks after the final clinical data was submitted, the first test was licensed. We now have eight licensed ELISAs and one Western Blot test. Therefore, the means for protecting the blood supply is three- tiered. It involves self-exclusion of people who are at risk. It involves confidential donor unit exclusion. And it involves HIV antibody testing. And all of those are important components. The addition of HIV antibody testing, of course, was extraordinarily important and greatly enhanced blood safety. The risk even now, though, as you’ve heard this morning and earlier, is not zero. Doctor Ward, from the Center for Disease Control, had a paper in theNew England Journal of Medicine a few months ago describing 13 recipients of HIV blood from HIV test-negative persons, who had sero-converted, that is, who had become infected. Now, we believe that this circumstance is rare. It’s been estimated to be somewhere between one in 250,000 and one in 40,000. With one in 40,000 being a worst case estimate. I think 108 that not all of the protections, (in particular, the Confidential Donor Unit Exclusion) were not in place at the time these patients who were in Doctor Ward’s study were reported. In addition, the manufacturers have valiantly striven to improve the tests themselves. The tests have been modified a number of times to improve their fficacy. What additionally can we do? Well, there are at least two areas where I think that we could continue to improve the tests that we have. The tests are not 100 percent sensitive and specific. As you know, they are based on detecting antibody, which takes a period of time to develop, which results in the window period we’ve all heard discussed. Obviously, more sensitive tests might be developed and, in particular, antigen tests might be useful. We held a workshop several months ago on new tests using recombinant DNA-produced antigens and synthetic peptides. We heard very encouraging results from those early trials. We must be cautious, however, because we need to be very careful that the sensitivity and specificity of those new tests are equivalent to those that we currently have available. This is going to need careful evaluation and continued testing. Antigen tests. Antigen tests for screening the blood supply are currently a problem. They are not sensitive enough to stand on their own, and clearly are not valuable in screening donors at this time. But, I think that there is hope that there will be better tests and that in the coming year or so, again as you heard this morning, we believe that there will be tests that may very well be useful and will have a substantial new benefit for testing. What else can we do besides evaluating these new tests? One of the things that I think FDA can do in this area is to increase the amount of effort they put into public education. We need to educate a number of populations. One of the things that we need to educate people about and continue to stress is that the public is not at risk for AIDS from donating blood. We have said this for many years and there still in surveys is evidence of concern in the public that somehow donating blood puts them at risk and this is absolutely not true. We need to educate donors better about risk behavior and the reasons they should defer themselves. We need to educate physicians about the prudent use of blood and blood products, and about alternatives that we heard about in the last panel, such as autologous transfusions, and 109 intraoperative salvage of blood. We need to educate our own staff to help them to more effectively conduct the inspections of blood establishments, as you know they do every year. What obstacles do we have to moving along in our efforts? Obviously, rapid, high quality review is of high public interest. We have a situation now where the inventiveness of the American biologics industry has increased enormously the number of tests that are before us. Not only has the number increased, but these new tests have given us new issues to deal with, ethical issues, issues of bio-safety, issues of new products to quality control and to evaluate for performance. Each of these areas iS resource intensive with respect to the technical reviews and the research support for developing test standards for all these new products. Despite this, I think we’ve maintained the quality of our evaluation efforts in achieving the safest blood supply possible. It’s an expanding area, and obviously there’s a need for continued evaluation of our need for resources to do this job, both in terms of staff, space, and equipment. .AIDS and biotechnology have added together to increase our work load. I think we have a top-notch staff. I think they are very productive, and I’m very proud of Doctor Epstein and the staff. I think it isn’t recognized that their effort and their productivity has increased substantially, driven by this epidemic. There is such a thing as burn-out, however. I don’t think we’ve seen it, but I’m concerned about it. The federal system is not acutely attuned to the stresses posed by a disease like AIDS on the federal worker. I think that even though the resources that have been made available to us are relatively generous, there is a need to continue to assess our need for personnel to help us in this effort. Doctor Epstein’s group has about doubled in less than two years. They are a young and enthusiastic staff. Yet, we need to continue to attract high quality scientists and regulators to assist us in this effort. We may need to look carefully at the rigid grade and salary structures that the federal government puts on us and our ability to recruit such scientists. I think Admiral Watkins and several of you came out to see our work environment, and I think that you have seen that space and have spoken about it a number of times and are sympathetic to our needs. Obviously, we have funds for a new building in the current budget that is before the Congress. I certainly hope that work on that will go forward and can be expedited to provide us relief in that area. We were very pleased that you suggested a special award. I think such kinds of recognition of the important work that regulatory scientists 110 do has not commonly been given in the government, and we are pleased at your suggestion. We recognize the need for a balance of conflicting values in many areas that we deal with. We need to be careful of public resources. At the same time, we need to be timely in trying to discharge our mission. We need to be careful in resolving this conflict not to be penny-wise and pound-foolish. Our goal should be to encourage industry in new test development and not regulate them repressively. % On the other hand, our primary goal is to ensure in so far as humanly possible the safety of the blood supply by development and review of screening tests that help us do that. This Commission and the public, I am sure, would insist that we do no less and that we should strive to make the tests we regulate as perfect as possible. Transfusion-transmitted AIDS virus infection is extremely rare, one in 40,000 to one in 250,000. But, even this small risk is something we must continually strive to minimize. Thank you. DR. SERVAAS: Thank you. DR. SERVAAS: Doctor Epstein? DR. EPSTEIN: Doctor Parkman has spoken for bth of us on behalf of our Agency. I would just like to stress briefly my perceptions regarding obstacles that could be addressed, which is after all the main focus of the hearing. I think it’s important to realize in dealing with a federal agency, that there’s a time lag in making improvements. I’ve seen in the last three years an increasing allocation of monetary resources for the Agency and a slow but increasing allocation of personnel slots. However, we live in a situation where it takes time to recruit and it takes time to train and it takes time to expand facilities. I would say that it’s important to understand that regulatory work is a very people-intensive process, that it takes countless hours. The Commissioner has estimated that it takes more than 1,000 working hours to review a single biologics product application of average complexity. In the face of this, with a geometrically expanding work load, it’s clear that even a linearly expanding staff will not be adequate to meet the need. That’s also in the context of products which are seen as of the highest priority, whether they be specifically AIDS-related or other retrovirus-related. It will take us approximately two to three years, I believe, even if we can locate and bring into the government system qualified people, to bring them up to speed with respect to the laws of the Agency, the rules under which we work, and the specifics of 111 training as a reviewer. I would say that there’s another area which needs attention, which is specific incentives to career scientists who do regulation. The individual who chooses to be a scientist in a regulatory agency wears two hats. That person is subjected to the very same scientific peer review standard as any other scientist in the government service. Indeed, we are an integrated part of the NIH with respect to peer review and promotions. However, that individual by virtue of service at the FDA is tapped as a scientific expert and is expected to spend many hours reading applications and providing consultation to the manufacturer through either meetings or review letters. Those efforts go largely unrewarded, primarily because there’s no mechanism to reward. Therefore, scientists see themselves in jeopardy when they budget their time toward review work. They understand that it creates a career path towards staying at the FDA, but they also understand that it will decelerate their scientific work and publications, which fact may not go fully recognized when they’re under peer review at the NIH. Finally, I think that we have heard, at least from Doctor Bonewitz, a plea for flexibility in regulation. I think that Doctor Parkman has addressed the fact that there is a need for such flexibility, but I would hope that the Commission understands that achieving it is no easy matter. After all, we function under the law and we function under a body of statutes and interpretations and precedents which are accumulated over time. The system is simply not adapted to radical change without much thoughtful reflection. Therefore, it is our obligation whenever we are making a change to publicize the proposed change, to get comments, and to integrate change with existing policies through a public process. I think that the slowness of this approach has affected many of the companies and is one of the sources of their frustration, and is itself a matter that could be addressed at a high level such as the Commission report. Thank you. DR. SERVAAS: Thank you, Doctor Epstein. COMMISSIONER SerVAAS: We’1ll start the questioning with Doctor Primn. DR. PRIMM: I’m going to pass, Dr. SerVass, and you can come back to me. DR. SERVAAS: Doctor Lee? 112 DR. LEE: First, a welcome to Doctor Ledger from my home medical community. I have a couple of official questions from our Washington staff for Doctor Parkman and Doctor Epstein that are for the record. Are there any other federal agencies involved in the monitoring of the labs and blood banks? DR. PARKMAN: Yes. There is the Center for Disease Control, which is involved with looking at the HIV testing in laboratories. As a matter of fact, they have embarked upon a program of voluntary -- they don’t use the term "proficiency testing," but it is essentially that idea. In addition, the Health Care Finance Administration, which administers funds, also does work in looking at hospitals, including hospital laboratories. DR. LEE: HCFA and CDC? DR. PARKMAN: Yes. Doctor Epstein reminds me as well that OSHA has also been involved in looking at safety to workers, issues of worker safety. DR. LEE: And there’s another. We’d like, for the record, how many additional FTEs would you require to adequately monitor all of the HIV testing in labs and blood banks. DR. PARKMAN: Well, that’s a difficult question. We are currently, as you know, involved with inspecting blood banks, all of the blood banks. We have recently increased the number of inspections to annual. We are going to be inspecting them annually, and that is going to require a substantial increase in our effort. I’m not sure what the exact estimates are. I don’t have those with me. I think it’s somewhere in the neighborhood of 60 or so. DR. LEE: Sixty? DR. PARKMAN: Sixty. But, you asked a broader question, and that is monitoring laboratories, which is not part of our mandated responsibility right now. There could conceivably be a number of different ways of doing that and I don’t have good figures. I can’t give you a figure of the resources that would take. DR. LEE: A more subjective question. This morning we heard some witnesses tell us that they had criticism about the good-old-boy network at the FDA that transmits down through the blood banking system, that former employees go back and forth and so forth. Do you have any comment on this? 113 I was interested in your comment. I thought you said this, that there really is no problem with the blood supply. Did you say that? DR. PARKMAN: Well, I didn’t mean to say that. I said that I thought we were doing pretty well, actually, with the HIV tests. But, it isn’t perfect and I think we can make it better. So, in that sense, I think there is a problem and we/re all working on it, people in the industry and ourselves and the blood bankers themselves. The question you raised about our -- I heard the testimony about our advisory committees and I was sorry to hear that particular point of view. I think that you have a system for ~~ a fairly complicated system -- for developing advisory committees, to try to get a reasonable array of scientific talent, of knowledge about blood banking, balanced according to geographic area, and an attempt to include minorities and women on the committee, and an inclusion of both an industry representative and a consumer representative. So, I think that process, to my way of thinking, is a pretty fair process. I guess the good-old-boy who’s Chairman of our Advisory Committee is Doctor Louise Keating, who after all is an excellent person and a woman. And I know that there -- I’m not quite sure of the present system, but I think that we do have minorities. That’s one of the questions that was raised on our committee. So, I think it is a knowledgeable committee. I think one of the people who spoke this morning said they thought it was better. I won’t make any comparisons with earlier committees, but I think it is a very good committee and I’m satisfied with it. DR. LEE: Thank you. Well, one other note. I think Doctor Ledger put a lot of our testimony into perspective when he was talking about the OB/GYN cases that he sees that require blood; the hemorrhage being so massive, so sudden, that there really isn’t any alternative, is there, for standard blood banking. Or, is there? DR. PARKMAN: No, that’s correct. I think there are cases, at least for us, that appear out of the blue. They’re unexpected and they just appear on your doorstep. They’re going to occur. They’re infrequent, thank God, but they occur. We’re going to need a blood bank for those cases. DR. LEE: Thank you. That’s mine, Dr. ServVass. DR. SERVAAS: Kristine? 114 MS. GEBBIE: A couple of areas I’d like to pursue. Let me follow-up on this question of the existing advisory committee structure. Another piece we heard about this morning was the suggestion that for purposes of doing things better in the future, a very careful critique ought to be made of the experiences of, say, 1981 to 1985, in the blood banking industry on procedural changes or resistance to procedural changes on who made what decisions. And that the existing advisory committee structure would, perhaps, not be the appropriate place for that, that it has another mission and may even be too close to the subject to give that kind of critique. What would your response to that proposal be? Can you envision such an activity and can you envision how that might be carried out? DR. PARKMAN: Well, I can envision such an activity, because we are very commonly called to explain our actions, current and past. And so, I think that there was feeling that this whole period of time should be evaluated and perhaps there is some merit in that. I think that our blood products committee is very busy dealing with about 100 different issues. I think that to that committee, we do bring a lot of product-related issues. I think there’s more of a give and take than you might have thought from the testimony this morning, which indicated that we regimented the committee and only allowed them to look at things we were interested in. I think there is a good deal of resonance between the Agency and its committees. The committee chairman and the members of the committee can raise issues that they think should be discussed. I guess, since the people who were looking at it thought that the committee was such an integral part of that earlier period that they wanted to have some outside look at it. The Institute of Medicine was one of the areas that was suggested and I certainly think that they would have that as a capability and I would see no problem in asking them to do that. MS. GEBBIE: A second area that we have been hearing about, particularly on this panel, is the potential of introducing other tests that would screen the blood supply for other conditions. It begins to sound to me that the decision about any one test becoming a standard of practice across the industry is a rather -- I don’t want to say random one, but that there isn’t a set of criteria for when any one test that a researcher might identify should be uniformly applied. Is there in existence across the system some set of principles about the frequency with which a condition occurs, the validity of the test, the cost of the test, et cetera, which 115 forms a standard scale against which one decides that we will or won’t test for "HTLV 48" when the test get invented for that? Or is it a case by case decision based on whoever is there that day and works up the best case for something? DR. PARKMAN: I/’11 start off and maybe Jay would like to contribute because he’s involved with the Blood Committee a lot and is obviously involved in these decisions as well. HIV, the AIDS virus, is the Public Health Service’s number one priority. Obviously, those tests were being looked at with as much dispatch as possible to deal with them. Let me address HTLV-I. We generally try and deal with things on a consensus basis. I think the consensus was, in our own organization, in the blood community, including the American Red Cross and the AABB and the Council for Community Blood Centers, and just the advisory committee who we would have talked to, that it was time to start dealing with that particular issue. Obviously, as you know, it is a related virus and, although the incubation period is long and the incidence of its occurrence is very low, still it was felt that the technology was there and we should try and address it as a sort of a consensus thing. Jay, do you want to -- DR. EPSTEIN: Well, I don’t think that there is a single answer or a single formula that could cope with all situations. First, we’re talking about improvements to existing tests. Second, we’re talking about tests which could not supplant current tests but which might be ancillary. For example, the antigen test could not supplant the antibody test because antigen rapidly becomes undetectable as soon as antibody emerges. So, it could only be ancillary. Third, we’re talking about tests for new agents. In that category falls the test for HIV-2, for example, which is another class of AIDS virus which does not fully cross react serologically with HIV-1, and consequently we will probably need new tests. For totally new agents, such as HTLV-I or as yet undiscovered causes of blood transmitted disease, such as hepatitis non-A, non-B, new tests will also be needed. Clearly, the problems are different in each case. For example, with hepatitis non-A, non-B, we now have in place a test which is highly insensitive and non-specific. It’s a surrogate marker. We know that the test for antibodies to the core antigen of hepatitis B cannot be a true test for the non-A, non-B agent, and yet it is recommended for screening because of the epidemiologic association of the two conditions. We use it at a low sensitivity of only about 10 percent, and a specificity of only 96 percent. 116 Conversely, when we have a specific agent in hand, it would be folly to continue to use tests that were as non-specific as that. So, in that setting, we strive for the best that is feasible and implementable. Often we have better technology on the horizon, but we, of course, are willing to be pragmatic with the technology that is at hand. The focus then is not so much one of holding out for a better answer as it is assessment. In other words, the package insert of an approved or a licensed test should tell the user what to expect when using that test. So, much of what concerns the FDA is, in fact, measurement. We strive to measure test sensitivity, specificity, and reproduceability in the conditions of actual use. Much of the standard setting involves efforts to develop a standard that’s appropriate for the particular test at hand. We are heavily involved in setting up performance standards at the manufacturing level. In fact, the hidden part of our work is the manufacturing review that goes on before the product ever reaches an approval. Regulation of a licensed biologic starts with manufacturing and much of what we do has to do with validating manufacturing standards for quality control and lot release and so forth. I would say that the question of dealing with tests that may have a high cost in relation to benefit is somewhat new and is very stressful. It would be helpful if there were outside agencies that had widespread support in the medical community and were accepted as arbiters, both scientifically and ethically which could help us discuss the question of low benefit to cost ratio. This question affects a lot of the technology which could be implemented as ancillary testing for HIV today. In summary whereas there’s no single rule that applies to all situations, what runs throughout this is the concept of doing what is the most feasible thing technologically at a point in time as well as that which is the most ethically responsible. There may be points of debate on our view of any of those issues, but I believe I have described our posture. DR. MONTAGNA: I think another perspective might be the fact that there has to be some mechanism to adequately perform surveillance for what viruses or what transfusion agents we might be concerned about. I would venture a guess that when our firm filed an IND, and I believe we were the first firm to file such an application, I don’t think anybody at FDA, and perhaps even ourselves, were really quite sure what we would find. Then when we finally determined that there were HTLV-I antibodies present in the random donor population, we’re now confronted with a regulatory issue that I happen to agree with the FDA on. That is they have to come up with some mechanism of ~ 117 licensing the test based on some sort of standardized panel that they must have in their hands. I know they’ve been working very hard and they’ve sought the cooperation of manufacturers and they’ve sought the cooperation of the people in the field and everyone has been scampering around to try to help the agency provide such a panel. I think one of the other issues, and I’d like just to briefly comment on a comment that Doctor Parkman made and then relate it to something that Doctor Epstein said, was this issue of burnout. I think one of the strengths with the Food and Drug Administration, particularly the Division of Blood and Blood Products, also turns out to be its weakness in that these are scientists who act as scientists and have to be reviewed as scientists. They are subject to peer review based on the amount of publications and all of the efforts that a typical scientist must be reviewed for, and at the same time they have to wear a hat that says they’re a regulator and turn into a bureaucrat. They have to be able to review these enormous applications. I know that we are a relatively small firm in this field and I know that we bombard them with paperwork. I know we bombard them with updates on our existing license and we are continually throwing in new license applications for additional products. It must be a terribly stressful environment to get the kind of phone calls that we provide to them continually to keep them moving or to find out how we can keep things moving, and at the same time they’re dealing with those same issues from a number of other sources and also acting as a scientist. From our standpoint, it makes a lot of sense to be dealing with someone who is a scientist because they can review those applications from a different standpoint rather than simply reviewing it as a regulator and as a bureaucrat. They’re actually reviewing these things as a scientist. I think it’s important. How you get to the point where you can allow that to happen and not create burnout, I think that’s a challenge that this Commission needs to deal with. MS. GEBBIE: I move away from that with a request for some written comments, really from any of you but particularly from Doctor Epstein, I think. I am less than fully satisfied with that answer. We have a scientific community. We heard from a major research laboratory this morning that’s out there researching the blood supply day and night, trying to invent new things, which is very appropriate and needs to happen. We have a society that’s confronting the fact that we maybe cannot and should not implement everything we can invent, for a variety of reasons. We’re beginning to confront that ethical dilemma. 118 That leads me to think we need to think in advance of what the principles are on which we will base the decision to go ahead with some invention. To say you look at some areas isn’t fully satisfactory. I have a feeling you, in fact, have some criteria in your head that you use that are a little more definitive than that we’ve been able to talk about here today and I‘d appreciate seeing some of those written out a little bit further, obviously within a very short time. My final question is for Doctor Ledger and it’s, again, to follow up on something we talked about with another panel earlier this morning. That is the issue of informed consent as a tool, not just as a protection for the patent, an ethical protection for the patient, which I think is very appropriate, but as a tool for education. In the course of obtaining informed consent, a patient could learn about some other options and consider what might be safer than a transfusion in a given situation. We spent some time discussing the question of whether that push toward a more elaborate, complete, informed consent for transfusion ought to be handled through the usual course of changing medical practice, or ought to be legislated in some way. I would appreciate any reflection you could have on that. DR. LEDGER: Well, I’m not optimistic about legislation. I’m not optimistic about change coming totally from within the profession. What I’ve seen in New York City is the pressures from the consumer. The consumer in New York City is terrified of the blood supply and the consumer that needs an obstetric or gynecologic operative procedure or is contemplating one says very clearly to physicians at least in Manhattan, "I don’t want anything from the blood bank." That was the pressure that initiated the autologous donation program. That was also the pressure that started specific donors for these patients and that’s been the pressure that’s kept the process moving. Another example that’s off this subject, but I think is a very similar thing. In England, years ago, elective induction of labor was the practice of choice of many obstetricians. That is no longer done in England. It did not come from the obstetricians. It came from the BBC running a special on the dangers of induction of labor and the practice ceased. So, I think that informed consent is a help, but I think if the public is educated, and is aware of these dangers, then the pressure comes from the public, "We don’t want that.” And the doctors, I think, will respond to that. MS. GEBBIE: And you see that as the more appropriate way to handle it? 119 DR. LEDGER: Absolutely. MS. GEBBIE: Thank you. DR. CRENSHAW: The point that you just made about educating the public I think is critical about alternatives to homologous blood. I/’d appreciate your thoughts on some of the dilemmas, at least that I see. There waS a major press conference and press release from the Red Cross just April 20th that talked about the blood and the programs for education they were going to do for the public in the work place and so forth. There wasn’t a syllable about autologous blood in either form, intraoperative or pre- donated. They are the major educators of the public from what I can see. I know that they have material that they have produced on intraoperative autologous transfusion and they are taking a greater part now in pre-donation processes and programs. There is an ostensible economic conflict of competing with themselves by recommending a process that doesn’t utilize their product. What could we do to encourage them or to come up with some other sources, if you could suggest them, that could reach the general public effectively with responsible scientific information about this? I agree with you, the consumer, if they’re informed, will ask of their doctors and that will encourage the physicians to come up with alternatives. I’m open to anyone’s input on this. DR. LEDGER: I think the Surgeon General now is doing a number of things, that are very wonderful and are going to help in increasing the education level of the public. I can only comment on setting up and attempting to set up the autologous transfusions and also the directed donations. It’s a lot more work for whatever group is collecting the blood and is running the blood bank. It’s much more complicated. You’re dealing with a new group of people and it’s directed for that one patient. It really is not what they want. But if it’s what the consumer wants, then I think physicians respond to that and I think the blood bank will respond because they’re, in effect, a service industry. I think there has to be some rewards for the blood banking industry for doing this service. Those rewards, I think, have to be monetary so they’re not going to lose money. I would think that this Commission should focus on the problem of informing the public of the whole picture and not the picture as seen by special interest groups, whether it be doctors or blood banking groups. I think that’s the Commission’s job, to come up with those recommendations. 120 DR. CRENSHAW: Thank you. I really agree with what you’re saying. I think that’s really important. MR. DeVOS: As long as you’re on that note, is ita aatter of terminology? We can’t even say the words. Antoelegous? How about a blood laundering operation or something? DR. CRENSHAW: Is that sort of like money laundering? DR. LEDGER: Laundering is a bad term in New York City. MR. DeVOS: When you try to sell a product, you get the words people can deal with. You’re dealing with words and trying to get over the public, you’re not going to make it. You’ve got e blood laundering operation over here, man. I think people will listen to you. DR. SERVAAS: I think that’s right. MR. DevOS: I can’t even pronounce the words. DR. CRENSHAW: Thank you for your editorial comments there. Doctor Parkman, I wanted to thank you for your letter. [ had raised this issue with the FDA in New York about what the FDA might be able to do because of the supervision they have over these products and learned from you that there’s a process in olace now where you’re going to be evaluating all of these chaings. The one request that I would make is given some of these potential political problems, economic problems, ‘nterdisciplinary problems between physicians and blood bankers, et cetera, and so forth, is there some way that you could champion on behalf of the Commission or the safety of blood to gee that the various forms of autologous transfusion get highly featured rather than just incidentally mentioned in the fine eprint on the last page? DR. PARKMAN: Right. I think that one of the things I alluded to in my remarks is I think we do have an educational role. We do have some publications actually our FDA consumer magazine is an award-winning publication that is distributed to censumers. We have the Drug Bulletin which has a mailing list of over a million health professionals and we have devoted several Sssues of this Bulletin AIDS issues. I think that our efforts in +hat area are important and we’re enthusiastic about them. DR. CRENSHAW: Great. I really think that you’re a *remendous resource because you’ve got all of these mechanisms in 121 place to accomplish that job or to so much of it. I wanted to ask you also about the safety of other blood products that we don’t hear about so much or drugs, vaccines, et cetera, that are derived from blood. A few instances where concern has come up about, for example, Rhogam, which was settled and reassured, seemed to be brought up by the public sector and resolved eventually. I imagine that all along we’ve been taking a look at all products that come from blood or are derived thereof. Is that correct? I’m really not very well informed on this. DR. PARKMAN: Yes. As soon as it the virus was isolated, and it was realized it was transmitted by blood and blood products, we did embark upon, in our own laboratories, a series of studies to try and show whether the processes that are used to make these products inactivate AIDS virus. For example, we showed that the process that’s used in making gamma globulin, which Rhogam is a variety of, and albumin, in fact, was very good at inactivating AIDS virus, but virus present in the products used to treat hemophiliacs was not inactivated satisfactorily, resulting as you know in many, many infections unfortunately. In the year since that, there has been a continual effort to upgrade those products and to add heating and other kinds of processes to make those products as safe as they can be. Those efforts have borne fruit and the safety of the treatment of hemophilia with these new products is -- the safety has been enormously increased. DR. CRENSHAW: Is there any place where there is a list of all the things that are derived from blood that might not ever have occurred to us? DR. PARKMAN: Oh, yes. We can provide you with a list of products, certainly. DR. CRENSHAW: Now, going from the sublime perhaps to the absurd, I remember a time when cosmetics and things of that sort, I understand, in some circumstances they contained materials that were problematic. I remember a time when a wrinkle cream contained ground up human placenta. I don’t believe that happens any longer, but it was quite popular a number of years ago. I just happened incidentally to have thought of that one, but are things like that on the market anymore? Is there any cause for concern about these hidden potions and lotions? DR. PARKMAN: I must -- DR. CRENSHAW: Or am I even correct about that? DR. PARKMAN: Yes, I believe you are. I must confess that I’m not much involved with the cosmetics part of the 121 agency. I believe that there are not such products, but I would say I will check for you. I do not believe there are such products. DR. CRENSHAW: Thanks. That’s not a real high priority issue, but I was curious. The last comment I’d like to make is to thank Doctor Ledger very much for bringing women’s issues again before us in protecting women who otherwise would be unnecessarily exposed, both themselves and their children and their sexual partners, to unsafe consequences of contaminated blood. One of the questions that I posed to the earlier panel that I’d like to ask you too. In certain of the real high blood loss circumstances, that if someone is really bleeding profusely, you’ve got to act on the spot and you obviously have no time to use some of the autologous intraoperative devices. Once someone is in the operating room, if they haven’t lost too much blood on the way to the hospital, the machines are equal to ruptured aneurysms and a variety of other things. If you had a set up on standby in the emergency room that was ready to suction and available and portable units in your mobile trauma units or ambulances, would this change the picture for even those unusual cases where you’ve got to move immediately? DR. LEDGER: I think it would change it. It’s certainly not going to catch all, but I think it is a change and I think it’s going to be part of the practice of the future. I think the focus this morning is going to be increasingly on that. I think that will be part of standard hospital operation. DR. CRENSHAW: Is that something we could, as a Commission, encourage to occur more quickly and, if so, how? What would you recommend? DR. LEDGER: Well, I think the Commission certainly can note that it’s available. You may be able to get some information on how -- the technology is there and get some idea of how much it is being used across the country. I would say in obstetrics and gynecology it’s, I think, rarely used at the present time. That’s going to require some people using it and publishing on it and then I think it will be used much more. DR. CRENSHAW: Thank you very much. DR. SerVASS: Doctor Montagna and Doctor Parkman, I’m anxious to hear both of you talk about this because I’m confused. 122 In your paper, Doctor Montagna, you said that you had found one per 10,000 in the HTLV-I. DR. MONTAGNA: One per 1,000. DR. SerVASS: Point one per thousand, wasn’t it? DR. MONTAGNA: One per thousand. DR. SerVASS: One per thousand? In HTLV-I? DR. MONTAGNA: Correct. e DR. SerVASS: The Red Cross found one per 40,000, was it? DR. MONTAGNA: There were ten per 40,000. DR. SerVASS: Ten per 40,000. Okay. So, that’s a lot more. It’s ten times more in your study then -- DR. MONTAGNA: In reality, about three times. But as I stated, I think we have to be careful that there are some hot spots and even the Red Cross study that was published just last week inScience indicated that there were certain cities within that study that had prevalence rates up that high, where other cities that nothing that was detectable. DR. SerVASS: And the Red Cross study was done last summer? Is that when it was done or just when was that done? DR. MONTAGNA: That study began -- we began providing test kits immediately after getting IND approval, which was back in -- if I remember correctly, Doctor Epstein, it was around the end of December, 1986. DR. SerVASS: ‘86 is when your test kits were finished? DR. MONTAGNA: Is when the trials began. DR. SerVASS: For the trial? DR. MONTAGNA: Yes. DR. SerVASS: And then, as of last October when the blood bankers said, "Yes, it’s unconscionable not to be testing for this," but now the ball is in your court, Doctor Parkman, and that’s the reason that you’re here. Indeed, it was last October and they said it’s unconscionable, the Red Cross said "We must be testing for this," and all the blood bankers raised their hands and said, "We must. We have to do it as soon as possible." So, 123 even though we don’t have a perfect test, if we don’t want to repeat what we did with HIV, shouldn’t we be doing it now? And I just wanted to tell you where I’m coming from because we had testimony here in Washington, D.C., from one of the state commissioners who said -- well, he’s from Hawaii, and he said to me, "I know the figures are that one in 1500 will get leukemia lymphoma from this HTLV-I, but I personally believe," and he’s a physician who works with this, "that it will be one in 500." Now, since it’s such a long time in coming and we don’t know, I feel that we should bend a little and what some of the doctors this morning suggested, that we don’t repeat what we did with HIV. Could we not expedite it, even though it isn’t a perfect test. We have a combination test with Doctor Montagna that wouldn’t cost anymore to do both at once than to do one. I believe that your company and maybe Abbott too have HTLV-I tests that are ready to go. They’re waiting. We want to know, how can we in the Presidential AIDS Commission here do our job in our final report of really pinpointing just like the admiral pinpointed the lack of funding and help? Then we want to talk about your award. DR. PARKMAN: Yes. I think all of the blood organizations have indicated that they believe that it is important to test for HTLV-I. I think that they have, at least in their recent pronouncements, indicated, however, that they thought it was prudent that they begin testing with a licensed test because they felt that there were important issues about the quality of the test and they wanted to be certain that it had passed muster as far as its sensitivity and specificity were concerned. So, we are involved in a review of these tests and are moving as rapidly as we can. I think the question always is, "At what point do you say, ‘We have enough’"? I think we’re trying to be flexible in that regard. I think the discussions we’ve had internally suggest that we are going to be flexible and we are going to go ahead and approve these tests. I think probably every I will not be dotted and every T will not be crossed in the same way as you would today with an HIV test that came to you. But we’re moving on it and we’re going to get those tests approved. At the same time, you want to be sure they’re good quality tests because you want to be sure that the tests means something and that if you get a positive result you aren’t presenting to people something that is misleading. It’s a serious diagnosis and we don’t want to tell them in an unreasonable way that their test is positive. You want to be sure of what the test shows and what you’re doing. 124 , DR. SerVASS: Doctor Bonewitz and Doctor Montagna seem to be telling us that there are good confirmatory tests for it. Doctor Montagna -- could we let him tell us? DR. MONTAGNA: I think from the prospective of HIV, when blood screening was commenced, there were probably some questions about what is the meaning of a confirmatory test. In other words, what type of a Western Blot pattern is consistent with infection or confirmatory from a standpoint of it really confirms the existence of antibodies specific for that particular virus? I think we went through an education process. There were some issues in the very beginning where people would say that a particular kind of pattern was consistent with a true HIV anti-body response and then with the advent of the licensed Western Blot by DuPont, it became clear that the definition was made more stringent. I think that’s probably what we will see happen with HTLV-I. If we turn the clock back, it’s probably 1985 revisited from the standpoint that I’m not sure everyone has a good handle on what is the ultimate confirmatory test for HTLV-I. We have presented our own views to the agency and I think we have to go through a scientific review of that to determine whether our views are consistent with what is in the interest of the Public Health Service. It’s a difficult situation. I think what we see as the longest delay is the issue of the development of the sensitivity panel. It is a monumental task. I think they’re moving forward on it and we have been waiting for quite some time now to subject our test to the stringency that would come from evaluation of that panel. DR. SerVASS: On your slide, Doctor Montagna, you showed the HTLV-I passes to family members who aren‘’t sexually engaged perhaps. Can you explain the difference in the virus that -- is there a scientific understanding of why HTLV-I passes that way and HIV does not? DR. MONTAGNA: I’m not sure we can say that HIV does not do that. Certainly maternal transmissions have been documented. Why we’re seeing it more with HTLV-I, I frankly don’t know. DR. SerVASS: Do you know the incidence of HTLV-II? There’s' one reported in MMWR, the man who I think had some link with Korea or something and got HTLV-I and leukemia and died. But do we have very many of these cases as yet, deaths from HTLV- I? 125 DR. MONTAGNA: Well, the disease is more endemic to Japan, where I would suspect we’re talking a total of 300, 350 cases reported up through within the last year or so. Here in the United States, I cannot give you a number. I don’t know if anyone else here on the panel has a number. I would suspect that we’re in the less than 100 range, but I really don’t know. I think the issue here is to take a step ahead of time, learn from our mistakes with HIV and take the steps now to prevent the problem. Certainly, I wouldn’t want anybody walking out of here today thinking we have a terrible problem in the United States. What we want to do is prevent a problem and take & look at implementing screening now. The concern that we have is /that if you do see these familial transmissions and you can have a mother passing it onto her child, since the incubation period is so long, the child may represent the most significant innocent victim in this whole disease because that child’s life exp ctancy is beyond the duration for the incubation period of, the virus and may very well have enough time to develop the diseaSe manifestations that that child’s adult parent may never have developed because the life expectancy of the adult may not have been sufficient to even allow the disease to take place. I think we have to protect the children in this case rather than whe jadults. DR. BONEWITZ: Dr. SerVaas, if I may-- DR. ServVASS: Yes. \ DR. BONEWITZ: With respect tl the premise of your question which you addressed to Doctor Montagna and myself, so that the record is correct, it was not ‘ny testimony that confirmatory tests for HTLV-I were, in fact, available. I didn’t address that issue. DR. SerVASS: Okay. DR. BONEWITZ: In fact, as we’ve learned from the HIV experience, confirmatory is probably not a good choice of words. The FDA chooses to use, and has been generally adopted, the term “additional more specific tests" in the case of HIV. I would suspect that that’s what we’re likely to see in the case of ETLV-I in order to have another test after the screening test to rule out false positives. It was, however, my testimony that ETLV-I screening tests are developed and are at the FDA now. It’s our observation that they’re being reviewed by the same group as responsible for reviewing HIV tests. Therefore, the possibilities for rapid approval of future HIV tests, including diagnostic tests, may thereby be somewhat compromised. That’s the point that I made in my testimony. 126 DR. SerVASS: Doctor Parkman, do you have a comment about that? DR. PARKMAN: Which of the various things did you want me to comment on? DR. SerVASS: Well, I’1ll ask you a different question then because I’d really like to know. You said that right now we're really not very--I had the feeling, like one of the other Commissioners, that you weren’t so concerned about -- that our blood supply was as safe as we could probably make it now. Do we really know how safe it is, when we’re not testing the people who get blood transfusions -- would anyone on the panel care to address this? Do you panel members believe that we should test people who get blood transfusions for the HIV antibody and call them back in so that we’d have a way to really understand better how many are becoming infected since there’s the lag time? Would you all think we should be doing that routinely, voluntarily? DR. PARKMAN: There was, aS you know, a period of time before testing was instituted and there was a recommendation that people who received blood in that period might wish to be tested. There, in addition, are studies currently going on by the National Heart, Lung and Blood Institute, looking at blood transfusion recipients. I think both of those things are appropriate and things that should be done. I don’t think at the moment that we would want to recommend that everyone who received a transfusion in the present time should get tested for HIV antibodies. DR. SerVASS: Because of the cost? DR. PARKMAN: Well, what you’d be doing is testing a population that if you figure that -- say that the incidence of HIV infection is in between the two figures I gave earlier, say it’s one in 100,000 -- DR. SerVASS: Well, we wouldn’t know that without testing. DR. PARKMAN: Well, no, but I think even one to 40,000, that is a great number of people to be tested. You would be testing a population in which you’d have to do very, very large programs and test lots of people. In those groups of people you would be testing, you’re going to get some false positives and you’d have to do additional testing. I think we ought to examine the results of the current studies before embarking on a program of routine testing at this time. 127 DR. SerVASS: I think the galactosemia for babies is one in 30,000 or something and we do test all infants in most all states now for galactosemia so that we can prevent mental illness. I’m not sure that’s the right number. But since that tests in the Army cost $4.00 for HIV, it just seems a pretty inexpensive test to not do routinely in order to pick up more information about the disease and what we can do with these people early on with AZT and help them when they’re first infected instead of waiting for them to get sick. / That’s what I’m wondering how you other panel members who are scientists -- Doctor Montagna, do you -- DR. MONTAGNA: Well, one comment I’d like to make, and it kind of ties your question with that of Doctor Crenshaw’s earlier, namely what kind of education do we need to make available? I think for unfortunate reasons, we have created an environment where we have labeled potential high risk groups as culprits in these diseases, whether we’re talking about HIV or HTLV-I when in reality those behaviors are risky and anyone who participates in those behaviors is putting themselves at risk. But because of the confidentiality issues that arise from putting labels on those groups, to a certain extent we’re handcuffing the medical community to be able to effectively monitor the disease. With any other sexually transmitted diseases, we have the ability to go and monitor their sexual partners. We have the ability to screen for the benefit of those individuals. With HIV and hopefully with HTLV-I, we have to have an ability to monitor people, particularly because of what we’re seeing within families. If people go through life living in a fool’s paradise, thinking that because they’re not displaying any disease symptoms they are free of the virus, particularly in this case HTLV-I, we could create a worse problem than we already have. . Somehow or other, we’ve got to be able to monitor people, but within an environment that is sensitive to the confidentiality issues. I don’t know how you go about doing that. But I think the first thing we have to do is educate the American public that this is not a disease of particular risk groups. This is a disease that is brought about or it can be -- it is a disease caused by a virus and you can get that virus by a variety of different methods. Some of them as innocent as a young child being effected by its mother. DR. SerVASS: Women like our witness this morning would probably welcome being monitored and wouldn’t object. Admiral? 128 CHAIRMAN WATKINS: Doctor Parkman, this morning, and you may have been here for it, Doctor Asher made some comments about the dichotomy between plasma products versus fresh blood products, that we treat them differently. The former is competitive bid, the latter is sole source voluntary program, not for profit. He didn’t seem to think that was right. He seemed to think we’d gone beyond the point where that was a useful approach and there should be more flexibility in the system. Would you comment on that? What do you think about it? He more or less brought you all into the game with some rather severe criticism, as well as did Ms. Dutton who was here. What are your comments about that? Does the structure of the blood industry need review and does there need to be something that provides that inherent accountability and responsibility issue that we generally don’t fingerpoint at not- for-profit voluntary people because of their goodness and so forth, that would help create a better environment, a self- policing environment within the blood supply? DR. PARKMAN: I think that the basic differences and between blood for transfusion and plasmapheresis. There are reasons why plasma donors are generally not voluntary. There are important differences in the procedures. In plasmapheresis, it takes a number of hours to do the procedure, so donors have to be in the blood bank, within the plasmapheresis center, for a substantial period of time. The procedure is done repetitively. It could be done repeatedly without the long intervals as when you're taking whole blood. So, there are reasons why paying donors for plasmapheresis is a reasonable thing to do. I think they laid out this morning why it was that in the ‘60s and early ’70s the paid donor and the volunteer donor differentiation was made. Blood was labeled that way because people did show, scientists did show, that the incidence of hepatitis antigen, for example, was different between the groups. Paid donors tended to have more positive results than volunteer donors. Now, that wasn’t true in certain specific locations. Doctor Tazwell’s location at Mayo was different. But overall, not dealing with special separate locations, overall it seemed then that to label blood as paid and volunteer had a beneficial effect on the quality of the blood and allowed people to know that there was that difference and that in itself had a beneficial effect. There was less use of paid blood and more of volunteer. Paying donors doesn’t necessarily make them unsafe. On the other hand, if you start paying donors again and opening that up, it seems to me that there is a risk that by having that financial reward you will begin to get operations which are less 129 well monitored. A substantial financial incentive may makes donors less likely to be forthcoming. So, I have real concerns about that proposal. I think, as with everything, you need to rethink things. I think it’s worthwhile thinking about a different system, but I don’t think we‘re ready to go that way tomorrow. DR. SerVASS: Doctor Parkman, I just wanted you to see this award for excellence. I told you we would talk about the award and get your opinion of what you think. We’ve used an artist here, but this is the FDA and the President and it says, "The President of the United States of America, for outstanding leadership, commitment and dedication in the fight again human immunodeficiency virus epidemic." Now, if you have any suggestions that we can lobby the rest of the Commissioners and get the award that would help get more good people into the FDA so that we can all rest easy about the blood supply, this is for you to see before you go back to Washington and give us your ideas. Thank you. DR. PARKMAN: Thank you. It looks very nice. DR. PRIMM: I had just a couple of questions for Doctor Montagna and Doctor Bonewitz. Have we looked at any archived blood to see the presence of HTLV-I as far back as we have looked at other archived blood for the presence of HIV-1? I don’t know whether we have or not. I’d like your comment on that. And then, because there have been reports by previous people who have come here to testify that the presence of HIV-1 and HTLV-I together sort of speeds the progress of people who are HIV infected onto full-blown AIDS and opportunistic infections, it would be beneficial, particularly for me because we are doing studies now in my program where we are finding a number of narcotic addicts who have HTLV-I presence and, of course, HIV presence. Almost 50 percent of the people that we have looked at with the study, done jointly with the Abbott Laboratories, we have found thus. That’s one thing that I’d like to hear about. DR. BONEWITZ: Doctor Primm, with respect to HTLV-I archived samples, the first one that comes to my mind is a study published recently from the blood bank at Sloan Kettering Hospital. I don’t know how old those samples were. They were the ones which had been studied for HIV, so they had been around for some small time. They were able to identify -- the samples, by the way, were from patients who had received large numbers of transfusions as part of their therapy -- and identified a small number -- and I don’t remember exactly the number. I think it was about six or 130 seven patients who were found to have been HTLV-I sero- positive. And of that group there were, I believe, three who were found to have become sero-positive during the course of their transfusion therapy. And so, the conclusion was, not having had donor specimens to test but rather to look at the recipients, the conclusion was that this seemed to suggest that HTLV-I infectious material was present in the blood that had been used to give transfusions to these patients. That’s the one that comes most rapidly to mind. I’m not aware of anything older than that. DR. EPSTEIN: I believe that the NIH also has been doing a retrospective study of donor recipient pairs, it has not yet been published. DR. PRIMM: What about the archived blood at the Addiction Research Center? It would seem to me they have blood that goes back as far as the early 70’s that they collected at Lexington from the addict population. Possibly, one could get some idea of the onset of disease after infection from those kinds of populations, that is, of HTLV-I disease. I just throw that out, because it’s really important to me and my colleagues who are dealing with intravenous drug abusers. Because, we are finding people who are infected with HTLV-I and not at all massive numbers of people and not all infected with HIV. So, I think it would behoove you to begin to look at some of that data. One more question, Doctor Epstein. You talked about the titre of HIV antigen falling once you have the titre rising of the envelope and core antibodies. In the Finnish study or the Scandinavian study, for example, I don’t know whether antigen titres were up when they did antibody studies on these people and found them negative for the HIV antibody but still had been exposed constantly with at-risk behavior for a period of a year and a half to almost two years. How do you explain that phenomenon, or is it explainable? DR. EPSTEIN: Could you just restate what phenomenon? DR. PRIMM: The phenomenon of antigen titres remaining high without the formation of, or the possibility of them remaining high without the formation of antibody titres at all going up for a long period of time. DR. EPSTEIN: I don’t think that’s exactly what they found. I think you’re referring to the paper by Rank, the lead author -- 131 DR. PRIMM: Sure. DR. EPSTEIN: -- and the last author in the Lancet. I believe that their observation was that there had been individuals who had incomplete patterns of sero-conversion over a period of many months, I think the longest time period was upward of 30 months, some of whom had a detectable viral marker either by a culture, a gene probe, or an antigen test at some point during that time period. The majority were not devoid of any serologic marker, although there definitely were points at which there was no positive antibody test and yet there was either at that time a positive antigen or some other marker. DR. PRIMM: That’s exactly what I mean. DR. EPSTEIN: The issue seems to be not so much persistence of antigen as how long it takes to fully sero- convert post infection. I think that the implication of that paper as well as a set of other papers that have come out before suggests that in some individuals, and we don’t know what proportion of all infected individuals, it may take a lot longer to seroconvert than the conventional eight to twelve weeks that has been observed, particularly in individuals infected by transfusion. I would say that putting it in its broader context, we don’t know whether it takes longer to seroconvert if you get infected by the sexual route, perhaps because of the route of infection or the dose of virus. These findings have .given the scientific community some pause in thinking that we know that everyone seroconverts, which may not be true, or’how long it takes, which may be longer than we thought. Specifically addressing the question of persistence of the virus in the blood stream, there hasn’t been a method to determine whether virus persists in the blood stream routinely in the infection. When we measure antigen, we’re measuring antigen accessible to being captured by antibody’ in an assay system. As antibody rises in the infected person, one would expect the antigen to be complexed and perhaps not detectable even though virus might still be present. So, we don’t really know the answer to that question and it probably awaits different forms of study for example, of the immune complexes, or looking for other kinds of virus marker. But, what seems to be a routine observation is that detectable antigen, given the limitations of that technology, disappears promptly when antibodies rise to the point where antigen, I believe in data presented by Abbott Labs, is only found approximately eight to ten percent of the time in an asymptomatic person who is antibody positive. 132 Now, antigen seems to -- at least detectable antigen, seems to reemerge later in the course of infection when there are symptoms. In ARC patients, about 40 percent may have a positive antigen test. In AIDS, about sixty percent may have a positive antigen test. But, whether there really has been circulating virus all along, ‘we just don’t really know. But, I don’t think that was quite the point of the Lancet paper. DR. PRIMM: Yes. Well, I’m thinking of why not do the antigen test? DR. EPSTEIN: Well, it’s really a different question. DR. PRIMM: It would seem to me that we can’t completely depend upon the antibody test to give us a clean bill of health in terms of donating of blood that we are going to use. DR. EPSTEIN: Yes. There are really two ways to look at that question. One is, does the test work. And the other is, is it beneficial in relation to cost. The studies that have been done in donors have mainly been done abroad. In the U.S., only a couple of thousand donors were tested and they were all negative for antigen. In the Federal Republic of Germany, I believe that at this time they’ve tested close to 400,000 donors. Their prevalence of HIV antibodies, while ten-fold less than ours, is still significant. They too have found zero antigen-positive, antibody-negative donors. One may also take the data from high-risk groups. The only data that I know of that’s in the literature is from Oklahoma City. Dr. Gilcher studied individuals at STD clinics. In a subgroup of those, they were able to determine that for every 100 antibody-positives that they picked up, they could pick up one that was antigen-positive, antibody-negative. Five out of six of individuals in that category would have been picked up by other markers that are already in place, particularly hepatitis B markers, or the surrogate marker for non-A, non-B. So, with antigen testing, you’re picking up only one per 100, and then maybe only one out of six of those requires the test. We’ve been able to estimate that you might pick up somewhere between one to three per million using this test in the overall U.S. population. That’s at an added cost of testing of between $50 million and $70 million. Now, there are two ways you can look at that cost. You can say, "Well, since it’s distributed, it just means that everybody’s got to pay another five or ten dollars for the unit that they receive, Even if you only protected ten people a year, that’s worth it because that individual only paid ten dollars." 133 The other way to look at it is, is to ask where the next $70 million of health care dollars should go, especially in the face of what may be a rather insensitive test. The best available data suggests that if you do cultures on plasma to see if virus is present and then you do antigen capture, you’ll only pick up about 40 percent when the virus is actually there and measurable. So, a trade has to be made. I think that it’s a question of clinical efficacy and the alternative is better donor exclusion. It’s been proven that in about 85 percent of individuals found with a positive antibody test, if you bring those people back for an interview, they have risk factors that they’re aware of and could have admitted. The question is, why didn’t we communicate with them? I think that another way to put the question is, if you have $70 million annually that you want to spend starting tomorrow, couldn’t you do something with education just to get those donors to self-defer? They know who they are, although not im every case I don’t want to raise the whole social question of how we deal with the seropositive donor. But, I think that use of the antigen test to screen blood is a question of allocation of resources, and it’s a question of whether the test is efficacious in the donor environment. It’s clear that if you’re dealing with a high-risk population, the cost benefits are very different. But, that’s a Clinical diagnostic issue and not a blood screening issue. DR. PRIMM: Thank you very much. DR. BONEWITZ: Doctor Primm, if I may extend the remarks of Doctor Epstein just briefly, I’d like to mention that we’ve become aware that the various blood banking organizations in the country are planning a study of this issue, that is to say the prevalence in the blood donor population of individuals who are negative for antibody but positive for the HIV antigen. I think really only by that study will we have the clean data set that we need to be able to answer your question. DR. EPSTEIN: If I might, the FDA reviewed with its advisory committee the question of whether screening for antigen was indicated. That occurred in September of ’87 and we got strong reinforcement of the view that there wasn’t a data base that showed efficacy and therefore we couldn't approve it for that indication at that point in time. We ourselves recommended a large-scale study to resolve the matter. We have since that time worked constructively with the American Association of Blood Banks, which included the American Red Cross as well as the CDC and the NHLBI, to devise a 134 study that we hope will take place in the near future to survey 500,000 donors in an eight week period and determine whether there are positives for antigen when there are negative antibodies. This gets back to the point that Ms. Gebbie was raising, when she asked what are the standards or criteria for bringing about a new test. We don’t have an answer to the question of what must the prevalence of a condition be for it to be worth implementing the test, and at what cost. If we get zero out of 500,000, the statistical assessment would be that there could still be as many as six per million according to the Poisson Distribution which means 60 per year on 10 million donations. Now, is that or isn’t that the point at which you should spend $70 million? You’re talking about $1 million per case of detection which is not even per case of disease prevention because 60 percent of the recipients would be expected to die of their underlying condition within two years and the AIDS incidence is only about 50 percent at 10 years. So, it’s a very difficult question and there’s no preexisting standard. Our position is that there ought to be a database to help cope with such a difficult technological and social issue. DR. PRIMM: Well, what did the sero-prevalence study in the Federal Republic of Germany show out of the 400,000 that were looked at? What was the sero-prevalence? DR. EPSTEIN: Oh, you mean the antibody prevalence? DR. PRIMM: Yes. DR. EPSTEIN: I don’t know that figure off the top of my head. When I last saw the data, it was somewhere between one-fifth and one-tenth of ours, but that was when they'd studied the first 150,000. I don’t know where they are today. DR. BONEWITZ: I can comment on that. The data most recently published from that study showed almost exactly one- tenth the prevalence of the United States. The prevalence among first-time blood donors in the U.S. is about .04 percent, according to the Red Cross, and .004 percent in this study from Germany. Doctor Primm, if I may also just take a minute to set the record straight about the antigen test so that you will not perhaps be unaware of it. Abbott has submitted for a licensure to the FDA, an application for the antigen test. However, that was for and is for diagnostic application, some of which I cited in my testimony and specifically not for blood screening. 135 DR. LEE: Just to clarify the Sloan-Kettering thing, these few cases go back to the late ’70s. They were in- leukemics who had been transfused, et cetera. None of them had T-cell leukemias. So, the report couldn’t come up with any conclusions except that they found these few cases in the heavily transfused coterie. DR. BONEWITZ: Yes. DR. SerVASS: Thank you all very much for coming. I hope you’ll all send your written material, if you haven’t already. If you have anything else to submit about these subjects, please do so immediately. The final report is getting very close. Thank you. MR. CARMAN: I am Charles Carman. I am Director of Polymer Composites for the B.F. Goodrich Company, Cleveland, Ohio. I am also Chairman of the Board of the National Hemophilia Foundation and serve as Chairman of its AIDS task force, a post that I’ve held since AIDS was discovered among persons with hemophilia in 1982. I have another qualification for appearing before you today. I was born with hemophilia, a chronic, hereditary blood clotting disorder that effects males almost exclusively. I am also 49 years old, married, father of three sons and one daughter. Our family understands how hemophilia and now how AIDS directly effects a family setting. Hemophilia is caused by a deficiency of a protein in the blood called anti-hemophilic factor, or AHF, or factor 8. Persons untreated by replacement of factor 8 may suffer spontaneous internal hemorrhage which can lead to severe pain, crippling joint disease and even death. Because of my age, I have seen the treatment of persons with hemophilia progress from the use of whole blood collected from friends and neighbors to the use of fresh, frozen plasma and ultimately to the use of factor 8 which is separated from whole blood and plasma products that we know today. In the late 1960’s, cryoprecipitate was discovered. This is a factor-rich substance isolated from blood by freezing. This, in turn, led to the development of AHF concentrate which has revolutionized the lives of persons with hemophilia. These new blood products freed us from dependence upon hospital emergency rooms and lengthy hospital stays. In turn, it enabled us to administer our own therapy at home or in our offices on a timely basis without the ultimate disruption of our lives. Coupled with the availability of AHF concentrate, Congress created in 1975 the Federal Comprehensive Hemophilia 136 Treatment Center Program. Beginning in 1976, the first year of federal support for this program, provided funding for the development of 24 comprehensive hemophilia treatment centers and 60 affiliates established on a regional basis across the U.S.A. About 10,000 persons with hemophilia, or approximately half of those that are affected, are now served by these centers. These centers provide multi-disciplinary services, including psychosocial, financial, vocational counseling, in addition to the medical, dental and orthopedic care. This amazing federal treatment center program accelerated the use of home care which has revolutionized the lives of those with hemophilia. A few statistics will show how lives have been changed. The number of days per year lost from school or work declined an amazing 73 percent, from 14 and a half in 1974 to 3.9 days lost on an average in 1985. In that same ten year period, the percent of unemployed adults fell from 36 percent of the population of those affected to nine percent, for an unemployment rate comparable to that of the United States in the same time period. By the 1970s, the lives of persons with hemophilia had been dramatically changed. No longer was our average life span 11 years, but it was now 21 years. No longer could we look forward only to a life of pain and dependence, often unable to attend school or to hold jobs. For the first time, persons with hemophilia were a part of the mainstream of American life. Those people that were affected jumped into that stream and swam with all their might. We attended colleges, obtained advanced degrees, married, raised families, obtained executive positions in corporations and became a thriving, productive part of the American dream. Our self-treatment and training literally allowed us to travel around the world, wherever our jobs might take us, because our AHF factors could be carried in our briefcases or at our sides and used when needed, without the necessity of a physician on the ready. Then suddenly, in 1982, this dream became a nightmare. I’ll never forget the realization of many of our worst fears when this new scourge, which is called acquired immunodeficiency syndrome, AIDS, was confirmed to be spread through blood products. The fears were not only for myself and my family, but for the entire hemophilia community. For in the course of working together over many years to improve blood products and develop comprehensive care, this group of patients, families and treaters had, in fact, become an extended family and now this group faced a crisis together. In the months that followed the first discovery that AIDS was spread through blood, we determined that the new tragedy 137 would not destroy us. From the outset, the National Hemophilia Foundation worked closely with the Centers for Disease Control and others in the government to seek remedies to the blood safety issues. By 1985, in the space of three years, a heat treated process for blood products was developed. In addition, a triple safety net comprised of donor screening, blood testing and the heat treated factor 8 product was in place. By 1985, blood products were markedly improved from contamination by HIV. But certainly the problem was far from being resolved. By that time, thousands of persons with hemophilia had become infected with the virus and several hundred had already contracted full-blown AIDS. These were not mere statistics to us. They were people, friends and co-workers with whom we had fought the good fight to develop comprehensive care and carry the treatment of hemophilia into a model system for all the world to be following. Always in the back of our minds, and in my mind, a small voice as saying, "There but for the grace of God, go I," because each of us with hemophilia were, in effect, carrying an unloaded pistol which seemed to be ready to fire at any time. It was a terrible irony that the blood products which have provided us with freedom from pain and disability and which enabled us to become a fully integrated part of a normal life type within the U.S. has, in fact, been identified as the very source of our vulnerability to AIDS. The hemophilia treatment centers, particularly with respect to risk reduction and psychosocial care, have provided anchors of support over the past six years. Without these treatment centers, there surely would have been widespread panic among the hemophilia community. However, as they watched over yesterday’s success story, it was becoming a grim tragedy of a new medical crisis, for the statistics today are indeed grim. One in every 30 individuals with hemophilia have contracted AIDS. Ninety percent of persons with severe hemophilia have been exposed to HIV. This grim statistic also carries emotional hammers. It means wondering every time you get a cold whether it is, in fact, only a cold. It means worrying what others, an employer, a wife, a friend, thinks when you’re tired after a week of a heavy work load. Is it, indeed, just being tired? It means adolescents and the young adults must worry about the relationships that they’re developing with girlfriends. Will they, in fact, be avoided or shunned in the mistaken impression that they can give AIDS by their mere presence? It also means an added responsibility which this group carries to be responsible in their relationships as they grow into adulthood. 138 Nineteen wives of men with hemophilia have contracted AIDS. One might say 19 is a small number, but with a disease like AIDS there is no "only." These are 19 women who are forced to endure an unspeakable ordeal, 19 families who have already been disrooted and blighted. More than that, it means that the men who love these women, to all those with hemophilia, there is the possibility of transmitting AIDS to a loved one and this is the greatest fear and sadness imposed upon this group. It is estimated that 10 to 20 percent of sexual partners of people with hemophilia have converted to HIV positive antibody status. Therefore, counsel must be provided to young couples, couples with their entire lives before them, to consider the consequences of childbearing which for many means to defer having children. I am thankful that my three sons and my one daughter, all of whom I love dearly, were born long before AIDS. I thank God that they’re beautiful, bright and healthy and a constant delight to me and my wife. But I can’t answer what I would have said 27 years ago if I were told that my choice were to jeopardize the health of both my wife and an unborn child if one had to defer the fulfillment that can only come with children and a family. These are difficult times, but the answers must be faced. An increased number of AIDS cases have been reported in persons or patients with mild and moderate hemophilia. The translation of this means that people who once led lives that were normal in every respect, in fact normal to the point that people could not even tell they were affected, now too run the risk of being sick and even dying, though they possess no outward symptoms. Discrimination is an additional possibility that causes great concern for those with hemophilia. Children have been barred from classrooms, discrimination is occurring in the work place. This discrimination is based on the fact that the persons involved have hemophilia, not necessarily because the public has an awareness of the implication and the true implication of how AIDS is transmitted. There is a growing additional concern on my part that I’d like to express on behalf of all of us with hemophilia. This has to do with the cost of the new purer, more viral safe clotting factor products. Through the encouragement of the National Hemophilia Foundation, there are products now available that are unquestionably more safe than any factor 8 products previously available. But these new generation products are four to eight times more expensive. Consequently, there is considerable concern that third-party payments from private and governmental insurance programs could be jeopardized and access to these products could be denied. 139 Comprehensive care has been the key to placing persons with hemophilia into the normal walk of the American life, enabling productive contributors to our society to be the result. If the state of the art factor products are denied, then comprehensive care stands the chance of digressing to a state it experienced three decades ago. This would be both a moral and a human tragedy. We’re working for the day when there will be a cure for AIDS as well as a cure for hemophilia. But meanwhile, we need the support of a sympathetic, educated and informed public, one that knows how AIDS is spread and how it is not. We need friends, both in the public and in the private sector to maintain the safest of blood products available to all the American public, and we need the continuation of comprehensive care. I appeal to you as a Commission to help us in that fight. I would like to thank the Commission for its efforts in behalf of those affected by AIDS and for allowing me to testify here today. Thank you. DR. SerVASS: Thank you, Mr. Carman. DR. SerVASS: Doctor Evatt? DR. EVATT: I’m Bruce Evatt, Director of the Division of Host Factors, Center for Infectious Diseases for the Centers for Disease Control. I’m pleased to meet with the Commission to discuss the current issues concerning the safety of clotting factor concentrates in the hemophilia community. The first case of AIDS in a person with hemophilia was reported to CDC in January 1982. By the end of 1982, investigators suspected that non-heat treated factor 8 preparations were the vehicle of transmission of the causative agent. Identification of the blood borne causative agent, now called human immunodeficiency virus, soon followed. Untreated clotting factor concentrates which were known to transmit viruses such as hepatitis B and non-A, non-B were ideal vehicles for the transmission of the newly discovered HIV. Any given lot of commercially prepared factor 8 concentrate can contain plasma from between 2500 and 25,000 blood or plasma donors and thus the probability of contamination from a single infected donor to the pool is greatly amplified. The appearance of HIV in the blood of hemophilia patients inspired a resurgence of investigative activities and the methods of inactivating viruses and factor concentrates. HIV was found to be very heat labile and heating concentrates in either liquid or in the lyophilized or freeze-dried state was a relatively inexpensive and rapid way to activate the virus in vitro. 140 Heat treated concentrates became the standard therapy for hemophilia patients in mid to late 1985 and those products produced a dramatic reduction in the infectivity rate of HIV among hemophilia patients. However, once investigations began to reduce the risk of HIV by new methods of virus inactivation and clotting concentrates, manufacturers, research scientists and consumers all press for a further goal to develop safe products, free of viruses besides HIV. Several new processes, including heat treatment, have been developed and are being tested for the ability to reduce the risk of infection with human immunodeficiency virus and hepatitis viruses. The effectiveness of each process is influenced by many factors in the manufacturing process. In addition, other factors, such as the number of donors in the so-called window period of infection, that is donors who are infected but have not yet developed an antibody response, can affect the amount of virus inoculum in any given pool. The effectiveness of various processes has been assessed by an in vitro assays for virus. Such an artificial measurement of the safety of the product only approximates in vivo infectivity or the infectivity in the human. Continual monitoring of the population for sero-conversion is a necessary sequel to the in vitro testing. Using surveillance data and several different estimates of the number of people at risk as a denominator, the annual rate of sero-conversion of hemophilia patients on donor screened virus and activated clotting factor products seems to be well below one case per 1,000 sero-negative individuals. The appearance of any sero-conversion necessitates a thorough investigation to rule out the following: one, a risk factor other than virus inactivated concentrates; two, breakdown in the manufacturing processes; or, three, errors in screening and HIV antibody testing procedures. Hepatitis virus, especially non-A, non-B hepatitis, has been much more difficult to inactivate in preparations of concentrates. In addition, testing for inactivation is also very difficult because the chimpanzee animal model is not adequate to determine safety in humans. At present, trials include hemophilia patients who have not been previously treated with blood products and who receive the various new products. Several products using newly developed viral inactivation techniques are currently being studied in many centers. It appears that non-A, non-B hepatitis is not inactivated by dry heating concentrate to up to 72 hours at 68 degrees centigrade, a relatively inexpensive means of inactivating HIV virus. Preliminary data does suggest that several other processes many inactivate non-A, non-B hepatitis as well as HIV. 141 Four of the five major manufacturers in the United States have decided they will no longer offer products treated with dry heat at equal to or less than 68 degrees centigrade to the hemophilia population. These manufacturers may believe that materials dry heat treated by some processes may not be as safe for other infectious viruses such as hepatitis non-A, non-B. Liability must have been considered in making these corporate decisions. The effect of the withdrawal of dry heat treated products on the marketing of clotting concentrates is substantial. The newer products, although offering an increased margin of safety for non-A, non-B hepatitis and other viruses, increases the cost of therapy by as much as 400 to 800 percent. In addition, there has been some concern that in the immediate future the elimination of dry heat treated products from the American market may create a temporary shortage of clotting factor for these patients. On January the 11th, 1988, Centers for Disease Control hested a meeting in Atlanta, Georgia to review the safety of hemophilia therapeutic products now in use. The purpose was for hemophilia health care providers and other consultants to share current epidemiologic and clinical data and to obtain views on therapeutic issues raised by these data. AS an outgrowth of that conference, the National Hemophilia Foundation’s Medical and Scientific Advisory Council reviewed data presented by the speakers at these sessions and revised their guidelines for therapeutic uses of materials currently available to the American hemophilia population. These new guidelines address the choice of material in relat‘onship to known safety of products and will be updated as more information becomes available. In summary, manufacturers of blood products have developed new blood products that today are currently virtually sree of risk of transmission, transmitting known infectious disease to hemophilia patients. The introduction of these products has produced a transition period that is notable because ef the unanticipated high cost. This sudden escalation of cost adds censiderably to the financial burden for families of hemophilia patients, third-party health care payees, and hemophilia treatment centers. The disjunction between the availability of product, produced to some extent by safety concerns, and the demand for inexpensive products produced by financial concerns will persist until mechanisms are in place to pay for this increased safety. In addition, the hemophilia community will need continued financial support to care for the increasing number of 142 cases exposed before treated products were available and to support necessary education and counseling to prevent the spread of HIV to hemophilia wives. Thank you. DR. SerVASS: Thank you, Doctor Evatt. DR. SerVASS: Doctor Rickles, Professor of Medicine at the University of Connecticut, School of Medicine and Dentistry and Director of the Comprehensive Hemophilia Center at that institution. DR. RICKLES: Thank you for allowing me today to share my experiences as a hemophilia center treatment director. I’ve been involved in the care of the patients with hemophilia since 1960 when, as a student, I began to work in a medical research laboratory on problems related to the understanding of human blood clotting and the defects responsible for bleeding disorders like hemophilia. As you’ve heard from Mr. Carman, at that time patients with hemophilia rarely lived to middle age and most of our adult patients were confined to wheelchairs due to joint damage caused by repeated bleeding episodes. As you’ve also heard from Mr. Carman, all of that has changed since the discovery of methods for concentrating the missing clotting factors responsible for the two major forms of hemophilia. It’s been a remarkable experience for me to participate in this transition, from a time when patients were absolutely dependent on the health care system to the current era of independence and relative self-confidence. My patients now include the past captain of the Cornell swimming team, a young man who competes in long distance bike races, a master of tai- kwon-do and many others who are physically fit -- people who are the beneficiaries of this replacement therapy in a remarkable way. For many hematologists like myself who have been involved in the treatment of other blood disorders such as leukemia and lymph node cancers where the outcome of therapy is not always favorable, the care of patients with hemophilia became a real upper. It is with a particular sense of frustration therefore, that I speak with you today about the devastating effect AIDS has had on these individuals and the importance of maintaining quality treatment with products of high purity. As you've already heard, approximately 60 to 90 percent of patients in the United States with severe hemophilia are HIV antibody positive, having been exposed to HIV prior to 1985 when the factor concentrates became heat treated to inactivate the virus. In my center, one child with hemophilia has already died of AIDS, two adults are now disabled due to the infectious 143 complications of AIDS and two children and two adults have AIDS- related complex. However, as noted by Doctor Evatt, it appears that the clotting factor concentrates are now free of HIV and many of the newer more highly purified products may also be free of both the hepatitis B virus and the so-called non-A/non-B hepatitis viruses, both of which have contributed to a disturbing incidence of chronic liver disease in our patients. These new products are an important step forward for our younger patients who have not yet been exposed to these viruses and we hope that these products will protect them from exposure to other viruses as well. Given the relatively small but continued risk of HIV and the unknown consequences of continued exposure to non-A/non- B and other viruses, and other foreign proteins in those already infected with HIV, serious consideration should be given to the use of recently introduced processes for preparing concentrates that offer substantially reduced viral contamination and higher purity. I would simply point out to you the fact that the previous factor concentrates represent less than one percent factor VIII and greater than 99 percent contaminating proteins. Based on the data presented at the January 11, 1988 CDC meeting to which Dr. Evatt alluded, National Hemophilia Foundations Medical and Scientific Advisory Council issued the following recommendations to physicians treating patients with factor concentrates. First, in regard to the human immunodeficiency virus, there is accumulating evidence that improved viral depleting processes have resulted in factor VIII products with substantially reduced risk for transmission of human immunodeficiency virus. Products that are heated in aqueous solution or pasteurized, detergent-solvent treated, monoclonal antibody purified or heated in suspension in organic media or dry heated at high temperatures for long periods of time are preferred for the treatment of hemophilia A for substantially reducing the risk of HIV transmission. In regard to non A/non B hepatitis, preliminary data suggests that some improved methods of viral inactivation may result in a reduced risk of hepatitis transmission. These new products are those that are heated in aqueous solution, pasteurized, detergent-solvent treated or monoclonal antibody purified. Heating factor VIII in suspension in organic media or dry heat treated at high temperatures for long periods of time may not be as efficient in attenuating or eliminating hepatitis viruses as the previous approaches. It is recognized that this information is preliminary and more clinical data are urgently needed. 144 As Doctor Evatt has noted, because of the failure to achieve total viral safety with some treatment methods, particularly for non-A/non-B hepatitis all manufacturers except one have ceased to provide dry heat treated product and are now providing only products that are either pasteurized, detergent solvent treated and/or monoclonal antibody column purified. The amount of clinical data available for these new processing techniques varies considerably from product to product. Preliminary data, however, appears very promising in supporting the effectiveness of these methods for substantially reducing the risk for transmission of hepatitis viruses. Nevertheless, a number of my colleagues are concerned about the long term effects in people with hemophilia produced by the continuous exposure to even small amounts of residual viruses contaminating the products. Lastly, there is in-vitro and in-vivo epidemiologic evidence that progression of HIV infection is accelerated by concurrent infection with other viruses. In these times when a majority of people with severe hemophilia are positive for the HIV antibody, there is concern at least about the hypothetical possibility that introduction of other viruses will serve as a cofactor in the progression of asymptomatic HIV infection to full blown AIDS. Therefore, I believe if price were no object most, if not all, hemophilia physicians would prefer to use these new products. But price is an object. Price is a serious problem that has risen as the new challenge to us, a challenge to be able to continue to treat hemophilia without unnecessary exposure to viruses or foreign proteins. Patients in my state are already being threatened with the loss of insurance coverage for their hemophilia care because of the increased costs of these new HIV~-free products. I’m already observing a gradual slippage of the quality of care that I can give to patients due to the costs of the new products. I hope that we will not have the patients with hemophilia pay for the progress we've made in rendering blood products AIDS virus free by eliminating their health care entirely. Thank you for this opportunity. DR. SerVASS: Mr. Brownstein? MR. BROWNSTEIN: Thank you. I’m Alan Brownstein. I am the Executive Director of the National Hemophilia Foundation. And as you have just heard, the accumulating data and the introduction of a number of a new viral and activation and purification processes offer a great deal of hope for truly safe blood products for present and future generations of people with hemophilia. This is a direct result of AIDS. We had to have safer products and the scientists in government and in industry 145 and the hemophilia community worked together towards that end. However, with these advances there are major setbacks that loom before us with respect to the price and supply of these products. A major problem in the use of viral safe highly purified infinity column generated cloning factor concentrates is their price, which is considerably more expensive than the price of dry heated concentrates, most of which are no longer available, as you heard before. The prices of the other products utilizing processes other than dry heat are also considerably higher than the dry heated products. In December, 1987 heated concentrates could be purchased at six to nine cents per unit. [In April 1988 concentrates prepared with the infinity column purified method are now at a wholesale price of 55 to 62 cents per unit. The manufacturers who offer the infinity column purified products have now totally ceased production of dry heated concentrates. And in my attachments in table 1 I include a list of comparative prices of all the products that are available between 1987 and 1988. In terms of what this means for the patient is what used to cost $8000 to $10,000 per year now costs between $50,000 and $75,000 per year. This will surely be financially catastrophic for thousands of families effects by hemophilia. It will also lead to 25 state programs, state hemophilia programs, becoming bankrupt well before their fiscal years have ended. Basically what we’re talking about is a price that has gone up by more than 700 percent or as much as 700 percent in just three or four months. Because of AIDS we now have safer products but now we also have a new problem of catastrophic proportions. In 1987 dry heated concentrates constituted about 90 percent of the market, 90 percent of the total consumption of factor VIII. In 1988 there is now a maximum of 170 million units of factor VIII, dry heated factor VIII, that will be available. The remaining availability of factor VIII is from the products that are derived from the higher priced processes. The 1988 demand for the dry heated product may be as high as 350 million units, but the availability is, again, only 170 million units. Thus, we are in the middle of a serious supply shortage during what we consider to be an important transitional period. The demand for the dry heated product is largely price driven, as many physicians acknowledge that they would prefer product derived from the other processes that appear to be more effective with respect to viral inactivation and purity. On the 146 other hand, a number of physicians are not convinced that the preliminary data warrant conversion of their patients, particularly those who have already been exposed to HIV and non- A/non-B hepatitis. In fact, these physicians resent that they are being forced to use these products only because the less expensive products are not available. Another component of physician thinking is that the prudent course is to provide all their patients with those products that offer the greatest potential of viral safety and/or purity at the earliest possible time. Clearly there is much controversy here that is largely masked by the compelling economic issues of supply and price. Due to the shortage of dry heated products, even the intermediate price products -- that Doctor Rickles referred to that are pasteurized or detergent solvent treated are limited in supply. Until a few weeks ago it appeared that the availability of column purified factor VIII concentrate would be adequate to meet the U.S. needs assuming that patients, state hemophilia programs and third party payers are capable of handling the costs. While a good deal of the demand for these infinity column purified products is based on physician preference, a significant portion of that demand can be attributed to the lack of availability of other less expensive options. But as of last Friday, three days ago, we learned that the demand for the infinity column products increased so much that now this supply is almost drained. The supply and cost of factor VIII products that are pasteurized and infinity column purified is, in part, related to the significantly lower factor VIII yields associated with these processes in the manufacturing process. Thus, the demand for source plasma for factor VIII has increased. But unfortunately, it has increased at a time when the overall availability of plasma has decreased due to the worldwide reduction in demand for albumin. Efforts to improve the safety of blood products have now placed us in a serious and rapidly deteriorating situation with respect to price and supply. In response, the National Hemophilia Foundation has issued a supply watch bulletin to alert the hemophilia community about this problem, which is your attachments. We have also requested assistance from the Office of the Assistant Secretary for Health and the Public Health Service AIDS office. We have also initiated nationwide activity to improve public and private third party reimbursement and other forms of financing for higher price products. Fourth, we have initiated a nationwide data collection effort to quantify the shifts in supply. And lastly, with the situation worsening, we issued supply watch bulletin number two, 147 which is included in your package, which lists 11 treatment options to be considered that would reduce demand. Many of these options represent a compromise in treatment for patients and physicians. In response to this supply crises we are most pleased that of the Public Health Service AIDS office is convening leaders from government, industry and the National Hemophilia Foundation this week to cooperatively explore over a dozen options to relieve the supply shortage. And this situation is a very compelling situation for us that is related to AIDS. And I would like to sum up with a few recommendations that I will just highlight for you because the details of those recommendations are included in your packets. First, we think it is very important that you consider supporting research to improve the safety and supply of blood products used by people with hemophilia. The FDA serves as a scientific gatekeeper for the introduction of these new processes to improve blood product safety. Their review of the safety and efficacy of these products is essential. Equally important is the post licensure epidemiologic and laboratory work of the CDC to determine the safety of the largest scale in-vivo use of these new products. Thanks to the excellent surveillance work of CDC’s Division of Host Factors, probable safety gaps in some of the blood product preparation processes were identified to enable us to recast our criteria regarding HIV and perhaps hepatitis safety as Doctor Evatt reported earlier. And while FDA and CDC are addressing the short term issues of safety and efficacy, the work of the National Heart, Lung and Blood Institute is critical for assessing the intermediate and long term health consequences of the new viral completing processes and purification techniques. So we think that expanded support of FDA, CDC and NHLBI is very important to help us reach our goal of truly safe blood products. In addition, we have a number of other recommendations for you to consider and these recommendations are included in the written testimony. These include support of AIDS research, expansion of federal support of the hemophilia treatment center network to address AIDS treatment concerns, expansion of the provision of risk reduction and social support services to the hemophilia community, improving the environment for voluntary HIV testing, which we think is very important, and a need to expand pediatric AIDS support. Also, the critical issues of supply and price must be addressed. We are very worried. We are very concerned about this. As a result of AIDS we have much safer products now, but 148 the price is not affordable by any stretch of the imagination and ithe cupboard is almost bear. We hope you can alert the White House to this problem because as the severity of this problem becomes better defined in the weeks ahead, we anticipate that public support may be needed. Even though we have many needs, I want to point out that as a result of the enormous collaborative efforts between the public and private sectors, there has been substantial progress in reducing the risk of AIDS among patients and families effected by hemophilia. And this, too, is documented, the specific steps of progress are documented in the testimony. But concern remains, however, about the potential that a large percentage of people with hemophilia who are antibody positive have for transmitting HIV to their sexual partners. Fear exists regarding the potential of social isolation as a result of HIV related discrimination. Serious concern exists regarding the high prices and short supply of blood products. And special attention is needed to address the AIDS related stress among patients and families. But most important of all, concern persists as to how many of the 90 percent of the people with hemophilia who are HIV positive will succumb to AIDS. Ninety percent. In closing I would like to leave with you the thoughts of Becky. Becky is from a midwestern state and her husband has hemophilia. One and a half years ago Becky was diagnosed with AIDS. Her comments are included in the attachments offering three poignant AIDS prospective; that of a woman, that of a mother and that of a wife. We are very appreciative of this opportunity to meet with you today. Thank you. DR. SerVASS: Thank you, Alan Brownstein. DR. SerVASS: We’re going to start questioning with Doctor Lilly. And I wanted to say, just so it’s fair and we can all get a question in and we do have to be out of this room at 5:00, we’ll have it limited to one question per Commissioner. DR. LILLY: I’d like to address my first question to either Doctor Evatt or Doctor Rickles. I have two questions. It basically concerns what is the likelihood that we will have ever have a recombinant factor VIII? I believe that that gene has already been cloned, has it not? DR. RICKLES: Correct. DR. LILLY: If it is prepared in usable form, then it will stand an extremely large likelihood of being free of HIV and of any other virus infectious for humans. On the other hand, I’m not sure that it will solve the price problem and I wonder if I could get just a brief discussion of that? 149 DR. RICKLES: The gene for factor VIII has been cloned, as you’ve pointed out. Indeed, it has been expressed and recombinant factor VIII is currently being used in clinical trials. There have been technical problems with getting enough recombinant material to meet the needs of even clinical trials, let alone standard treatment for the hemophilia community. And you’re also quite correct in saying that it won’t solve the price problem because it simply escalates the technological costs of producing that product for a number of years. DR. LILLY: I must say that personally I’m rather discouraged that there will ever again be another drug as cheap as aspirin. Virtually everything that comes out for the treatment of anything is extremely expensive and beyond the ability of anyone to cope with it who has to take it over a long period of time. I don’t have a solution to that problem to offer. I’d like to ask Mr. Carman, just to expand briefly on your very interesting statement that the discrimination that is experienced by the hemophilia community is due to the fact that the person has hemophilia and not that they have AIDS or HIV infection. MR. CARMAN: It’s actually due to the fear of AIDS and HIV infection, but the trigger point is because of the discrimination and realization that most of those with hemophilia, at least the severe, has in fact been exposed to HIV and are in most likelihood HIV antibody positive. Consequently there are cases where -- the very large national case was the Ray boys in Florida, but there are numerous cases where hemophilia children have been excluded who are asymptomatic, who are healthy, who have no physical reason for being excluded and similarly in the work place there are cases where -- let me digress for a moment. There’s always been some lack of -- or some denial syndrome among those with hemophilia anyway that the Hemophilia Foundation has worked with to try to enable the person when they’re seeking employment to tell their employers that they have hemophilia and to work through the process of discrimination due to handicap laws that are already in existence. But now there’s the additional fear -- DR. LILLY: You’re implying that even before AIDS there was -- MR. CARMAN: Even before AIDS. Even before AIDS this was a problem with hemophilia and the hemophilia community worked very aggressively with legislative bodies, with local concerns to try to prevent the discrimination which came from just the 150 handicapped issues. But now there is the additional concern that because of AIDS and HIV antibody positiveness that jobs, in fact, have been denied. It’s particularly acute with many employers who now require testing for HIV antibody positivity and persons with hemophilia then either are faced with lying on their medical forms, which some have done, and that’s not acceptable, to in fact losing employment opportunities because they test antibody positive. MR. BROWNSTEIN: If I may, I would like to add that many years ago there was a considerable amount of discrimination related to hemophilia because of the disabilities associated with it. But within the last ten years because of all the progress that Mr. Carman referred to before, virtually all people with hemophilia were proud and would say that they have hemophilia and acknowledge that in areas where there was comprehensive care where training and the education could be provided. But ever since the AIDS issue, and I’ve been with the Foundation before the AIDS era, the difference has been dramatic in terms of the fear of discrimination because of AIDS. It’s specifically AIDS and HIV related. And it is so serious that we actually hide -- we hide the hemophilia connection. And I would like to present to Commission members an example of, you know, these credit cards where you raise funds for various organizations. You’ve all received this in your mail, you know, with your alumni associations and other organizations. Sadly, the board of the National Hemophilia Foundation had to put NHF instead of the National Hemophilia Foundation on our card, and you can pass it down if you promise to return it to me. But basically it’s a very sad commentary because we do feel proud of our association with the Hemophilia Foundation as winners, as people who have overcome these barriers, who have really stepped into the mainstream of American life and now we have to hid our identity as NHF, not National Hemophilia Foundation because that’s what’s on the billing statements and return envelopes. And people are so concerned. Not because of hemophilia but because of a connection to AIDS. DR. SerVASS: Doctor Gebbie? DR. LILLY: I’d like just to summarize that the gay community feels a great deal of sympathy with this -- which is the process of experiencing very much the same type of reaction. With respect to your use of initials, I would like to say that the Gay Men’s Health Crisis, about the largest organization dealing with social services and so forth on AIDS, does not feel able to put its name, but uses GMHC on return envelopes. DR. SerVASS: Doctor Gebbie? Mrs. Gebbie? MRS. GEBBIE: I answer to almost anything. I would appreciate some.discussion, and it may take a couple of you to 151 fully answer this question, about the various references to the need for increased support for comprehensive hemophilia centers. zt hear in that a blending of a need for more centers because apparently the nation isn’t fully blanketed by them, of new and aifferent or broader services because of this epidemic and of money because things now cost more. Can any or all of you put ali of that into prospective in terms of priority in which they shouid happen and in terms of total cost were somebody to recommend that that happen, or whether I have misinterrupted what i’ve heard through the various testimonies? MR. BROWNSTEIN: Basically, we receive $3.5 million a year for seed money to support a number of hemophilia treatment centers across the country and what we have done is we have regionalized this care in a very cost effective way, which is documented in the data that was summarized by some of the other members of the panel where we have really reduced the cost of care for hemophilia. Now, what is very interesting is that this regionalized network has become the anchor for AIDS treatment and it only covers half of the population. MRS. GEBBIE: For those centers that exist, that $3.5 million is what percent of their needed money? You said it’s seed money. MR. BROWNSTEIN: Oh, only a small percent. It’s seed money. We’re talking about hundreds of -- I don’t have the figures. I can provide it to the Commission. MRS. GEBBIE: Would you provide them these figures please? MR. BROWNSTEIN: I certainly will, but it’s only a very fractional percentage and, in fact, just in the state of Georgia where Doctor Evatt is from only a small infusion of funds to Emory University provided the development of comprehensive care only a few years ago where hemophilia comprehensive care did not exist in Georgia and in the few short years the capacity to provide this comprehensive care, which also now thankfully is a vehicle through which AIDS services are provided, now exists in Georgia. DR. RICKLES: I can tell you that if Connecticut is a microcosm for the nation, the hemophilia treatment subsidy is only ten percent of the overall required budget. That is to say the Comprehensive Hemophilia Care Centers federal program provides only ten percent of the costs of running the centers. MRS. GEBBIE: I’m always looking for what we might recommend. Given that, do you need most -- more seed money to cover the other half of the country, do you need more money per 152 center to do certain things and if so, how much and what things do you need more money for? MR. BROWNSTEIN: We estimate that to expand the regionalized network, which is weak or nonexistent in 25 states, it would take about $3 million of seed money through the regionalized network. MRS. GEBBIE: Per year? MR. BROWNSTEIN: Yes. In addition, that is not the AIDS support services, that is strictly to put in the building blocks, the framework for the delivery of these services. MRS. GEBBIE: And no estimate of increased costs for these other things? MR. CARMAN: One thing I’d like to clarify in case it wasn’t clear, and that is some of the discussion that has been repeated through the theme of several as to the impact on the third party system of caring for the factor VIII product, none of the federal treatment center funds go to product reimbursement. And that’s very, very important to realize that none of the $3.5 million goes towards in any way factor VIII product. MRS. GEBBIE: I’m going to be more explicit. I thought several of you were suggesting that some support for factor VIII might be appropriate, but nobody took me up on that opening so I’m now going to assume that you don’t need it for that. DR. RICKLES: I haven’t had a chance yet, but I will. We do need support for factor VIII. The problem is that you’ve asked an extremely complex question and there are probably ten answers to it in order of priority. CHAIRMAN WATKINS: Let me have a follow-up on that. Have you had a chance to review the interim report that we sent on the 15th of March to the President? Under the health care delivery system section we specifically wanted to get something in the record, even though we hadn’t had these hearings yet. Obviously we can expand on our interim report which suggest that "current funding to the comprehensive hemophiliac diagnostic and treatment centers should be increased to cover the costs of HIV testing, counseling, evaluation of immune system functions, supportive services for the patient and family. Funding of the immune system evaluation will enhance the use of the centers for clinical research. Estimated cost in federal dollars, $4 million." That’s from the report. Did you read that and did you agree with that? Should that be changed or altered as a result of any of the information 153 you presented to us today? I don’t want to keep running -- stumbling over our own words in this thing, so would you let me have some specifics. If that needs to be altered, should it be altered, is the amount of funding approximately right? We did considerable research to look at that funding stream to see what would be necessary to bring it up to speed. MR. BROWNSTEIN: Okay. And we were aware of that and the number that we are sharing with you is in the neighborhood of $6.5 to $7 million, which I think is reasonably close to what you’re referring to. Now, the question of HIV antibody testing and that sort of thing, that’s a mix because that’s included in your report based on Doctor Janco’s testimony presented in Tennessee. He included a mix of different items needing support such as treatment center services, etc., keep in mind that some of those services are reimbursed through third parties, but not always. I’m talking about, for example, HIV antibody testing, by in large, is being reimbursed. So that’s lumped in there. But I would say $6.5 to $7 million for the comprehensive care network is a good number but it doesn’t answer the question that Ms. Gebbie was raising which does not include the reimbursement, the third party reimbursement and financing for the payment of clotting factor products. MRS. GEBBIE: Does that 6.5 include the $3 million you just mentioned to extend the centers the rest of the way across the country? The number that Admiral Watkins just quoted? MR. CARMAN: No, that’s superimposed on the current centers money. MRS. GEBBIE: So there’s that money for -- you need $3 million to make centers everywhere, then is that $6 million enough on top for that whole nationwide network to do the additional or is that just for the existing ones? DR. RICKLES: That’s just for the existing centers. MR. BROWNSTEIN: That’s for the seed money for existing centers. That’s just for existing centers. MRS. GEBBIE: So that number would be off? If we made the centers nationwide, that number would be too small? MR. BROWNSTEIN: That’s correct. MRS. GEBBIE: And then in addition there’s whatever might be needed if we were to become interested in factor VIII funding because there was a concern that it’s not adequately being paid for by whatever mechanism? 154 Mr. BROWNSTEIN: Correct. MRS. GEBBIE: Could somebody try and write that down for us a little more plainly? MR. BROWNSTEIN: Okay. Fine. MRS. GEBBIE: Thank you. CHAIRMAN WATKINS: It would be helpful for us to have you take a lead from our interim report to make the recommendation in very specific terms of how we would modify that to include these issues and let us take a look at that. DR. SerVASS: Mr. DeVos? MR. DevoS: I’m the most innocent of all this because I know the least about blood, and that’s why any question is only an informational one. I hear a great cry for a shortage of available product. We’ve also learned today, or I have, of the two main sources. One is the Red Cross type program where free donors go and the other one is a pay for blood and that seems to be the one where they break it down and supply. Is there one of those sources or both? MR. BROWNSTEIN: We’re talking about 85 percent of the blood or 80 percent of the material that we use is from source plasma which means it’s directly harvested primarily from the commercial sector through plasma phacesis. So what you have heard from the Red Cross, while they have what we call recovered plasma which also goes into our pool for the creation of the products for people with hemophilia, by in large it’s about 80 percent from the .commercial sector and 20 percent that is derived from recovered plasma from whole blood. So what you heard from the Red Cross is a different story than our story because ours has to do with the plasma supply and demand rather than the other problems that they referred to earlier. MR. DevOS: Well, I hear a tragic story of shortage here, which means somebody’s got to do a great sales job on the American people to give blood, which gets back to the whole problem of trying to give the right kind of blood. But in your case it can be treated. But, you know, somebody really got to crank up here to find sources of blood and I don’t know what your recommendations are relative to how you expect that should be done. DR. SerVASS: Let me ask a follow-up to Mr. Devos’ question. Is there a shortage in the commercial plasma where they buy the blood? 155 MR. BROWNSTEIN: Significant -- there’s a significant shortage that has occurred within six months and it is becoming more of a concern to us each week. As I mentioned, the cupboard may be bare within a few weeks. Now, what we’re having is emergency meetings with other government agencies to try to figure out a way of managing this problem. MR. DevOS: I can almost live with price, but you can’t live with it if you don’t have the product. You can just forget it. And so I’m just trying to get that clear because it’s confusing to me as to how we’re going to get that job done now. MR. BROWNSTEIN: We agree with you. We can live with price. At this point we must have enough material to stop bleeding. MR. DeVOS: Go ahead. DR. EVATT: If I might add something. You have to understand how the blood plasma industry works and how it prices things. When they make plasma they divide it into a number of different fractions which includes albumin and so forth. One of these products usually drive the market, what they call drive the market. In essence, it’s the product for which the material’s obtained. Then the other products that fall out of that are in excess and are by products. Until recently albumin was the major material that drove the market and most of that went to Japan and was exported overseas. There has been a dramatic decrease in the use of albumin by the Japanese and so there is less and less reason to obtain the material. So byproducts, which is the clotting factor, has been but really there was not the plasma to make the clotting factor. Now, if clotting factor begins to drive the product, it will be an additional reason to greatly accelerate the cost because they’1ll have to purchase all of it just for the clotting factor and they’11 throw all the rest of it away. They won’t have a use for it. MR. DevOS: I’m trying to figure out whether the problem is accelerated by increased demand or whether there’s a drop-off on people supplying blood in the first place. MR. BROWNSTEIN: Both. MR. DevOS: Both? MR. CARMAN: Plus there’s another complicating factor and that is the processes themselves are less efficient so this means it takes twice as much product to make the same amount that it did six months ago. 156 MR. DeVOS: Okay. Because the heat treating -- MR, CARMAN: Exactly. The heat treating -- MR. Devos: You have a 50 percent loss? MR. CARMAN: You have a 50 percent loss over processes that were used six months ago, which certainly we do not want brought back. DR. RICKLES: And if I may add, even another factor is the fact that those processes which are less efficient for making factor VItI or more efficient for making albumen, thus dropping the price of albumen still further and driving the market still farther up for factor VIII. MR. DeVOS: Do you have a recommendation? Do you know what you’re going to do about this or are you meeting on that? DR. RICKLES: Yes. MR. DeVOS: Well, we should love to have copies of what you’re going to recommend and then we can look at that. CHAIRMAN WATKINS: When will you be meeting, Mr. Brownstein? MR. BROWNSTEIN: Pardon me? CHAIRMAN WATKINS: When will you be meeting? MR. BROWNSTEIN: On the 12th of May, this Thursday. CHAIRMAN WATKINS: I think it will be very important for us to get a quick look of that conference report if you could get it to us. We want to be as helpful as we can recognizing we've got to stay focused on the HIV, but we’ve got a relationship here and perhaps we can get the best of minds and get your input so we can have some impact in our final report. MR. BROWNSTEIN: Okay. Very good. DR. SerVASS: Doctor Crenshaw? DR. CRENSHAW: I think you are making some of the best arguments for increased utilization of homologous blood that I virtually heard today. One of the arguments given for that is conservation of the homologous blood supply for people who can’t use anything else. And I hope we’ll be coming out with some recommendations on this strongly. Do you have any thoughts to add to that? De you agree with me or do you think that is there 157 anything we can do to strengthen those recommendations or any comments whatsoever? DR. RICKLES: As a hematologist, I would certainly Support vour comments. It’s a practice that we push very avidly for those individuals for whom it’s appropriate. DR. SerVASS: Ms. Pullen? Doctor Primm? Doctor Lee? DR. LEE: We’ve come up against this problem in the past. Tell me how closely does this improved process for treating AHG relate to the increased price? .Are we looking at profiteering? | DR. RICKLES: I think the process for improvement of the quality of the product is fairly dramatic. As I suggested to you, the previous concentrates, the dry heat treated concentrates probably should be referred to more propefly as) contaminated with factor VIII. They contain less than one percent factor VIII by protein. The recombinant preparations scheats approximately three to 5,000 units per milligram of protein as opposed to less than ene unit per milligram of protein inithe older products. what escalation in purification, I think, |properly must be looked at aS a very costly escalation coupled with the fact that there really has been no price increase for factbr VIII for ten years. The price of factor VIII has been kept down somewhat artificially, I think, by some of the issues you’ve heard already addressed, such as the albumin market and the subsidization of the factor VIII market in this country by very high prices in Europe. So I think to some extent we’re looking at appropriate price for the product. DR. LEE: $75,000? \ DR. RICKLES: I beg your pardon? \ \ DR. LEE: $75,000 a year? \ DR. RICKLES: As opposed to $10,000 per year. About a Six to seven and a half fold increase in cost. : MR. BROWNSTEIN: I would like to comment on that also. if you consider six months ago for all intents and purposes we had one product of choice on the market. Within a few months we now have a total of five different processes to choose from, three of which are almost, for all intents and purposes, totally new. And, you know, I don’t wish to comment on profiteering because I cannot determine that because the pharmaceutical companies are not going to share their books with us. However, I think that FDA sees the priority of reviewing new product 158 licenses for new products for people with hemophilia. And we believe that as new product licenses are awarded and license amendments are provided, we believe that the competitive forces in the marketplace will become more lively and we will see the prices go down. We don’t know how much they will go down, but, you know, I wish to add that to this. And I think that the introduction of these new products and more competition will be helpful. DR. LEE: We're struck with who will pay and $75,000, of course, no one can pay. So this is a real problen. DR. PRIMM: From the time you wrote your paper, Mr. Brownstein, until today you had 21,000 to 56,000 in your paper and then in your oral testimony you went from 50 to 75,000. MR. BROWNSTEIN: Right. Inflation moves quickly. You pointed out an inconsistency that is based on an error in my written testimony that was brought to my attention today by my colleagues on this panel. DR. PRIMM: You wrote this yesterday, right? MR. BROWNSTEIN: Right. My colleagues pointed out that there was an inconsistency in my testimony with respect to -- I made specific reference to the monoclonal products. But in the price range I provided, I included in the intermediate priced products as well. So they corrected me and I changed it. If you refer to table one and you plug in the intermediate priced products, it works out. So, in other words, yes it is -- it has been changed and I thank my colleagues for bringing it up and I’m glad you raised the question because that is exactly the reason why. MR. CARMAN: Essentially, if I might, the figures in his report are not new generation products but are for the interim product which, of course, is going to be phased out and, in fact, already are becoming difficult to find. DR. RICKLES: Already the interim product has been phased out. Yes. In effect, we’re looking at about a six to seven and a half fold increase depending on what your baseline price was. DR. LEE: Does the Hemophilia Foundation raise that type of money to fund this kind of product escalation? MR. BROWNSTEIN: No. But what we do do and we have done reasonably effectively is, we have enhanced third party reimbursement, we speak to third party payers both private and public sector. We have had a series of meetings, we’ve met with 159 14 officials from HCFA, from the Health Care Finance Administration, concerning these new products. And we have increased insurance coverage in ten years from 74 percent to 94 percent where people with hemophilia are now much more insured than they ever have been before. And that’s primarily from the private sector. From the price side we have also aggressively pursued efforts to keep the price down. Some of the artificial price constrains that Doctor Rickles referred to are the pressures that have been imposed by the National Hemophilia Foundation by publishing prices, by holding conferences on methods of bringing the price of clotting factor down and promoting these through workshops that we’ve run for providers and consumers. We have threatened to publish prices nationwide to stimulate the reduction of prices and we have done) that in the past. Here to, we will also be promoting the reduction -- we will be fighting it from all sides; from the price side, |from the reimbursement side, wherever we can find the point where \our constituents can have their needs met. But I wish to underscore the point that was made by Doctor Rickles and that is that there is good reason for a substantial increase in the price. (\I say, "God, just give me a 200 percent increase." You know, and \that’s really perverse when you think about price increases. But lin this day and age we are looking for something much less than the 700 percent and we will be pursing that as well. \ DR. SerVASS: Alan Brownstein, is there any advantage in the orphan drug law? You just have far too many hemophiliacs to be considered an orphan drug product, your factor VIII? MR. BROWNSTEIN: Well, in fact, we do come under the orphan drug guidelines and some instances and some of my colleagues might know more about it because I know that factor VIII was designated and --but I believe it’s under 200 or 250,000. So certainly we fall within that criteria. And I would say that generally we like the competition because we have seen in 1983 when heat treating clotting factor was first presented, 22 cent a unit up from ten cents to 22 cents a unit. Eight months later the other pharmaceutical companies produced heated treated factor VIII, curiously overnight the price went down to 13 cents. DR. SerVASS: Thank you. And thank you all for this very enlightening set of recitations here. And I’1l turn the questions over now to our Chairman. CHAIRMAN WATKINS: I just want to close out the panel by thanking you for coming here today. We’ve had extensive testimony from members of the hemophilia community who have been infected with the virus. A sad tale of discrimination. I think we’re very sensitive to the issues. They’ve been brought before 160 us both on the field trips as well as our hearings. What you’re giving is today is a much stronger set of underpinnings for our final report. We do need the information that we asked you for, and we've asked for a lot today. Normally the process would be that you would get an official letter signed out by me to follow-up on these questions. We‘re not going to have time to do that so we're going to have to rely on you. If you want us to be of help to you, you’ve got to give us the best information you can, the shortest period of time. And I’m talking like within a week. So this means you’re going to have to get it to us, perhaps overnight mail, if you want to make an impact on our report. We’re just going to have to keep moving it because we don’t have much time left, but I think it’s a very important set of issues that you’ve raised and one that, I think, obviously has caught our attention. So I ask you if you please would do everything you can to expedite the inputs to us, it will be to all of our interests to do that. And with that we’ll close out the hearing for today and we’ll adjourn until 9:00 tomorrow morning here. (Whereupon, at 5:01 p.m. the hearing was adjourned, to reconvene tomorrow at 9:00 a.m.) 161